Addison’s disease is characterized by inadequate secretion of corticosteroids resulting from partial or complete destruction of the adrenal glands.
Pathophysiology and causes
In this condition there is destruction of the entire adrenal cortex. Glucocorticoid, mineralocorticoid and sex steroid production are therefore all reduced. (This differs from hypothalamic-pituitary disease, in which mineralocorticoid secretion remains largely intact, being predominantly stimulated by angiotensin II. Adrenal sex steroid production is also largely independent of pituitary action.) In Addison’s disease reduced cortisol levels lead, through feedback, to increased CRH and ACTH production, the latter being directly responsible for the hyperpigmentation.
Incidence. Addison’s disease is rare, with an incidence of 3-4/million/year and prevalence of 40-60/million. Primary hypoadrenalism shows a marked female preponderance and is most often caused by autoimmune disease (> 90% in UK) but in countries with a high prevalence of HIV/AIDS, tuberculosis is an increasing cause. Autoimmune adrenalitis results from the destruction of the adrenal cortex by organspecific autoantibodies, with 21-hydroxylase as the common antigen. There are associations with other autoimmune conditions in the polyglandular autoimmune syndromes types I and II (e.g. type 1 diabetes mellitus, pernicious anaemia, thyroiditis, hypoparathyroidism, premature ovarian failure).
Primary adrenocortical insufficiency
EPIDEMIOLOGY & DEMOGRAPHICS
PREVALENCE: 5 cases/100,000 persons
PREDOMINANT SEX: Female:male ratio of 2:1
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Hyperpigmentation: more prominent in palmar creases, buccal mucosa, pressure points (elbows, knees, knuckles), perianal mucosa, and around areolas of nipples
• Generalized weakness
• Amenorrhea and loss of axillary hair in females
These are shown in Figure 1.2 The symptomatology of Addison’s disease is often vague and non-specific. These symptoms may be the prelude to an Addisonian crisis with severe hypotension and dehydration precipitated by intercurrent illness, accident or operation. Pigmentation (dull, slaty, grey-brown) is the predominant sign in over 90% of cases. Postural systolic hypotension, due to hypovolaemia and sodium loss, is present in 80-90% of cases, even if supine blood pressure is normal.
Fig. 1.2 Primary hypoadrenalism (Addison’s disease) - symptoms and signs. Bold type indicates signs of greater discriminant value.
• Autoimmune destruction of the adrenal glands (80% of cases)
• Tuberculosis (15% of cases)
• Carcinomatous destruction of the adrenal glands
• Adrenal hemorrhage (anticoagulants, trauma, coagulopathies, pregnancy, sepsis)
• Adrenal infarction (arteritis, thrombosis)
• Other: sarcoidosis, amyloidosis, postoperative, fungal infections, AIDS (adrenal insufficiency develops in 30% of patients with AIDS)
Sepsis, hypovolemic shock, acute abdomen, apathetic hyperthyroidism in the elderly, myopathies, GI malignancy, major depression, anorexia nervosa, hemochromatosis, salt-losing nephritis, chronic infection
• If the clinical picture is highly suggestive of adrenocortical insufficiency, the diagnosis can be made with the rapid ACTH (Cortrosyn) test:
1. Give 250 mg ACTH by IV push and measure cortisol levels at 0 and 30 min.
2. Cortisol level <18 mg/dl at 30 or 60 min is suggestive of adrenal insufficiency.
3. Measure plasma ACTH. A high ACTH level confirms primary adrenal insufficiency.
• Secondary adrenocortical insufficiency (caused by pituitary dysfunction) can be distinguished from primary adrenal insufficiency by the following:
1. Normal or low plasma ACTH level following rapid ACTH (Cortrosyn test)
2. Absence of hyperpigmentation
3. No significant impairment of aldosterone secretion (because aldosterone secretion is under control of the renin-angiotensin system)
4. Additional evidence of hypopituitarism (e.g., hypogonadism, hypothyroidism)
• Increased potassium, decreased sodium and chloride
• Decreased glucose
• Increased BUN/creatinine ratio (pre-renal azotemia)
• Mild normocytic, normochromic anemia, neutropenia, lymphocytosis, eosinophilia (significant dehydration may mask hyponatremia and anemia)
• PPD and antiadrenal antibodies
• Chest x-ray examination may reveal a small heart.
• Abdominal x-ray film: adrenal calcifications may be noted if the adrenocortical insufficiency is secondary to TB or fungus.
• Abdominal CT scan: small adrenal glands generally indicate either idiopathic atrophy or long-standing TB, whereas enlarged glands are suggestive of early TB or potentially treatable diseases.
• Perform periodic monitoring of serum electrolytes, vital signs, and body weight; liberal sodium intake is suggested.
• Periodic measurement of bone density may be helpful in identifying patients at risk for the development of osteoporosis.
Patients should carry a Medic Alert bracelet and an emergency pack containing hydrocortisone 100 mg ampule, syringe, and needle. Patients and partners should be educated on how to give IM injection in case of vomiting or coma.
ACUTE GENERAL Rx
Addisonian crisis is an acute complication of adrenal insufficiency characterized by circulatory collapse, dehydration, nausea, vomiting, hypoglycemia, and hyperkalemia.
1. Draw plasma cortisol level; do not delay therapy while waiting for confirming laboratory results.
2. Administer dexamethasone sodium phosphate 4 mg q12h or hydrocortisone 100 mg IV q6h for 24 hr; if patient shows good clinical response, gradually taper dosage and change to oral maintenance dose (usually prednisone 7.5 mg/day).
3. Provide adequate volume replacement with D5 NS solution until hypotension, dehydration, and hypoglycemia are completely corrected. Large volumes (2 to 3 L) may be necessary in the first 2 to 3 hr to correct the volume deficit and hypoglycemia and to avoid further hyponatremia. Identify and correct any precipitating factor (e.g., sepsis, hemorrhage).
• Give hydrocortisone 15 to 20 mg PO every morning and 5 to 10 mg in late afternoon or prednisone 5 mg in morning and 2.5 mg hs.
• Give oral fludrocortisone 0.05 mg/day to 0.20 mg/day: this mineralocorticoid is necessary if the patient has primary adrenocortical insufficiency. The dose is adjusted based on the serum sodium level and the presence of postural hypotension or marked orthostasis.
• Instruct patients to increase glucocorticoid replacement in times of stress and to receive parenteral glucocorticoids if diarrhea or vomiting occurs. Typical supplementation varies from 25 mg PO qd of hydrocortisone for minor medical and surgical stress to 50-100 mg IV hydrocortisone every 8 hr for sepsis-induced hypotension or shock.
• The administration of dehydroepiandrosterone 50 mg PO qd improves well-being and sexuality in women with adrenal insufficiency.
• Lifelong medical supervision is necessary to monitor adequacy of therapy and prevent complications.
• Adrenal function is rarely recovered.
• Life expectancy is in the normal range if adequately treated.