In the ACTH stimulation test, if the cortisol concentration does not rise above 18 g/dL at 0, 30 or 60 minutes following the stimulation dose, the results indicate adrenal insufficiency (1, 4, 18). aided by several factors including 1) history, including salt craving, features consistent with orthostatic hypotension, and GI complaints including nausea, vomiting and pain, 2) physical examination findings of increased pigmentation and small or unidentifiable adrenal glands, 3) serologic testing for 21-hydroxylase antibodies, PIM447 (LGH447) 4) serum cortisol concentrations, and 5) vitreous electrolyte testing. While the listed historical information, the increased pigmentation, decreased serum cortisol concentrations, and evidence of hyponatremia may be found in all forms of Addison disease, small or unidentifiable adrenal glands and 21-hydroxylase antibodies are found exclusively in the autoimmune form of PIM447 (LGH447) Addison disease. While other causes of Addison disease, such as tuberculosis, metastatic tumor, or other infiltrative processes would have enlarged adrenal glands, these diseases would lack 21-hydroxylase antibodies. The purpose of this paper is to focus on the diagnosis of autoimmune Addison disease. Currently, in the United States and other developed countries, most cases PIM447 (LGH447) of Addison disease are an autoimmune process affecting the adrenal glands (1, 5). Due to the nonspecific and subtle signs and symptoms of the chronic phase of Addison disease, the clinical diagnosis may be missed until the acute decompensation phase, known as an adrenal crisis, which may manifest in response to a physiologic stressor, most often a gastrointestinal (GI) infection (6, 7). As an adrenal crisis may be the first presentation of Addison disease and may cause sudden death, awareness of Addison disease and specifically how to make the diagnosis at autopsy is important information for the practicing forensic pathologist. Discussion PIM447 (LGH447) Causes of Adrenal Insufficiency Adrenal insufficiency is a descriptive diagnostic term for the pathophysiologic changes induced by a variety of medical conditions that, as their endpoint, can impair the normal production of adrenocortical hormones, including mineralcorticoids (i.e., aldosterone) and glucocorticoids (i.e., cortisol). Adrenal insufficiency can be either a primary, secondary, or tertiary disorder and the onset can be either acute or chronic (1, 2). Secondary and PIM447 (LGH447) tertiary causes of adrenal insufficiency, originating in the pituitary gland and hypothalamus, respectively, can be combined under the label of central adrenal insufficiency (3); however, some authors choose to group disorders causing tertiary adrenal insufficiency within the category of secondary adrenal insufficiency (1, 8). Secondary and tertiary adrenal insufficiency are due to disruption of the normal hormonal axis that stimulates the adrenal gland (1). Abnormalities of the hypothalamus, leading to decreased production of corticotrophin-releasing hormone (CRH), or pathology of the pituitary gland leading to decreased production of adrenocorticotrophic hormone (ACTH) both can lead to adrenal insufficiency (1). Damage to the pituitary gland can occur due to a variety of conditions, including hemorrhage and necrosis (e.g., pituitary apoplexy), neoplasms (e.g., pituitary adenoma, craniopharyngioma), autoimmune disease (e.g., lymphocytic hypophysitis), infiltrative processes (e.g., sarcoidosis), exogenous use of glucocorticoids, and empty sella syndrome (1, 2). Empty sella syndrome is caused by pituitary gland atrophy secondary to herniation of arachnoid through an incompetent diaphragm sella. The most common cause of tertiary adrenal insufficiency is the use of exogenous glucocorticoids; however, damage to the hypothalamus from tumors (e.g., craniopharyngioma), surgery, infections or an infiltrative processes ID1 (e.g., tuberculosis, hemochromatosis), and trauma (e.g., fracture of the base of the skull) can also lead to tertiary adrenal insufficiency (9). Primary adrenal insufficiency is due to destruction of the adrenal cortex, leading to decreased production of adrenal cortical hormones, namely aldosterone, cortisol, and androgens. This destruction can be either acute in onset or part of a chronic disease process. Acute causes of primary adrenal insufficiency include hemorrhage, infarction and thrombosis, such as occur in meningococcal infection associated Waterhouse-Friderichsen syndrome, sepsis, warfarin therapy, or a coagulopathy, including anti-phospholipid antibody syndrome (2). The list of diseases that cause chronic primary adrenal insufficiency is long, including autoimmune adrenalitis (Image 1), infectious organisms (e.g., em Mycobacterium tuberculosis /em , various fungi, cytomegalovirus), primary or metastatic neoplasms, and infiltrative processes (e.g., sarcoidosis, amyloidosis, hemochromatosis) (1, 2). In children, congenital adrenal hyperplasia can also cause chronic primary adrenal insufficiency (1). The label of Addison disease can be applied to any form of chronic.