ADRENOCORTICAL DEFICIENCY Hasan AYDIN, MD Endocrinology and Metabolism Yeditepe University Medical Faculty

Definition Deficient adrenal production of glucocorticoids or mineralocorticoids

Steroidogenesis Cholesterol Pregnenolone Progesterone 11-Deoxycorticosterone Corticosterone Aldosterone 17-Hydroxypregnenolone 17-Hydroxyprogesterone 11-Deoxycortisol Cortisol DHEA Androstenedione Testosterone Estradiol 3β hydroxysteroid dehydrogenase 21β-hydroxylase 11β-hydroxylase Aldosterone synthase Cholesterol desmolase 17α-hydroxylase17,20 lyase Glomerulosa Fasciculata Reticularis

Primary Adrenal Insufficiency Causes Anatomic destruction of gland Metabolic failure in hormone production ACTH-blocking antibodies Mutation in ACTH receptor gene Adrenal hypoplasia congenita

Secondary Adrenal Insufficiency Hypopituitarism due to hypothalamic-pituitary disease Suppression of H-P-A axis - By exogenous steroid - By endogenous steroid from tumor

Causes of Adrenal Insufficiency Primary adrenal insufficiency Autoimmune (70%of patients) Infections Tuberculosis (20% of patients) menincococcus,pnumococcus, fungal,HIV Medications (ketoconasole, dilantin,phenobarbital,rifampin,etomidate, metyrapone) Malignancy (Primary,metastatic) Adrenal hemorrhage (spontaneous, traumatic,coagulopathy/heparin/coumadin) Familial Infiltrative diseases (amyloidosis, sarcoidosis,hemochromatosis) Secondary adrenal insufficiency Exogenous glucocorticoid withdawal Following cure of cushing’s sydrome Hypothalamic or pituitary disease (Tumor,sarcoidosis,hemorrhage, autoimmune,postoperative) Isolated adrenocorticotropic hormone deficiency

Adrenal Insufficiency After Long-term Corticosteroid Therapy More than 20mg of prednisolone daily for more than 3 weeks, within the previous year Any patient who has clinical Cushing’s syndrome (from any steroid dose) HPA axis suppresssion

Adrenal Insufficiency After Long-term Corticosteroid Therapy Dose equivalent to 5 mg/d or less of prednisolone given for any length of time once daily in the morning Any dose of glucocorticoid given for less than 3 weeks Safe withdraw dose and duration

Primary Adrenal Insufficiency (Addison’s disease) - Involve > 90% of the glands

Pathophysiology Gradual adrenocortical destruction - Initial phase: Decreased adrenal reserve Basal steroid secretion- Normal Not increase in stress response - Further loss of cortical tissue Impair basal secretion of glucocorticoid and mineralocorticoid Plasma ACTH elevation- Earliest and most sensitive indication

Anatomic Destruction of Gland Idiopathic atrophy: Autoimmune, leukodystrophy Surgical removal Infection: TB, Fungus, Virus esp. in AIDS Hemorrhage Invasion: Metastasis eg. CA thyroid, breast, kidney, lymphoma

Idiopathic Atrophy Most common cause 70-80% Autoantibody: adrenal cortex Ab, 21-hydroxylase Ab Isolated or associated with polyglandular autoimmune syndrome PGA syndrome 2 types PGA type1- more common PGA type2

PGA Syndrome PGA type1 (Autoimmune Polyendocrinopathy- Candidiasis- Ectodermal Dysplasia) - Autosomal recessive (no HLA association) - Childhood onset - 2/3 of these clinicals :Chronic mucocutaneous candidiasis :Chronic hypoparathyroidism :Autoimmune adrenal insufficiency - Other: Hypogonadotropic hypogonadism, DM type1, Autoimmune thyroid disease, Lymphocytic hypophysitis, Pernicious anemia, Chronic active hepatitis, Vitiligo, Alopecia

PGA Syndrome PGA type2 - Polygenic, asso. with HLA DR3,DR4 - Adult onset - Primary adrenal insufficiency, Grave’s disease, Autoimmune thyroiditis, DM type1, Primary hypogonadism, celiac disease

Metabolic Failure in Hormone Production Congenital adrenal hyperplasia. Inborn error of cortisol synthesis. 5 types ( classified by type of enz. deficiency) - Most common: 21-hydroxylase deficiency - 2 nd most common: 11-hydroxylase deficiency Drugs - Enzyme inhibitors: Metyrapone, phenytoin, barbiturate, ketoconazole, aminoglutethimide - Cytotoxic agent: Mitotane

Slow Onset Auto-immune atrophy (cmst) TBC Metastatic CA ( lung, breast, kidney) or lymphoma) Systemic fungal infections ( histoplasmosis, cryptococcosis, blastomycosis ) Amyloid Granulomatous disease Late stage of AIDS ( CMV, bacterial or protozoal infection or Kaposi’s ) Schilder's disease ( hereditary leucodystrophy and adrenocortical atrophy ) Wolman's disease ( adrenal insufficiency, HSM,steatorrhoea with lipid- filled lysosymes )

Abrupt Onset Adrenal haemorrhage, necrosis or thrombosis in: meningococcal or other sepsis coagulation disorders as a result of warfarin therapy anti-phospholipid syndrome

Presentation Highly variable Duration of disease Whether deficiency is primary or secondary

Potential Clinical Manifestations Glucocorticoid deficiency Cardiovascular hypotension,impaired response to catecholamines Gastrointestinal anorexia, nausea, weight loss, abdominal pain, diarrhea Cutaneous hyperpigmentation (secondary to ACTH precursors) vitiligo (secondary to autoimmune disease) Muscular fatigue,weakness,malasie Neurologic confusion, apathy, lethargy, psycosis Mineralocorticoid Deficiency Cardiovascular hypovolemia, decreased cardiac output, impaired response to catecholamines

Clinical Features of Primary Adrenocortical Insufficiency Percent Weakness, fatigue, anorexia, weight loss 100 Hyperpigmentation 92 Hypotension 88 Gastrointestinal disturbances56 Salt craving 19 Postural symptoms 12

Other Autoimmune Endocrinopathies Hypo and hyperthyroidism Type 1 DM Premature ovarian failure with ovarian auto-antibodies Primary hypoparathyroidism Pernicious anaemia Alopecia Mucocutaneous candidiasis

Acute Adrenal Crisis Acute adrenal insufficiency occurs in patients with Addison’s disease who are exposed to the stress of infection, trauma, surgery or dehydration

Clinical Features of Acute Adrenal Crisis Hypotension and shock Fever Dehydration, volume depletion Nausea, vomiting, anorexia Weakness, apathy, depressed mentation Hypoglycemia

Laboratory Findings of Adrenal Insufficiency Glucocorticoid deficiency Lymphopenia Eosinophilia Hypogycemia Anemia Minerolocorticoid deficiency Hyponatremia Hyperkalamia Acidosis Azotemia Hypercalcemia ECG: features are low voltage,vertical QRS axis, nonspesific ST-T wave abnormalities

Diagnosis

Diagnosis of Adrenocortical Insufficiency Since basal levels of adrenocortical steroids in either urine or plasma may be normal in partial adrenal insufficiency, tests of adrenal cortical reserve are necesseary to establish the diagnosis Cortisol > 20 mg/day at any time of day -diagnosis very unlikely Hemodynamic instability - cortisol < 20 mg/day - suspicious

ACTH Stimulation Test Performed at any time of day A baseline cortisol sample is obtained 250 mg/day synthetic ACTH (cosyntropin) is then administered intravenously. Cortisol samples are drawn 30 and 60 min later. Plasma cortisol >18 mcg/dl excludes the diagnosis

Other Tests Insulin stress test, Corticotrophin releasing hormone test Metyrapone test can be used to diagnose secondary adrenal insufficiency

Tests to confirm 2ry adrenal insufficiency Prolong ACTH stimulation - Baseline plasma cortisol - Cosyntropin 250 ug iv q 8 hr for 48 hr. : Primary adrenal insufficiency- plasma cortisol no change : Secondary adrenal insufficiency- progressive increase in plasma cortisol, and level >18 ug/dL

Tests to Confirm 2ry Adrenal Insufficiency Insulin induced hypoglycemia - Suspected hypothalamic or pituitary disease - Short acting insulin u/kg at morning - Blood for plasma glucose and cortisol at 30, 60, 90, and 120 min Normal response- if BG 18 ug/dl ( Avoid when hypoglycemia is contraindicated, 1ry adrenal insufficiency, stroke, epilepsy)

Tests to Confirm 2ry Adrenal Insufficiency Short metyrapone test - Metyrapone 30 mg/kg orally at PM - Blood for cortisol and 11-deoxycortisol at 8.00 AM Normal- cortisol < 8 ug/dl deoxycortisol > 7ug/dl (Metyrapone not available in Turkey)

Plasma ACTH Level Used to differentiate primary and secondary forms Secondary adrenal insufficiency plasma ACTH <30 pg/mL ( 7pmol/L) Primary adrenal insufficiency plasma ACTH >52 pg/mL

Suspected Adrenal Insufficiency Rapid ACTH stimulation test AbnormalNormal Decreased ACTH reserve not excluded Metyrapone or insulin hypoglycemia testing Adrenocortical insufficiency Plasma ACTH ElevatedNormal or low 1ry Adrenal insufficiency 2ry Adrenal insufficiency AbnormalNormal Exclude 2ry Adrenal insufficiency Exclude 1ry Adrenal insufficiency

Differential Diagnosis CA TB Salt-losing nephropathy Anorexia Malnutrition Severe GI disease Malabsorption Congenital adrenal hyperplasia

Treatment

Treatment of Acute Adrenal Crisis Glucocorticoid replacement Administer hydrocortisone sodium phosphate or sodium succinate, 100 mg IV every 6 hour for 24 hours. When the patient is stable, reduce the dosage to 50 mg every 6 hours. Taper to maintenance therapy by day 4 or 5 and add mineralocorticoid therapy as required. Maintain or increase the dose to mg/d if complications persist or occur. General and supportive measures Correct volume depletion, dehydration, and hypoglycemia with intravenous saline and glucose. Evaluate and correct infection and other precipitating factors.

Regimen for Maintenance Therapy Hydrocortisone, mg in AM and 10 mg orally at 4-5 pm Fludrocortisone, mg orally in AM. Clinical follow-up: Maintenance of normal weight, blood pressure, and electrolytes with regression of clinical features. Patient education plus identification card or bracelet. Increased hydrocortisone dosage during "stress.''

If Adrenal Crisis Suspected Blood drawn for cortisol and start hydrocortisone immediately without waiting the result Or Intravenous ACTH stimulation test done and start hydrocortisone immediately without waiting the result

In Acute Adrenal Failure 100 mg hydrocortisone iv 100 mg iv every 6-8 hours Equivalent dose other corticosteroids

After 24 hours 25 mg hydrocortisone im every 8 hours Day 3 25 mg hydrocortisone im every 12 hours Day 4 oral replacement doses

SteroidGlucocorticoidMineralocorticoidEquivalent dose Cortisone Hydrocortisone1201 Prednisone450.8 Prednisolone450.8 Methypprednisolone540.5 Triamcinolone540 Paramethasone1520 Dexamethasone Bethametasone Aldosterone0400-

Fludrocortisone doses should be enough to abolish postural hypotension return Na and K to normal maintain plasma renin in upper normal range sustain well being

Fludrocortisone Doses Usually mcg daily Excessive doses of fludrocortisone or hydrocortisone may result in: unacceptable weight gain edema hypertension

Steroid and the surgical patient

Effect of Surgery Stress activates the HPA axis, increased plasma ACTH and cortisol concentration. The degree of activation depend on the type of surgery and anesthesia Cortisol increase to mg/d, normal: 15-20mg/d

Effect of Surgery The increase in cortisol: cariac output, sensitivity to catecholamine, work capacity of skeletal muscle, ability to mobilize energy source. Greatest ACTH secretion: reversal of anesthesia, during extubation, during the immediated postoperative recovery period.

Steroid Coverage for Major Surgery Correct electrolytes, blood pressure, and hydration if necessary. Give hydrocortisone sodium phosphate or sodium succinate, 100 mg intramuscularly, on call to operating room. Give 50 mg intramuscularly or intravenously in the recovery room and then every 6 hours for the first 24 hours. If progress is satisfactory, reduce dosage to 25 mg every 6 hours for 24 hours and then taper to maintenance dosage over 3-5 days. Resume previous fludrocortison dose when the patient is taking oral medications. Maintain or increase hydrocortisone dosage to mg/d if fever, hypotension, or other complications occur

Steroid Therapy Schedule For a Patient with Adrenal Insufficiency Undergoing Surgery---minor surgery 100 mg of hydrocortisone is given intravenously with the induction of anesthesia. followed by usual maintenance dose (approximately 20 mg/d of hydrocortisone)

Corticosteroid Insufficiency in Acutely Ill Patients

The Hypothalamic–Pituitary–Adrenal Axis in Acute illness During severe illness, many factors can impair the normal corticosteroid response.

Head injury; CNS depressants Pituitary infarction Ketoconazole Adrenal hemorrhage in septicemia or coagulopathy High level of inflammatory cytokines in sepsis p’t directly inhibit adrenal cortisol synthesis Extensive destruction by tumor or infection

The Hypothalamic–Pituitary–Adrenal Axis in Acute illness Develop during an illness Transient “Functional adrenal insufficiency” -- no obvious structral defects in HPA axis “Relative adrenal insufficiency” -- insufficient to control the inflammatory response

Diagnosis of Corticosteroid Insufficiency during Acute illness Corticosteroid insufficiency associated with acute illness -- difficult to discern clinically, but there are some features that suggest the diagnosis.

Features suggesting corticosteroid insufficiency common in patients with acute severe illness. Easy been masked by fluid replacement, especially in ICU Relatively uncommon

Laboratory Investigations Randomly measured cortisol levels More useful would be the identification of a minimal threshold level and a maximal threshold level. 15 µg/dl (10 µg/dl to 34 µg/dl) best identifies persons with clinical features of corticosteroid insufficiency or who would benefit from corticosteroid replacement

Laboratory Investigations Corticotropin stimulation test IV or IM 250 µg of Cosyntropin Check plasma cortisol levels 0, 30, ( 60 ) mins after administration

Laboratory Investigations Corticotropin stimulation test Prognostic implications -- < 9 µg /dl  increased risk of death. > 34 µg /dl: unlike. <15 µg /dl: likely.

In Summary Adrenal failure can be primary or secondary Clinical features can be variable Diagnosed by basal cortisol and ACTH stimulation test Treated with glucocorticoids + mineralocorticoids