Introduction
Background
In 1855, Thomas Addison first described adrenal insufficiency, which was subsequently named after him. The basis of Addison disease has dramatically changed since its initial description. Originally, the disease usually resulted from an infection of the adrenal gland; the most common infection was tuberculosis, which is still the predominant cause of Addison disease in developing countries. Currently, in developed countries, Addison disease most commonly results from nonspecific autoimmune destruction of the adrenal gland.
Pathophysiology
Adrenal insufficiency can manifest as a defect anywhere in the hypothalamic-pituitary-adrenal axis. Primary adrenal insufficiency is a result of destruction of the adrenal cortex. The zona glomerulosa, the outer layer of the adrenal gland, produces aldosterone. Cortisol is produced in both the zona fasciculata and the zona reticularis, the middle and innermost layers of the adrenal gland, respectively. Dehydroepiandrosterone is produced in the zona reticularis.
Clinical findings are noted after 90% of the adrenal cortex has been destroyed. Precipitating events are multifactorial and include autoimmune, infectious (eg, mycobacterial, fungal), neoplastic (eg, primary, metastatic), traumatic, iatrogenic (eg, surgery, medication), vascular (eg, hemorrhage, emboli, thrombus), and metabolic (eg, amyloidosis) events. With the destruction of the adrenal cortex, feedback inhibition of the hypothalamus and anterior pituitary gland is interrupted, and corticotropin is secreted continuously. Corticotropin and melanocyte-stimulating hormone (MSH) are both components of the same progenitor hormone. When corticotropin is cleaved from the prohormone, MSH is concurrently released. The increased MSH level results in a characteristic bronze hyperpigmentation. Hyperpigmentation is generally noted in primary adrenal insufficiency associated with increased levels of corticotropin and MSH.
Frequency
United States
The reported incidence of Addison disease is 5 or 6 cases per million population per year, with a prevalence of 60-110 cases per million population.
Mortality/Morbidity
The mortality rate for Addison disease is 1.4 deaths per million cases per year. This estimate is outdated because the incidence of tuberculosis-related Addison disease was greater when these data were compiled than it is now. A Swedish study reported that the relative rate of death in Addison disease patients was 2-fold higher than in background patients.1 Malignancy, infectious diseases, and cardiovascular events were the responsible causes of this higher mortality rate. Diabetes mellitus was noted in 12% of this population, but it contributed only a small amount to the overall higher mortality rate.
Sex
The male-to-female ratio is 1:1.5-3.5.
Age
Addison disease can occur in persons of any age; however, it is most common in people aged 30-50 years. The expression of adrenal cortex antibodies (ACAs) in patients without symptoms of Addison disease represents a significant risk of progression to adrenal insufficiency. The risk varies with age; children have a high risk of progression compared with adults, in whom the expression of ACAs represents a 30% risk of progression to Addison disease.
Clinical
History
Symptoms are often nonspecific and include fatigue, weakness, anorexia, nausea, abdominal pain, gastroenteritis, diarrhea, and mood lability.
- Weakness and weight loss of 1-15 kg are universal features of Addison disease in the adults.
- Nausea, vomiting, and diffuse abdominal pain are present in approximately 90% of patients and usually represent an impending addisonian crisis.
- Diarrhea is less common than nausea, vomiting, and abdominal pain and occurs in approximately 20% of patients.
- If diarrhea is present, it complicates the patient's already poor hydration status.
- Mood disturbances include depression, irritability, and decreased concentration. Diagnosis may be delayed because of comorbid depression or other psychiatric illness.
- Recurrent subtle flulike symptoms have been reported in few cases.2
Physical
Physical findings include hyperpigmentation of the skin and mucous membranes, decreased pubic and axillary hair in women, vitiligo, dehydration, and hypotension. Oral mucous membrane hyperpigmentation is pathognomonic for the disease.3,4
- Hyperpigmentation of the skin (see Media Files 1-2) is considered a hallmark of Addison disease and is present in 95% of patients with chronic primary adrenal insufficiency.
- However, hyperpigmentation is not a universal sign of adrenal insufficiency.
- The presence of normal-appearing skin does not exclude the diagnosis.
- The skin may appear normal, or vitiligo may be present.
- Increased pigmentation is prominent in areas of the skin that are subject to increased pressure, such as over the knuckles or the skin creases.
- Hyperpigmentation is also prominent on the nipples, axillae, perineum, and buccal mucosa (see Media Files 3-4).
- Longitudinal melanonychia has been reported as a presenting sign in rare cases.5
- Women may have loss of androgen-stimulated hair, such as pubic and axillary hair, because androgens are produced in the adrenal cortex.
- Men do not have hair loss because androgens in males are produced primarily in the testes.
- Usually, systolic and diastolic blood pressures are reduced; the systolic blood pressure is lower than 110 mm Hg.
Causes
Insults to the adrenal glands are multifactorial and include autoimmune, infectious (eg, mycobacterial, fungal), neoplastic (eg, primary, metastatic), traumatic, iatrogenic (eg, surgery, medication), vascular (eg, hemorrhage, emboli, thrombus), and metabolic (eg, amyloidosis) events.
Most causes of Addison disease previously believed to be idiopathic are currently postulated to have an autoimmune etiology. Autoimmune destruction of the adrenal glands may be isolated or part of a multiorgan process. Isolated autoimmune insufficiency involves destruction of only the adrenal cortex, with no other organ involvement.
- Polyglandular autoimmune diseases are primarily of 2 types: polyglandular autoimmune disease I (PGAD I) and polyglandular autoimmune disease II (PGAD II).
- PGAD I is described as destruction of the adrenal and thyroid glands resulting in adrenal insufficiency, hypothyroidism, and chronic candidiasis. PGAD I may also be associated with type 1 diabetes mellitus, hypogonadism, chronic hepatitis, immunoglobulin A (IgA) deficiency, chronic atopic dermatitis, keratoconjunctivitis, vitiligo, or alopecia.
- PGAD II, also called Schmidt syndrome, is characterized by autoimmune-mediated adrenal insufficiency and may involve autoimmune-mediated thyroiditis and/or autoimmune-mediated type 1 diabetes mellitus.
- Antibodies to the adrenal cortex mediate autoimmune destruction of the adrenal glands.
- Three ACAs have been described: Antibodies to steroid 21-hydroxylase (21-OH) are the most common and specific for autoimmune adrenal destruction. Antibodies to steroid 17-hydroxylase (17-OH) and cytochrome P-450 (P-450 side chain–cleaving [P-450SCC] antibodies) are not as specific as antibodies to 21-OH because they are found in other tissues. (Steroid 17-OH is found in the gonads, and P-450MSCC, in the gonads and the placenta.)
- The expression of ACAs in patients without symptoms of Addison disease represents a significant risk of progression to adrenal insufficiency. The risk varies with age; children have a high risk of progression compared with adults, in whom the expression of ACAs represents a 30% risk of progression to Addison disease.
More on Addison Disease |
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| Differential Diagnoses & Workup: Addison Disease |
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| Follow-up: Addison Disease |
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| References |
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Further Reading
Keywords
Addison disease, Addison's disease, primary adrenal insufficiency, chronic adrenal insufficiency, hypoadrenalism, polyglandular autoimmune diseases, polyglandular autoimmune disease I, PGAD I, polyglandular autoimmune disease II, PGAD II, Schmidt syndrome, addisonian crisis, adrenocorticotropic hormone, ACTH, corticotropin, melanocyte-stimulating hormone, MSH
