Addison's disease

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

[1], [2]

Epidemiology

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

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

Causes of the addison's Disease

About 70% of cases in the US are associated with idiopathic atrophy of the adrenal cortex, probably caused by autoimmune processes. The remaining cases are the result of the destruction of the adrenal glands by granulomas (eg, tuberculosis), tumor, amyloidosis, bleeding or inflammatory necrosis. Hypohydrenocorticism can also be caused by the appointment of drugs that block the synthesis of glucocorticoids (eg, ketoconazole, anesthetic etomidate). Addison's disease can be combined with diabetes mellitus or hypothyroidism in the syndrome of polyglandular insufficiency.

[8], [9], [10]

Pathogenesis

There is a shortage of mineralocorticoids and  glucocorticoids.

Deficiency of mineralocorticoids leads to increased excretion of Na and a decrease in excretion of K, mainly with urine, but also with sweat, saliva and from the gastrointestinal tract. As a result, a low concentration of Na and a high concentration of K in the plasma are observed. Impossibility of urine concentration in combination with electrolyte imbalance leads to severe dehydration, plasma hypertension, acidosis, a decrease in the volume of circulating blood, hypotension and ultimately to circulatory collapse. However, in the case of adrenal insufficiency caused by a disturbance in ACTH production, the level of electrolytes often remains within normal limits or moderately changed.

Deficiency of glucocorticoids contributes to hypotension and causes a change in sensitivity to insulin and violations of carbohydrate, fat and protein metabolism. In the absence of cortisol, the necessary carbohydrates are synthesized from proteins; As a result, hypoglycemia and a decrease in glycogen stores in the liver are observed. Developed weakness, in part due to the lack of neuromuscular functions. Also, resistance to infection, trauma and other types of stress decreases.

Myocardial weakness and dehydration reduce cardiac output, and circulatory insufficiency may develop. A decrease in plasma cortisol levels leads to increased production of ACTH and an increase in the level of beta-lipotropein, 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 of the addison's Disease

Early symptoms and signs include weakness, fatigue and orthostatic hypotension. Hyperpigmentation is characterized by diffuse darkening of naked and less closed parts of the body, especially in places of pressure (bony projections), skin folds, scars and extensor surfaces. Black pigment spots are often observed on the forehead, face, neck and shoulders. 

Appear areas of vitiligo, as well as cyanotic black staining of nipples, mucous lips, mouth, rectum and vagina. Anorexia, nausea, vomiting and diarrhea are common. There may be a decrease in tolerance to cold and a decrease in metabolic processes. Dizziness and syncope are possible. The gradual onset and nonspecificity of early symptoms often lead to an incorrect diagnosis of neurosis. For later stages of Addison's disease, weight loss, dehydration and hypotension are characteristic.

The adrenal crisis is characterized by deep asthenia; pain in the abdomen, lower back, legs; peripheral vascular insufficiency, and, finally, renal insufficiency and azotemia.

Body temperature can be lowered, although severe fever is often observed, especially if the crisis was preceded by an acute infection. In a significant number of patients with partial loss of adrenal function (limited adrenocortical reserve), the adrenal crisis develops under conditions of physiological stress (for example, surgery, infection, burns, severe diseases). The only signs may be shock and fever.

[17], [18], [19]

Diagnostics of the addison's Disease

Based on clinical symptoms and signs, adrenal insufficiency can be presumed. Sometimes the diagnosis is made only if characteristic changes in the electrolyte level are detected, including low Na (<135 meq / L), high K (> 5 meq / L), low HCO ₃  (15-20 meq / L) and high levels of urea blood.

The results of studies that allow suspected Addison's disease

Blood chemistry	Low Na (<135 meq / L). High level K (> 5 meq / L). The ratio of Na: K in plasma is 30: 1. Low fasting glucose level [<50 mg / dl (<2.78 mmol / l)]. Low level of HC0 3  (<20 meq / L) High level of blood urea [> 20 mg / dL (> 7.1 mmol / L)]
General blood analysis	High hematocrit. Leukopenia. Relative lymphocytosis. Eosinophilia
Visualization	Symptoms: calcification in the adrenal gland of renal tuberculosis of pulmonary tuberculosis

Research

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

If the levels of ACTH and cortisol are at the normal limits and there are suspicions of adrenal insufficiency in clinical observations, especially in patients preparing for surgery, provocative tests should be performed. If time does not allow (for example, an emergency operation), it is necessary to administer the patient hydrocortisone empirically (for example, 100 mg intravenously or intramuscularly), and provocative tests are subsequently carried out.

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

The ACTH stimulation test consists in the introduction of a synthetic analog of ACTH at a dose of 250 μg intravenously or intramuscularly. (According to some authors, if suspicion of secondary adrenal insufficiency is used instead of 250 mcg, the study should be performed at a low dose of 1 mcg intravenously, as higher doses are administered in such patients.) Patients taking glucocorticoids or spironolactone skip the reception. The normal plasma level of cortisol before injection is 5 to 25 μg / dL (138-690 mmol / L), it doubles within 30-90 minutes, reaching at least 20 μg / dL (552 mmol / L). Patients with Addison's disease have low or low normal levels that do not rise above 20 μg / dl for 30 minutes. A normal reaction to a synthetic analog of ACTH can be observed with secondary adrenal insufficiency. However, due to the fact that pituitary insufficiency can cause adrenal atrophy, it may be necessary to administer 1 mg of ACTH long-acting intramuscularly to the patient once a day for 3 days before the investigation if a pituitary disease is suspected.

A prolonged ACTH stimulation test is used to diagnose secondary (or tertiary - hypothalamic) adrenal insufficiency. A synthetic analog of ACTH is administered at a dose of 1 mg intramuscularly, the level of cortisol is determined within 24 hours at intervals. The results during the first hour are similar to the results of the short test (determination within the first hour), but with Addison's disease after 60 minutes no further increase occurs. With secondary and tertiary adrenal insufficiency cortisol levels continue to grow for 24 hours or more. Only in cases of prolonged adrenal atrophy for the excitation of the adrenal glands is it necessary to introduce ACTH long-acting. Usually, a short test is first conducted, if a normal response is present, further study is considered.

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

Differential diagnosis

Differential diagnosis of Addison's disease

Hyperpigmentation can be observed with bronchogenic carcinoma, intoxications with salts of heavy metals (for example, iron, silver), chronic dermatoses, hemochromatosis. The Peitz-Jägers syndrome is characterized by pigmentation of the mucous cheeks and rectum. Often there is a combination of hyperpigmentation and vitiligo, which may indicate a disease of Addison, although it occurs in other diseases.

The weakness that develops with Addison's disease decreases after rest, in contrast to neuropsychiatric weakness, which is stronger in the morning compared with physical exertion. It is possible to differentiate the majority of myopathies according to their distribution, the absence of pigmentation, and the characteristic laboratory features.

In patients with adrenal insufficiency on an empty stomach develops hypoglycemia due to a decrease in gluconeogenesis. In contrast, in patients with hypoglycemia caused by hypersecretion of insulin, seizures can occur at any time, they often have an increased appetite with an increase in body weight, and there is also a normal function of the adrenal glands. It is necessary to differentiate the low level of Na in patients with Addison's disease from that of patients with heart and liver diseases (especially those taking diuretics), hyponatremia in the syndrome of ADH secretion, salt jade. These patients are not prone to hyperpigmentation, hyperkalemia with an elevated blood urea level.

[26], [27],

Treatment of the addison's Disease

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

Normal hydration and the absence of orthostatic hypotension testify to adequate replacement therapy. In some patients, fludrocortisone causes hypertension, which is corrected by lowering the dose or by prescribing antihypertensive non-diuretic drugs. Some clinicians prescribe too low doses of fludrocortisone, trying to avoid the appointment of antihypertensive drugs.

Concomitant diseases (eg, infections) are potentially dangerous, and their treatment should be given great importance; during the disease, the dose of hydrocortisone should be doubled. When there is nausea and vomiting, oral administration of hydrocortisone requires a transfer to parenteral administration. Patients should be trained when taking supplemental prednisolone and as in emergency situations administer hydrocortisone parenterally. The patient should have a filled syringe with 100 mg hydrocortisone. With an adrenal crisis, a bracelet or a card that informs the diagnosis and dose of glucocorticoids can help. With severe salt loss, as in hot climates, an increase in the dose of fludrocortisone may be required.

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

Emergency care for adrenal gland

Assistance must be provided urgently.

ATTENTION! With an adrenal crisis, the delay in carrying out glucocorticoid therapy, especially in the presence of hypoglycemia and hypotension, can be fatal.

If the patient has an acute disease, confirmation with ACTH stimulating test should be postponed until the condition improves.

For 30 seconds, 100 mg hydrocortisone is injected intravenously, followed by infusion of 1 liter of 5% dextrose in a 0.9% saline solution containing 100 mg hydrocortisone for 2 hours. Additionally, 0.9% saline is injected intravenously before correction of hypotension, dehydration, hyponatremia. During rehydration, serum level K may decrease, which requires replacement therapy. Hydrocortisone is administered continuously 10 mg / h for 24 hours. With the introduction of high doses of hydrocortisone, mineralocorticoids are not required. If the condition is less acute, hydrocortisone can be administered intramuscularly at 50 or 100 mg. Within 1 hour after the first dose of hydrocortisone, recovery of blood pressure and improvement of general condition should occur. Before the effect of glucocorticoids, inotropic agents may be required.

During the second 24-hour period, a common dose of hydrocortisone 150 mg is usually given with a significant improvement in the patient's condition, on the third day - 75 mg. Supporting oral doses of hydrocortisone (15-30 mg) and fludrocortisone (0.1 mg) are taken daily in the future, as described above. Recovery depends on the treatment of the cause (eg, trauma, infection, metabolic stress) and adequate hormonal therapy.

For patients with partial adrenal function, in which the crisis develops in the presence of a stress factor, the same hormonal therapy is necessary, but the need for a liquid can be much lower.

[28]

Treatment of Complications of Addison's Disease

Sometimes dehydration is accompanied by fever above 40.6 ° C. Antipyretics (for example, aspirin 650 mg) may be administered orally with caution, especially in cases with a drop in blood pressure. Complications of glucocorticoid therapy may include psychotic reactions. If psychotic reactions are observed after the first 12 hours of therapy, the dose of hydrocortisone should be reduced to a minimum level, which allows maintaining blood pressure and a good cardiovascular function. Antipsychotic medications may be needed temporarily, but their administration should not be prolonged.

When treated, Addison's disease usually does not reduce the expected life expectancy.