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BCQ s

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BCQ s

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  1. Pakistan Society Of Chemical PathologistsDistance Learning Programme In Chemical PathologyLesson No 18Miscellaneous Endocrine Disorders and Tumour Markers(Short Name: MEDTM)By Surg Commodore Aamir IjazMCPS, FCPS, FRCP (Edin)Professor Of Pathology / Consultant Chemical PathologistBahria University Medical & Dental College / PNS SHIFA Karachi

  2. BCQs

  3. d. Iatrogenic Q 1: The most common cause of Cushing Syndrome is:a. Adrnocortical Hyperplasiab. Cushing diseasec. Ectopic ACTH secretiond. Iatrogenice. Pseudo-Cushing Syndrome

  4. Slides on CUSHING SYNDROME and ADDISON DISEASE were Initially Prepared by Dr Mehreen Hassan (PNS SHIFA)

  5. Cushing’s Syndrome Iatrogenic is most common cause. Other causes are: ACTH dependent: Cushing’s disease (70%) Ectopic ACTH (15%) ACTH independent: Adrenal hyperplasia (10%) Adenoma or carcinoma

  6. a. Adrenocortical Carcinoma Q 2: A 54 y male is having Cushing Syndrome. His cortisol and other steroid profile is as following:• Serum Cortisol: Increased• Serum DHEAS: Markedly increased• Urinary 17-ketosteroids : Markedly Increased• Serum Aldosterone: Low• Aldosterone precursors : IncreasedWhat is the most probable cause of Cushing Syndrome in this patient?a. Adrenocortical Carcinomab. Adrenal Adenomac. Bilateral ACTH-independent macronodular hyperplasia d. Ectopic cortisol secretion e. Primary pigmented nodular adrenocortical disease

  7. Adrenocortical Carcinoma Can present as Hirsutism Characterised by increased metabolites of Cortisol and Aldosterone Increased DHEAS

  8. e. Morning (0900) Q 3: A 36 y old Registered Nurse is performing night duty for the last 2 years with the habit of going to bed at 0800 h in the morning. She has developed some features suggestive of Cushing Syndrome and referred to you for appropriate investigations. At what time of the day (24 h) you will like to collect her sample:a. Afternoon (1500 h)b. Early evening (1900 h)c. Mid day (1200 h)d. Midnight (0000 h)e. Morning (0900)

  9. Timing of Cortisol Sampling For Cushing Syndrome (CS): Late Evening Sample : To see the loss of Diurnal variation i.e. higher cortisol in the evening Exact Time: One hour after usual sleeping time. (True for Serum or Salivary Cortisol timing). For Addison Disease (AD): Morning sample at 0800 h.

  10. e. Urinary Free Cortisol Q 4: A 32 y pregnant lady has been referred to you for investigation of Cushing Syndrome. As per recent Guidelines which of the following should be the first line tests in this patient?a. 48-h, 2 mg/d Dexamethasone Suppression test (DST) b. Late evening Salivary cortisolc. Midnight Sleeping Serum Cortisold. Overnight 1mg DSTe. Urinary Free Cortisol

  11. Urinary Free Cortisol (UFC) 24 h urine sample is required Better test in Pregnancy and patients on OCP due to increased CBGs in these conditions Should NOT be done in patients with renal impairment In pregnancy Dexamethasone test should NOT be done

  12. First line Tests for CS Late evening Salivary Cortisol Urinary Free Cortisol (UFC) 1 mg Dexmamethasone Test (DMT)

  13. Evening Serum cortisol (1 h after sleep) Done for confirmation of CS Can be done in two ways: Sleeping: Difficult to perform but better method Wakening: Also quiteuseful

  14. Pseudo-Cushing Syndrome • Stress • Obesity • Depression • High estrogen state • Glucocorticoid resistance syndrome • Drugs (phenytoin, phenobarbital etc)

  15. Low-dose dexamethasone suppression test Oral administration of 0.5 mg dexamethasone every 6h for 2 days Plasma cortisol >5 µg / dl on 3rd day morning ------ hypercortisolism

  16. Determination of the Cause of Syndrome Serum ACTH levels Plasma ACTH < 20 pg / ml indicates adrenal tumor High-dose Dexamethasone suppression test Overnight 8 mg test Obtain baseline 0800h plasma cortisol Oral administration of 8 mg dexamethasone at 2300h Obtain plasma cortisol on next morning at 0800h (< 50% of baseline value -------- significant suppression) Two day test Oral administration of 2 mg dexamethasone every 6h for 2 days

  17. e. Tuberculosis Q 5:The most common cause of Chronic Adrenal Insufficiency Worldwide (including developing countries) is:a. Autoimmune diseaseb. Drugsc. Fungal Infectiond. Malignant Metastasise. Tuberculosis

  18. Chronic Adrenal insufficiency Primary adrenal insufficiency \ Addison’s disease (AD) Inadequate production of glucocorticoids and mineralocorticoids involving destruction of >90% of adrenal cortex Secondary adrenal insufficiency: Inadequate secretion of glucocorticoids caused by pituitary insufficiency

  19. Causes of adrenal insufficiency Causes of AD Idiopathic atrophy (autoimmune adrenalitis) Granulomatous disease Tuberculosis(more common in our population) Histoplasmosis Sarcoidosis Infectious( Viral(AIDS),fungal, CMV) Neoplasticinfiltration Haemochromatosis Amyloidosis Following bilateral adrenalectomy

  20. Routine investigations: Blood complete picture: Neutropenia Relative lymphocytosis Eosinophilia Mild anaemia Serum electrolytes: Hyperkalaemia Hyponatraemia Hypercalcaemia

  21. Routine investigations (contd) Serum urea - Serum creatinine Plasma glucose Hypoglycemia Acidosis

  22. Diagnosis of AD Morning Serum Cortisol < 10 Ug/Dl Plasma ACTH Assay > 150 Pg/MlDynamic Function Tests ACTH stimulation tests: • Short synacthen test • Long synacthen test

  23. Short Synacthen Test Indication:Investigation of adrenal insufficiency Contraindication:Pituitary surgery Principle: To evaluate the ability of adrenal cortex to produce cortisol in response to synthetic ACTH Side effects: Hypersensitivity in rare cases Preparation: No dietary restrictions performed in morning Requirements:Two plain tubes 250µg synacthen (1 vial) paed dose: 36 µg/kg body weight

  24. Short synacthen test - protocol (contd) Procedure: 0 mins 3ml blood for cortisol Injsynacthen 250 µg I/V or I/M 30 mins 3ml blood for cortisol 60 mins 3ml blood for cortisol Interpretation:Ifpost-synacthencortisol >18 µg/dL or post-synacthencortisol increases by an increment of 8 µg/dL Primary adrenal insufficiency is ruled out

  25. Long SynacthenTtest To differentiate between primary & secondary adrenal insufficiency Prolonged stimulation of adrenal glands by synthetic ACTH improves adrenal response Blood samples drawn: basal cortisol sample, then injsynacthen 250µg I/M & Cortisol samples at 1,2,4,8 & 24 hrs Gradual rise in cortisol & peak at 24 hrs indicates secondary adrenal insufficiency No response or initial (1hr) response which is not sustained indicates primary adrenal insufficiency Gradual rise in cortisol & peak at 4-8 hrs is normal ACTH assay has reduced the significance of long synacthen test

  26. d. Increased Plasma Renin Activity Q 6:As per reported natural history of Addison Disease (due to autoimmune etiology) the first Endocrine abnormality is :a. Decreased cortisol response to ACTHb. Decreased morning cortisolc. Increased CRHd. Increased Plasma Renin Activitye. Raised morning ACTH

  27. e. Simultaneous estimation of Serum Cortisol and Plasma ACTH Q 7:As a Consultant Chemical Pathologist in a tertiary care hospital, you want to develop a strategy for immediate determination of diagnosis and cause of adrenal insufficiency. Which of the following test you would like to use at the time of patient presentation:a. Estimation of early morning Serum Cortisol b. Estimation of evening Serum Cortisol c. High dose ACTH Stimulation test with 250 µgd. Low dose ACTH Stimulation test with 1µg e. Simultaneous estimation of Serum Cortisol and Plasma ACTH

  28. c. Discriminate between Primary and Secondary Adrenal Insufficiency Q 8:Corticotropin-releasing hormone (CRH) stimulation test is used in various adrenal abnormalities. All of the following are indications of CRH stimulation test EXCEPT:a. As part of inferior petrosal sinus sampling for ACTH-dependent Cushing's syndrome.b. Discriminate between pseudo-Cushing's and Cushing's syndrome.c. Discriminate between Primary and Secondary Adrenal Insufficiencyd. Discriminate between Secondary and Tertiary Adrenal Insufficiencye. Discriminate between patients with an ectopic or a pituitary ACTH-secreting tumour.

  29. c. Extra-Pituitary Acromegaly Q 9:A 72 y male industrialist is suspected of Acromegaly because of sudden increase in his shoe size and enlargement of fingers. He is not a known case of Diabetes Mellitus or liver disease. He was thoroughly investigated for the diagnosis of Acromegaly and determining the cause of excess Growth Hormone (GH) if present. The results of his investigations showed following results:• IGF-1: 452 ng/ml (ref range: 135-449)• OGTT with GH (by Chemiluminescence method) o GH basal : 0.2 ng/mlo GH level at 2 h : 0.6 ng/ml• Pituitary MRI: Normal What is the most probable diagnosis?a. Equivocal resultsb. Extra-pancreatic islet tumourc. Extra-Pituitary Acromegalyd. Normal for agee. Pituitary Adenoma

  30. For Detail Account Of GH Disorders Please See PPT Prepared ByDr ShaguftaYousaf

  31. Diagnosis of Acromegaly in this pt IGF1 is normally decreases in elderly In this patient IGF 1 is markedly increased There is paradoxical rise of GH which is an indication of Acromegaly Normal MRI of pituitary indicates extra-pituitary acrmegaly GHRH Acromegaly can be the final diagnosis

  32. e. Psychogenic polydipsia requiring WDT for confirmation. Q 10:A 39 y female complains of polyuria with 24 h urinary volume more than 4.0 litre which has developed gradually over the last one year. She has been referred to you for ‘Water Deprivation Test’ (WDT) for the diagnosis or exclusion of Diabetes Insipidus (DI). You perform some preliminary tests which show following results:• Serum Sodium : 124 mmol/L (132-142)• Urine osmolality: 118 mOsmol/Kg Now how will you proceed with this patient? Please select the best option:a. Central DI requiring WDT for confirmationb. DI and Psychogenic polydipsia excluded not requiring WDT.c. Nephrogenic DI requiring WDT for confirmationd. No clue of any disorder requiring WDT e. Psychogenic polydipsia requiring WDT for confirmation.

  33. For Detail Account Of Diabetes Insipidus Please See PPT Prepared ByDr ShaguftaYousaf

  34. e. Levels decrease without any treatment. Q 11:All the following are characteristics of an Ideal Tumour Marker EXCEPT:a. Can be used for evaluating prognosis b. Can be used for prediction of therapeutic responsec. Elevated at early stage of the diseased. High levels at the time of diagnosis e. Levels decrease without any treatment

  35. d. Hepatocellular Carcinoma. Q 12:A 52 y male who is a known patient of Cirrhosis of liver as a sequale of Hepatitic C. His Alpha Fetoprotein (AFP) has been monitored regualrly and usually remains below 200 ng/ml. A recent report, howevr, shows AFP 545 ng/ml and on repeating the test a simialr values was obtained. What is the most probable cause of rise of AFP in this patient:a. Carcinoma of Colonb. Carcinoma of the pancreasec. Extension in Cirrhosis d. Hepatocellular Carcinomae. Testicular germ cell tumour

  36. a. In combination with AFP. Q 13:CA-125 is a time-honoured marker of Carcinoma Ovaries. There are efforts to imporve its efficiency ad diagnostic marker for Stage 1 Ovarian Carcinomas. All of the following are situations when CA-125 can be used as a better marker for the diagnosis of Ovarian Carcinoma EXCEPT:a. In combination with AFPb. In combination with Carcinoembryonic Antigen c. In combination with Human Epididymis Proteind. Serial monitoring of CA 125e. Use in post-menopausal women

  37. b. CA-27.29. Q 14:For the monitoring of Carcinoma Breast several biochemical or circulating tumour markers have been found useful. Which of the following tumour markers have been approved by FDA for the detection of recurrent Breast Carcinoma:a. CA-15-3b. CA-27.29c. CA-549d. Extracellular domain of HER2 (HER 2 ECD)e. Mucinlike Carcinoma Associated Antigen (MCA)

  38. b. BRCA mutation. Q 15:Research in Oncogene has led to discovery of certain gene which can predict certain cancers with reasonable accuracy. A subset of these Oncogene have been found quite commonly in otherwise healthy women raising the moral and ethical issues of prophylactic surgery.Which of the following oncogenes is a suppressor gene used for inherited prediction of Breast Cancer in a family with the patients of these cancers:a. APC mutationb. BRCA mutationc. Her-2/neu gened. N-ras mutatione. VHL Mutation

  39. For Detail Account of Tumour Markers Please See PPT Prepared ByDrs Anwar Magsi and Fawad Sana

  40. SAQs

  41. Q:16: Diagnosis of Growth Hormone Deficiency in short stature children is one of the most common Endocrine challenges a Chemical Pathologist has to face. As a Consultant Chemical Pathologist you have been instructed by your University Administration to establish an “Auxology Clinic” i.e. Growth Clinic in the hospital in collaboration with Consultant Paediatricians. Please address following issues in this regard:   Please make a list of essential equipment and charts etc. required for clinical examination of the children referred to this ‘Growth Clinic’ from Primary Care Services. A major problem in diagnosis of Growth Study is selection of children who have high pre-test likelihood ratio i.e. they have higher chance of testing positive for Growth Hormone Deficiency (GHD). Such screening is essential for a cost effective and efficient “Auxology Clinic”.   Please make a FIVE line criteria for selecting children to undergo GHD studies. Name the specific tests which are carried out for the diagnosis of GHD without any stimulation. Name the provocative tests which can be used for the confirmation of GHD. .

  42. Suggested Answer to Q.16a Please make a list of essential equipment and charts etc. required for clinical examination of the children referred to this ‘Growth Clinic’ from Primary Care Services.  (Plz see next slide)

  43. Equipment and Charts for Growth Clinic Weighing machine Vertical stadiometer for children ˃2 years of age Neonanometer for children ˂2years of age Glucometer with strips Refrigerator ( to keep insulin at optimal temperature) WHO growth charts for length for age for girls and boys for less than 2 years age CDC growth charts for height for age for girls and boys for more than 2 years age

  44. Equipment and Charts for Growth Clinic (Cont) Height velocity chart for boys and girls Calculators to calculate midparental height in boys and girls Calculator for calculating CDC height for age percentiles in boys and girls Charts to estimate bone age Syringes (insulin, 5 cc, 10cc, iv canulas) 25% dextrose, 5% dextrose saline, distilled water Sample collection tubes for serum (growth hormone) and plasma glucose Other emergency drugs in a tray like antiemetic, solucortef, etc.

  45. Suggested Answer to Q.16b A major problem in diagnosis of Growth Study is selection of children who have high pre-test likelihood ratio i.e. they have higher chance of testing positive for Growth Hormone Deficiency (GHD). Such screening is essential for a cost effective and efficient “Auxology Clinic”.   Please make a FIVE line criteria for selecting children to undergo GHD studies (Plz see next slide)

  46. Selection of Patients for GH Studies Height progressively decline to lower percentile usually < 3rd percentile Weight increasing with chronological age Reduced Growth velocity Delayed bone age Other systemic cause of short stature / constitutional delay are ruled out e.g. Hypothyroidism, Coeliac Disease etc.

  47. Suggested Answer to Q.16c Name the specific tests which are carried out for the diagnosis of GHD without any stimulation. IGF 1 IGF BP3

  48. Suggested Answer to Q.16d Name the provocative tests which can be used for the confirmation of GHD. Exercise Stimulation Test L-Dopa Stimulation Test Arginine Test Insulin Stimulation Test

  49. Q:17:Use of Prostate Specific Antigen as a marker for screening of Prostatic Cancer has been one of the most controversial topics in cancer management. The levels of Serum PSA from 4.0 to 10 ng/ml present a diagnostic dilemma. Many strategies have been proposed to improve the diagnostic accuracy of PSA for prostatic carcinoma, though there is no consensus about acceptance of these PSA modifications.   Please name the strategies proposed for improvement of diagnostic performance of PSA. Write brief description of THREE of these strategies (not more than two lines for each). (Plz see next slide)

  50. Strategies proposed to improve the diagnostic performance of PSA For PSA between 4 -10.0 ng/mL. PSA velocity (change in PSA over time), PSA density (PSA per unit volume of prostate), Free PSA Complexed PSA Age specific reference ranges Race specific reference ranges

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