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Case 7-09 Electrolytes Patient ID 41-year-old female Patient Location Medical Outpatients Clinical Notes on Request Form Polyuria and polydipsia. Cause? Case Details Early morning spot urine Osmolality 611 mmol/kg Additional Information Other laboratory results taken at the same time: Serum Sodium 145 mmol/L (134–146) Potassium 4.3 mmol/L (3.4–5.0) Urea 8.5 mmol/L (3.0–8.0) Creatinine 84 µmol/L (45–90) Glucose 5.1 mmol/L (3.5–5.4) Ionised Calcium 1.23 mmol/L (1.12–1.32) Osmolality 302 mmol/kg (275–295) Suggested Comment Suboptimal urine concentration in the setting of raised serum osmolality suggests possible partial diabetes insipidus. Suggest document degree of polyuria and consider fluid deprivation challenge with DDAVP administration to differentiate central from nephrogenic causes. Further endocrine review may be appropriate depending upon findings. Rationale Timed urine collection helps document the degree of polyuria, and by definition should be >2.5–3 L/day. The present case shows raised serum osmolality, which makes primary polydipsia less likely. Urine is inadequately concentrated as one would expect a urine osmolality of >750 mmol/kg with this serum osmolality. This suggests (partial) diabetes insipidus, of either central or nephrogenic origin. The former is caused by inadequate antidiuretic hormone (ADH) production while the latter is due to inadequate ADH action on the renal tubules. Formal fluid deprivation protocol (1) can help to resolve differential diagnosis with lack of further urine concentration following DDAVP in nephrogenic cases. Hypokalaemia, hyperglycaemia and renal impairment have been excluded as causes, although drugs, particularly lithium, may be contributory. Endocrine review with further pituitary studies may be appropriate depending on the findings. Reference 1. Baylis PH. Investigation of suspected hypothalamic diabetes insipidus. Clin Endocrinol (Oxf) 1995;43:507-10. PREFERRED KEY WORDS Consistent with dehydration Consider diabetes insipidus Suggest water deprivation test ± DDAVP Inadequately concentrated urine ?Nephrogenic diabetes insipidus ?Central diabetes insipidus Suggest endocrinology consultation ?Drug therapy ?Lithium Rx LESS RELEVANT KEY WORDS Serum osmolality raised ?Diuretic use Suggest urine Na/electrolytes Slightly increased urea Suggest 24 h urine collection Normal serum Na/glu/Ca/K Diabetes mellitus excluded Suggest ADH No osmolar gap ?Renal disease ?Ethanol High normal sodium Normal kidney function No evidence 1°/psychogenic polydipsia Normal biochemical profile Suggest urine MC&S Creatinine upper end reference range Suggest eGFR Consider trial DDAVP Renal disease UNACCEPTABLE KEY WORDS Appropriate concentration of urine ?Osmotic diuresis No evidence of diabetes insipidus Suggest assess patient fluid status Suggest repeat tests 1°/psychogenic polydipsia Suggest thyroid studies ?Salt and water overload Assess risk/investigate diabetes mellitus Suggest other tests Elevated urine osmolality Suggest CNS imaging/investigation Suggest urine urea ?SIADH Increased osmolar gap Suggest ACTH, cortisol ?Pregnant Suggest urine sodium Serum osmolality normal ?Hypoaldosteronism with salt wasting Suggest aldosterone:renin ratio ?Fanconi syndrome ?Hyperthyroidism No comment ?Hyperalimentation Avoid nicotine, alcohol, caffeine Suggest urine drug screen ?Unmeasured solute SIADH unlikely Suggest abdominal imaging No polyuria by urine:serum osmolality Normal urea, creatinine Case 8-05 Electrolytes Patient ID 51-year-old male Patient Location Emergency Department Clinical Notes on Request Form Acute confusional state. On risperidone. Case Details Plasma Sodium Potassium Creatinine Urea Osmolality 108 mmol/L 4.1 mmol/L 80 µmol/L 2.0 mmol/L 227 mmol/kg (136–146) (3.5–5.5) (50–110) (2.7–7.8) (280–300) Urine Sodium Potassium Osmolality 12 mmol/L 8 mmol/L 70 mmol/kg Suggested Comment Severe hyponatraemia and a hypo-osmotic plasma with appropriately dilute urine and no evidence of salt wasting. This pattern is in keeping with primary (psychogenic) polydipsia with water intoxication. While risperidone is not necessarily the cause of the polydipsia, an alternative atypical antipsychotic may be more effective in improving psychogenic polydipsia. Rationale Hyponatraemia is classified based on hydration status and plasma osmolality. The kidney’s response allows assessment of whether the cause is renal salt wasting. In this instance renal sodium loss is close to the <10 mmol/L usually applied to exclude renal salt loss and certainly below the >20 mmol/L used to rule-in salt wasting. The urine is appropriately almost maximally dilute, and is not suggestive of SIADH or dehydration (1). The results are most consistent with polydipsia, most commonly due to psychiatric illness and frequently affecting chronic schizophrenic patients. While antipsychotics are a well-recognised cause of hyponatraemia (secondary to SIADH), the literature surrounding their effects on polydipsia is controversial. ‘Typical’ antipsychotics have been associated with aggravating polydipsia, while atypical antipsychotics have been reported to be useful in treating these patients (2). Risperidone has not been shown to be clearly effective in this group. At least one case in the literature cites risperidone as the likely cause (3). References 1. Burtis CA, Ashwood ER, Bruns DE (eds). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th Edition. St Louis: Elsevier Saunders; 2006. pp. 1751-53. 2. Bersani G, Pesaresi L, Orlandi V, et al. Atypical antipsychotics and polydipsia: a cause or a treatment? Hum Psychopharmacol 2007;22:103-7. 3. Kar N, Sharma PS, Tolar P, et al. Polydipsia and risperidone. Aust N Z J Psychiatry 2002;36:268-70. PREFERRED KEY WORDS Severe hyponatraemia Low urine osmolality Low urine sodium Consistent with polydipsia ?Psychogenic polydipsia Suggests water intoxication Secondary water intoxication Acute water overload ?Polydipsia ?Due to risperidone Urine appropriately dilute Not suggestive of SIADH Evaluate total body water Dilutional hyponatraemia Suggest withdrawal risperidone LESS RELEVANT KEY WORDS Low plasma osmolality Hyponatraemia ?Other drugs Confusion due to hyponatraemia ?Extra-renal loss Suggest thyroid function tests Due to risperidone Low plasma urea Action required Patient history required Cerebral oedema risk Suggest fluid restriction Suggest glucose Monitor results Suggest liver function tests Central pontine myelinolysis risk with rapid correction Risk of death Check results repeated Patient likely requires hypertonic saline Renal function tests normal Check protein/lipids Risk rhabdomyolysis during treatment Low plasma sodium ?Patient on fluid replacement Suggest drug screen Contact Pathologist ?Beer potomania UNACCEPTABLE KEY WORDS ?SIADH Suggest water deprivation test ?Adrenal insufficiency ?Hypothyroidism Suggest cortisol / synacthen stimulation test ?Cardiac/liver failure ?Renal loss ?Hyperglycaemia Urine not maximally dilute Suggest ADH ?Alcoholism ?Disease causing oedema ?Diabetes insipidus Check pituitary function Suggest serum/urine myoglobin ?Patient non-compliance ?Increased sodium loss Sodium depletion unlikely Suggest renal function tests ?Pseudohyponatraemia ?Low salt intake ?Renal failure ?Reset osmostat Case 8-09 Electrolytes Patient ID 78-year-old man Patient Location Nursing Home Clinical Notes on Request Form Demented, percutaneous endoscopic gastrostomy (PEG) fed Case Details Sodium Potassium Chloride Bicarbonate Urea Creatinine 169 mmol/L 3.6 mmol/L 121 mmol/L 37 mmol/L 18.0 mmol/L 90 µmol/L (135–145) (3.5–5.0) (98–107) (21–32) (2.0–8.5) (60–110) Suggested Comment Profound hypernatraemia with raised urea/creatinine ratio is suggestive of marked dehydration. Suggest urgent review of clinical volume status and fluid balance. Rationale Marked hypernatraemia with elevated urea to creatinine ratio is consistent with dehydration, specifically water depletion. Percutaneous endoscopic gastrostomy (PEG) feeding tubes are increasingly used for patients who cannot maintain adequate nutrition with oral intake. They include patients with neurological disorders, other conditions where swallowing is impaired, or there is obstruction of the upper gastrointestinal tract. Artificial feeding may cause metabolic problems, including deficiencies or excess of fluid, electrolytes, vitamins and trace elements. Hypernatraemia is usually due to inadequate water intake. Loss of water in excess of sodium may also be contributory. It may develop rapidly in patients who are unable to experience or communicate their thirst, and especially in institutionalised subjects, who are reliant on caregivers to maintain their fluid intake. Reference 1. Gault MH, Dixon ME, Doyle M, et al. Hypernatremia, azotemia, and dehydration due to high-protein tube feeding. Ann Intern Med 1968;68:778-91. PREFERRED KEY WORDS Consistent with marked dehydration Marked hypernatraemia ?Inadequate water intake ?Hypovolaemic hypernatraemia Increased urea/creatinine ratio ?Dehydration Water/hypotonic fluid depletion Check hydration status Review feed composition Suggest fluid replacement ?Insufficient water in PEG feed Suggest IV fluid replacement Urgent treatment required Check urine volume LESS RELEVANT KEY WORDS Elevated urea Hypernatraemia Elevated bicarbonate Suggest urine/plasma osmolality Elevated chloride ?Metabolic alkalosis ?Diarrhoea/stomal loss ?Vomiting Consider urine sodium ?Diabetes insipidus Suggest urine electrolytes Suggest glucose estimation ?Increased salt intake ?Diuresis ?Pre-renal renal failure Suggest clinical review Suggest blood gas analysis Consistent with tube feeding syndrome Low normal potassium level ?Skin/respiratory water loss ?Secondary hyperaldosteronism Excessive salt intake is rare ?Hyperaldosteronism Suggest repeat urea and electrolytes Haemoconcentration ?Head injury ?Potassium depletion Monitor results during fluid treatment ?Diuretic therapy Exclude hypertonic fluid therapy ?Gastrointestinal bleed ?Loss of thirst reflect Risk coma/death ?Meningitis/meningoencephalitis ?Creatinine low due to muscle mass Suggest urine creatinine ?Malnourished ?Saline-responsive metabolic alkalosis Artefact unlikely Suggest review fluid management ?Mineralocorticoid Rx UNACCEPTABLE KEY WORDS ?Drip arm ?Renal failure ?Catabolism ?Cushing’s disease Suggest occult blood No comment Suggest cortisol/aldosterone ?Compensated respiratory acidosis Suggest CK ?Rhabdomyolysis Case 9-07 Electrolytes Patient ID 55-year-old male Patient Location General Practice Clinical Notes on Request Form Increased blood pressure Case Details Sodium Potassium Chloride Bicarbonate Urea Creatinine Cholesterol Triglyceride 146 mmol/L 3.6 mmol/L 106 mmol/L 29 mmol/L 5.1 mmol/L 100 µmol/L 5.8 mmol/L 1.4 mmol/L (135–145) (3.5–5.0) (96–109) (23–32) (3.5–7.5) (40–120) (3.9–5.5) (0.6–2.0) Suggested Comment In the setting of borderline hypokalaemia and high-normal bicarbonate, consider possible secondary causes of hypertension. Measurement of renin and aldosterone might be helpful and further investigations of mineralocorticoid excess, if clinically indicated. Suggest repeat full fasting lipid profile and evaluate in context of absolute cardiovascular risk status. Rationale Borderline hypokalaemia and high-normal bicarbonate in the setting of hypertension should prompt review for secondary causes such as diuretic therapy. Renin and aldosterone would be appropriate to investigate possible mineralocorticoid excess. This should be considered in patients with blood pressures of >160 mmHg (systolic and >100 mmHg (diastolic), drug-resistant hypertension, hypertension with: spontaneous hypokalaemia or diuretic-induced hypokalaemia, adrenal incidentaloma, family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years), and patients with first degree relatives diagnosed with primary aldosteronism. Investigations for Cushing’s syndrome would depend on clinical index of suspicion. Full fasting lipid profile should be repeated and any intervention determined by the absolute cardiovascular risk status, which depends on full clinical evaluation and cannot be assigned on the basis of the results alone. It is not appropriate to comment on any possible drug intervention. Reference 1. Chao CT, Wu VC, Kuo CC, et al. Diagnosis and management of primary aldosteronism: an updated review. Ann Med 2013;45:375-83. PREFERRED KEY WORDS Mild hypernatraemia High normal bicarbonate Low normal potassium ?1°/2° hyperaldosteronism Suggest renin/aldosterone ?Cushing’s syndrome Suggest mid-stream urine test Suggest further investigations Assess cardiovascular disease risk factors Cholesterol and triglyceride insufficient to assess cardiovascular disease risk Assess 2° causes hyperlipidaemia Review lifestyle associated risk factors Suggest fasting glucose Mildly elevated cholesterol Suggest fasting lipid profile Suggest HDL/LDL ?Drugs ?Diuretic therapy LESS RELEVANT KEY WORDS Hypertension noted Increased risk cardiovascular disease Assess 2° causes hypertension ?Diabetes mellitus Suggest TSH Suggest repeat testing Suggest cortisol/ACTH Consider drug therapy if clinically indicated Exclude liquorice ingestion eGFR=67 mL/min/1.73m2 ?Phaeochromocytoma Suggest liver function tests Suggest repeat urea and electrolytes Triglycerides within normal range Hypertension probably idiopathic Patient most likely fasting Relative hypochloraemia Normal bicarbonate Normal urea Moderately elevated cholesterol Suggest 24 hour urine cortisol Suggest baseline liver function tests Suggest fT4 ?Renal artery stenosis Review history of familial hypercholesterolaemia Proceed to glucose tolerance test if glucose ≥6.1 mmol/L Mild renal disease not excluded Suggest calcium eGFR=72 mL/min/1.73m2 ?Stage II chronic kidney disease Hypokalaemic metabolic alkalosis ?Dehydration Suggest plasma metanephrines UNACCEPTABLE KEY WORDS Suggest microalbumin Suggest urate Suggest angiotensin Suggest urine and serum osmolality National Heart Foundation target for high risk total cholesterol <4.0 mmol/L Chronic renal failure excluded Suggest ECG Treat cardiovascular risk factors aggressively No comment Normal electrolytes, urea, creatinine Case 10-02 Electrolytes Patient ID 32-year-old woman Patient Location Emergency Department Clinical Notes on Request Form Marked weakness – poor diet, but no anorexia; denies laxatives and diuretics use. Case Details Sodium Potassium Chloride Bicarbonate Urea Creatinine eGFR Calcium Magnesium Phosphate Total protein Albumin Bilirubin ALT GGT ALP TSH fT4 139 mmol/L (134–146) 1.4 mmol/L (3.4–5.0) 110 mmol/L (98–108) 15 mmol/L (22–32) 6.5 mmol/L (3.0–8.0) 118 µmol/L (45–90) 49 mL/min/1.73m2 (>60) 2.44 mmol/L (2.15–2.60) 1.26 mmol/L (0.70–1.10) 0.42 mmol/L (0.80–1.40) 83 g/L (60–80) 41 g/L (35–50) 10 μmol/L (<20) 92 U/L (<35) 84 U/L (<40) 104 U/L (35–135) 20.6 pmol/L (0.4–4.0) 9.0 mU/L (9.0–19.0) Additional Information Hb 157 g/L WCC 23.5 x109/L Platelet 528 x109/L Hct 0.44 MCV 91 fL MCH 32 pg (115–160) (4.0–11.0) (150–400) (0.37–0.47) (80–100) (27–32) Suggested Comment Severe hypokalaemia and hypophosphataemia with a normal anion-gap metabolic acidosis and renal impairment. The differential includes renal tubular acidosis (RTA, distal or proximal), and acute diarrhoea or laxative abuse. Hypothyroidism, leucocytosis and thrombocytosis and raised ALT noted. Suggest blood gases, urine pH, urine ammonia, and electrolytes. Possible muscle source for ALT - suggest measurement of CK to confirm. Rationale This complex case involves a 32-year-old woman with profound hypokalaemia and a normal anion gap metabolic acidosis. Additionally she has moderate hypophosphataemia, hypermagnesaemia, renal impairment, hypothyroidism, a leucocytosis/thrombocytosis and a raised ALT. The comment should focus on the major abnormality (severe hypokalaemia) and should discuss the differential diagnoses of hypokalaemic acidosis rather than the much broader differential of hypokalaemia. Renal tubular acidosis (RTA, distal or proximal), acute diarrhoea, and dialysis treatment are all possibilities. Carbonic anhydrase inhibitors or transplantation of the ureters into the colon should be excluded also. Further investigations should include blood gases, urine pH (>5.5 in distal RTA; <5.5 in proximal RTA), urine ammonia (<33 μmol/min in distal RTA; >33 μmol/min in proximal RTA), electrolytes, and a laxative screen if suspicion remains. The urine pH and ammonia should be measured when patient is in acidosis. Muscle is the possible cause of the raised ALT; a CK measurement would be useful to confirm this. Recommend repeat thyroid function tests after resolution of the acute episode would be useful. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS Marked hypokalaemia Moderate hypophosphataemia Acidosis Normal anion gap metabolic acidosis Hypokalaemic metabolic acidosis Renal tubular acidosis ?Renal potassium loss ?GI loss ?diarrhoea ?vomiting ?Laxative abuse Meds review ?Carbonic anhydrase inhibitors Suggest blood gas analysis Suggest urine/plasma pH Suggest urine K, pH, PO4, Mg, Ca, anion gap ?Drug use/screen Hypothyroidism Repeat thyroid function tests after illness settled Potassium replacement required Hypokalaemia with associated myopathy Suggest serum CK/AST ?Ureteral diversion and/or obstruct ?Fanconi’s syndrome Suggest urine amino acids Renal impairment Suggest glucose/insulin/glucose tolerance test/urine glucose Hepatocellular injury ?Autoimmune disease ?Hashimoto’s Suggest thyroid antibodies Hyperchloraemia ?Sepsis, suggest further investigation ?Diuretic use/abuse Leucocytosis and thrombocytosis Hypermagnesaemia ?Malnutrition ?Antacids use/abuse - high magnesium Exclude urinary tract infection/ microscopy, culture and sensitivity ?Lithium - suggest levels ?Diabetic ketoacidosis/insulin Physician consultation required - urgent Suggest urine protein ?Hypokalaemic periodic paralysis Hypothyroid hypokalaemic periodic paralysis Sick euthyroid syndrome Suggest urine uric acid/PO4/NH4 Faecal electrolytes/Mg confirm high Mg Possible refeeding syndrome Infection/allergy/inflammation - suggest CRP NH4Cl loading test for renal tubular acidosis Repeat renal function tests Potassium redistribution to cells insulin/B-agonists Phosphate supplement required Hypokalaemia Toluene abuse Exclude artefactual potassium reduction Exclude transient cause of low potassium ?Respiratory alkalosis Exclude hypertension Suggest 24 h urine cortisol/creatinine/K ?Past treatment for hyperthyroidism ?Respiratory alkalosis ?Carcinoma ?villous tumour No evidence of poor diet Suggest urine protein Marked hypophosphataemia ?Ethanol- induced liver dysfunction Suggest cortisol/ACTH ?Malignancy ?Wilson’s disease, investigate further ?Adrenal insufficiency Suggest cortisol/synacthen test ?Cushing’s syndrome ?Secondary hyperthyroidism ?Steroids ?Possible hyperparathyroid Marked hyponatraemia ?Pituitary adenoma with 2° hypothyroidism ?Excessive liquorice ingestion Suggest HIV screen Suggest TRH test for differential diagnosis Suggest B12/folate and iron ?Liddle’s/Bartter’s syndrome Normal magnesium level Suggest TSH with different method ?heterophile antibodies Suggest serum/urine electrophoresis Suggest autoimmune screen - ANA/ENA Suggest renin/aldosterone ?Hyperaldosteronism Suggest serum electrolytes, Mg, Ca Suggest urine/plasma osmolality ?Light chains Case 14-10 Electrolytes Patient ID 78-year-old woman Patient Location General Practice Clinical Notes on Request Form Polyuria. Case Details Sodium Potassium Chloride Bicarbonate Urea Creatinine eGFR Serum Osmolality Urine Osmolality 146 mmol/L (136–145) 3.9 mmol/L (3.5–5.1) 104 mmol/L (98–107) 31 mmol/L (22–29) 4.8 mmol/L (3.5–7.2) 86 µmol/L (44–80) 55 mL/min/1.73m2 (>90) 299 mOsm/kg (280–300) 166 mOsm/kg (40–1400) Suggested Comment The inappropriately dilute urine for the given serum osmolality may indicate diabetes insipidus (DI). Recommend serum calcium measurement and a review of medications for possible causes, and consider referral for endocrinology review. Rationale Diabetes insipidus (DI), the inability to concentrate urine, is an important differential diagnosis in the investigation of polyuria. A high urine volume coupled with low urine osmolality measured in the setting of a supervised or overnight water deprivation test is pathognomonic. A low osmolality (<200 mOsm/kg) in a random urine sample is unhelpful unless the serum osmolality at the same time is >295 mOsm/kg, indicating relative dehydration. By contrast a high urine osmolality >700 mOsm/kg in a random urine sample can be useful to exclude DI, often suggesting urinary frequency rather than true polyuria. Psychogenic polydipsia, the main differential diagnosis for polyuria typically presents with low or low-normal plasma osmolality, as the primary problem here is excessive water intake. Causes of DI may be central (antidiuretic hormone (ADH) deficiency) e.g. head trauma, pituitary disease, or nephrogenic (ADH resistance) e.g. hypercalcaemia, lithium therapy. Response to exogenous ADH distinguishes these two major forms. References 1. Bichet DG. Diagnosis of polyuria and diabetes insipidus. In: UpToDate, Sterns RH and Emmett M (Eds), UpToDate, Waltham, MA; 2013. 2. Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a complex disease. Cleve Clin J Med 2006;73:65-71. PREFERRED KEY WORDS High normal serum osmolality Low urine osmolality Inappropriate dilute urine Inappropriate diuresis Urine osmolality consistent with water diuresis Excessive water loss ?Diabetes insipidus (DI) Suggest serum/plasma calcium Review drugs/medications History of polyuria noted ?Lithium therapy ?Cranial/central or nephrogenic DI ?Medication related Suggest (endocrine) referral Dehydration ?Hypercalcaemia Discuss fluid intake with patient LESS RELEVANT KEY WORDS Suggest water deprivation test Borderline hypernatraemia 24 h urine volume to confirm polyuria Decreased eGFR ?Diuretic therapy related Suggest urinalysis Desmopressin to differentiate cranial/nephrogenic DI Suggest ADH Mildly elevated creatinine Mildly elevated bicarbonate Mild (metabolic) alkalosis Urine osmolality < serum osmolality ?Osmotic diuresis ?Renal ADH resistance Phone GP ?Metabolic ?Iatrogenic ?Urinary tract infection Review family history Suggest referral to nephrologist NOT SUPPORTED KEY WORDS ?Primary polydipsia Creatinine consistent with stage 3 renal disease ?Chronic kidney disease (CKD)/ renal disease Suggest imaging ?Cushing’s/Conn’s Repeat early morning urine osmolality Suggest aldosterone/renin ratio ?Diabetes mellitus Suggest serum electrophoresis ?Thyrotoxicosis/suggest thyroid function tests Normal osmolar gap Suggest serum cortisol ?Liquorice use Suggest 24 h urine cortisol Suggest comprehensive biochem profile Suggest full blood count Suggest hospital referral ?High water intake Suggest HbA1C Primary water deficit Suggest ACTH Suggest microalbumin Stage II CKD MISLEADING KEY WORDS ?Age related Suggest repeat in 3–6 months Inappropriate ADH secretion Suggest renal biopsy Case 12-04 Acid-Base Patient ID 75-year-old man Patient Location Emergency Department Clinical Notes on Request Form Renal failure. Dizzy. Case Details Blood Gases Sample type: venous pH 7.22 (7.35–7.45) pCO2 54 mmHg (35–45) pO2 75 mmHg (80–110) HCO3 22 mmol/L (22–30) Base Excess -6 mmol/L (-3/+3) O2 Sat. 92 % Na 121 mmol/L (135–148) K 7.3 mmol/L (3.5–5.3) iCa 1.05 mmol/L (1.13–1.32) Note: all reference intervals shown are for arterial blood only. Suggested Comment Critical electrolyte and calcium results, while consistent with renal failure, require confirmation by repeat sample before initiating treatment. Serum creatinine and urea should also be measured urgently. Provided the patient is not in circulatory shock, the pH reliably indicates an acidaemia; most likely metabolic but also with a respiratory component given the high pCO2. Assessment of oxygenation is unreliable and if required, should be assessed by pulse oximetry and arterial blood gas analysis. Rationale There is growing evidence that, in certain situations, venous blood gas analysis provides adequate and reliable information to allow one to avoid the more painful and potentially dangerous practice of arterial blood sampling. Venous sampling is particularly useful in diabetic ketoacidosis and uraemic patients. There is currently insufficient evidence to support its use in compromised circulatory states (e.g. arrest/ shock) and mixed acid-base disorders as the relationship between arterial and venous blood gas parameters may change in these situations. pH and bicarbonate results are virtually interchangeable with arterial values, thus allowing for acid-base assessment. pCO2 values are generally 6 mmHg higher in venous blood. At the diagnostic cut-off of 45 mmHg (i.e. the arterial blood cut-off), venous pCO2 has high sensitivity (nearly 100%) but poor specificity (56%) as a screening test for arterial hypercarbia. pO2 values are less than half of those in arterial blood and consequently no comment regarding hypoxia should be made from venous samples. Hyperkalaemia due to haemolysis is always possible but less of a concern here given the pattern of abnormalities and the clinical context. Communication should focus clinical staff on immediate confirmation of these abnormal results before urgent medical treatment. References 1. Kelly AM. Review article: can venous blood gas analysis replace arterial in emergency medical care. Emerg Med Australas 2010;22:493-8. 2. Verma AK, Roach P. The interpretation of arterial blood gases. Aust Prescr 2010;33:124-9. PREFERRED KEY WORDS Venous blood gas sample Critical hyperkalaemia and hyponatraemia Severe hyperkalaemia Severe hyponatraemia Acidaemia ?Low Ca 2° to renal failure Consistent with mixed respiratory and metabolic acidosis Consistent with renal failure Na, K, Ca consistent with renal failure Suggest repeat electrolytes/Ca Suggest renal function tests ?Respiratory disease/pneumonia/ pulmonary oedema Venous pO2 not reliable Urgent medical attention required LESS RELEVANT KEY WORDS NOT SUPPORTED KEY WORDS Recollect arterial blood sample Metabolic acidosis Suggest glucose ?High potassium due to haemolysis, excess cold ?Drugs/medications ?Diabetic ketoacidosis Suggest test for adrenocortical insufficiency ?Respiratory failure Respiratory acidosis Reference intervals are for arterial blood Low pH and high pCO2 Suggest urine K, Na, protein ?Diuretics/spironolactone Suggest anion gap Suggest serum and urine osmolality ?O2 therapy Bicarbonate loss ?Adrenal insufficiency Suggest CXR Hypercarbia ?Spurious hyperkalaemia Hyperkalaemia caused by acidosis Acidosis Acute respiratory acidosis High K, low Ca Mild hypocalcaemia Suggest cardiac monitoring ?Clinical symptoms due to low Na ?Lactic acidosis No respiratory compensation Suggest nephrology review Hyponatraemia due to renal failure Severe acidosis No comment ?Dizziness due to hypocalcaemia Mixed acid base disorder Consistent with arterial sample Suggest dialysis Respiratory compensation Suggest PTH/Ca/Mg/Vitamin D/ALP ?Specimen contamination Suggest urine pH ?Renal tubular acidosis Difficult to assess respiratory component Lack of renal composition Low Ca due to critical illness Venous blood gas difficult to comment Suggest renal ultrasound SIADH ?Chronic respiratory acidosis Acute on chronic respiratory acidosis Metabolic compensation Mixed metabolic acidosis and respiratory alkalosis Suggest Cl for RTA MISLEADING KEY WORDS ?Cerebral disease O2 status acceptable for elderly Hypoxia and cyanosis Case 13-06 Acid-Base Patient ID 52-year-old woman Patient Location Emergency Department Clinical Notes on Request Form No information provided Case Details Sodium Potassium Chloride Bicarbonate Urea Creatinine 150 mmol/L 3.0 mmol/L 127 mmol/L 13 mmol/L 24.9 mmol/L 102 µmol/L (137–145) (3.5–4.9) (100–109) (22–32) (2.7–8.0) (50–100) Previous renal surgery Venous blood gas analysis pH 7.22 pO2 31 mmHg pCO2 29 mmHg Calc. Bicarb 12 mmol/L (7.34–7.45) (25–40) (40–50) (22–31) Suggested Comment Significant metabolic acidosis with hypokalaemia and normal anion gap. Hypernatraemia suggests dehydration. Possible causes include: renal tubular acidosis, severe diarrhoea, or ureteric diversion. If the cause is unknown, suggest check urinary pH and electrolytes. If considering parenteral bicarbonate, it is important to normalise potassium beforehand. Rationale Normal anion gap metabolic acidosis can occur due to bicarbonate loss (e.g. severe diarrhoea, ureteric diversion to the colon, or proximal renal tubular acidosis, also known as type II RTA); failure of acidification in the distal renal tubule (type I RTA); or excess ammonium retention (e.g. ureteric diversion to the colon). If the ureter is diverted to the ileum, acidosis is unlikely unless there is obstruction and prolonged urine-gut contact. Loss of bicarbonate and fluid volume leads to compensatory retention of sodium and chloride, and hyperchloraemia. Urine pH should be <5.3 in acidosis, if renal acidification is normal. However, severe volume depletion may increase urine pH. High urine pH can be followed up by loading tests with bicarbonate or ammonium if necessary to localise the site of RTA. Increasing blood pH shifts potassium into cells so it is important to correct the hypokalaemia, then monitor potassium closely during treatment of any acidosis. References 1. Walmsley RN, White GH. Normal “anion gap” (hyperchloremic) acidosis. Clin Chem 1985;31:309-13. 2. Cruz DN, Huot SJ. Metabolic consequences of urinary diversions: an overview. Am J Med 1997;102:477-84. 3. Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160-70. PREFERRED KEY WORDS Normal anion gap metabolic acidosis Hypernatraemia/dehydration/increased urea:creatinine ?Renal tubular acidosis Type II (proximal) renal tubular acidosis Type I (distal) renal tubular acidosis Metabolic acidosis ?Diarrhoea/gastrointestinal loss Suggest urinary electrolytes Suggest urine pH ?Urinary diversion ?Obstructed ileal bladder ?Vesicocolic fistula LESS RELEVANT KEY WORDS Hypokalaemia History of renal surgery (Partial) respiratory compensation ?(Acute) renal impairment ?Carbonic anhydrase inhibitors Suggest serum/urine osmolality Suggest glucose/insulin Low bicarbonate Suggest albumin/total protein/phosphate/Ca/Mg Suggest urine ammonia ?Renal or gastrointestinal disease Further clinical info needed Loss of bicarbonate Low pH/ acidaemia Low pCO2 Venous blood gas sample noted Suggest specialist referral Phone result ?Dietary intake ?Chronic laxative abuse ?Villous adenoma Suggest lactate/citrate Suggest repeat testing Diuretic phase following acute tubular necrosis Suggest troponin/cardiac markers/ECG ?Nephrolithiasis Suggest ammonia chloride loading ?Increased osmotic diuresis NOT SUPPORTED KEY WORDS ?(Resolved) diabetic ketoacidosis Suggest serum electrolytes, urea, creatinine Uncompensated metabolic acidosis ?Vomiting/ infection Treat with IV potassium and insulin ?Salt ingestion/water depletion Ingestion of ammonium chloride ?Drug reaction UNACCEPTABLE KEY WORDS ?Saline/IV contamination ?Diuretics ?Mineralocorticoid excess Fluid status unknown ?Cholestyramine Case 6-06 Renal Patient ID 58-year-old woman Patient Location General Practice Clinical Notes on Request Form Newly diagnosed with type II diabetes mellitus. ?Microalbuminuria Case Details Sample: morning spot urine Albumin Creatinine ACR 12 mg/L 3.9 mmol/L 3.1 mg/mmol (<3.5) Additional Information No previous urine results. Suggested Comment Normal results. Suggest repeat in one year. Rationale Patients with type II diabetes mellitus should be tested for albuminuria annually starting from the time of diagnosis. The albumin:creatinine ratio (ACR) is the preferred method for assessment of albuminuria in both diabetic and non-diabetic individuals. The ACR should be measured using a first morning spot urine specimen; however, a random urine sample is also acceptable when the former is not possible or practical. Alternately, the albumin excretion rate (AER) may be measured using 24 h urine collection. Microalbuminuria is indicated by ACR 2.5–25 mg/mmol in males ACR 3.5–35 mg/mmol in females OR AER 30–300 mg/24 h in either gender Macroalbuminuria is indicated by: ACR >25 mg/mmol in males ACR >35 mg/mmol in females OR AER >300 mg/24 h in either gender If the ACR or AER is positive for microalbuminuria, the person should have one to two additional ACR/AER within three months. Microalbuminuria is confirmed if two of three tests are positive. If the ACR or AER showed macroalbuminuria, total protein should be measured in a 24 h urine collection. If the ACR is normal, as it is in this patient, testing should be repeated annually. Reference 1. Johnson DW, Jones GR, Mathew TH, et al.; Australasian Proteinuria Consensus Working Group. Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement. Med J Aust 2012;197:224-5. PREFERRED KEY WORDS Normal result Recheck 6–12 months Further monitoring suggested LESS RELEVANT KEY WORDS Results exclude microalbuminuria Suggest AER Criteria 2/3 in 6 weeks = microalbuminuria Repeat ACR Suggest HbA1c No comment ACR borderline Morning urine preferred Suggest plasma creatinine Monitor cardiovascular risk factors Suggest three timed overnight urines Microalbuminuria may develop later Albumin fragments may not be detected Suggest creatinine clearance Suggest lipids UNACCEPTABLE KEY WORDS No nephropathy Urine creatinine low, ?diluted Microalbuminuria present Exclude urinary tract infection, exercise, cystic fibrosis AER >20 x2 = microalbuminuria AER <20 not microalbuminuria ADS recommends 12 month monitor Urine albumin and creatinine slightly high Incomplete and inappropriate sample Check urine glucose level ACR unreliable, dilute urine Case 6-10 Renal Patient ID 32-year-old male Patient Location Medical Ward Clinical Notes on Request Form Paroxysmal nocturnal haemoglobinuria Case Details Sodium Potassium Bicarbonate Urea Creatinine 136 mmol/L 4.0 mmol/L 21 mmol/L 26.7 mmol/L 552 µmol/L (134–146) (3.4–5.0) (22–32) (3.0–8.0) (60–120) Additional Information Total Protein 63 g/L (60–80) Albumin 34 g/L (35–50) Bilirubin 55 µmol/L (<20) Haemoglobin 94 g/L (135–180) Reticulocytes 4.1% (0.2–2.0) Blood film features suggest active haemolysis. Haem Index 470 (<100) Suggested Comment This patient has renal failure. Elevated serum haemoglobin indicates haemolysis. Clinical note of paroxysmal nocturnal haemoglobinuria suggests in vivo haemolysis, in which case the measured potassium reflects circulating concentration. Repeat measurement of potassium is recommended for confirmation. Rationale Paroxysmal nocturnal haemoglobinuria is a condition characterised by the clonal expansion of one (usually the red blood cell line) or more haemopoietic stem cells that are deficient in certain surface proteins. These are acquired through somatic mutations, which predispose the blood cells to complement-mediated haemolysis, particularly in acidic conditions. This may lead to haemoglobinuria/haemosiderinuria that can damage the kidneys. Traditionally, the haemolysis is thought to occur in paroxysms during sleep-induced acidosis. More recent evidence suggests it can occur throughout the day but the haematuria is more notable in the concentrated overnight urine. The clinical note given with the biochemistry results should assist with the interpretation of those specific results. The patient is clearly in renal failure. The evidence for intravascular haemolysis is the raised serum haemoglobin as measured by the haem index, bilirubin and reticulocytes, and blood film features. Other supportive features of this intravascular haemolytic condition include elevated serum lactate dehydrogenase, low/absent haptoglobin, haemoglobinuria/haemosiderinuria. Complications of paroxysmal nocturnal haemoglobinuria include iron deficiency anaemia, hyoplastic bone marrow and thrombosis, which may involve the liver, brain, abdominal and lower limb venous systems, and can be fatal. Reference 1. Krauss JS. Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria. Ann Clin Lab Sci 2003;33:401-6. PREFERRED KEY WORDS Renal failure Intravascular haemolysis Consistent with paroxysmal nocturnal haemoglobinuria Suggest haptoglobin Sample haemolysed In vivo potassium okay ?In vitro or in vivo haemolysis Bilirubin affected by haemolysis Repeat potassium on nonhaemolysed sample LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS Expected higher potassium Suggest cell markers by flow cytometry Hyperbilirubinaemia Haemolytic anaemia ?Renal haemosiderosis Active red blood cell production/ increased reticulocytes Anaemia/low haemoglobin ?Renal failure due to haemoglobinuria Suggest LDH Elevated urea and creatinine Suggest complete haematology Anaemia multifactorial Renal failure 2° to paroxysmal nocturnal haemoglobinuria Suggest liver function tests and direct/indirect bilirubin Suggest iron studies/erythrocyte folate Suggest direct Coombs’ Test ?Other concurrent disease Suggest haematology consultation ?Thrombotic thrombocytopaenic purpura and haemolytic uraemic syndrome Suggest urine protein/casts Consult with renal physician Suggest monitor renal failure ?Creatinine underestimated ?Clinical information ?Disseminated intravascular coagulation Haemolytic jaundice ?Clinical dehydration Suggest renal biopsy ?Paroxysmal cold haemoglobinuria Suggest urine haemoglobin and haemosiderin Suggest Ham test ?Renal failure 2° to thrombosis No comment Monitor serum potassium ?Previous renal function history ?Non-paroxysmal nocturnal haemoglobinuria cause of renal failure Recommend dialysis/exchange transfusion ?Blood transfusion ?Soluble transferrin receptor assay ?Erythrocytes protoporphyrin high ?Sepsis or thrombotic thrombocytopaenic purpura Suggest MRI/CT scans Suggest neutrophil ALP score Categorise paroxysmal nocturnal haemoglobinuria by CLST Suggest cardiac markers Suggest Donath-Landsteiner test Liver function okay Suggest B-haem streptococcus culture Suggest fine needle aspiration Renal recovery as potassium normal Transfusions and iron therapies Manage complications of paroxysmal nocturnal haemoglobinuria Low albumin due to proteinuria Suggest eGFR Case 7-04 Renal Patient ID 45-year-old female Patient Location General Practice Clinical Notes on Request Form Routine health check. Fit and well. Case Details Urea Creatinine eGFR Glucose (random) Bilirubin ALP GGT ALT 6.1 mmol/L (2.7–7.8) 120 µmol/L (50–110) 45 mL/min/1.73m2 (80–120) 4.7 mmol/L (3.5–7.8) 6 μmol/L (3–21) 54 U/L (30–120) 17 U/L (10–35) 50 U/L (0–30) Additional Information No previous laboratory results. Suggested Comment Mildly elevated creatinine and decreased eGFR suggests possible renal impairment, along with a minor increase in ALT. eGFR is not reliable in the presence of extreme lean body mass, high protein, vegetarian diets or creatine supplements. Consider urine protein, mid-stream urine sample and formal creatinine clearance if there is suspicion that eGFR may be incorrect and review patient for causes of increased ALT. Rationale The estimated Glomerular Filtration Rate (eGFR) is derived from serum creatinine, age and sex using the CKD-EPI equation and it should be automatically reported with every creatinine requested in subjects >18 years of age (1). eGFR results may be unreliable or misleading in subjects with the following: acute changes in kidney function, on dialysis, exceptional dietary intake (e.g. vegetarian diet, high protein diet, creatine supplements), extremes of body size, skeletal muscle diseases, and severe liver disease. An elevated ALT in an asymptomatic subject may be due to alcohol-related liver injury, chronic hepatitis B or C, autoimmune hepatitis, fatty liver disease, haemochromatosis, Wilson’s disease, or alpha-1-antitrypsin deficiency (2). Non-hepatic causes include coeliac sprue, muscle diseases, and strenuous exercise. References 1. Kidney Health Australia. http://www.kidney.org.au 2. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000;342:1266-71. PREFERRED KEY WORDS Check urine albumin/protein Increased creatinine Reduced eGFR Increased ALT Renal impairment/disease Repeat creatinine/eGFR ?Medication/drugs Suggest viral/hepatitis serology Suggest creatinine clearance ?Hepatitis Suggest mid-stream urine sample ?Increased muscle mass eGFR not valid in some situations Extreme body composition eGFR not validated ?Diet Suggest clinical review LESS RELEVANT KEY WORDS Moderate chronic kidney disease Assess cardiovascular risk factors Mild liver disease Renal referral recommended Repeat liver function tests Monitor results Follow-up required Suggest full liver function tests C-reactive protein / lipids ?Fatty liver ?Alcohol Refer to Kidney Foundation website ?Creatinine method interference Full blood count Normal urea Suggest Cockcroft-Gault/body surface area calculation Check glomerular haematuria Review renal risk factors UNACCEPTABLE KEY WORDS ?Immunological Measure blood pressure Check for diabetes PTH/calcium studies Measure calcium/phosphate Fasting glucose No dehydration HS/iron studies ?Acute renal failure No comment Consider starting renal therapy Consider liver imaging Suggest other miscellaneous tests Case 10-01 Renal Patient ID 72-year-old man Patient Location General Practice Clinical Notes on Request Form ?Renal impairment. Blood pressure normal Case Details Sodium Potassium Glucose Bicarbonate Urea Serum creatinine eGFR 139 mmol/L (134–146) 4.6 mmol/L (3.4–5.0) 5.1 mmol/L (3.0–5.4) 28 mmol/L (22–32) 8.2 mmol/L (3.0–8.0) 133 μmol/L (60–110) 49 mL/min/1.73m2 (>60) Additional Information Previous serum creatinine 129 μmol/L 6 months ago Suggested Comment eGFR between 30 and 60 mL/min/1.73m2 on two occasions 6 months apart indicates stage 3 chronic kidney disease (CKD). Minimal change in serum creatinine indicates stable kidney function. Suggest assess coronary vascular disease (CVD) risk and check for albuminuria (urine albumin:creatinine ratio, ACR) and haematuria (dipstick). If ACR/dipstick is normal, re-assess in 12 months. If albuminuria and/or haematuria present, repeat ACR/dipstick tests (considered present if two of three repeat tests are positive for ≥3 months) and consider further investigation including renal U/S and referral to a nephrologist. Rationale and References eGFR should be estimated by applying CKD-EPI equation on isotope dilution mass spectrometry-traceable creatinine assays. Age-related decision points for eGFR in adults are not recommended, as an eGFR < 60 mL/min/1.73 m2 carries significantly increased risks of adverse clinical outcomes without consistent age association. Hence, whilst it is very common in older people, it should not be considered a normal part of ageing. Initial further investigations suggested include (preferably first morning void) urine albumin:creatinine ratio (ACR) and dipstick (for haematuria), monitoring of serum creatinine and cardiovascular risk assessment. If no abnormalities are found, a wait-and-watch approach is appropriate with yearly reviews. Note the reduced GFR should be taken into account when making drug-dosing decisions, and attention paid to cardiovascular risk reduction. However, if the investigations show abnormalities, the need for further investigations and specialist referral should be considered. References 1. Johnson DW, Jones GR, Mathew TH, et al. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations. Med J Aust 2012;197:224-5. 2. Kidney Health Australia – Health Professionals section. http://www.kidney.org.au PREFERRED KEY WORDS eGFR suggests moderate CKD (stage 3) Consistent with renal impairment Stable creatinine result eGFR declines with age Interpret eGFR with caution in elderly Typical for age if stable and no other abnormalities If stable, no other abnormalities, unlikely CKD Assess CVD risk factors Suggest ACR Suggest test for proteinuria Suggest test for haematuria Suggest fasting lipid profile Monitor eGFR 3–6 monthly Beware renal excretion for drugs with low GFR Investigate further Refer to nephrologist if indicated LESS RELEVANT KEY WORDS Slightly raised creatinine and urea Low eGFR Mild renal impairment ?Lifestyle habits/underlying causes ?Normal GFR for age Suggest spot protein/creatinine ratio Suggest 24 h urine protein excretion Suggest Ca/PO4/PTH/vit D ?Renal impairment Apply eGFR as recommended No comment ?Muscle mass and dietary intake Due to postrenal or ?intrarenal cause Clinical correlations required Suggest cystatin C Suggest mid-stream urine examinations eGFR by MDRD uses creatinine, sex and age ?Drugs that interfere with eGFR Consider patient age and creatinine uncertainty of measurement Electrolytes normal Review patient (Kidney Health Plan) ?Hydration status eGFR 10th percentile for age & sex Use surface area corrected eGFR eGFR use in stable medical conditions eGFR inappropriate for drug dosing Suggest iron studies Suggest imaging UNACCEPTABLE KEY WORDS Suggest creatinine clearance Deterioration of renal impairment Suggest glucose Suggest PSA Suggest full blood count and INR Repeat after overnight fast Unlikely to be CKD Suggest renin, aldosterone Suggest protein electrophoresis ?Diabetic eGFR suggests severe CKD (stage 4) Case 11-03 Renal Patient ID 3 years & 10 months old girl Patient Location General Practice Clinical Notes on Request Form Febrile. Nephrectomy for Wilm’s tumour 2.5 years ago. Case Details Serum Sodium Potassium Glucose Bicarbonate Urea Creatinine 139 mmol/L 5.0 mmol/L 4.6 mmol/L 17 mmol/L 6.9 mmol/L 45 μmol/L (132–143) (3.5–5.0) (3.0–5.5) (17–30) (1.1–5.7) (23–37) Additional Information C-reactive protein 110 mg/L (< 8.0) Previous serum creatinine 27 μmol/L 18 months ago (reference interval 16–31 μmol/L) Suggested Comment Results indicate renal impairment. An acute infective or inflammatory process is likely. Causes of acute deterioration in renal function including dehydration, urinary tract infection or drug toxicity should be excluded. Interference in the creatinine result (for creatinine assays based on Jaffe reaction), especially from cephalosporins, should be excluded. In a child of this age, age-specific creatinine is a guide only, and an estimation of glomerular filtration rate (eGFR) will improve assessment of renal function. Rationale The important finding here is of renal impairment in a child already at risk with a history of solitary kidney and Wilm’s tumour. The rise relative to the reference interval since the previous test suggests this is not due to the previous nephrectomy, but represents a new disease process. The clinical notes and markedly elevated Creactive protein (CRP) suggest an acute infective/inflammatory process is likely. Thus in the first instance, causes of acute renal deterioration including dehydration, urinary tract infection or drug toxicity should be excluded. It is important to recognise that in a child with a history of previous illness may still be small for age. For these patients, age-based creatinine reference intervals are only a guide and the GFR may be lower than the creatinine suggests. There is limited data in estimating GFR in children with solitary kidney, using either the modified Schwartz formula or cystatin C-based formulas; however the relationship appears no worse than in the general paediatric population. The KDOQI guidelines for evaluating kidney disease in children and adolescents recommend estimation of GFR using a creatinine-based formula (1). The guidelines also recommend a first morning urine specimen for protein:creatinine ratio, although random specimens are acceptable, for assessment of proteinuria. Some medications may interfere with creatinine result obtained from assays based on Jaffe reaction, and should be enquired for, especially cephalosporins. Specific to children with a history of Wilm’s tumour, a survey suggests renal failure is a rare (<0.26%) complication in children with unilateral nephrectomy (2); the more frequent causes of kidney failure in that group include Denys-Drash syndrome (in males; pseudohermaphroditism and diffuse mesangial sclerosis), progressive tumour in the remaining kidney, radiation nephritis and other causes, including hyperfiltration injury. References 1. Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification and stratification. Pediatrics 2003:111:1416-21. 2. Ritchey ML, Green DM, Thomas PR et al. Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 1996;26:75-80. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Renal failure ?acute ?chronic Deterioration renal function compared to previous urea and electrolytes Impaired renal function ?Pre-renal renal impairment ?Dehydration ?secondary to infection ?Urinary tract infection ?Infection/sepsis ?Cephalosporin interference - Jaffe Suggest urine microscopy, culture and sensitivity/casts/crystals Suggest urine creatinine/protein/ albumin/microalbumin Suggest ultrasound of kidney/lower abdomen Suggest monitor renal function test, calcium and liver function tests Estimate eGFR - Schwartz formula Exclude pyelonephritis Suggest urine protein/creatinine ratio a.m. sample ?Trimethoprim blocking creatinine excretion ?Tumour recurrence Elevated urea and/or creatinine Elevated C-reactive protein ?Inflammation Febrile status Suggest full blood examination/ESR Further investigation required Low to low normal bicarbonate Suggest referral to specialist Acidosis Suggest timed urine protein/creatinine clearance Suggest arterial blood gases Borderline hyperkalaemia Metabolic acidosis High normal potassium Suggest blood cultures ?Nephritis ?Radiation adverse effects ?Medication history ?Intrinsic renal disease ?Extrinsic renal disease ?Recent meat intake Low creatinine/urea ratio Exclude glomerulonephritis ?Chemotherapy adverse effects Hyperkalaemia Suggest referral to emergency department/admission Reduced eGFR Suggest urine electrolytes Wilm’s tumour - urogenital malformation ?Hyperventilating Suggest loss of heterozygosity karyotyping for Ip/16q ?Blood pressure status Consider empiric antibiotics Unable to calculate eGFR due to age ?Previous tx related impairment renal failure Recommend rehydration Suggest intravenous pyelogram Exclude tumour lysis ?WAGR (Wilms’ tumour, aniridia, genitourinary anomalies, and mental retardation ) syndrome ?Long term complication of one kidney Suggest CT scan of remaining kidney If renal failure persists - renal imaging Aggressive management and phone GP UNACCEPTABLE KEY WORDS Suggest repeat tests when patient well Suggest renal biopsy ?Denys-Drash syndrome ?Compensatory hypertrophy of kidney Suggest tumour markers e.g. CEA Suggest serum am cortisol Suggest immunoglobulins Suggest chest CT scan Suggest IGF-II Suggest coagulation studies Case 11-07 Renal Patient ID 26-year-old man, refugee clinic Patient Location General Practice Clinical Notes on Request Form Generalised oedema, eosinophilia Case Details Fasting serum Sodium Potassium Chloride Bicarbonate Glucose Urea Creatinine Urate Phosphate Total Calcium Albumin Protein Total Bilirubin GGT ALP ALT Additional Information Fasting serum Cholesterol Triglyceride 138 mmol/L 4.6 mmol/L 101 mmol/L 27 mmol/L 5.2 mmol/L 5.8 mmol/L 63 μmol/L 0.63 mmol/L 1.62 mmol/L 2.10 mmol/L 7 g/L 37 g/L 2 μmol/L 51 U/L 88 U/L 37 U/L (137–145) (3.5–4.9) (100–109) (22–32) (3.2–5.5) (2.7–8.0) (50–120) (0.15–0.45) (0.65–1.45) (2.10–2.55) (34–48) (65–85) (2–24) (<60) (30–110) (<55) 23.7 mmol/L (<5.5) (desirable) 7.5 mmol/L (0.3–2.0) Suggested Comment Severe hypoalbuminaemia and hyperlipidaemia in the clinical setting of oedema consistent with nephrotic syndrome. In view of the history of refugee status and the eosinophilia, helminthic parasites are a likely aetiology. Recommend urine protein/creatinine ratio and faecal microscopy. Rationale Severe hypoalbuminaemia and hyperlipidaemia with oedema are typical signs of nephrotic syndrome. The lack of gastrointestinal symptoms and presence of hyperlipidaemia make a protein-losing enteropathy unlikely. There are many causes of nephrotic syndrome but the history of refugee status and presence of eosinophilia raise the possibility of parasitic infestation as the cause. Helminthic parasites such as strongyloides, filariae, schistosoma and echinococcus are more commonly associated with eosinophilia than other parasites. Initial investigations should focus on the cause of hypoalbuminaemia. A spot protein/creatinine and/or albumin/creatinine ratio will confirm the presence of macroalbuminuria and form the basis for subsequent monitoring. A 24 h urine protein collection will help clarify nephrotic range proteinuria. Faecal microscopy may help identify a parasitic cause if this is present. References 1. van Velthuysen ML, Florquin S. Glomerulopathy associated with parasitic infections. Clin Microbiol Rev 2000;13:55-66. 2. Mawhorter SD. Eosinophilia caused by parasites. Pediatr Ann 1994;23:405,409-13. PREFERRED KEY WORDS Severe hypoproteinaemia Severe hypoalbuminaemia Marked hyperlipidaemia Liver enzymes normal Generalised oedema Eosinophilia ?Nephrotic syndrome Suggestion of nephrotic syndrome ?Parasitic infestation ?HBV/HIV/syphilis/hepatitis ?Protein-losing enteropathy Secondary lipid abnormalities Suggest referral to specialist Suggest 24 h urine protein/albumin Urine protein/creatinine ratio Suggest stool examination ?Infiltrations LESS RELEVANT KEY WORDS Hyperlipidaemia Hyperuricaemia Hypoalbuminaemia Hypoproteinaemia Allergies/inflammation/autoimmune Suggest hepatitis/parasite serology ?Malnutrition/malabsorption Check full blood examination/ film/ PT/ Coagulation ?Drug related Suggest serum and urine electrophoresis Hyperphosphataemia Suggest autoimmune markers ?Viral/chronic infection ?Haematological malignancy Urgent medical attention required Suggest faecal alpha 1 antitrypsin Suggest ionised calcium ?Diabetes/hypertension ?Glomerular disease Suggest examine urinary sediment Increased cell turnover Associated with renal dysfunction ?Liver disease/failure Interference from lipaemia ?Renal biopsy if indicated Suggest thyroid function tests ?Renal disease Repeat glucose Suggest urine microscopy and culture ?Hypothyroidism Adjusted calcium high Suggest urea/creatinine/creatinine clearance ?Post-streptococcal glomerulonephritis Borderline low calcium Check urine lipiduria ?Dilutional due to oedema Suggest electrolytes with direct ISE method ?Sickle cell anaemia Suggest CRP Repeat albumin/protein UNACCEPTABLE KEY WORDS Primary lipid disorder not excluded Suggest PTH ?Inherited analbuminaemia ?Gout / increased salt intake / LeschNyhan syndrome Suggest cardiac risk analysis Diabetes mellitus unlikely ?Cushing's disease ?Thyrotoxicosis ?Decreased synthesis Case 12-10 Renal Patient ID 40-year-old female Patient Location General Practice Clinical Notes on Request Form Newly diagnosed with diabetes mellitus Case Details Sample: Random spot urine Time: 2:00 pm Albumin:creatinine ratio 5.5 mg/mmol creatinine (<3.5) Additional Information HbA1c HbA1c (IFCC) 7.4% 57 mmol/mol Suggested Comment Mild elevation of urine albumin:creatinine ratio in a newly diagnosed patient with diabetes. Random collection noted; first morning void collections are recommended to exclude exercise and posture effects. Sample collection should also avoid acute heavy exercise within 24 hours, febrile illness, nonsteroidal antiinflammatory drugs, menstruation and vaginal discharge. Two of three positive samples within three months are required for diagnosis. Rationale Urine albumin:creatinine ratio (ACR) is the preferred test for assessing proteinuria in diabetic patients. As this is a newly diagnosed case at age 40, it is likely that this is type 2 diabetes and it is appropriate to test for ACR at the time of diagnosis. For a diagnosis of persistent albuminuria there is a requirement for at least two out of three separate collections to be positive. This is due to the high within-subject biological variation of ACR (CVi 30–60%) as well as the many causes of false positive results. The laboratory is in a good position to advise on appropriate sample collection. The preferred specimen is a first morning collection with avoidance of acute heavy exercise within 24 hours, febrile illness, nonsteroidal anti-inflammatory drugs, menstruation or vaginal discharge. Other factors which can increase urine albumin excretion but which may not be able to be controlled are congestive cardiac failure and some drugs, especially ACE inhibitors and angiotensin II receptor blockers (ARBs). The use of timed urine collections, either overnight or 24 hour is not required, but it is recommended to use gender-specific cut points (<3.5 mmol/mg for women and <2.5 mg/mmol for men) to provide an approximate correction for the increased creatinine output in men. There are many factors that must be managed for a patient with newly diagnosed diabetes, and it is not possible to cover them all in a comment attached to a urine ACR. The comment should focus on the interpretation and responses to this specific test, as laboratories are generally unaware of the other factors that may influence management. References 1. Martin H. Laboratory measurement of urine albumin and urine total protein in screening for proteinuria in chronic kidney disease. Clin Biochem Rev 2011;32:97-102. 2. Royal Australian College of General Practitioners (RACGP). Guidelines for preventive activities in general practice. 6th edition. Melbourne: RACGP; 2005. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Borderline raised ACR Confirm microalbuminuria Exclude transient microalbuminuria Suggest repeat spot early morning urine (1st void) for test Suggest repeat ACR Confirm 2/3 urines in 3–6 months ACR>3.5 Exclude fever/urinary tract infection/exercise/menses Exclude diabetic nephropathy Exclude heart failure If eGFR >60 then cardiovascular disease risk low ADS recommends ACR<3.5 Urine ACR unreliable, collected at 2 pm Exclude pregnancy Suggest glycaemic control and review Suggest serum urea and electrolytes, creatinine Suggest eGFR Results suggest microalbuminuria Exclude hypertension/check BP ADS recommends HbA1c ≤7.0 Elevated urinary albumin HbA1c result confirms diabetes Elevated ACR Suggest lipid/HDL profile and monitoring Suboptimal glycaemic control Patient at risk of cardiovascular disease HbA1c target of <6.0% desirable ?Degree of renal damage Persistent raised ACR - nephropathy Assess cardiovascular disease risk factors Check weight/BMI/diet Suggest lifestyle modification Exclude poor glycaemic control Suggest liver function tests Suggest thyroid function tests ?Chronic kidney disease If microalbuminuria - treatment advised Suggest urine collection – fasting and supine Suggest retinal screening Suggest foot screening ?High ACR due to low muscle mass ?Weight loss ?Polydipsia/polyuria ?Family history of diabetes Exclude smoking NOT SUPPORTED KEY WORDS Suggest follow up testing annually Confirm diabetes mellitus Suggest 24 h urine protein Suggest fasting glucose monitoring Microalbuminuria clinically significant Chronic kidney disease indicated Suggest repeat HbA1c Suggest 24 h urine for albumin Test >2 h postprandial Hb variants can affect HbA1c value Suggest endocrine/diabetes review Suggest overnight urine albumin collection Goal for Type II DM HbA1c <6.5% MISLEADING KEY WORDS Suggest therapy e.g. ACE inhibitor Suggest repeat urine albumin when HbA1c <6.0% HbA1c shows good diabetic control Case 14-02 Renal Patient ID 20-year-old female Patient Location General Practice Clinical Notes on Request Form Feeling run down; past medical history unremarkable. Case Details Sodium Potassium Urea Creatinine eGFR 138 mmol/L (134–145) 5.1 mmol/L (3.4–5.0) 34.1 mmol/L (3.0–7.0) 256 µmol/L (44–80) 21 mL/min/1.73m2 Additional Information Thyroid function tests were within normal limits. Full blood count showed a haemoglobin of 9.7 g/dL (11.5–16). Red cells were normochromic normocytic. A repeat electrolytes, urea, creatinine was performed, and was essentially similar. Suggested Comment Serum creatinine and eGFR indicates severe reduction in renal function. In view of coexistent anaemia, chronic kidney disease (CKD) is likely, however, exclusion of causes of acute renal failure is recommended. Urgent referral to a nephrologist is recommended with additional testing for fasting glucose, lipids, bicarbonate, calcium, phosphate, parathyroid hormone (PTH) and spot urine albumin. Blood pressure should be checked and haematuria assessed using a urine dipstick. Rationale A persistent eGFR between 15 and 29 mL/min/1.73m2 constitutes stage 4 chronic kidney disease (CKD). While the requirement for the definition of CKD is two tests greater than three months apart, referral to a nephrologist should be performed urgently in view of the age of the patient, and lack of information on the rate of progressive decline in renal function. Further investigations may be performed in the meantime to look for common related conditions, which may be the cause/consequence of CKD, or interact with CKD to increase morbidity/mortality. Anaemia of CKD is related to both reduced erythropoietin production by the kidney and resistance to the action of erythropoietin. High blood pressure is both a cause and an effect of CKD, and should be detected early and treated. Diabetes is a common cause of CKD and, if present, should be treated rigorously, but would also impact on the management of other aspects of CKD. CKD constitutes a significant risk factor for cardiovascular events and death; an absolute risk approach is recommended. Changes in metabolism of calcium, phosphate, parathyroid hormone (PTH) and vitamin D typically start to occur once GFR is <60 mL/min/1.73m2, and are associated with an increased risk of fracture and increased cardiovascular mortality. Haematuria, if present, could be consistent with glomerulonephritis. Renal ultrasound may be considered to exclude structural abnormalities as a cause of chronic kidney damage. Reference 1. Kidney Health Australia. http://www.kidney.org.au PREFERRED KEY WORDS Severe renal function impairment Coexistent anaemia Chronic kidney disease is likely Consistent with stage 4 chronic renal failure ?Proteinuria/suggest spot urine albumin Suggest calcium/phosphate (PO4)/parathyroid hormone (PTH) Suggest microscopy and culture Suggest urine albumin/creatinine ratio Suggest fasting glucose Review medications/drugs Check blood pressure ?Urinary tract infection/ pyelonephritis/ polycystic kidney disease/ drug toxic Mild hyperkalaemia Urgent referral to nephrologist recommended Assess haematuria ?Diabetes Suggest electrolytes, urea, creatinine, bicarbonate ?Hypertension Suggest HbA1c Suggest lipids High potassium secondary to reduced renal function Avoid nephrotoxic agents eGFR needs to be elevated >3 months ?Glomerulonephritis/vasculitis/acute tubular necrosis LESS RELEVANT KEY WORDS Suggest renal imaging ?Acute renal injury/failure Raised urea and creatinine Low eGFR Suggest protein/albumin/liver function tests Monitor kidney function Exclusion of causes of acute kidney injury recommended Confirm with repeat sample Suggest clinical assessment ?Family history kidney disease Repeat tests twice in next 3 months Suggest iron studies Suggest repeat urea/creatinine Low haemoglobin Suggest 24h protein Assess volume status Confirm eGFR Suggest C-reactive protein NOT SUPPORTED KEY WORDS Suggest 24h urine electrolytes/ urea/ creatine/calcium/PO4 ?Systemic lupus erythematosus Suggest serum and urine osmolality ?Dehydration ?eGFR unreliable due to body size/diet Suggest hCG to exclude pregnancy ?Cardiac muscle damage Suggest urine myoglobin ?Synthetic cannabis use Suggest renal biopsy Suggest CK/CKMB ?Pre-renal cause ?Acute blood loss Suggest erythropoietin levels Screen for ANA/ANCA/GBM antibodies MISLEADING KEY WORDS ?Stage 3 chronic kidney disease Suggest bone marrow studies Case 14-03 Renal Patient ID 72-year-old male Patient Location General Practice Clinical Notes on Request Form Presents with malaise and generalised muscle pain. No medications. Case Details Na K Cl HCO3 Urea Creatinine Glucose (random) 136 mmol/L 6.0 mmol/L 104 mmol/L 25 mmol/L 16.5 mmol/L 180 µmol/L 9.5 mmol/L (135–145) (3.5–4.5) (98–108) (23–33) (3.0–8.0) (60–120) (3.0–5.5) Suggested Comment Disproportionately raised potassium with chronic kidney disease (CKD) stage 3b (eGFR: 32 mL/min/1.73m 2) in an elderly person with hyperglycaemia is suggestive of hyporeninaemic hypoaldosteronism. Please repeat urgently on a plasma sample to confirm potassium and renal status. Recommend further investigation with fasting glucose, creatine kinase, morning cortisol, renin and aldosterone and urine albumin (first morning void). NB acute causes for reduced GFR should be excluded. Rationale Effective renal excretion of potassium is typically maintained until the eGFR falls below ~15 mL/min, i.e. stage 5 chronic kidney disease (CKD). Hence this elevation in potassium is higher than expected for this degree of renal impairment. Pseudohyperkalaemia should be excluded by urgent repeat testing. Syndrome of hyporeninaemic hypoaldosteronism is a relatively common but often overlooked cause of hyperkalaemia with some authors suggesting it may account for 10% of all cases of hyperkalaemia. The typical patient is an elderly with diabetes mellitus; often the syndrome is triggered by stressors such as dehydration, acute illness or the introduction of medications such as non-steroidal anti-inflammatory drugs or angiotensin converting enzyme inhibitors (although this patient was stated not to be on medications). Once true hyperkalaemia is confirmed, adrenal insufficiency should be excluded and renin/aldosterone evaluated. A reduced GFR at any age is indication for investigation and follow-up. Acute reduction in GFR must always be excluded. The CKD management guidelines (2012) are available at www.kidney.org.au and provide guidance on response to a first abnormal result (repeat with albumin:creatinine ratio within 2 weeks) as well as guidance for further testing and treatment based on both the eGFR and the albumin:creatinine ratio. References 1. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1041-2. 2. Hollander-Rodriguez JC, Calvert JF Jr. Hyperkalemia. Am Fam Physician 2006;73:283-90. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS NOT SUPPORTED KEY WORDS Critical hyperkalaemia Potassium is higher than expected Renal impairment and with hyperkalaemia High urea, creatinine and potassium consistent with CKD eGFR 32 mL/min consistent with stage 3b CKD if present for 3 months eGFR suggest stage 3 CKD Moderate renal dysfunction ?Acute renal failure ?Acute/chronic kidney disease Exclude pseudohyperkalaemia Suggest repeat electrolytes/bicarbonate Check potassium on both heparin and serum samples Suggest eGFR Moderate hyperglycaemia ?Hyporeninaemic hypoaldosteronism Increased risk of diabetes Suggest fasting glucose/HbA1c Suggest GTT Suggest creatine kinase to assess muscle pain Suggest urine albumin:creatinine ratio/ protein/ microalbumin ?Diabetes mellitus Suggest repeat serum creatinine, urea and glucose ?Adrenal insufficiency/Addison's Suggest morning cortisol Suggest aldosterone/renin Suggest synacthen stimulation test Suggest full blood count and platelets Urgent clinical review Kidney injury secondary to type 2 diabetes mellitus (DM) Check for previous results Refer to www.kidney.org.au ?RTA type 4 Exclude acute causes for reduced GFR Suggest urinalysis/culture and sensitivity Increased random glucose Check and monitor blood pressure Increased potassium, urea and creatinine Suggest calcium, phosphate, vitamin D, parathyroid hormone, magnesium, iron Suggest renal ultrasound/imaging Suggest fasting lipids Suggest thyroid function tests ?Rhabdomyolysis Suggest liver function tests Suggest electrocardiogram Low sodium /high potassium ?Dehydration Assess cardiovascular disease risk factors Suggest CK, CKMB, myoglobin, AST, troponin I Check specimen for haemolysis Suggest C-reactive protein/autoimmune testing ?Metabolic/inflammatory/malignancy Review of medications Normal sodium/chloride ?Family history of kidney disease HbA1c not Medicare rebatable ?Low insulin ?Renal failure ?Glomerulonephritis ?Lupus Offer advice on lifestyle change Suggest arterial blood gas Calculated osmolarity: 310 mmol/kg Renal failure risk factors: >60y/obese/smoker Prerenal cause of renal dysfunction Mild hyperkalaemia Hyperkalaemia due to renal impairment Refer nephrologist/urologist Suggest plasma and urine electrophoresis CARA guide-31 eGFR is stage 4/5 eGFR indicates advanced CKD Suggest serum/urine osmolality Suggest viral serology MISLEADING KEY WORDS Check creatinine after 6–12 weeks ?Aging kidney Case 6-04 Ca/Mg/Phos Patient ID 43-year-old male Patient Location General Practice Clinical Notes on Request Form Cramps Case Details Sodium Potassium Bicarbonate Urea Creatinine Total Protein Albumin Bilirubin ALT Gamma GT Alk Phos Calcium, adjusted Phosphate 142 mmol/L 4.3 mmol/L 29 mmol/L 5.6 mmol/L 0.1 mmol/L 75 g/L 45 g/L 15 μmol/L 21 U/L 14 U/L 67 U/L 1.55 mmol/L 1.8 nmol/L (136–145) (3.5–5.1) (21–32) (2.0–8.5) (0.06–0.11) (60–80) (35–52) (<21) (0–40) (12–64) (<110) (2.10–2.60) (0.8-1.5) Suggested Comment The severe hypocalcaemia and the mild hyperphosphataemia in the presence of normal renal function suggest hypoparathyroidism. Suggest repeat calcium together with PTH, and also exclude hypomagnesaemia. Rationale The low calcium and high phosphate in the absence of renal failure suggest hypoparathyroidism. To exclude other causes of hypocalcaemia, the measurement of 25-OH vitamin D, magnesium and a clinical history would be useful. The most likely causes for hypoparathyroidism are post neck surgery and autoimmune disease. Reference 1. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863-75. PREFERRED KEY WORDS ?Hypoparathyroidism PTH deficiency ?Clinical history Suggest PTH Suggest magnesium ?Hypomagnesaemia LESS RELEVANT KEY WORDS Hypocalcaemia Raised phosphate Suggest vitamin D Check ionised calcium Normal renal function ?Vitamin D deficiency ?Other causes ?Pseudohypoparathyroidism ?Drugs/medications Suggest thyroid function tests Low corrected calcium Phone to discuss with doctor Normal ALP Consider calcium replacement Suggest other test Contamination unlikely Suggest parathyroid antibodies Normal albumin UNACCEPTABLE KEY WORDS Suggest 24h urine calcium/phosphate Suggest amylase/lipase ?Acute pancreatitis Tetany suggested ?Artefactual causes Suggest CK Suggest acute referral Suggest creatinine clearance ?Hyperparathyroidism ?Renal disease Hypercalcaemia ?Vitamin D intoxication Suggest calcitonin Suggest ALP isoenzymes Suggest osmolality Case 7-03 Ca/Mg/Phos Patient ID 58-year-old female Patient Location Surgical Ward Clinical Notes on Request Form Post-colectomy Case Details Sodium Potassium Urea Creatinine Calcium Phosphate Albumin 146 mmol/L 3.6 mmol/L 4.0 mmol/L 50 µmol/L 2.1 mmol/L 0.2 mmol/L 31 g/L (136–146) (3.5–5.0) (2.7–8.0) (60–110) (2.2–2.6) (0.8–1.4) (35–50) Additional Information Pre-operative biochemistry unremarkable. Suggested Comment Severe hypophosphataemia may indicate phosphate depletion, possibly accentuated by refeeding. Consider urgent parenteral supplementation. Rationale Phosphate is the most abundant intracellular anion and only <0.1% is found in the extracellular fluid. Serum measurement of phosphate is not a sensitive reflection of intracellular stores. Hypophosphataemia is a relatively common abnormal biochemistry finding among hospitalised patients. These are usually mild and self-limiting. Hypophosphataemia can be caused by intracellular shifts driven by insulin, catecholamine or alkalosis, such as refeeding syndrome, recovery from diabetic ketoacidosis, respiratory/ metabolic alkalosis, and glucose or insulin administration. It may also be due to decreased intestinal absorption, such as vomiting, diarrhoea, malabsorption/malnutrition, and vitamin D deficiency. Lastly, an increase in renal excretion may precipitate hypophosphataemia, for example in primary/secondary hyperparathyroidism or disorders of renal handling (e.g. Fanconi’s syndrome, hypophosphataemic rickets, oncogenic osteomalacia). In acute care setting, severe hypophosphataemia is associated with alcoholism and refeeding without phosphate replacement. In this case there is no evidence of long-standing hypovitaminosis D or renal phosphate wasting and an acute mechanism should be suspected. Severe hypophosphataemia leads to central nervous system effects (irritability, somnolence), cardiac dysfunction and rhabdomyolysis. In the presence of rhabdomyolysis the phosphate level increases again. References 1. Singhal PC, Kumar A, Desroches L, et al. Prevalence and predictors of rhabdomyolysis in patients with hypophosphatemia. Am J Med 1992;92:458-64. 2. Troup S. Phosphate monograph. http://www.acb.org.uk/Nat%20Lab%20Med%20Hbk/Phosphate.pdf PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Marked hypophosphataemia Phone results ?On total parenteral nutrition ?Refeeding syndrome ?Malabsorption post-colectomy ?Gastrointestinal tract loss ?Respiratory alkalosis ?Phosphate loss/sequestration Suggest repeat/monitor levels Suggest phosphate replacement Suggest other electrolytes/ vitamins/ protein tests Suggest magnesium Risk of myopathy and associated problems Risk of rhabdomyolysis Suggest assess acid-base ?IV glucose ?Intracellular shift with glucose load ?Parenteral nutrition without phosphate ?Malnutrition Corrected calcium okay Hypoalbuminaemia ?Renal losses ?Drug effect Suggest calcium/phosphate excretion studies ?Alcoholism Suggest ionised calcium / corrected calcium Suggest PTH Check glucose Refer to pathologist Low albumin ?due to acute response ?Artefact ?Hyperparathyroidism ?Acid-base imbalance Suggest nutritional review Suggest clinical review ?Magnesium deficiency Low normal potassium History of post-colectomy Low creatinine May not reflect cellular phosphate High normal sodium ?Aldosterone activation UNACCEPTABLE KEY WORDS Hypocalcaemia ?Sepsis ?Due to pre-op preparation ?IV overhydration ?Treated diabetic ketoacidosis Suggest creatine kinase ?Liver disease Suggest troponin/BNP/ECG ?Magnesium supplementation ?Neuroleptic malignant syndrome Generally unremarkable No comment on this case ?Recovery from burns Suggest calcium replacement ?On respiratory ventilation ?Cardiac event Case 9-08 Ca/Mg/Phos Patient ID 57-year-old male Patient Location Medical Outpatients Clinical Notes on Request Form Family history of hypercalcaemia. Case Details Serum Na 139 mmol/L (135–145) K 4.5 mmol/L (3.5–5.0) Cl 103 mmol/L (96–109) Bicarbonate 31 mmol/L (23–32) Urea 5.8 mmol/L (3.5–7.5) Creatinine 95 μmol/L (40–120) Calcium 2.64 mmol/L (2.10–2.60) Phosphate 0.7 mmol/L (0.8–1.5) Albumin 48 g/L (35–50) PTH 5.0 pmol/L (1.6–6.9) Fasting Spot Urine Urine Calcium <0.30 mmol/L Urine Creatinine 1.5 mmol/L Calcium/Creat. Ratio <0.20 mol/mol Suggested Comment Suggest check ionise calcium, repeat plasma phosphate (fasting) and consider 24 hour urine calcium/creatinine clearance ratio to investigate for possible familial hypocalciuric hypercalcaemia. Rationale Familial hypocalciuric hypercalcaemia (FHH) is a rare (1:70,000) autosomal dominant inherited condition caused by heterogeneously distributed inactivating mutations within the calcium sensing receptor (CASR) gene. It is characterised by persistent asymptomatic hypercalcaemia, relatively low urine calcium and inappropriately normal or elevated parathyroid hormone. It is important to differentiate FHH from primary hyperparathyroidism as the former requires no specific treatment while the latter requires surgery. A variety of methods have been advocated to adjust serum total calcium to estimate ionised calcium but all have their limitations. It is advisable to measure ionised calcium directly to clarify the diagnosis in this case. In the setting of hypercalcaemia, either a 24 h urine calcium:creatinine clearance ratio [Ca/CrCl, (24-h Ucalcium/P- calcium, total)/(24-h U-creatinine/P-creatinine)] of <0.01 or a fasting urine calcium excretion (CaE) of <30 μmol/L GFR are consistent with the diagnosis of FHH. The use of either a spot urine calcium or spot urine calcium/creatinine ratio is insufficiently robust for diagnostic purposes. The mutations associated with FHH are widely distributed in the extracellular calcium sensing or the signal transduction domain of the CASR gene, so targeted genetic testing is insufficient for diagnosis. The relatively low serum phosphate appears incongruous with FHH and assessment of a repeat serum/plasma phosphate and urine TmPi is advisable, as mild primary hyperparathyroidism is also possible in this case and urine Ca/CrCl or CaE can overlap in both conditions. Ultimately, in some cases, family studies of serum ionised calcium and urine Ca/CrCl may still be required. References 1. Glendenning P. Diagnosis of primary hyperparathyroidism: controversies, practical issues and the need for Australian guidelines. Intern Med J 2003;33:598-603. 2. Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008;69:713-20. PREFERRED KEY WORDS Consistent with familial hypocalciuric hypercalcaemia (FHH) ?Familial hypocalciuric hypercalcaemia Consistent with familial hypercalcaemic syndrome Suggest ionised calcium Repeat phosphate Suggest 24h urine calcium LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS Mild hypercalcaemia Urinary calcium low Hypophosphataemia Family history of hypercalcaemia ?Primary hyperparathyroidism Normal PTH level Inappropriately normal PTH Corrected calcium normal FHH asymptomatic, benign condition Suggest magnesium Due to calcium sensing receptor (CASR) gene mutation Suggest repeat testing Autosomal dominant condition Suggest vitamin D ?Multiple endocrine neoplasia (MEN) 1 or 2a PTH top end reference range Urine dilute, low creatinine Suggest thyroid function tests Suggest family screening Suggest ALP Normal renal function ?Drug induced hypercalcaemia Urine Ca/Cr diagnosis of FHH or l° hyperparathyroidism Ca/Cr ratio difficult to interpret Low calcium/creatinine clearance Repeat non-fast, no tourniquet ?Malabsorption, renal loss, alkalosis ?Familial hyperparathyroidism ?Excess vitamin D Parathyroidectomy contraindicated Low PO4 ? intake/antacids/non-fasting Repeat PTH No comment Need clinical history FHH requires no treatment Inappropriate PTH or PHrP secretion Suggest endocrinology review ?l° hyperPTH + vitamin D deficiency ?Fasting sample Suggest genetic testing for CASR ?Neoplasm Suggest parathyroid scan FHH may lead to hyperCa crisis Hyperparathyroidism unlikely Suggest succinic dehydrogenase mutation Consistent with hypoparathyroidism ?Milk-alkali syndrome ?Chrondrocalcinosis, gall stones Suggest calcitonin ?Hypocalciuria 2° to PTH Renal impairment not excluded Suggest PHrP Suggest 1,25 OH vitamin D Case 10-08 Ca/Mg/Phos Patient ID 31-year-old female Patient Location Endocrine Clinic Clinical Notes on Request Form Muscular dystrophy. ? Disuse bone loss Case Details Fasting morning spot urine Creatinine 3.8 mmol/L Calcium 3.37 mmol/L N-Telopeptide 404 nmol BCE/L Calcium/Creatinine 0.89 mol/mol (0.10–0.58) N-Telopeptide/Creat. 106 nmol BCE/mmol (<50) (BCE = Bone Collagen Equivalents) Additional Information Plasma Calcium, Adjusted Phosphate Creatinine Alkaline Phosphatase PTH 25-OH Vitamin D 2.51 mmol/L 1.00 mmol/L 29 μmol/L 84 U/L 3.3 pmol/L 107 nmol/L (2.15–2.60) (0.80–1.50) (45–90) (35–135) (0.7–7.0) (>50) Suggested Comment Low muscle mass and the resultant low creatinine production makes interpretation of the urine creatinine ratios unreliable. A 24 h urine sample or fractional excretion is suggested to estimate renal calcium losses. A bone turnover marker in serum or in a 24 h urine sample is recommended in place of N-telopeptide/creatinine ratio. Rationale The use of creatinine ratios for analytes in urine is commonly used with the aim of reducing the effect of hydration on the analyte concentration. This process however introduces an additional variability due to between-person differences in the rate of creatinine production, which is directly proportional to the muscle mass of the patient. This process is generally robust but may produce misleading results in patients with extremes of muscularity. Subjects with a large muscle mass will produce lower results for urine analytes after creatinine correction and subjects with low muscle mass will give elevated results. In this case there are three pieces of evidence that the patient has a low creatinine production and therefore creatinine correction may produce spuriously elevated results. These factors are the history of muscular dystrophy, the very low serum creatinine and the low urine creatinine concentration. Of these, the serum creatinine of 27 μmol/L is the strongest indication of the very low muscle mass. The key feature in this case is to identify this effect and not proceed with an inappropriate interpretation. This effect was not recognised in over half the responses with consequent inappropriate interpretations. In order to obtain the information sought with these requests it is necessary to use tests that are not affected by the creatinine, such as timed urine collections or serum tests. PREFERRED KEY WORDS Low creatinine/muscle wasting Ratios false 2° to low creatinine Normal plasma ALP Suggest 24h urine calcium Suggest P1NP Suggest 24h urine NTx Suggest C-Telopeptide Suggest serum osteocalcin Suggest calculate fasting urine Ca excretion Suggest serum NTx Suggest P1CP LESS RELEVANT KEY WORDS Increased bone resorption/loss High urine NTx/creatinine ratio Suggest BMD scan High urine NTx High calcium/creatinine ratio Bone resorption/osteoporosis due to immobilisation ?Osteoporosis Hypercalciuria Suggest TSH/TFT Normal vitamin D/adequate supplementation. NTx marker of increased bone resorption Normal PTH ?Glucocorticoid Rx ?Hyperthyroidism Normal plasma calcium Normal plasma phosphate ?Antiresorptive Rx ?Calcium/vitamin D supplements ?Increased NTx 2° circadian variation/exercise Suggest sequential bone mineral markers Results consistent with muscular dystrophy ?Menstrual variation/menopause Does not support disuse bone loss No comment ?Preanalytical/sample collection factors ?Drug effect Check dietary calcium intake Collect fasting 2nd void urine NTx ?Hypercalciuria NTx not useful for osteoporosis diagnosis ?Endocrine disorder Hyperparathyroidism excluded Paget’s disease excluded Bone demineralisation not increased turnover Normal calcium homeostasis Suggest CK Elevated vitamin D Low plasma albumin Suggest bone formation markers Suggest tests to confirm bone loss Suggest TRACP5b UNACCEPTABLE KEY WORDS ?Hyperparathyroidism ?Metastatic bone disease Consider increase antiresorptive therapy Consider hypogonadism if very unwell Increased risk fractures Consider genetic cause/lifestyle ?GIT disease ?Pregnancy Suggest 24h UFC/?Cushing’s Exclude multiple myeloma ?Paget’s disease Suggest BALP, ICTP Refer to endocrine clinic Case 11-01 Ca/Mg/Phos Patient ID 79-year-old woman Patient Location General Practice Clinical Notes on Request Form Osteoporosis. No medication. Case Details Fasting serum Sodium Potassium Chloride Bicarbonate Urea Creatinine Total Bilirubin ALP GGT ALT Total Protein Albumin Globulin Calcium Phosphate Calcium, Adjusted 25OH Vitamin D PTH 139 mmol/L 4.2 mmol/L 104 mmol/L 23 mmol/L 5.5 mmol/L 67 μmol/L 5 μmol/L 124 U/L 31 U/L 23 U/L 77 g/L 48 g/L 29 g/L 2.8 mmol/L 1.2 mmol/L 2.73 mmol/L 36 nmol/L 4.1 pmol/L (135–145) (3.5–5.5) (95–110) (20–32) (3.5–9.5) (45–90) (3–15) (30–115) (5–35) (5–40) (63–80) (36–47) (23–39) (2.15–2.55) (0.80–1.50) (2.20–2.60) (75–250) (1.6–6.9) Suggested Comment Mild hypercalcaemia and non-suppressed PTH is most likely due to primary hyperparathyroidism (PHPT). Familial hypocalciuric hypercalcaemia (FHH) and lithium therapy can also present with mild parathyroiddependent hypercalcaemia. FHH should be excluded by reviewing previous results and estimation of either fasting urine calcium excretion or 24 h urine calcium creatinine clearance ratio. Mild vitamin D deficiency is common with PHPT and may exacerbate bone disease. Rationale The degree of hypercalcaemia and the non-suppressed PTH in the context of investigation of osteoporosis indicate primary hyperparathyroidism is likely. A review of past results would be helpful in this case. Familial hypocalciuric hypercalcaemia (FHH) is a rare (1:70,000), autosomal dominant inherited condition characterised by persistent, asymptomatic hypercalcaemia, low urine calcium excretion and inappropriately normal/ elevated parathyroid hormone due to a mutation of the calcium sensing receptor (CASR) gene. In the setting of parathyroid dependent hypercalcaemia two tests of urine calcium are helpful. A 24 h urine calcium clearance ratio involves assessment of serum calcium, serum creatinine, urine calcium and urine creatinine. A clearance ratio of <0.01 is typical in FHH and >0.02 is common in primary hyperparathyroidism. Note the clearance ratio [(24-h U-calcium/P- calcium, total)/(24-h U-creatinine/P-creatinine)] is not the same test as a urine calcium/creatinine ratio. Alternatively, a fasting urine calcium excretion (urinary calcium/ urinary creatinine × serum creatinine) of <30 μmol/L GFR is also consistent with FHH. The differentiation of FHH is important to prevent unnecessary surgical neck exploration. Since there are many mutations within the CASR gene, no single simple genetic test is available to exclude this diagnosis. PREFERRED KEY WORDS Mild hypercalcaemia Inadequately suppressed PTH Mild vitamin D deficiency ?Primary hyperparathyroidism ?Hyperparathyroidism ?FHH ?Drug history (Li or thiazides) Review previous results Suggest 24h Ca, Ca/creatinine ratio LESS RELEVANT KEY WORDS Low vitamin D Hypercalcaemia Normal PTH Suggest ionised calcium Mildly increased ALP Suggest vitamin D replacement Repeat calcium Suggest bone turnover/formation markers Suggest thyroid function tests Raised ALP due to bone formation Repeat PTH Repeat tests after vitamin D supplement Repeat collection with no stasis Increased bone turnover Suggest protein electrophoresis-serum, urine Consistent with osteoporosis ?Ca supplementation Suggest 1,25 dihydroxy vitamin D Suggest PTHrP Suggest bone mineral density scan ?Immobilisation ?Paget’s disease Moderate vitamin D deficiency Suggest serum magnesium ?Hyperthyroidism ?Myeloma Repeat testing Repeat 25-OH vitamin D Severe vitamin D deficiency Contribute to osteoporosis Normal phosphate Suggest full blood examination Not typical vitamin D deficiency Raised ALP 2° to vitamin D deficiency ?Healing bone fractures Normal renal function Albumin elevated Low vitamin D due to inadequate sunlight Repeat test with adequate hydration ?Vitamin D dietary shortage Suggest parathyroid ultrasound scan Low vitamin D due to primary PHPT ?Magnesium deficiency ?Transient hypercalcaemia Suggest genetic studies for FHH ?Osteomalacia Repeat on fasting specimen Low vitamin D prevents Ca absorption ?Decreased intestinal absorption vitamin D Repeat test before vitamin D supplement Not consistent with osteoporosis UNACCEPTABLE KEY WORDS ?Malignancy ?Sarcoidosis or TB ?Hypercalcaemia age related Hyperparathyroidism unlikely PHPT excluded Suggest renal imaging Suggest ACE Suggest chest X-ray ?Acromegaly Suggest X-rays for bone fractures ?Secondary hyperparathyroidism ?Hyperglycaemia No vitamin D replacement ?Hypothyroidism Case 12-02 Ca/Mg/Phos Patient ID 45-year-old female Patient Location General Practice Clinical Notes on Request Form No history of fractures or falls. Strong family history of autoimmune disease and cancer. Case Details 25OH vitamin D 62 nmol/L Additional Information Serum Creatinine Calcium Albumin Calcium, Adjusted Parathyroid Hormone 63 μmol/L 2.32 mmol/L 43 g/L 2.30 mmol/L 8.9 pmol/L (60–105) (2.15–2.65) (38–50) (2.15–2.65) (1.1–7.2) Suggested Comment Borderline raised PTH with intact renal function, unremarkable adjusted total calcium and vitamin D is unlikely to be pathologically important. Rationale Mildly increased parathyroid hormone with unremarkable adjusted total calcium and serum creatinine are frequent laboratory findings. Current published guidelines by ANZBMS and recent recommendations by the Institute of Medicine (IOM) both advocate adoption of a target threshold of 50 nmol/L for 25OHD (1, 2). The IOM committee was concerned about some laboratories reporting higher 25OHD target thresholds and there was an urgent need for consensus target thresholds reported by laboratories. Whilst a variety of diseases have been associated with vitamin D deficiency, randomised clinical trial data demonstrating the benefit of vitamin D supplementation in these groups are lacking (3). Although ionised calcium is more sensitive than adjusted total calcium in the diagnosis of early primary hyperparathyroidism, the adjusted calcium result makes this diagnosis unlikely in this case (4). References 1. Working Group of the Australian and New Zealand Bone and Mineral Society: Endocrine Society of Australia; Osteoporosis Australia. Vitamin D and adult bone health in Australia and New Zealand: a position statement. Med J Aust 2005;182:281-5. 2. Slomski A. IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. JAMA 2011;305:453-6. 3. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer – ready for prime time? N Engl J Med 2011;364:1385-7. 4. Glendenning P. Diagnosis of primary hyperparathyroidism: controversies, practical issues and the need for Australian guidelines. Intern Med J 2003;33:598-603. PREFERRED KEY WORDS Vitamin D normal Vitamin D deficiency unlikely Normal calcium level Mild increase PTH Normal renal function ?Bisphosphonate therapy LESS RELEVANT KEY WORDS Elevated PTH Suggest Mg/Phos/ALP Suggest ionised calcium Repeat PTH Suggest 2° hyperparathyroidism ?Malabsorption ?Drug ?anticonvulsants Repeat serum calcium ?Adequate dietary calcium intake Suggest repeat Ca/VitD/PTH after supplement Repeat vitamin D Strong family history autoimmune disease Suggest coeliac screening ?Early hyperparathyroidism Mild 2° hyperparathyroidism Suboptimal vitamin D level ?Normocalcaemic hyperparathyroidism ?Diuretic therapy ?Malnutrition No reference range given for vitamin D PTH assay interference to be excluded Repeat testing 3–6 months Repeat PTH in 3 months ?Adequate vitamin D Normal corrected calcium Suggest renal panel/albumin ?Chronic vitamin D deficiency Suggest fasting morning PTH Suggest fasting calcium Further investigation required Interpret results with seasons Consistent with mild physiologic vitamin D deficiency Suggest diabetes screening Suggest liver function tests Repeat fasting PTH at 8pm ?D2, D3 or both No formal comment issued PTH inappropriate for calcium level Suggest review in 2–3 months Normal albumin NOT SUPPORTED KEY WORDS Suggest vitamin D supplementation Increased risk cancer/autoimmune disease Vitamin D low Suggest 24h Ca/PO4 excretion ?Primary hyperparathyroidism Exclude adenoma/malignancy if clinically indicated Due to family history increased vitamin D beneficial Suggest thyroid screening Suggest bone turnover markers Suggest urinary Ca/creatinine 2° hyperparathyroidism unlikely Vitamin D indeterminate ?Familial hypocalciuric hypercalcaemia Exclude MEN I and II Suggest full blood examination/ESR Check renal function Suggest total protein and protein electrophoresis Suggest increase sunshine exposure/dietary intake Recommend referral to specialist Suggest uric acid maybe Suggest calcium supplementation MISLEADING KEY WORDS ?Bone densitometry Mildly low PTH ?Patient on vitamin D masking low vitamin D Case 13-03 Ca/Mg/Phos Patient ID 22-year-old male Patient Location Hospital in-patient Clinical Notes on Request Form In hospital 4 months following head injury. Case Details Total Calcium Albumin Phosphate Alkaline Phos PTH 25OH Vitamin D 2.93 mmol/L 38 g/L 1.46 mmol/L 84 U/L 0.6 pmol/L 111 nmol/L Additional Information Sodium Potassium Bicarbonate Urea Creatinine eGFR 147 mmol/L (134–146) 3.5 mmol/L (3.4–5.0) 32 mmol/L (22–32) 8.7 mmol/L (3.0–8.0) 69 μmol/L (60–110) >60 mL/min/1.73m2 (2.15–2.60) (35–50) (0.8–1.50) (35–135) (0.7–7.0) (>50) Suggested Comment Mild hypercalcaemia with suppressed PTH suggests hypercalcaemia of immobilisation given the history and the age of the patient. Dehydration exacerbates hypercalcaemia. Consider thyroid function tests to exclude thyrotoxicosis. Rationale Immobilisation hypercalcaemia mainly results from rapid bone turnover and may be seen after spinal cord injury or long bone fracture in children and adolescents with growing bones and after cerebrovascular accident in the elderly, especially in the presence of high turnover states such as Paget’s disease. The exact mechanisms of immobilisation hypercalcaemia are unclear, but are not PTH-dependent. The generally accepted explanation is the loss of mechanical stress (mechanostat theory) leading to increased osteoclastic bone resorption and decreased bone formation, which are the hallmarks in bone biopsy. The serum calcium level depends on the rate of bone resorption and the capacity of renal calcium excretion. The median interval between initiation and immobilisation and onset of hypercalcaemia is 4 weeks, but may be extended to 16 weeks in patients with normal renal function. In chronic renal insufficiency the interval is shortened and may range from 3 to 16 days. Hypercalcaemia itself can induce acute impairment of renal function via glomerular arteriolar vasoconstriction, volume depletion, and nephrocalcinosis and then in turn, compromise calcium clearance and accentuate the degree of hypercalcaemia. Other possible causes such as Grave’s disease may be considered, and rarely granulomatous diseases such as sarcoidosis. Reference 1. Cheng CJ, Chou CH, Lin SH. An unrecognized cause of recurrent hypercalcemia: immobilization. South Med J 2006;99:371-4. PREFERRED KEY WORDS Mild hypercalcaemia Due to immobilisation Prolonged hospitalisation Due to excessive bone turnover Hyperparathyroidism unlikely PTH independent/ non-parathyroid Not vitamin D mediated hypercalcaemia Slightly increased urea ?Dehydration Replacement fluid will decrease calcium ?Hyperthyroidism Suggest thyroid function tests Suggest ongoing monitoring Significant increased corrected calcium LESS RELEVANT KEY WORDS Hypercalcaemia Reduced PTH Need to exclude malignancy Raised Na Suggest 24h urine calcium/ phos ?Due to medications ?Chronic granulomatous disease Suggest ionised calcium Suggest 1,25 vitamin D ?Sarcoidosis Suggest repeat total calcium/PTH Suggest N-telopeptide/bone markers ?Diabetes insipidus Suggest urine osmolality/volume/Na Normal albumin High/normal phosphate Normal 25-hydroxyvitamin D Suggest cortisol Normal ALP Suggest ACTH/GH/FSH/LH/prolactin ?Hyperaldosteronism ?Increased renal retention Low creatinine Suggest ALP Suggest serum/urine electrolytes Elevated serum calcium Suggest clinical and radiological exam Suggest magnesium Renal cause unlikely Normal creatinine/ eGFR ?Increased 1,25 vitamin D intake NOT SUPPORTED KEY WORDS Suggest PTHrP ?Familial hypocalciuric hypercalcaemia ?Increased vitamin D intake Suggest ACE Suggest urine electrophoresis/ immunofixation 25OH vitamin D raised ?Sepsis Suggest vitamin A Exclude factitious cause ?Paget’s disease Suggest water deprivation test ?Rhabdomyolysis Mild 2° hypoparathyroidism ?Increased intestinal absorption ?Hypothyroidism ?Milk-alkali syndrome Recommend urgent consultation Case 14-06 Ca/Mg/Phos Patient ID 82-year-old female Patient Location General Practice Clinical Notes on Request Form Presents with back pain. Case Details Albumin Calcium (Total) Calcium (Adjusted) Intact PTH 29 g/L 2.60 mmol/L 2.83 mmol/L 3.2 pmol/L (32–46) (2.15–2.55) (2.15–2.55) (1.3–6.8) Additional Information Ionised Calcium 1.27 mmol/L (1.12–1.32) Sample pH 7.41 (7.35–7.45) Ion Ca (pH-adjusted) 1.28 mmol/L (1.12–1.32) Suggested Comment The significant discrepancy between the ionised calcium measurement and the albumin-adjusted calcium suggests the possibility of an abnormal globulin binding to calcium; recommend serum and urine protein electrophoresis to investigate. Rationale In normal physiology, approximately half of serum calcium exists in free (ionised) form while the other half is protein-bound, mainly to albumin. The direct measurement of ionised calcium plays an important role in the diagnosis of pseudohypercalcaemia. It is an infrequent but important condition in monoclonal gammopathy (e.g. multiple myeloma and Waldenström macroglobulinaemia), where monoclonal immunoglobulins cause raised total/albumin-adjusted calcium and normal ionised calcium. Several method-dependent mechanisms may explain this apparent discrepancy. The paraproteins may act as carrier proteins in a similar fashion to albumin, causing increased binding of calcium. Paraproteins may also increase the solid phase of the serum, causing a 'water exclusion' effect and may affect indirect ion-selective electrode methods. Finally, paraproteins may precipitate during laboratory analysis, affecting photometric methods. If ionised calcium measurement is not available, a simple two-time dilution or use of an alternate assay with different methodology may clarify the situation. Whilst pseudohypercalcaemia is uncommon, the clinical presentation of back pain and discrepant total calcium compared with ionised calcium justify further investigation for a possible paraproteinaemia in this case. References 1. Loh TP, Yang Z, Chong AT, et al. Pseudohypercalcaemia in a patient with newly diagnosed Waldenstrom macroglobinaemia. Intern Med J 2013;43:950-1. 2. Annesley TM, Burritt MF, Kyle RA. Artifactual hypercalcemia in multiple myeloma. Mayo Clin Proc 1982;57:572-5. 3. Schwab JD, Strack MA, Hughes LD, et al. Pseudohypercalcemia in an elderly patient with multiple myeloma: report of a case and review of literature. Endocr Pract 1995;1:390-2. PREFERRED KEY WORDS Ionised and adjusted calcium discrepant Poor correlation between adjusted and ionised calcium Increased protein (non-albumin) bound calcium ?Pseudohypercalcaemia ?Multiple myeloma ?Paraproteinaemia Suggest serum electrophoresis Suggest urine Bence-Jones protein/electrophoresis Suggest serum free light chains Suggest immunoglobulins LESS RELEVANT KEY WORDS Normal ionised calcium Normal parathyroid hormone (PTH) Hypercalcaemia Increased serum total/adjusted calcium ?Malignancy Suggest repeat calcium/PTH for confirmation Hypoalbuminaemia Clinical status/back pain Suggest full blood count Suggest renal function tests Suggest urine calcium Suggest serum total protein Suggest electrolytes, urea, creatinine Normocalcaemia Suggest erythrocyte sedimentation rate ?Inflammation Suggest bone marrow aspirate Suggest beta-2 microglobulin If confirmed patient should be referred Check total calcium with different assay NOT SUPPORTED KEY WORDS ?Hyperparathyroidism Suggest phosphate Suggest vitamin D Suggest alkaline phosphatase (ALP) ?Drug/medication induced ?Secreting PTH-related peptide ?Exogenous vitamin D Suggest liver function tests Consider renal failure Suggest review clinical history/status ?Familial hypocalciuric hypercalcaemia ?Breast/lung/kidney cancer Suggest magnesium ?Increased calcium due to tourniquet time Suggest bone markers ?Liver disease Suggest TSH Suggest fasting calcium ?Chronic disease Suggest urine protein/albumin Euparathyroidism Monitoring of patient calcium level required Suggest vitamin D supplementation Albumin should be corrected too Hyperparathyroidism unlikely Exclude recent blood transfusion MISLEADING KEY WORDS Suggest bone scan/CT/imaging Sarcoidosis ?Hyperthyroidism ?Malnutrition ?Renal/GIT loss ?Dehydration No abnormality Suggest repeat in 3 months Not clinically significant hypercalcaemia Not suggestive of malignancy GI loss unlikely Suggest calcitonin Case 9-04 Urate Patient ID 55-year-old male Patient Location General Practice Clinical Notes on Request Form Check-up Case Details Serum Urate 0.48 mmol/L (0.20–0.42) Suggested Comment Mild hyperuricaemia may be associated with renal failure, high purine diet, ethanol, diuretics and increased cell turnover states. Hyperuricaemia is associated with an increased risk of gout. Further investigation/management would be based on context of test request. Rationale Factors that increase serum urate include renal failure, high purine diet, ethanol, diuretics and increased cell turnover states, as well as rare enzyme defects such as phosphoribosylpyrophosphate (PRPP) synthetase superactivity and hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. A 24-hour urine collection on a standard diet excluding alcohol and drugs known to affect urate metabolism will allow differentiation of overproduction of uric acid versus undersecretion, but this is rarely required in routine practice. The diagnostic test for gout is the demonstration of urate crystals in joint aspirate. Serum urate is the most important risk factor for gout and reduction of serum urate in this context is beneficial. However, only a small minority of people with hyperuricaemia (defined as serum urate >0.42 mmol/L) will develop gout. About 40% of patients presenting with acute gout have serum urate <0.42 mmol/L, but note that serum urate is a negative acute phase reactant and may decrease during an acute attack. In absolute terms, at any given level of serum urate, the risk of gout is the same for men and women. Hyperuricaemia is associated with insulin resistance, obesity, hypertension and hypertriglyceridaemia. It has been suggested to be an independent risk factor for cardiovascular disease and for the future development of hypertension and renal disease. However, the role of serum urate as a marker for cardiovascular risk is not established and it is not included in risk calculation. There is no conclusive evidence yet to recommend uratereducing therapy in this context. References 1. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Ann Rheum Dis 2006;65:1301-11. 2. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 1987;82:421-6. 3. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-90. PREFERRED KEY WORDS Mild hyperuricaemia ?Asymptomatic hyperuricaemia Hyperuricaemia alone not diagnostic for gout ?Urate underexcretion ?Urate overproduction ?Renal impairment ?Excess alcohol ?Diuretics/aspirin/drugs ?Increased purine intake Maintain urate <0.36 mmol/L if on treatment Suggest full history/clinical examination Suggest urea/creatinine/electrolytes Increased risk of gout Associated/assess metabolic syndrome Associated/assess cardiovascular disease Suggest fasting blood sugar concentrations Suggest fasting lipids Suggest full blood count Suggest liver function tests Suggest tests for secondary disease Suggest monitoring Risk of urolithiasis ?Obesity ?Hypertension ?Hypothyroid Consider diet/lifestyle changes ?Abnormal lipid profile Suggest calcium/phosphate LESS RELEVANT KEY WORDS Hyperuricaemia ?Gout ?Diabetes ?Arthritis ?Hyperparathyroidism ?Primary or secondary disorder Suggest urate pre/post low purine diet ?Prolonged fasting/stress/exercise No comment issued routinely ?Lead poisoning Risk of gout if urate >0.42 mmol/L ?Idiopathic Urate lowering treatment if clinically indicated ?Dehydration Treatment dependent on overproduction/underexcretion Suggest urine albumin/pH/microscopy Urate levels higher in males Suggest electrophoresis ?Genetic cause Urate antioxidant properties ?Sarcoidosis Repeat urate with normal diet/exercise Acute gout not excluded Genetic causes less likely Suggest 24 h urine urate/creatinine ?Psoriasis ?Malignancy/haematological disorder/chemotherapy UNACCEPTABLE KEY WORDS Repeat urate on fasting sample Consider diurnal/seasonal variation Advise urate lowering treatment Risk of gout if urate >0.32 mmol/L ?Fasting Suggest HbA1c Risk of gout if urate >0.60 mmol/L Low risk gout at this level ?Probable insignificant increase in urate Consistent with gout Moderate hyperuricaemia Suggest rheumatoid factor/anti-nuclear antibodies ?Vitamin B12 deficiency ?Hypoparathyroid Case 7-07 Glucose Patient ID 84-year-old male Patient Location Emergency Department Clinical Notes on Request Form Collapsed Case Details Plasma Sodium Potassium Bicarbonate Urea Creatinine Glucose CK cTroponin T 122 mmol/L 3.7 mmol/L 27 mmol/L 7.5 mmol/L 99 µmol/L 0.6 mmol/L 13,800 U/L 0.02 μg/L (134–146) (3.4–5.0) (22–32) (3.0–8.0) (60–110) (3.0–5.4) (30–190) (see below) Additional Information <0.03 Myocardial damage unlikely 0.03–0.09 May suggest increased cardiac risk in the setting of acute coronary syndrome ≥0.10 Consistent with myocardial infarction if associated with ischaemic symptoms or ECG changes Suggested Comment Profound hypoglycaemia – suggest check insulin, C-peptide, and possible inappropriate sulphonylurea ingestion. Concomitant hyponatraemia suggests possible adreno-cortical insufficiency. Suggest urine electrolytes, cortisol, thyroid function tests, endocrine review and pituitary investigations as appropriate. Marked CK elevation is of likely skeletal muscle origin, possibly due to seizure or compartment syndrome, although hypothyroidism may be contributory. Rationale The cause of collapse in this patient is likely due to hypoglycaemia. For investigation of low glucose, other samples should have ideally been taken prior to the result, especially for insulin, C-peptide, drug screen (sulphonylurea and others) and cortisol. Non-suppressed insulin and C-peptide would favour inappropriate sulphonylurea ingestion and be an indication for drug screen. Insulin administration is possible, in which case C-peptide would be suppressed. Combination of hypoglycaemia with hyponatraemia suggests possible adrenocortical insufficiency (1, 2). One should elicit evidence of clinical volume depletion and salt wasting (urine electrolytes). Clinical endocrine review would corroborate clinical features, discern primary from secondary adrenal insufficiency, and determine the need for a synacthen test and pituitary investigations. Lownormal potassium and normal bicarbonate favour secondary adrenal insufficiency. Hypothyroidism may be associated with, and contributory to, hyponatraemia and CK elevation. Elevated CK is disproportionate to the just-detectable troponin and suggests skeletal muscle aetiology, possibly secondary to compartment syndrome (if immobile for a long time), seizure (secondary to hypoglycaemia), or hypothyroidism. If clinical probability of acute coronary syndrome is low, just-detectable troponin should still be regarded as a prognostic factor. References 1. Frost P, Williams AB. A 57 year old woman admitted to the emergency department with hyponatraemia and hypoglycaemia. Crit Care Resusc 2000;2:308-9. 2. Diederich S, Franzen NF, Bähr V, et al. Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases. Eur J Endocrinol 2003;148:609-17. PREFERRED KEY WORDS ?Exogenous/endogenous insulin ?Oral hypoglycaemic agents Suggest toxicology screen Suggest C-peptide and insulin ? Suggest serum and urine sodium and osmolality ?Adrenal insufficiency/failure Suggest cortisol/adrenal studies Suggest thyroid function tests ?Hypopituitarism Suggest pituitary test(s) Muscle damage/rhabdomyolysis At risk of renal failure LESS RELEVANT KEY WORDS Hypoglycaemia Elevated CK Hyponatraemia Review medications / drug history Suggest repeat/serial troponin T ?Alcohol abuse Non-cardiac cause Cardiac injury not excluded Immediate glucose administration required Suggest liver function tests Suggest clinical endocrine review ?Seizure activity ?Hypothyroidism Suggest/monitor electrolytes/glucose Suggest alcohol level ?SIADH Monitor renal function ?Malignancy ?Liver dysfunction Excess sodium loss ?Inadequate salt intake UNACCEPTABLE KEY WORDS History of collapse Non-elevated troponin Suggest myoglobin ?Artefact Suggest CK isoenzymes ?Fluid/electrolyte redistribution ?Septicaemia/sepsis ?Physical activity ?Cerebral event ?Diabetic coma ?Renal disease ?Other rare causes Suggest miscellaneous tests ?Prolonged hypothermia ?Trauma ?Hyperthermia Normal potassium Repeat tests to confirm Suggest muscle autoantibodies This troponin level uninterpretable No renal failure ?Congestive cardiac failure Adequate hydration required Case 8-01 Glucose Patient ID 46-year-old woman Patient Location General Practice Clinical Notes on Request Form Past history of gestational diabetes. Case Details 75 g oral glucose tolerance test 0 min glucose 5.8 mmol/L 60 min glucose 13.1 mmol/L 120 min glucose 5.6 mmol/L Additional Information Previous fasting glucose 6.1 mmol/L Suggested Comment Normal glucose tolerance test. Suggest repeat fasting glucose in 12 months’ time. Rationale The three main questions on this case are the diagnosis, the tool to use for follow-up (fasting glucose or oral glucose tolerance test, OGTT) and the timing of any follow-up. With regard to diagnosis there is difficulty deciding which guidelines to follow. Several professional bodies, including the Royal College of Pathologists of Australasia, the Australasian Association of Clinical Biochemists and World Health Organization define impaired fasting glucose (IFG) as a fasting glucose result in the range 6.1 to 6.9 mmol/L. Since 2003, the American Diabetes Association guidelines have expanded this to 5.6 to 6.9 mmol/L. Briefly, arguments for the lower cut point include: the higher cut point is associated with lower test sensitivity for diabetes, the narrower biochemical definition of IFG meant poorer test reproducibility (i.e. patients are more likely to be differently classified on different occasions) as the within-individual biological variation for glucose is relatively large, lower IFG cut point may allow more patients with undiagnosed diabetes to be subjected to OGTT, in certain studies using receiver operating curve analyses, lower IFG cut points of 5.2–5.7 mmol/L are optimal for predicting diabetes risk. Conversely, arguments against the lowering of cut point include: marked increase in the prevalence of IFG in adult population (30–40% vs 7–10%), poorer risk prediction for diabetes, poorer risk prediction for all-cause and cardiovascular mortalities and the potentially enormous public health costs to manage the significantly increased number of patients classified as IFG. The excellent point-counterpoint arguments can be found in the references and are highly recommended readings. With this conflict between guidelines laboratories must choose which is more appropriate for use. The assessment of this case has been made using the local guidelines on the grounds that most clinicians would be more familiar with them. The local guidelines support following up testing with fasting plasma glucose (rather than OGTT) at one year for patients at high risk, which is appropriate as this patient has a recent result indicating IFG as well as a history of gestational diabetes. References 1. Shaw JE, Zimmet PZ, Alberti KG. Point: impaired fasting glucose: The case for the new American Diabetes Association criterion. Diabetes Care 2006;29:1170-2. 2. Dekker JM, Balkau B. Counterpoint: impaired fasting glucose: The case against the new American Diabetes Association guidelines. Diabetes Care 2006;29:1173-5. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Normal glucose tolerance Normal fasting blood glucose Not diabetic Previous impaired fasting glucose results increase risk History of gestational diabetes increases risk Retest glucose at 1 year Impaired fasting glycaemia Suggest repeat OGTT 1–2 years Measure glucose (other than at 1 year) Fasting blood glucose results increase risk High 1h glucose Normal 2h glucose Monitor patient Lifestyle modification suggested Clinical evaluation/history required Previous impaired fasting glycaemia 1h glucose result increases risk Elevated fasting blood glucose Suggest renal function tests Indeterminate results Repeat OGTT <12 months Suggest assess cardiovascular risk factors 1h glucose not interpretable Diabetes unlikely ?Rapid gastric emptying ?Hyperthyroidism ?Abnormal glucose metabolism Early glucose intolerance Suggest lipids Equivocal fasting blood glucose ?Patient fasted correctly Consider insulin resistance Adequate glucose absorption UNACCEPTABLE KEY WORDS Impaired glucose tolerance Suggest HbA1c 1h glucose indicates diabetes Suggest insulin measurement Suggest repeat OGTT 3 years Suggest thyroid function tests for ?hyperthyroidism Case 9-03 Glucose Patient ID 45-year-old male Patient Location Emergency Department Clinical Notes on Request Form Dizziness, sweating and confusion. Not on any medication. Case Details Serum glucose 2.5 mmol/L (3.0–5.4) Additional Information Sodium 141 mmol/L (134–146) Potassium 4.0 mmol/L (3.4–5.0) Bicarbonate 27 mmol/L (22–32) Urea 5.2 mmol/L (3.0–8.0) Creatinine 72 μmol/L (60–110) eGFR >60 mL/min/1.73m2 (>60) Total protein 83 g/L (60–80) Albumin 48 g/L (35–50) Calcium 2.35 mmol/L (2.15–2.60) Bilirubin 10 μmol/L (<20) Alk. Phos. 63 U/L (35–135) ALT 44 U/L (< 40) Gamma GT 38 U/L (< 60) Suggested Comment The symptoms are consistent with the neurological manifestation of hypoglycaemia (neuroglycopaenia), which is supported by the low serum glucose. Adult hypoglycaemia presentations to emergency departments are most commonly due to complications of diabetes therapy or alcohol abuse. If aetiology is uncertain, useful tests may include insulin, C-peptide, cortisol and sulphonylurea screen. The latter three may be added to the original sample, if sufficient volume remains. Rationale The presenting symptoms and low serum glucose in this case are consistent with the neuroglycopaenia. An important confirmatory factor is the resolution of the symptoms with administration of glucose (Whipple’s triad). Once confirmed, investigation of the hypoglycaemia will depend on the history and relative likelihood of possible causes. In the Emergency Department, diabetes therapy (most importantly, insulin and sulphonylurea) and alcohol account for the majority of hypoglycaemia presentations. However, the history in this case indicates no medications. Renal and hepatic failures can cause hypoglycaemia, and are excluded by the normal renal and liver function tests. Other causes include adrenal failure, insulin-secreting tumour and factitious hypoglycaemia, which are relatively rare but may also be important. The choice of tests will be directed by the clinical picture. Another important consideration is the need to obtain appropriate samples at the time of a hypoglycaemic episode for some tests. It may be useful to take this opportunity to investigate this case further, especially if there have been previous episodes. Insulin, C-peptide, cortisol and sulphonylurea screen may be the best first-line tests during an episode, with additional testing later if indicated. Note that sulphonylurea screens are performed on serum and not urine samples. PREFERRED KEY WORDS Symptomatic hypoglycaemia Marked hypoglycaemia ?Hypoglycaemic agents Iatrogenic causes most common ?Drug-induced ?Exogenous insulin ?Insulinoma ?Adrenal insufficiency Test during hypoglycaemic episode Suggest insulin Suggest C-peptide ?Alcohol Suggest insulin if clinically indicated Suggest C-peptide if clinically indicated Suggest sulphonylurea screen if clinically indicated Suggest sulphonylurea screen Suggest cortisol Suggest pituitary and adrenal tests Suggest further investigation LESS RELEVANT KEY WORDS Hypoglycaemia Suggest repeat glucose ?Reactive hypoglycaemia ?Fasting or postprandial glucose ?Early diabetes Other biochemistry normal ?Endocrine disorder History of no medications noted Request detailed history ?Prolonged fasting Suggest glucose replacement Suggest OGTT (extended) if clinically indicated Suggest investigate with prolonged fast Marginally elevated ALT/total protein ?Functional hypoglycaemia Fluoride oxalate collection Suggest OGTT Exclude artefactual causes Suggest growth hormone ?Factitious hypoglycaemia ?Symptom recovery with normal blood sugar level Suggest drug screen Suggest TSH Suggest ACTH Investigate diet ?Post-gastrectomy ?Pancreatic tumour ?Extrapancreatic tumours Artefact unlikely Consider imaging Insulinomas are rare Suggest insulin antibodies ?Septicaemia Differentiate endogenous vs exogenous insulin Suggest IGF/IGFII/IGFBP3 No investigation if single episode ?Diarrhoea/vomiting ?Islet cell hyperplasia ?Overdose hypoglycaemics/ ?noncompliant ?Immune hypoglycaemia Hypoglycaemia 2° to liver disease unlikely Suggest short synacthen if clinically indicated Specialist opinion may be required Suggest investigate with 24 h fast ?Endocrine neoplasms Pituitary and adrenal disease less likely UNACCEPTABLE KEY WORDS Suggest urine hypoglycaemic agent screen ?Galactosaemia ?Glycogen storage disease ?Dehydration Suggest hepatitis serology Suggest catecholamines Insulinoma is a common cause ?Liver/renal failure Suggest glucagon measurement ?Leucine/fructose Suggest DHEAS Suggest proinsulin Suggest electrolytes Nil Suggest ketones Mild hypoglycaemia Suggest lactate Insulin overdose excluded Case 10-09 Glucose Patient ID 2-year-old boy Patient Location Emergency Department Clinical Notes on Request Form History of convulsions soon after awakening Case Details Results from the Emergency Department Plasma glucose 1.7 mmol/L (Fasting: 3.5–5.5) Urine ketones 4+ Calcium 3.37 mmol/L Suggested Comment These results are consistent with a diagnosis of idiopathic ketotic hypoglycaemia. Other endocrine, metabolic and toxicological causes should be excluded with tests collected whilst the patient is hypoglycaemic. These should include electrolytes, creatinine and liver function tests, cortisol, growth hormone, insulin, lactate, betahydroxybutyrate, free fatty acids, blood gases, ammonia, organic acids and acylcarnitines. The raised ketones make insulin excess and fatty acid oxidation defects less likely. Rationale Idiopathic ketotic hypoglycaemia (IKH) is a condition characterised by fasting hypoglycaemia and increased concentrations of ketones. By contrast, ketones are usually low in children with fatty acid oxidation defects or those who have insulin-secreting tumours or those who have ingested sulphonylureas. IKH is the most likely cause of the findings in this case, although careful history and testing are needed to exclude other causes. IKH usually occurs after 12 months of age and resolves over several years. In a recent case series, IKH is the most common cause of hypoglycaemia in previously healthy children presenting to the Emergency Department. They usually first present before the age of 5 years with symptomatic hypoglycaemia, which resolves after administration of glucose, and ketonuria during the morning hours after a moderate fast. They are more likely to be Caucasian, male gender, and have a low body weight. The underlying pathophysiology of IKH is yet to be fully understood. It is often associated with low plasma concentrations of alanine, an important substrate for gluconeogenesis, and may involve impaired ketone body metabolism or transport. It is sometimes called ‘accelerated starvation’ and is more common in babies that were small for dates and had neonatal hypoglycaemia. References 1. Daly LP, Osterhoudt KC, Weinzimer SA. Presenting features of idiopathic ketotic hypoglycemia. J Emerg Med 2003;25:39-43. 2. Marcus C, Alkén J, Eriksson J, et al. Insufficient ketone body use is the cause of ketotic hypoglycemia in one of a pair of homozygotic twins. J Clin Endocrinol Metab 2007;92:4080-4. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Idiopathic ketotic hypoglycaemia Ketotic hypoglycaemia Exclude inborn errors of metabolism ?Drug ingestion ?medications ?overdose ?reaction ?Adrenal insufficiency ?Addison’s ?Hypopituitarism ?Hypocortisolism Ketosis, fatty acid oxidation disorders less likely Collect samples when hypoglycaemic Suggest insulin/C-peptide Suggest cortisol/ACTH Suggest growth hormone Suggest lactate Suggest urine/plasma organic acids Suggest free fatty acids - exclude fatty acid oxidation disorders Suggest amino acid screen Suggest carnitine/acylcarnitine screen Suggest electrolytes/renal function tests/liver function tests/glucose/Ca/Mg Suggest β-hydroxybutyrate/urine ketones Suggest blood gas/pH Suggest urine metabolic screen Suggest ammonia ?Growth hormone deficiency Suggest urine amino acids Urgent oral/IV glucose/admit hospital Repeat glucose regularly Marked hypoglycaemia Ketosis/ketonuria Exclude endogenous/exogenous insulin excess ?Malnutrition ?starvation ?long fast Hypoglycaemia Suggest thyroid function tests ?Glycogen storage disease ?Salicylate/paracetamol/alcohol overdose Refer to endocrinologist/specialist ?Gluconeogenic defect ?Organic acidaemia ?Liver disease ?hepatic enzyme defect Suggest supervised diagnostic fast ?Sepsis – complete blood picture/blood/urine cultures Ketosis - hyperinsulinaemia less likely Exclude MCAD ?Family history Ketosis excludes hyperinsulinaemia Assume correct specimen collection Review original Guthrie screen Exclude respiratory chain disorders ?Galactosaemia ?Fructose intolerance ?Leucine sensitivity ?Reye’s syndrome UNACCEPTABLE KEY WORDS ?Intercurrent illness ?Hormone deficiency ?Insulin dependent diabetes mellitus Suggest urine reducing substances Convulsion from hypoglycaemia ?Pyruvate metabolism disorder Suggest IGF-1 ?Tissue biopsy for inborn errors of metabolism investigation Suggest glucagon Suggest HbA1c Suggest urine microalbumin ?Adrenoleukodystrophy or congenital adrenal hyperplasia Suggest 17OHP Suggest genetic test if amino acid positive Suggest G6PD Risk of mental retardation/seizures ?Low weight for height ?Abdominal mass ?Neoplasm Ketosis excludes fatty acid oxidation disorders Case 11-10 Glucose Patient ID 31-year-old female Patient Location General Practice Clinical Notes on Request Form 28/40 pregnant. OGTT (75 g oral glucose load) Case Details Fasting glucose 1 h glucose 2 h glucose 5.1 mmol/L 10.3 mmol/L 5.3 mmol/L Suggested Comment The latest Australian Diabetes in Pregnancy Society definitions for gestational diabetes (GD) using 75 g oral glucose tolerance test (OGTT) are: fasting glucose <5.1 mmol/L, 1 hour <10.0 mmol/L and 2 hour <8.5 mmol/L. Under these guidelines, this patient should be managed as for GD, including an OGTT 6–8 weeks post-partum. Rationale Previously, the lack of international consensus on the diagnosis of gestational diabetes (GD) makes it difficult to be sure what criteria to apply. In 1998 the Australian Diabetes in Pregnancy Society re-affirmed 1991 recommendations of the Australian Diabetes Society to define GD as a fasting blood sugar level (BSL) of ≥5.5 mmol/L or 2 hour post 75 g load BSL of ≥8.0 mmol/L; the 2 hour threshold was derived by rounding the WHO level of 7.8. In 1992 the New Zealand Society for the Study of Diabetes raised the 2 hour threshold to 9.0 mmol/L for New Zealand. The American Diabetes Association favours the 3 hour 100 g OGTT but also use two abnormal readings [≥5.3 mmol/L (fasting), ≥10.0 mmol/L (1 hour) and ≥8.6 mmol/L (2 hour)] post 75 g load. After publication of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, which conclusively links multiple adverse pregnancy outcomes with degrees of hyperglycaemia less severe than those diagnostic of diabetes, the International Association of Diabetes and Pregnancy Study Groups recommended a uniform approach to GD diagnosis. The proposal includes: 1. Use of random/fasting BSL or HbA1c in 1st trimester to exclude undiagnosed overt diabetes. 2. Diagnosis of GD based on either BSL ≥5.1 mmol/L (fasting), 10.0 mmol/L (1 hour) or 8.5 mmol/L (2 hour) post 75 g load at 24–28 weeks. These figures represent the average BSL exceeded in HAPO where the odds ratio for adverse outcomes reached 1.75. While not directly addressed, the non-fasting ‘screening’ test will be redundant. These criteria are now adopted by the Australian Diabetes in Pregnancy Society and World Health Organisation. Reference 1. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676-82. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS Raised 1h result Gestational diabetes by IADPSG criteria Gestational diabetes Suggest manage patient as gestational diabetes mellitus Pregnancy OGTT guidelines differ Continue to monitor post-partum Repeat OGTT post-partum 75 g glucose load Repeat GTT if clinically indicated Glucose tolerance can deteriorate in later pregnancy Suggest further tests if risk factors Check specimen integrity and order Guidelines suggest fasting plasma glucose, HbA1c 1st trimester Increased risk of diabetes mellitus Interpret with caution during pregnancy Review of gestational diabetes mellitus criteria from HAPO ?Patient fasting Check pre-test conditions 1h suggests normal absorption of glucose Repeat GTT 3rd trimester if clinically indicated If non-fasting, positive 1h result Raised 1h result ?rapid absorption Confirm gestational diabetes mellitus diagnosis Suggest polycose screen (GCT) Gestational diabetes mellitus indicated by ADA criteria GTT protocol not followed Gestational diabetes mellitus using ADIPS 1998 Normal GTT Normal GTT using ADIPS criteria Not suggestive of gestational diabetes mellitus Normal GTT using WHO criteria No gestational diabetes mellitus using ADA 1999 Case 12-07 Glucose Patient ID 42-year-old male Patient Location General Practice Clinical Notes on Request Form Diabetes monitoring Case Details HbA1c HbA1c (IFCC) 6.8% 51 mmol/mol Additional Information Type 2 diabetes for 5 years. On metformin. Suggested Comment As the general target for HbA1c in a patient with type 2 diabetes for 5 years on metformin therapy alone is 6.0% (42 mmol/mol), the management of this patient should be reviewed. If the patient has clinical cardiovascular disease a higher target may be appropriate. Rationale The Australian Diabetes Society has produced guidelines for the individualisation of HbA1c targets based on a range of factors (1, 2). Factors to consider with these individualised targets include the type of diabetes (type I or type II), the duration of diabetes, treatment, presence of cardiovascular disease, pregnancy, recurrent hypoglycaemia and hypoglycaemia unawareness. In the supplied case, a number of these factors were specified (type II diabetes mellitus, duration five years, metformin only) for which the target HbA1c is <6.0% (<42 mmol/mol). A higher value may be appropriate in this patient if there is clinical cardiovascular disease. It is difficult for the laboratory to be aware of all these factors when issuing an interpretive comment, but care should be taken not to place a comment which conflicts with these guidelines. Participants in countries other than Australia should refer to relevant guidelines in their own country. Responses suggesting a specific course of action were generally marked as ‘Less Relevant’. From the laboratory, it is not possible to determine whether changes in lifestyle, metformin dose or drug treatment is the preferred option. References 1. Cheung NW, Conn JJ, d’Emden MC, et al. Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust 2009;191:339-44. 2. Jones GR, Barker G, Goodall I, et al. Change of HbA1c reporting to the new SI units. Med J Aust 2011;195:45-6. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Results above limits 6% or 42 mmol/mol Short term diabetes mellitus without cardiovascular disease target <6%, 42 mmol/mol Short term DM without CVD target 6– 6.5% HbA1c target 6–6.5% (45–49 mmol/mol) If cardiac risk target <6.5% If long-term or cardiovascular disease, target <7%, 53 mmol/mol Targets should be individualised Need to lower HbA1c levels Recommend lifestyle changes ± metformin target <6% Suggest repeat HbA1c in three months Refer Aust. Diabetes Society guidelines Refer Med J Aust 2011 position statement Refer Med J Aust 2009 position statement Refer NZ guidelines Type 2 DM (2011) HbA1c general target <7% or 53 mmol/mol Check lipids, urine albumin/creatinine, renal function Dual reporting of units Check other cardiovascular risk factors Recommend annual urine albumin/creatinine, lipids Early control lowers microvascular/ macrovascular complications ADA, BPAC NZDA, IDF target 6.5% Recommend lifestyle changes HbA1c 5–6% reduces cardiovascular disease ?Variant Hb produce artefacts ?Compliance Repeat HbA1c in six months Consider hypoglycaemic episodes ?Modify metformin dose Recommend lifestyle changes (<6% or <42 mmol/mol) ?Lower target with new diabetics ?Consider lower target no cardiovascular disease Reporting IFCC units UKPDS early treatment of DM beneficial Check fasting glucose HbA1c <1% above reference limit 4–6% Suggest microalbumin Check for hypertension ?Suggest sulfonylurea or insulin Not using IFCC units Care required when interpret increased red blood turnover Consider patient symptoms ?Medication to reduce symptoms Patient risk of retinopathy Consider oral anti-diabetic therapy Follow-up 3–6 months Refer Clin Chem guidelines 2011 Review of diabetes management suggested if HbA1c =>7.0% Target for type 2 DM 50–55 mmol/mol For younger people tighter control required NOT SUPPORTED KEY WORDS Good glycaemic control Poor diabetic control Targets balanced against risk of hypoglycaemia ?Risk hypoglycaemia 2° to treatment Change treatment if >8.0% (64 mmol/mol) Should achieve <6% accord to UKPDS MISLEADING KEY WORDS Very good glycaemic control No change medication/dosage require Case 14-01 Glucose Patient ID 66-year-old female Patient Location General Practice Clinical Notes on Request Form Previous impaired fasting plasma glucose (FPG). Normal body mass index (BMI) and no family history of diabetes mellitus. Case Details HbA1c (IFCC) Fasting plasma glucose 48 mmol/mol 6.4 mmol/L Additional Information Previous FPG as part of a screening for being a possible live kidney donor showed a FPG of 6.1 mmol/L. This was followed up by an HbA1c and an oral glucose tolerance test (OGTT): HbA1c (IFCC) 46 mmol/mol OGTT 0 hour glucose 5.2 mmol/L 2 hour glucose 5.5 mmol/L All haematology was normal. Suggested Comment (Australia) Single HbA1c result above the diagnostic threshold for diabetes mellitus together with a fasting blood glucose in the range for impaired fasting glucose. A repeat HbA1c test in 3 months is recommended for confirmation of diagnosis of diabetes. (New Zealand) HbA1c result in the pre-diabetic range. Repeat testing in 6–12 months is recommended to assess progression. Rationale HbA1c is now approved for the diagnosis of diabetes mellitus (DM) in Australia (1) and New Zealand (2), providing it is measured in an accredited laboratory using a National Glycohemoglobin Standardization Program (NGSP)-certified method. Briefly, in Australia, the WHO criterion (3) of two results ≥48 mmol/mol (6.5%) in an asymptomatic patient has been adopted. In New Zealand the criterion is two results ≥50 mmol/mol (6.7%) for asymptomatic patients. Either venous plasma glucose or HbA1c are valid for the diagnosis of DM and if either testing protocol is positive the diagnosis is made. It is not recommended that both glucose and HbA1c testing protocols be used in the same patient at the same time. Doctors may choose HbA1c to test patients who are not fasting. HbA1c should not be used in patients with factors that make testing unreliable including iron deficiency, stage 4 or 5 chronic kidney diseases, haemolytic anaemia or other cause of reduced red blood cell survival and haemoglobinopathies that affect the laboratory method in use. HbA1c should not be used for diagnosis of acute onset DM (e.g. Type 1) or for gestational DM. While HbA1c is a valid test for diabetes in Australia, details on recommended testing protocols (e.g. retesting frequency) are still under development. In contrast, in New Zealand HbA1c is recommended as the preferred test unless there are specific contraindications. In this case, where results are available for fasting plasma glucose, oral glucose tolerance test and HbA1c, unless there are specific contraindications it would seem that HbA1c is likely to be the more sensitive test for diagnosis and should be used for further assessment. References 1. d'Emden MC, Shaw JE, Colman PG, et al. The role of HbA1c in the diagnosis of diabetes mellitus in Australia. Med J Aust 2012;197:220-1. 2. Braatvedt GD, Cundy T, Crooke M, et al. Understanding the new HbA1c units for the diagnosis of Type 2 diabetes. NZ Med J 2012;125:70-80. 3. World Health Organization. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. 2011. http://www.who.int/diabetes/publications/report-hba1c_2011.pdf PREFERRED KEY WORDS Borderline HbA1c Not diagnostic of diabetes (Aus) DM cut-off HbA1c ≥48 mmol/mol Oral glucose tolerance test (OGTT) and HbA1c discordant NZSSD position statement prediabetic Consistent with pre-diabetes Fasting plasma glucose (FPG) consistent with impaired fasting glucose HbA1c above diabetes mellitus (DM) cut-off High risk of developing diabetes Recommend lifestyle review Recommend cardiovascular disease risk assessment Use repeat HbA1c to confirm DM Repeat screening HbA1c in future Suggest lipid profile Confirm DM if asymptomatic Re-screen DM in future OGTT or HbA1c results diagnose DM HbA1c - WHO criteria for Type II DM Assuming valid HbA1c LESS RELEVANT KEY WORDS Normal OGTT Clinical/previous history noted Re-screen in future with OGTT Re-screen in future with FPG Australian guidelines confirm DM FPG and HbA1c discordant still diagnostic HbA1c not funded for diagnosis of DM Check urine albumin/creatinine ratio ?Technical problem with OGTT Suggest fasting glucose Australian Diabetes Society HbA1c targets for diabetics Impaired fasting glucose consistent with insulin resistance HbA1c better diagnostic tool Confirm DM with OGTT NOT SUPPORTED KEY WORDS Impaired glucose tolerance HbA1c - impaired glucose tolerance HbA1c not supported in Australia for diagnosis MISLEADING KEY WORDS Normal HbA1c level Repeat HbA1c to monitor DM Case 6-09 Liver Patient ID 29-year-old man Patient Location General Practice Clinical Notes on Request Form Acutely ill with nausea and vomiting Case Details Plasma Liver Function Tests Albumin 28 g/L Bilirubin 61 µmol/L ALT 2627 U/L AST 2196 U/L Alk Phos 69 U/L Gamma GT 198 U/L (35–50) (<20) (<46) (<33) (35–135) (<44) Additional Information Other laboratory results: Urea and electrolytes unremarkable Suggested Comment Results indicate acute hepatitis. Consider viral hepatitis serology, possible adverse drug reactions, and exclude paracetamol or other toxic substances. Rationale It is a good general rule to go for the obvious and gross when looking at results. In this case the transaminases are very high indicating acute hepatitis, and other minor abnormalities are likely to be secondary to this. The causes of ALT >1000 are few - viral hepatitis, toxins such as paracetamol, adverse drug reactions, ischaemic hepatitis secondary to hypotension, and ante-mortem with severe heat stroke. In a man of this age and with the history given, the latter two can probably be ruled out. In this patient, viral hepatitis and adverse drug reactions of one sort or another are highly likely. Of note, an early and rapid rise of LDH, AST:LDH ratio of <1.5 and rapid fall in AST after the initial rise are features suggestive of ischaemic liver injury rather than viral hepatitis. Remember that drug screens and paracetamol concentration may be difficult to interpret, as it may be some time since ingestion and the drug may be nearly absent or at low concentration. PREFERRED KEY WORDS Acute hepatitis Hepatocellular pathology ?Drugs/chemicals ?Viral infection Suggest viral serology Suggest paracetamol levels LESS RELEVANT KEY WORDS Acute insult Elevated AST/ALT ?Ethanol ?History Increased GGT/bilirubin Abnormal liver function tests Suggest INR/clotting studies ?Other causes Mild jaundice Suggest ethanol level ?Autoimmune disease Suggestive of hepatitis A Suggest toxicology screen No obstruction AST/ALT indicate non-alcoholic Suggest glucose Hospitalisation/management recommended UNACCEPTABLE KEY WORDS Acute biliary obstruction ?Hypoxic insult Suggest other tests Suggest radiography Suggest serial liver function tests Suggest lipase/amylase ?Haemolysis ?Gilberts ?Hepatic failure ?Extensive trauma ?Cholecystitis Viral hepatitis unlikely Screen contacts Case 7-02 Liver Patient ID 49-year-old man Patient Location General Practice Clinical Notes on Request Form History of gout. Family history of Type II diabetes and cardiovascular disease. Case Details Total protein Albumin Bilirubin ALT AST ALP GGT 70 g/L 44 g/L 11 µmol/L 48 U/L 22 U/L 89 U/L 79 U/L Additional Information Sodium 143 mmol/L Potassium 4.2 mmol/L Urea 4.2 mmol/L Creatinine 80 µmol/L Glucose 5.8 mmol/L Urate 0.66 mmol/L Cholesterol 7.9 mmol/L Triglyceride 4.5 mmol/L (60–80) (35–50) (<20) (<40) (<43) (35–135) (<60) (134–146) (3.4–5.0) (3.0–8.0) (50–110) (3.0–5.4) (0.12–0.45) (<5.5) (<2.01) Suggested Comment Mild elevations of ALT and GGT in the setting of mixed hyperlipidaemia and impaired fasting glycaemia suggest possible fatty liver disease. Alcohol and drugs should be considered as possible contributory factors. If history is supportive, hepatitis serology may be indicated. Rationale Non-alcoholic fatty liver disease (NAFLD) should be considered in patients with asymptomatic elevated aminotransaminases. Liver enzyme elevations are absent in 78% of NAFLD patients, and when present are modest, with AST:ALT ratio <1. GGT when raised is less than in alcohol-induced liver injury. The diagnosis of NAFLD requires 1) imaging or histologic evidence of fatty infiltration of the liver, 2) the absence of excessive alcohol ingestion (men: <21 drinks/week; women <14 drinks/week), 3) no competing aetiologies for hepatic steatosis, and 4) no co-existing cause of chronic liver disease. Obesity, type 2 diabetes mellitus, hypertension, hypertriglyceridaemia, low HDL-cholesterol and metabolic syndrome are risk factors associated with NAFLD. Competing causes of hepatic steatosis, such as hepatitis C, medications, parenteral nutrition, Wilson’s disease, severe malnutrition as well as other causes of chronic liver disease should be excluded by clinical evaluation and serological testing. Confirmation of diagnosis is by imaging studies, although liver biopsy should be considered in patients with metabolic syndrome, high NAFLD Fibrosis Score, and in whom competing aetiologies or chronic liver disease cannot be excluded without a biopsy. Reference 1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-23. PREFERRED KEY WORDS Mild liver enzyme abnormalities ?Alcohol and/or drugs ?Fatty liver disease ?Metabolic syndrome Suggest hepatitis serology LESS RELEVANT KEY WORDS Hyperuricaemia Hyperlipidaemia Recommend oral glucose tolerance test Recommend repeat fasting lipids & HDL Hyperglycaemia Consistent with gout ?Fasting Suggest repeat fasting glucose Suggest lifestyle changes ?Viral hepatitis Suggest repeat tests later Suggest further liver investigation ?Hepatocellular injury Suggest clinical review At cardiovascular risk ?Obesity Suggest urinalysis/ urine microalbumin ?Insulin resistance Review cardiac risk factors Recommend HbA1c Suggest other tests Normal renal function tests Suggest insulin levels Suggest further lipid tests Recommend liver imaging UNACCEPTABLE KEY WORDS ?Diabetes mellitus Suggest statin/pharmacotherapy Suggest thyroid function tests Familial hypercholesterolaemia ?Increased cell turnover/malignancy ?Pancreatitis Hepatic impairment No comment Case 9-06 Liver Patient ID 25-year-old male Patient Location General Practice Clinical Notes on Request Form 135 kg, bipolar on Epilim (sodium valproate) 2 x 200 mg BD Case Details Bilirubin ALP AST ALT GGT LD 12 µmol/L 81 U/L 193 U/L 124 U/L 21 U/L 238 U/L Additional Information Epilim 22 mg/L (3–20) (30–115) (5–40) (5–40) (5–65) (100–225) (50–100) Suggested Comment Hepatocellular dysfunction may be related to valproate toxicity even though the valproate concentration is below the usual therapeutic range. Other causes of liver disease should be investigated. The disproportionate increase in AST compared with ALT may be seen in ethanol-associated liver disease or with concurrent muscle injury. Measurement of serum CK may be helpful. Rationale Initial and chronic ingestion of valproate may cause dose-dependent, reversible minor elevation of hepatic transaminases. On the other hand, valproate can cause fatal idiosyncratic hepatotoxic reactions. Anyone can be affected but children under 2 years old with organic brain disease, congenital metabolic disorders, developmental delay and taking multiple medications may be at increased risk. The idiosyncratic hepatotoxicity may not be related to increased serum valproate concentration. Therapeutic drug monitoring of valproate is less useful than other anticonvulsants like phenytoin because of a weaker correlation between serum concentrations and therapeutic effect or toxicity. Reference 1. Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006;38:33-8. PREFERRED KEY WORDS Consistent with hepatocellular damage Epilim hepatotoxicity Sub-therapeutic Epilim level Exclude other causes of liver disease Assess patient clinically ?Alcohol ?Muscle involvement Suggest CK/CK-MB Epilim may cause acute liver failure Review pre-Epilim liver function tests LESS RELEVANT KEY WORDS Raised liver transaminases noted Monitor liver function tests ?Concurrent drug therapy ?Viral hepatitis ?Non-alcoholic fatty liver disease Review Epilim dose Obesity noted Suggest PT/fibrinogen levels Slightly raised LDH ?Non-compliance Normal GGT/ALP/TBil Suggest hepatitis serology ?Transient Suggest albumin /total protein AST>ALT ?Recent commencement Clinical symptoms better than Epilim level Consider alternative drug for bipolar disorder If no other cause stop Epilim Restrict salicylate/same metabolic path ?Hepatocellular disease ?Manic episodes or fitting Details of last dose not stated ?Autoimmune disorder ?Cirrhosis Monitor Epilim levels Suggest ammonia ?hepatic encephalopathy Valproate highly protein bound ?Cardiac involvement Epilim doses lower in bipolar disorder Suggest renal function tests Epilim can cause obesity Suggest fasting glucose/lipids ?Risk of pancreatitis AST from other tissues ?Liver disease with haematologic disturbance Suggest urine myoglobin ?Neurometabolic disease Suggest liver ultrasound In liver disease ALT>AST Suggest full blood examination No comment Suggest troponin T, CK and BNP ?Early hepatic failure Suggest free valproic assay ?Acute episode No evidence of cholestasis In non-alcoholic fatty liver disease, AST<ALT ?Urea cycle disorder UNACCEPTABLE KEY WORDS Not likely hepatic dysfunction due to Epilim ?2° to metabolic syndrome ?Renal damage No evidence hepatotoxicity Suggest hormone levels Suggest thyroid function tests ?End-stage AIDS Suggest C-Peptide Deaths seen in patients on Epilim Case 9-10 Liver Patient ID 23-day-old baby Patient Location Paediatric Ward Clinical Notes on Request Form Increasing jaundice. Case Details Bilirubin 367 μmol/L Conjugated bilirubin 10 μmol/L Suggested Comment Prolonged, marked, unconjugated hyperbilirubinaemia. Breast milk jaundice may be considered after excluding hypothyroidism, sepsis and haemolytic disorders. Suggest thyroid function tests, full blood examination with blood film, direct Coomb’s test, blood group subtyping of mother and baby, glucose-6phosphate dehydrogenase (G6PD) screen, and urine culture. Clinical advice regarding management is recommended. Rationale Hyperbilirubinaemia beyond two weeks of age (three weeks if premature) is considered ‘prolonged’. The exclusion of conjugated hyperbilirubinaemia is important, as they are always pathological, requiring urgent attention. Unconjugated hyperbilirubinaemia is most commonly due to breast-feeding but this cannot be assumed without excluding hypothyroidism, haemolysis (from red blood cell abnormalities and atypically late presentations of blood group incompatibility) and infection. It is also important to ensure that routine metabolic screening (including congenital hypothyroidism screening) has been performed. At this level of bilirubin, treatment advice should be sought. It is worthwhile for laboratories to be familiar with local paediatric hospital guidelines, which usually have treatment thresholds relating the levels of bilirubin with the baby’s age and clinical state. References 1. Evans N. Neonatal jaundice. Australian Doctor 2008;8th Feb:21-28. 2. NICE clinical guideline 98: Neonatal jaundice. http://www.nice.org.uk/guidance/cg98 PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Unconjugated hyperbilirubinaemia Marked hyperbilirubinaemia Prolonged hyperbilirubinaemia/jaundice ?Breast milk jaundice ?Sepsis ?G6PD deficiency/other red cell enzyme defect ?Haemolytic condition ?Hypothyroidism Review clinical picture/history Suggest full blood examination Suggest thyroid function tests Suggest haemolytic screen Suggest blood group and rhesus and antibody status of mother and baby Suggest sepsis investigations Suggest red cell G6PD assay Suggest blood film Check newborn screening done Suggest urine microscopy, culture and sensitivity ?Crigler-Najjar Suggest liver function tests ?Pathological impaired liver conjugation Risk of kernicterus Suggest further investigation ?Baby premature ?Galactosaemia Suggest reducing substances Monitor Consider phototherapy ?Gilbert’s syndrome Hyperbilirubinaemia Outside timeframe for physiological jaundice Suggest TORCH(S) screen ?Inborn error of metabolism ?Congenital infection ?Hereditary red cell membrane defect Refer to paediatrician ?Inadequate caloric intake Cease breastfeed to assess No comment Consider treatment ?Thalassaemia/haemoglobinopathy ?Prolonged physiological jaundice Treat to reduce bilirubin if increase continues ?Drug effect Suggest hepatitis screen Repeat total and direct bilirubin in one day ?Excessive red blood cell turnover Suggest glucose Suggest C-reactive protein ?Lucy Driscoll syndrome ?Secondary to acute illness Suggest serum albumin UNACCEPTABLE KEY WORDS Immediate treatment required Consider exchange transfusion ?Obstructive liver disease No intervention necessary Bilirubin level excludes Gilbert’s Bilirubin level excludes haemolytic disorder ?Hypopituitarism ?Hypoxia Case 10-04 Liver Patient ID 60-year-old male Patient Location Emergency Department Clinical Notes on Request Form Decreased conscious state. Case Details Plasma ammonia 375 μmol/L (10–50) Additional Information Na 142 mmol/L (134–146) K 3.8 mmol/L (3.4–5.0) Bicarb. 23 mmol/L (22–32) Urea 6.4 mmol/L (3.0–8.0) S. Creat. 110 μmol/L (60–110) eGFR >60 mL/min/1.73m2 (>60) Glucose 6.9 mmol/L (3.0–5.4) Protein 67 g/L (65–85) Albumin 30 g/L (34–47) T. Bilirubin 26 μmol/L (<22) ALP 106 U/L (30–120) GGT 147 U/L (10–71) ALT 12 U/L (5–40) Lipase 27 IU/L (13–60) cTnI 0.04 μg/L ABG pH 7.47 pCO2 31 mmHg pO2 97 mmHg O2 sat. 98 % Lactate 1.8 mmol/L (<0.04) (7.35–7.45) (35–45) (80–100) (>95) (<1.3) Suggested Comment Marked hyperammonaemia is most likely the cause of the decreased conscious state and respiratory alkalosis. Further investigation for liver and non-liver causes of ammonia toxicity such as drugs (valproate), infective agents, or urea cycle defects is recommended. Suggest hepatitis screen, INR, sepsis screen, urine organic acids, orotic acid and plasma and urine amino acids. Rationale Mild hyperammonaemia is frequently caused by poor specimen integrity and/or collection technique. Marked hyperammonaemia in the clinical setting of decreased conscious state and respiratory alkalosis makes a spurious result unlikely. Such high ammonia values are most frequently seen in patients with liver failure. The relatively preserved albumin, mildly raised bilirubin and mildly abnormal liver function tests are not consistent with end stage liver failure, as synthetic capacity seems to be at least partly preserved. An INR will be helpful to confirm this. Non-liver causes of hyperammonaemia, many of which are reversible, should be investigated. Urea cycle (e.g. ornithine transcarbamylase deficiency), fatty and organic acid defects need to be considered as they may present at any age. Valproate can cause hyperammonaemia by N-acetyl-glutamate depletion; although valproate and liver function tests are usually within therapeutic/reference limits. Excessive amino acid load (e.g. gastrointestinal bleeding; unlikely here given the normal urea concentration) and haematologic malignancies are other possibilities. The mildly raised troponin in this setting is difficult to interpret and might be due to a cardiac condition (e.g. cardiac failure) or severe illness (e.g. sepsis). In this particular patient the final explanation was severe right heart failure impeding the ability of the liver to metabolise ammonia loads caused by increased protein intake. Reference 1. Walker V. Severe hyperammonaemia in adults not explained by liver disease. Ann Clin Biochem 2012;49:214-28. PREFERRED KEY WORDS ?Chronic hepatic disease Marked hyperammonaemia Respiratory alkalosis Compensated respiratory alkalosis Hyperammonaemia coupled with loss of consciousness ?Hepatic encephalopathy Suggest further investigation of hyperammonaemia ?Drug/toxin effect ?Sepsis ?Valproate aetiology ?Urea cycle metabolic defect ?Inborn error of metabolism Late onset ornithine transcarbamylase deficiency Suggest plasma/urine amino acids Suggest urine organic acids ?Hepatotoxicity/acute hepatic injury Suggest clotting profile Suggest plasma acylcarnitine Suggest valproate level ?Hyperalimentation LESS RELEVANT KEY WORDS Hyperammonaemia ?Ethanol toxicity/alcoholic liver disease Elevated GGT ?Sample integrity/preanalytical interference Hypoalbuminaemia Suggest recollection/repeat ammonia ?Salicylate aetiology/level Hyperbilirubinaemia Correlate with clinical findings Mildly abnormal liver function tests Liver function tests not significantly abnormal ?Acetaminophen aetiology/level ?Surgery/portal shunt ?Chemotherapy effect Near normal albumin Suggest urine/blood drug/toxin screen Suggest ethanol levels Suggest urine microscopy, culture and sensitivity Monitor ammonia Urea and electrolytes not significantly abnormal Unlikely metabolic defect due to age Normal ALT ?Viral hepatitis/serology Decreased protein Consistent with severe liver disease ?Muscle ischaemia/prolonged immobilisation Suggest CRP Suggest repeat cTnI in 6–12 h ?Primary/secondary malignancy Suggest full blood examination Monitor liver function tests ?Hashimoto's encephalopathy Check liver function tests / urea and electrolytes Monitor blood gas cTnI suggests myocardial injury Suggest chloride level ?Random glucose result Lactate not significantly elevated Do not monitor therapy with ammonia levels Suggest anion gap Normal bilirubin Borderline cTnI Elevated cTnI due to stress response Refer to clinical pathologist Suggest phosphate Mild renal failure UNACCEPTABLE KEY WORDS Hyperlactataemia ?Gastrointestinal haemorrhage Unlikely chronic liver disease ?Urinary tract infection Metabolic acidosis/compensated Hyperglycaemia ?Carbamazepine aetiology Suggest BNP/?heart failure Markedly increased lipase ?Tumour of prostate Portal hypertension Not consistent with hepatic encephalopathy ?Exogenous ammonia Case 11-08 Liver Patient ID 59-year-old female Patient Location General Practice Clinical Notes on Request Form Itchy Case Details Total Protein Albumin ALP Total Bilirubin GGT AST ALT 70 g/L 33 g/L 163 U/L 8 μmol/L 143 U/L 37 U/L 47 U/L (60–81) (35–50) (40–140) (<25) (<51) (<41) (<41) Additional Information Similar results one month ago. Suggested Comment The liver enzyme pattern is consistent with focal cholestasis. Persistent increase in ALP and GGT in a woman with a history of itch suggests a diagnosis of primary biliary cirrhosis. Measurement of antimitochondrial antibodies (AMA) would be useful. Other causes of abnormal liver function tests such as ethanol and medications should be considered. Liver ultrasound may be helpful. Rationale The combination of itch with raised cholestatic enzymes in a middle-aged woman raises the possibility of primary biliary cirrhosis (PBC), an autoimmune liver disease, which is characterised by the presence of antimitochondrial antibodies in the serum. Other autoantibodies such as anti-nuclear antibodies (ANA) may also be present in these patients. Serum immunoglobulin M, cholesterol and bile acids may be increased in advanced disease but these are not useful in early diagnosis. Many other conditions such as drug reactions, alcohol and primary sclerosing cholangitis (PSC) may be accompanied by increased cholestatic enzymes. Clinical suspicion for PBC and PSC are increased by the presence of other autoimmune disease and inflammatory bowel disease, respectively, The fact that the results were similar one month ago is reassuring but liver ultrasound may be useful to exclude a focal lesion in the liver such as a malignant tumour. References 1. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009;50:291-308. 2. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005;172:367-79. PREFERRED KEY WORDS Liver function tests suggest cholestatic liver disease Primary biliary cirrhosis ?Primary biliary cirrhosis ?Primary sclerosing cholangitis ?Alcoholic liver disease ?Neoplastic liver disease ?Autoimmune disease ?Pruritus due to cholestasis ?Intrahepatic cholestasis ?Infiltrative liver disease Suggest anti-mitochondrial antibodies Exclude biliary obstruction/gall stones Suggest hepatobiliary imaging Suggest autoantibodies Request drug history LESS RELEVANT KEY WORDS Hypoalbuminaemia Suggest immunoglobulins Suggest lipid studies Elevated ALP and GGT Mildly elevated fiver function tests Suggest viral serology Suggest full blood examination Persistent itch/middle aged woman Low albumin suggests chronic liver disease Normal bilirubin level Persistent moderately raised GGT ?Obesity/diabetes mellitus/metabolic syndrome Suggest renal function test and anion gap ?Hodgkin's disease/lymphoma Suggest bile acids Suggest AFP Suggest bone markers ?Cirrhosis Request clinical history Suggest repeat/monitor liver function tests ?Chronic renal failure ?Polycythaemia/haematological Suggest glucose ?Fatty liver disease Suggest INR/APTT Mildly elevated ALP Abnormal liver function tests ?Pancreatitis/suggest amylase/lipase Hepatobiliary disease Mildly elevated ALT ?Thyroid disorder/suggest thyroid function tests Suggest protein electrophoresis ?Early Paget's disease Consistent with chronic obstructive jaundice Suggest gastroenterologist consultation Low alb/poor nutrition/increased loss Normal AST and ALT Suggest fat-soluble vitamins ?Reference interval correct ?Inflammatory bowel disease UNACCEPTABLE KEY WORDS ? Chronic viral hepatitis Exclude other causes of pruritus ?Iron overload/suggest iron studies Suggest liver biopsy ?Infection ?Hepatocellular injury ?Primary biliary sclerosis Hepatitis unlikely Suggest serum/urine osmolality ?Cause not related to itch ?Chronic infection ?Wilson's disease Suggest serum copper/α1-antitrypsin Suggest ACE to exclude sarcoidosis Case 12-09 Liver Patient ID 49-year-old female Patient Location General Practice Clinical Notes on Request Form Recent weight gain despite reduction in alcohol consumption. Case Details Total Bilirubin Total Protein Albumin ALP GGT ALT AST 17 μmol/L 76 g/L 44 g/L 63 U/L 136 U/L 59 U/L 31 U/L (<21) (62–80) (38–48) (30–130) (≤60) (5–55) (5–55) Additional Information Setting: General practice review as a component of Medicare incentive for chronic disease prevention. Suggested Comment Mild increases in GGT and ALT are consistent with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis if alcohol abuse is excluded. Consider obesity, insulin resistance, dyslipidaemia, drugs and continued alcohol use. Exclude common causes of hepatocellular liver damage. A small proportion of patients with this profile may progress to non-alcoholic steatosis and cirrhosis. Rationale Mild increases in GGT and ALT are consistent with non-alcoholic fatty liver disease. Obesity, insulin resistance and dyslipidaemia are often associated with this condition, which may be confirmed by hepatic imaging. Drugs, continued alcohol use and common causes of hepatocellular liver damage, such as hypothyroidism should be excluded. A small proportion of patients may progress to non-alcoholic steatosis, fibrosis and cirrhosis but liver biopsy is not indicated unless the problem is severe or sustained. Weight loss, alcohol avoidance and review of medications are the most likely means by which results may be improved. Reference 1. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 2009;49:306-17. PREFERRED KEY WORDS ?Metabolic syndrome ?Fatty liver disease ?Non-alcoholic fatty liver disease ?Non-alcoholic steatohepatitis ?Continued alcohol intake ?Drugs/medication ?Iron storage disease/haemochromatosis ?Hepatic steatosis ?Insulin resistance Suggest lose weight, avoid alcohol, drugs Suggest hepatitis serology Suggest diabetes screen Suggest lipid profile Suggest thyroid function tests LESS RELEVANT KEY WORDS ?Elevated GGT due to alcohol Liver enzyme induction ?Alcohol Suggest repeat in 1–3 months Mildly elevated ALT Mild hepatocellular damage Elevated GGT Suggest hepatic imaging Weight gain Weight gain, increased GGT and slight increase in ALT Mild elevation of GGT ?Chronic viral hepatitis ?Autoimmune disease Mildly elevated GGT and ALT ?Obesity Suggest cardiovascular risk assessment ?Cirrhosis ?Diabetes mellitus ?Toxins Suggest carbohydrate-deficient transferrin Suggest healthy active lifestyle ?Other cause chronic liver disease ?Dyslipidaemia Suggest albumin:creatinine ratio GGT may be raised for 1 month No routine comment ?Herbal remedies Suggest urate Repeat after no alcohol and weight loss AST/ALT ratio <1 Suggest BMI NOT SUPPORTED KEY WORDS Mild non-specific hepatopathy ?Infection ?Increased appetite ?Hepatobiliary disease Suggest morning cortisol ?Advanced fibrosis Suggest full blood examination Suggest liver biopsy Not hepatobiliary disease Lowering of bilirubin MISLEADING KEY WORDS ALT, AST not significantly elevated Case 13-01 Liver Patient ID 33-year-old male Patient Location General Practice Clinical Notes on Request Form Recent travel to the Middle East. Tiredness, lethargy, nausea and anorexia. Case Details Total Protein Albumin ALP Total Bilirubin GGT AST ALT LD 74 g/L 33 g/L 135 U/L 96 μmol/L 376 U/L 947 U/L 3117 U/L 463 U/L (60–82) (35–50) (30–120) (<25) (<50) (<41) (<51) (50–280) Suggested Comment Markedly raised transaminases are consistent with predominant hepatocellular damage. The enzyme pattern and recent travel history suggest viral hepatitis, particularly hepatitis A, as the most likely cause. Recommend serology to confirm the diagnosis. Paracetamol toxicity is less likely but should also be considered. Rationale Marked elevation in AST and ALT with ratio <<1 suggests acute hepatocellular damage. The highest transaminase concentrations are seen in ischaemic/toxic liver damage and viral hepatitis. Recent travel to the Middle East suggests infection as the most likely aetiology and of the many possibilities; hepatitis A is the most common cause in this setting. Acute hepatitis can also be due to toxins and ischaemia although the AST/ALT ratio in these cases is usually >1. Of toxins, paracetamol should be considered urgently due to time constraints for treatment, however in addition to the low AST/ALT ratio, the relatively low LD makes paracetamol toxicity less likely. Alcohol is less likely due to the low AST/ALT ratio. The relatively low LD and patient age make ischaemic causes unlikely. Autoimmune causes are possible but less likely with this degree of transaminase elevation and should be considered only when the more likely causes have been excluded. Reference 1. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005:172 367-79. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS NOT SUPPORTED KEY WORDS Predominantly hepatocellular pathology Liver function tests suggest viral hepatitis Liver function tests suggest hepatitic picture Results consistent with parenchymal liver disease ?Cytotoxic liver damage Hepatocellular disease Low AST/ALT ratio-viral origin/acute Exclude paracetamol toxicity ALT and AST markedly elevated Results consistent with acute hepatitis Consider hepatitis A ?Acute hepatitis ?Infectious hepatitis Exclude viral hepatitis Suggest hepatitis serology (A,B,C,D,E) Exclude drug/toxin/herbal induced ?Drug/toxin/herbal induced Suggest repeat liver function tests Phone results to referring doctor ?EBV, CMV, Coxsackie, HSV Suggest coagulation profile Suggest full blood examination/differential Some degree of cholestasis Suggest renal function Suggest HIV serology Exclude ischaemic liver damage Cholestasis and reduced synthetic ability Suggest iron studies Suggest serum copper and caeruloplasmin Suggest α1-antitrypsin, anti-smooth muscle antibodies ?Acute cholangitis Raised GGT consistent with cytotoxic damage ?Accompanying haemolysis Suggest indirect bilirubin ?Leptospirosis Ischaemic liver damage less likely Less common EBV, CMV, Coxsackie, herpes simplex 1 virus ?Autoimmune hepatitis Suggest malaria study/thick and thin film ?Alcohol induced ?Wilson's disease Suggest amoebic serology ?Acute on chronic infection Low albumin metabolism Suggest glucose level Suggest ultrasound of hepatobiliary system Raised liver function tests consistent with alcohol/toxins Suggest hepatology review Suggest schistosomiasis Exclude Katayama fever Suggest rickettsial studies Suggest ethanol level Exclude parasitic infections Suggest toxoplasmosis Suggest radiology for lesions Suggest urine drug screen ?Dengue fever/?Q fever Suggest blood cultures Suggest stool examination Exclude hypoxia ?Secondary to cholestatic jaundice Exclude fatty acid oxidation disorder suggest acylcarnitine ?Brucellosis ?Yellow fever ?Typhoid Exclude biliary obstruction Suggest carbohydrate-deficient transferrin Case 14-08 Liver Patient ID 65-year-old female Patient Location Intensive Care Unit Clinical Notes on Request Form Gastric ulcer. Case Details GGT ALP ALT AST LD Bilirubin Albumin 79 U/L 51 U/L 3349 U/L 2325 U/L 4219 U/L 6 μmol/L 13 g/L (<60) (30–110) (<55) (<45) (110–230) (2–24) (34–48) Additional Information Urea 23.5 mmol/L (2.7–8.0) Creatinine 83 μmol/L (50–100) Hb 63 g/L (115–155) Suggested Comment Marked elevation in transaminases suggests acute hepatitis. Drug effects and hypoxia should be considered. Viral hepatitis is less likely due to significantly raised lactate dehydrogenase (LD) and normal bilirubin. Markedly low albumin may include effect of recent gastrointestinal bleed but protein-losing states should be excluded. Recommend coagulation studies and search for underlying conditions, particularly paracetamol and other medications, heart failure and sepsis. Rationale Hypoxic hepatitis (HH) occurs in up to 1% of ICU admissions. Mortality is over 50% during hospitalisation and 25% after one year, and is related to underlying medical conditions. The diagnosis of HH requires (1) clinical setting of acute cardiac, respiratory or circulatory failure; (2) a sharp but transient increase in serum aminotransferases activity, reaching at least 20 times the upper reference limit; (3) exclusion of other causes of acute liver cell necrosis, particularly viral or drug-induced hepatitis. Contrary to expectation, shock was absent in around half of reported HH patients. Severe blood loss alone is not usually sufficient to cause HH. In more than 90% of cases, the patient has a severe underlying pathology, particularly heart failure and septic shock. Renal failure is common (15–65% of cases) and is an independent marker of poor prognosis due to organ hypoperfusion. Of note, the elevated urea is likely the result of catabolism of the haemoglobin from the gastric ulcer. Massive elevation in transaminases due to paracetamol poisoning typically occurs 2 to 5 days after ingestion, when the paracetamol concentration is usually undetectable. A careful history of paracetamol ingestion, including slow release forms, is the best diagnostic approach. Reference 1. Henrion J. Hypoxic hepatitis. Liver Int 2012;32:1039-52. PREFERRED KEY WORDS Marked elevation of transaminases Severe anaemia Acute hypoxic liver injury Acute hepatitis Viral hepatitis unlikely Consistent with upper gastrointestinal tract (GIT) bleed ?Massive bleed - gastric ulcer ?Ischaemia ?Drugs, alcohol or toxins Suggest coagulation studies Review drug history ?Hypoperfusion due to blood loss Poor prognosis Investigate low albumin LESS RELEVANT KEY WORDS Elevated urea Elevated lactate dehydrogenase (LD) Hypoalbuminaemia Low haemoglobin Suggest hepatitis serology ?Viral hepatitis Hepatocellular damage Clinical history noted Normal creatinine Normal bilirubin Suggest full blood count ?Severe shock Normal ALP ?Impaired hepatic synthesis ?Haemorrhagic shock Liver function tests acute/chronic impairment Suggest electrolytes Elevated urea/creatinine ratio Mildly elevated GGT Probable hepatic necrosis Consistent with hepatitis Cholestasis unlikely ?Pre renal acute kidney injury Monitor liver function tests Rule out helicobacter pylori infection Dissociation urea and creatinine Correlate with clinical history ?Hyperlactataemia ?Encephalopathy Suggest renal function tests Hepatic liver function tests pattern Suggest lactate and glucose Non-obstructive picture Suggest total protein NOT SUPPORTED KEY WORDS Suggest paracetamol levels ?Acute liver failure ?Autoimmune hepatitis ?Malignancies Suggest arterial blood gas Isolate bleed/transfuse ?Haematological disorder ?Perforated gastric ulcer Suggest endoscopy Suggest creatine kinase ?Mucosal erosion in GIT Suggest amylase ?Zollinger-Ellison syndrome MISLEADING KEY WORDS ?Chronic liver disease Suggest liver ultrasound Suggest gastrin ?Muscle injury Suggest lipase Suggest haptoglobin ?Nephrotic syndrome Suggest faecal occult blood Suggest urine protein ?Hepatic dysfunction Exclude haemoglobinopathy Case 8-07 Enzymes Patient ID 85-year-old female Patient Location Cardiology Clinical Notes on Request Form Past history of heart valve replacement. Case Details Total Bilirubin ALP AST ALT GGT LD 12 μmol/L 66 U/L 36 U/L 25 U/L 45 U/L 481 U/L (3–20) (30–115) (<40) (<40) (5–65) (100–225) Additional Information Hb HcT RCC Retic MCV WCC 134 g/L 0.41 4.5 x 1012 33 x 109 93 fL 8.7 x 109 (110–160) (0.34–0.47) (3.7–5.4) (10–100) (80–100) (3.5–10.0) Suggested Comment The elevated lactate dehydrogenase (LD) may be due to intravascular haemolysis caused by the prosthetic heart valve. The normal reticulocyte count, haemoglobin and bilirubin levels indicate that the haemolysis is mild. Suggest monitor to ensure condition is stable, or consider other causes of raised LD, if clinically indicated. Rationale A mild degree of intravascular haemolysis is common among patients (prevalence 50–90%) with normally functioning prosthetic heart valves and is attributed to mechanical destruction of red blood cells. Clinically significant haemolysis is rare and occurs mainly with malfunctioning valves accompanied by paraprosthetic valvular regurgitation (1). Elevated serum lactate dehydrogenase (LD) activity in patients with prosthetic heart valves is well documented and correlates with the level of haemolysis (2). Depending on the degree of haemolysis there may be an increase in the reticulocyte count, serum bilirubin and a reduction in serum haptoglobin. However, LD is a non-specific marker and can be raised due to delayed separation, myocardial infarction, liver disease, skeletal muscle disease and malignancy. In this case, a full clinical history and the appropriate choice of tests should assist with the diagnosis. References 1. Ismeno G, Renzulli A, Carozza A, et al. Intravascular hemolysis after mitral and aortic valve replacement with different types of mechanical prostheses. Int J Cardiol 1999;69:179-83. 2. Mansuroğlu D, Omeroğlu SN, Izgi A, et al. LDH levels and left atrial ultrastructural chances in patients with mitral paraprosthetic regurgitation. J Card Surg 2005;20:229-33. PREFERRED KEY WORDS Subclinical haemolysis ?Haemolysis Consistent with prosthetic valve replacement Haemolysis due to heart valve ?Intravascular haemolysis Suggest cardiac markers (troponin, creatinine kinase) LESS RELEVANT KEY WORDS Increased LD Suggest serum haptoglobin Normal full blood count Bilirubin normal ?Myocardial injury ?Collection artefact ?Myocardial infarction Hepatic enzymes normal Suggest clinical evaluation ?Muscle damage Suggest blood film Elevated LD non-specific Normal reticulocyte count Monitor test results Results not typical of haemolysis Other results normal ?Paravalvular leakage/dysfunction No anaemia - haemoglobin normal Check if sample haemolysed ?Pulmonary embolus ?Other haematological disorders Suggest repeat LD LD unlikely liver origin Suggest renal function tests ?Cell injury/inflammation Suggest potassium ?Macro-LD ?Due to warfarin therapy Check previous LD results Check INR Check haemolysis index Suggest platelet count No megaloblastic anaemia ?Myocardial disease UNACCEPTABLE KEY WORDS ?Malignancy Suggest LD isoenzymes ?Kidney or lung damage Intravascular haemolysis unlikely Increased AST:ALT/high AST No comment Suggest investigations for malignancy Suggest urine Hb/haemosiderin ?Hypothyroidism ?Liver disease ?Type of valve Isoenzymes not indicated Not iron deficiency anaemia Suggest Schumm test Not due to liver disease or haemolysis Due to aspirin therapy Suggest C-reactive protein Case 8-08 Enzymes Patient ID 16-month-old male Patient Location General Practice Clinical Notes on Request Form Post upper respiratory tract infection Case Details Serum Sodium Potassium Chloride Bicarbonate Urea Creatinine Glucose, random Protein Albumin Globulin T Bilirubin ALP AST ALT GGT LDH 144 mmol/L 4.5 mmol/L 109 mmol/L 19 mmol/L 4.8 mmol/L <20 µmol/L 4.7 mmol/L 63 g/L 38 g/L 25 g/L 3 µmol/L 5150 U/L 29 U/L 14 U/L <5 U/L 294 U/L (135–145) (3.5–5.0) (97–107) (20–28) (1.8–7.5) (30–70) (3.6–7.7) (60–75) (35–50) (15–25) (3–20) (60–300) (25–80) (5–40) (5–65) (100–405) Suggested Comment In the absence of liver or bone disease the isolated marked elevation of the alkaline phosphatise (ALP) in this child makes the diagnosis of benign transient hyperphosphatasaemia of infancy and childhood likely. Suggest ALP isoenzyme testing and repeat ALP in 2–3 months. Rationale The clinical history of an isolated marked elevation of alkaline phosphatise (ALP) in a young child after a viral infection makes the diagnosis of benign transient hyperphosphatasaemia (BTH) of infancy and childhood likely. The occurrence of BTH is not rare, and is mainly seen in winter. Most patients with BTH present during the first year of life. It is associated with a wide variety of clinical disorders, including gastrointestinal diseases, respiratory infections, congenital anomalies/inborn errors of metabolism, anaemia, and malignancies. The differential diagnosis includes liver (such as biliary obstruction, and liver disease associated with malignancy) and bone diseases (such as juvenile Paget’s disease or rickets). In patients with BTH, ALPisoenzyme electrophoresis shows increases in bone and liver ALP and ALP typically returns to normal in 2–3 months. In the Australian setting, it was seen in a third of children with increased ALP >1000 U/L in a tertiarycare teaching hospital. In the community setting the likelihood of BTH of infancy would be much higher. References 1. Stein P, Rosalki SB, Foo AY, et al. Transient hyperphosphatasemia of infancy and early childhood: clinical and biochemical features of 21 cases and literature review. Clin Chem 1987;33:313-8. 2. Behúlová D, Bzdúch V, Holesová D, et al. Transient hyperphosphatasemia of infancy and childhood: study of 194 cases. Clin Chem 2000;46:1868-9. 3. Carroll AJ, Coakley JC. Transient hyperphosphatasaemia: an important condition to recognize. J Paediatr Child Health 2001;37:359-62. PREFERRED KEY WORDS Isolated increased ALP ?Benign transient hyperphosphatasaemia of infancy (BTHI) BTHI seen in young children BTHI often post infection Expect normal ALP <3 months Expect normal ALP in 3–6 months Resolves spontaneously ?Familial hyperphosphatasaemia ?Bone disease excluded ?Liver disease excluded Consider vitamin D deficiency Suggest repeat ALP ≤3 months Suggest ALP isoenzymes Monitor ALP Suggest follow-up Consider rickets LESS RELEVANT KEY WORDS Suggest calcium/phosphate Suggest clinical evaluation Other liver function tests normal Suggest vitamin D/PTH Likely bone origin Repeat ALP 3–6 months Low creatinine ?ALP due to viral illness Repeat ALP Mild metabolic acidosis Creatinine consistent with low muscle mass Suggest screen family members ?Healing fracture No further investigation required Consult with Chemical Pathologist Suggest consult specialist Repeat liver function tests ?Malnutrition ?Renal disease Marginally low bicarbonate Elevated chloride ?GGT artefactual UNACCEPTABLE KEY WORDS ?Malignancy Not hepatic origin Suggest magnesium ?Paget’s disease ?Medication-induced Repeat GGT ?Creatinine interference, suggest repeat Suggest bone turnover marker Suggest CT/X-ray ?Chronic respiratory alkalosis Consider hyperparathyroidism Likely leukocyte origin Suggest white cell count/diff ?Osteomyelitis Suggest liver ultrasound Reye’s syndrome unlikely Repeat full blood count Suggest urinalysis Suggest blood gases Suggest serology testing Intestinal origin May be due to growth spurt Consider bone scan Case 9-01 Enzymes Patient ID 61-year-old male Patient Location Emergency Department Clinical Notes on Request Form Abdominal pain. Case Details Serum lipase 5169 IU/L (13–60) Additional Information Serum Protein 77 g/L Albumin 42 g/L T Bilirubin 27 µmol/L ALP 131 U/L GGT 362 U/L ALT 46 U/L Adjusted Ca 3.19 mmol/L Glucose 19.2 mmol/L (65–85) (34–47) (<22) (30–120) (10–71) (5–40) (2.10–2.60) (3.0–7.7) Suggested Comment Marked elevation of lipase together with abdominal pain is likely caused by acute pancreatitis. A C-reactive protein concentration might provide prognostic information. Hyperglycaemia early in the course of the pancreatitis may resolve. The main causes of pancreatitis are gallstones and alcohol; hypercalcaemia is rarely the cause of acute pancreatitis and needs to be further investigated. Rationale Marked elevation of lipase together with abdominal pain is likely caused by acute pancreatitis. A lipase of >3 times the upper reference limit has a diagnostic specificity of about 98% for pancreatitis. The magnitude of lipase elevation is a poor prognostic indicator. Severity of the pancreatitis can be assessed using a number of scoring systems, the most popular being the APACHE II. An APACHE II score of ≥8 is associated with significant mortality risk. A CRP concentration >150 mg/L provides further prognostic information. Hyperglycaemia early in the course of the pancreatitis may be due to acute pancreatic dysfunction. Later, it is a marker for disease severity. The main causes of pancreatitis are gallstones and alcohol; hypercalcaemia is rarely the cause of acute pancreatitis and needs further investigations. While hypercalcaemia increases the risk for pancreatitis, additional gene mutations might contribute to the absolute risk. The elevated GGT is not helpful in diagnosing alcoholic pancreatitis with an AUC of 0.51 for this purpose (3). The ALT is not elevated enough to indicate a gallstone aetiology (4). Of note, the diagnosis of diabetes mellitus using random fasting glucose requires 1) glucose of ≥11.0 mmol/L, and 2) classical symptoms of hyperglycaemia or hyperglycaemic crisis. The diagnosis of diabetes mellitus should not be made in a patient who is systematically ill. References 1. Lankisch PG, Burchard-Reckert S, Lehnick D. Underestimation of acute pancreatitis: patients with only a small increase in amylase/lipase levels can also have or develop severe acute pancreatitis. Gut 1999;44:542-4. 2. Working Party of the British Society of Gastroenterology, et al. UK guidelines for the management of acute pancreatitis. Gut 2005;54:iii1-9. 3. Methuen T, Kylänpää L, Kekäläinen O, et al. Disialotransferrin, determined by capillary electrophoresis, is an accurate biomarker for alcoholic cause of acute pancreatitis. Pancreas 2007;34:405-9. 4. Tenner S, Dubner H, Steinberg W. Predicting gallstone pancreatitis with laboratory parameters: a metaanalysis. Am J Gastroenterol 1994;89:1863-6. 5. Felderbauer P, Karakas E, Fendrich V, et al. Pancreatitis risk in primary hyperparathyroidism: relation to mutations in the SPINK1 trypsin inhibitor (N34S) and the cystic fibrosis gene. Am J Gastroenterol 2008;103:368-74. PREFERRED KEY WORDS Significantly elevated lipase Consistent with acute pancreatitis ?Secondary to alcohol Hypercalcaemia may cause pancreatitis Glucose - endocrine pancreatic dysfunction ?Hyperparathyroidism Suggest PTH Investigate raised calcium Suggest fasting lipids Hypertriglyceridaemia may cause pancreatitis ?Secondary to gallstones Suggest CRP LESS RELEVANT KEY WORDS Hypercalcaemia noted ?Cholestatic/biliary disease Hyperglycaemia Elevated GGT Hyperglycaemia due to stress/inflammation Liver function tests abnormalities Suggest fasting plasma glucose/GTT post resolution Suggest renal function tests, eGFR Diabetes mellitus not excluded Suggest radiology chest/abdomen ?Chronic pancreatitis ?Drugs Suggest full blood examination, LDH Acute on chronic pancreatitis Suggest phosphate Suggest ionised calcium Repeat calcium Liver function tests and plasma glucose secondary to pancreatitis ?Diabetic ketoacidosis ?Calcium infusion therapy Liver function tests suggest hepatobiliary disease Suggest blood gases for acidaemia Exclude renal failure No evidence lipaemia Repeat liver function tests Calcium lower after first day ?Antacids cause hypercalcaemia Possible acute pancreatitis UNACCEPTABLE KEY WORDS Suggest amylase (lipase:amylase) ?Malignancy in pancreas Pancreatitis may cause hypercalcaemia ?Diabetic nephropathy Suggest vitamin D ?Raised calcium due to dehydration ?Pseudohyperparathyroidism Suggest urinary albumin, protein ?Pancreatic glucagonoma Liver function tests suggest hepatocellular disease Myeloma excluded Glucose suggests diabetes Malignancy causing hypercalcaemia Case 12-01 Enzymes Patient ID 47-year-old female Patient Location General Practice Clinical Notes on Request Form Previously raised CK, 5 months ago. Case Details CK 242 U/L LD 220 U/L (<150) (110–230) Additional Information Albumin 42 g/L Globulins 35 g/L Protein 77 g/L Total bilirubin 11 µmol/L GGT 13 U/L ALP 41 U/L ALT 30 U/L AST 33 U/L (34–48) (21–41) (65–85) (2–24) (<60) (30–110) (<55) (<45) 5 months earlier: CK 465 U/L LD 246 U/L (<150) (110–230) Suggested Comment Persistent mild elevation in creatine kinase (CK) suggests muscle damage, probably of skeletal origin. Troponin, which is a more specific marker for cardiac muscle injury may be considered, if clinically suspected. Possible causes of a raised CK of this level include medications (especially statins), hypothyroidism, exercise, myositis, or metabolic conditions. Macro-CK may produce this pattern and should be screened for if other causes cannot be identified. Recommend TSH and review of medication initially. Rationale Mildly (<10× upper reference limit) raised creatine kinase (CK) is a common laboratory finding. Most of these normalise upon repeat testing, after asking the patient to refrain from exercise and alcohol consumption. Up to 11% of patients on statins have CK in this range; CK increase is dose-dependent and may be exacerbated by exercise or other medications. To meet prescribing criteria for a statin, patients should have an increased risk of cardiac disease, so it is not possible to rule out an acute coronary syndrome (ACS) in the absence of clinical notes. It is important to exclude common clinical problems such as ACS, medication or hypothyroidism before recommending more extensive investigations such as testing for macro-CK or muscle biopsy. Nonetheless, a considerable number of patients with persistently elevated CK have subclinical neuromuscular pathology demonstrable on histology or electromyography, although most of these conditions are benign. References 1. Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002;249:305-11. 2. Dabby R, Sadeh M, Herman O, et al. Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates. Isr Med Assoc J 2006;8:110-3. PREFERRED KEY WORDS Persistent elevation of CK Skeletal muscle origin cannot be excluded ?Skeletal muscle origin ?Skeletal myopathies ?Myositis ?Myopathy ?Muscle trauma/injury/surgery Exclude statins Exclude exercise/excess/?athlete Exclude hypothyroidism Review medication, ?drug associated Exclude thyroid abnormalities/suggest thyroid function tests LESS RELEVANT KEY WORDS Consider macro-CK Suggest CK isoenzymes-electrophoresis Exclude cardiac source Elevated CK Normal AST/LD Isolated CK elevation Check medical history ?Clinical features of muscle disorder Exclude alcohol excess Mild elevation of CK ?Muscular dystrophy carrier Exclude inflammation/infection Normal liver function tests Moderately elevated CK Suggest ANA/exclude systemic lupus erythematosus ?Kidney disease/renal function ?Metabolic myopathy Suggest electrolytes, ?hypokalaemia Suggests non-cardiac source Suggest complete blood picture/ESR/film Suggest monitor CK ?Family history of muscular dystrophy Suggest calcium/phosphate ?Clinically consistent - phone to discuss Myocardial injury unlikely Suggests muscle origin ?Polymyalgia rheumatica ?Periodic paralysis Suggest transaminase assay Elevated CK consistent with muscle damage Check occupational history Consider forearm ischaemic test Suggests non-skeletal muscle origin NOT SUPPORTED KEY WORDS ?Intramuscular injection ?Muscular dystrophy ?Rhabdomyolysis/suggest myoglobin Suggest cortisol ?Seizures ?Brain origin ?Malignancy e.g. colon, kidney No comment and/or CK <1000 U/L Suggest specialist referral ?Rheumatoid arthritis ?Guillain-Barre syndrome Suggest DNA genetic markers Suggest fasting lipid screen Suggest vitamin D Exclude malignant hyperthermia ?Neuroleptic malignant syndrome ?Coeliac disease MISLEADING KEY WORDS Consider muscle biopsy Suggest electromyography Exclude diabetic ketoacidosis/suggest blood glucose Suggest metabolic bone studies Case 13-02 Enzymes Patient ID 48-year-old male Patient Location General Practice Clinical Notes on Request Form Chronic alcoholic Case Details Amylase Lipase 1530 U/L 49 U/L (<100) (<60) Additional Information Renal and liver function tests requested. Elevated GGT, otherwise no abnormalities. Suggested Comment Elevated serum amylase with normal lipase. This may be due to an extra-pancreatic source of amylase such as parotid disease, which can be clarified by measurement of pancreatic and salivary amylase. Macroamylase should also be considered. If parotid inflammation is not present clinically then exclusion of macroamylase by measurement of urine amylase or other technique is recommended. Rationale Amylase and lipase are both elevated in cases of pancreatitis, although amylase tends to rise and fall sooner than lipase. In alcoholic patients, lipase has a higher clinical sensitivity for pancreatitis than amylase. Serum amylase is made up of two main types. The P-type amylase comes from the pancreas while the S-type amylase comes from the salivary glands. Causes of elevated amylase without elevation of lipase include secretion from other organs such as salivary glands, fallopian tubes and cyst fluid, gastrointestinal tract, testes, lungs, thyroid, tonsils, and some malignant neoplasms. Of note, acute pancreatitis secondary to hypertriglyceridaemia may not be associated with elevations in serum amylase. The laboratory can contribute to the management of this patient by excluding the presence of macroamylase, which are amylase enzymes with autoantibodies attached to them. This may be performed by measuring urine amylase (normal in macroamylase due to size exclusion by glomerulus, and elevated in other causes), polyethylene glycol (PEG) precipitation or other separative methods. Pancreatic amylase can be measured, and when it is not elevated, confirms an extra-pancreatic source. In this patient the pancreatic amylase was within normal limits, and was consistent with parotitis as the source of elevated amylase. Reference 1. Harper SJ, Cheslyn-Curtis S. Acute pancreatitis. Ann Clin Biochem 2011;48:23-37. PREFERRED KEY WORDS Elevated amylase with normal lipase Pancreatitis unlikely Consistent with non-gastrointestinal cause ?Macroamylasaemia ?Alcohol related salivary amylase ?Salivary amylase ?Parotiditis ?Acute abdominal condition Suggest amylase isoenzymes Suggest amylase clearance ratio (ACCR) Suggest urine amylase Suggest pancreatic amylase Suggest PEG precipitation or gel filtration LESS RELEVANT KEY WORDS ?Clinical symptoms Suggest repeat testing Suggest imaging ?Active biliary disease May be seen in acute pancreatitis Results phoned Consistent with chronic alcoholism ?Pancreatic pseudocyst NOT SUPPORTED KEY WORDS ?Neoplastic disease Increased GGT consistent with clinical notes ?Renal failure ?Anti-epileptic medication Suggest lipid studies ?Alcoholic pancreatitis ?Pancreatitis ?Heterophile antibodies ?Head injury/stroke ?Diabetic ketoacidosis Lipase inhibited by bile acids ?Alcohol intoxication Result not phoned Suggest protein electrophoresis Consistent with chronic pancreatitis Suggest reanalysis on different instrument Case 14-07 Enzymes Patient ID 46-year-old female Patient Location Pre-admission outpatient clinic Clinical Notes on Request Form Awaiting elective surgery for cholecystectomy. Family history of prolonged post-surgical apnoea. Case Details Total Bilirubin 32 µmol/L Albumin 37 g/L Total Protein 62 g/L GGT 158 U/L ALT 65 U/L AST 71 U/L Butyryl-cholinesterase 5 kU/L (<21) (38–48) (62–80) (<35) (5–55) (5–55) (6–14) Additional Information Further inquiry reveals that the family history consisted of a brother who required prolonged ventilation after receiving an anaesthetic that included suxamethonium. Suggested Comment The family history raises the possibility of hereditary butyryl-cholinesterase deficiency. This should be investigated further by genotyping. Phenotyping of the enzyme with inhibitors such as fluoride and dibucaine is being phased out because it is less reliable. The possibility of prolonged post-anaesthetic apnoea should be communicated to the surgical and anaesthetic team. The increase in serum bilirubin, aminotransferases and glutamyltransferase is consistent with causes of liver dysfunction including cholelithiasis. Borderline reduction in serum albumin and total protein is consistent with mild impairment of hepatic synthetic capacity, so measurement of international normalised ratio (INR) is suggested. Cholelithiasis alone is insufficient explanation for the observed reduction in the activity of butyryl-cholinesterase, but other causes of reduced hepatic synthesis can cause this degree on butyryl-cholinesterase reduction. Rationale Butyryl-cholinesterase (pseudocholinesterase) is an enzyme produced by the liver, circulating in the plasma. Its activity is a sensitive marker of hepatic synthetic capacity. It is also a specific indicator of the adequacy of the enzyme that is required for the catabolism of a number of xenobiotic compounds, including suxamethonium. Suxamethonium, or succinylcholine, is a nicotinic acetylcholine receptor agonist commonly used to induce muscle relaxation before intubation in anaesthesia. In normal individuals, approximately 90–95% of an intravenous dose of suxamethonium is metabolised by circulating plasma butyryl-cholinesterase before reaching the neuromuscular junction. Deficiency of this enzyme can result in high concentration of suxamethonium reaching the neuromuscular junction. This causes prolonged paralysis of up to 8 hours. The activity of the enzyme in the plasma is inhibited by organophosphate insecticide toxicity. Conditions such as uncomplicated cholelithiasis, cholestasis or mild cirrhosis rarely diminish its activity. Butyryl-cholinesterase can decline following major acute illnesses and in malnutrition, or when hepatic synthesis declines in the face of acute hepatitis, cirrhosis or hepatic metastasis. Less severe decline can occur in the presence of muscular dystrophy, chronic renal disease and pregnancy. The family history raises the possibility of hereditary butyryl-cholinesterase deficiency, which should be investigated further by genotyping because phenotyping of the enzyme with inhibitors such as fluoride and dibucaine fails to fully characterise the presence and pattern of hereditary enzyme deficiency. Reference 1. Yen T, Nightingale BN, Burns JC, et al. Butyrylcholinesterase (BCHE) genotyping for postsuccinylcholine apnea in an Australian population. Clin Chem 2003;49:1297-308. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Low cholinesterase level/ activity Borderline butyryl-cholinesterase deficiency Family history of suxamethonium apnoea Inherited suxamethonium apnoea ?Risk of post suxamethonium/scoline apnoea Avoid suxamethonium/ mivacurium/ succinylcholine Notify anaesthetist/surgeon ?Pseudocholinesterase deficiency Cholestasis/biliary obstruction Suggest family genotyping Suggest repeat butyryl-cholinesterase when liver function tests normal Suggest screening of relatives Suggest genotyping on brother Suggest phenotyping and genotyping Suggest genotyping Suggest screening of relatives Suggest cholinesterase genotyping Suggest phenotyping OR genotyping Avoid curare-derived drugs Mild impairment hepatic synthetic capacity Suggest INR/PT ?Malnutrition Need pre-op review by surgical team ?Low cholinesterase due to liver disease Raised serum bilirubin, AST and GGT Suggest phenotyping Borderline low cholinesterase Hypoalbuminaemia ?Biliary stones/ cholelithiasis Suggest ALP, bilirubin, AST, GGT and lipase ?Renal disease Consider drug/alcohol Hepatocellular damage ?Acquired cholinesterase deficiency ?Genetic variant ?Exposure to organophosphates Suggest urea, electrolytes, creatinine Suggest genotyping if required ?Possible suxamethonium/ succinylcholine sensitivity Suggest medical warning card ?Chronic/acute hepatitis Abnormal cholinesterase phenotype ?Alcoholic liver disease Suggest full blood count Suggest repeat liver function tests post op ?Hypothyroidism Suggest repeat cholinesterase Inhibition test maybe inconclusive NOT SUPPORTED KEY WORDS ?Uraemia Steatohepatitis Autoimmune/viral hepatitis ?Diabetes Suggest ultrasound ?Liver cirrhosis ?Oestrogen therapy Low cholinesterase can’t be due to liver disease Consistent with cholecystitis MISLEADING KEY WORDS Suggest renal function test ?Collagen disease Case 14-09 Cardiac Patient ID 63-year-old female Patient Location Emergency Department Clinical Notes on Request Form Chest pain since morning. To exclude acute myocardial infarction. Case Details Troponin I Collection Time 11:30pm Result <2 ng/L Reference Interval <16 ng/L Additional Information Past medical history: nil of note. ECG, urea, electrolytes and creatinine and full blood examination normal. Troponin performed on Abbott Architect by hs-TnI assay; 10% CV at 6 ng/L. Suggested Comment An undetectable troponin measured with a high sensitivity assay more than 6 hours after onset of chest pain in the absence of clinical and/or electrocardiogram (ECG) evidence would indicate a low probability of acute myocardial infarction (AMI). Suggest repeat measurement in 2–3 hours if clinically indicated. Rationale The third universal definition of acute myocardial infarction (AMI) requires the detection of a rise and/or fall of a cardiac biomarker above the 99th percentile of a reference population (15 ng/L in this case) together with evidence of ischaemia (clinical symptoms, electrocardiogram changes or imaging evidence for loss of viable myocardium). The major advantage of high sensitivity-cardiac troponin (hs-Tn) assays is to allow the earlier exclusion of AMI in emergency departments in low risk patients presenting with chest pain. Diagnostic sensitivity approaching 100% may be achieved by measuring a second sample within three hours of presentation and 6 hours of onset of pain. An accelerated diagnostic protocol suggests that a TIMI (thrombolysis in myocardial infarction) score of ≤1, a normal ECG and troponin at 0- and 2-hours in patients presenting <12 hours after onset of pain will safely rule out an AMI. Whilst an undetectable hs-cTnT at presentation has very high negative predictive value, which may be considered to rule out AMI in low risk patients, this has not been shown with hs-cTnI assays. Ultimately, the decision for repeat measurement/s has to be guided by clinical presentation. The actual infarction (luminal occlusion) may occur at any stage from symptom onset. Hence, if this occurred just prior to presentation (which may have prompted the late presentation), then a single sample at presentation may miss the rise in troponin. References 1. Cullen L, Mueller C, Parsonage WA, et al. Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome. J Am Coll Cardiol 2013;62:1242-9. 2. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol 2011;58:1332-9. 3. Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252-7. PREFERRED KEY WORDS No rise in TnI 12 h post chest pain Result positive if ≥16 ng/L TnI not elevated within 6 h of symptoms Low probability of AMI Acute myocardial infarction (AMI) unlikely Myocardial injury is unlikely Exclude AMI If TIMI score 0 or 1 repeat at 2 h Suggest repeat 2–3 h post sample collect Suggest TnI 2–3 h post presentation Suggest repeat TnI in 2 h Suggest repeat TnI after 3 h Suggest repeat hs-TnI after 3 h Suggest repeat 4 h post first sample Suggest repeat troponin I (TnI) in 3–6 h Clinical correlation recommended Exclude other causes for chest pain Rise and/or fall required for diagnosis If repeat normal, AMI unlikely For MI TnI >upper reference limit (URL) at 3 or 6 h and >50% change Exclude stable coronary ischaemia LESS RELEVANT KEY WORDS Normal TnI Results provided exclude AMI Normal ECG Suggest repeat 6–8 h post chest pain ?Pulmonary infection/inflammation Results do not exclude AMI Suggest repeat ECG Suggest lipid profile Suggest repeat TnI at 3 and 6 h Confirm non-ST elevation myocardial infarction (NSTEMI; rise TnI >50% URL) ?Clinical suspicion Follow local guidelines 50% increase in TnI suggests cardiac Exclude pericarditis Result negative if <16 ng/L and change <50% Exclude other acute coronary syndrome Suggest serial 6 h TnI, CK or myoglobin ?Heterophilic Ab on original TnI Suggest re-run sample-use different method Suggest further investigations for unstable angina Suggest observe patient Suggest repeat testing at 9–12hrs ?>30% rise at 4 h post first sample Suggest D-Dimer ?Aortic aneurysm ?Chest/lung pathology Suggest BNP/NT-proBNP Suggest exercise tolerance testing ?Stress Tn may take ≥6 h to rise post pain A <30% delta Tn is less likely AMI ?Pulmonary embolism NOT SUPPORTED KEY WORDS Exact time of chest pain not given ?Digestive disorder Suggest repeat with TnT assay within 24 h ?Musculoskeletal chest pain Repeat TnI not indicated Reference interval should be <6 ng/L ?Breast pathology Suggest thoracic scan Falsely low TnI with high Hb concentration Suggest creatine kinase (CK)/CK-MB Suggest liver function tests/creatinine Suggest C-reactive protein Suggest microbial cultures Case 12-06 Proteins Patient ID 50-year-old female Patient Location General Practice Clinical Notes on Request Form Back pain Case Details Serum Protein Electrophoresis: IgG (kappa) monoclonal band detected. Quantification: 3 g/L Additional Information IgG 7.3 g/L IgA 0.8 g/L IgM 0.6 g/L (6.5–14.5) (0.7–3.5) (0.6–2.6) X-ray of spine, full blood count, ESR and liver function tests are unremarkable. Suggested Comment Small IgG (kappa) band with probable mild immune paresis is of uncertain significance at this time. Recommend first morning urine for electrophoresis and serum free light chains measurement. Serum calcium, renal function tests and skeletal survey should also be done for completeness. While monoclonal gammopathy of undetermined significance (MGUS) is likely, clinical consideration of oligosecretory conditions e.g. amyloid is important. Suggest review of serum and urine by electrophoresis initially in 3 to 6 months. Rationale The small band size, heavy chain type IgG and the lack of anaemia, and normal x-ray of the spine all point to MGUS. Mild immune-paresis is not incompatible with this diagnosis, nor is the presence of free light chains in urine were these to be found. The diagnosis of MGUS can only be made when serum monoclonal protein is <30 g/L, clonal bone marrow plasma cells <10% (if performed) and there is absence of hypercalcaemia, renal impairment, anaemia and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder. Therefore, serum calcium, renal function tests and skeletal survey are required. Smouldering multiple myeloma is defined by serum monoclonal protein ≥30 g/L and/or ≥10 to <60 percent bone marrow clonal plasma cells and absence of CRAB complications. While the overall progression rate to myeloma is 1% per year, the monoclonal band size is the most potent predictor for progression and this band is very small. IgG band types are also less likely to progress than IgA or IgM types. While bone marrow biopsy is part of the classification, this is probably unnecessary at this band size unless CRAB are positive, in which case the diagnosis is myeloma regardless of band size. Small monoclonal bands can sometimes be associated with other lymphoproliferative disease. Of these, systemic Amyloid Light-chain (AL) amyloidosis is often diagnosed late; clinical suspicion and serum free light chains are important for timely diagnosis. On available data, this patient appears to be at low risk for progression; however, indefinite follow up is essential. A short repeat time is prudent in the first instance and initial check periods of up to 6 months are suggested in various guidelines. References 1. Mollee P. Current trends in the diagnosis, therapy and monitoring of the monoclonal gammopathies. Clin Biochem Rev 2009;30:93-103. 2. Cook L, Macdonald DH. Management of paraproteinaemia. Postgrad Med J 2007;83:217-23. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Small monoclonal band ?significance Borderline immuneparesis of immunoglobulins Low normal IgG, IgA, IgM ?Suppression of polyclonal immunoglobulin No signs of bone marrow failure ?MGUS ?Primary lymphoproliferative disorder ?AL amyloidosis Results suggest MGUS Multiple myeloma unlikely Exclude multiple myeloma Suggest urine Bence Jones Protein/urine protein electrophoresis Suggest serum creatinine, urea & creatinine Suggest serum calcium/phosphate levels Suggest serum free light chains (FLC ratio) Suggest follow up testing Suggest skeletal survey/?lytic lesions Suggest urine immunofixation electrophoresis Continue to monitor ?progression Clinical correlation required Use same lab for consistency Suggest regular clinical review Suggest beta-2-microglobulin Suggest serum electrophoresis/immunofixation Suggest urine protein/albumin excretion ?History of auto-immune disease e.g. rheumatoid arthritis Monoclonal band - benign paraprotein ?Type of clonal gammopathy IgG discrepancy due to monoclonal protein Back pain common in multiple myeloma Elevated risk of progression to multiple myeloma NOT SUPPORTED KEY WORDS Suggest bone marrow biopsy Suggest liver function tests Suggest complete blood count/ESR Suggest CRP Suggest urine microscopy, culture and sensitivity testing Exclude nephropathy/urinary tract infection Referral to Haematologist ?Multiple myeloma No immuneparesis ?Smouldering multiple myeloma ?Inflammation/infection ?Solitary plasmacytoma Suggest phenotype of plasma cells MISLEADING KEY WORDS MGUS unlikely No evidence suggestive of B cell lymphoma Results suggest polyclonal globulins raised No comment on these results ?Macroglobulinaemia Exclude free light chains only myeloma ?Waldenstrom’s macroglobulinaemia Case 13-04 Proteins Patient ID 39-year-old woman Patient Location General Practice Clinical Notes on Request Form 34 weeks gestation. Hypertension. Case Details Protein 47 g/L Albumin 18 g/L Total bilirubin 5 µmol/L ALP 113 U/L ALT 6 U/L GGT <5 U/L Uric acid 0.50 mmol/L (64–83) (36–46) (<20) (35–105) (<33) (<38) (0.14–0.34) Suggested Comment The presence of hypertension beyond 20 weeks gestation increases the risk of pre-eclampsia, which also requires evidence of end organ or foetal involvement. Although hyperuricaemia is common in this disorder, it is not diagnostic. The significant hypoproteinaemia may indicate proteinuria and should be investigated with a urinary protein:creatinine ratio. Full blood examination and ultrasound assessment of the pregnancy are also suggested but should not delay urgent clinical review in a hospital setting. Rationale Pre-eclampsia is a multi-system disorder characterised by hypertension and the involvement of one or more organ systems and/or the foetus. Complications may include renal and liver impairment; haematological manifestations of haemolysis or disseminated intravascular coagulation; seizure and other neurological disturbances; pulmonary oedema; foetal growth restriction and placental abruption. The condition can arise de novo or be superimposed on chronic or gestational hypertension. Findings such as hyperuricaemia and oedema, while common in this disorder, are not diagnostic features. Similarly, proteinuria is frequently seen but not required for diagnosis. Urgent clinical assessment is essential as management is influenced by severity of hypertension and clinical findings in mother and foetus. Although some women will be managed as an outpatient, initial assessment should be performed as an inpatient. In the long term, women with history of pre-eclampsia or gestational hypertension are at increased cardiovascular morbidity. References 1. Brown MA, Lowe SA. Current management of pre-eclampsia. Med J Aust 2009;190:3-4. 2. Society of Obstetric Medicine of Australia and New Zealand. Guidelines for the management of hypertensive disorders of pregnancy 2008. http://www.somanz.org/pdfs/somanz_guidelines_2008.pdf PREFERRED KEY WORDS Hypoproteinaemia Hypoalbuminaemia Hypertension associated with gestation ?Pre-eclampsia ?Proteinuria ?Renal loss Suggest spot urine protein/albumin/ creatinine Suggest complete blood examinations including platelet count Suggest 24h urine protein/albumin/ creatinine Suggest urine protein Suggest urgent specialist referral Suggest clinical review/monitor Suggest ultrasound/foetal assessment Phone GP LESS RELEVANT KEY WORDS Hyperuricaemia ALP consistent with gestation Hypertension Hospital (emergency) admission Suggest coagulation profile Review to pregnancy reference intervals Monitor renal function tests ?Nephrotic syndrome Monitor blood pressure Monitor haemolysis Monitor liver function test and lactate dehydrogenase ?HELLP syndrome Gestational related oedema ?Protein loss Significant abnormal results Monitor platelets Risk of early delivery Raised ALT in preeclampsia ?Early onset preeclampsia Quantification of proteinuria ?Perinatal risk Exclude HELLP Pre-eclampsia depends on level of blood pressure and total protein Results consistent with gestational proteinuric hypertension/pre-eclampsia ?Hypertension nephropathy NOT SUPPORTED KEY WORDS Monitor oedema Monitor urine output Oliguria Suggest free T4 and TSH Suggest repeat sample Suggest Doppler blood flow studies Urine microscopy hyaline/granular casts Monitor proteinuria MISLEADING KEY WORDS Protein and albumin consistent with gestation Liver function tests normal for gestation Case 6-07 Lipids Patient ID 43-year-old male Patient Location General Practice Clinical Notes on Request Form Nausea and vomiting Case Details Total Cholesterol Triglyceride 13.5 mmol/L (<5.5) 38.5 mmol/L (<1.7) Additional Information Albumin Bilirubin Alk. Phosphatase ALT 26 g/L 60 µmol/L 254 U/L 300 U/L (35–50) (<20) (35–135) (<40) Suggested Comment Marked hypertriglyceridaemia and hypercholesterolaemia in a setting of abnormal liver function tests. Suggest exclude secondary causes such as diabetes, alcohol abuse and obesity. There is an increased risk of pancreatitis due to high triglyceride concentrations. Suggest measure lipase or amylase levels. Rationale Lipid disorders can occur as either a primary event or secondary to some underlying disease. Severe hypertriglyceridaemia may be due to the rare (<1 in a million) disorder lipoprotein lipase deficiency. Other rare genetic conditions with a similar presentation include apoC-II and apoA-V deficiency (1). Secondary causes of severe hypertriglyceridaemia are more common. They are often due to a combined genetic defect and an acquired condition resulting in an overproduction and delayed clearance of triglyceriderich lipoproteins. Such acquired conditions include diabetes mellitus, alcohol abuse and obesity. The abnormal liver function tests in this case suggest liver disease secondary to alcohol abuse is a likely cause. Evidence suggests when triglyceride concentrations are >11 mmol/L, there is an increased risk of chylomicron-induced pancreatitis and therefore either an amylase or lipase test should be performed (2). Of note, hypothyroidism, nephrotic syndrome, dysgammaglobulinaemia, cholestatic disorders of the liver, anabolic steroids and protease inhibitor for HIV treatment are associated with elevated total cholesterol and LDL. On the other hand, elevated triglycerides and VLDL may be due to underlying chronic renal failure, type 2 diabetes mellitus, obesity, excessive alcohol intake and hypothyroidism, oestrogen and corticosteroid (endogenous or exogenous) effects. References 1. Viljoen A, Wierzbicki AS. Diagnosis and treatment of severe hypertriglyceridemia. Expert Rev Cardiovasc Ther 2012;10:505-14. 2. Ferns G, Keti V, Griffin B. Investigation and management of hypertriglyceridaemia. J Clin Pathol 2008;61:1174-83. PREFERRED KEY WORDS Marked hypertriglyceridaemia Marked hyperlipidaemia Abnormal liver function tests ?Secondary hyperlipidaemia ?Ethanol Exclude pancreatitis Exclude diabetes/suggest glucose Suggest lipase/amylase ?Clinical history Phone GP to discuss results LESS RELEVANT KEY WORDS Liver disease Hypercholesterolaemia ?Familial/primary hyperlipidaemia ?Obstructive liver disease ?Hepatitis/toxin Cholestasis Suggest lipoprotein electrophoresis /ApoE genotype Urgent refer Suggest hepatitis serology Acute pancreatitis Suggest INR/coagulation studies Pathologist review ?Chronic liver disease Suggest viral serology ?Acute illness No comment UNACCEPTABLE KEY WORDS Repeat on fasting sample Suggest other liver function tests Suggest TSH/thyroid function tests Suggest electrolytes/renal function tests Suggest HDL/LDL/apolipoproteins Lipaemic sample - interference Excess VLDL and ?chylomicrons Suggest stat urine protein ?Fatty liver Elevated risk of coronary disease Suggest dietary/medication treatment Urgent hepatic ultrasound ?Obesity/metabolic syndrome Suggest liver biopsy Repeat tests 6–8 weeks Suggest full blood examination Suggest immunoglobulin quantitation Suggest calcium Suggest ammonia/lactate/blood gases Moderate cholesterolaemia Suggest lipowash/ultracentrifugation Suggest CK/troponinI/ ECG ?Hepatoma Suggest anti mitochondrial antibody ?Cushing’s disease/suggest cortisol Case 7-08 Lipids Patient ID 33-year-old female Patient Location General Practice Clinical Notes on Request Form Check-up Case Details Plasma lipids (patient was fasting) Cholesterol 6.0 mmol/L Triglyceride 0.5 mmol/L HDL-cholesterol 3.7 mmol/L LDL-cholesterol 2.1 mmol/L Additional Information Cholesterol Triglyceride HDL-cholesterol LDL-cholesterol Desirable Target <5.5 <2.0 >1.0 <3.0 NHF Target <4.0 <1.5 >1.0 <2.0 Suggested Comment The increased total cholesterol is due to the increased HDL-C, which is usually considered to be cardioprotective, although not necessarily in all cases. The LDL-C is within the desirable target. Oestrogen therapy, alcohol intake, and genetic causes may be contributory factors. Suggest review in context of absolute cardiovascular risk status. Rationale The reason for the ‘check-up’ in this patient is not stated in the request. Lipid screening is not indicated in a healthy 33-year-old woman unless she belongs to a high-risk group that includes patients with diabetes mellitus, previous personal/family history of atherosclerotic disorders, smoking history, hypertension and obesity (1). Cardiovascular risk management should be based on absolute risk assessment of the patient. Thus knowledge of the presence or absence of evidence of atherosclerosis or other risk factors is important in advising action on lipid results. HDL is more tightly controlled by genetic factors (which determine 40–50% of the variation) than for the other lipoproteins. In general, plasma HDL concentration is inversely correlated with the prevalence and mortality rates for coronary heart disease. However, emerging evidence suggests that HDL are heterogeneous particles and their quality (functional or physical subclasses), rather than simply absolute concentration, may be more important in their cardioprotective effects. Environmental factors causing a high HDL-C include oral oestrogen therapy (by ~20%), alcohol consumption (by ~0.1 mmol/L) and extensive aerobic exercise (by 3–9%). Oestrogens, depending on the type, dose and route of administration, increase synthesis of the principal apoprotein of HDL, apoA-I. In general, progestagens oppose these effects according to type and dose. Fibrates increase HDL-C by 10–25%, statins by 5–15%, and niacin by 20–35%. The rare genetic deficiency of CETP is associated with a high HDL, especially in the Japanese; others include apoA-I mutations. The HDL concentration in this case may be due to genetic and environmental factors including endogenous oestrogens. Reassurance is appropriate for a patient with a raised HDL trait who is asymptomatic with no other risk factors. Reference 1. U.S. Preventive Services Task Force. Screening for Lipid Disorders in Adults. http://www.uspreventiveservicestaskforce.org/uspstf/uspschol.htm PREFERRED KEY WORDS Total cholesterol predominantly HDL LDL-C & triglyceride desirable HDL cardio-protective Good lipid profile HDL:LDL/Chol ratio good Low cardiovascular risk Review clinical risk factors ?On E2 Rx/pregnant ?Alcohol abuse LESS RELEVANT KEY WORDS Total cholesterol above target Elevated HDL-C Suggest repeat tests 2–24 months ?Familial (hyperalphalipoproteinaemia) ?Other drugs ?Family history of cardiovascular disease ?Excessive exercise Acceptable if not high risk group ?CETP deficiency Suggest liver function tests ?On lipid medication Suggest CHD risk calculator Suggest Apo A &/ B levels Suggest confirm results Treatment not indicated Targets vary with clinical risk No comment UNACCEPTABLE KEY WORDS Suggest low cholesterol diet/dietician Suggest thyroid function tests Suggest lifestyle changes ?Hypothyroidism Increased cardiovascular risk Suggest glucose/diabetes lx Increased cardiovascular risk with very high HDL Consider lipid drug Rx ?Diabetes ?Renal disease ?Pre-/analytical error Suggest renal function tests ?Polycystic ovarian syndrome Aim for lower total cholesterol on treatment Suggest follow-up relatives Suggest lipoprotein(a) Suggest CK ?Cholestasis Case 8-03 Lipids Patient ID 33-year-old female Patient Location General Practice Clinical Notes on Request Form Non-alcoholic steatohepatitis (NASH) for a number of years. BMI=38. Case Details Cholesterol Triglycerides LDL-cholesterol HDL-cholesterol 7.4 mmol/L 2.0 mmol/L 4.7 mmol/L 1.8 mmol/L Additional Information Not on any medication. Suggested Comment Raised total and LDL-cholesterol and a history of NASH are both associated with increased risk of cardiovascular disease. Exclude secondary causes of hypercholesterolaemia and perform a full cardiovascular risk assessment. Lifestyle interventions to increase exercise and promote weight loss are recommended. Rationale Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disease from steatosis to NASH, cirrhosis, and rarely hepatocellular carcinoma may develop as a complication. Prospective studies have shown that survival with NASH is reduced from cardiovascular- and liver-related causes. NAFLD is strongly associated with obesity and insulin resistance and other features of the metabolic syndrome. This is a case of a severely obese lady with documented NASH and lipid studies showing raised total and LDL-cholesterol. The lipid results in this case are not typical of metabolic syndrome (low HDL and raised triglycerides), making it important to exclude treatable secondary causes, in addition to doing a full cardiovascular risk assessment. Although insulin resistance is central to NAFLD, routine insulin measurement is not helpful. Regression of histological features of NASH has been demonstrated with weight loss. Reference 1. Riley P, O’Donohue J, Crook M. A growing burden: the pathogenesis, investigation and management of non-alcoholic fatty liver disease. J Clin Pathol 2007;60:1384-91. PREFERRED KEY WORDS Predominantly hypercholesterolaemia Undesirable LDL-C Increased risk of cardiovascular disease Exclude secondary causes ?Hypothyroidism Suggest fasting glucose Suggest diet/lifestyle review Suggest review of cardiovascular risk factors Suggest thyroid function tests LESS RELEVANT KEY WORDS Obesity/high BMI Combined hyperlipidaemia ?Insulin resistance/glucose intolerance Note history of NASH Consistent with steatohepatitis/NASH Suggest liver function tests Refer to Lipid Guidelines Repeat fasting lipid profile Suggest lipid-lowering medication Hypertriglyceridaemia Suggest monitor lipids High risk of Type 2 diabetes ?Patient fasting Suggest OGTT Suggestion of metabolic syndrome ?Familial causes Consider metabolic syndrome HDL-C level associated with low risk ?Nephrotic syndrome ?Cholestasis Suggest apolipoproteins Suggest review by specialist Risk of cirrhosis Suggest urine protein ?Pregnancy ?Alcohol intake ?Other metabolic problems Suggest urea, creatinine & electrolytes HDL-C due to ethanol Suggestion of insulin resistance UNACCEPTABLE KEY WORDS Lipid ratio suggests low risk ?Polycystic ovary syndrome Triglyceride level low risk Suggest insulin level Normal LDL-C and HDL-C Suggest lipid electrophoresis Cardiac risk ratio - low risk Suggest androgen levels ?Pancreatic disease Case 9-02 Lipids Patient ID 47-year-old male Patient Location Emergency Department Clinical Notes on Request Form Unwell. Dizzy. Case Details Total protein Albumin Bilirubin AST ALT ALP GGT LD 69 g/L 33 g/L 35 µmol/L 368 U/L 144 U/L 580 U/L 6728 U/L 435 U/L Additional Information Na 140 mmol/L K 4.3 mmol/L Cl 102 mmol/L Bicarb 25 mmol/L Anion gap 13 mmol/L Creatinine 80 µmol/L (62–83) (33–47) (<20) (10–45) (5–45) (40–110) (10–70) (100–200) (135–145) (3.2–4.5) (100–110) (22–33) (5–15) (50–110) Urea Urate Gluc Lipase Chol Trig 3.1 mmol/L (3.0–8.0) 0.45 mmol/L (0.15–0.50) 5.2 mmol/L (3.6–7.7) 164 U/L (25–300) 30.2 mmol/L (2.6–3.5) 168.4 mmol/L (0.5–2.0) Suggested Comment The extremely elevated GGT and increased AST/ALT ratio suggest alcohol-related liver disease. The marked hypertriglyceridaemia confers an increased risk of acute pancreatitis. A combination of a secondary cause on a genetic background of dyslipidaemia (lipoprotein lipase and apoC-II deficiency) is a possible cause of the marked hypertriglyceridaemia. Two secondary causes, diabetes mellitus and renal disease, can be presumptively excluded by the normal random glucose and creatinine. Other secondary causes of hyperlipidaemia, including obesity, alcohol and drugs should be sought. Suggest measure the lipid profile after treatment when the patient is in better health. Rationale This patient presented with massively increased triglycerides and liver function test results that suggest alcohol or drug related liver disease. Although there are many secondary causes of hypertriglyceridaemia that require exclusion, most do not produce such gross elevations, raising the possibility of a primary dyslipidaemia aggravated by a secondary insult. Hypertriglyceridaemia (>10 mmol/L) is associated with an increased risk of pancreatitis, and is the most common cause of acute pancreatitis not due to alcohol or gallstones, accounting for 7% of all cases. Moreover, hypertriglyceridaemia is a (non-major) risk factor for cardiovascular disease. Reference 1. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 2007;176:1113-20. PREFERRED KEY WORDS Marked elevation of GGT Mixed cholestatic and hepatitic pattern Marked hyperlipidaemia Marked hypertriglyceridaemia AST/ALT ratio >2 ?Alcoholic liver disease ?Alcohol-induced dyslipidaemia ?Primary dyslipidaemia ?Drugs/medications ?Hepatic steatosis ?Lipoprotein lipase/apoCII deficiency ?Dysbetalipoproteinaemia Consistent with alcoholic hepatitis Increased risk pancreatitis Drug/alcohol history Suggest APOE genotyping Hyperlipidaemia requires further investigation Lipaemia expected to improve with abstinence LESS RELEVANT KEY WORDS Raised liver function tests Suggest repeat fasting lipids Exclude hypothyroidism ?Diabetes mellitus Suggest lipoprotein electrophoresis ?Increased lipids 2° to liver disease ?Obstructive biliary disease Suggests chronic liver disease Suggest imaging/ultrasound ?Cholestatic liver disease Increased GGT/ALP ?Neoplasm/liver tumour Predominately cholestatic liver function tests Suggest blood ethanol Exclude nephrotic syndrome Suggest full blood count/ coagulation Suggest amylase Suggest hepatitis serology Suggest lipoprotein profile ?Cardio/cerebro vascular disease Suggest clinical review/family history No evidence pancreatitis Suggest HDL/LDL cholesterol measurement Suggest apolipoprotein A/B Increased ratio triglyceride/cholesterol ?Increased chylomicrons/VLDL remnants ?Viral hepatitis Pancreatitis not excluded ?Familial combined hyperlipidaemia Suggest other specialised lipid tests Suggest VLDL/chylomicron measurement ?Familial combined lipoproteinaemia Suggest troponin Suggest iron study Suggest AFP/HCG/PSA Suggest carbohydrate-deficient transferrin Repeat lipase Suggest CK Suggest LD isoenzymes Raised LD ?Familial hypertriglyceridaemia ?Lipoprotein X ?Obesity-induced dyslipidaemia Non-alcoholic fatty liver disease Assess cardiovascular risk factors Exclude primary biliary cirrhosis Exclude other causes of liver disease ?Cholangitis ?Pancreatitis ?Hepatosplenomegaly Increased triglycerides interferes with lipase measurement UNACCEPTABLE KEY WORDS ?Non-fasting Suggest oral glucose tolerance test Possible factitious lipids ?Dietary cause for increased lipids Consistent with acute pancreatitis Recollect sample Consider biopsy No comment Exposure to petrochemical solvents Monitor liver function tests ?Gall stones Repeat liver function tests in 3 days ?Xanthomata Hyperlipidaemia increases risk of diabetes mellitus, coronary heart disease ?Zieve’s syndrome ?Infiltrative liver disease Exclude haemolysis Case 12-05 Lipids Patient ID 64-year-old woman Patient Location Medical Outpatient Clinical Notes on Request Form Diabetes; lipid monitoring Case Details Total Cholesterol Fasting Triglyceride HDL Cholesterol LDL Cholesterol Result 5.9 mmol/L 5.5 mmol/L 1.02 mmol/L 2.1 mmol/L Target <4.0 <2.0 >1.0 <2.5 Additional Information On therapy with Metformin and Sulphonylurea Suggested Comment Confirm fasting status and consider secondary causes, especially alcohol use and renal impairment. Predominant hypertriglyceridaemia consistent with type 2 diabetes. Despite meeting target concentrations, the HDL-C is low for female gender. LDL-C was measured directly because the Friedewald equation is invalid if triglycerides exceed 4.5 mmol/L. Although LDL-C meets target for uncomplicated diabetes, it is likely to underestimate cardiovascular disease (CVD) risk in the presence of raised triglycerides. Consider non-HDLCholesterol (Total – HDL-C), or apoB as preferred CVD risk markers in the presence of raised triglycerides. Rationale The moderate predominant hypertriglyceridaemia is adequately explained by the presence of type 2 diabetes, but alternative causes should be considered and excluded. Exacerbation may cause progression to severe hypertriglyceridaemia. The HDL target is based on the bottom of the reference interval for men. Women have concentrations that are about 30% higher than men. Women with diabetes may lose their gender-specific protection from CVD. When triglycerides exceed 4.5 mmol/L, the presence of chylomicrons becomes more likely. They differ from VLDL in terms of composition, so the Friedewald equation no longer applies. Direct measurement of LDL-C is required. When triglycerides are elevated, cholesterol ester transfer protein acts to reduce HDL-C and transform LDL into small dense LDL. These small dense LDL have less cholesterol per particle, but do more damage per particle. In these circumstances, LDL-C will underestimate CVD risk. There is one apoB per atherogenic particle, so this is the best way to measure harmful lipoproteins when LDL has been confounded by elevated triglycerides. Non-HDL-Cholesterol (Total – HDL-C) is the next best option. PREFERRED KEY WORDS High triglycerides may affect LDL result High triglycerides may affect HDL result Consistent with diabetic dyslipidaemia Confirm fasting specimen ?Poorly controlled diabetic ?Alcohol excess ?Renal involvement / suggest renal function tests Consider fibrate therapy Assumed LDL measured not calculated Exclude secondary causes LESS RELEVANT KEY WORDS Hypertriglyceridaemia Suggest modify lifestyle Clinical history noted High risk of cardiovascular disease Suggest HbA1c Target levels different in diabetes Suggest lipid lowering therapy Hypercholesterolaemia Optimise glucose control Suggest cardiovascular disease risk assessment ?Patient obese ?Hypothyroidism / suggest thyroid function tests Refer to relevant guidelines Suggest urine microalbumin Review medication Moderate hypertriglyceridaemia Refer National Heart Foundation Guidelines Suggest ApoE phenotyping Elevated cholesterol/HDL ratio ?Levels secondary to diabetes HDL target >1 mmol/L LDL target <2 mmol/L Triglycerides target <1.5 mmol/L Mild hypercholesterolaemia Borderline HDL level Suggest lipoprotein electrophoresis Marked hypertriglyceridaemia Total cholesterol target <4 mmol/L ?Smoking Request previous results Suggest glucose Consider statin therapy Reduced HDL-C Hyperlipidaemia ?Liver disease ?Insulin resistance/metabolic disease Triglycerides target <2 mmol/L Mildly elevated triglyceride ?Frederickson type IV Normal LDL/HDL ratio 2.06 LDL target <2.5 mmol/L LDL target <2 if coronary heart disease present Highest risk LDL<2.0 HDL>1.0 triglycerides <1.5 High risk LDL<2.5 HDL>1.0 triglycerides <1.7 Elevated triglycerides/HDL ratio NOT SUPPORTED KEY WORDS Monitor lipids ?Type III hyperlipidaemia ?Patient compliance Request further clinical history Suggest baseline CK levels/liver function tests ?Autoimmune / steroids LDL above diabetes target value ?Increased intermediate density lipoprotein ?Commence insulin Moderate hypercholesterolaemia Refer to Framingham Risk Tables ?Familial dyslipidaemia Consider niacin therapy Consistent with Fredrickson Type IIb pattern Suggest insulin/OGTT Marked cholesterolaemia Suggest familial defective apoB100 mutation Normal risk TC<5.5 LDL<3.5 HDL>1 triglycerides <1 MISLEADING KEY WORDS Normal LDL Cholesterol Normal HDL Cholesterol Case 13-09 Lipids Patient ID 24-year-old female Patient Location General Practice Clinical Notes on Request Form General check prior to embarking on plans to become pregnant Case Details Total Cholesterol HDL Cholesterol Fasting Triglyceride LDL Cholesterol 7.9* mmol/L 1.4 mmol/L 1.6 mmol/L 5.7* mmol/L (≤5.2) (1.0–2.5) (≤2.0) (≤3.0) Additional Information Creatinine Total bilirubin Alkaline Phosphatase AST ALT GGT Creatine Kinase TSH 69 μmol/L 7 μmol/L 56 U/L 28 U/L 34 U/L 14 U/L 106 U/L 0.65 mU/L (50–90) (0–18) (0–145) (5–55) (5–55) (0–40) (0–175) (0.35–5.5) Suggested Comment Marked hypercholesterolaemia due to LDL accumulation. Many secondary causes, including hypothyroidism, anorexia and cholestasis, are not supported by intercurrent results. Assess family history and signs (corneal arcus, tendon xanthomas), estimate Dutch Lipid Clinic Score and calculate absolute risk of cardiovascular disease. Consider familial hypercholesterolaemia and genetic testing. Cholesterol concentrations are likely to increase in the event of pregnancy but pharmacological treatment is contraindicated. Rationale Familial hypercholesterolaemia (FH) is a prevalent genetic cause of increased LDL cholesterol concentrations due to mutations in any of several genes (LDLR, APOB, PCSK9) that affect the LDL receptor pathway. The condition accelerates the progression of atherosclerosis so that cardiovascular disease (CVD) events occur 20 to 40 years sooner. Affected individuals are recognised by the presence of elevated LDL cholesterol concentrations, a dominant family history of high cholesterol and premature CVD, and the variable presence of cholesterol accumulation in other tissues. Total cholesterol is a poor discriminator in later age, but elevated concentrations in young patients are suggestive. The likelihood of FH is best evaluated by applying the Dutch Lipid Clinic Score. Cases of probable or definite FH warrant consideration of confirmatory genetic testing with genetic counselling to facilitate Family Cascade Screening. Reference 1. Watts GF, Sullivan DR, van Bockxmeer FM, et al. A model of care for familial hypercholesterolaemia: key role for clinical biochemistry. Clin Biochem Rev 2012;33:25-31. PREFERRED KEY WORDS Raised LDL-C Normal liver/thyroid/renal function tests ?Familial hypercholesterolaemia Check family history Risk of coronary heart disease ?Tendon xanthoma ?Corneal arcus Refer Dutch Lipid Clinic criteria ?Primary hypercholesterolaemia ?Familial Defective ApoB-100 Suggest genetic screening Exclude anorexia nervosa Lipids increase in pregnancy Exclude statins during pregnancy LESS RELEVANT KEY WORDS Suggest monitor/change lifestyle Exclude nephrotic syndrome Assess cardiovascular disease risk Hypercholesterolaemia Significant hypercholesterolaemia Suggest repeat lipid studies Suggest serum/urine total protein, albumin, globulins Hypothyroidism unlikely ?Oral contraceptive/oestrogen pills Consult specialist Normal triglyceride and HDL Cholestasis unlikely ?Polycystic ovarian syndrome Nephrotic syndrome unlikely Manage with Familial Hypercholesterolaemia Australasia Network Consensus ?Isolated hypercholesterolaemia ?Familial combined hyperlipoproteinaemia Exclude pregnancy Exclude nephrotic syndrome and cholestasis Consistent with Frederickson Type IIa Raised cholesterol and HDL ratio Monitor thyroid function tests during pregnancy Check post-partum Manage with National Vascular Disease Prevention Alliance Guidelines Pregnancy not contraindicated NOT SUPPORTED KEY WORDS Exclude diabetes mellitus Suggest fasting glucose ?Medications/alcohol Suggest thyroid function tests Risk of pre-eclampsia ?Hypothyroidism Suggest urea, creatinine, electrolytes, liver function tests and CRP Suggest full lipid studies Risk of hypertension Exclude Cushing's syndrome Risk of preterm birth Suggest oestrogen, FSH, LH, prolactin, 17-ketosteroids ?Secondary hypothyroidism Suggest albumin:creatinine ratio Suggest repeat lipid studies 1–6 months ?Secondary hypercholesterolaemia ?Hypergammaglobulinaemia Suggest serum electrophoresis ?Dysglobulinaemias ?Metabolic disorder Exclude insulin resistance syndrome Suggest serum insulin Repeat lipid studies in 3 months Suggest assess pituitary function Refer to New Zealand Guidelines MISLEADING KEY WORDS Suggest lipid lowering drugs Risk of atherosclerosis in infant Lower lipids pre-pregnancy Suggest statins Case 6-03 Thyroid Patient ID 55-year-old female Patient Location General Practice Clinical Notes on Request Form Subclinical hypothyroidism, repeat as suggested. Case Details TFTs Free T4 TSH Additional Information Fasting Plasma Cholesterol Triglyceride Glucose Previous Results: Free T4 TSH 14 pmol/L (10–23) 3.4 mIU/L (0.40–4.00) 4.5 mmol/L 1.3 mmol/L 4.9 mmol/L 12 pmol/L 4.1 mIU/L Suggested Comment Borderline TSH persists. Consider repeating in one year with thyroid autoantibodies (TPO antibodies). Rationale TSH has an intra-individual (day-to-day) biological variability of 19.7%. Incorporating this biological variability, the 95% confidence interval of any TSH result is ±40%, and higher if analytical variability is also considered. Therefore, both TSH results are borderline with respect to the upper reference limit. Similarly, population studies have failed to separate TSH levels of >2.5 mIU/L from levels of >4.0 mIU/L when predicting future development of hypothyroidism. TSH exhibits diurnal variation, peaking at night during sleep and decreasing by 50% by 8 a.m. and remains relatively constant until late afternoon, when a smaller trough occurs. The afternoon trough often disappears in disease. The diurnal variation is probably of little relevance to routine testing as blood sampling occurs mostly during the nadir. Elevated TSH concentrations are often seen in the elderly, with the 97.5th percentile increasing by 0.3 mIU/L/decade of life after 30–39 years old. In older population, mild elevation in TSH may represent natural aging process instead of pathology. Subclinical hypothyroidism is characterised by TSH above upper reference limit and a normal free T4. The risk of progression to overt hypothyroidism is about 2–3% per year, but this increases significantly when TPO antibodies are positive. Although increased cardiovascular risks have been described in patients with subclinical hypothyroidism, the lack of prospective controlled trial means treatment on this basis remains debatable. However, thyroxine replacement should be considered in patients with TSH >10 mIU/L, symptomatic for hypothyroidism, positive TPO antibodies, or evidence of atherosclerotic cardiovascular disease, heart failure, or risk factors associated with these diseases. Guidelines for subclinical hypothyroidism generally suggest assessment of TPO antibody and yearly monitoring. Reference 1. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 2012;18:988-1028. PREFERRED KEY WORDS Normal thyroid function tests Previous results borderline Suggest monitor thyroid function tests Suggest anti-TPO Abs LESS RELEVANT KEY WORDS TSH high normal Risk developing hypothyroidism ?Subclinical hypothyroidism Normal lipids and glucose No comment ?Thyroiditis Subclinical hypothyroidism unlikely ?Transient hypothyroidism Borderline low thyroid function tests ?Previous non-thyroidal illness Assess cardiovascular disease risk Normal fasting glucose ?Diurnal variation effect History noted Results similar to previous No treatment required ?Non-thyroidal illness ?Goitre ?Clinical history Previous results - ? other causes No further action Transient compensated hypothyroid No clinical risk TSH <10 UNACCEPTABLE KEY WORDS Suggest clinical exam Non-steady state thyroid function tests Aim lower cholesterol target Suggest T4 replacement Suggest FT3 T4 replacement effective ?Drug-induced TSH Repeat glucose and lipids ?Suboptimal replacement ?Age-related Suggest lipids and cardiac markers ?Reference range of 1st results Suggest thyrotropin releasing hormone stimulation test Assay CV checked Consider T4 replacement Case 8-04 Thyroid Patient ID 31-year-old female Patient Location General Practice Clinical Notes on Request Form Feeling tired and lethargic. Case Details Free T4 TSH Free T3 20 pmol/L 0.02 mIU/L 5.5 pmol/L (9–19) (0.40–4.00) (3.0–5.5) Additional Information Not on any medication. Suggested Comment The suppressed TSH and high-normal free T4 and free T3 suggest hyperthyroidism, commonly due to Graves’ disease; less common causes are thyroiditis, nodular thyroid disease and surreptitious thyroxine intake. TSHreceptor antibodies and thyroid scan may be useful. However, low TSH may be found in early pregnancy, which should be excluded. If the patient is pregnant, repeat thyroid function tests in 6 weeks. Rationale The combination of a suppressed TSH (<0.l mIU/L) and borderline/raised free T3 and free T4 concentrations suggests hyperthyroidism (due to Graves’ disease, thyroiditis, or surreptitious T4 intake). TSH-receptor antibodies and thyroid uptake scan may be indicated. However in a woman of childbearing age pregnancy should be considered, as TSH may be lowered in the first trimester of pregnancy, although such extremes of TSH and free T4 (in response to a significantly increased hCG) are usually seen in the hyperemesis group. If she was found to be pregnant, the tests should be repeated in 6 weeks’ time. If free T4 and free T3 were clearly elevated as opposed to borderline in a pregnant woman, then the diagnosis would be gestational thyrotoxicosis, which warrants treatment. Reference 1. UK Guidelines for the Use http://www.acb.org.uk/docs/TFTguidelinefinal.pdf of Thyroid Function Tests. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Suppressed TSH Borderline/elevated free T4 Borderline/elevated free T3 Consistent with hyperthyroidism Consider early/borderline hyperthyroidism Consider subclinical hyperthyroidism ?Thyroiditis ?Graves’ disease ?Pregnant ?Recent thyroxine ingestion ?Thyroid nodules ?Ingestion of iodine Suggest thyroid antibody studies Repeat thyroid function tests 1-3 months Suggest thyroid scan Consider non-thyroid illness Repeat thyroid function tests ?Goitre Repeat thyroid function tests 3-6 months ?Thyroid disease Repeat thyroid function tests <1 month Suggest follow-up/review Monitor thyroid function tests regularly ?Non-T4 medication ?Patient post-partum ?Treated thyroid disease Recommend hCG TSH not fully suppressed Symptoms not consistent with hyperthyroidism Suggest erythrocyte sedimentation rate Suggest thyroglobulin Normal free T4 Consistent with euthyroidism Suggest endocrine review Suggest specialist review ?Positive thyroid antibodies UNACCEPTABLE KEY WORDS Suggest clinical examination ?Pituitary dysfunction Suggest glucose Suggest thyroid ultrasound scan Resolved thyrotoxicosis Suggest FSH/LH/PRL/GH/ACTH Suggest liver function tests and lipids ?Ingestion of caffeine Suggest TRH ?Immune-deficient Case 10-05 Thyroid Patient ID 21-year-old woman Patient Location Emergency Department Clinical Notes on Request Form 32/40 pregnant, headache. Case Details Free T4 TSH Free T3 21.2 pmol/L (10.0–19.0) <0.03 mIU/L (0.50–4.00) 4.3 pmol/L (3.5–6.5) Additional Information Serum hCG: 5710 IU/L Suggested Comment Assuming the subject is not on thyroxine, the TSH is suppressed and free T4 inappropriately elevated for a woman of this gestational age. This is not hCG driven and is suggestive of subclinical thyroid pathology such as Graves’ disease. Suggest measure thyroid antibodies including thyroid-stimulating antibodies and be vigilant for potential complications of pregnancy. Rationale It is tempting to interpret the results given as normal for pregnancy, although this is not the case. During early pregnancy, the reference interval for thyroid-stimulating hormone (TSH) is lower than in non-pregnant women, although this returns to the pre-pregnancy range by the third trimester. Human chorionic gonadotrophin (hCG) concentrations increase during the first trimester, peaking between 7 and 13 weeks. hCG has mild TSH-like activity, leading to slightly increased free T4 during early pregnancy and in turn, leading to a feedback decrease in TSH with balanced thyroid function. When the hCG elevation or activity is exaggerated, it will lead to the syndrome of gestational transient hyperthyroidism (or thyrotoxicosis, if symptomatic), which is seen in 2.5–11% of pregnant women. This is characterised by mildly increased free T4 and suppressed TSH. It is usually associated with hyperemesis gravidarum and spontaneously resolves within 2-3 weeks. It can be distinguished from Graves’ disease by the absence of thyroid ophthalmopathy, thyroid antibodies (particularly TSH receptor antibodies) and transient nature of the illness. The TSH suppression and elevated free T4 are abnormal for the present case (at 32 weeks gestational age), and are suggestive of thyroid pathology. Moreover, the lower hCG concentration seen in this case (appropriate for gestational age) could not account for the pattern of thyroid function observed. With Graves' disease there is an increased risk of complications of pregnancy, and small increased risk of neonatal thyrotoxicosis, although not usually seen with this degree of abnormality. Anti-thyroperoxidase autoantibodies (TPOAb) are the most sensitive test for thyroid autoimmune disease, including Graves’ disease. Anti-thyroglobulin autoantibodies (TgAb) test is less sensitive and is generally not used for this purpose. Measurement of anti-TSH receptor autoantibodies (TRAb) is a quantitative test for Graves’ disease, whilst thyroid-stimulating immunoglobulin (TSI) is a bioassay test that characterises the stimulating effects of TRAb. An elevated TRAb/TSI helps differentiate Graves’ disease from gestational thyrotoxicosis in the first trimester. Women with Graves’ disease and negative TRAb are highly unlikely to result in foetal hyperthyroidism. By contrast, high titres of TRAb in pregnancy require careful foetal monitoring. References 1. Rodien P, Jordan N, Lefèvre A, et al. Abnormal stimulation of the thyrotrophin receptor during gestation. Hum Reprod Update 2004;10:95-105. 2. http://www.thyroidmanager.org/chapter/thyroid-regulation-and-dysfunction-in-the-pregnant-patient/ 3. Barbesino G, Tomer Y. Clinical review: Clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013;98:2247-55. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS Mildly elevated free T4 Suppressed TSH Not consistent with 3rd trimester thyroid function tests Consistent with hyperthyroidism Suggestive of hyperthyroidism ?Early hyperthyroidism ?Subclinical hyperthyroidism in pregnancy Gestational transient hyperthyroidism unlikely hCG consistent with gestational age TSH suppressed in pregnancy ?Graves' disease ?On T4 replacement Suggest TRAb / TSI testing Suggest anti TPO/Tg antibodies Suggest review by specialist Repeat thyroid function tests postpartum Use reference range for pregnancy Suggest thyroid function tests in newborn ?Clinical review/Patient history Increased risk pre-eclampsia, intrauterine growth retardation Monitor thyroid function tests Repeat thyroid function tests Normal free T3 ?Thyroiditis Risk of neonatal thyrotoxicosis in Graves' Increased risk hydrops, preterm delivery Suggest urine creatine/protein Suggest serum uric acid, liver function tests ?Autonomous thyroid nodule Suggest full blood examination/ESR Thyroid uptake scan contraindicated in pregnancy ?Anti-thyroid drug Interpret pregnant TSH with caution Suggest FSH/LH/prolactin Suggest ultrasound scan Not trophoblastic disease Measure total T4 Phone results Subclinical hyperthyroidism no adversity to pregnancy Graves' can worsen post-partum High hCG can cause hyperthyroidism 1st trimester Increased risk obstetric complications ?Iodine-induced hyperthyroidism ?Transient gestational hyperthyroidism ?Sick euthyroid ?Assay interference hCG not consistent with gestational age ?Due to elevated hCG Euthyroid results ?Trophoblastic disease ?Hypopituitarism Repeat free T4/free T3 by different assay Repeat hCG ?Corticosteroid excess Total T4 of greater value than free T4 Check erythrocyte zinc Not indicative of thyroid disease ?Germ cell tumour Suggest thyroid uptake scan ?Transient gestational hyperthyroidism Suggest TBG Suggest full pre-eclampsia screen Case 12-03 Thyroid Patient ID 30-year-old female Patient Location General Practice Clinical Notes on Request Form Past history of papillary thyroid cancer Case Details TSH Free T4 0.89 mIU/L 15 pmol/L (0.5–4.0) (10–25) Additional Information Previous total thyroidectomy. On thyroxine. Suggested Comment In a patient with a history of thyroid cancer, aim to suppress thyroid-stimulating hormone (TSH) below 0.1 mIU/L to minimise the risk of recurrence. If the patient has been disease free for at least 5 years, American Thyroid Association guidelines suggest maintaining TSH between 0.1 and 0.5 mIU/L may be appropriate. Rationale Most papillary thyroid cancers express the thyroid-stimulating hormone (TSH) receptor; high dose thyroxine TSH suppression therapy reduces tumour cell growth and survival. Meta-analysis of initial management of all, except stage I papillary thyroid cancer supports suppression of serum TSH below 0.1 mIU/L. This concentration was probably chosen because of inclusion of historical data using earlier generation TSH assays; some studies support complete TSH suppression. For low risk patients, initial suppression of serum TSH at or slightly below normal (0.1–0.5 mIU/L) is considered appropriate. Longer-term management has lower quality evidence with regards to the degree of TSH suppression recommended. In persistent disease, the consensus is to maintain suppression below 0.1 mIU/L indefinitely. In patients who have high-risk disease and are disease free, TSH suppressive therapy should be maintained to achieve serum TSH concentration of 0.1–0.5 mIU/L for 5–10 years. In patients who are at low risk and are disease free, the consensus is that TSH may be allowed to rise to between 0.3 and 2.0 mIU/L (evidence level C). The risk profile of a patient depends on completeness of tumour resection, presence of tumour invasion/ metastasis, histological features of tumour and presence of 131I uptake outside of thyroid bed after thyroid remnant ablation. Of note, biochemical surveillance of recurrent disease should include concurrent measurement of thyroglobulin and anti-thyroglobulin (TgAb) antibodies. An elevated TgAb may interfere with thyroglobulin measurement, rendering the result unreliable. When present, the titre of TgAb may be used as a surrogate tumour marker. Reference 1. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167214. PREFERRED KEY WORDS TSH <0.1 mIU/L for high risk disease Inadequate suppression of TSH TSH suppression recommended Refer to American Thyroid Association Guidelines TSH 0.1–0.5 if high risk disease free Low-normal TSH OK if 5–10 yrs disease free Achieve TSH <0.1 mIU/L TSH <0.1 mIU/L for persistent disease TSH 0.3–2.0 if disease free and low risk Suggest monitor Suggest thyroglobulin ? Likelihood of recurrence Suggest thyroglobulin antibodies LESS RELEVANT KEY WORDS Clinical history noted Euthyroid Review thyroxine dose Normal reference range does not apply ?Patient compliance Increase thyroxine dose ?Extent of the disease TSH 0.1–2.0 mIU/L for low risk disease TSH 0.1–0.5 mIU/L for low risk ?Residual thyroid disease Ideal TSH <0.01 mIU/L ?Treatment by specialist Ideal TSH 0.1–0.5 mIU/L Tailor thyroxine therapy Review patient's current clinical detail TSH total suppression for high risk disease Maintain TSH between 0.1–0.01 mIU/L TSH should be <0.03 mIU/L NOT SUPPORTED KEY WORDS Adequate thyroxine replacement Refer to Endocrinologist Suggest 131-I scan if indicated Suggest calcium and PTH Suggest TSH stimulation thyroglobulin TSH 0.05–0.1 mIU/L for low risk TSH <0.01 mIU/L for high risk TSH <0.1 mIU/L for low risk disease Risk of hyperparathyroidism FT4 level only if ?compliance Suggest lipids Low thyroglobulin negative predictor MISLEADING KEY WORDS Inadequate medical history No comment Suggest free T3 Average TSH inversely associated with relapse Case 13-07 Thyroid Patient ID 32-year-old woman Patient Location General Practice Clinic Clinical Notes on Request Form Pre-conception testing. Nil Medication. Case Details TSH Free T4 TPO Antibodies 4.5 mU/L 14 pmol/L 42 kIU/L (0.5–4.0) (10–25) (<30) Suggested Comment Confirm subclinical hypothyroidism by repeat testing. If confirmed, consider thyroxine replacement. Poor pregnancy outcomes have been described in women with raised TSH. Rationale Thyroid dysfunction during pregnancy can result in serious complications for both mother and foetus. Current US Endocrine Society Guidelines recommend prenatal measurement of TSH for individuals considered high risk for thyroid disease. They include women with personal/family history of thyroid disorders, autoimmune disorders (including type 1 diabetes mellitus), goitre, symptoms or signs of hypothyroidism, positive thyroid antibodies, > 30 years old, infertility or history of miscarriage and preterm labour. Individuals with TSH >2.5 mIU/L confirmed by repeat testing prior to conception, should be treated with lowdose thyroxine therapy with an aim to reduce TSH to <2.5 mIU/L. Subclinical hypothyroidism should be treated irrespective of whether the TPO antibody is positive or negative. The aim of treatment is to maintain TSH <2.5 mIU/L in the 1st trimester and <3.0 mIU/L in the 2nd and 3rd trimester, or within method- and trimester-specific TSH reference intervals, where available. Repeat testing should be performed at 6–12 weeks and 6 months postpartum as there is a higher incidence of postpartum thyroiditis in antibody positive women. Therapy can be discontinued if pregnancy is not achieved or postpartum. In the absence of an elevated TSH, a woman with known elevations of TPO antibodies should be screened for thyroid abnormalities before pregnancy and during the first and second trimesters. Reference 1. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and post partum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543-65. PREFERRED KEY WORDS Subclinical hypothyroidism Slightly raised TSH Maintain TSH in trimester specific reference range Increased risk pregnancy/foetal complications ?Risk of overt hypothyroidism ?Subclinical hypothyroidism ?Early/borderline hypothyroidism Delay pregnancy until diagnosis Increased risk of postpartum thyroiditis Autoimmune thyroid disease Suggest replacement T4 Suggest T4 replacement - aim TSH<2.5 Suggest referral to endocrinologist Suggest repeat thyroid function tests Suggest treatment/counselling Call GP to discuss LESS RELEVANT KEY WORDS Low positive TPO Ab titre Suggest monitor thyroid function tests Normal FT4 Consider Hashimoto's thyroiditis Increased TSH Exclude non-thyroidal disease Repeat thyroid function test in 1–3 months Suggest lipid studies Repeat thyroid function test in 6 weeks Consider patient/family history ?Iodine deficiency ?Evolving autoimmune thyroiditis ?Associated with infertility Suggest check for goitre Exclude TSH heterophile antibody Exclude non-toxic goitre Suggest physical examination Suggest TSH receptor Abs Suggest cortisol levels Repeat thyroid function tests at early 1st trimester ?Primary hypothyroidism NOT SUPPORTED KEY WORDS Suggest antithyroglobulin Abs Suggest monitor TPO Ab levels Suggest thyroid ultrasound Suggest ANA/dsDNA/AMA Suggest rheumatoid factor Exclude multinodular goitre Exclude thyroid carcinoma Exclude hypogonadism Exclude hypoparathyroidism Suggest 21-hydroxylase Ab Suggest transglutaminase IgA Ab Suggest anti-gliadin Ab Exclude idiopathic myxoedema Suggest iodine supplementation Exclude drug interferences Suggest glucose/HbA1c tests Suggest ECG Suggest CK level Suggest full blood examination MISLEADING KEY WORDS Exclude Grave's Disease Suggest test for FT3 Euthyroid results Repeat thyroid function tests in 6 months Case 10-06 Pituitary Patient ID 18-year-old female Patient Location Medical Ward Clinical Notes on Request Form Amenorrhoea, nausea and vomiting. Case Details Prolactin 3145mU/L (<500) Additional Information Previous results (a few days ago in Emergency Department) Prolactin 195 mU/L All reproductive hormones were within reference intervals and hCG negative. Suggested Comment Assuming both samples were measured by the same method and laboratory errors have been excluded, the most likely cause of a rapid increase in prolactin concentration with the given the history would be medications that block the dopamine receptors e.g. antiemetics, antipsychotics, antidepressant and antihypertensive. Recommend repeating prolactin after discontinuation of interfering medication. If hyperprolactinaemia persists, further investigations are warranted. Rationale There are many causes of a raised prolactin including pregnancy, nipple stimulation, stress, prolactinomas, hypothalamic and pituitary disorders, oestrogens, drugs, hypothyroidism, chest wall injury, and chronic renal failure. Hyperprolactinaemia may also be due to idiopathic causes and macroprolactinaemia. In this case, there has been a rapid rise in the prolactin concentration over a few days and it is not possible to know which result is correct. It is important to exclude any error in the total testing process, such as stress of phlebotomy, sample mix-up or the use of a different analytical method that may be affected by macroprolactin or hook effect. This patient has amenorrhoea, which may be due to the elevated prolactin. She also has nausea and vomiting that could have been treated with an antiemetic drug. Prolactin concentrations of >3,000 mU/L are usually due to pregnancy, drugs, prolactinomas, hypothalamic and pituitary disorders. In this case pregnancy has been ruled out, and prolactinomas, hypothalamic and pituitary disorders usually develop over a longer period of time and are unlikely to present in such an acute manner. Therefore, the most likely cause of the hyperprolactinaemia would be medications e.g. antiemetics. The prolactin should be remeasured after stopping any interfering medications for four days. The amenorrhoea is possibly due to another cause and may warrant further investigations. References 1. David SR, Taylor CC, Kinon BJ, et al. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;22:1085-96. 2. Dostál C, Marek J, Moszkorzová L, et al. Effects of stress on serum prolactin levels in patients with systemic lupus erythematosus. Ann N Y Acad Sci 2002;966:247-51. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Marked hyperprolactinaemia Previous normal prolactin level Acute rise in serum prolactin Discrepancy between two prolactin results Repeat prolactin - no drugs, no stress Pituitary disease unlikely Pituitary disease unlikely, consider drugs Macroprolactin unlikely Recent negative hCG noted Pregnancy unlikely ?Drug interaction ?Tricyclics, antihypertensives, psychotropic ?Antiemetic medication ?Antipsychotic medication ?Dopamine antagonist drugs ?Acute stress e.g. illness ?Different prolactin methods and units ?Previous result high dose hook effect Suggest medication review Suggest repeat prolactin Suggest clinical review Retest both samples in dilution ?Pituitary tumour/prolactinoma Hyperprolactinaemia Suggest screen for macroprolactin ?Stress, anxiety, exercise Suggest thyroid function tests ?Hypothyroidism Suggest pituitary MRI Suggest repeat hCG ?Wrong specimen Suggest FSH, LH, oestradiol, progesterone, 17OH progesterone ?Galactorrhoea/lactation Suggest pituitary function tests Suggest cortisol ?Epileptic seizure Suggest renal function tests and liver function tests Rerun with PEG precipitation or different method ?Hypothalamic dysfunction Note nausea and vomiting Exclude heterophile antibodies Secretion pulses and various stimuli Amenorrhoea consistent with hyperprolactinaemia ?Subarachnoid haemorrhage Re-run both samples to confirm prolactin ?Chest wall damage Reserpine may cause nausea and vomiting Idiopathic hypersecretion of prolactin UNACCEPTABLE KEY WORDS ?Non-pituitary disease e.g. renal failure, cirrhosis, polycystic ovaries Exclude pregnancy ?Pregnancy Suggest BMI for anorexia nervosa ?Breast manipulation Suggest TRH stimulation test Case 9-05 Adrenal Patient ID 48-year-old female Patient Location Medical Outpatients Clinical Notes on Request Form Previous microadenoma Case Details Dexamethasone Suppression Test Day Time (h) Cortisol (nmol/L) Reference Interval 1 0900 319 (160–650) 1 2300 1.0 mg oral dexamethasone given 2 0900 286 (<50) Additional Information Day 1 0900 AM ACTH 21 ng/mL (9–51) Suggested Comment There was inadequate cortisol suppression following dexamethasone suppression test. Failure to suppress is consistent with Cushing’s syndrome. However, other causes of non-suppression include exogenous oestrogens, alcoholism, depression, non-compliance or malabsorption of dexamethasone and due to certain drugs e.g. phenytoin. Given the past history and an ACTH within the reference interval this is suggestive of pituitarydependent Cushing’s syndrome. Rationale Cushing’s syndrome is an uncommon disease of cortisol excess, which may be endogenous or exogenous in origin. The clinical diagnosis is often not straightforward and requires additional tests. The initial screening tests include urine free cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-hour dexamethasone suppression test. The former two tests require at least two separate measurements. The 1 mg overnight dexamethasone suppression test (given between 2300 and 0000 h, with serum cortisol measured next morning at 0800 h), at a cut-off of 50 nmol/L, has a sensitivity >95% and a specificity of 80%. False positive results occur with variable absorption and metabolism of dexamethasone. Drugs that induce the hepatic enzymatic clearance through the CYP3A4 pathway, such as phenytoin and alcohol, can have this effect. Up to 50% of women taking the oral contraceptive pill fail to suppress due to increased levels of cortisol binding protein. If an initial test returns positive, the finding should be confirmed with an alternate test. The diagnosis of Cushing’s syndrome is established by concordantly positive results from two different tests. The underlying cause of the hypercortisolism should be investigated accordingly. Patients with suspected Cushing’s syndrome should be referred to an endocrinologist for further evaluation. Reference 1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-40. PREFERRED KEY WORDS Inadequate suppression of cortisol Suggests Cushing’s syndrome ?Stress, illness, infection, alcohol ?Drug therapy e.g. phenytoin ?Dexamethasone non-compliance/ malabsorption ?Depression ?Cushing’s disease ?Oestrogen therapy ?Enhanced dexamethasone metabolism ?Pseudo-Cushing’s syndrome Suggest extended DST Suggest high dose DST Refer to Endocrinologist Recommend follow up Adrenal cause unlikely LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS ?Obesity, eating disorder, weight loss Normal baseline ACTH Suggest recurrence of functional microadenoma ?Ectopic ACTH production Suggest ACTH-dependent Cushing’s disease Normal baseline cortisol False positive possible ACTH not suppressed Change in hypothalamic/pituitary/adrenal axis Review clinical presentation Suggest pituitary and thyroid function tests Suggest MRI Suggest late evening cortisol level Measure ACTH with dexamethasone suppression test ?Diabetes Suggest CRH stimulation test ?Adrenal tumour ?Exogenous steroid ?Pituitary disease Suggest salivary free cortisol ?Hyperthyroidism/acromegaly Suggest 24 hour urine free cortisol Suggest 2 mg dexamethasone suppression test Suggest serum potassium Adrenocortical hyperfunction Suggest low dose dexamethasone suppression test Suggest day 2 dexamethasone level Hypercortisolism Suggest petrosal sinus ACTH and cortisol Result inconclusive Normal response Excludes Cushing’s syndrome ?Metabolic syndrome ?Cyclic Cushing’s syndrome Pituitary disease unlikely Suggest insulin hypoglycaemia test Exclude pituitary-independent Cushing’s Case 11-05 Adrenal Patient ID 65-year-old female Patient Location Medical Outpatients (Diabetes Unit) Clinical Notes on Request Form Type 2 diabetes; to exclude Cushing's syndrome Case Details Dexamethasone Suppression of Cortisol Day Time (h) Cortisol (nmol/L) Reference Interval 1 0900 414 (160–650) 1 2300 1.0 mg oral dexamethasone given 2 0900 329 (<50) Additional Information Two weeks earlier: Dexamethasone Suppression of Cortisol Day Time (h) Cortisol (nmol/L) Reference Interval 1 0900 358 (160-650) 1 2300 1.0 mg oral dexamethasone given 2 0900 <35 (<50) Suggested Comment Cortisol is not suppressed after 1 mg dexamethasone in contrast to the results two weeks earlier. This could be due to a lack of compliance in the current test or specimen mix-up in either the previous or this test. Serum dexamethasone measurement could clarify compliance and specimen identity. Rare possibility of cyclical Cushing’s could be considered. Recommend assessment of midnight salivary cortisol or 24 hour urine free cortisol. Rationale Poorly controlled diabetes mellitus can be associated with mild hypercortisolism and abnormal dexamethasone suppression tests. However, a clearly suppressed test a fortnight previously with a clearly unsuppressed result now should prompt consideration of non-compliance with dexamethasone in the second test or sample mix-up in either the first or the second test. Measurement of serum dexamethasone concentration may clarify these, but the test is expensive and not commonly available. Increased metabolism of dexamethasone by ethanol abuse or glitazone therapy initiated in the interim is unlikely in view of the short interval. Other causes of false positive dexamethasone suppression test such as obesity, depression and oestrogen therapy are not considered for the same reason. Further testing with midnight salivary cortisol or with 24 hour urine free cortisol would be useful if pre-test probability of Cushing’s syndrome is high. References 1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-40. 2. Yanovski JA, Cutler GB Jr, Chrousos GP, et al. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudoCushing's states. JAMA 1993;269:2232-8. 3. Vagnucci AH, Evans E. Cushing's disease with intermittent hypercortisolism. Am J Med 1986;80:83-8. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Inadequate suppression of cortisol Discordant dexamethasone suppression test compared with previous ?Compliance with dexamethasone ?Acute illness/stress ?Cyclical Cushing’s syndrome ?Test protocol followed ?Mislabel of patient or sample ?Malabsorption/rapid metabolism ?Exogenous steroid/glucocorticoid ?Alterations in medication ?Transient Cushing’s syndrome Review clinical and medication history Suggest dexamethasone assay Suggest repeat dexamethasone suppression test Suggest 24 hour urinary free cortisol Suggest midnight salivary cortisol Suggest 2x24 hour urinary free cortisol Suggest 2x late night salivary cortisol Difficult to interpret in diabetics Results confirmed by repeat analysis ?Anticonvulsant therapy ?Depression ?Alcoholism Drug-induced rapid liver metabolism ?Glitazone effect Suggest ACTH ?Cushing's Syndrome ?False positive ?Obesity ?Pseudo-Cushing’s ?Exogenous oestrogen Suggest late evening cortisol ?Poorly controlled diabetes Suggest 2 mg dexamethasone suppression test ?Reason for repeat ?Change in patient’s condition Suggest dexamethasone-CRH test Suggest HbA1c ?Cause of discordant dexamethasone suppression test Suggest pre/post dexamethasone 24 h urine cortisol ?Ectopic ACTH production ?Renal status Results inconclusive UNACCEPTABLE KEY WORDS Suggest high dose dexamethasone suppression test Previous normal DST excludes Cushing’s Suggest imaging of pituitary and adrenal Suggest cortisol binding globulin Case 7-05 Reproductive Patient ID 22-year-old female Patient Location General Practice Clinical Notes on Request Form None Case Details Serum hCG 14 IU/L (<5) Additional Information Two weeks earlier: hCG 21 IU/L Clinical notes: LMP 15 weeks ago, inconclusive ultrasound Two months earlier: hCG 121 IU/L Clinical notes: ?pregnant Suggested Comment Persistent low human β-chorionic gonadotrophin (hCG) suggests likely miscarriage with retained products of conception. Differential diagnosis includes low-grade gestational trophoblastic neoplasia or false positive hCG due to laboratory interference. Sample has been forwarded for analysis by another method. Suggest check urine pregnancy test. Rationale Following the termination of normal pregnancy in the first trimester, the human β-chorionic gonadotrophin (hCG) concentrations fall in two trajectories. In the first two days, the half-life of hCG is approximately 0.63 days and increases to 4 days in the subsequent two weeks. By contrast, in termination of ectopic pregnancy, the hCG decreases by approximately 25% in the first two days. In trophoblastic neoplasia or persistent trophoblast following termination of pregnancy, the hCG concentrations may fall at even slower rate or rise. Therefore, possibilities in this case are the following: failing ectopic pregnancy, incomplete miscarriage, failing second pregnancy, analytical problem (hook effect, heterophile antibody). The fact that the level is falling makes the presence of heterophile antibody less likely. The clinical note of normal menstrual period supports retained products of conception rather than an artefact. It may be prudent to check the hCG against another assay. References 1. van der Lugt B, Drogendijk AC. The disappearance of human chorionic gonadotropin from plasma and urine following induced abortion. Acta Obstet Gynecol Scand 1985;64:547-52. 2. Silva C, Sammel MD, Zhou L, et al. Human chorionic gonadotropin profile for women with ectopic pregnancy. Obstet Gynecol 2006;107:605-10. 3. Kadar N, Romero R. Further observations on serial human chorionic gonadotropin patterns in ectopic pregnancies and spontaneous abortions. Fertil Steril 1988;50:367-70. PREFERRED KEY WORDS Slow decay in hCG level ?Recent miscarriage ?Retained products of conception ?Ectopic pregnancy ?Non-viable pregnancy ?Incomplete miscarriage Suggest assay by different method LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS ?False positive hCG Suggest repeat/monitor hCG ?Molar pregnancy Persistent low hCG Suggest clinical review Suggest urine pregnancy test Decreasing hCG level Suggest ultrasound or imaging Suggest further review Suggest heterophile Ab pretreatment Patient not pregnant Suggest oestradiol and progesterone hCG may be present for 6 weeks hCG half-life is 1-3 days ?Malignancy Equivocal pregnancy result ?Non-pregnancy source hCG ?hCG assay type and reference range Suggest rheumatoid factor Suggest investigation for miscarriage ?New pregnancy Low levels for gestational age Suggest beta/hyperglycosylated hCG assay Suggest FSH, LH Malignancy unlikely Consider D&C Suggest prolactin Previous results noted Suggest group and Rh Ab Suggest full blood count Case 7-06 Reproductive Patient ID 31-year-old male Patient Location Endocrinology Outpatients Clinical Notes on Request Form Gynaecomastia Case Details FSH LH Oestradiol Testosterone SHBG 3 U/L 3 U/L 179 pmol/L 6.5nmol/L 18 nmol/L (<10) (<9) (55–165) (11–40) (10–70) Additional Information Alpha Fetoprotein 4 µg/L hCG <2 IU/L Prolactin 426 mIU/L (<12) (<2) (<500) Suggested Comment The results indicate hypogonadotrophic hypogonadism, which is a known cause of gynaecomastia, although other clinical signs of hypogonadism would be expected. Drug causes, hyperthyroidism, renal failure and cirrhosis should be excluded. Oestrogen-secreting testicular or adrenal tumour cannot be excluded. Rationale Gynaecomastia is the abnormal enlargement of breast tissue in males due to an absolute or relative (to androgen) excess of oestrogen concentration, or sensitivity. It is most commonly physiologic, being associated with puberty and aging, or idiopathic. Nonetheless, medically important causes must be excluded. The most common identifiable causes are drug effects, which must be sought by history. Cirrhosis (particularly alcoholic cirrhosis), renal failure (with reduced testosterone and elevated gonadotropin values) and hyperthyroidism (due to increased aromatase activity and SHBG) may be accompanied by gynaecomastia. These causes are likely to have been identified by general pathology testing before the more specific tests are requested in the endocrine outpatient setting, as indicated in this case. It is however necessary to ensure that these factors are excluded. Primary or secondary hypogonadism are important causes of gynaecomastia and the testosterone and LH results presented in this case are consistent with secondary hypogonadism. HCG-negative feminising tumours of the testes or adrenals are rare but may also cause this hormonal profile by feedback inhibition of gonadotrophins. References 1. Ismail AA, Barth JH. Endocrinology of gynaecomastia. Ann Clin Biochem 2001;38:596-607. 2. Case Records of the Massachusetts General Hospital. Case 12-2000. A 60-year-old man with persistent gynaecomastia after excision of a pituitary adenoma. N Engl J Med 2000;342:1196-204. PREFERRED KEY WORDS Abnormal oestradiol/testosterone ratio ?Drugs/exogenous oestrogen ? Hypopituitarism/hypothalamic ?Hypogonadotrophic hypogonadism ?Testicular neoplasm ?Liver disease ?Renal failure ?Secondary hypogonadism ?Hyperthyroidism Suggest urea and electrolytes Suggest testicular imaging Suggest thyroid function tests Suggest liver function tests Suggest pituitary tests/imaging LESS RELEVANT KEY WORDS Low testosterone Increased oestradiol LH/FSH low/normal ?Obesity Consistent with gynaecomastia Suggest clinical review ?Alcohol ?Cancer (other/not specified) Suggest adrenal tests/imaging ?Adrenal neoplasm ?Genetic low testosterone Suggest karyotyping Normal AFP, hCG and prolactin Suggest iron studies Increased conversion testosterone to oestradiol ?Haemochromatosis Suggest repeat tests Oestrogen secreting tumour Suggest repeat am sample Normal SHBG Androgen deficiency syndrome Low calculated free testosterone Suggest testicular tests UNACCEPTABLE KEY WORDS ?Primary hypogonadism No evidence testicular tumour No evidence of tumour ?Secondary to severe illness No comment Refer to Endocrinologist ?Hypothyroidism Reduced SHBG Measure free testosterone ?Gender correction/reassignment Normal free androgen index ?Tissue androgen insensitive No evidence pituitary disease Refer to Chemical Pathologist Suggest tumour markers Case 10-07 Reproductive Patient ID 53-year-old female Patient Location General Practice Clinical Notes on Request Form Hirsutism, hoarse voice, increased libido for investigation. On L-thyroxine replacement. Case Details Total Testosterone 10.4nmol/L (<3.2) Additional Information Free T4 and TSH within reference interval. Prolactin 189 mIU/L (<500) Suggested Comment An androgen-secreting tumour must be excluded given the extremely high serum testosterone and signs of virilisation. Serum androgen profile including DHEA-S, and imaging would assist in distinguishing between adrenal and ovarian malignancy. Assess drug history as medication effect is possible but other causes of androgen excess (PCOS, CAH and Cushing's syndrome) are less likely at this testosterone concentration. Clinical endocrine review is recommended. Rationale In terms of frequency, hirsutism is typically idiopathic or associated with polycystic ovarian syndrome (PCOS). The diagnosis of PCOS requires two of the following: 1) oligo/amenorrhoea, 2) clinical or biochemical evidence of hyperandrogenism, 3) polycystic ovaries on ultrasound. Less common causes are hyperprolactinaemia, drugs, congenital adrenal hyperplasia (CAH) and Cushing's syndrome. 17OH progesterone is a useful screening test for CAH while Cushing’s syndrome can be evaluated by using 24 h urinary free cortisol, dexamethasone suppression test or midnight salivary cortisol tests. Androgen-secreting adrenal or ovarian tumours are rare causes of hirsutism, but should be suspected when the onset of virilisation is rapid, symptoms appear in the third decade of life or later, or when serum testosterone concentrations are markedly elevated. This has been variously defined as testosterone concentrations greater than 5.2–6.9 nmol/L or 2.5 times the upper reference limit for any assay. Although such tumours may cause more modest testosterone elevations (at concentrations usually seen in PCOS, CAH, etc), it is unusual for these non-malignant conditions to cause very high testosterone concentrations. DHEA-S, because of its almost exclusive production by the adrenal glands, is an important follow-up investigation. Concentrations greater than 13.6 μmol/L suggest an adrenal tumour. Reference 1. Barbieri RL, Ehrmann DA. Evaluation of premenopausal women with hirsutism. In: Basow DS, ed. UpToDate. Waltham, MA, 2013. PREFERRED KEY WORDS Markedly raised testosterone Hyperandrogenism Clinically virilising condition Unlikely PCOS/Cushing’s given degree of elevation ?Androgen-secreting tumour ?Adrenal neoplasm/hyperplasia ?Ovarian neoplasm ?Exclude drugs/medications Suggest ovarian/adrenal imaging Suggest full androgen profile Suggest DHEAS/DHEA Suggest androstenedione DHEAS to test adrenal or ovary origin Refer to endocrinologist Further testing required LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS ?PCOS Suggest FSH/LH Suggest testosterone/SHBG ?21 hydroxylase deficiency (CAH) Suggest free testosterone / FAI Raised testosterone Suggest 17OH progesterone ?Cushing’s syndrome Suggest progesterone/oestradiol Suggest cortisol Suggest urine adrenal/androgen screen Suggest LH:FSH ratio Suggest 24h urine cortisol Suggest dexamethasone suppression test Repeat and confirm results Repeat testosterone by RIA or LCMS/MS ?Family history Suggest insulin resistance study Normal thyroid function tests/prolactin Suggest ACTH ?Acromegaly Repeat testosterone after extraction Suggest glucose ?Ovarian hyperthecosis Suggest 17OH pregnenolone Suggest 21 deoxycortisol Suggest GH Suggest midnight cortisol ?Trophoblastic tumour Suggest IGF1 DHEAS/oestradiol cross react with total testosterone ?11hydroxylase deficiency Increased androgens associated with cardiovascular risk Suggest thyroid function tests and prolactin Not hypothyroidism Suggest adrenal/ovarian tumour markers Suggest CEA/CA125 ?Menopause ?MEN II syndrome Suggest Synacthen stimulation test Suggest hCG Exclude pregnancy Case 11-02 Reproductive Patient ID 22-year-old woman Patient Location General Practice Clinical Notes on Request Form Hirsutism. ?PCOS Case Details Fasting serum Testosterone 3.4 nmol/L (0.2–2.6) SHBG >180 nmol/L (20–120) FAI 1.7 (<6) Additional Information Oestradiol <75 pmol/L LH <1 U/L Progesterone <0.6 nmol/L FSH <1 U/L Suggested Comment Elevated SHBG and previously suppressed gonadotrophins are consistent with the use of the oral contraceptive pill (OCP). OCP use often invalidates biochemical assessment of androgen status. If OCP use is excluded, suggested further investigation includes thyroid function tests. Note that SHBG concentrations may not return to baseline for many months after cessation of the OCP. Rationale The most common cause of this pattern of results, especially in women of this age, is treatment with the OCP. Exogenous oestrogens commonly are not detected by routine assays but are bioactive leading to low LH, FSH and oestradiol and elevated SHBG. Further interpretation depends on confirmation that the patient is on the pill or not. Note that in this case we are commenting on the testosterone, SHBG and free androgen index (FAI) results rather than the gonadotrophins and hormones and the comment should focus in this direction. Given the clinical notes (?PCOS), it is likely that the requesting doctor is seeking biochemical evidence of hyperandrogenism to support a diagnosis of polycystic ovarian syndrome (PCOS). At this time, the normal FAI does not support or exclude the diagnosis of PCOS. The preferred approach would be to take the patient off the OCP and reassess the androgens. The benefits of confirming the diagnosis must be weighed against the effects of cessation of the pill. If the patient is not receiving the OCP, investigation for other causes of raised SHBG (and hypogonadotrophic hypogonadism) should be performed. This may include thyroid function tests (hyperthyroidism causes raised SHBG) and prolactin. Further investigation without confirmation of the patient’s medications is not warranted. PREFERRED KEY WORDS Increased SHBG contributing to increased testosterone Mild elevation of testosterone ?Exogenous hormone effect e.g. OCP Oestrogens cause increase in SHBG Review patient’s meds/drug history Repeat tests after cessation OCP LESS RELEVANT KEY WORDS Elevated SHBG Suggest prolactin Suppressed FSH/LH Suggest thyroid function tests Suggest DHEAS/DHEA Suggest 17OH progesterone Suppressed oestradiol/progesterone ?CAH/Late onset CAH Suggest cortisol ?Hypogonadotrophic hypogonadism FAI is normal ?PCOS ?Hyperprolactinaemia Increased testosterone ?Hyperthyroidism ?Increased adrenal/ovarian androgens Suggest androstenedione ?Excessive weight loss/exercise Perform pelvic ultrasound ?Hypopituitarism Hirsutism ?Cushing syndrome ?Tumour/lesion Suggestive of hyperandrogenism ?Chronic liver disease Repeat testing Suggest glucose/insulin/IGF1 Hypothalamic/pituitary disorder Suggest 24h urine cortisol Consistent with PCOS ?Pituitary disease Adrenal/ovarian tumour unlikely Rotterdam criteria assist PCOS diagnosis ?Exclude phenytoin/carb interference ?Assay interference Suggest karyotype ?Turner’s Clinical history required Suggest ACTH Suggest refer to specialist/endocrinologist Suggest family history Investigate for porphyria LH usually increased in PCOS Normal free testosterone ?FAI should be <1.7 ?Mild androgen deficiency Indicative anovulatory condition ?Ovarian failure Suggest 3 alpha-AG ?Haemochromatosis/iron studies Check iron studies Suggest pituitary imaging Suggest dexamethasone suppression test Aromatase inhibitor SHBG is elevated in hypogonadism UNACCEPTABLE KEY WORDS Not consistent with PCOS ?Adrenal/ovarian cancer ?Pregnancy/suggest hCG PCOS unlikely ?Idiopathic hirsutism ?Hypothyroidism Case 13-05 Reproductive Patient ID 30-year-old male Patient Location General Practice Clinical Notes on Request Form Erectile dysfunction. ? cause. Case Details Total Testosterone SHBG 1.0 nmol/L <2.0nmol/L (8.0–27.8) (10–70) Suggested Comment Severe hypogonadism and very low SHBG indicate exogenous androgen abuse is the more likely cause of the results. Consider assessing fasting lipids. Rationale Sex hormone binding globulin (SHBG) is a protein that is regulated by sex hormones, thyroid and growth hormone. Oestrogen and thyroid hormone elevate SHBG while androgens and growth hormone suppress it. In hypogonadal males, SHBG concentrations are higher than in eugonadal men. Consequently, reduced concentrations of SHBG are unexpected in uncomplicated male hypogonadism and assessment of LH in this setting is unlikely to be helpful. Of note, pharmacologic androgens may not be detected by routine testosterone assays and may return suppressed results. Reduced SHBG can also occur in obesity, hyperinsulinism, hyperprolactinaemia, severe hypothyroidism, acromegaly, nephrotic syndrome and exogenous androgen abuse. However, the extremely low SHBG concentration in this case and clinical presentation make androgen abuse a more likely cause of this combination of abnormal results. Hence, testing for other causes is not recommended until androgen abuse has been excluded. Other expected biochemical findings in men who abuse androgens include elevated triglycerides, increased LDL-cholesterol, reduced HDL-cholesterol and increased haematocrit (1). Reference 1. Dickerman RD, McConathy WJ, Zachariah NY. Testosterone, sex hormone-binding globulin, lipoproteins, and vascular disease risk. J Cardiovasc Risk 1997;4:363-6. PREFERRED KEY WORDS Very low SHBG ?Exogenous androgen use Suggest fasting lipids LESS RELEVANT KEY WORDS NOT SUPPORTED KEY WORDS Suggest LH, FSH, prolactin Low testosterone ?Diabetes, obesity, metabolic syndrome Suggest thyroid function tests ?Hypothyroidism Repeat morning testosterone/SHBG ?Supplements/medications/drugs Suggest glucose/glucose tolerance test/HbA1c/BMI Suggest ACTH, GH, IGF-1, cortisol Suggest liver function tests/urea and electrolytes/Iron studies Low testosterone due to low SHBG Suggest urine anabolic steroids Refer to endocrinologist Evaluate hypothalamus-pituitary-gonadal axis Hypogonadism Unable to calculate free testosterone ?Nephrotic syndrome Suggest 24h urine protein ?Primary or secondary hypogonadism ?Congenital/genetic disease ?Hyperprolactinaemia/ pituitary tumour Suggest free testosterone ?Pituitary disease ?Cushing’s syndrome ?Hyperinsulinism Suggest full blood examination ?Orchitis/ haemochromatosis/ irradiation/ chemotherapy ?Malnutrition, exercise, stress ?Hypothalamic Erectile problems due to hypogonadism Consistent with physiological not psychological ?Liver/renal disease, anaemia ?Kallman’s syndrome, HIV, inflammation ?Developmental trauma Secondary hypogonadism Suggest semen analysis ?Interferences; use different method Suggest pituitary imaging Suggest test for haemochromatosis ?Psychological problems Suggest urine testosterone:epitestosterone Calculated free testosterone high Obesity, opiate, pituitary disease less likely MISLEADING KEY WORDS Consistent with androgen deficiency ?Hyperandrogenism Case 13-10 Reproductive Patient ID 49-year-old woman Patient Location General Practice Clinical Notes on Request Form Amenorrhoea Case Details hCG 9 IU/L (<2) Additional Information FSH 91 U/L Oestradiol <37 pmol/L Reference interval Follicular Mid-cycle Luteal FSH U/L 2–10 7–24 1–10 Oestradiol pmol/L 110–180 550–1650 180–840 Suggested Comment In post-menopausal women, hCG concentrations up to10 IU/L are not uncommon due to pituitary production. If a malignant source is suspected, suggest repeat testing after 2–3 weeks of high dose oestrogen to suppress pituitary hCG. Rationale Low concentrations of hCG from pituitary production are common in peri- and post-menopausal women. The median concentration (range) in women <50 years and women ≥50 is 7 IU/L (2–19) and 10 IU/L (4–33), respectively (1). FSH levels have a strong negative predictive value for patients with hCG 5–14 IU/L to discriminate between placental (pregnancy, resolving abortion, gestational trophoblastic disease) and nonplacental sources. At FSH cut-off of <45 U/L, hCG of placental origin can be identified with 100% sensitivity and 75% specificity. On the other hand, FSH of >45 U/L is never observed in patients with elevated hCG of placental origin (2). Additional tests to determine the source of the hCG include: repeat testing; assay free beta hCG; heterophile antibody testing; and repeat testing after 2–3 weeks of high dose oestrogen oral contraceptive pill to suppress pituitary hCG (1). References 1. Cole LA, Laidler LL, Muller CY. USA hCG reference service, 10-year report. Clin Biochem 2010; 43:1013-22. 2. Gronowski AM, Fantz CR, Parvin CA, et al. Use of serum FSH to identify perimenopausal women with pituitary hCG. Clin Chem 2008;54:652-6. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS FSH and oestradiol consistent with peri/menopause Low +hCG seen peri/post menopause hCG consistent with benign pituitary production Elevated FSH Mild elevation of hCG hCG level normal for menopause Low oestradiol Consistent with primary ovarian failure Amenorrhoea noted Pregnancy not indicated Exclude heterophile antibodies Exclude 2° causes of +hCG Exclude trophoblastic tumour Exclude hCG of pituitary origin Exclude malignancy Exclude germ cell tumour Exclude non-trophoblastic tumour Hormone replacement x 2 weeks / repeat hCG Suggest serial hCGs Suggest OCP for 2–3 weeks / repeat hCG Repeat hCG Repeat hCG in 1–2 weeks Premenopause/non-pregnant reference range 49 year old female ?Specificity of hCG assay Elevated LH expected Exclude liver disorders Reference range of <2 noted Suggest TSH ?Hypothyroidism Request further clinical history Exclude pregnancy Suggest LH levels ?History gestational trophoblastic disease Elevated hCG Markedly elevated FSH Exclude gastrointestinal tract disorders NOT SUPPORTED KEY WORDS Repeat hCG at 48 h exclude pregnancy Premature ovarian failure Repeat FSH/oestradiol Exclude dyslipidaemia Exclude familial persistent hCG Suggest prolactin Exclude hormone therapy Suggest progesterone levels Exclude autoimmune disease Exclude diabetes hCG result not normal Suggest renal function tests MISLEADING KEY WORDS Suggest ultrasound Suggest bone scan Exclude osteoporosis Suggest abdominal CAT scan Case 14-04 Reproductive Patient ID 22-year-old female Patient Location Endocrinology Outpatients Clinical Notes on Request Form Amenorrhoea ?polycystic ovarian syndrome. Case Details Total Testosterone DHEAS SHBG 17-OH Progesterone Prolactin 5.1 nmol/L 4.2 µmol/L >180 nmol/L 14.4 nmol/L 2119 mIU/L (0.5–2.6) (4.0–10) (27–109) (Follicular phase 0.5–3.3; Luteal phase 2.1–9.4) (59–619) Suggested Comment The combination of a markedly elevated sex hormone binding globulin (SHBG) with raised androgens and prolactin are consistent with pregnancy. Measurement of human chorionic gonadotropin (hCG) is advised. Rationale Undiagnosed pregnancy (typically at the first or early second trimester) is always a differential diagnosis for amenorrhoea. Sustained increases in hCG, oestradiol and progesterone (including 17-OH progesterone) are early hormonal changes required for the viability of the embryo. During trimesters 1 and 2, sex hormone binding globulin (SHBG) production is stimulated by the increasing oestrogen levels, and consequently results in increased total (but not free) testosterone levels. At the same time, DHEAS levels decline due to increased metabolic clearance while prolactin increases in preparation for lactation. Another significant change (not included in this case) is a decline in TSH often to values well below those seen in non-pregnancy. The unique combination of all these findings is only seen in pregnancy and can be easily confirmed with measurement of human chorionic gonadotropin (hCG). References 1. Handbook of Clinical Laboratory Testing During Pregnancy. Ed: Gronowski AM. Totowa, NJ: Humana Press, 2004. 2. McClamrock HD. Androgen Production and metabolism in normal pregnancy. In: UpToDate, Barbieri RL (Ed), UpToDate, Waltham, MA; 2013. PREFERRED KEY WORDS Results consistent with pregnancy Raised sex hormone binding globulin (SHBG), testosterone, prolactin consistent with pregnancy Exclude pregnancy Suggest serum human chorionic gonadotropin (hCG) LESS RELEVANT KEY WORDS Suggest FSH, LH Exclude macroprolactinaemia Hyperprolactinaemia Exclude oral contraceptives ?Congenital adrenal hyperplasia Results do not suggest polycystic ovarian syndrome (PCOS) Elevated 17-OH progesterone Suggest oestrogen Raised SHBG, testosterone, prolactin Raised SHBG - PCOS unlikely Exclude exogenous hormonal therapy Raised testosterone due to raised SHBG Specialist management noted NOT SUPPORTED KEY WORDS Exclude PCOS Exclude drug related/stress Suggest synacthen test with 17-OH progesterone Suggest ovarian ultrasound ?Pituitary adenoma Suggest morning cortisol ?Prolactinoma Exclude ovarian and adrenal tumours Exclude Cushing's Syndrome Exclude pituitary disease Suggest IGF-1 ?Anorexia nervosa Suggest electrolytes and glucose Suggest 17-OH progesterone Suggest androstenedione Repeat morning prolactin Normal DHEAS - adrenal tumour unlikely Suggest liver function tests Euthyroid Exclude renal impairment Suggest insulin ?Cirrhosis Suggest urinary steroid profile ?Causes of androgen excess Suggest CYP21A2 gene testing Clinical correlation recommended. Suggest repeat tests after 3 months off oral contraceptive pills Suggest dexamethasone suppression test Exclude acromegaly Raised SHBG ?liver disease Suggest free testosterone Confirm with raised blood pressure, ACTH and progesterone Suggest progesterone and oestradiol Normal free androgen index Investigate virilisation Exclude obesity Normal DHEAS excludes congenital adrenal hyperplasia If PCOS - risk of gestational diabetes Elevated prolactin not consistent with PCOS ?Dopamine suppression Would not usually comment Results possibly consistent with oestradiol therapy Suggest thyroid function tests Suggest 2h oral glucose tolerance test with HbA1c Suggest fasting lipids Consider idiopathic hirsutism Consider hypothalamus amenorrhoea Suggest HbA1c Suggest 11-deoxy cortisol Suggest 11-deoxy corticosterone MISLEADING KEY WORDS ?Late onset congenital adrenal hyperplasia Exclude hypothyroidism Raised testosterone and SHBG consistent with PCOS Results consistent with late onset congenital adrenal hyperplasia Hyperandrogenism with elevated free androgen index Suggest growth hormone Normal TSH excludes pituitary adenoma Raised prolactin and testosterone consistent with PCOS Suggest 21-hydroxylase level Elevated testosterone suggestive of PCOS Case 6-08 Iron Patient ID 44-year-old man Patient Location Medical Ward Clinical Notes on Request Form Severe anaemia Case Details Serum Iron Studies Iron Transferrin Transferrin Saturation Ferritin 45 µmol/L 23 µmol/L 97% 2170 µg/L Additional Information Previous result 4 weeks ago: Iron Transferrin Transferrin Saturation Ferritin 13 µmol/L 27 µmol/L 23% 122 µg/L (10–30) (18–33) (13–47) (20–300) Recently transfused 2 units. Suggested Comment These results are incompatible with previous results and suggest iron overload. Markedly elevated ferritin could be caused by infection/inflammation or liver damage, but one would expect low iron and transferrin in the acute phase. Suggest liver function tests, C-reactive protein and repeat sample collection. Rationale While frequent transfusion, as seen in patients with thalassaemia and after bone marrow transplantation, can cause iron overload and increase serum iron indices, a single transfusion does not elevate ferritin and only transiently elevates (<36 hours) iron and transferrin saturation (1, 2). Haemolysis after a transfusion reaction can release red cell ferritin, but a unit of packed red cells contains around 250 µg/L of ferritin and cannot explain the markedly changed result. The observed changes could be due to a sample mix-up or a combination of different factors elevating both the ferritin (inflammation, liver injury) and the iron (iron therapy). References 1. Ho CH. The effects of blood transfusion on serum ferritin, folic acid, and cobalamin levels. Transfusion 1992;32:764-5. 2. Saxena S, Shulman IA, Johnson C. Effect of blood transfusion on serum iron and transferrin saturation. Arch Pathol Lab Med 1993;117:622-4. PREFERRED KEY WORDS Ferritin too high for transfusion only ?Acute phase/infection /inflammation ?IV/IM iron therapy ?Liver disease ?Sample mix-up Suggest liver function tests Suggest C-reactive protein/ESR Seek more clinical info Recollect sample LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS Increased iron/saturation/ferritin Iron overload Repeat 4-12 weeks Previous normal iron studies Suggest full blood count/haemoglobin studies ?Haemolysis Iron studies unreliable due to transfusion Iron deficiency unlikely ?Haemochromatosis ?Previous transfusions Not iron overload Consult pathologist Secondary to transfusion ?Transfusion reaction Suggest haemolysis markers/screen ?Ineffective erythropoiesis ?Chronic disease/malignancy Suggest B12/folate Suggest HFE gene testing Suggest renal function tests/glucose/CA125/other Haemochromatosis excluded Anaemia of chronic disease ?Aged/haemochromatosis blood product Suggest liver biopsy, CT scan Cease iron therapy ?Acute iron toxicity Suggest protein electrophoresis Treat with iron chelators No comment Ferritin too high for inflammation only Case 7-01 Iron Patient ID 44-year-old female Patient Location Medical Ward Clinical Notes on Request Form Inflammatory bowel disease. ?Iron deficient Case Details Iron Transferrin Transferrin Saturation Ferritin 2 µmol/L 24 µmol/L 4% 57 µg/L (11–32) (23–46) (13–48) (30–220) Additional Information Haemoglobin Platelets Leucocytes Haematocrit MCV MCH MCHC C-Reactive Protein 100 g/L 371 x109 12.4 x109 0.310 85 fL 27.9 pg 326 g/L 22 mg/L (115–155) (150–400 x109) (4.0–10.0 x109) (0.36–0.49) (81–98) (29.0–33.0) (320–360) (<10) Suggested Comment A low-normal transferrin and normal MCV suggests that anaemia due to chronic disease is more likely than iron deficiency. However, a normal ferritin level does not exclude iron depletion in the presence of inflammation. Rationale Anaemia is the most common systematic complication of inflammatory bowel disease (IBD). In patients with mild/remitting disease, this should be screened for using haemoglobin, C-reactive protein and ferritin every 612 monthly. In active disease, the testing frequency should be at least 3 monthly. Serum ferritin is a positive acute phase reacting protein and may be raised when inflammation is present. In IBD patients without clinical or biochemical evidence of inflammation, a serum ferritin of <30 µg/L would indicate iron deficiency. In the presence of inflammation, the lower limit of serum ferritin indicating normal iron stores is >100 µg/L. Red cell indices may help in differentiating iron deficiency anaemia from anaemia of chronic disease, with a normal MCV favouring the latter diagnosis in this case. However, vitamin B12 and folic acid deficiency, if present, may complicate the picture, as they cause macrocytosis. The red cell distribution width may help in this scenario: a low value makes combined effects of vitamin and iron deficiency much less likely. Measurement of soluble transferrin receptor (with the calculation of TrR/log ferritin ratio) has been advocated in this situation although it is not widely accepted yet. References 1. Gasche C, Lomer MC, Cavill I, et al. Iron, anaemia, and inflammatory bowel diseases. Gut 2004;53:1190-7. 2. Gasche C, Berstad A, Befrits R, et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 2007;13:1545-53. PREFERRED KEY WORDS Transferrin borderline low Normal MCV Inflammation Iron study affected by inflammation Ferritin is acute phase reactant ?Anaemia of chronic disease ?Effect chronic illness Iron deficiency not excluded Suggest soluble transferrin receptor LESS RELEVANT KEY WORDS Iron deficiency Ferritin normal Elevated C-reactive protein Iron low Transferrin saturation low Anaemia evident ?Infection Elevated leucocyte count Suggest repeat at later date Suggest trial iron therapy Low MCH/MCHC Unable to assess iron status Suggest blood film Haemoglobin low Reduced iron stores Suggest vitamin B12/folate ?Blood loss ?Malabsorption Ferritin lower than expected Iron deficiency unlikely ?Nutritional state Consistent with clinical notes Suggest occult blood and faecal culture Suggest reticulocytes ?Intestinal iron loss Transferrin normal Suggest bone marrow aspiration Suggest gliadin antibodies ?Ineffective erythropoiesis Low haematocrit UNACCEPTABLE KEY WORDS Normal iron stores ?Diurnal variation ?Malignant disease Suggest liver function tests Suggest imaging ?Haemoglobinopathy ?Protein losing state Suggest sigmoidoscopy Erythrocyte parameters normal Suggest examination ?Haemolysis Case 8-10 Iron Patient ID 57-year-old female Patient Location Medical Outpatient Department Clinical Notes on Request Form Iron deficiency? Case Details Iron Transferrin TIBC Transferrin Saturation Ferritin 6 µmol/L 3.8 g/L 86 µmol/L 7% 7 µg/L (9–30) (2.2–4.0) (50–90) (15–45) (20–150) Additional Information Hb MCV RDW PLT WCC 104 g/L 69.8 fL 16.2% 252 x109 8.6 x109 (110–180) (80–98) (<14.5) (150–400 x109) (4.0–15.0 x109) Suggested Comment Results consistent with iron deficiency. Suggest further investigation for underlying causes such as blood loss, malabsorption or dietary deficiency. Rationale In iron deficiency, serum ferritin, iron and transferrin saturation may be decreased while total iron binding capacity (TIBC), red cell protoporphyrin and soluble transferrin receptor (sTfR) may be increased. Of these, serum ferritin is the most powerful test. The diagnostic cut-off is 12–15 µg/L, but <50 µg/L with co-existent disease. sTfR/logl0 serum ferritin ratio provides superior discrimination in patients with chronic disease. Microcytosis and hypochromia are sensitive indicators of iron deficiency in the absence of co-existent B12 or folate deficiency, but are also present in haemoglobinopathies (e.g. thalassaemia), in sideroblastic anaemia and in some anaemias of chronic disease. Gastrointestinal blood loss is the commonest cause in adult men and post–menopausal women (exclude colonic and gastric carcinoma by endoscopy). Malabsorption (exclude coeliac disease), poor dietary intake, blood donation, gastrectomy and use of non-steroidal anti-inflammatory (NSAID) medications are other common causes. Reference 1. British Society of Gastroenterology Guidelines for the Management of Iron Deficiency Anaemia. http://www.bsg.org.uk/pdf_word_docs/iron_def.pdf PREFERRED KEY WORDS Consistent with iron deficiency Iron deficiency Stage III (anaemia) Microcytic anaemia Thalassaemia unlikely ?Blood loss ?Gastrointestinal tract blood loss ?Dietary/nutritional deficiency ?Malabsorption ?Coeliac disease Suggest gastroscopy/colonoscopy Suggest coeliac antibodies Iron supplementation recommended LESS RELEVANT KEY WORDS Low serum ferritin Low serum iron Low transferrin saturation Suggest occult blood Clinical assessment recommended High normal transferrin Increased total iron binding capacity ?Thalassaernia trait Microcytic Increased red cell distribution width Investigate cause, post-menopausal Monitor iron studies/full blood count Suggest haemoglobin electrophoresis Suggest blood film review Suggest soluble transferrin receptor assay Anisocytosis Suggest MCH, red cell count ?Intravascular haemolysis Depleted iron stores Monitor therapy with reticulocyte count Iron deficiency Stage II Suggest follow up (not specified) ?Abnormal vaginal bleeding UNACCEPTABLE KEY WORDS The facts speak for themselves ?Pulmonary haemosiderosis Case 11-04 Iron Patient ID 28-year-old male Patient Location General Practice Clinical Notes on Request Form ?Abnormal LFTs. ?Cause Case Details Serum Iron Studies Iron 60 μmol/L Transferrin 2.73 g/L Saturation 88% Ferritin 1230 μg/L Haemolysis + Icterus ++ Additional Information T. Protein 68 g/L Albumin 36 g/L ALP 304 U/L Bilirubin 134 μmol/L GGT 300 U/L AST 2407 U/L ALT 2019 U/L LD 505 U/L (10–27) (1.50–3.00) (20–50) (30–400) (60–82) (35–50) (30–120) (<25) (<50) (<41) (<51) (50–280) Suggested Comment This patient has acute hepatocellular injury, which can cause markedly elevated ferritin levels. The increased serum iron concentration raises the possibility of haemochromatosis, although the latter does not usually present with acute hepatitis. Repeat iron studies after resolution of hepatitis are suggested and if persistently abnormal, genetic testing for haemochromatosis is indicated. The most common causes of acute hepatitis are viral hepatitis, alcohol, drugs, toxins, autoimmune hepatitis, and Wilson's disease. Rationale In acute hepatocellular injury there are marked increases in ferritin. As the liver ferritin is rich in iron, the percentage iron in transferrin stays the same. Iron is not commonly elevated in this setting (1). In acute phase reaction, not only are ferritin levels elevated but iron and transferrin are suppressed, which is not seen here. The typical changes seen in iron overload and genetic haemochromatosis are elevated iron and iron saturation, with concomitant high ferritin levels; however, transaminases are not markedly abnormal and only in advanced cirrhosis do the bilirubin levels increase. Therefore in this case the cause of the acute hepatitis needs to be investigated and explained before further attention is given to the iron studies. Reference 1. Brill S, Weinberg M, Graff E, et al. The status of serum iron and transferrin saturation in acute nonhepatotrophic viral infections. J Med 2000;31:271-7. PREFERRED KEY WORDS Abnormal iron studies secondary to liver disease Acute liver disease Hepatocellular damage Interpret iron in context of liver disease Atypical of haemochromatosis alone ?Alcohol/drugs/toxins ?Hepatitis ?Acute viral hepatitis ?Wilson's disease ?Metabolic/toxic/ischaemic injury ?Autoimmune hepatitis ?Acute alcohol hepatitis ?Infectious mononucleosis Suggest repeat iron studies when liver function tests normalise Suggest hepatitis serology Suggest EBV serology Suggest CMV serology LESS RELEVANT KEY WORDS ?Haemochromatosis Suggest HFE gene mutation analysis ?Iron overload High ferritin Abnormal liver function tests Increased transferrin saturation Elevated serum iron ?Haemolysis Marked transaminitis Suggest full blood examination Abnormal iron studies Suggest clinical evaluation ?Haematological disorder ?Iron overdose Suggest drug screen (including paracetamol) Suggest autoantibodies Mixed hepatocellular/cholestasis ?Inflammatory process ?Cholestasis Suggest repeat iron studies Suggest clotting studies ?Repeat blood transfusion ?Chronic liver disease Suggest caeruloplasmin/copper ?Porphyria cutanea tarda ?Anaemia/B thalassaemia major Suggest conjugated bilirubin ?Acute phase response ?Infection Repeat iron studies on fasting specimen ?Autoimmune disease Suggest blood alcohol Suggest testosterone/thyroid function tests Normal transferrin Suggest imaging studies ?Juvenile haemochromatosis Suggest repeat liver function tests ?Herbal supplements Suggest alpha-1-antitrypsin/phenotype Suggest diabetes mellitus screening Suggest porphyrin screen ?Fatty liver Suggest renal function tests Suggest urine copper Iron overload unlikely Haemolysis not cause of abnormal iron studies Haemolysis can cause abnormal iron studies UNACCEPTABLE KEY WORDS Iron overload resulting in liver disease ?Neoplasia Suggest liver biopsy Suggest test/monitor AFP Suggest desferrioxamine challenge test ?Vitamin B12/folate deficiency Case 13-08 Iron Patient ID 58-year-old male Patient Location General Practice Clinical Notes on Request Form Rheumatoid arthritis. Case Details Serum Iron Transferrin % Saturation Ferritin AST 5 μmol/L 3.0 g/L 7% 48 μg/L 31 U/L Additional Information Hb 140 g/L MCV 85 fl MCH 28 pg (10–27) (1.5–3.0) (15–45) (30–250) (5–55) (130–180) (82–98) (27–52) Suggested Comment Iron studies suggest non-anaemic iron deficiency in the context of chronic inflammatory disease. Borderline low MCH also noted. Suggest consider oral iron replacement trial and repeat iron studies and full blood examination in 3 months with CRP. Consider gastrointestinal investigation for malabsorption (coeliac disease) or blood loss, if iron stores decline further or anaemia develops. Rationale Ferritin is a positive acute phase reactant. In the setting of a chronic inflammatory condition such as rheumatoid arthritis, a ferritin of 48 μg/L does not guarantee normal iron stores. Rather, a level <50–60 μg/L together with the low iron saturation, borderline low MCH and borderline high transferrin all support iron deficiency; anaemia only occurs in the final stage of iron deficiency and is not (yet) present in this case. The prevalence of gastrointestinal malignancy is low in iron deficiency without anaemia and given the borderline results in this case, a conservative approach to further invasive investigation seems reasonable. British guidelines suggest empirical oral iron replacement for 3 months and coeliac screen (by anti-tissue transglutaminase antibody testing) in this setting, although upper and lower gastrointestinal investigations could be considered in men >50 years depending on the clinical setting. Finally, patients with rheumatoid arthritis and iron-deficiency anaemia are likely to have more severe joint disease, but will respond to treatment if anaemia is corrected. References 1. Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency anaemia. Gut 2011;60:1309-16. 2. Pasricha SR, Flecknoe-Brown SC, Allen KJ, et al. Diagnosis and management of iron deficiency anaemia: a clinical update. Med J Aust 2010;193:525-32. 3. Wilson A, Yu HT, Goodnough LT, et al. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med 2004;116 Suppl 7A:50S-57S. PREFERRED KEY WORDS Borderline iron stores Ferritin <100mg/L Chronic inflammatory rheumatoid disease False normal ferritin ?Fe deficiency Absence of anaemia Iron deficiency not excluded Transferrin and ferritin acute phase reactants Inflammation masks iron deficiency Inflammation can elevate ferritin Possible low iron stores ?Iron deficiency due to immunosuppressive drugs ?Chronic/acute inflammation ?Blood loss ?Chronic disease ?Iron deficiency with acute phase reaction Suggest soluble transferrin receptor Suggestive of iron deficiency Suggest CRP/ESR Monitor full blood examination Suggest creatinine/liver function tests Suggest ratio sTfR and log ferritin Diet and drug review Monitor 1–2 monthly LESS RELEVANT KEY WORDS Low serum iron Low transferrin saturation Normal Hb and erythrocyte indices Normal ferritin Borderline/high transferrin Suggestive of diurnal variation of serum iron Low/normal ferritin Suggest rheumatoid factor Suggest vitamin B12/erythrocyte folate Normal transferrin Monitor ferritin Suggest repeat fasting early am iron studies Low/normal MCV Check collection time Suggest hepcidin on GCMS Suggest reticulocyte-haemoglobin equivalent and use Thomas plot NOT SUPPORTED KEY WORDS Anaemia of chronic disease Possible iron deficiency anaemia Suggest bone marrow aspirate/bone marrow iron stores ?Normocytic normochromic anaemia Complicated by anaemia Suggest erythropoietin Suggestive of normal iron studies Iron deficiency anaemia not indicated Mild disease/no progression or treatment High ferritin Anaemia of chronic disease unlikely Acute phase reaction unlikely Suggest gastrointestinal endoscopy MISLEADING KEY WORDS Suggest faecal occult blood Iron deficiency unlikely Suggest iron sufficiency Normal iron stores Case 10-03 Tumour Markers Patient ID 70-year-old woman Patient Location Oncology Outpatients Clinical Notes on Request Form Mass in head of pancreas (of unknown aetiology) with stent placed 4 weeks ago for obstructive jaundice. Case Details Serum CA 19-9 22 U/mL Additional Information Previous result (4 weeks ago): Serum CA 19-9 5010 U/mL (<38) (<38) Suggested Comment Provided specimen integrity and resection are excluded, the marked decrease in CA 19-9 is consistent with relief of biliary obstruction. The CA 19-9 concentration post-stenting does not differentiate a malignant from a non-malignant lesion and should be evaluated in the context of further clinical investigations. Rationale CA 19-9 is the sialylated Lewis blood group antigen, and is absent in individuals with Lewis Le (a-b-) that make up 5% of Caucasian and 20–25% of African Americans. CA 19-9 concentrations greater than 1000 U/mL are observed in non-malignant conditions including obstructive jaundice, cholangitis, acute liver failure, acute hepatitis, alcoholic liver disease and acute pancreatitis. In patients with jaundice and elevated CA 19-9, it is recommended that CA 19-9 be repeated after relief of jaundice. The half-life of CA 19-9 has been variously estimated at between <1 day and 4-8 days. CA 19-9 is not recommended for the diagnosis of pancreatic cancer but is recommended for monitoring of treatment of patients with pancreatic cancer. References 1. Goonetilleke K, Siriwardena A. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007;33:266-70. 2. Chintanaboina J, Badari AR, Gopavaram D, et al. Transient marked elevation of serum CA 19-9 levels in a patient with acute cholangitis and biliary stent. South Med J 2008;101:661. 3. Mauer KR, Lopatin RN, Hoffman WA, et al. Decrease in a markedly elevated CA19-9 level after stenting of a benign pancreatic ductal stricture. Gastrointest Endosc 1995;42:261-3. PREFERRED KEY WORDS Marked decrease in CA 19-9 CA 19-9 not a diagnostic tumour marker Benign/malignant not differentiated CA 19-9 <38 U/mL tumour not excluded Half-life is 4–8 days consistent with drop Drop consistent with obstructed duct stenting Non-cancer conditions can cause elevation ?High CA 19-9 due to obstructive jaundice ?Normal CA 19-9 due to lab error ?Obstructive hepatobiliary disease Suggest further investigations Monitor CA 19-9 in pancreatic cancer LESS RELEVANT KEY WORDS UNACCEPTABLE KEY WORDS CA 19-9 normal range post surgery Pancreatic malignancy unlikely High CA 19-9 in pancreatic tumour Suggest CEA to exclude malignancy Request clinical information Clinical information not consistent with Suggest biopsy of pancreatic mass CA 19-9 drop High CA 19-9 in pancreatitis Likely malignancy Suggest repeat CA19-9 ?Heterophile antibody Monitor CA 19-9 Poor prognosis Interpret CA 19-9 with caution ?Sclerosing cholangitis/ ?Antigen excess/hook effect cholangiocarcinoma ?High levels due to inflammation Removal of tumour pancreas/ ?Hepatobiliary inflammation gastrointestinal tract Raised CA 19-9 in gastrointestinal tract tumours ?Other causes of high CA 19-9 ?Chemo/radiotherapy/resection Reassay CA 19-9 22 U/mL in dilution Good response to treatment ?High CA 19-9 due to chronic liver disease Suggest imaging Monitor liver function tests ?Surgery to remove mass Reassay CA 19-9 22 U/mL sample No comment ?High CA 19-9 due to cholangitis CA 19-9 increased in gastrointestinal tract conditions CA 19-9 levels related to tumour size Suggest liver function tests pre/post stent High CA 19-9 in ovary/ breast tumour High CA 19-9 in biliary cancer ?Both CA 19-9 done on same platform CA 19-9 excreted in bile Pancreatic mass causes jaundice Post surgery Exclude autoimmune pancreatitis Assume hook effect excluded No evidence of resection Input of oncologist not required Case 11-09 Tumour Markers Patient ID 44-year-old male Patient Location General Practice Clinical Notes on Request Form Screening Case Details PSA 2.2 µg/L (<2.51) Additional Information No previous results Suggested Comment A total PSA above the median for this age may be associated with a modest increased risk of prostatic neoplasia. Suggest repeat with free to total PSA ratio and mid-stream urine examination. PSA sample should be collected at least 48 hours after any prostate manipulation or ejaculation. Rationale The Urological Society of Australia and New Zealand supports selected screening with PSA and digital rectal examination (DRE) in men after 40 years. It is assumed knowledge for the medical practitioner that the positive predictive value of PSA is increased when used in combination with DRE. This man’s PSA is above his age-related median, which is approximately 0.6–0.8 µg/L depending on method. It confers increased risk for prostate cancer. Assuming that the request in a man of this age was generated due to family history or significant personal concern, it seems reasonable to try and clarify the patient’s risk in a timely manner rather than waiting 12 months or more, even though his absolute risk of prostate cancer is small. There are no guidelines on repeat testing interval. However, in Australia, the Medicare Benefits Schedule will rebate for one measurement of free to total PSA ratio in a calendar year for this case, where the total PSA is between the median and the upper limit of age-related reference interval to support early diagnosis. Urinary tract infections or prostate manipulation due to DRE, sexual intercourse, strenuous bike riding etc can elevate PSA. Free PSA is labile under normal laboratory storage and handling conditions. Retrospective testing for free PSA is unreliable unless performed within 24 hours of collection or the serum has been frozen at the time of sample preparation. A fresh, optimal sample is preferred for free to total PSA ratio estimation. Reference 1. Urological Society of Australia and New Zealand PSA Testing Policy 2009. PREFERRED KEY WORDS PSA above age-related median Prostatic carcinoma not excluded ?Increased risk of prostatic neoplasia ?Preanalytical variables Suggest follow-up Suggest free/total PSA ratio Suggest clinical correlation Suggest digital rectal exam Suggest repeat PSA Exclude lower urinary tract infection Monitor PSA using same assay Consider complexed PSA Exclude acute causes LESS RELEVANT KEY WORDS PSA within reference limits PSA within age-related reference limits Review family history Suggest repeat PSA in 12 months Consider PSA velocity Not an ideal screening test Suggest repeat PSA ratio in 12 months Assess other risk factors Patient should be informed before testing PSA at upper end of reference range Suggest repeat PSA in 6 months Screening benefits not proven Suggest repeat PSA in 6–12 months ?Reference range PSA <10 µg/L Suggest repeat PSA in 2 years Suitable as a screening test ?Medians for PSA UNACCEPTABLE KEY WORDS Suggest repeat screening in 2–4 years Check PSA for hook effect Low PSA Suggest repeat PSA in 5 years PSA testing not useful at this age No comment Inform clinician of assay calibration Recheck result with different assay Case 7-10 Toxicology/TDM Patient ID 45-year-old man Patient Location Emergency Department Clinical Notes on Request Form Acute liver inflammation. ?cause Case Details Mini toxicology screen (serum): Paracetamol Not detected Salicylate 116 mg/L Ethanol Not detected Additional Information Sodium 141 mmol/L Potassium 3.9 mmol/L Urea 1.8 mmol/L Creatinine 65 µmol/L Albumin 21 g/L Total Protein 52 g/L Bilirubin 408 µmol/L Alk. Phos. 155 U/L ALT 3670 U/L (134–146) (3.4–5.3) (3.0–8.0) (60–110) (35–50) (63–80) (<20) (35–105) (<41) Suggested Comment Undetectable serum paracetamol does not exclude paracetamol-induced liver toxicity, if the sample was collected sufficiently long after exposure. Salicylate concentration is below the toxic range for recent acute exposure or ongoing chronic exposure. Note that hepatocellular damage is an uncommon outcome of salicylate exposure in adults. Viral studies as directed by history are suggested. Addition of serum AST is suggested. Rationale A set of toxicology results has been produced for a patient with liver function tests consistent with acute on chronic liver disease with a note on the request form recognising the acute liver inflammation and querying the cause. Of the drugs measured on this request, paracetamol is the most important liver toxin and most frequent toxicologic cause of liver transplant. Importantly, a negative result doesn’t exclude paracetamol overdose as a cause of the acute liver damage at a time sufficiently long before the blood test for the paracetamol to have cleared from the circulation (half-life of paracetamol: 1–3 hours). Salicylate overdose is a rare cause of acute hepatitis in adults, particularly when no other metabolic consequences of salicylate toxicity are noted. The undetectable serum alcohol makes this a less likely cause of the acute hepatitis. Note that for interpretation of all the drug concentrations, history taking and other evidence are important to determine the possible timing and extent of any overdose. Addition of AST may be of assistance as an elevated AST/ALT ratio would be consistent with hepatic necrosis due to a toxic insult. Note only those comments directly related to the results currently being reported are being scored as ‘preferred’ with exception of a suggestion for viral studies. Comments related to less common causes of hepatitis are marked ‘less relevant’ as they would most likely be second-line tests after common causes have been excluded. Many submitted comments were directed at interpreting the liver function tests and would not normally be attached to a set of toxicology results. PREFERRED KEY WORDS Paracetamol toxicity not excluded Salicylate below toxic levels Salicylate unlikely cause Ethanol toxicity not excluded ?Time of ingestion ?Drug history ?Viral infection Suggest hepatitis serology Suggest ALT/AST ratio Bilirubin interferes with salicylate analytically LESS RELEVANT KEY WORDS Acute onset Hepatocellular damage Hepatic inflammation/hepatitis Low albumin Salicylate toxicity not excluded High bilirubin ?Toxic insult Suggest coagulation studies High ALT Severe disease Low urea Synthetic/conjugation impairment Underlying chronic disease Suggest AST/GGT/LDH Hepatic failure Paracetamol not detected Mixed obstructive hepatic Suggest acid-base investigations ?Clinical history Monitor salicylate ALT mildly elevated Suggest ammonia Suggest liver imaging Ongoing insult ?Protein intake/loss Suggest drug screen Suggest liver autoantibodies Suggest further investigations No evidence renal failure Suggest clinical examination ?Wilson’s disease Suggest full blood examination Suggest haemolysis markers ?Adult Reye’s Syndrome ?Acute biliary obstruction Suggest conjugated and unconjugated bilirubin ?Ischaemic insult Suggest alpha-l-antitrypsin ALP due to cells swelling Repeat liver function tests ?Haemolysis Suggest copper studies Suggest iron studies ?Alcohol abuser Discuss with requesting doctor ?Reduced drug clearance ?Autoimmune hepatitis ?Primary biliary cirrhosis Monitor Risk of liver failure Suggest monitor creatinine Risk of metabolic acidosis ?Non-viral infection Suggest glucose ?Acute or chronic disease UNACCEPTABLE KEY WORDS Refer to pathologist Suggest immunoglobulins Vitamin K may be required Suggest AFP Repeat paracetamol Chronic onset ?Malignancy Case 8-02 Toxicology/TDM Patient ID 92-year-old woman Patient Location Nursing Home Clinical Notes on Request Form ?Temporal arteritis. Increased ESR. Diltiazem CR 240mg. Case Details Serum carbamazepine level: <3 umol/L Additional Information List of medications: isosorbide, diltiazem, aspirin, hydrochlorothiazide, thyroxine, neo-cytamen, caltrate, ostelin, macu-vision, losec and prednisone. Suggested Comment Carbamazepine was undetectable in the sample. Suggest check authenticity of request and compliance to medication. Rationale Carbamazepine is not detected in the patient sample and is not amongst the many medications listed. One therefore questions whether the request is an authentic one. If so, one may question medication compliance, although this is usually expected to be well supervised in a nursing home environment. One might consider drug interaction with cytochrome P450 3A4 (CYP3A4)-inducing agents, leading to a reduced concentration, although none of the other drugs listed fall into this category. On the contrary, diltiazem is an inhibitor of CYP3A4 and might be expected to increase carbamazepine levels. PREFERRED KEY WORDS Carbamazepine not detected Check if patient is taking carbamazepine Carbamazepine not included in drug history Subtherapeutic carbamazepine level ?Correct test ordered Check request correct Check if carbamazepine prescribed Results suggest patient not taking carbamazepine Other medications unlikely to cause low carbamazepine ?Correct dose carbamazepine given LESS RELEVANT KEY WORDS Check collection time ?Drug interaction (not specified) ?Hepatic enzyme induction Review patient’s medication Repeat/monitor level ?Preanalytical error No comment ?Malabsorption ?Patient withdrawn from diltiazem Check electrolytes/renal function Test because ?accidental ingestion UNACCEPTABLE KEY WORDS Diltiazem increases levels/decreases clearance carbamazepine ?Non-steady state Suggest thyroid function tests Suggest liver function tests Note diltiazem levels unavailable Urgent review required Monitor patient ?Due to interaction with diltiazem Suggest other tests Suggest increase carbamazepine dose Repeat test in steady-state Consider peak levels ?Patient fitting ?Interference Suggest measure free carbamazepine Consider preanalytical factors Suggest temporal artery biopsy Review thyroxine replacement Carbamazepine can alter thyroid function test results Case 9-09 Toxicology/TDM Patient ID 51-year-old female Patient Location Emergency Department Clinical Notes on Request Form Paracetamol overdose 16 hours ago. Case Details Paracetamol 30 mg/L Additional Information ALT 165 U/L (<40) Suggested Comment Serum paracetamol concentration is potentially toxic and may warrant N-acetylcysteine (NAC) therapy since the blood concentration is above the toxic line on the treatment nomogram at 16 hours post ingestion. Moderately increased ALT suggests liver injury. Repeat ALT at end of NAC infusion together with INR, urea and electrolytes, blood gases and glucose. Rationale The absorption of paracetamol in the small intestine is rapid, giving peak serum concentrations within 1-2 hours with pill formulations and sooner with liquid preparations (30 minutes). Ninety percent of absorbed paracetamol undergoes hepatic conjugation with sulphate and glucuronide, and are excreted in the urine. The remainder is metabolised into the highly reactive intermediary compound N-acetyl-p-benzoquinone imine (NAPQI) via the cytochrome P450 (mainly 2E1 and 3A4) pathways. Normally, the NAPQI is immediately conjugated by intracellular glutathione and excreted in the urine. In the presence of excess paracetamol, and thence NAPQI, glutathione stores may become depleted, leaving NAPQI to bind with other proteins, causing hepatotoxicity. When this happens, N-acetylcysteine (NAC) is administered and works by serving as a glutathione replacement, a free radical scavenger, binding NAPQI directly and increasing microcirculatory oxygenation. Treatment with NAC within 8 hours can prevent all serious hepatic injury, but the efficacy decreases with increasing delay. There are now well-defined guidelines for management of a single episode of acute paracetamol overdose. The treatment nomogram relates the paracetamol concentration and the known time elapsed since ingestion to determine potential toxicity and treatment recommendations. However, the treatment nomogram cannot be applied for repeated or staggered doses, or when time of ingestion is uncertain. ALT is used for assessment of liver damage and response to NAC therapy. Most patients develop AST/ALT elevations within 24 hours of ingestion and almost all will have elevations at 36 hours. Maximal hepatotoxicity occurs at 72–96 hours. A schedule for recommended investigations is detailed. References 1. Daly FF, Fountain JS, Murray L, et al. Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. Med J Aust 2008;188:296301. 2. Algren DA. Review of N-acetylcysteine for the treatment of acetaminophen (paracetamol) toxicity in paediatrics. Geneva: World Health Organization; 2008. PREFERRED KEY WORDS Toxic paracetamol level at 16 hours Nomogram paracetamol above treatment line Elevated ALT consistent with hepatotoxicity Risk of hepatotoxicity Refer to Med J Aust 2008 Guidelines Treatment required Treat immediately N-acetylcysteine therapy recommended Monitor treatment Repeat ALT ?Pre-existing liver dysfunction ?Aetiology of increased ALT N-acetylcysteine effective up to 36 hour LESS RELEVANT KEY WORDS Elevated ALT/transaminase ALT consistent with paracetamol hepatotoxicity Suggest liver function tests Suggest repeat paracetamol level Request drug and alcohol history Suggest electrolytes Assess extent of hepatic damage Confirm dose information ?Normal or slow release paracetamol Suggest AST/ALT Suggest platelet count Suggest biochemical reassessment Suggest blood gas Liver damage usually >24 hour post paracetamol overdose N-acetylcysteine efficacy declines at 18 hour Contact lab for further advice Clinical hepatitis Phone results ?No clinical contraindications ?Fasting state Suggest anion gap Suggest full blood picture Consult poisons information Pancreatitis reported in paracetamol overdose Suggest prothrombin time/international normalised ratio Suggest urea and creatinine Suggest glucose Is metabolic acidosis present? UNACCEPTABLE KEY WORDS Likelihood of paracetamol toxicity low Suggest NH4, lactate Borderline paracetamol level No comment Suggest calculation of half life Case 11-06 Toxicology/TDM Patient ID 54-year-old male Patient Location General Practice Clinical Notes on Request Form Polyuria for investigation Case Details Serum osmolality Urine osmolality 315 mmol/kg (275–295) 210 mmol/kg Additional Information Sodium Potassium Bicarbonate Urea Creatinine Glucose Calcium Albumin Corrected calcium 140 mmol/L 3.8 mmol/L 28 mmol/L 4.5 mmol/L 63 µmol/L 4.3 mmol/L 2.32 mmol/L 43 g/L 2.30 mmol/L (134–146) (3.4–5.5) (22–32) (3.0–8.0) (60–105) (fasting <5.5) (2.15–2.65) (38–50) (2.15–2.65) Suggested Comment Consider ethanol ingestion given the raised osmolar gap of 26 mmol/kg in the setting of history of polyuria. Ethanol can be measured, if required, in blood or detected in urine. Measurement of liver function tests may support regular ethanol use. A timed urine sample can be useful to separate urinary frequency from polyuria. Rationale The raised osmolar gap [= measured osmolality – (2 × sodium + urea + glucose), normally ≤ 10 mmol/kg] suggests a substance found in significant concentrations such as ethanol, which can cause polyuria due to nephrogenic diabetes insipidus, rather than lithium etc, which are not found in concentrations to explain an osmolar gap of >20 mmol/kg. Urine osmolality suggests water diuresis rather than osmotic diuresis. Methanol, ethylene glycol etc, can cause a raised osmolar gap but in such concentrations would be expected to cause a significant acidosis and toxic effects. Metabolic acidosis is unlikely given the normal bicarbonate. References 1. Purssell RA, Pudek M, Brubacher J, et al. Derivation and validation of a formula to calculate the contribution of ethanol to the osmolal gap. Ann Emerg Med 2001;38:653-9. 2. Ogata M, Mendelson JH, Mello NK. Electrolyte and osmolality in alcoholics during experimentally induced intoxication. Psychosom Med 1968;30:463-88. PREFERRED KEY WORDS LESS RELEVANT KEY WORDS Increased serum osmol gap ?Unmeasured osmoles No metabolic acidosis ?Alcohol ?Ethanol ?Ethanol- induced polyuria Suggest serum ethanol level Urine osmolality consistent with water diuresis Suggest 24 h/timed urine - check volume Suggest check liver function tests Diabetes mellitus excluded ?Medical history/medication Suggest repeat serum osmolality Inappropriately low urine osmolality ?Diabetes insipidus Elevated serum osmolality ?Ethylene glycol ?Methanol ?Mannitol ?Psychogenic polydipsia Suggest urinary electrolytes ?Polydipsia Exclude neurogenic diabetes insipidus Exclude nephrogenic diabetes insipidus Exclude diuretics Suggestive of diabetes insipidus ?Hyperproteinaemia ?Hyperlipidaemia Differentiate central from nephrogenic diabetes insipidus Suggest first morning urine osmolality ?Isopropyl alcohol ?Pituitary/head injury Suggest recollection of urine and serum Endocrinologist referral ?Sorbitol Suggest drug screen ?Genetic nephrogenic diabetes insipidus Nephrogenic diabetes insipidus not indicated ?Propylene glycol Renal deficiency not indicated ?Tetracyclines Consider further investigation Suggest plasma chloride Exclude analytical error Suggest carbohydrate-deficient transferrin Exclude renal disease/concentration defect Suggest urine creatinine level Exclude specimen contamination Suggest urine microscopy, culture and sensitivity UNACCEPTABLE KEY WORDS Suggest water deprivation test Suggest DDAVP in water deprivation test Suggest lithium levels Suggest ADH levels ?Ketoacidosis Suggest blood gas ?Lactic acidosis Suggest head-spacer gas analysis ?Fanconi syndrome Suggest phenytoin levels Suggest MRI of brain Suggest lateral X-ray of skull Suggest chromosome analysis Suggest urine amino and organic acids Suggest renin/aldosterone Suggest TSH levels Contact duty biochemist ?Evaporation artefact Suggest urine glucose Normal serum chemistry Case 14-05 Inborn Errors of Metabolism Patient ID 9-day-old baby boy Patient Location Emergency Department Clinical Notes on Request Form Term baby, 600 g weight loss and jaundice. Case Details Total bilirubin Conjugated bilirubin Unconjugated bilirubin 442 µmol/L 74 µmol/L (0–10) 368 µmol/L Additional Information Random glucose 1.9 mmol/L (Urine reducing substances +++) Suggested Comment The results are consistent with hyperbilirubinaemia due to galactosaemia. Recommend patient be placed on a lactose free diet until confirmation of galactosaemia by erythrocyte galactose-1-phosphate uridyltransferase (GALT) test. During this time other causes of hyperbilirubinaemia should be considered and assessed where appropriate. Rationale This case is a typical presentation of classical galactosaemia in a newborn baby with hyperbilirubinaemia, hypoglycaemia and positive urine reducing substances. This combination should trigger the possibility of galactosaemia, even if the baby has had a normal newborn screening test (NBS). This is because the clinical features of galactosaemia may be delayed until breast-feeding has commenced. Furthermore, false negative NBS may be observed in patients who have a blood transfusion or soy-based formula prior to the NBS. Classic galactosaemia is an autosomal recessive disorder of carbohydrate metabolism secondary to severe deficiency of the galactose-1-phosphate uridyltransferase (GALT) enzyme. Lactose should be eliminated from the diet immediately and samples should be collected for erythrocyte GALT and galactose-l-phosphate (Gal-1P). In some centres, urinary galactitol is measured. Failure to cease lactose allows toxic metabolites to continue to accumulate resulting in rapid progression to liver failure, sepsis and death. Other causes of hyperbilirubinaemia should be excluded. Note: not all Australian States (e.g. Victoria) offer galactosaemia testing as a part of NBS. References 1. Gilmour SM. Prolonged neonatal jaundice: when to worry and what to do. Paediatr Child Health 2004;9:700‐4. 2. Malone JI, Diaz‐Thomas A, Swan K. Problems with the newborn screen for galactosaemia. BMJ Case Rep 2011; doi 10.1136/bcr.01.2011.3769. 3. Berry GT. Galactosemia: when is it a newborn screening emergency? Mol Genet Metab 2012;106:7‐11. PREFERRED KEY WORDS Conjugated and unconjugated hyperbilirubinaemia ?Galactosaemia ?Inborn error of metabolism Suggest red cell GALT activity Suggest lactose free diet Suggest galactose-1-phosphate Suggest galactitol LESS RELEVANT KEY WORDS NOT SUPPORTED KEY WORDS Hyperbilirubinaemia - investigate Hypoglycaemia Reducing substance in urine Suggest liver function test/ thyroid function tests/ renal function tests/ electrolytes Suggest specialist referral Weight loss/failure to thrive Unconjugated hyperbilirubinaemia Check newborn screening results Conjugated hyperbilirubinaemia Suggest metabolic screen Suggest amino acids Suggest liver ultrasound Liver failure/dysfunction/obstruct Conjugated bilirubin >15% of total investigate At risk of kernicterus Suggest C-reactive protein/ erythrocyte sedimentation rate Suggest blood gas Suggest urine chromatography for galactose Suggest α-1 antitrypsin Hospital admission Breast fed/lactose formula Suggest ketones ?Fatty/organic acid disorders Review neonatal hypoglycaemia Suggest urine non-glucose reducing substances ?Glycosuria Give glucose Suggest test parents for galactosaemia Accumulation of galactose-1-phosphate/ galactose Isoelectric focusing for Duarte variants ?Deficiency of gluconeogenic enzyme Repeat LFT to monitor progress Conjugated bilirubin >30 µmol/L pathological Suggest lactate Suggest urine glucose ?Acute infection/sepsis Suggest full blood count including morphology ?Red cell destruction/haemolysis ?Hypothyroidism Suggest Coombs test Suggest septic screen Phototherapy/exchange transfusion ?Neonatal hepatitis Suggest Rubella/Toxo/CMV/HCV/HepB ?Glucose-6-phosphate dehydrogenase deficiency/phenylketonuria Suggest ammonia ?Hereditary fructose intolerance Suggest blood group/antibody test ?Tyrosinaemia Suggest clotting studies ?Maternal diabetes Suggest urine microscopy Suggest urine bile acids Suggest insulin ? α-1 antitrypsin deficiency Suggest cortisol/growth hormone Suggest DNA testing ABO/Rh incompatibility ?Endocrine disorder ?Lactose intolerance Dubin Johnson and Rotor syndrome ?Lipoidosis Suggest acylcarnitine Check for delta bilirubin on Vitros ?Renal tubular problems Suggest haptoglobin/lactate dehydrogenase/plasma viscosity ?Hypopituitarism Some POCT meters interference by galactose ?Trisomy 18,21/hereditary syndromes ?Glycogen storage disease Suggest galactose-free diet MISLEADING KEY WORDS ?Biliary atresia Exclude inadequate breastfeeding ?Breast milk jaundice ?Delayed bowel motility Suggest haemoglobin electrophoresis/ stool exam
