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Case (15) CUSHING’S SYNDROME Chief complaint: Extreme weakness in arms & legs, headache, insomnia & oedema. History of patient illness: Yaser hasn’t been feeling well for the past 2 months with a marked weight gain of 10 kg. His mood has become irritable & depressed lately & had to leave work due to general weakness & fatigue. Family history: His parents were hypertensive. His grandmother was diabetic & grandfather was recently diagnosed for prostate cancer. Medications: Captopril x 5 yr + Hydrochlorothiazide x 5 yr Lab values: Na+ 190 mEq/L K: 108 mEq/L Glu fasting: 155 mg/dl Serum cortisol: 30 µg/dL Serum ACTH: 6 pg/ml 1- How would you diagnose this condition? Cushing’s syndrome. 2- Mention the causes & symptoms of such disorder? Causes: Prolonged ttt with ACTH or GCs, or Pituitary ACTH dependent ↑ ACTH secretion ↑ GC Pituitary ACTH independent (Adrenal tumor) (↑ GC ↓ ACTH) most probably the cause of this case (look at lab. value) Tumor outside the normal pituitary-adrenal system, which produces ACTH (ectopic syndrome). Symptoms: Thinning of skin (↑ protein catabolism & ↑ lipolysis of subcutaneous fat) Myopathy & muscle weakness (↑ protein catabolism & electrolyte imbalance) Uneven fat redistribution moon face, buffalo hump & central obesity Hypertension (↑ Na and H2O reabsorption as GC has mineralocorticoid activity at high GC level) also GCs enhance epinephrine’s vasoconstrictive effect) Poor wound healing (↑ protein catabolism and low anabolism) ↑ susceptibility to infection (↓ immune system) ↑ hair growth (↑ adrenal androgen) Osteoporosis (↑ Ca resorption from bone, ↑ catabolism of bone matrix, potentiates PTH action & ↑ Ca excretion, inhibit osteoblasts activity and Glucocorticoids have negative feed back effect on gonadotrophin releasing enzyme ↓ LSH and FSH ↓ estrogen.) Euphoria, psychosis or depression. Red stria (2ry to loss of underlying connective tissue and thinning of skin) 3- Would an overnight dexamethazone test be of any use? What would it indicate? This test is useful to differentiate between pituitary ACTH dependent Cushing’s disease and ACTH independent Cushing’s syndrome. High dexamethasone dose is given at night & plasma cortisol & ACTH are measured the next morning: 1 Cortisol Interpretation Not suppressed Adrenal CS Ectopic CS Suppressed Pituitary CS 4- What are the goals of therapy? To morbidity & mortality. Return the patient to a normal functional state by removing the source of hypercorticolism without causing any pituitary or adrenal insufficiencies. 5- What drug & non-drug therapies might be useful for this patient? Surgical removal of the tumor (if any) – ttt of choice Use of adrenal antagonists (e.g. mifepristone) or inhibitors of adrenocorticoid biosynthesis (e.g. trilostane, aminoglutithimide, metyrapone). 6- Explain why the patient's fasting blood glucose is high? Due to the following effects of GCs on Carbohydrate metabolism: GCs mobilization of amino acids from extrahepatic tissues GCs lipolysis glycerol GCs gluconeogenesis by inducing gluconeogenic enzymes in the liver form glucose from amino acids and glycerol. GCs insulin sensitivity peripheral uptake and utilization of glucose into muscles 7- If the patient is not controlled what are the possible disorders he may under risk? Diabetes mellitus or impaired Glucose tolerance (anti-insulin activity) Hypertension Osteoporosis Peptic ulcer ( PGs, HCl and mucous secretion) Electrolyte abnormalities ( Na K Ca) Susceptibility to infections, oral thrush (Oral candidiasis) Glaucoma & cataracts ( IOP) 8- Choose the correct answer (i) All the following are symptoms of this order EXCEPT: a. Edema b. Increased appetite c. Poor wound healing d. Positive nitrogen balance (ii) Yaser was found to have red stria. This is probably due to: a. Excessive sun light exposure b. Skin allergy c. Weight gain d. All of the above e. Non of the above 2 Case (16) CUSHING’S SYNDROME Chief complaint: Rapid fatigability & profound weakness. History of patient illness: A 77-year-old woman. She was well before last August but then had a rapid onset of symptoms. Polyuria & polydypsia led to a diagnosis of type 2 DM. She lost 23.5 kg in weight over 6 months & later developed dark hair on her face, pitting edema to the knees & profound fatigue. She had progressive muscle weakness & by Dec. was bed bound. Hypertension was diagnosed. She was a lifetime nonsmoker. At the time of admission, the most striking feature was her profound weakness, she was unable to sit up in bed or lift her head off the pillow. She had a small buffalo hump but lacked an obvious moon-face. There was no abnormal pigmentation. There were many terminal hairs noted in the beard distribution but no other evidence of virilization. Family history: There was no history of endocrine disease in her family. Medications: Glyburide: 20 mg q AM + Atenolol 50 mg q AM Lab values: K: 2.7 mEq/L Na: 175 mEq/L Serum cortisol: 28 mg/dL Glu (fasting): 195 mg/dL Serum ACTH: 96 pg/ml BUN: 28 mg/dL (protein catabolism) HbA1c: 7.2% S Cr: 0.8 mg/dL ALT: 21 IU/L AST: 15 IU/L 1. Apart from this case, what are other features of Cushing's syndrome can you nominate? Thinning of skin & red stria (loss of collagen and connective tissue). Poor wound healing & ↑ susceptibility to infection. Osteoporosis. Euphoria, psychosis or depression. Gastric pain or ulcer 2. What's the cause of hair growth on the patient's face? May be due to –ve feed back effect of GCs on hypothalamus deceasing the level of GnRH. And due to elevations androgen. 3. What's the possible cause of patient's syndrome? (case 13 – Q2) 4. What's the cause of fatigue? Account for the occurrence of the same symptom in case of hypofunction. GCs catabolism of skeletal muscles proteins and electrolyte imbalance myopathy & weakness of muscles. In hypofuction, muscle weakness also occurs, because GCs are essential for normal muscle work and due to electrolyte imbalance. 5. Is the condition of type 2 DM related in any way to the patient's hormonal profile? Discuss. Yes, it may have occurred due to GCs for long period which has anti-insulin activity 6. What are the goals of therapy? (as Q4, case 13) 3 7. What is the renal condition of this patient? Normal (prolonged hypertension in untreated cushing’s could affect renal function by increasing the thickness of capillaries and blood vessels supplying kidney causing damage of both the large arteries leading to kidneys and the tiny blood vessels (glomeruli) within the kidneys). Diabetic nephropathy is the predicted outcome of poor glycemic control. 4 New case (17) Chief complaint Fatigue, weakness, headache, lethargy, decreased concentration, decreased memory over the last 18 months and weigh gain History of patient illness: A 41-year-old Caucasian female was diagnosed as a hypertensive patient, on physical examination, she was hypertensive despite the multiple antihypertensive medications that had been prescribed to her by various physicians during her numerous hospitalizations. She had moon face, facial plethora, and a dorsal fat pad. She had diffuse anasarca (generalized edema) and her abdomen was centrally obese and firm with thick, purple, abdominal striae. Computed tomography (CT) showed adrenal glands hyperplasia but without evidence of adenoma. A magnetic resonance imaging (MRI) examination of the pituitary did not show any abnormal findings. Family history: None Lab value: potassium 3.1 mEq/L (3.6–4.8 mEq/L) glucose 134 mg/dL (70–100 mg/dL). pH 7.55 (7.35–7.45) bicarbonate 32.3 mEq/L (22–26 mEq/L). Serum cortisol 39.5 μg/dL (5–25 μg/dL) Plasma ACTH was 133 pg/mL (10–60 pg/mL) Blood urea nitrogen and creatinine levels were normal Complete blood cell count was within normal limits. Medications losartan, clonidine, amlodipine, and ramipril 1-How would you diagnose this condition? Tumor outside the normal pituitary-adrenal system, which produces ACTH (ectopic syndrome). CT scans must be done to find the tumors lung carcinoid Islet cell tumors of the pancreas Medullary carcinoma of the thyroid Tumors of the thymus gland 2-Do you think that patient suffers from hyperpigmentation? Why? yes 3- Suggest treatment for her case. Treatment depends on the type of tumor and if it is cancerous. Cancerous tumors can grow quickly, and spread to other organs. They may not be treatable. Tumors are usually removed with surgery, if possible. 5 . If the cancer is widespread, chemotherapy may be used to try and shrink the tumors. Treatment with drugs that inhibit GCs syntheis and action can be used long-term for patients with ectopic corticotropin secretion, but adrenalectomy may be preferred. 6 Case (18) ADDISON’S DISEASE Chief complaint: “I had a penetrating pain in my legs, lower back & abdomen. I also suffer from severe vomiting & diarrhea.” History of patient illness: A 45-year-old man suffered from progressive weight loss, muscle weakness, fatigue & orthostatic hypotension. Areas of skin hyperpigmentation in both exposed & nonexposed parts of the body were also observed. Family history: No family history. Medications: None Lab values: Glu: 30 mg/dl Na: 80 mEq/L K: 8 mEq/L RBCs: 3.5x106/mm3 Hb: 12 g/dL Hct: 35% 1. What is the cause of hyperpigmentation? ACTH, which has structural similarity to MSH MSH production as a by-product of ACTH synthesis ↑ melanin production by melanocytes 2. Which hormone is responsible for this disorder? ACTH 3. What are the goals of therapy? Establishment of the lowest effective dose of GCs which can mimic the normal diurnal adrenal rhythm. 4. How would you treat this case? Replacement therapy with GC as prednisolone +Mineralocorticoid as fludrocortisone 5. Why does she exhibit hypotension? GCs & MCs Na+-water reabsorption plasma volume & blood pressure. 6. Why does she exhibit hyponatremia and hyperkalemia? Due to secretion of aldosterone which promotes reabsorption of Na+ and secretion of K+. 7. Explain why ACTH level is high. GCs –ve feedback on anterior pituitary gland ACTH 8. Account for the occurrence of muscle weakness & fatigue? Give all the possible causes. Because GCs are essential for normal muscle work, GCs and electrolyte imbalance muscle weakness 9. Is hypoglycemia related to the patient's hormonal condition? Why? Yes, as in this case GCs level is decreased insulin sensitivity at peripheral tissue BGL 10. What is the renal condition of this patient? Renal dysfunction due to BP and hypovolaemia renal blood flow and GFR 7 Case (19) PRIMARY HYPERALDOSTERONISM: CONN’S SYNDROME Chief complaint: Severe headache & intense weakness characterized by incapacity to perform normal activities such as sweeping the floor & washing the clothes. History of patient illness: Cindy is 52-year-old female. In 1992, arterial BP was diagnosed but satisfactory blood pressure control was achieved by using antihypertensive drugs. In 1999, BP control deteriorated & the prescription was changed. However, no satisfactory BP control was achieved. She also has gastritis for 8 years & hypertriglyceridemia for 4 years. Family history: The patient reported 4 hypertensive paternal uncles, 2 with deep venous thrombosis, 1 with myocardial infarction & another with stroke, her mother was hypertensive. Medications: Since 1992, hydrochlorothiazide (50 mg/day), methyl dopa (1.5 g/day). In 1999, the prescription was changed to indapamide (2.5 mg/day), perindopril (4 mg/day) & nadolol (80 mg/day). Lab values: Na: 220 mEq/L K: 1.5 mEq/L HCO3: 33 mEq/L Aldosterone : 56.2 ng/dL Renin: 0.17 ng/mL/hr Aldosterone/renin ratio: 93.2 1. In 1992, the hypothesis of secondary hypertension due to primary hyperaldosteronism was very remote…why? Secondary hypertension was not suspected as the results of the basic laboratory tests (glycemia cholesterol, electrolytes….) were within the normal range. In addition the patient had a favorable response to the treatment used all these favored the diagnosis of controlled primary hypertension. 2. What is the cause of metabolic alkalosis? Metabolic alkalosis is due to an increase in the serum level of bicarbonate resulting from urinary loss of potassium and hydrogen ions. 3. The patient was on indapamide, hydrochlorothiazide therapy for long time, they both induce hypokalemia. How can you make sure that it is an indicator for hyperaldosteronism? i) If there is difficulty in maintaining K levels despite the concomitant use of K supplements and ii) K levels not normalized after suspending the diuretic. 4. Suggest suitable drug therapy for this case. Aldosterone antagonist e.g. spironolactone. 5. What non-drug therapy might be useful for this patient? Laparoscopic adrenalectomy is now used worldwide to resect adrenal adenoma. 6. How can u differentiate between 1ry and 2ry hyperaldosteronism?. (new) the aldosterone-to-renin ratio is abnormally increased in primary hyperaldosteronism, and decreased or normal but with high renin in secondary hyperaldosteronism. Choose the most appropriate answer(s): (i) This case is characterized by a. hypokalemia b. metabolic acidosis c. kaliuresis 8 d. metabolic alkalosis e. hyponatremia f. hyporeninemia (ii) The symptoms of primary hyperaldosteronism are due to a. hypertension b. high TG level c .low Hb d. low glucose level e. low WBCs count f. hypokalemia ( (iii) Although the presence of spontaneous hypokalemia in a hypertensive patient is strong indicator for primary hyperaldosteronism, it may be due to: a. use of diuretic b. high K intake c. hypoaldosteronism d. low Ca intake e. use of antihyperlipidemic f. deficiency of vit K 9 Case (20) HYPORENINAEMIC HYPOALDOSTERONISM (HRHA) Chief complaint: The patient developed problems of unsteadiness & light headness. She was admitted to hospital following a fainting attack. She continued to complain of dizziness & was noted to have significant postural hypotension with hyperkalemia. History of patient illness: A 74-year-old lady visited hematology clinic for assessment of chronic anemia. Her GP had prescribed some drugs for treatment but there had been no response. She had been aware of tiredness & lethargy for several years but her weight had remained steady. There was a past history of angina, hypothyroidism & diverticular disease. She was non-smoker, drank very little alcohol occasionally. An autoantibody screen including adrenal cortex antibody was negative. Family history: None Medications: Iron, vit B12, folic acid supplementation along with thyroxin & analgesics. Lab values: Na: 125 mEq/L Hb: 10.6 g/dL K : 5.9 mEq/L ESR: 28 mm/hr SCr: 5 mg/dl Vit B12: 991 ng/L BUN: 50 mg/dl Folate: 354 mg/L Aldosterone: 125 mmol/L Ferritin: 268 mg/L Cortisol: 440 mmol/L Glu: 5.9 mmol/L Plasma renin activity: <0.2 mmol/ml/hr Renin: undetectably low Erythropoietin: 7mu/ml ACTH: 33 ng/L 1. What is the cause of aldosterone deficiency in this case? As the patient is suffering from renal impairment that leads to secretion of renin and subsequently aldosterone 2. The lady didn’t respond to the treatment with folic acid, vitB12 & iron….Why? Because her anemia is due to low erythropoietin production but her vitB12, folate, ferritin levels are within the normal range. 3. Suggest another treatment for her case. Replacement therapy with erythropoietin and aldosterone or fludrocortisone. 4. Choose the most appropriate answer(s): (i) Deficiency of aldosterone leading to: a. hypokalemia b. hyperkalemia c. hyponatremia d. hypernatremia e. natriuresis f. kaliuresis (ii) The patient has renal impairment detected by high level of: a. glucose b. cortisol c. urea d. ACTH e. creatinine (iii) Aldosterone is secreted from: a. hypothalamus b. adrenal medulla c. adrenal pituitary d. adrenal cortex e. juxaglomerular apparatus f. Hb 10 Notes Most people with primary Addison's have darkening (hyperpigmentation) of the skin, including areas not exposed to the sun; characteristic sites are skin creases (e.g. of the hands), nipples, and the inside of the cheek (buccal mucosa), also old scars may darken. This occurs because melanocyte-stimulating hormone (MSH) shares the same precursor molecule as adrenocorticotropic hormone (ACTH); an increase in ACTH production also increases MSH. In secondary and tertiary forms of Addison's, skin darkening does not occur. 11