Addisons disease is a disorder characterized by a deficiency of glucocorticoids and in some cases mineralocorticoids. In this disorder, adrenal gland secretion of the above mentioned steroids is impaired either by direct pathology (autoimmune, cancerous, hemorrhagic, infarctions, or infectious) to the adrenal glands or by a blunted stimulation of the adrenals (decreased ACTH production) resulting from direct pituitary pathology or from impaired hypothalamic stimulation of the pituitary. The above etiologies are considered to be primary, secondary and tertiary, respectively. Abrupt cessation of chronic steroid therapy for chronic disease (rheumatic conditions, asthma, COPD, etc.) is a common cause. The more common form of the above etiologies is primary addisonian failure. The most common form of primary disease is autoimmune adrenalitis which is caused by cytotoxic lymphocyte mediated destruction of the adrenal glands. Autoimmune adrenalitis can occur without associated pathology or as part of the autoimmune polyendocinopathy syndromes types 1 or 2. Adrenomyeloneuropathy is an X-linked disorder of long-chain fatty acid metabolism seen in young men, and it is characterized by spastic paralysis and impaired adrenal function. Adrenal invasion by infectious (mycobacterium, cytomegalovirus, cryptococcus, histoplasmosis, or coccidioidomycosis) agents or malignant elements are potential etiologies especially in AIDs patients. Less common etiologies include infiltrative disorders (amyloidosis, hemochromatosis, sarcoidosis, malignant metastasis, etc.) adrenal hemorrhage (Waterhouse-Fredrickson syndrome, anticoagulation therapy), or infarction (antiphospholipid syndrome). Medications which may impair adrenal function include ketoconazole, etomidate, aminoglutethimide, and mitotane.
Clinical features of this disorder include fatigue, anorexia, nausea, vomiting, hypotension, diarrhea, weight loss, abdominal pain, mental confusion, fever, weakness, amenorrhea and loss of libido. In long standing disease, hyperpigmentation of the palmar creases, elbows, knees and lips may be noted on physical exam along with scant pubic and axillary hair. Hyperpigmentation will be present when the pathology involves the adrenal glands (primary disease), and hypopigmentation is commonly noted when ineffective pituitary stimulation is the etiology (secondary disease). Salt craving is another symptom which is indicative of primary disease. The diagnosis should be suspected in patients with hypotension that is resistant to intravenous catecholamine (dopamine or norepinephrine) therapy. Associated lab abnormalities include hyponatremia, hyperkalemia, azotemia, normocytic anemia, eosinophilia, acidosis, lymphocytosis, hypoglycemia and hypercalcemia. Hyperkalemia, acidosis and an elevated creatinine are three lab abnormalities which are indicative of primary disease. Cardiac cachexia which manifests as a narrow cardiac silhouette on standard chest radiography is a characteristic abnormality of this disorder, and its presence should prompt further evaluation.
Measurement of the serum cortisol from samples taken between 8 and 9a.m. serves as a good initial screening test. If the level is less than 3 micrograms/dL, the diagnosis is established and no further testing is needed other than a serum ACTH level which will determine if the pathology is primary (ACTH > 100 pg/mL) versus secondary (low or normal ACTH). Serum cortisol levels greater than 19 micrograms/dL conclusively eliminate the diagnosis. Levels in between 4 and 18 micrograms/dL indicate the need for further testing. It is important to note that a normal cortisol level in an acutely ill patient does not eliminate the diagnosis.
When further testing is required to establish the diagnosis, the cosyntropin test may be employed and is conducted in the following manner:
1) obtain baseline ACTH, cortisol and aldosterone levels
2) administer cosyntropin 0. 25 mg IM or IV
3) 60 minutes after cosyntropin administration, obtain repeat values of serum cortisol and aldosterone
Interpretation:
Primary adrenal insufficiency is diagnosed when there is an elevation in baseline values of serum ACTH and a low serum cortisol. Primary adrenal insufficiency also exhibits an undetectable serum aldosterone level which shows no response to cosyntropin stimulation. Secondary adrenal insufficiency is characterized by a low baseline ACTH and cortisol, but cortisol and aldosterone exhibit a response to cosyntropin stimulation.
Three other tests may be used to establish the diagnosis of secondary adrenal insufficiency. Intravenous insulin (0.1 to 0.15 units of regular insulin/kg) can be administered to induce hypoglycemia. The test should be performed in the morning, and plasma glucose and cortisol levels should be drawn at 0, 15, 30, 45, 60, 75 and 90 minutes after the insulin bolus. The plasma cortisol should increase to at least 20 micrograms/dL, and patients with an inappropriate response are diagnosed with adrenal insufficiency. This test should not be performed in patients with known or suspected coronary artery disease or seizures.
The short metyrapone test is performed by administering 30 mg/kg of metyrapone along with a snack at midnight and then measuring the serum cortisol and 11-deoxycortisol levels at 8 a.m. the next morning. If the plasma cortisol is less than 8 micrograms/dL then an 11-deoxycortisol level less than 7 micrograms/dL establishes the diagnosis. The 11-deoxycortisol level is not useful for diagnosis if the cortisol level is greater than 8 micrograms/dL.
The third test is the corticotropin-releasing hormone test. This test is performed by administering 1 microgram/kg but no more than 100 microgram/kg intravenously. Serum samples for plasma ACTH and cortisol are then drawn every 15 minutes for a total of 90 minutes. The benefit of this test is that it helps distinguish between hypothalamic and pituitary pathology; however, the test is less sensitive than the above mentioned studies.
Once the diagnosis has been established, further testing is necessary to determine the etiology. In patients with primary disease (adrenal pathology), indirect immunofluoresence techniques can detect antibodies against the adrenal cortex and are indicative of autoimmune adrenalitis or polyendocrinopathy syndromes types 1 or 2. If there are positive autoantibodies in conjunction with hypoparathyroidism or mucosal candidiasis, autoimmune polyendocrinopathy syndrome type 1 is diagnosed. When there is type 1 diabetes mellitus or autoimmune thyroid disease then polyendocrinopathy syndrome type 2 is present. If the adrenal antibody assay is negative, very long-chain fatty acid testing should be performed in male patients to rule out adrenoleukodystrophy. All patients with primary disease except those with autoimmune adrenalitis, polyendocrinopathy syndromes type 1 or 2, or adrenoleukodystrophy should undergo imaging of the adrenals with CT scanning. Adrenal enlargement is indicative of tuberculous infection, fungal infection, lymphoma, AIDs or metastatic disease. In cases of tuberculosis, adrenal enlargement on CT scanning is indicative of active disease and the need for aggressive treatment with antituberculous drugs. Patients with secondary or tertiary disease should be subjected to imaging studies of the pituitary and hypothalamus. MRI is superior to CT scanning. If bone invasion by a pituitary tumor or craniopharyngioma is suspected, a lateral skull radiograph or CT scan is indicated.
Treatment entails replacement therapy with oral steroids in the form of hydrocortisone 15 mg QAM and 10 mg QPM or 10 mg TID. Patients should be instructed to double their usual dosages when they become ill and to continue taking the increased dosage until they are well. No reliable objective end point for assessing adequacy of treatment has been established. Emergency treatment of Addisonian crisis entails administering hydrocortisone 100 mg intravenously every eight hours for a twenty four hour period. If the patients condition responds, then hydrocortisone may be tapered to 50mg every six hours intravenously on the second day and tapering may continue as permitted until the patient is able to tolerate oral medications. If myxedema coma and Addisonian crisis occur simultaneously, then the patient must receive hydrocortisone treatment before thyroxine therapy is begun. All patients with Addisons disease should be counciled to wear a medical alert bracelet or necklace, and they should carry a card with information on their usual current therapy and emergency recommendations.