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Adrenal Insufficiency

Adrenal Insufficiency . Drs. Swibinski and Raja Chief Round 10/11/10. Lets look at a case: . A 24-year-old Caucasian F presents to ED with a sudden episode of nausea, vomiting and collapse, having become acutely unwell whilst at work. PE: appears drowsy and unwell

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Adrenal Insufficiency

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  1. Adrenal Insufficiency Drs. Swibinski and Raja Chief Round 10/11/10

  2. Lets look at a case: • A 24-year-old Caucasian F presents to ED with a sudden episode of nausea, vomiting and collapse, having become acutely unwell whilst at work. • PE: appears drowsy and unwell • VS: BP: 103/56, no postural changes, P: 101, afebrile BMI: 23 • Initial laboratory studies: NA: 127 mmol/l, K 3.2 mmol/l, Bun/creatinine: 77/3.2, Glucose: 96 • CT and MRI of the brain normal • Patient at this point continued to be drowsy, admitted to ICU

  3. CSF done, showed no abnormality • Started on antibiotics and acyclovir for acute meningioencephalitis , plus IV fluids • Patient improved within 24 hours and transferred to medical ward • Subsequent history - patient reported generalized fatigue and sometimes falling asleep at work. • Further examination - generalized hyperpigmentation with facial melasma were noted, no buccal pigmentation. • Marked pigmentation of recent scar over left shoulder.

  4. Cosyntropin stimulation test was performed and demonstrated adrenal insufficiency. • Basal cortisol level at 231 nmol/l, 30 min cortisol 265 nmol/l and 60 min at 200 nmol/l. • Adrenal auto-antibodies were negative • Her Adrenocorticotropic hormone (ACTH) was high @ 278 pmol/l consistent with adrenal insufficiency • Started on hydrocortisone 10mg BID and fludrocortisones 50mcg replacement therapy and discharged. • Two weeks later patient was feeling much better.

  5. Adrenal Histology

  6. Adrenal Cortex: Steroid Hormone Production • Aldosterone, sex hormones, cortisol • Synthesized from cholesterol–steroid ring

  7. Adrenal Cortex: Steroid Hormone Production Figure 23-2: Synthesis pathways of steroid hormones

  8. History • 1855 Thomas Addison described clinical syndrome characterized by "general languor and debility, feebleness of the heart's action, irritability of the stomach, and a peculiar change of the color of the skin“.

  9. Etiology • Estimated incidence of 0.8 cases per 100,000 • Prevalence of 4 to 11 cases/100,000 • affects both males and females equally • Acquired forms of primary insufficiency are rare • Due to common use of steroids, secondary adrenal insufficiency is relatively common

  10. Pathogenesis • Results from progressive destruction of adrenals • Must involve >90% of gland before symptoms appear • Frequent site for chronic granulomatous diseases • Including TB, histoplasmosis, coccidiomycosis • In early series TB was responsible for 70-90% of cases • Most frequent cause now is idiopathic atrophy • Likely autoimmune mechanism is responsible (70% ) • Rare causes include adrenoleukodystrophy, bilateral hemorrhage, tumor metastasis, HIV, CMV, amyloidosis or scarcoidosos

  11. In 75 % cases, adrenal auto antibodies can be detected • 50 % patient have other associated autoimmune disease (thyroid being most common) • Some medications such as, rifampin, phenytoin, ketoconazole, megestrolacetate and opiates may cause or potentiate adrenal insufficiency

  12. PRIMARY: ADDISON'S DISEASE • Autoimmune      • Sporadic      • Infections      • Tuberculosis    •  Fungal infections      • Cytomegalovirus      • HIV    • Metastatic tumor    • Infiltrations      • Amyloid • Hemochromatosis • Intra-adrenal hemorrhage (Waterhouse-Friderichsen syndrome) after meningococcal septicemia    • Adrenoleukodystrophies • Congenital adrenal hypoplasia • DAX-1 mutations    • SF-1 mutations    • ACTH resistance syndromes      • Mutations in MC2-R • Triple A syndrome    • Bilateral adrenalectomy

  13. Clinical features: • Patient with primary adrenal failure usually have both glucocorticoid and mineralocorticoid deficiency • Secondary adrenal insufficiency have an intact renin-angiotensin –aldosterone system • Obvious feature that differentiates primary from secondary hypoadrenalsim is skin pigmentation present in primary disease and absent secondary

  14. Pigmentation is seen in sun-exposed areas, recent scars, axillae, nipples, palmar creases, pressure points and mucus membrane (buccal, vaginal vulval, anal) • Pigmentation likely due to increased stimulation of melanacortin-1 receptor by ACTH itself. • Clinical symptoms relate to the onset and severity of adrenal deficiency • Usually insidious onset and diagnosis usually made when patient presents with acute crisis.

  15. 18 y.o. with autoimmune polyendocrine syndrome B and C patient before and after treatment with hydrocortisone D-60 y.o. with TB and addisondis Williams Book of Endocrinology E-buccal pigmentation in D

  16. CLINICAL FEATURES OF PRIMARY ADRENAL INSUFFICIENCY Symptom, Sign, or Laboratory Finding Frequency (%) SYMPTOM • Weakness, tiredness, fatigue 100 % • Anorexia 100 % • Gastrointestinal symptoms 92% • Nausea 86 % • Vomiting 75% • Constipation 33 % • Abdominal pain 31% • Diarrhea 16% • Salt craving 16% • Postural dizziness 12% • Muscle or joint pains %6-13

  17. SIGNS • Weight loss – 100% • Hyperpigmentation -94 % • Hypotension (<110 mm Hg systolic) 88-94 % • Vitiligo 10-20% • Auricular calcification 5 % LABORATORY FINDING • Electrolyte disturbances 92 % • Hyponatremia 88 % • Hyperkalemia 64 % • Hypercalcemia 6 % • Azotemia 55 % • Anemia 40 % • Eosinophilia 17 %

  18. Addisonian crisis • is a medical emergency manifesting as hypotension and acute circulatory failure • Anorexia early feature, my progress to nausea, vomiting and diarrhea

  19. CLINICAL AND LABORATORY FEATURES IN ADRENAL CRISIS • Dehydration, hypotension, or shock out of proportion to severity of current illness • Nausea and vomiting with a history of weight loss & anorexia • Abdominal pain • Unexplained hypoglycemia • Unexplained fever • Hyponatremia, hyperkalemia, azotemia, hypercalcemia, or eosinophilia • Hyperpigmentation or vitiligo • Other autoimmune endocrine deficiencies, such as hypothyroidism or gonadal failure

  20. Diagnosis • In primary adrenal insufficieny, hyponatremia is about 90 % cases and hyperkalemia 65% • Hypercalemia is present 6% cases • Free thyroxine concentration is low or normal • TSH values are moderately elevated, directly due to glucocorticoid deficiency • In primary insufficiency, renin levels are elevated • In secondary insufficiency, renin-angiotensin-aldosterone system is intact

  21. HPA Axis • Basal cortisol value greater then 400 nmol/L (14.5mg/dl) indicates intact HPA axis. • All patient suspected of having adrenal insufficiency should have ACTH stimulation test. • Patient suspected of having addisonian crisis, should be treated right away and stimulation test should be tested later • Normal subject serum cortisol concentration are higher early in the morning (about 6am), ranging from 10-20 • So low early morning cortisol suggest adrenal insufficieny

  22. William book of endocrinology

  23. ACTH Stimulation Test • Administration of 250mg of tetracosactin comprising first 24 amino acid of normally secreted ACTH • Plasma cortisol levels are measured at 0 and 30 minutes • A normal response is defined as peak plasma cortisol greater then 550 nmolL (>20mg/dL). • Response unaffected by time of the day and can still be performed in patient who have commenced treatment

  24. Healthy individuals have greatest cortisol response in the morning • Response to consynotropin is same in morning and afternoon in individual with renal insufficiency • Best to perform test in the morning to avoid falsely abnormal result • Normal response to high-dose (250mcg as IV bolus) is a rise in serum cortisol to a peak of 18 to 20 after 30 0r 60 mins • Subnormal response confirms diagnosis of adrenal insufficiency

  25. Low dose vs. high ACTH • Low dose (1mcg or 0.5 mcg) ACTH stimulation test criteria for cortisol response is 17 to 22.5 mcg/dl after 20 to 30 mins • At 95 % specificity, the sensitivity of high dose test for primary adrenal insufficiency is 97.5 % and 57 % secondary adrenal insufficiency • So a normal response excludes the diagnosis of primary adrenal insufficiency, but does not exclude the diagnosis of secondary adrenal insufficney

  26. Lets look at another case: • Patient is 24 y.o. female with PMH of Hypo-parathyroidism, Addison’s diease and Hypothyroidism who presented to ED with fatigue X 3 days. During same time, reports sore throat and inability to take her medication. Today she was unable to get out of bed, felt "generalized fatigue" with myalgias. • ED VS 82/46, P 108, Sat 99% on RA • Patient vomited a few times in ED • FS showed glucose 0f 54, D50 and IV fluid started

  27. Patient seen by ED, concerned for Addison’s disease due to fever, hypotension and medication non-compliance. • Ordered Hydrocortisone 100mg IV and Labs including cortisol level 131 94 12 50 3.4 18 0.6 Cortisol < 0.3 • Patient “dramatically improved” after administration of hydrocortisone • Patient seen by endocrine consult, recommended to reduce hydrocortisone to 50mg Q 6hrs and change to PO in am

  28. Patient started on hydrocortisone 40mg BID • Advised to get medic alert bracelet alert health team patient is steroid dependent • Started florinef 0.1 mg daily prior to discharge the next day

  29. Secondary Hypoadrenalism • Often due to sudden cessation of exogenous glucocorticoid therapy • Glucocorticoid therapy suppress HPA axis with consequent adrenal atrophy • Occurs in anyone who taken equivalent of 30mg hydrocortisone/day orally for more than 3 weeks

  30. SECONDARY Hypoadrenalism • Exogenous glucocorticoid therapy • Hypopituitarism • Selective removal of ACTH-secreting pituitary adenoma • Pituitary tumors and pituitary surgery, craniopharyngiomas • Pituitary apoplexy • Granulomatous disease (tuberculosis, sarcoid, eosinophilicgranuloma) • Secondary tumor deposits (breast, bronchus) • Postpartum pituitary infarction (Sheehan's syndrome) • Pituitary irradiation (effect usually delayed for several years) • Isolated ACTH deficiency • Idiopathic • Lymphocytic hypophysitis • TRIT gene mutations • POMC processing defect • POMC gene mutations

  31. DX of secondary hypoadrenalism • Prolong ACTH stimulation test involves administrating cosynotropin for 24 to 48 hours • In normal subjects, plasma cortisol at 4 hours is greater then 1000 nmol/L (36mg/dl) • Patient with secondary hypoadrenalism show a delayed response with usually much higher value at 24 and 48 hours then at 4 hours • In primary disease, no response at either dose is seen

  32. TREATMENT OF ACUTE ADRENAL INSUFFICIENCY (ADRENAL CRISIS) • EMERGENCY MEASURES • Establish intravenous access with a large-gauge needle. • Draw blood for stat serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH. Do not wait for laboratory results. • 2 to 3 liter of IV fluid (NACL) • Inject intravenous hydrocortisone (100 mg immediately and every 6 hr) • Use supportive measures as needed.

  33. SUBACUTE MEASURES AFTER STABILIZATION OF THE PATIENT • Cont IV fluid • Search for and treat possible infectious precipitating causes of the adrenal crisis. • Perform a short ACTH stimulation test to confirm the diagnosis of adrenal insufficiency, if patient does not have known adrenal insufficiency. • Determine the type of adrenal insufficiency and its cause if not already known. • Taper glucocorticoids to maintenance dosage over 1 to 3 days, if precipitating or complicating illness permits. • Begin mineralocorticoid replacement with fludrocortisone (0.1 mg by mouth daily) when saline infusion is stopped.

  34. TREATMENT OF CHRONIC PRIMARY ADRENAL INSUFFICIENCYMAINTENANCE THERAPY • Hydrocortisone 15 to 20 mg on awakening and 5 to 10 mg in early afternoon. • Monitor clinical symptoms and morning plasma ACTH. • Fludrocortisone 0.1 (0.05 to 0.2) mg orally. • Monitor orthostatics , edema, serum potassium, and plasma renin activity. • Educate patient about the disease, how to manage minor illnesses and major stresses, and how to inject steroid intramuscularly.

  35. Adrenal Insufficiency in acute Ill • An increase corticosteroid is an important response • Dirunal variation is lost • Due to increase in production of CRH and lost of negative feed back • Stimulation of HPA is cause by circulating cytokines • Corticosteroid binding globulin decreases during critical illness • Neutrophil elastase cleaves corticosteroid binding globulin

  36. Corticosteroid insufficiency can occur during course of acute illness • CRH secretion can be impaired due head injury, CNS depressant and pituitary infarction • High level of cytokines during sepsis can directly inhibit adrenal cortisol synthesis • Corticosteroid insufficiency associated with acute illness can be difficult to discern clinically • Symptoms and sign prior to illness • Hemodynamic instability despite adequate fluid resuscitation

  37. Expected cortisol levels vary with type and severity of disease, making it difficult to define normal range • Highest levels found in severest illness • Both low and high levels associated with poor prognosis • Proposed minimum levels range from 10 ug/dl (276 nmol/l to 34 ug/dl (938 nmol/l) • Adrenal insufficiency is unlikely if when random cortisol level is greater 34 ug/dl and likely if serum cortisol level is below 15 ug/dl in severe illness • 15-34 ug/dl indicates possible adrenal insufficiency and need for supplemental corticosteroids

  38. Use of cosyntropin stimulation test remains controversial • Increment response after administration in critically ill may be prognostic factor • Less than 9 ug/dl increase from baseline at 30 or 60 minutes is associated with increase risk of death

  39. The End

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