When first described by Addison, tuberculosis was by far the most common etiology of adrenal insufficiency. Today, tuberculosis remains a major cause of adrenal insufficiency in the developing world with adrenal involvement occurring in 5% of patients wi

When first described by Addison, tuberculosis was by far the most common etiology of adrenal insufficiency. Today, tuberculosis remains a major cause of adrenal insufficiency in the developing world with adrenal involvement occurring in 5% of patients with active tuberculosis. In industrialized countries, however, autoimmune destruction of the adrenal gland accounts for 80% to 90% of cases of primary adrenal insufficiency.3,4 Autoimmune Addison's disease is often associated with other autoimmune diseases, most frequently with autoimmune thyroid disease, pernicious anemia, and diabetes mellitus.6 In fact, in approximately 60% of these cases, autoimmune Addison's disease occurs as part of an autoimmune polyendocrine syndrome (APS) with a female preponderance (Table 1).7-9 Autoimmune polyendocrine syndrome type II is the most common poly-endocrine syndrome and comprises autoimmune adrenal insufficiency (100%) and autoimmune thyroid disease (69%). Type 1 diabetes mellitus (52%), primary gonadal failure (4%), vitiligo (5%), and autoimmune gastritis can also be seen as part of APS type II.6,8 Autoimmune polyendocrine syndrome type II is inherited in autosomal-dominant fashion with incomplete penetrance. Other causes of primary adrenal insufficiency are rare in developed countries, but include various infections, genetic disorders, bilateral adrenal hemorrhage, infiltrating diseases or metastasis, or drug-induced (Table 2).3,7Under normal physiological circumstances, glucocorticoids are secreted from the adrenal cortex under the control of the hypothalamus and pituitary gland, which secretes corticotropin (ACTH). Mineralocorticoid secretion from the adrenal cortex is under the control of the renin-angiotensin system. Thus, mineralocorticoid secretion is lost in primary adrenal insufficiency (adrenal failure), but maintained in secondary adrenal insufficiency (pituitary or hypothalamus failure).3 Whether due to autoimmune destruction or another cause, Addison's disease is now recognized as a primary failure of the adrenal cortex to synthesize and secrete glucocorticoid and mineralocorticoid hormones.10 The symptoms and signs of primary adrenal insufficiency are directly attributable to the loss of these vital hormones.

Addison's disease can mimic a gastrointestinal disorder (with abdominal cramps, persistent nausea and vomiting, or diarrhea) or a psychiatric disease. Patients are sometimes misdiagnosed as having depression or anorexia nervosa.5,10 Unexplained weight loss, malaise, fatigue, and anorexia are common. The most specific sign of primary adrenal insufficiency is hyperpigmentation which is most pronounced in areas of skin exposed to increased friction (knuckles, palmar creases, scars, oral mucosa).4,10 Hyperpigmentation is due to stimulation of melanocyte-stimulating hormone by high plasma ACTH levels.3,5 Another specific symptom of primary adrenal insufficiency is salt craving.10Unless a patient presents with acute adrenal crisis, the diagnosis of adrenal insufficiency is often delayed. The most common problem in missed diagnosis is lack of clinical suspicion mainly because the signs and symptoms are nonspecific.11 In some reports, up to 50% of patients have signs and symptoms of Addison's disease for more than one year before the diagnosis is established.12 Furthermore, a survey of patients with the disease revealed that 60% had sought medical attention from two or more physicians before the correct diagnosis was even considered.5Acute adrenal insufficiency with a previously unknown adrenal disorder is life threatening and can also be diagnostically challenging. The possibility of adrenal insufficiency in critically ill patients should always be considered. Patients with acute adrenal crisis typically present with severe hypotension or hypovolemic shock, acute abdominal pain, vomiting, and often fever.3 This presentation may lead to the misdiagnosis of an acute abdomen. In one series of 91 patients with Addison's disease, acute adrenal crisis was the initial presentation of the disease in 50%.12 If acute adrenal insufficiency is suspected, biochemical testing should be performed and immediate high-dose hydrocortisone therapy should be considered or instituted.10In patients with chronic adrenal insufficiency, many laboratory abnormalities are common. Hyponatremia (90% of patients with primary adrenal insufficiency), hyperkalemia (65%), acidosis, anemia, and mild eosinophilia are typical.3,4 The diagnosis of primary adrenal insufficiency is verified by combined measurement of early morning (between 8 and 9 a.m.) serum cortisol (low) and plasma ACTH (high) levels. Morning plasma cortisol concentrations less than or equal to 3 mcg/dL indicate adrenal insufficiency and obviate the need for further tests, whereas, concentrations greater than or equal to 18 mcg/dL rules out adrenal insufficiency. Patients with cortisol concentrations between 3 and 18 mcg/dL need further evaluation with corticotropin stimulation testing (see below). In primary adrenal insufficiency, serum cortisol levels are typically low and plasma ACTH concentrations nearly always exceed 100 pg/dL. Measurement of basal ACTH levels can also be used to differentiate between primary and secondary adrenal insufficiency as normal plasma ACTH levels rule out primary adrenal insufficiency.10 While not routinely measured, serum aldosterone concentrations are low or in the low-normal range, with plasma renin activity concurrently elevated above the normal range.3The impaired ability of the adrenal cortex to respond to ACTH can be demonstrated by corticoptropin stimulation testing. The test involves measurement of serum cortisol before intravenous or intramuscular injection of 250 mg of 1-24 ACTH (cosyntropin) and 30 or 60 minutes following the injection. The test may be performed at any time during the day. As guide, if the basal or post-cosyntropin plasma cortisol concentration is at least 18 mg per deciliter, adrenal function is considered to be normal. Adrenal insufficiency is present if the level is less than 18 mg per deciliter following corticoptropin injection.11 In patients with primary adrenal insufficiency, the adrenal cortex is already maximally stimulated by endogenous ACTH, and exogenous hormone administration does not evoke any further increase in serum cortisol.3,10If results are not straightforward or further testing is needed, endocrinology consultation is suggested.

In searching for the underlying cause of adrenal insufficiency, adrenal antibody testing is important. Adrenocortical autoantibodies (against the enzyme 21-hydroxylase) are present in around 90% of patients with Addison's disease, and their detection almost always precedes the onset of disease.7,8,10 Measurement of these autoantibodies can be helpfulin patients with isolated primary adrenal insufficiency and no family history of autoimmune diseases. If adrenal autoantibodies are not detected, then a search for alternative causes of adrenal insufficiency is required. As mentioned previously, more than 50% of patients with autoimmune Addison's disease have other autoimmune disorders as part of an APS.4,9 In APS type II, autoimmune Addison's disease can be associated with autoimmune thyroid disease and other autoimmune disorders, and endocrinology consultation and screening for other autoimmune diseases is recommended.

Adrenal imaging is unnecessary in patients with a diagnosis of primary adrenal insufficiency from an autoimmune cause. If infection, hemorrhage, infiltration, or neoplastic disease is suspected, a computed tomography (CT) scan of the adrenal glands should be done. The adrenal glands are enlarged in patients with adrenal insufficiency caused by tuberculosis, fungal infections, metastatic cancer, lymphoma, and AIDS. A CT-guided needle biopsy of adrenal masses may be helpful for diagnosis. Except in a case where a pituitary or hypothalamic tumor is suspected (symptoms of headache or visual disturbances), radiologic tests should only be considered after an endocrinologic diagnosis is established by hormonal testing. Magnetic resonance imaging (MRI) is the test of choice to evaluate the hypothalamic-pituitary region for a space-occupying lesion in most cases of secondary adrenal insufficiency.3,10If acute adrenal insufficiency is suspected, treatment should be started immediately. A high dose of intravenous hydrocortisone (100 mg bolus followed by 100-200 mg over the next 24 hours) along with intravenous isotonic saline in patients with hypovolemia and hyponatremia is the standard treatment. In cases of newly diagnosed or suspected adrenal insufficiency, baseline levels of cortisol, ACTH, and optionally plasma renin activity and aldosterone should be drawn immediately before hydrocortisone administration.3,4 If corticotropin stimulation testing needs to be done, intravenous dexamethasone should be given initially because it will not interfere with test results. In most patients, oral therapy can be started or resumed within two days.10 It should be noted that in patients with suspected concominant Addison's disease and hypothyroidism, thyroid replacement therapy should not precede glucocorticoid replacement, since thyroid replacement may precipitate adrenal crisis due to increased hepatic corticosteroid metabolism. Additionally, in some patients with newly diagnosed Addison's disease, thyrotropin (TSH) levels may normalize after glucocorticoid replacement.8For maintenance therapy, an initial daily dose of 15 to 25 mg of hydrocortisone is usually given in two separate doses (early morning and afternoon). The dose can be gradually reduced with the goal to use the smallest dose that relieves the patient's symptoms, in order to prevent side effects such as weight gain and osteoporosis. No objective assessment has proven to be reliable for monitoring glucocorticoid replacement quality. Adrenocorticotropic hormone, urinary 24hour free cortisol, and random serum cortisol values have all proven to be ineffective in monitoring replacement adequacy. Thus, treatment surveillance of chronic replacement is mainly based on clinical grounds and should be done by an experienced physician.3,10Patients with primary adrenal failure also need mineralocorticoid replacement with fludrocortisone (0.05

0.2 mg/day). The dose can be guided by measurements of blood pressure, serum potassium, and plasma renin activity, which should be in the upper-normal range.10Very few studies have evaluated the effectiveness of different regimens and long-term management by an endrocrinologist is suggested. It is controversial whether replacement of dehydroepiandrosterone should be given, but in some patients it may have positive effects on well-being and mood.3 Despite adequate glucocorticoid and mineralocorticoid replacement, patients often have impaired health-related quality of life and commonly complain of fatigue, lack of energy, depression, and anxiety.3In regards to the long-term management of Addison's disease, patient education about the prevention and management of adrenal crisis is imperative. All patients with adrenal insufficiency should carry a card with information about current therapy and recommendations for treatment in emergency situations. A warning bracelet or necklace is also recommended. Patients should add 5 to 10 mg hydrocortisone to their normal regimen before strenuous activities such as hiking. For more severe physical stress such as febrile illness or injury, the daily dose should be doubled until recovery. In the event of vomiting or diarrhea, glucocorticoids should be administered parenterally or rectally. For major surgery, trauma, or severe illnesses, patients should receive intravenous hydrocortisone (100-150 mg daily).3,5,10In conclusion, primary adrenal insufficiency or Addison's disease is a rare condition that can be life threatening if overlooked. A high index of suspicion for this disease is critical as symptoms are often nonspecific and delays in diagnosis are common. Once suspected, laboratory diagnosis and treatment are well established. By far the most frequent cause in industrialized countries is autoimmune destruction of the adrenal glands. Patients should be screened for other autoimmune disorders as part of a autoimmune polyendocrine syndrome. Patient education regarding adrenal crisis is essential and long-term management under the direction of an experienced physician is critical.