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Clinical Investigation Unit Testing

Clinical Investigation Unit Testing. Endocrinology Rounds July 28, 2010 Selina Liu PGY5 Endocrinology. Outline. Background - Dynamic Endocrine Testing Clinical Investigation Unit - Available Tests Examples Growth Hormone Deficiency Adrenal Insufficiency Other. Background.

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Clinical Investigation Unit Testing

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  1. Clinical Investigation Unit Testing Endocrinology Rounds July 28, 2010 Selina Liu PGY5 Endocrinology

  2. Outline • Background - Dynamic Endocrine Testing • Clinical Investigation Unit - Available Tests • Examples • Growth Hormone Deficiency • Adrenal Insufficiency • Other

  3. Background • What can we measure? • basal hormone levels • stimulated or suppressed hormone levels • Why do we do dynamic endocrine testing? • test of secretory reserve

  4. Background • INSUFFICIENCY/DEFICIENCY • OVERPRODUCTION Stimulate! Suppress!

  5. Available Tests • Which glands/axes can we stimulate or suppress? • Pituitary • Other

  6. Pituitary Hormones http://cal.man.ac.uk/student_projects/2002/MNBY9APB/Project_Images/pithormones1.gif

  7. Pituitary Hormone Disorders Hormone Underproduction Overproduction GH GH Deficiency Acromegaly LH/FSH Hypogonadotropic Hypogonadism TSH Central Hypothyroidism Central Hyperthyroidism ACTH Central Adrenal Insufficiency Cushing’s Hyperprolactinemia Prolactin Diabetes Insipidus ADH

  8. Pituitary Hormone Disorders Hormone Underproduction Overproduction GH IGF-1 GH GH Deficiency Acromegaly /normal LH, FSH, estradiol, testosterone LH/FSH Hypogonadotropic Hypogonadism TSH /normal TSH, fT3, fT4 Central Hypothyroidism Central Hyperthyroidism /normal ACTH,  cortisol ACTH Central Adrenal Insufficiency Cushing’s Hyperprolactinemia Prolactin Diabetes Insipidus ADH

  9. Available CIU Tests Insulin Tolerance Test GH Deficiency Hypogonadotropic Hypogonadism GnRH Stimulation Test Triple Bolus Test TRH Stimulation Test Central Hypothyroidism ACTH Stimulation Test CRH Stimulation Test Insulin Tolerance Test Adrenal Insufficiency Diabetes Insipidus Water Deprivation Test Glucose Tolerance Test Acromegaly

  10. Examples • Growth Hormone Deficiency

  11. Growth Hormone Secretion GHRH = GH releasing hormone SRIF = somatotropin release inhibiting factor (aka somatostatin) IGFBP = IGF binding protein Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  12. Growth Hormone Secretion • pulsatile secretion • healthy adult ~10 pulses/day • longest ~1h after sleep onset • if suspect GH deficiency, random GH level not useful Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  13. GH Deficiency - Causes http://www.endo-society.org/guidelines/final/upload/042506_CG_HormoneBook.pdf

  14. GH Deficiency – Clinical Presentation • CV Risk factors • abnormal lipid profile, atherosclerosis, insulin resistance • Body composition • increased body fat mass with altered distribution, increased waist:hip, decreased lean body mass • Exercise capacity • reduced muscle mass, impaired max oxygen uptake • QOL • decreased energy, poor concentration, low self-esteem

  15. GH Deficiency - Diagnosis • screening test - IGF-1 level ? • IGF-1 – affected by age, obesity, nutrition, comorbidities etc. • Marzullo P et al. 2001 Usefulness of Different Biochemical Markers of the Insulin-Like Growth Factor (IGF) Family in Diagnosing Growth Hormone Excess and Deficiency in Adults J Clin Endocrinol Metab 26:3001-3008

  16. 58 healthy, 83 acromegalic, 34 GH deficient subjects • GH deficient: 34 hypopituitarism • prev pituitary tumour/craniopharyngioma/meningioma resection, except for 2 with idiopathic GH deficiency • diagnosed based on arginine-GHRH stimulation test • 19 female, 15 male • ages 18-60 2001 J Clin Endocrinol Metab 26:3001-3008

  17. GH deficient subjects had significantly lower mean IGF-1 levels vs healthy control subjects Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008

  18. Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008

  19. Sensitivity: IGF-1 41% therefore – not a good screening test! Marzullo P et al. 2001 J Clin Endocrinol Metab 26:3001-3008

  20. 2006. J Clin Endocrinol Metab 91:1621-1634

  21. Growth Hormone Deficiency Endocrine Society Clinical Practice Guidelines (2006) Recommendation: “Do it” or “Don’t do it” – indicating a judgement that most well-informed people would make Suggestion: “Probably do it” or “Probably don’t do it” – indicating a judgement that a majority of well-informed people would make but a substantial minority would not

  22. Growth Hormone Deficiency Endocrine Society Clinical Practice Guidelines (2006) Suggestion: IGF-1 • if normal – does not exclude GH deficiency • if in context of pituitary disease, provocative testing is mandatory (level of evidence – high) • if low, and no catabolic disorders, liver disease, indicates severe GH deficiency • may be useful in identifying patients who will benefit from treatment (level of evidence – moderate)

  23. Growth Hormone Deficiency • Dynamic tests: • insulin tolerance test (ITT) – GOLD STANDARD • others arginine-GHRH arginine alone clonidine arginine + l-dopa (arginine – decreases SRIF from hypothalamus)

  24. Growth Hormone Secretion arginine - GHRH = GH releasing hormone SRIF = somatotropin release inhibiting factor (aka somatostatin) IGFBP = IGF binding protein Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  25. Insulin Tolerance Test • first described in 1941

  26. Insulin Tolerance Test • To diagnose GH deficiency • also to diagnose adrenal insufficiency, panhypopituitarism • Contraindications: • seizure disorder, cerebrovascular disease, coronary artery disease • can precipitate adrenal crisis • check baseline 08:00 am cortisol – do not do if <100 nmol/L • need close monitoring, physician supervision

  27. Growth Hormone Deficiency • Insulin Tolerance Test (ITT) • symptomatic hypoglycemia and fall in BG < 2.2 mmol/L • will increase GH to a maximal level >10 mg/L increment of 6 mg/L = normal • plasma cortisol should peak at least 496-552 nmol/L Gardner DG & Shoback D (eds) 2007 Greenspan’s Basic & Clinical Endocrinology, Eighth Edition

  28. (5.6 mmol/L) (827.7 nmol/L) (4.4 mmol/L) Normal ITT mg/L (3.3) (2.2) (275.9 nmol/L) (1.1 mmol/L) http://ocw.tufts.edu/data/14/134087/134097_medium.jpg

  29. Recommended Test Sensitivity (95% CI) to diagnose adult GH deficiency Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  30. 39 subjects - multiple pituitary hormone deficiency (MPHD) • 13 female, 26 male, aged 26-70 • adult onset hypothalamic-pituitary disease • 34 matched controls (age, sex, BMI, estrogen status) • 14 female, 20 male, age 24-68 2002. J Clin Endocrinol Metab 87:2067-2089

  31. Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

  32. 100% sens 100% spec AUC 1.0 • MPHD subjects vs. matched controls Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

  33. To minimize misclassification: • ITT – peak serum GH 5.1 mg/L (96% sens, 92% spec) • Arg-GHRH – peak serum GH 4.1 mg/L (95% sens, 91% spec) Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

  34. Biller BMK et al. • the ITT and the arginine-GHRH provided the greatest accuracy in discriminating between patients with MPHD and their matched controls • arginine- GHRH test – better preferred by patients • arginine-GHRH test – good alternative to ITT • arginine-L-dopa – reasonable 3rd option • basal IGF-1 < 77 mg/L was 95% specific for GH deficiency Biller BMK et al. 2002. J Clin Endocrinol Metab 87:2067-2089

  35. 2006. J Clin Endocrinol Metab 91:1621-1634

  36. Growth Hormone Deficiency Endocrine Society Clinical Practice Guidelines (2006) Recommendations: • adults with structural hypothalamic/pituitary disease, surgery or irradiation to these areas, or other pituitary hormone deficiencies should be considered for evaluation for acquired GH deficiency (level of evidence – high)

  37. Growth Hormone Deficiency Endocrine Society Clinical Practice Guidelines (2006) Recommendations: • The ITT or arginine-GHRH test is the preferred test for establishing the diagnosis of GH deficiency • but – in those with clearly established recent hypothalamic causes of GH deficiency, i.e. irradiation, arginine-GHRH test may be misleading (level of evidence – high) • GHRH directly stimulates pituitary

  38. Growth Hormone Deficiency Endocrine Society Clinical Practice Guidelines (2006) Suggestions: • the presence of deficiencies in > 3 pituitary axes strongly suggests GH deficiency, and in this context, provocative testing is optional (level of evidence – moderate)

  39. 2007. Eur J Endocrinol 157:695-700

  40. Growth Hormone Deficiency Growth Hormone Research Society Consensus Statement (2007) • ITT, arginine-GHRH, GHRH-GHRP, glucagon tests all well-validated in adults • glucagon useful if ITT contraindicated, if GHRH or GHRP not available • IGF-1 good screening test • normal IGF-1 does not exclude GH deficiency

  41. Examples • Adrenal Insufficiency • Primary • low cortisol, high ACTH • Secondary/Tertiary (Central) • low cortisol, low or normal ACTH

  42. ACTH and Cortisol Secretion Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  43. ACTH and Cortisol Secretion • pulsatile secretion • circadian rhythm • highest in a.m. 24:00 08:00 12:00 20:00 Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  44. Adrenal Insufficiency - Causes • Primary – adrenal • Secondary – pituitary • Tertiary – hypothalamus

  45. Primary Adrenal Insufficiency - Causes www.uptodate.com

  46. Secondary Adrenal Insufficiency - Causes • Panhypopituitarism • Isolated ACTH Deficiency - ?autoimmune • Familial Cortisol-Binding Globulin Deficiency • Megestrol acetate • Opiates • Traumatic brain injury www.uptodate.com

  47. Tertiary Adrenal Insufficiency - Causes • Chronic high dose glucocortioid therapy • Post-cure Cushing’s syndrome • Other • tumours • cranial irradiation • infiltrative diseases i.e. sarcoidosis www.uptodate.com

  48. Adrenal Insufficiency – Clinical Presentation www.uptodate.com

  49. Adrenal Insufficiency – Clinical Presentation www.uptodate.com

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