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DIFFERENTIALS Tiredness: Cardiovascular • Valvular disorders • Cardiomyopathy/CHF • Pericarditis • Varicose veins • CVA • MI • Anaemia • Thalassemia Respiratory • Pulmonary oedema • COPD • Interstitial disease / fibrosis GIT: • Liver disease (cirrhosis, fatty liver) • Hypoglycaemia / Diabetes • Obesity • Metabolic / endocrine disorder • Deficiency Other: • Infection • Neoplastic • Allergy • Drugs / Poisons • Trauma • Pregnancy / Menopause • Hypoxic environment • Radiation exposure • Psychogenic – depression, anxiety, ... PBL Case – Feeling Tired Agnes B, 92F — GP practice • Tired, not eating, light‐headed, giddy, ↓wt • Dx: Pernicious Anaemia HPC: • Light‐headedness: faintness, not vertigo • Appetite: not interested in cooking, meat 2/7, fruit & veg • Normal bowel movements • Always thin, clothes now "hanging off" her PMHx: • Stomach ulcer operation 10 years ago SHx: • Ø smoking, Ø drinking, Ø medications • Lives alone, ? able to care for herself, neighbor does shopping EXAMINATION: • Pale, slightly jaundiced, some vitiligo • Refuses breast examination • MMSE not indicated, no indication of depression Examination Findings 110/70 sitting 105/70 standing 80 bpm, regular Vitals 47 kg (was 50kg) 1.58M → BMI 18.8 Cardioresp HS dull, no murmur, chest clear Tongue red & sore (?dentures) Other Conjunctival pallor INVESTIGATIONS: • Full blood count & film Investigations Haemoglobin 80 RCC 2.0 Haematocrit 0.24 MCV 117 HCH 40 HCHC 342 WCC 3.5 Neutrophils 1.75 Platelets 135 120 – 150 3.6 – 5.2 0.33 – 0.46 90 – 98 27 – 35 310 – 365 4.5 – 10.5 2.0 – 7.5 150 – 450 g/L x 10¹²/L fL pg g/L x 10⁹/L x 10⁹/L x 10⁹/L L L L H H Causes of Tiredness in the Elderly Sleep‐deprived: Non‐sleep‐deprived: – OSA – Endocrine (hypothyroidism, Adisons) – Insomnia – Metabolic (diabetes) – Pain – Anaemia – Chronic disease – Diet – Infection – Drugs (benzos, antihistamines) L L L Oval macrocytes (sphereocytes) and hyper‐segmented neutrophils Coagulation Tests: ‐ aPTT: intrinsic pathway – PT: extrinsic pathway – Thrombin time: fibrinogen → fibrin Test Serum Iron: Poor test of status Blood film Bilirubin LD Investigations 35 350 0 – 20 μmol/L 120 – 250 μmol/L H H INITIAL MANAGEMENT: • Stomach ulcer was malignant – partial gastrectomy – no evidence of recurrance in 3 years Investigations Vitamin B12 50 130 – 660 pg/L L Red cell folate 520 360 – 1450 nmol/L Intrinsic factor antibody Positive • B12 injections initially, orally after Repeat FBC (10 days later) Haemoglobin 92 110 – 160 g/L L Reticulocytosis 150 10 – 100 x 10⁹/L H • Refuses gasteroenterologist referral for endoscopy 4 Feeling Tired (Pernicious Anaemia) GERIATRIC GIANTS Instability Incontinence Immobility Intellectual deterioration Iatrogenic IRON STUDIES Elevated TIBC (transferrin): apotransferrin : transferrin Ferritin: Proportional to Fe stored inside cells Low Liver dz, hypoplastic Chronic disease, ↓Fe, anaemia, ↓erythropoesis, post‐surgery ↓Fe ↓Fe, pregnancy, OCP ↑Fe ↑Fe, liver disease, infection, inflammation, malignancy ↓Fe, hypothyroidism, ascorbate deficiency Hepsidin: ↑Fe ↓enterocyte Fe absorption ↓Fe 7 Masqueraders: – Can present differently • Diabetes • Drugs • Depression • UTI • Spinal dysfunction • Thyroid • Anaemia p1 PBL Case – Feeling Tired Six Weeks Later: • Worried health has deteriorated, ? can't live at home any more • Requests weekly B12 injections Repeated FBC (6 weeks) Haemoglobin 100 120 – 150 g/L L MCV 84 80 – 100 fL WCC 6.4 3.5 – 10.0 x 10⁹/L L Platelets 350 150 – 400 x 10⁹/L Vitamin B12 830 130 – 660 pg/L H Serum ferritin 5 10 – 200 μg/L L TIBC 90 15 – 55 μmol/L H B12:Protein pepsin B12:R binder proteases B12:IF IF receptor @ terminal ileum • Accepts GI endoscopy referral now – Endoscopy: Atrophic gastritis in remaining stomach – Colonoscopy: normal • Started on iron supplements OUTCOME • Recovered 2 months later, coping well Repeated FBC (2 months) Haemoglobin 125 120 – 150 g/L MCV 86 80 – 100 fL Vitamin B12 DNA Synthesis Fatty acid synthesis – Important for all cells B12 (Cobalumin) Metabolism: — sources: meat, milk, eggs • Absorption requires intrinsic factor (parietal cells) 1. Freed from binding proteins by pepsin 2. B12 binds to salivary proteins (cobalophilins / R‐binders) 3. B12 released by pancreatic proteases, binds to IF 4. B12‐IF endocytosed in terminal ileum 5. B12 bounds to transcobalumin II, secreted into plasma 6. Transcobalumin II‐B12 to liver, BM, GIT lining B12 Deficiencies: FOLATE: purine nucleotide synthesis • ↓ Intake: inadequate / vegetarian One enzyme in purine pathway requires BOTH B12 & Folate • ↓ absorption: Deficiency: pancytopenia, neural tube defects (pregnancy) – Achlorhydria & loss of pepsin pdn Methotrexate/Trimethoprim: block DHF reductase – Loss of pancreatic exocrine fxn → similar effects as folate deficiency – IF deficiency: pernicious a., gastrectomy – Malabsorption – Intestinal disease (lymphoma, resection, ileitis) – Competitive uptake (tapeworm) • ↑ requirement: pregnancy, hyperthyroidism, disseminated cancer Erythropoiesis: Sites: long bones → flat bones Extra‐medullary: liver, spleen Stimulated: EPO (released from JGA @ Kidneys) Proerythroblast: committed stem cell Normoblast: expels nucleus → reticulocyte → RBC Proerythroblast Normoblast – expels nucleus 4 Feeling Tired (Pernicious Anaemia) Anisocytosis: varied RBC size Poikilocytosis: varied RBC shape Abnormal Blood Cell Types: seen on blood smear Hypersegmented nϕ: megaloblastic anaemia (>5 lobes) Target cells: ↓Fe, liver disease (codocyte) Acanthocyte: spiny, shar‐shaped – liver disease Burr cell: blunt projections – chronic renal disease Sickle cell: genetic disorder Ovalocyte: genetic disorder Spherocyte: auto‐hemolytic anaemia – genetic disorder Sideroblast: ring of iron surrounding nucleus – genetic Schisocytes: RBC fragments Tear‐drop cells: ↓Fe, myelofibrosis, thalassemia major p2 A reduction below normal limits of total circulating red cell mass → ↓ haematocrit or ↓ blood [Hb] Anaemia Mechanisms: 1. Blood loss (eg trauma, menses, haematochesia, malena, haematuria) • Loss of intravascular volume → interstitial fluid shift → ↓Hct – Leukocytosis, ↑ reticulocytes, thrombocytosis • Chronic loss: anaemia only when no Fe or loss > pdn 2. ↑ destruction • Intrinsic (RBC): membrane / enzyme / Hb problems • Extrinsic: Ab's, mechanical, infection, chemicals, hypersplenism 3. ↓ production • Stem cells: leukaemia, aplastic (all BM lines), renal failure, endocrine disorders • Erythroblasts: defective DNA synth (B12/folate deficiencies), ↓Fe, thalassaemia • Others: sideroblastic a. & a. of chronic disease, infection ➔ TICS & RACH = BLOOD Anaemia Types Microcytic Normocytic Macrocytic Thalassaemia Renal failure B12 deficnecy Iron‐deficiency Aplastic Bone Marrow Liver disease Chronic disease Chronic disease FOlate deficiency Sideroblastic Haemorrhage EtOH Drugs Aplastic a.: pancytopenia & hypocellular BM (aplasia) Haemolytic a.: RBC destruction, acquired or inherited Iron Deficiency a.: loss or insufficient uptake – bleeding, pregnancy, growth, ↓ absorption, poor diet A. of chronic disease: ↓ RBC proliferation + ↓ Fe utilization • Infections: osteomyelitis, infective endocarditis, TB • Neoplasm: Hodgkin's lymphoma, lung/breast carcinoma • Immune: rheumatoid arthritis, SLE, enteritis, Crohn's • Renal failure – ↓Fe release from BM into RBCs + ↓ EPO from cytokines Sideroblastic a.: protoporphyrin doesn't bind Fe • (heme precursor) → Excess Fe + ring sideroblasts Megaloblastic a.: delayed nuclear maturation • B12/folate deficiency: malabsorption, coeliac, pernicious a. Normoblastic a.: EtOH, ↑ reticulocytes, hypothyroidism, drugs (azathipine – immunosuppressant), pregnancy dUMP Folate‐B12‐DNA Synthesis Folate (diet) DHF Methionine THF B12 5,10‐MTHF dTMP 5‐MTHF Homocystine DNA Syndrome, not Dx! Cell Indices: • Haematrocrit (Hct): % of whole blood occupied by RBCs • Red Cell Count (RCC): RBCs / L • Mean Cell Volume (MCV): Hct / RCC (μm³) • Mean Cell Hb (MCH): Average Hb mass per RBC (pg) • Mean Cell [Hb] (MCHC): Average [Hb] per RBC (g/dL) • RBC Distribution Width (RDW): measure of RBC size variation • Reticulocyte count: immature RBCs / L • LD: abundant in RBCs — ↑ LD = haemolysis Cell Changes: 1. Cell size: {micro,normo,macro}cytic 2. Haemoglobinization: {normo,hypo}chromic 3. Special features: shape etc CLINICAL FEATURES: Compensations: • Pallor • ↑ CO: ↑ HR & ↑ SV – angina, dyspnoea, heart failure • Tachycardia • ↑ RR: ↑ O2 saturations • Wide pulse pressure • Peripheral vasodilation: ↓BP, postural hypotension • Weakness • ↑ 2,3‐BPG: ↑ intracellular pH / respiratory alkalosis • Malaise • ↑ Erythropoesis: ↑ EPO • Easily fatigued • Dyspnoea on mild exertion • Koilynichia (concave nails) • Atrophic glossitis (B12,Folate & iron deficiencies) • Angular stomatitis • Fatty change: liver, myocardium, kidney • Angina pectoris • Headache, dimness of vision, faintness • Organomegaly FOLATE‐DEFICIENCY ANAEMIA Folate: intermediate in one‐carbon transfers Aetiology: • ↓ intake: raw green vegies & some fruits; alcohism & infancy • ↓ absorption: malabsorptive states, intrinsic intestinal dz, drugs • ↑ loss: haemodialysis • ↑ requirement: pregnancy, infancy, cancer, ↑↑ haematopoiesis • Impaired use: folic acid antagonists (methotrexate) Diagnosis: • Megaloblastic a., hypersegmented neutrophils • Normal serum B12, ↓ serum folate Management: • Folate therapy – B12 deficiency: folate may exacerbate neurological degeneration PERNICIOUS ANAEMIA: B12 deficiency anaemia Clinical Features: • Immunologically‐mediated gastric mucosal destruction • Insidious onset – often severe a. by presentation • Results in achlorhydria & absence of IF F>M • Moderate‐severe megaloblastic a. • ↑: early graying, blue eyes, blood group A, FHx • Leukopaenia, hypersegmented granulocytes • Associated Dz: vitiligo, myxoedema, Hashimoto's, • Mild‐moderate thrombocytopaenia Addison's & hypoparathyroidism • Mild jaundice (ineffective erythropoiesis + peripheral haemolysis) • Antibodies develop against IF‐secreting cells • Neurological changes (posteriolateral spinal tracts) – Type I: Blocks B12‐IF binding (75%) – Ø methionine = CNS demyelination → parasthesia, peripheral neuropathy – Type II: Prevents B12‐IF binding to ileal receptor • Achlorhydria (even after histamine stimulation) – Type III: bind to α & β units of gastric proton pump (90%) • ↓ serum B12 / ↑ serum homocystine & methyl malonic acid • Results: • Striking reticulocyte response & Hct levels ~5 days after parenteral B12 1. Loss of parietal cells Management: ovalocytes 2. Infiltrate of plasma cells & lymphocytes • Lifelong parenteral B12 administration (4/year) 3. Megaloblastic changes in mucosa similar to RBC precursors – Cure anaemia, reverse/halt neurological changes • Pathology: – Doesn't affect gastric mucosal changes – Megaloblastic a., pancytopenia, BM hyperplasia hypersegmented neutrophil – Atrophic glossitis (shiny, glazed, beefy tongue) – Chronic gastritis (fundic atrophy, intestinilization, ↑ GI cancer) – CNS lesions: demyelination in dorsal & lateral tracts Spastic paraparesis, sensory ataxis, severe parathesia in lower limbs Unsteady gait, + Babinski, loss of deep tendon reflexes 4 Feeling Tired (Pernicious Anaemia) p3 Medical Overservicing Medicare: insurance to pay health costs – NOT to pay doctors Medicare Australia Responsibilities: 1. Administer Medicare & PBS 2. Aust. Childhood immunization register 3. Aust. Organ Donor register 4. Practice incentives 5. Rural retention program 6. DVA (inc. repatriation‐PBS) 7. Family Assistance Office 8. Private health insurance rebates Inappropriate practice: • Conduct that would be unacceptable to members of that profession • Allowing employed practitioner to engage in inappropriate conduct Medical Overservicing: 1. Seeing too many patients 2. Ordering too many investigations 3. Ordering inappropriate medications 4. Accepting benefit for referral/recommendation 5. Offering benefit for referral/recommendation 6. Failure to disclose interest in referral/recommendation 7. Poor record keeping 8. Unnecessary medications 9. Unorthodox medicine 80/20 Rule: 80 consults in 20 days/month for 12 months is overservicing Medicare's Role in Professional Service Review Scheme: Negotiated Settlement: 1. Identify inappropriate practice Disadvantages for Dr: Advantages: 2. Practitioner Review Program • Admission of guilt • Matter remains private – Advice practitioner in writing of concerns • Repayment • End of proceedings – Interview: address concerns • Disqualification/sanctions (< 3 years) → dismiss case, offer counseling/opportunity to correct practice • 2nd time: 5 year disqualification 3. Review period – after time, review by Medicare's Medical Director 4. Medical director can request Professional Services Review Professional Services Review Independent statutory authority (Health Insurance Act 1973) Role: examine health practitioner's conduct: inappropriate practice/prescription • Protect Medicare & PBS Determining Authority • Protect patients & community from risks of inappropriate practice Statutory authority, independent from PSR & Medicare • Protect Commonwealth from costs of inappropriate practice • Reviews PSR decisions & determining sanctions 5. Director of PSR reviews case • Made up of medical practitioners & lay person – Dismiss case – Negotiate settlement: reprimand, partial/full disqualification from medicate (up to 3 years), repayment of benefits for services – Establish Professional Services Review Committee to conduct inquiry • Agreements must be ratified by Determining Authority (DA) 6. Professional Service Review Committee • New committee formed for each case: chaired by Dr + 2 Drs from same discipline, includes other health practitioners • Formal hearing (under oath), legal counsel allowed • If "serious threat to life of health of any person" → referred to medical board 7. Federal Court: appeals against Final Determination 8. High Court: appeals against Federal Court Decision Medicare Australia Referrals PSR Director Not inappropriate Inappropriate Agreement with person Determining Authority (Impose sanctions /ratify agreement) Inappropriate Referral to PSRC PSR Committee 4 Feeling Tired (Pernicious Anaemia) Not inappropriate Inappropriate p4