Addison Disease

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:

• Comprehensive metabolic panel
• Complete blood cell (CBC) count
• Thyroid-stimulating hormone (TSH) levels
• Autoantibody testing: Thyroid and/or adrenal autoantibodies may be present
• Prolactin testing: Modest hyperprolactinemia has been reported in cases of Addison disease and also in secondary adrenocortical insufficiency

Imaging studies include the following:

• Chest radiograph:
• Computed tomography (CT) scan: An abdominal CT scan may be normal but may show bilateral enlargement of the adrenal glands in patients with Addison disease because of tuberculosis (TB), fungal infections, adrenal hemorrhage, or infiltrating diseases involving the adrenal glands

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.

• References

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.^[6]

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.^[7]

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.^[8]

A study by Skov et al indicated that females with autoimmune Addison disease are at increased risk of ischemic heart disease, with an adjusted hazard ratio (aHR) of 2.15 compared with controls. The aHR in males, however, was just 1.16. In women, but not in men, higher glucocorticoid and mineralocorticoid replacement doses were independently correlated cardiovascular disease risk. The investigators found that overall in patients with autoimmune Addison disease, there were 10.7 events of first cardiovascular disease/1000 person-years, compared with 7.0 events/1000 person-years in controls.^[9]

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^[10] concomitant with Addison disease also increase the risk, according to White and Arlt.^[11]

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.^[12]

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.

• References

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.^[13]

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.^[14]

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.^[15]

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.^[16]

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.

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Physical

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

• Patients show evidence of dehydration, hypotension, and orthostasis.
• Female patients may show an absence of axillary and pubic hair and decreased body hair. This is due to loss of the adrenal androgens, a major source of androgens in women.
• Addison disease caused by another specific disease may be accompanied by clinical features of that disease.
• Calcification of the ear and costochondral junctions is described but is a rare physical finding.

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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.^{[17, 18]}

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.^{[19, 20]}

Patients may have a hereditary predisposition to autoimmune Addison disease.^[21]

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).

• Celiac disease^{[22, 23, 24]}
• Idiopathic hypoparathyroidism
• Mucocutaneous candidiasis
• Type 1 diabetes mellitus^[16]
• Hashimoto thyroiditis
• Graves disease
• Vitiligo
• Alopecia areata, totalis and universalis
• Premature ovarian or testicular failure
• Pernicious anemia
• Myasthenia gravis
• Idiopathic hypophysitis
• Chronic active hepatitis
• Primary biliary cirrhosis
• The association of Addison disease and Hashimoto thyroiditis is known as Schmidt syndrome.
• The association of Addison disease with hypoparathyroidism and mucocutaneous candidiasis is described as polyglandular autoimmune syndrome type 1. It may have an autosomal recessive mode of inheritance. It has no human leukocyte antigen (HLA) associations.^[25] . It is also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). It is caused by mutations in the autoimmune regulator gene (AIRE).
• The association of Addison disease with type 1 diabetes mellitus and Hashimoto thyroiditis or Graves disease is described as polyglandular autoimmune syndrome type 2 and may be associated with HLA-B8 and DR-3.^{[26, 27]}
• Other autoimmune phenomena, as outlined above, can occur in either of the 2 polyglandular syndromes.

Additional causes of chronic Addison disease:

• Chronic granulomatous diseases^[17]

  • TB, sarcoidosis, histoplasmosis, blastomycosis, and cryptococcosis could involve the adrenal glands.
  • In the preantibiotic era, TB was the most common cause and still may be a major consideration in areas where TB is common. It tends to involve both the adrenal cortex and the medulla; however, medullary involvement may not have any major consequences.
  • TB of the adrenal glands usually is a tertiary disease due to the hematogenous spread of infection to the adrenal glands, but clinical evidence of the primary infection is not always present.

   

  

   
• Hematologic malignancies

  • Malignant infiltration of the adrenal cortices, as with Hodgkin and non-Hodgkin lymphoma and leukemia, may cause Addison disease.
  • Hodgkin and non-Hodgkin lymphoma initially could present with adrenal gland involvement and features of adrenocortical insufficiency.

   

  

   
• Metastatic malignant disease - Bilateral involvement of the adrenal glands could occur in the setting of metastatic cancer of the lung, breast, or colon or renal cell carcinoma.
• Infiltrative metabolic disorders - Amyloidosis and hemochromatosis could involve the adrenal glands and lead to primary adrenocortical insufficiency.
• Acquired immunodeficiency syndrome (AIDS)^{[28, 29, 30]}

  • The adrenocortical insufficiency in patients with AIDS tends to occur late and usually in the setting of a low CD4 cell count.
  • It is caused by opportunistic infections such as cytomegalovirus, Mycobacterium avium intracellulare, cryptococci, or Kaposi sarcoma.
  • Adrenocortical hypofunction in patients with HIV may be due to glucocorticoid resistance syndrome. These patients tend to present with features of adrenocortical insufficiency and mucocutaneous hyperpigmentation but also with increased plasma and urinary cortisol levels and a slight elevation in ACTH levels. Hyperpigmentation in patients with HIV is thought to be due to elevated alpha-interferon levels.
  • Another possible cause of adrenocortical insufficiency in patients with AIDS is the use of megestrol acetate (Megace) as an appetite stimulant to stem HIV wasting disease. However, this causes secondary adrenocortical insufficiency and not Addison disease. The glucocorticoid effect of megestrol acetate suppresses pituitary ACTH production and leads to secondary adrenocortical insufficiency.

   

  

   
• Allgrove syndrome ^{[31, 32]}

  • Although patients with congenital adrenocortical unresponsiveness to ACTH (Allgrove syndrome) may present with features of glucocorticoid deficiency and skin hyperpigmentation, the aldosterone production and function in these patients is normal and responds appropriately to low sodium intake.
  • This typically presents in childhood with failure to thrive, features of adrenocortical insufficiency, and hypoglycemia.
  • Some patients may have components of alacrima and achalasia.^[33] It is also sometimes called triple A syndrome.

   

  

   
• Abnormalities of beta oxidation of very-long-chain fatty acids

  • These patients (usually men) present with adrenocortical insufficiency and features of progressive demyelination of the CNS. It is caused by mutation in the ABCD1 gene. it is the most common cause of adrenal insufficiency in a male child less than 7 years of age.
  • This is caused by the accumulation of very-long-chain fatty acids (VLCFA) in various organs, including the adrenal cortex, brain, testis, and liver.
  • These disorders are X-linked recessive, with poor penetrance.
  • Other symptoms include cognitive dysfunction, behavioral problems, disturbance of gait, and emotional lability.
  • Two subtypes are described. The first subtype is adrenoleukodystrophy (ALD). This usually presents in childhood. Thirty percent of cases may present with adrenal insufficiency before the onset of neurologic symptoms. Other features include severe hypotonia, seizure disorder, retinitis pigmentosa, and optic atrophy. The second subtype is adrenomyeloneuropathy (AMN).^[34] This usually is mild. It tends to present in the 20- to 40-year age group with features of adrenal insufficiency and progressive CNS demyelination.

   

  

   
• Congenital adrenal hyperplasia

  • Primary adrenocortical insufficiency may occur in patients with the StAR^[35] or 20,22-desmolase enzyme deficiency, 3-beta hydroxysteroid dehydrogenase enzyme deficiency, and the severe form of the 21-hydroxylase enzyme deficiency (virilizing and salt wasting).
  • Infants usually present in shock, with hypoglycemia and adrenal insufficiency.
  • In 3-beta hydroxysteroid dehydrogenase enzyme deficiency, female infants appear virilized, whereas male infants may have pseudohermaphroditism from insufficient androgen activity.
  • Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis. Male infants usually have features of pseudohermaphroditism due to an associated deficiency of gonadal steroids.^{[35, 36]}
  • The rapid ACTH test usually helps to establish the diagnosis. Patients with CAH respond with a marked increase in 17-OH progesterone levels, an increase in other precursors preceding the enzyme block, and a subnormal cortisol response.

   

  

   
• Drug-related causes

  • Ketoconazole inhibits the adrenal cytochrome P450 steroidogenic enzymes.
  • Aminoglutethimide blocks the early conversion of cholesterol to pregnenolone by inhibiting the 20,22-desmolase enzyme.
  • Mitotane (O,P'-DDD) blocks adrenal mitochondrial steroid biosynthesis.
  • Busulphan, etomidate, and trilostane inhibit or interfere with adrenal steroid biosynthesis.
  • Methadone, perhaps by depleting pituitary ACTH, may cause secondary adrenocortical insufficiency in some patients.^[37]

   

  

   
• Abdominal irradiation

  • Addison disease could result from situations where a radiation field involves the adrenal glands.
  • The lag time to onset of disease usually is 2-7 years, but the disease could occur earlier depending on the dose of the radiation.

   

  

   
• Hypogandotropic Hypogonadism and DAX-1 gene mutation^[38]

Causes of acute Addison disease:

• Stress - Acute adrenal crisis precipitated by infection, trauma, surgery, emotional turmoil, or other stress factors may be the initial presentation of Addison disease in as many as 25% of cases.
• Failure to increase steroids

  • Failure to appropriately increase daily replacement steroid doses in patients with adrenocortical insufficiency in times of stress could precipitate an adrenal crisis.
  • Failure to adjust the replacement steroid dose in patients on cytochrome P450 enzyme-inducing medications such as rifampin and Dilantin also could precipitate an adrenal crisis.^{[39, 40]}

   

  

   
• Bilateral adrenal hemorrhage

  • This may be the cause of an acute adrenal crisis, and it may occur as a complication of bacterial infection with Meningococcus or Pseudomonas species, as in Waterhouse-Friderichsen syndrome.
  • It also may occur as a complication of pregnancy, anticoagulant therapy with heparin or warfarin, and as a complication of coagulopathies such as antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE).
  • The mechanism of action of adrenal hemorrhage is not fully understood. Diagnosis usually is made in the setting of a critically ill patient on anticoagulants (or with any of the causes mentioned above) who becomes acutely hypotensive with tachycardia, nausea, vomiting, fever, and confusion or disorientation. Abdominal or flank pain with associated tenderness may develop.
  • A rapid ACTH test usually should be performed in this setting, and the patient should be started on hydrocortisone without waiting for the results. When time is critical, a random cortisol should be drawn and the patient started on hydrocortisone in stress doses. An abdominal computed tomography (CT) scan often reveals bilateral adrenal gland enlargement.

   

  

   
• Bilateral adrenal artery emboli and bilateral vein thrombosis

  • This is a very rare cause of Addison disease but may occur in critically ill patients on heparin as a complication of heparin-induced thrombosis (HIT) or as a complication of other states that predispose to thrombosis.
  • It also may occur as a complication of radiographic contrast studies involving the adrenal glands.

   

  

   
• Bilateral adrenalectomy for any reason

  • The surgical removal of a unilateral cortisol-producing adrenal adenoma in a patient with Cushing syndrome can cause an acute adrenal crisis from secondary adrenocortical insufficiency.
  • This is due to the atrophy of the normal adrenal cortex from lack of the stimulant effect of pituitary ACTH.

   

  

   

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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.

• 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 ACTH stimulation test (Cortrosyn, cosyntropin, or Synacthen).^[2]

  • ACTH, through complex mechanisms, activates cholesterol esterase enzymes and leads to the release of free cholesterol from cholesterol esters. It also activates the 20,22-desmolase enzyme, which catalyzes the rate-limiting step in adrenal steroidogenesis and increases the NADPH (nicotinamide adenine dinucleotide phosphate) levels necessary for the various hydroxylation steps in steroidogenesis.
  • Within 15-30 minutes of ACTH infusion, the normal adrenal cortex releases 2-5 times its basal plasma cortisol output.
  • Although ACTH stimulation is not normally the major stimulus for aldosterone production, it increases aldosterone production to peak levels within 30 minutes. This response, however, is affected by dietary sodium intake.
  • An increase in the plasma cortisol and aldosterone levels above basal levels after ACTH injection reflects the functional integrity of the adrenal cortex.

   

  

   
• Performing the rapid adrenocorticotrophic hormone test^[41]

  • Blood is drawn in 2 separate tubes for baseline cortisol and aldosterone values.
  • Synthetic ACTH (1-24 amino acid sequence) in a dose of 250 mcg (0.25 mg) is given IM or IV. Smaller doses of synthetic ACTH, as low as 1 mcg, have been used with accuracy approaching the standard test. Proponents of this modified test argue that a dose of 1 mcg or lower is more physiologic, whereas the 250-mcg dose is pharmacologic. However, the modified test is more sensitive only for the 30-minute samples, not the 60-minute samples.
  • Thirty or 60 minutes after the ACTH injection, 2 more blood samples are drawn; one for cortisol and one for aldosterone. No significant reason exists to draw both the 30-minute and 60-minute samples because the sensitivity of the 30-minute value for accurate diagnosis is well documented. The baseline and 30-minute samples usually are adequate to establish the diagnosis.

   

  

   
• Interpreting the rapid adrenocorticotrophic hormone test^{[42, 43, 44, 45]}

  • Two criteria are necessary for diagnosis: (1) an increase in the baseline cortisol value of 7 mcg/dL or more and (2) the value must rise to 20 mcg/dL or more in 30 or 60 minutes, establishing normal adrenal glucocorticoid function.
  • A low aldosterone value of less than 5 ng/100 mL that fails to double or increase by at least 4 ng/100 mL 30 minutes after ACTH administration denotes abnormal mineralocorticoid function of the adrenal cortex.
  • The 30-minute aldosterone value is more sensitive than the 60-minute value because aldosterone levels actually have been shown to decrease in the 60-minute sample.
  • The absolute 30- or 60-minute cortisol value carries more significance than the incremental value, especially in patients who may be in great stress and at their maximal adrenal output. These patients may not show a significant increase in cortisol output with ACTH stimulation.
  • A normal 30- or 60-minute rapid ACTH test excludes Addison disease but may not adequately exclude mild impairment of the hypothalamic pituitary adrenal axis in secondary adrenal insufficiency.
  • In patients with Addison disease, both cortisol and aldosterone show minimal or no change in response to ACTH, even with prolonged ACTH stimulation tests lasting 24-48 hours.
  • When the results of the rapid ACTH test are equivocal and do not meet the 2 criteria mentioned above, further testing might be required to distinguish Addison disease from secondary adrenocortical insufficiency. Plasma ACTH values and prolonged ACTH stimulation tests may be useful in making this distinction.
  • ACTH levels often are elevated to higher than 250 pg/mL in patients with Addison disease. However, ACTH is unstable in plasma, and specimen collection and storage may require special attention. The specimen should be collected in iced anticoagulated plastic containers and frozen immediately.
  • Importantly, note that ACTH levels also may be high in patients recovering from steroid-induced secondary adrenocortical insufficiency and in patients with ACTH-refractory syndromes.
  • ACTH-inducing tests such as metyrapone stimulation and insulin-induced hypoglycemia, which may be useful in the evaluation of some cases of secondary adrenocortical insufficiency, have no role in the diagnosis of Addison disease and may in fact be lethal to the patient with Addison disease.

   

  

   
• 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.

  • A random plasma cortisol value of 25 mcg/dL or greater effectively excludes adrenal insufficiency of any kind. However, a random cortisol value in patients who are acutely ill should be interpreted with caution and in correlation with the circumstances of each individual patient. Random cortisol levels should also be interpreted cautiously in critically ill patients with hypoproteinemia (serum albumin < 2.5 g/dL). Approximately 40% of these patients will have baseline and cosyntropin-stimulated cortisol levels below the reference range even though the patients have normal adrenal function (as evidenced by the measurement of free cortisol levels). This phenomenon is because more than 90% of circulating cortisol in human serum is protein bound.
  • Cortisol is known to be elevated by stress, but exactly how high it should rise to constitute a normal response in times of severe stress is not known.
  • An abnormal test result should prompt a proper evaluation of the hypothalamic pituitary adrenal axis after the patient's condition improves before committing a patient to lifelong steroid replacement.
  • In order to perform the ACTH stimulation test in this situation, the patient should be switched to dexamethasone and then tested 24-36 hours later. Dexamethasone does not interfere with the cortisol assay, as does hydrocortisone or prednisone. However, dexamethasone may interfere with interpretation of the random cortisol value drawn after dexamethasone already has been initiated. Dexamethasone also does not have any mineralocorticoid activity, which may be needed in patients with Addison disease.

   

  

   
• Other laboratory tests

  • Comprehensive metabolic panel
    • The most prominent findings are hyponatremia, hyperkalemia, and a mild non–anion-gap metabolic acidosis due to the loss of the sodium-retaining and potassium and hydrogen ion-secreting action of aldosterone.
    • Urinary and sweat sodium also may be elevated.
    • The most consistent finding is elevated blood urea nitrogen (BUN) and creatinine due to the hypovolemia, a decreased glomerular filtration rate, and a decreased renal plasma flow.
    • Hypercalcemia, the cause of which is not well understood, may be present in a small percentage of patients. However, hypocalcemia could occur in patients with Addison disease accompanied by idiopathic hypoparathyroidism.
    • Hypoglycemia may be present in fasted patients, or it may occur spontaneously. It is caused by the increased peripheral utilization of glucose and increased insulin sensitivity. It is more prominent in children and in patients with secondary adrenocortical insufficiency.
    • Liver function tests may reveal a glucocorticoid-responsive liver dysfunction.
  • CBC count
    • CBC count may reveal a normocytic normochromic anemia, which, upon initial presentation, may be masked by dehydration and hemoconcentration. Relative lymphocytosis and eosinophilia may be present.
    • All of these findings are responsive to glucocorticoid replacement.
  • Thyroid-stimulating hormone^[46]
    • Increased thyroid-stimulating hormone (TSH), with or without low thyroxine, with or without associated thyroid autoantibodies, and with or without symptoms of hypothyroidism, may occur in patients with Addison disease and in patients with secondary adrenocortical insufficiency due to isolated ACTH deficiency. These findings may be slowly reversible with cortisol replacement.^[47]
    • In the setting of both adrenocortical insufficiency and hypothyroidism that requires treatment, corticosteroids should be given before thyroid hormone replacement to avoid precipitating an acute adrenal crisis.

   

  

   
• Autoantibody testing - Thyroid autoantibodies, specifically antithyroglobulin (anti-Tg) and antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies, and/or adrenal autoantibodies may be present.
• Prolactin testing

  • Modest hyperprolactinemia has been reported in cases of Addison disease and also in secondary adrenocortical insufficiency. It is responsive to glucocorticoid replacement.
  • The cause of the hyperprolactinemia is thought to be the hyperresponsiveness of the lactotroph to thyrotropin-releasing hormone (TRH) in the absence of the steroid-induced or steroid-enhanced hypothalamic dopaminergic tone.

   

  

   

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Imaging Studies

Chest radiograph:

• The chest radiograph may be normal but often reveals a small heart.
• Stigmata of earlier infection or current evidence of TB or fungal infection may be present when this is the cause of Addison disease.

CT scan:^{[17, 48]}

• Abdominal CT scan may be normal but may show bilateral enlargement of the adrenal glands in patients with Addison disease because of TB, fungal infections, adrenal hemorrhage, or infiltrating diseases involving the adrenal glands.
• In Addison disease due to TB or histoplasmosis, evidence of calcification involving both adrenal glands may be present.
• In idiopathic autoimmune Addison disease, the adrenal glands usually are atrophic.

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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.

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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.^[17]

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

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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.

• In stress situations, the normal adrenal gland output of cortisol is approximately 250-300 mg in 24 hours. This amount of hydrocortisone in soluble form (hydrocortisone sodium succinate or phosphate) should be given, preferably by continuous infusion.^[49]

  • Administer 100 mg of hydrocortisone in 100 cc of isotonic sodium chloride solution by continuous IV infusion at a rate of 10-12 cc/h. Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus. Some hospitals mix 300-400 mg in 1 liter saline and infuse over 24 h to avoid needing to renew the infusion every 8-10 hours.
  • An alternative method of hydrocortisone administration is 100 mg as an IV bolus every 6-8 hours.
  • The infusion method maintains plasma cortisol levels more adequately at steady stress levels, especially in the small percentage of patients who are rapid metabolizers and who may have low plasma cortisol levels between the IV boluses.

   

  

   
• Clinical improvement, especially blood pressure response, should be evident within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of adrenal insufficiency would be questionable.
• After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150 mg, infused over a 24-hour period, irrespective of the patient's clinical status. This is to avoid stress gastrointestinal bleeding.
• As the patient improves and as the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the next 4-5 days to daily replacement doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily oral replacement doses, when oral intake is possible.
• As long as the patient is receiving 100 mg or more of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary. The mineralocorticoid activity of hydrocortisone in this dosage is sufficient.
• Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid replacement should be instituted in doses equivalent to the daily adrenal gland aldosterone output of 0.05-0.20 mg every 24 hours. The usual mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in doses of 0.05-0.10 mg per day or every other day.
• Patients may need to be advised to increase salt intake in hot weather.

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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.

• When continuous IV infusion is not practical, an intermittent IV bolus injection every 6-8 hours may be used.
• After the procedure, the hydrocortisone may be rapidly tapered within 24-36 hours to the usual replacement doses, or as gradually as the clinical situation dictates.
• Mineralocorticoid replacement usually can be withheld until the patient resumes daily replacement steroids.

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Consultations

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

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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.^[50]

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Medication Summary

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

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Prednisone (Deltasone, Sterapred, Orasone)

• Dosing, Interactions, etc.

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

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Fludrocortisone (Florinef)

• Dosing, Interactions, etc.

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

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Hydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)

• Dosing, Interactions, etc.

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.

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Class Summary

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

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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.^[47]

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.^[51] 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.^[52]

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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.^[7]

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.^[53]

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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.

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