Addison Disease

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Practice Essentials

Addison disease (or Addison's disease) is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed.

Thomas Addison first described the clinical presentation of primary adrenocortical insufficiency in 1855 in his classic paper, On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules.[1]

Workup

The diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by use of the rapid adrenocorticotrophic hormone (ACTH) stimulation test (Cortrosyn, cosyntropin, or Synacthen).[2]

In acute adrenal crisis, where treatment should not be delayed in order to do the tests, a blood sample for a random plasma cortisol level should be drawn prior to starting hydrocortisone replacement.

Other tests performed in the diagnosis of Addison disease include the following:

Imaging studies include the following:

Management

Corticosteroid drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency.[3, 4] Hydrocortisone sodium succinate or phosphate is the drug of choice for daily maintenance in these conditions and in the treatment of acute adrenal crisis.

In patients in acute adrenal crisis, intravenous (IV) access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible.

Epidemiology

Frequency

United States

The prevalence of Addison disease is 40-60 cases per 1 million population.

International

The occurrence of Addison disease is rare. The reported prevalence in countries where data are available is 39 cases per 1 million population in Great Britain and 60 cases per 1 million population in Denmark. A study by Olafsson and Sigurjonsdottir found the prevalence of primary adrenal insufficiency in Iceland to be 22.1 per 100,000 population.[5]  A study by Hong et al found the prevalence of primary adrenal insufficiency in Korea to be 4.17 per 1 million population.[78]

Mortality/Morbidity

Morbidity and mortality associated with Addison disease usually are due to failure or delay in making the diagnosis or a failure to institute adequate glucocorticoid and mineralocorticoid replacement.[6]

If not treated promptly, acute addisonian crisis may result in death. This may be provoked either de novo, such as by adrenal hemorrhage, or in the setting of an acute event superimposed on chronic or inadequately treated adrenocortical insufficiency.

With slow-onset chronic Addison disease, significant low-level, nonspecific, but debilitating, symptomatology may occur.

Even after diagnosis and treatment, the risk of death is more than 2-fold higher in patients with Addison disease. Cardiovascular, malignant, and infectious diseases are responsible for the higher mortality rate.[7]

White and Arlt examined the prevalence of and risk factors for adrenal crisis in patients with Addison disease, utilizing a survey of Addison patients in the United Kingdom, Canada, Australia, and New Zealand. The authors' results indicated that approximately 8% of patients diagnosed with Addison disease require annual hospital treatment for adrenal crisis. In addition, the investigators concluded that exposure to gastric infection is the most important risk factor for adrenal crisis in the presence of Addison disease; diabetes and/or asthma[8] concomitant with Addison disease also increase the risk, according to White and Arlt.[9]

A study by Chantzichristos et al indicated that in patients with type 1 or 2 diabetes, those who also have Addison disease have a higher mortality rate than do those with diabetes alone. Over a median follow-up period of 5.9 years, the mortality rate for diabetes patients with Addison disease was 28%, compared with 10% for those without Addison disease. The increase in the estimated relative overall mortality risk was 3.89 for the Addison disease patients compared with the other group. Although cardiovascular deaths accounted for the highest mortality rate in both groups, the death rate from diabetes complications, infectious diseases, and unknown causes was greater in the patients with Addison disease than in those with diabetes alone.[10]

Race

Addison disease is not associated with a racial predilection.

Sex

Idiopathic autoimmune Addison disease tends to be more common in females and children.

Age

The most common age at presentation in adults is 30-50 years, but the disease could present earlier in patients with any of the polyglandular autoimmune syndromes, congenital adrenal hyperplasia (CAH), or if onset is due to a disorder of long-chain fatty acid metabolism.

History

Patients usually present with features of both glucocorticoid and mineralocorticoid deficiency. The predominant symptoms vary depending on the duration of disease.

Patients may present with clinical features of chronic Addison disease or in acute addisonian crisis precipitated by stress factors such as infection, trauma, surgery, vomiting, diarrhea, or noncompliance with replacement steroids.

Presentation of chronic Addison disease

The onset of symptoms most often is insidious and nonspecific.

Hyperpigmentation of the skin and mucous membranes often precedes all other symptoms by months to years. It is caused by the stimulant effect of excess adrenocorticotrophic hormone (ACTH) on the melanocytes to produce melanin. The hyperpigmentation is caused by high levels of circulating ACTH that bind to the melanocortin 1 receptor on the surface of dermal melanocytes. Other melanocyte-stimulating hormones produced by the pituitary and other tissues include alpha-MSH (contained within the ACTH molecule), beta-MSH, and gamma-MSH. When stimulated, the melanocyte changes the color of pigment to a dark brown or black.

Hyperpigmentation is usually generalized but most often prominent on the sun-exposed areas of the skin, extensor surfaces, knuckles, elbows, knees, and scars formed after the onset of disease. Scars formed before the onset of disease (before the ACTH is elevated) usually are not affected. Palmar creases, nail beds, mucous membranes of the oral cavity (especially the dentogingival margins and buccal areas), and the vaginal and perianal mucosa may be similarly affected.

Hyperpigmentation, however, need not be present in every long-standing case and may not be present in cases of short duration.[11]

Other skin findings include vitiligo, which most often is seen in association with hyperpigmentation in idiopathic autoimmune Addison disease. It is due to the autoimmune destruction of melanocytes.

Almost all patients complain of progressive weakness, fatigue, poor appetite, and weight loss.

Prominent gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea. Glucocorticoid-responsive steatorrhea has been reported.[12]

Dizziness with orthostasis due to hypotension occasionally may lead to syncope. This is due to the combined effects of volume depletion, loss of the mineralocorticoid effect of aldosterone, and loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.

Myalgias and flaccid muscle paralysis may occur due to hyperkalemia.[13]

Patients may have a history of using medications known to affect adrenocortical function or to increase cortisol metabolism.

Other reported symptoms include muscle and joint pains; a heightened sense of smell, taste, and hearing; and salt craving.

Patients with diabetes that previously was well-controlled may suddenly develop a marked decrease in insulin requirements and hypoglycemic episodes due to an increase in insulin sensitivity.[14]

Impotence and decreased libido may occur in male patients, especially in those with compromised or borderline testicular function.

Female patients may have a history of amenorrhea due to the combined effect of weight loss and chronic ill health or secondary to premature autoimmune ovarian failure. Steroid-responsive hyperprolactinemia may contribute to the impairment of gonadal function and to the amenorrhea.

Presentation of acute Addison disease

Patients in acute adrenal crisis most often have prominent nausea, vomiting, and vascular collapse. They may be in shock and appear cyanotic and confused.

Abdominal symptoms may take on features of an acute abdomen.

Patients may have hyperpyrexia, with temperatures reaching 105° F or higher, and may be comatose.

In acute adrenal hemorrhage, the patient, usually in an acute care setting, deteriorates with sudden collapse, abdominal or flank pain, and nausea with or without hyperpyrexia.

Physical

Physical examination in long-standing cases most often reveals increased pigmentation of the skin and mucous membranes, with or without areas of vitiligo.

Causes

The most common cause of Addison disease is idiopathic autoimmune adrenocortical insufficiency resulting from autoimmune atrophy, fibrosis, and lymphocytic infiltration of the adrenal cortex, usually with sparing of the adrenal medulla. This accounts for more than 80% of reported cases. Idiopathic autoimmune adrenocortical atrophy and tuberculosis (TB) account for nearly 90% of cases of Addison disease.[15, 16]

Antibodies against the adrenal tissue are present in a significant number of these patients, and evidence of cell-mediated immunity against the adrenal gland also may be present. The steroidogenic enzyme 21-hydroxylase (21OH) is the main autoantigen, but antibodies against this enzyme are not directly involved in the tissue destruction.[17, 18]

Patients may have a hereditary predisposition to autoimmune Addison disease.[19]

Idiopathic autoimmune Addison disease may occur in isolation or in association with other autoimmune phenomena (eg, Schmidt syndrome, polyglandular autoimmune disease types 1 and 2).

Additional causes of chronic Addison disease:

Causes of acute Addison disease:

Laboratory Studies

A quick review of the clinical presentation, physical examination findings, and laboratory findings (when available) quickly heightens the index of suspicion and possibly leads to more appropriate tests and diagnosis. A high index of suspicion is necessary for diagnosis.

Imaging Studies

Chest radiograph:

CT scan:[15, 46]

Other Tests

ECG may show low-voltage QRS tracing with nonspecific ST-T wave changes and/or changes due to hyperkalemia. These changes are reversible with glucocorticoid replacement.

Sputum examination, examination of gastric washings for acid-fast and alcohol-fast bacilli, and a Mantoux or purified protein derivative (PPD) skin test may be needed if TB is thought to be the cause.

Histologic Findings

In cases due to idiopathic autoimmune adrenocortical atrophy, the adrenal glands usually are atrophic, with marked lymphocytic infiltration and fibrosis of the adrenal capsule. The adrenal medulla is spared.

In cases due to TB, the adrenal glands may be enlarged and contain caseating granulomas. Diffuse calcification may be evident, and the adrenal medulla usually is involved.[15]

In patients with AIDS, the adrenal glands may show necrotizing inflammation, hemorrhage, and infarction.

Medical Care

In patients in acute adrenal crisis, IV access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible.

Surgical Care

Parenteral steroid coverage should be used in times of major stress, trauma, or surgery and during any major procedure.

During surgical procedures, 100 mg of hydrocortisone should be given, preferably by the IM route, prior to the start of a continuous IV infusion. The IM dose of hydrocortisone assures steroid coverage in case of problems with the IV access.

Consultations

Whenever possible, an endocrinologist should be involved in both the acute care and on-going treatment of these patients.

Guidelines Summary

Recommendations from the French endocrinology society and the French pediatric endocrinology society discuss the management, for adults and children, of primary and secondary adrenal insufficiency. Among the recommendations, the societies state that in cases of persistent doubt regarding the presence of secondary adrenal insufficiency in adults, adolescents, and children over age 2 years, an insulin hypoglycemia test should be administered. The initial test to find the cause of primary adrenal insufficiency should be measurement of anti-21-hydroxylase antibodies. Negative autoantibody tests should be followed by an adrenal computed tomography (CT) scan; it is recommended that in young males, an assay for very-long-chain fatty acids then be performed.[77]

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Prednisone (Deltasone, Sterapred, Orasone)

Clinical Context:  Used for glucocorticoid hormone replacement. Longer acting than hydrocortisone, with a biologic half-life of 18-36 h.

Fludrocortisone (Florinef)

Clinical Context:  Synthetic adrenocortical steroid with very potent mineralocorticoid activity. For use in Addison disease and states of aldosterone deficiency.

Hydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)

Clinical Context:  Drug of choice for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. Has both glucocorticoid and mineralocorticoid properties. Biologic half-life is 8-12 h. Easiest way to set up infusion is to have pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9 saline.

Class Summary

These drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency.[3, 4]

Further Outpatient Care

Patients on steroid replacement therapy need to be closely monitored by their primary care physician and by an endocrinologist.

Close monitoring for any signs of inadequate replacement (eg, morning headaches, weakness, and dizziness) and any signs of over-replacement (eg, cushingoid features) should prompt appropriate dosage adjustment. A periodic bone dual-energy radiographic absorptiometry scan may be useful in detecting early osteoporosis in patients who are inadvertently over-replaced with maintenance steroids.

Additional concerns may include hypothyroidism, pregnancy, and bone loss.

Hypothyroidism

Hypothyroidism occurring in association with Addison disease may be steroid-responsive and may not require thyroxine replacement. Some patients who have symptoms of hypothyroidism may need only temporary levothyroxine replacement during the symptomatic phase. Therefore, holding off or delaying levothyroxine replacement may be prudent in asymptomatic patients until a variable period on steroid replacement has passed before committing them to unnecessary lifelong thyroxine replacement.[45]

Patients who require thyroxine replacement need periodic monitoring to assess the recovery of thyroid function. Levothyroxine should be withheld for 6-8 weeks or longer until further clinical evaluation and repeat TSH testing is performed. Additionally, if it has not already been done, steroid replacement should be given before thyroid replacement is instituted. If a question about adrenal insufficiency remains and thyroid replacement must be instituted urgently (ie, profound hypothyroidism), corticosteroids should be given and the adrenal status should be sorted out later.

Pregnancy

In pregnancy, the usual steroid replacement doses should be maintained. Occasionally, dose adjustments may need to be made depending on the patient's well being and the presence or absence of symptoms of adrenal insufficiency.

Pregnancy increases the production of cortisol-binding globulins (CBGs) and, therefore, cortisol binding. Free cortisol is proportionately increased so no dose adjustments should be needed.

In labor and delivery, vaginal or caesarean, parenteral stress-dose steroid coverage should be used as at other times of major stress. Stress-dose steroids also may be needed during the stress related to hyperemesis gravidarum.

The preferred mode of steroid administration is by continuous IV infusion and then rapid dose-tapering to the usual maintenance doses when the clinical situation allows.

Bone loss

A cross-sectional study by Lovas et al of 293 patients with Addison disease indicated that the dosage of glucocorticoids administered to individuals with this condition, a higher level than would be delivered through normal endogenous production, reduces bone mineral density in the femoral neck and lumbar spine.[48] In addition, the authors stated that, according to blood sample findings in their study, individuals who have a common polymorphism in the efflux transporter P-glycoprotein may be particularly susceptible to glucocorticoid-induced osteoporosis. The investigators indicated that, based on their results, patients may benefit if hydrocortisone dosages conventionally administered for Addison disease are lowered.

A prospective study by Schulz et al indicated that in patients with primary adrenal insufficiency or congenital adrenal hyperplasia undergoing glucocorticoid replacement therapy, a reduction in daily hydrocortisone equivalent doses (from 25.2 mg to 21.4 mg) increases bone mineral density, with the investigators finding a significant rise in lumber spine and hip Z-scores. It was reported that dose reduction did not lead to an increased adrenal crisis risk.[49]

Further Inpatient Care

With the exception of treatable causes such as TB, where adequate and timely treatment may allow recovery of normal adrenal function, patients need glucocorticoid and mineralocorticoid replacement for life.[6]

Fludrocortisone replacement therapy

Some patients may not need fludrocortisone replacement, or they may need it only in hot weather.

The fludrocortisone daily replacement dose should be titrated to maintain normal blood pressure and normal sodium and potassium levels. No dose adjustment is needed in stressful situations.

Periodic monitoring is needed to assess general well being, weight, blood pressure, electrolytes, the presence or absence of pedal edema, and the presence of cushingoid features.

Hydrocortisone replacement therapy

The usual daily replacement dose of hydrocortisone should be given in a way that mimics the circadian rhythm and keeps with the daily basal cortisol production rate of 8-12 mg/m2/d.

Patients who are thin may require smaller doses, whereas patients who are obese may require larger doses.

Patients on medications that induce the action of the cytochrome P450 enzyme require higher replacement doses. Patients with decreased cortisol clearance, as in liver disease, may require lower replacement doses.

The individual daily hydrocortisone or prednisone replacement dose should be titrated to the patient's general well being and the presence or absence of symptoms of adrenal insufficiency.

The intermediate-acting steroids, such as prednisone or prednisolone, may be used for daily replacement therapy in place of hydrocortisone. The equivalent daily replacement dose is 5-7.5 mg. A study by Chandy and Bhatia, however, indicated that prednisolone therapy in male patients with primary adrenal insufficiency can result in a small, but significant, reduction in bone mineral density.[50]

Patient Education

Patients should wear an emergency medical alert bracelet.

Patients should be instructed to double or triple their steroid replacement doses in stressful situations, such as a common cold or tooth extraction.

Patients should be instructed to contact their regular physician or to go to the emergency department in case of illness.

Patients should be instructed on how to give themselves IM injections. They should be given a prescription for parenteral hydrocortisone for use on occasions when oral intake may not be possible or when marked vomiting or diarrhea occurs. No adjustment needs to be made on the mineralocorticoid replacement dose in stressful situations.

What is Addison disease?When was Addison disease first described?How is adrenocortical insufficiency in Addison disease diagnosed?Which lab testing should be performed prior to treatment of an acute adrenal crisis in Addison disease?Which lab testing and imaging studies should be performed in the diagnosis of Addison disease?Which drugs are used for replacement therapy in Addison disease and what is the drug of choice?How is acute adrenal crisis in Addison disease managed?What is the prevalence of Addison disease in the US?What is the international prevalence of Addison disease?What causes morbidity and mortality in Addison disease?What is a potential outcome of acute addisonian crisis if not treated promptly?How is slow-onset chronic Addison disease characterized?What is the risk of death in patients with Addison disease after diagnosis and treatment?Which conditions increase the risk for adrenal crisis in Addison disease?What are mortality rates in patients with Addison disease and type 1 or 2 diabetes?What is the racial predilection of Addison disease?Is Addison disease more common in men or women?What are the age-related demographics of Addison disease?How is the typical presentation of Addison disease characterized?How is the onset of symptoms characterized in Addison disease?How is hyperpigmentation of the skin in Addison disease characterized?What are other skin findings in Addison disease?Which constitutional symptoms are associated with Addison disease?Which GI symptoms are associated with Addison disease?What are the symptoms and causes of syncope in Addison disease?What causes myalgias and flaccid muscle paralysis in Addison disease?What medication history may be associated with Addison disease?Which types of pain and sensory symptoms are associated with Addison disease?How can Addison disease affect the course of diabetes that was previously well-controlled?Which reproductive systems can be affected by Addison disease?What is the presentation of acute adrenal crisis in Addison disease?What are the physical exam findings in Addison disease?What is the cause and pathophysiology of Addison disease?Which autoimmune conditions are associated with chronic Addison disease?How do chronic granulomatous diseases cause chronic Addison disease?How do hematologic malignancies cause chronic Addison disease?Which metastatic malignancies are associated with the development of chronic Addison disease?How do infiltrative metabolic disorders cause chronic Addison disease?What is the role of AIDS in the development of chronic Addison disease?What is the relationship between Allgrove syndrome and chronic Addison disease?How do abnormalities of beta oxidation of very-long-chain fatty acids cause chronic Addison disease?How does congenital adrenal hyperplasia cause chronic Addison disease?Which drugs can cause chronic Addison disease?How does abdominal irradiation cause chronic Addison disease?How does stress cause acute Addison disease?How does failure to adjust steroid medications cause acute Addison disease?What is the role of bilateral adrenal hemorrhage in the development of acute Addison disease?How do bilateral adrenal artery emboli and bilateral vein thrombosis cause acute Addison disease?How does bilateral adrenalectomy cause acute Addison disease?What are the differential diagnoses for Addison Disease?When should Addison disease be suspected?What is the role of the rapid ACTH stimulation test in the workup of Addison disease?How is a rapid adrenocorticotrophic hormone test performed in the workup of Addison disease?How is the rapid adrenocorticotrophic hormone test interpreted in the workup of Addison disease?What is the role of random plasma cortisol testing in the workup of Addison disease?How is a comprehensive metabolic panel used in the workup of Addison disease?How is a CBC used in the workup of Addison disease?How is a thyroid-stimulating hormone (TSH) test used in the workup of Addison disease?How is autoantibody testing used in the workup of Addison disease?How is prolactin testing used in the workup of Addison disease?How is chest radiography used in the workup of Addison disease?How is CT scanning used in the workup of Addison disease?What findings may be demonstrated in an ECG in the workup of Addison disease?Which tests are indicated when TB is suspected as the cause of Addison disease?What are the histologic findings of Addison disease in cases due to idiopathic autoimmune adrenocortical atrophy?What are the histologic findings of Addison disease in cases due to TB?What are the histologic findings of Addison disease in patients with AIDS?What is the initial medical care for acute adrenal crisis in Addison disease?What is the initial medical care for stress situations in Addison disease?How soon after medical care is initiated should clinical improvement be evident in acute adrenal crisis in Addison disease?How is stress GI bleeding avoided in Addison disease?When should the initial hydrocortisone infusion be transitioned to mineralocorticoid replacement for acute adrenal crisis in Addison disease?What should patients with Addison disease be advised to do in hot weather?When is parenteral steroid coverage indicated in the management of Addison disease?How is steroid therapy adjusted during and after surgical procedures in Addison disease?When is consultation with an endocrinologist recommended in the treatment of Addison disease?What are the treatment guidelines for primary and secondary adrenal insufficiency by the French Endocrinology Society and the French Pediatric Endocrinology Society?What are the goals of pharmacotherapy in Addison disease?Which medications in the drug class Corticosteroid are used in the treatment of Addison Disease?

Author

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Steven B Nagelberg, MD, Clinical Professor, Department of Medicine, Division of Endocrinology and Metabolism, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Sylvester Odeke, MD, FACE, Vidant Medical Group Endocrinology, Diabetes & Metabolism, Greenville, NC

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Acknowledgements

This chapter is dedicated to the late Dr. James C. Melby.

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