Dermatologic Aspects of Addison Disease 

Updated: Jul 18, 2017
Author: Elizabeth A Liotta, MD; Chief Editor: William D James, MD 

Overview

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.

Epidemiology

US frequency

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.

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.

Prognosis

With proper control, the long-term prognosis is good. Overall mortality rate is normal in treated patients. 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.14 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.

Patient Education

Advise patients to wear medical alert tags at all times to reduce the time to the treatment and diagnosis of an addisonian crisis. Inform patients about salt loss during vigorous exercise.

 

Presentation

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. Recurrent subtle flulike symptoms have been reported in few cases.[1]

Mood disturbances include depression, irritability, and decreased concentration. Diagnosis may be delayed because of comorbid depression or other psychiatric illness.

Physical Examination

Physical findings include hyperpigmentation of the skin[2] 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 the images below) 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.

Hyperpigmented scar on diffusely hyperpigmented (t Hyperpigmented scar on diffusely hyperpigmented (tanned) skin. Courtesy of Dirk M. Elston, MD.
Hyperpigmented scars from ear piercing. Courtesy o Hyperpigmented scars from ear piercing. Courtesy of Dirk M. Elston, MD.

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 the images below).

Pigmented patches of mucous membrane and pigmented Pigmented patches of mucous membrane and pigmented longitudinal nail bands. Courtesy of Dirk M. Elston, MD.
Hyperpigmented gingival patches. Courtesy of Dirk Hyperpigmented gingival patches. Courtesy of Dirk M. Elston, MD.

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.

Autoimmune diseases begin with a genetic predisposition and then are triggered by an environmental agent. The active autoimmune process ensues, resulting in the metabolic abnormalities and physical symptoms of the disease. One half of 1% of type 1 diabetes mellitus patients are found to have Addison disease.

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.

 

DDx

Diagnostic Considerations

Also consider the following:

Pregnancy increases the physiologic stress on the patient. The diagnosis of Addison disease may be delayed in pregnant women because the presenting symptoms of nausea, vomiting, and skin hyperpigmentation may be confused with symptoms of pregnancy. Glucocorticoid and mineralocorticoid doses may need to be adjusted in patients who are pregnant. For example, the fludrocortisone dose may need to be decreased if preeclampsia develops. Glucocorticoid and mineralocorticoid doses may need to be increased, especially during labor. Commonly, 1-3 doses of hydrocortisone 100 mg are intramuscularly or intravenously administered during labor.

Differential Diagnoses

 

Workup

Laboratory Studies

The evaluation of patients with suspected Addison disease involves the diagnosis of adrenal insufficiency and then the identification of the site of the defect in the hypothalamic-pituitary axis. Addison disease is a primary adrenal insufficiency with the defect in the adrenal gland. Once the adrenal insufficiency is identified, the etiology of the adrenal insufficiency may be determined.

Initially, serum electrolytes should be checked but a normal potassium level does not rule out Addison disease. Because aldosterone is absent, hyponatremia, with low chloride and hyperkalemia are often present. Hyponatremia is the most common finding and occurs in 90% of patients (see Serum Sodium). Hyperkalemia is found in 60-70% of patients. Hypercalcemia is uncommon and found in approximately 5-10% of patients (see Serum Calcium).

The preliminary test for adrenal insufficiency is the measurement of serum cortisol levels from a sample of blood obtained in the morning, although some prefer to order a corticotropin level. This is an insensitive screening test. Because of variations in cortisol levels due to the circadian rhythm, blood should be drawn when the levels are highest, usually between 6:00 and 8:00 am. Morning cortisol levels greater than 19 mcg/dL (reference range, 5-25 mcg/dL) are considered normal, and no further workup is required. Values less than 3 mcg/dL are diagnostic of Addison disease. Values in the range of 3-19 mcg/dL are indeterminate, and further workup is needed.

The hypothalamic-pituitary axis can be evaluated by using 3 tests: the corticotropin (Cortrosyn) stimulation test, the insulin tolerance test, and the metyrapone test. Synthetic adrenocorticotropin 1-24 at a dose of 250 mcg works as a dynamic test. The elevated levels of renin and adrenocorticotropin verify the presence of the disease.

Cortrosyn is a synthetic corticotropin, which is intravenously administered with a dose of 350 mg. Serum cortisol levels are measured from blood samples drawn after 30 and 60 minutes. Peak serum cortisol levels greater than 18 mcg/dL exclude the diagnosis of adrenal insufficiency because the response to stimulation is considered adequate at this level. Cortisol levels of 13-17 mcg/dL are indeterminate. Cortisol levels of less than 13 mcg/dL suggest adrenal insufficiency.

The insulin tolerance test is sensitive for adrenal insufficiency. This test involves hypoglycemic stress to induce cortisol production. The test requires close monitoring of the patient and is contraindicated in patients with a history of seizures or cardiovascular disease. The peak serum cortisol response is measured after an insulin challenge of 0.1-0.15 U/kg. A cortisol level of less than 18 mcg/dL and a serum glucose level of less than 40 mg/dL suggest adrenal insufficiency.

The metyrapone test involves disruption of the cortisol production pathway by inhibiting 11 B-hydroxylase, the enzyme that converts 11-deoxycortisol (11-s) to cortisol. Metyrapone (30 mg/kg) is intravenously injected at midnight, and cortisol and 11-s levels are measured 8 hours afterward. A normal response is an increase in serum 11-s levels to more than 7 mg/dL. Levels of 11-s that are less than 7 mg/dL are diagnostic of adrenal insufficiency.

Once the diagnosis of adrenal insufficiency is confirmed, the site of the defect in the hypothalamic-pituitary axis should be determined by using corticotropin sampling, corticotropin provocative testing, or corticotrophin-releasing hormone (CRH) provocative testing.

A serum corticotropin level of greater than 100 pg/mL is diagnostic of primary adrenal insufficiency.

A corticotropin infusion can help in differentiating primary insufficiency from a hypothalamic-mediated or pituitary-mediated adrenal insufficiency. An 8-hour intravenous infusion of 250 mg/d for 3-5 days is administered, and daily urine samples are checked for 17-hydroxysteroid levels. By day 5, a 3- to 5-fold increase in the urine 17-hydroxysteroid level is diagnostic of a secondary or tertiary insufficiency; in primary adrenal insufficiency, the urine 17-hydroxysteroid level does not increase.

The CRH test involves stimulation of the pituitary gland and measurement of serum cortisol and corticotropin levels. The CRH test can be used to differentiate primary, secondary, and tertiary adrenal insufficiencies.

After adrenal insufficiency is diagnosed and the defect in the hypothalamic-pituitary-adrenal axis is identified, the cause of the adrenal insufficiency can be evaluated. Because primary adrenal insufficiency has numerous causes, the workup must be directed at the clinical findings.

Autoimmune disease and infectious etiologies are the 2 predominant causes; therefore, a workup for adrenal antibodies and tuberculosis should be part of the initial diagnostic evaluation.

Autoantibodies against 21-hydroxylase may be detected in patients with autoimmune polyglandular syndrome. These patients may also have type 1 diabetes mellitus, autoimmune thyroid disease, autoimmune gastritis, celiac disease, and/or vitiligo.

Imaging Studies

Both computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate a diminished adrenal gland in patients with autoimmune destruction and an enlarged adrenal gland in patients with infection. CT adequately shows the calcification that occurs in adrenal failure caused by tuberculosis. The calcification may be apparent in the acute phase of infection, but it is usually recognized in the chronic phase of infection.

Both CT and MRI reveal adrenal hemorrhages. MRI is superior to CT in differentiating adrenal masses, but MRI cannot distinguish a tumor from an inflammatory process.[9]

Other Tests

Tissue cultures in patients with tuberculosis reveal acid-fast bacilli.

Histologic Findings

Histological features reported include hyperpigmentation of the basal layer as well as variable spongiosis, hyperkeratosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate.[10] Melanin pigment incontinence and lipofuscin in eccrine glands may contribute to skin darkening.

Histopathologic findings vary with the mechanism of destruction. Autoimmune destruction is characterized by a lymphocytic infiltrate. Surviving cortical cells show increased cytoplasm and nuclear atypia, which is believed to result from prolonged stimulation by corticotropin. Noncaseating granulomas are found when adrenal destruction is the result of sarcoidosis or a malignancy. Caseating granulomas are seen in patients with tuberculosis.

 

Treatment

Medical Care

Promptly treat patients in whom acute adrenal insufficiency is suspected; follow up with a workup for adrenal insufficiency. In Addison disease, the adequate replacement of glucocorticoids and mineralocorticoids is the primary goal. Studies show that dehydroepiandrosterone therapy improves the patient's quality of life.[11, 12]

Admit patients with any of the systemic manifestations of Addison disease to the hospital. Immediately treat patients with acute adrenal insufficiency with glucocorticoid replacement. Hydrocortisone can be administered both as a bolus and as an infusion. Treat hypovolemia and hyponatremia with intravenous fluid and sodium replacement until the patient's condition is stable and he or she can tolerate oral fluids. Consider treating the patient on an outpatient basis once the symptoms of adrenal insufficiency improve enough to enable oral replacement therapy.

Consultations

The need for consultation depends on the cause of the adrenal insufficiency and may involve the following specialists:

  • Endocrinologist

  • Rheumatologist

  • Infectious diseases specialist

Diet

Advise patients not to restrict salt in their diets. In patients with concurrent primary hypertension, salt intake may be restricted instead of discontinuing mineralocorticoid replacement. Advise patients who live in warm climates to increase their salt intake because of their increased loss of salt as a result of sweating.

Activity

No restrictions on activity are required; however, inform patients about salt loss during vigorous exercise.

Complications

Pay attention to potential drug interactions. Concomitant use of rifampin, phenytoin, or barbiturates increases the metabolism of replaced hormones; therefore, the patient's hormone levels may decrease to subtherapeutic levels.

Excessive sodium loss may result from the use of diuretics.

Prevention

Avoid the use of diuretics to prevent excessive sodium loss.

Long-Term Monitoring

Monitoring glucocorticoid and mineralocorticoid replacement therapy is perhaps more of an art than a science. The ideal dose of glucocorticoids in replacement therapy adequately supplements the adrenal insufficiency while minimizing any adverse effects. If the dose of the replacement glucocorticoids is too low, adrenal insufficiency continues. In children, nocturnal hypoglycemia may result in seizures. Overdoses of replacement glucocorticoids result in many undesired adverse effects, including weight gain and osteoporosis. Correct dosing may be guided by monitoring urine cortisol levels.

Monitor mineralocorticoid replacement by observing the patient's blood pressure levels, which are low when doses of the mineralocorticoid are too low. Monitor serum potassium levels to ensure resolution of the initial hyperkalemia. Plasma renin concentrations may be monitored as well. An overdose of fludrocortisone is difficult to assess, but overdoses may result in hypokalemia and increased atrial natriuretic peptide levels.

Exact dosing of both glucocorticoid and mineralocorticoid replacement is elusive.

Recognize and manage cases of adrenal crisis. Eight percent of diagnosed patients require hospital therapy annually for adrenal crisis. Gastric infection and fever are the most frequent precipitating causes of adrenal crisis. Other physical and mental stress, surgery, and pregnancy can less frequently induce a crisis.

 

Medication

Medication Summary

With optimum dosing (which is often a challenge), the glucocorticoids are adequately replaced with minimal adverse effects. Underdosing of glucocorticoids results in continued adrenal insufficiency. In children, nocturnal hypoglycemia can result in seizures. Overdosing of glucocorticoids results in weight gain, increased blood pressure, and osteoporosis. The effects of steroid replacement are assessed with clinical examination.

The resolution of symptoms and the correction of electrolyte abnormalities are the customary signals in determining the adequacy of replacement. In patients at risk for osteoporosis, monitor serum and urine cortisol levels; this method appears to be the best available assessment of steroid dosing.

The titration of mineralocorticoid replacement is achieved by monitoring electrolyte levels and plasma rennin concentrations and by evaluating clinical findings such as dizziness or weight gain. Weakness, decreased diastolic blood pressure, low serum sodium levels, and increased plasma rennin concentrations occur with an underdosing of fludrocortisone. Overdosing is difficult to determine. Decreased serum potassium levels may be seen. Increased levels of atrial natriuretic peptide have been proposed to be more accurate in determining an overdose.[13]

Some cases of multifocal disseminated lipoatrophy as a result of intravenous corticosteroid administration have been reported in these patients with adrenal insufficiency.[14]

Corticosteroids

Class Summary

These agents are used to restore corticosteroid levels.

Cortisone (Cortone)

Cortisone is a drug of choice for patients with adrenocortical insufficiency.

Hydrocortisone (Hydrocortone, Cortef)

Hydrocortisone is a drug of choice because of its mineralocorticoid activity and glucocorticoid effects. Some cases of multifocal disseminated lipoatrophy as a result of intravenous corticosteroid administration have been reported in these patients with adrenal insufficiency.

Fludrocortisone (Florinef)

Fludrocortisone is used for partial replacement therapy in primary and secondary adrenocortical insufficiency.

Dexamethasone (Decadron, Baldex, Dexone)

Dexamethasone is a drug of choice for patients with adrenocortical insufficiency.