1 / 78

ADRENAL INSUFFICIENCY

ADRENAL INSUFFICIENCY. Background. 1855 Thomas Addison-clinical syndrome characterized by wasting and hyperpigmentation Cause as destruction of the adrenal glands 1994 life-saving steroid replacement therapy developed-Kendall, Sarett & Reichstein. Epidemiology. Primary & Secondary

marisa
Download Presentation

ADRENAL INSUFFICIENCY

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ADRENAL INSUFFICIENCY

  2. Background • 1855 Thomas Addison-clinical syndrome characterized by wasting and hyperpigmentation • Cause as destruction of the adrenal glands • 1994 life-saving steroid replacement therapy developed-Kendall, Sarett & Reichstein

  3. Epidemiology • Primary & Secondary • Chronic primary: 93-140/million, incidence 4.7-6.2/million (white, 4th decade, women > men) • Secondary: 150-280/million, peak 6th decade, women > men) • Therapeutic steroid use-most common cause

  4. Introduction • Medulla secretes epinephrine and norepinephrine into adrenal veins when stimulated • Cortex secretes steroids regulating metabolism, vascular tone, cardiac contractility, TBW/Na/K balance, androgenic function (GFR: aldosterone/mineralocorticoids, cortisol/glucocorticoids, testosterone/androgenic steroids)

  5. Physiology • Cyclic secretion controlled by time of day, HPA axis, renin-angiotensin system, serum potassium levels • Stress increases basal glucocorticoid and mineralcorticoid levels 5-10 fold • Occurs within minutes

  6. Definitions • Basal failure results in adrenal insufficiency • Leads to insidious wasting disease • Stress failure results in adrenal crisis • Life-threatening • Absence of glucocorticoids is most critical

  7. Glucocorticoids • Regulate fat, glucose, protein metabolism • Catecholamine and b-adrenergic receptor synthesis • Maintain vascular tone and cardiac contractility • Control endothelial integrity/vascular permeability

  8. Glucocorticoids • Cortisol • Controlled by HPA axis • Hypothalamus  CRH and arginine vasopressin in circadian rhythm (max 2-4am) • Anterior Pituitary  ACTH • Adrenal cortex  cortisol • Peak @ 8am; declines throughout day

  9. Glucocorticoids • Cortisol • 20-25mg produced daily (non-stressed) • 5-10% free and physiologically active • Remainder bound to cortisol-binding globulin • Becomes uncoupled in times of stress • Negatively feeds back to control hypothalamus • Role in adrenal insufficiency

  10. Mineralcorticoids • Regulated via renin-angiotensin system & serum potassium levels • Diminished GFR juxtaglomerular apparatus release of prorenin • Aldosterone release  Na & H2O resorption at distal tubules (K is lost) • Minor hyperkalemia can stimulate aldosterone secretion directly

  11. Adrenal Androgens • Controlled by ACTH • Diurnal pattern (like cortisol) • Significant source of androgens in females • Can cause signs/symptoms seen in adrenal insufficiency

  12. Adrenal Insufficiency • Primary = failure of adrenal glands • Secondary = failure of HPA axis • Usually due to chronic exogenous glucocorticoid administration • pituitary failure • Tertiary = Hypothalamic dysfunction

  13. Primary Adrenal Insufficiency • Loss of all three types of adrenal steroids • 90% of glands must be destroyed to manifest clinically • High functional reserve • Adrenoleukodystrophy = X-linked inherited d/o of very-long-chain fatty acid metabolism • Progressive neurological symptoms from white matter demyelination (mutation of the ABCD 1 gene encoding for the peroxisomal ALD protein) • Cerebral: 50%, early childhood, rapid progression • Adrenaomyeloneuropathy: 35% early adulthood, slow progression restricted to spinal cord and peripheral nerves • Accumulation of VLCFA • 15% adrenal insufficiency precedes onset of neurological symptoms

  14. Primary Adrenal Insufficiency • Addison disease =m.c. autoimmune d/o (40% male predominance; APS 60% female predominance) • Thrombosis/hemorrhage • Sepsis, DIC, antiphospholipid syndrome • Infiltrative diseases • Bilateral cancer metastasis • Amyloidosis, hemosiderosis (rare) Drug-induced -mitotane, aminoglutethimide, etomidate, ketoconazole, metyrapone

  15. Primary Adrenal Insufficiency • TB = m.c. infectious cause worldwide • HIV = m.c. infectious cause in US • 50% have degree of destruction • Only 5% have clinical symptoms of A.I. • CMV infection, ketoconazole use, macrophage-released cytokines are risk factors Fungal infection =m.c. in immunocompromised patients (cryptococcosis, histoplasmosis, coccidiomycosis) CAH = 21-OH def, 11b-OH def, 3b-HSD type 2 def, 17a-OH def (ambiguous genitalia, virilization, hypertension etc.)

  16. AutoimmumePolyglandular Syndrome (APS) • Classification (Betterle C et al. Endocr Rev 23: 237, 2002):

  17. APS type I • APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy)-15% • Adrenal insufficiency, hypoparathyroidism, chronic mucocutaneouscandidiasis (at least 2) • Onset during childhood • Associated with other autoimmune disorders • Childhood alopecia 40%, chronic active hepatitis 20%, and malabsorption 15% • Mutation in autoimmune regulator (AIRE) gene which modulates the transcription of peripheral self-antigens in the thymus presented by HLA molecules to mature T cells, autosomal recessive • Diagnosis: functional testing, interferon omega (100% sensitive), AIRE • Survey/Therapy: clinically q6m particular attention to AI development and replacement hormone, regular monitoring of calcium, antifungal (ketoconazole, fluconazole, ampho B, bx), blood smear for Howell-Jolly bodies; if asplenic: immunizations properly

  18. Halonen M et al. J ClinEndocrinolMetab. 87: 2568, 2002.

  19. Halonen M et al. J ClinEndocrinolMetab. 87: 2568, 2002

  20. APS type 2 • Most frequently seen • Adrenal insufficiency AND autoimmune thyroiditis (Schmidt’s), and/or DMI (Carpenter’s) • Other autoimmune diseases-vitiligo, chronic atrophic gastritis, celiac disease, pernicious anemia, myasthenia gravis • Autosomal dominant with incomplete penetrance; females > males; 1:20K prev • Strong association with HLA-DR/DQ/DP and CTLA-4, MICA5.1, PTPN22

  21. APS type 3 and 4 • APS type 3: AITD + other autoimmune disease processes (does not involve adrenal insufficiency or hypoparathyroidism) Sub-types: A, B, C, D based on various combinations of diseases; particularly sub-type 3D (frequent association with SLE/RA, systemic sclerosis, sjogren etc.) • APS type 4: two or more autoimmune diseases that do not meet criteria for 1, 2 or 3

  22. Secondary Adrenal Insufficiency • HPA axis failure • deficiency of glucocorticoids and adrenal androgens • mineralcorticoids are unaffected • #1 cause=chronic exogenous glucocorticoid • suppresses diurnal CRH/AV release • both time- and dose-related • reversible • recovery may take up to a year

  23. Secondary Adrenal Insufficiency • Less common causes • Postpartum necrosis (Sheehan syndrome) • Adenoma hemorrhage(s) • Pituitary destruction from head trauma • Pituitary/other tumors (craniopharyngioma, meningioma etc.) • Irradiation, lymphocytic hypophysitis, congenital syndromes (POMC defect/def, combined pituitary hormone def), infiltration (TB, fungal, histiocytosis X, sarcoidosis) • typically have associated focal neurological changes, visual deficits, diabetes insipidus or panhypopituitarism

  24. Secondary Adrenal Insufficiency MYTHBUSTERS! • Short course (2-3 weeks) is unlikely to suppress the HPA axis • Daily doses of prednisone 5mg or less are unlikely to cause secondary insufficiency

  25. Chronic Insufficiency CLINICAL PRESENTATION • Nonspecific • Fatigue, weakness (74-100%), anorexia, weight loss (56-1--%), loss of libido • Neurological • Headaches, visual changes, diabetes insipidus • Gastrointestinal (56%) • Pain, nausea, vomiting, diarrhea

  26. Chronic Insufficiency CLINICAL PRESENTATION • Hypotension/Orthostasis (59-88%) • Cachexia • Thin axillary and pubic hair in women • Hypoglycemia • Normocytic anemia, lymphocytosis, eosinophilia • Hypercalcemia (6-41%) due to increased GI absorption and decreased renal excretion • Muscle & joint pain

  27. Chronic Insufficiency CLINICAL PRESENTATION • Hyperpigmentation (92-96%) • Pressure points, axillae, palmar creases, perineum, oral mucosa • Usually seen early in primary AI • Caused by enhanced stimulation of skin MC1-receptor by ACTH & other POMC-related peptides • Pallor out of proportion to anemia (alabaster-colored skin) • Seen in secondary AI

  28. Chronic Insufficiency CLINICAL PRESENTATION • Hyponatremia (88-96%) • Primary = lack of aldosterone & Na wasting • Secondary = vasopressin secretion (dilutional effect) • Hyperkalemia (52-64%) • Only occurs in primary • mild with associated azotemia & met acidosis

  29. DHEA deficiency: Major precursor of sex-steroid synthesis Loss results in pronounced androgen deficiency in women (loss of axillary/pubic hair, dry skin, reduced libido) Potential antidepressant properties May contribute to the impairment of wellbeing

  30. Adrenal Crisis CLINICAL PRESENTATION • Life-threatening emergency • May be primary or secondary • HYPOTENSION • Typically resistant to catecholamine and IVF resuscitation

  31. Adrenal Crisis CLINICAL PRESENTATION • Abrupt adrenal failure usually from gland hemorrhage or thrombosis • Anticoagulation • DIC • Sepsis (Waterhouse-Friderichsen syndrome) • Usually have abdominal and flank pain • Can resemble ruptured AAA!!!

  32. Adrenal Crisis CLINICAL PRESENTATION • Catastrophic HPA axis failure • Head trauma • Hemorrhage of pituitary adenoma • Post-partum herniation (Sheehan syndrome) • Usually neurological deficits, headaches, visual field cuts and diabetes insipidus

  33. Diagnosis • Short corticotropinstim test • Get baseline level • Inject 250mcg cosyntropin (IV or IM) • Measure plasma cortisol level in 60 minutes • Excluded if basal or test level is > 18mcg/dL • Plasma cortisol levels between 8am-9am • Level < 3 mcg/dL rules IN • Level > 19 mcg/dL rules OUT Overnight metyrapone test (inhibits 11b hydroxylase) 30mg/kg max 3 g administered with a snack at midnight Healthy-deoxycortisol increases, cortisol < 8 Secondary AI- 11-deoxycortisol < 7 at 8 am

  34. Low dose corticotropin test • 1mcg ACTH • More sensitive • Need to dilute test amount from commercially available 250 mcg ACTH • Still results in hormone conc. greater than those for maximum cortisol release

  35. Burch W. EndocrPract 17:591, July/Aug 2011Using bedtime and early morning urine cortisol/creatinine (ng/ml) ratios to evaluate pituitary adrenal function in an office practice • Diurnal pattern (7-fold increase PM to AM P<0.0001) in 26 healthy controls (16 to 92), respective ranges 12.5-19 pm and 65-118 am; and 131 outpts without endocrine disease (but with fatigue, malaise, inability to lose weight)  AM/PM ratio=7; change AM-PM=76 • 11 Cushing’s syndrome: loss of diurnal pattern with pm urine level 127 and AM/PM ratio 1.16  consistent with known diagnosis • 11 hypopit pts: little to no increase in am compared to pm urine voids • Conclusions: AM/PM cortisol/creatinine ratios may offer a convenient outpatient method for assessing pituitary-adrenal function

  36. Special situations • Standard short ACTH test 4-6 weeks after pituitary surgery • In critically ill patients • Random sample serum cortisol and plasma ACTH follow by immediate hydrocortisone administration

More Related