Dr. Atallah Al-Ruhaily Consultant Endocrinologist ADRENAL DISORDERS Dr. Atallah Al-Ruhaily Consultant Endocrinologist

Adrenal Insufficiency Adrenocortical insufficiency (hypofunction of the adrenal cortex) includes all conditions in which there is deficient production of: Adrenal glucocorticoids Mineralocorticoids hormones.

Types of adrenal insufficiency These conditions are divided into 2 general groups according to the level of hypofunction: Primary adrenal insufficiency (Addison’s disease) due to primary hypofunction of the adrenal cortex. Secondary adrenal insufficiency adrenocortical failure secondary to a primary deficient secretion of ACTH from the pituitary gland.

Etiology of Primary Adrenal Insufficiency Anatomic destruction of gland (chronic & acute) “Idiopathic” atrophy (autoimmune) Surgical removal Infection (Tb., fungal, viral-esp. AIDS) Adrenal Hemorrhage Invasion: metastases, amyloidosis, sarcoidosis Metabolic failure in hormone production Congenital adrenal hyperplasia (CAH) Enzyme inhibitors: (Metyrapone, Ketoconazole, Aminoglutethemide) 3. Cytotoxic agents: (Mitotane) ACTH-blocking Antibodies

Etiology of Secondary Adrenal Insufficiency Hypopituitarism due to hypothalamic-pituitary disease. Suppression of hypothalamic-pituitary axis. Exogenous steroids (Iatrogenic) Endogenous steroids (from tumors)

Incidence Primary Adrenal Insufficiency: Relatively rare. Occurs at any age. affects both sexes equally.   Secondary Adrenal Insufficiency: Relatively common (because of common therapeutic use of steroids).

Etiology and Pathogenesis Addison’s Disease: Etiology and Pathogenesis Addison’s disease results from progressive destruction of adrenal cortex. At least 90% of gland is destroyed before signs of insufficiency appear.

Etiology and Pathogenesis Addison’s Disease: Etiology and Pathogenesis 50% of patients have +ve circulating adrenal Abs. Some Abs destroy the adrenal glands, others block the binding of ACTH to its receptors.  In addition, some patients have +ve Abs to thyroid, parathyroid and/or gonadal tissues. Polyglandular Autoimmune (PGA) syndromes

Associated Autoimmune Disorders Endocrine Disorders: Chronic lymphocytic thyroiditis Premature ovarian failure DM type 1 Primary hypothyroidism Hyperthyroidism Nonendocrine Disorders: Pernicious anemia Vitiligo Alopecia Chronic active hepatitis Nontropical sprue Myasthenia gravis

in chronic primary adrenal insufficiency Common Symptoms in chronic primary adrenal insufficiency Symptoms Frequency Asthenia (weakness, tiredness, fatigue) Anorexia Gastrointestinal symptoms Nausea Vomiting Constipation Abdominal pain Diarrhea Salt craving Postural dizziness Muscular or joint pains 100 90 85 75 30 15 10

in chronic primary adrenal insufficiency Common Signs in chronic primary adrenal insufficiency Signs Frequency Weight loss Hyperpigmentation of skin Pigmentation of mucous membrane Decreased axillary and pubic hair (in women only) Hypotension (systolic BP <110 mm Hg) with postural accentuation Vitiligo (with autoimmune) 100 95 80 60 15 10

Hyperpigmentation Generalized hyperpigmentation of skin & mucous membrane (the classical physical finding). Along with other features, suggests primary adrenocortical insufficiency. One of earliest manifestations of Addison’s disease.

Hyperpigmentation Increased at exposed areas and accentuated at pressure areas (knuckles, toes, elbows, knees) Associated with black or dark brown freckles. Hperpigmentation of buccal mucosa & gum is preceded by generalized hyperpigmentation of skin. Other areas: palmar creases, nail beds, nipples, areolae, perivaginal, perianal mucosa & scars that formed after onset of ACTH excess (but not older scars).

Hyperpigmentation in Addison’s disease

Hyperpigmentation in Addison’s disease

in chronic primary adrenal insufficiency Common Laboratory findings in chronic primary adrenal insufficiency Laboratory Findings Frequency Electrolytes disturbances Hyponatremia Hyperkalemia Hypercalcemia Azotemia Anemia Eosinophilia 90 65 5 55 40 15

Adrenal Imaging CT Scan Abdominal x-rays Adrenal calcification in 50% tuberculous cases & some other invasive or hemorrhagic causes. CT Scan more sensitive for adrenal calcification & enlargement Causes of bilateral adrenal enlargement: Tb Fungal infection CMV infection Infiltrative diseases (malignant or nonmalignant) Adrenal hemorrhage

Rt Adrenal mass

Acute Adrenal Crisis A state of acute adrenal insufficiency occurring in patients with Addison’s disease who are exposed to any form of stress. Precipitating stress factors: Infection Trauma Surgery Dehydration (Salt deprivation, vomiting, diarrhea) Discontinuation of steroids replacement therapy

Acute Adrenal Crisis: Clinical Features Common Clinical Features Hypotension & shock Fever (due to infection or hypoadrenalism per se) Dehydration, volume depletion Nausea, vomiting, anorexia Abdominal pain (may mimic acute abdomen) Weakness, apathy, depressed mentation Hypoglycemia (more in children) Shock and coma may rapidly lead to death in untreated patients.

Laboratory Findings Suggestive of Diagnosis Acute Adrenal Crisis Laboratory Findings Suggestive of Diagnosis Hyponatremia & Hyperkalemia (In a small number of acute cases). Azotemia (usual) Lymphocytosis Eosinophilia Hypoglycemia

Acute Adrenal Hemorrhage A progressively deteriorating condition resulting from bilateral adrenal hemorrhage and acute adrenal destruction in an already compromised patient with major illness.

Acute Adrenal Hemorrhage Manifestations Abdominal, flank or back pain & abdominal tenderness (Less frequently, abdominal distention, rigidity & rebound tenderness). Hypotension & shock Fever Nausea & Vomiting Confusion & disorientation Tachycardia

Acute Adrenal Hemorrhage With progression, the following manifestations may ensue: Severe hypotension Volume depletion Dehydration Hyperpyrexia Cyanosis Hypoglycemia Coma Death

Secondary Adrenal Insufficiency Causes ACTH deficiency most commonly due to exogenous glucocorticoid therapy. Pituitary & Hypothalamus tumors the most common causes of naturally occurring pituitary ACTH hyposecretion.

Secondary Adrenal Insufficiency Pathophysiology ACTH deficiency is the primary event. This leads to: Decreased Cortisol & Androgen secretion. But Aldosterone secretion remains normal except in few cases.

Secondary Adrenal Insufficiency Pathophysiology In early stages, Basal ACTH & cortisol levels may be normal. ACTH reserve is impaired. Response of ACTH & cortisol to stress is subnormal. With further loss of basal ACTH secretion, There is atrophy of Z. Fasciculata & Z. Reticularis. Basal cortisol secretion is decreased. The entire pituitary adrenal axis is impaired (i.e. Decreased ACTH responsiveness to stress & decreased adrenal responsiveness to stimulation with exogenous ACTH).

Secondary Adrenal Insufficiency Clinical Features Usually chronic nonspecific manifestations. Acute crisis occurs in: Undiagnosed patients Patients who do not receive increased steroid dosage during periods of stress.

Secondary Adrenal Insufficiency Clinical Features Clinical features differ from primary in that: Hyperpigmentation does not occur (Because of ACTH deficiency). Manifestations of mineralocorticoid deficiency are usually absent (Because Aldosterone secretion by Z. G. is usually preserved). Therefore: Volume depletion, dehydration & hyperkalemia usually absent. Hypotention is usually absent except in acute presentations. Hyponatremia may occur as a result of water retention.

Secondary Adrenal Insufficiency Clinical Features Prominent features (due to glucocorticoid deficiency) are nonspecific & include: Weakness, lethargy & easy fatigability anorexia, nausea & occasionally vomiting Arthralgias & myalgias Hypoglycemia Acute decompensation with severe hypotension or shock unresponsive to vasopressors.

Secondary Adrenal Insufficiency Associated Features The following additional features may be present: History of glucocorticoid therapy or Cushingoid features. Features of loss of other pituitary hormones (hypogonadism & hypothyroidism). Features of hypersecretion of GH or PRL from pituitary adenoma. Pressure symptoms from pituitary tumors.

Laboratory Workup for Adrenal Insufficiency

Cortisol Circadian Rhythm

Overnight single-dose Metyrapone Test - Procedure  Metayrapone : 30 mg/kg oral administration of Metyrapone at midnight with milk or snack. Serum 11-Deoxycortisol & Cortisol measurement (and ACTH level) 7:30 -9:30 AM next morning.

Overnight single-dose Metyrapone Test - Interpretation A normal response to the overnight single-dose test consists of: An 8 AM serum 11-deoxycortisol concentration of 7 to 22 mcg/dL (200 to 660 nmol/L). A serum cortisol concentration at 8 AM of less than 5 mcg/dL (138 nmol/L) confirms adequate.

Diagnosis of Adrenal Insufficiency 3 Stages of diagnosis confirmation: Inappropriately low cortisol secretion? .. Is cortisol deficiency dependent on or independent of corticotropin (ACTH) deficiency Evaluating mineralocorticoid secretion in patients without ACTH deficiency. Is there a treatable cause of the primary disorder?

Diagnosis of Adrenal Insufficiency Measuring non-specific anti-adrenal antibodies in serum by indirect immunofluorescence is not useful for establishing the diagnosis. Antibodies directed to 21-hydroxylase (P450c21) identify nearly all patients with autoimmune adrenal insufficiency and is not positive in any patient with adrenoleukodystrophy-associated adrenal insufficiency.

Diagnosis of Adrenal Insufficiency Basal levels of adrenocortical steroids in plasma or urine may be normal in partial adrenal insufficiency. Tests for adrenocortical reserve are necessary to establish the diagnosis. Rapid ACTH Stimulation Test Plasma ACTH Levels Metyrapone Test Insulin-induced Hypoglycemia CRH Stimulation

Diagnosis of Adrenal Insufficiency Other indirect clues: Features of hypersecretion of GH or PRL from pituitary adenoma. Pressure symptoms from pituitary tumors.

Evaluation of Suspected Adrenal Insufficiency Rapid ACTH Stimulation Test Abormal ACTH Stimulation Test: Adrenocortical insufficiency +ve. Which type? Plasma ACTH level: Elevated: Primary Adrenal Insufficiency +ve Normal or Low: Secondary Adrenal Insufficiency +ve

Evaluation of Suspected Adrenal Insufficiency Rapid ACTH Stimulation Test Normal ACTH Stimulation Test: This excludes Primary Adrenal Insufficiency & Adrenal atrophy. But does not exclude “Decreased ACTH Reserve” Metyrapone Test or Insulin-hypoglycemia Test or CRH stimulation Test: Normal: Exclude Adrenal Insufficiency Abnormal: Secondary Adrenal Insufficiency +ve

Treatment of Adrenal Insufficiency Acute Addisonian Crisis Glucocorticoid Replacement Cortisol (Hyrdocortisone succinate or phosphate) 100 mg every 6 hrs. for 24 hrs. When stable, reduce to 50 mg 6 hrs. Taper to maintenance therapy by day 4 or 5 & add mineralocorticoid as required. If complications persist or occur, maintain or increase the dose to 200-400 mg/d. General or Supportive Measures Correct volume depletion, dehydration, & hypoglycemia with I.V. saline and glucose. Evaluate and treat infection or other precipitating factors.

Treatment of Adrenal Insufficiency Maintenance Therapy Life-long replacement therapy with glucocorticoid and mineralocorticoid. Preparations: Cortisol (hydrocortisone) tablets First choice Maintenance dose: 15-30 mg/d. Usually, divided into 2 doses (2/3 AM & 1/3 PM) Cortisone acetate (37.5mg/d) Absorbed rapidly from GIT converted in the liver to cortisol.

Treatment of Adrenal Insufficiency Maintenance Therapy Synthetic Steroids: - Prednisone or Prednisolone 5 mg of prednisone tab is equivalent to 20 mg of hydrocortisone. - Fludrocortisone (9-alpha fludrocortisol) Used for mineralocorticoid therapy Usual dose: 0.05-0.1 mg/d PO AM

Treatment of Primary Adrenal Insufficiency Regimen Therapy Cortisol 15-20 mg AM & 10 mg at 4-5 pm Or prednisone 5.0-7.5 mg AM Fludrocortisone (Fluranif) 0.05 0.1 mg PO AM. Clinical Follow up: Maintenance of normal body weight, BP & electrolytes Regression of clinical features Patient education & identification card or bracelet Increased cortisol dosage during stress.