Adrenal Insufficiency Mahmood Soveid,M. D Adrenal Insufficiency Mahmood Soveid,M.D. Shiraz University of Medical Sciences

Agenda Primary adrenal insufficiency: Etiology ,diagnosis, treatment Diagnosis and treatment in pregnancy Adrenal insufficiency in critically ill patients Ref:Bornstein RS,etal.Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline.JCEM. 2016 Feb; 101(2): 364–389. Central hypoadrenalism Etiology,diagnosis,treatment Ref: Crowley RK,etal: Central Hypoadrenalism. JCEM.   2014; 99 (11): 4027-4036.  

Primary Adrenal Insufficiency Prevalence: Relatively rare disease, increasing prevalence In Europe 40-70 cases/mil in 1960, 93-144cases/mil at the end of 20th century .Central AI 125-280 cases / million

Clinical features Chronic adrenal insufficiency: fatigue, anorexia, wt loss, postural dizziness, and abdominal discomfort, hyper pigmentation, low back pain , salt craving Routine lab data: hyponatremia , hyperkalemia, hypoglycemia, hypercalcemia , eosinophilia, lymphocytosis, elevated TSH up to 20 mu/L. Adrenal crisis: severe weakness, syncope, abdominal pain, nausea, vomiting, acute abdomen (guarding and rebound), confusion, hypotension ,shock and death .

Etiology Autoimmune: isolated, APS type 1, APS type 2 Infectious adrenalitis: TB, HIV/AIDS, CMV, fungal Adrenal hemorrhage: sepsis, anticoagulants, anti cardiolipin/lupus anticoagulant syndrome Adrenal metastasis: lung, breast, colon, lymphoma , melanoma Infiltration: hemochromatosis, primary amyloidosis Bilateral adrenalectomy Congenital adrenal hyperplasia Adrenal hypoplasia congenita ACTH insensitivity syndromes: type 1,2, familial, triple A(Allgrove synd) : achalasia, Addison’s disease, alacrima (AAAS gene mutation) Drugs: adrenal enzyme inhibitors: mitotane, ketoconazole, metyrapone, etomidate, aminoglute thimide, Cortisol metabolism enhancers: levothyroxine,rifampin,anticonvulsants CTLA-4 inhibitors: enhance autoimmunity Metabolic disorders: mitochondrial diseases, adrenoleukodystrophy in male, wolman disease

Who should be tested for PAI? Low threshold needed Any patient with clinical symptoms and signs suggestive of PAI Acutely ill patients with unexplained volume depletion, hypotension, hyponatremia, hyperkalemia, abdominal pain and in children, hypoglycemia

Diagnostic tests: ACTH stimulation test: corticotropin test, Synacthen test, cosyntropin test ,tetracosactide test Standard test: 250µg for adults and children ≥ 2 yrs, 15µg/kg for infants, I.V. or IM any time of day, check cortisol after 30 or 60 min; cortisol < 18µg/dl (500nmol/L) indicates adrenal insufficiency 1 µg (low dose) corticotropin test when synacthen is in short supply (1µg/ml solution stable for 60 days) If synacthen not available: Morning (6-10 AM) cortisol < 5µg/dl(140nmol/L) suggestive of AI Measure ACTH, if cortisol deficiency is confirmed, ACTH > 2-fold UNL (>66pmol/L) is consistent with PAI.

Long stimulation test with 1 mg tetracosactide depot: 1hr 21 micg/dl 2hr 26 4hr 33 8hr 35 24 21 Ref: Jenkins RC, Ross RJM. Protocols for common endocrine tests. In: Grossman A (ed). Clinical Endocrinology. Blackwells Science, Oxford. 2nd edit 1998:1117-1134.

Mineralocorticoid evaluation: Measure plasma renin and aldosterone in PAI to determine the presence of mineralocorticoid deficiency. Elevated plasma renin concentration or activity in -combination with normal or low aldosterone is suggestive of PAI. In early phase of PAI, mineralocorticoid - deficiency may be the only endocrine abnormality.

If anti 21-hydroxylase antibody positive: 30% develop overt PAI in 5 yrs. Adrenal insufficiency may be the only presenting sign of adrenoleukodystrophy which usually presents in boys 2-10 yrs.

Treatment: Glucocorticoid replacement: Hydrocortisone 15-25 mg in 2-3 divided doses After awakening 15 mg, 2 hrs after lunch 10mg After awakening (10mg), at lunch (5mg), 4-6 hr before bedtime (5mg) Prednisolone 3-5 mg/d in 1 or 2 dose, if poor compliance Monitoring of glucocorticoid replacement: clinical assessment; body weight, energy levels, signs of frank cortisol excess. Mineralocorticoid replacement: Fludrocortisone 50-100 µg/d Monitoring: clinical; BP, salt craving, postural hypotension, edema, Lab: K+ , Na, renin in upper normal limit

Dehyroepiandrosterone replacement: In premenopausal women with PAI and low libido, depression symptoms, or low energy levels 6 months trial of DHEA 25-50 mg/day Monitoring: morning DHEA-S level in mid normal range

Additional monitoring: At least annual F/u, signs and symptoms of under or over treatment: BP, electrolyte. In cases of autoimmune PAI; thyroid: 50% of female and 25% of male develop autoimmune thyroid disease so annual TSH. Type 1 DM: In up to 10-15% , so annual HBA1c. Premature ovarian failure: overall 8%, if APS-1: 33%, APS -2:16%. Anti 11-hydroxylase antibody correlated with POF. Pernicious anemia: vitamin B12 level and CBC Celiac disease: In 5%, anti TTG and IgA level

Diagnosis and treatment in pregnancy Increase in CBG, so total cortisol level is increased 2-3 folds, from 22 wk free cortisol is also increased. Consider PAI in pregnant women with unusual hypotension and nausea, vomiting. Cosyntropin test is the test of choice: diagnostic cortisol cut offs: 25,29,32 µg/dl in 1st , 2nd, and 3rd trimesters. Treatment: Hydrocortisone or prednisolone, use the usual dose before 24th wk, increase by 20-40% (20-35mg/d)after 24 wk. At the start of labor: 100 mg hydrocortisone IV then 200 mg/24 hrs.

Prognosis and quality of life Mortality of PAI is increased compared with general population(up to 2folds). Adrenal crisis is a significant cause of death. Also overtreatment complications. 6-8% of patients experienced an adrenal crisis annually. Gastrointestinal and flu like illnesses are the most common triggers. Other important causes of adrenal crisis: drugs which increase cortisol metabolism: carbamazepine, phenytoin, levothyroxine, Rifampin. Double the dose. Prevention of adrenal crisis: Patient education(home management): In fever: double (>38° c) or triple (> 39°c) until recovery. Unable to tolerate oral medication: Hydrocortisone 100 mg IM or Sc. Minor surgery: Hydrocortisone 75 mg/24h IV for 1-2 days Major surgery: Hydrocortisone 100 mg IV then 200 mg/day IV infusion or 50 mg q 6 h IV or IM.

Management of adrenal crisis 1- Rapid infusion of 1000cc N/S or D/S in 1 hr followed by continuous isotonic saline. 2- Hydrocortisone 100 mg I.V. immediately then 200 mg/d as continuous infusion for 24 hrs, reduce to 100 mg/d next day. 3- If hypoglycemia, DW 25% 2-4 ml/kg, 2-3 ml/min 4- Cardiac and electrolyte monitoring

Relative (functional) adrenal insufficiency , AI in critically ill patients: Possible etiology: Cytokines Partial infarction of adrenals Hypoproteinemia Consider this in critically ill patients with unexplained persistent hypotension, and fever. No consensus on diagnostic criteria : Random cortisol < 15µg/dl in favor, >33µg/dl rules out, 15-33µg/dl needs stimulation test: < 9µg/dl rise of cortisol after cosyntropin test favors the diagnosis. Treatment: 240 mg/d I.V hydrocortisone (10 mg/hr) for 7 days in septic shock,1mg/kg methylprednisolone for ARDS.

Central hypoadrenalism When pituitary fails general sequence of failure: GH, LH, FSH, TSH, ACTH. In lymphocytic hypophysitis: ACTH deficiency may be the first and alone. Prevalence of central hypoadrenalism: 125-280 cases / million (underestimated) Manifestations: As in PAI except for absence of hyperpigmentation and hyperkalemia

Etiology 1- Glucocorticoid excess: exogenous or endogenous 2- Space occupying lesions 3- Ischemia, necrosis: Sheehan syndrome, pituitary apoplexy 4- Pituitary surgery, radiation, trauma 5- immune mediated : lymphocytic hypophysitis ,Wegener's granulomatosis , histiocytosis x 6- Infections 7- Genetic disorders

ACTH suppression by exogenous glucocorticoids: Can lead to adrenal crisis Any route: systemic, inhaled, topical, intra articular, ocular Consider inter individual variability in response to glucocorticoids. No absolute cut off values for the type of steroid taken, route of administration, duration of treatment, and duration of post withdrawal suppression. Usual minimum suppressive dose: 20 mg hydrocortisone, 5 mg predrisolone, 0.5mg dexamethasone fluticasone 1000 micg/yr can cause adrenal suppression. Duration for oral route: 3 wks to 3 mo After treatment of cushing syndrome due to pituitary or adrenal adenoma: Recovery of adrenal function is reported at a medium of 2 years.

Diagnosis of central hypoadrenalism Tetracosactide test: 250 µg test It should not be used to assess the patients after 3-6 weeks of acute pituitary insults such as pituitary surgery or apoplexy. ITT: gold standard for evaluation of HPA. Not to be used in patients with morning cortisol < 4 µg/dl. Contraindicated in IHD, CVD, or seizures. Metyrapone test: Measurement of 11- deoxycortisol after metyrapone.

Treatment: Hydrocortisone 15-20 mg in split dose Treatment: Hydrocortisone 15-20 mg in split dose. Mineralocorticoid is not needed. DHEA may benefit some patients. Interaction of glucocorticoids with other hormones: GH increases cortisol clearings by inhibition of 11-βHSD type 1 Oral estrogen: CBG Levothyroxine: Increases cortisol metabolism Hydrocortisone unmasks central DI

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