Addison's disease

Addison's disease (primary or chronic adrenocortical insufficiency) is a gradually developing, usually progressive, insufficiency of the adrenal cortex. It is characterized by various symptoms that include hypotension, hyperpigmentation, and may lead to adrenal crisis with cardiovascular collapse. Diagnosis is based on the detection of elevated plasma ACTH and low plasma cortisol. Treatment depends on the cause, but generally involves the administration of hydrocortisone and sometimes other hormones.

[ 1 ], [ 2 ]

Epidemiology

Addison's disease affects 4 people per 100,000 per year. It occurs in all age groups, with equal frequency in men and women, and most often manifests clinically in metabolic stress or trauma. The onset of severe symptoms (adrenal crisis) may be preceded by acute infection (a common cause, especially in septicemia). Other causes include trauma, surgery, and loss of Na due to increased sweating.

[ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Causes Addison's disease

About 70% of cases in the United States are due to idiopathic adrenal atrophy, probably caused by autoimmune processes. The remaining cases result from destruction of the adrenal gland by granulomas (eg, tuberculosis), tumor, amyloidosis, hemorrhage, or inflammatory necrosis. Hypoadrenocorticism may also be caused by the administration of drugs that block glucocorticoid synthesis (eg, ketoconazole, the anesthetic etomidate). Addison's disease may be associated with diabetes mellitus or hypothyroidism in polyglandular deficiency syndrome.

[ 8 ], [ 9 ], [ 10 ]

Pathogenesis

Deficiency of mineralocorticoids and glucocorticoids is observed.

Mineralocorticoid deficiency results in increased excretion of Na and decreased excretion of K, mainly in the urine but also in sweat, saliva, and the gastrointestinal tract. The result is low plasma Na and high plasma K. The inability to concentrate urine, combined with electrolyte imbalance, leads to severe dehydration, plasma hypertonicity, acidosis, decreased circulating blood volume, hypotension, and ultimately circulatory collapse. However, in adrenal insufficiency caused by impaired ACTH production, electrolyte levels are often normal or only moderately altered.

Glucocorticoid deficiency contributes to hypotension and causes changes in insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. In the absence of cortisol, the necessary carbohydrates are synthesized from proteins; this results in hypoglycemia and decreased liver glycogen stores. Weakness develops, partly due to neuromuscular failure. Resistance to infection, injury, and other types of stress is also reduced.

Myocardial weakness and dehydration reduce cardiac output, and circulatory failure may develop. A decrease in plasma cortisol levels leads to increased ACTH production and an increase in the blood beta-lipotropin level, which has melanocyte-stimulating activity and, together with ACTH, causes hyperpigmentation of the skin and mucous membranes characteristic of Addison's disease. Consequently, secondary adrenal insufficiency, which develops as a result of pituitary hypofunction, does not cause hyperpigmentation.

[ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ]

Symptoms Addison's disease

Early symptoms and signs include weakness, fatigue, and orthostatic hypotension. Hyperpigmentation is characterized by diffuse darkening of exposed and, to a lesser extent, non-exposed body parts, especially pressure points (bony prominences), skin folds, scars, and extensor surfaces. Black pigment spots are often seen on the forehead, face, neck, and shoulders.

Areas of vitiligo appear, as well as a bluish-black discoloration of the nipples, mucous membranes of the lips, mouth, rectum, and vagina. Anorexia, nausea, vomiting, and diarrhea are common. Decreased tolerance to cold and decreased metabolic processes may be observed. Dizziness and syncope are possible. The gradual onset and nonspecificity of early symptoms often lead to an incorrect diagnosis of neurosis. Weight loss, dehydration, and hypotension are characteristic of later stages of Addison's disease.

Adrenal crisis is characterized by profound asthenia; pain in the abdomen, lower back, legs; peripheral vascular insufficiency and, finally, renal failure and azotemia.

Body temperature may be low, although high fever is common, especially if the crisis has been preceded by acute infection. In a significant number of patients with partial loss of adrenal function (limited adrenocortical reserve), adrenal crisis occurs under conditions of physiological stress (eg, surgery, infection, burns, severe illness). Shock and fever may be the only signs.

[ 17 ], [ 18 ], [ 19 ]

Diagnostics Addison's disease

Adrenal insufficiency may be suspected based on clinical symptoms and signs. Sometimes the diagnosis is suspected only when characteristic electrolyte abnormalities are found, including low Na (< 135 mEq/L), high K (> 5 mEq/L), low HCO3 ₍ 15-20 mEq/L), and high blood urea.

Test results that suggest Addison's disease

Biochemical blood test	Low Na (< 135 mEq/L). High K (> 5 mEq/L). Plasma Na:K ratio 30:1. Low fasting glucose [< 50 mg/dL (< 2.78 mmol/L)] Low HCO3 ( < 20 mEq/L) High blood urea [> 20 mg/dL (> 7.1 mmol/L)]
Complete blood count	High hematocrit. Leukopenia. Relative lymphocytosis. Eosinophilia
Visualization	Signs: calcifications in the adrenal glands renal tuberculosis pulmonary tuberculosis

Research

Laboratory studies, beginning with plasma cortisol and ACTH measurements, confirm adrenal insufficiency. Elevated ACTH (>50 pg/mL) with low cortisol [<5 mcg/dL (<138 nmol/L)] are diagnostic, particularly in patients under severe stress or shock. Low ACTH (<5 pg/mL) and cortisol are suggestive of secondary adrenal insufficiency; it is important to note that normal ACTH levels may not correspond to very low cortisol levels.

If ACTH and cortisol levels are borderline normal and clinical observations suggest adrenal insufficiency, particularly in patients undergoing surgery, provocative testing should be performed. If time is of the essence (eg, emergency surgery), hydrocortisone should be given empirically (eg, 100 mg intravenously or intramuscularly) and provocative testing performed subsequently.

Addison's disease is diagnosed in the absence of an increase in cortisol levels in response to the introduction of exogenous ACTH. Secondary adrenal insufficiency is diagnosed using a stimulation test with prolonged ACTH, an insulin tolerance test, and a glucagon test.

The ACTH stimulation test involves the administration of a synthetic ACTH analogue at a dose of 250 mcg intravenously or intramuscularly. (According to some authors, if secondary adrenal insufficiency is suspected, the study should be performed with a low dose of 1 mcg intravenously instead of 250 mcg, since a normal response develops in such patients when higher doses are administered.) Patients taking glucocorticoids or spironolactone should skip a dose on the day of the study. Normal plasma cortisol levels before injection range from 5 to 25 mcg/dL (138-690 mmol/L), and within 30-90 minutes they double, reaching at least 20 mcg/dL (552 mmol/L). Patients with Addison's disease have low or low normal levels that do not rise above 20 mcg/dL within 30 minutes. A normal response to the synthetic ACTH analog may be seen in secondary adrenal insufficiency. However, because pituitary insufficiency can cause adrenal atrophy, it may be necessary to give the patient 1 mg of long-acting ACTH intramuscularly once daily for 3 days prior to testing if pituitary disease is suspected.

The prolonged ACTH stimulation test is used to diagnose secondary (or tertiary - hypothalamic) adrenal insufficiency. A synthetic analogue of ACTH is administered intramuscularly at a dose of 1 mg, the cortisol level is determined for 24 hours at intervals. The results during the first hour are similar to the results of the short test (determination during the first hour), but in Addison's disease there is no further increase after 60 minutes. In secondary and tertiary adrenal insufficiency, cortisol levels continue to rise for 24 hours or more. Only in cases of prolonged adrenal atrophy is it necessary to administer long-acting ACTH to stimulate the adrenal glands. Usually, a short test is performed first, and if there is a normal response, further testing is considered.

[ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ]

Differential diagnosis

Differential diagnosis of Addison's disease

Hyperpigmentation may be observed in bronchogenic carcinoma, intoxication with heavy metal salts (e.g. iron, silver), chronic dermatoses, hemochromatosis. Peutz-Jeghers syndrome is characterized by pigmentation of the mucous membranes of the cheeks and rectum. A combination of hyperpigmentation and vitiligo is often observed, which may indicate Addison's disease, although it also occurs in other diseases.

Weakness that develops in Addison's disease is relieved by rest, unlike neuropsychiatric weakness, which is worse in the morning compared to physical exertion. Most myopathies can be differentiated by their distribution, lack of pigmentation, and characteristic laboratory signs.

In patients with adrenal insufficiency, fasting hypoglycemia develops due to decreased gluconeogenesis. In contrast, patients with hypoglycemia caused by insulin hypersecretion may have attacks at any time, often have increased appetite with weight gain, and have normal adrenal function. It is necessary to differentiate low Na levels in patients with Addison's disease from those in patients with heart and liver disease (especially those taking diuretics), hyponatremia in the syndrome of inappropriate secretion of ADH, and salt-wasting nephritis. These patients are not prone to hyperpigmentation, hyperkalemia with increased blood urea levels.

[ 26 ], [ 27 ]

Treatment Addison's disease

Normally, the maximum excretion of cortisol occurs early in the morning, the minimum - at night. Therefore, hydrocortisone (analog of cortisol) is prescribed in a dose of 10 mg in the morning, 1/2 of this dose at lunch and the same in the evening. The daily dose is usually 15-30 mg. Nighttime intake should be avoided, as it can cause insomnia. In addition, it is recommended to take 0.1-0.2 mg of fludrocortisone 1 time per day to replace aldosterone. The easiest way to adequately select a dose is to achieve a normal renin level.

Normal hydration and absence of orthostatic hypotension indicate adequate replacement therapy. In some patients, fludrocortisone causes hypertension, which is corrected by reducing the dose or prescribing antihypertensive nondiuretic drugs. Some clinicians prescribe too low a dose of fludrocortisone in an attempt to avoid prescribing antihypertensive drugs.

Concomitant illnesses (eg, infections) are potentially dangerous and should be treated with great importance; during illness, the hydrocortisone dose should be doubled. If nausea and vomiting occur with oral hydrocortisone, conversion to parenteral administration is necessary. Patients should be taught when to take additional prednisolone and how to administer parenteral hydrocortisone in an emergency. The patient should have a prefilled syringe with 100 mg of hydrocortisone. In adrenal crisis, a bracelet or card giving the diagnosis and dose of glucocorticoids may be helpful. If salt loss is severe, as in hot climates, the dose of fludrocortisone may need to be increased.

In case of concomitant diabetes mellitus, the dose of hydrocortisone should not exceed 30 mg/day, otherwise the need for insulin increases.

Emergency care for adrenal crisis

Help must be provided urgently.

CAUTION: In adrenal crisis, delay in glucocorticoid therapy, especially in the presence of hypoglycemia and hypotension, can be fatal.

If the patient is acutely ill, confirmation with an ACTH stimulation test should be delayed until the patient's condition improves.

Hydrocortisone 100 mg is administered intravenously by jet stream over 30 s, followed by infusion of 1 liter of 5% dextrose in 0.9% saline containing 100 mg of hydrocortisone over 2 hours. Additionally, 0.9% saline is administered intravenously until hypotension, dehydration, and hyponatremia are corrected. During rehydration, serum K level may decrease, which requires replacement therapy. Hydrocortisone is administered continuously at 10 mg/h for 24 hours. When high doses of hydrocortisone are administered, mineralocorticoids are not required. If the condition is less acute, hydrocortisone can be administered intramuscularly at 50 or 100 mg. Blood pressure should be restored and the general condition should improve within 1 hour after the first dose of hydrocortisone. Inotropic agents may be required until the effect of glucocorticoids is achieved.

During the second 24-hour period, a total dose of 150 mg hydrocortisone is usually given if the patient's condition has improved significantly, and 75 mg on the third day. Maintenance doses of oral hydrocortisone (15-30 mg) and fludrocortisone (0.1 mg) are given daily thereafter as described above. Recovery depends on treatment of the underlying cause (e.g., trauma, infection, metabolic stress) and adequate hormonal therapy.

For patients with partial adrenal function who develop a crisis in the presence of a stress factor, the same hormonal therapy is required, but the fluid requirements may be much lower.

[ 28 ]

Treatment of complications of Addison's disease

Sometimes dehydration is accompanied by fever above 40.6°C. Antipyretics (eg, aspirin 650 mg) may be given orally with caution, especially in cases with a fall in blood pressure. Complications of glucocorticoid therapy may include psychotic reactions. If psychotic reactions occur after the first 12 hours of therapy, the hydrocortisone dose should be reduced to the minimum level that maintains blood pressure and good cardiovascular function. Antipsychotics may be needed temporarily, but their use should not be prolonged.

With treatment, Addison's disease usually does not reduce life expectancy.