Primary adrenal insufficiency (Addison's disease)

Definition, etiology and pathogenesis

Syndrome of clinical symptoms caused by a prolonged deficiency of adrenal cortex hormones (CN), mainly cortisol, due to direct damage to the adrenal glands. The reasons:

autoimmune (most common) - autoantigens are enzymes involved in steroidogenesis: predominantly 21-hydroxylase, less commonly 17-hydroxylase and 20–22-desmolase; may be accompanied by other autoimmune diseases, usually the thyroid gland → autoimmune polyendocrine syndromes; in the early stages of the disease, the adrenal glands can be enlarged (lymphocytic infiltrates), in the later stages - reduced (atrophy);
tuberculosis and other infectious diseases (histoplasmosis, cryptococcosis, blastomycosis, coccidioidomycosis; opportunistic infections with AIDS, CMV is most common) - Addison's disease symptoms with a lesion of ≈90% of KN tissues (preceded by subclinical Addison's disease); tuberculous and fungal granulations may undergo calcification (changes are visible during the WG examination and CT);
neoplasms (lymphomas, very rarely bilateral cancer, metastases, eg kidney cancer and lung cancer) - symptoms of Addison's disease only with a massive lesion of both adrenal glands;
metabolic disorders - amyloidosis, adrenoleukodystrophy, hemochromatosis;
congenital disorders - congenital adrenal hyperplasia, ACTH receptor resistance, Olgrove syndrome, "three A syndrome" - alacrimia (no tears), achalasia of the esophagus and addisonism - adrenal hypoplasia;
drug insufficiency of CN - mitotane (chloditan), aminoglutetimid, ketoconazole, metyrapone, etomidate, heparin; has a temporary nature and passes after the abolition of drugs; longest persists after treatment with mitotane.

Clinical picture and natural course

1. Subjective symptoms: persistent weakness, fainting (due to orthostatic hypotension or hypoglycemia), decreased exercise tolerance, weight loss, lack of appetite, sometimes nausea (less vomiting), craving for salty foods, loose stools, muscle and joint pain. Symptoms often occur in stressful situations: infection, severe trauma, etc. In cases of subclinical Addison's disease, episodes of weakness, loss of appetite and muscle pain appear only temporarily, in stressful situations, especially after prolonged physical exertion. Special attention should be given to pregnant women with persistent vomiting, weakness and low blood pressure.

2. Objective symptoms: the skin darkens, especially in places exposed to sunlight or pressure on it, with brown pigmentation on the elbows, skin folds of the palms and dorsum of the hands, nipple halos and scars, and in some cases also brown spots on the mucous membrane the membrane in the oral cavity, caused by an excess of ACTH and melan-stimulating hormone (MSH), the secretion of which is not sufficiently suppressed by cortisol in the feedback mechanism; low blood pressure and orthostatic hypotension.

3. Concomitant autoimmune disorders in other organs can change the clinical picture and the course of the disease. The accession of secondary failure of CN leads to the disappearance of skin hyperpigmentation. Prior to complete discoloration of the skin can reach with generalized vitiligo.

Diagnostics

Additional research methods

Values of laboratory parameters are applicable to studies performed using the Immulite 2000 apparatus.

1. Basic blood tests:

complete blood count - neutropenia, lymphocytosis, monocytosis and eosinophilia;
biochemical studies - hyperkalemia, hyponatremia, sometimes hypoglycemia (especially with long breaks between meals and after considerable physical exertion), rarely hypercalcemia, sometimes elevated levels of urea and creatinine (due to a decrease in glomerular filtration).

2. Hormonal studies: if carried out to verify the diagnosis → you must stop taking hydrocortisone for 24 hours before the test.

the gold diagnostic standard for primary hypocorticism is considered to be a short stimulation test using synthetic corticotropin (ACTH; tetracosactide) 0.25 mg i / v (m); a cortisolemia level of ≥500 nmol / L (18.1 μg / dL) at any stage of this test (0, 30, 60 min) rules out Addison's disease;
if it is impossible to perform the above test → it is necessary to determine the concentration of cortisol (screening study) and then ACTH in a blood sample collected in the morning; reduced levels of cortisol (<138 nmol / l [5 μg / dl]) and high levels of ACTH in the blood (most often higher than the upper limit of the norm) ≥2 while taking blood for both studies in the morning are typical hormonal disorders; an increase in the level of ACTH is the first symptom (if cortisolemia is within the normal range, the diagnosis of the subclinical form of the disease is established). At further stages of diagnosis, the possibility of confirming the diagnosis with a short test with synthetic corticotropin should be weighed.
a reduced concentration of DHEA-C, androstenedione (with the exception of congenital hypertrophy of the adrenal cortex) and aldosterone; increased ARP or renin concentration (early symptom).

3. Immunological studies: most often there are specific antibodies to adrenal antigens (to 21-hydroxylase, less often - to desmolase or 17-hydroxylase); over time, the antibody titer decreases due to a decrease in autoantigen; in the case of autoimmune polyendocrine syndrome - antibodies to thyroid antigens or to the tissues of other organs.

4. ECG: signs of hyperkalemia

5. Visualization research methods: abdominal WG, CT and ultrasound can reveal bilateral formations of the adrenal glands (for example, metastases, hemorrhages in the adrenal glands) or calcifications in the projection of the adrenal glands after suffering tuberculosis or fungal infection of the adrenal glands; with CT or MRI in the late stages of auto-immune Addison's disease, atrophy of the adrenal glands is detected. Bilateral tumors are often metastatic to the adrenal glands or lymphoma.

Diagnostic criteria

1. Subclinical adrenal insufficiency: elevated ACTH concentration, normal initial serum cortisol level, and abnormal result of the stimulation test using synthetic corticotropin.

2. Explicit adrenal insufficiency: elevated levels of ACTH, reduced initial serum cortisol levels and an abnormal result of the stimulation test using synthetic corticotropin; clinical symptoms → see above.

Treatment

Replacement Therapy

Treatment of primary hypocorticism consists in continuous, lifelong replacement therapy with glucocorticosteroids (GCS), mineralocorticosteroids (MKS) and, sometimes, androgens. In subclinical hypocorticism, substitution therapy is indicated only during periods of increased need for SCS. It is necessary to inform the patient about the principles of hydrocortisone dosage under conditions of increased stress (for infections, injuries, minor surgical interventions, for example, for tooth extraction, etc.) → see. below; the patient should receive and always have with him written information about the dosage of the drug. It is necessary to plan control studies. With an obvious (manifest) hypocorticism, it is necessary to fill the deficiency of GCS, ISS and androgens.

1. GCS replacement therapy: you must strive to reproduce the daily rhythm of cortisol release (maximum dose in the morning), you should take into account the duration of a single dose (4-8 hours), body weight and height, as well as an increased need for stressful situations. Adequate dosage for replacement therapy is assessed based on health and fitness, as well as serum sodium and potassium levels. Hydrocortisone is used in doses that correspond to its daily production (5–10 mg / m2 p. T.), For example, 20–30 mg / day. in 2 doses, for example, in the morning and around 15:00 (15–20 mg + 5–10 mg), or in 3 doses, that is, in the morning, around 1:00 and around 18:00 (10–15 mg + 5–10 mg + 5 mg). In selecting the dose, body weight and height should be considered.

The drug hydrocortisone in the form of tablets 5 and 20 mg with modified release can provide a more stable concentration of cortisol in the blood during use 1 time / day on an empty stomach. Do not routinely prescribe prednisone, dexamethasone, or other synthetic analogues of cortisol because of their low, compared with hydrocortisone, values during replacement therapy.

Principles of hydrocortisone dosage:

in the case of a moderate stress situation (eg, treatment at a dentist, an infection requiring antibiotic therapy), the patient should double the dose, or increase it by 10–30 mg / day;
in case of treatment at home of a disease that occurs with a fever of> 38 ° C → the patient must increase the dose of hydrocortisone by 2 times (or 3 times if the fever is> 39 ° C) and drink fluids containing electrolytes; treatment with an increased dose of hydrocortisone p / o the patient can be used for up to 3 days, provided that he has not developed an exacerbation of the disease that requires a visit to a doctor;
in case of vomiting or diarrhea, the patient should consult a doctor → 50 mg of hydrocortisone should be injected into the patient every 12 hours. In special cases (eg, with hypertension, edema), hydrocortisone can be replaced with prednisone in an equivalent dose (20 mg of hydrocortisone = 5 mg of prednisolone);
a disease with a severe course, for example, severe trauma or surgical treatment, requires intravenous or intramuscular injection of hydrocortisone;
before increased physical activity, the patient should additionally take 5-10 mg of hydrocortisone;
in hyperthyroidism, it may be necessary to increase the dose of hydrocortisone;
in patients with diabetes, an extra dose of 5 mg in the evening may prevent the development of nocturnal hypoglycemia.

2. Replacement therapy of MKS: fludrocortisone is 0.025–0.2 mg / day, in the morning (in hot weather - the upper limit of the previously selected dose) and do not limit sodium intake. Individual dose selection is required. Patients in hot climates should increase the intake of salt (given increased sodium loss from sweat), and in some cases also fludrocortisone dosage. It is necessary to reduce the dose or consider discontinuation of the drug in case of arterial hypertension and edema, especially in the elderly. It must be remembered that hydrocortisone also has a less pronounced mineralocorticoid activity. When receiving a properly selected dose of the ISS, orthostatic hypotension should not occur. In essential arterial hypertension, it is necessary to prescribe an appropriately selected antihypertensive drug, without introducing changes in replacement therapy (eg, an ACE inhibitor or an angiotensin receptor antagonist [APA], and if necessary, the next row of drugs is the dihydropyridine calcium channel blocker; the appointment of non-aldosterone antagonists shown). It is not necessary to prescribe diuretic drugs, because they can lead to a sudden decrease in pressure due to hypovolemia. A dose of 40 mg of hydrocortisone has a mineralocorticoid effect, corresponding to 100 µg of fludrocortisone.

3. Androgen replacement therapy: dehydroepiandrosterone (DHEA) 5–25 mg after breakfast, usually 10 mg / day, in women with a tendency to depression, decreased libido or with general weakness that persists despite full normalization of cortisol deficiency and MKS. The need for a dose of 25 mg / day can be weighed especially in women with a tendency to depression, and care should be taken not to cause androgenization symptoms; if for 6 months. this attempt at androgen replacement therapy does not improve, you can refuse to continue it. A helpful definition of DHEA-C in serum.

Monitoring

The main importance is the disappearance of symptoms, normalization of blood pressure and electrolyte disorders, as well as improvement of health. You must use the minimum effective dose of hydrocortisone and fludrocortisone.

The effectiveness of GCS replacement therapy is assessed on the basis of health and physical fitness. An increase in body weight and insomnia may indicate a too high daily dose of hydrocortisone. Weakness, nausea, loss of appetite, weight loss, and increased skin pigmentation indicate insufficient replacement therapy. The definition of ACTH is unsuitable because it can exceed the norm. If in the morning ACTH is at the lower limit of the norm or below the norm, then this indicates an excess of hydrocortisone → it is necessary to reduce its dose.

In addition to clinical evaluation (monitoring blood pressure, testing for orthostatic hypotension, searching for peripheral edema), monitoring of sodium, potassium, and renin concentrations, or plasma renin activity, is used to monitor therapy with the MKS.

Special situations

Pregnancy

As a rule, there is no need to change the dose of hydrocortisone; If a feeling of weakness appears in the third trimester of pregnancy, it may be necessary to increase the dose of hydrocortisone by 20–40%, for example. with 25 mg / day. up to 30 mg / day. In case of arterial hypertension, it is necessary to reduce the dose of fludrocortisone. You should not prescribe dexamethasone for the replacement of pregnant, because this drug penetrates the placenta in an unchanged condition. If there are doubts about the adequacy of maintenance with mineralocorticoid, it is worthwhile to determine the concentration of sodium and potassium in the blood serum. The definition of renin is not applicable, since during pregnancy, its concentration in the blood increases physiologically.

Prophylaxis with hydrocortisone during labor and the postpartum period in women with adrenal insufficiency: from the onset of labor - 100 mg i.v. + 50 mg i.v. or v / m every 6 hours; in the case of a decrease in blood pressure, an additional 100 mg IV drip in 500 ml of 0.9% NaCl; 1 and 2 days after delivery - 50 mg / m every 6-8 hours; between the 3rd and 6th day - 40–60 mg / day. p / o, in 3 doses, ranging from 7 days - the dosage as before birth. It is necessary to remember in / in infusions of 0.9% NaCl.

Surgical intervention

Hormonal prophylaxis with hydrocortisone for large surgical interventions under general anesthesia in patients with hypocorticism: the day before the operation - 40 mg / day p / o; on the day of surgery - 100 mg i.v. in cap., then 200 mg / 24 h by continuous i / v infusion (or 50 mg i.v. in every 6 h); The 1 st and 2 nd day after the operation - 50 mg i / m every 6 hours, and in the case of blood pressure reduction, an additional 100 mg by intravenous infusion. Follow this sequence of actions until the patient can eat and drink; then start therapy with hydrocortisone p / o - for two days, 2 times higher than before the intervention; then gradually reduce the dose so that by the end of the 1st week. reach the initial dose that the patient took before the intervention.

Hormonal prophylaxis with hydrocortisone for minor surgical interventions in patients with hypocorticism: as a rule, the dose of oral replacement therapy with hydrocortisone should be increased 2-3 times over 1-2 days. Before extraction of the tooth, you should recommend taking p / o 20 mg of hydrocortisone for 1 hour before the intervention, and double the current dose taken on the same day.

Hormonal prophylaxis with hydrocortisone in patients with hypocorticism who undergo colonoscopy: the patient must be hospitalized in the hospital; in the evening to introduce 50 mg of hydrocortisone in / in or in / m, as well as infusion solutions in / in, in order to fill the water balance; before starting the study, reintroduce v / v or i / m with 50–100 mg of hydrocortisone

Forecast

In patients receiving adequate replacement therapy, Addison's disease has no effect on life expectancy, but the development of adrenal crisis increases mortality among patients with hypocorticism; untreated addison disease inevitably leads to death. In cases of tuberculous etiology, the prognosis depends on the spread of infection, while in the case of bilateral tumor metastases in the adrenal glands or in the case of lymphoma, the prognosis is poor.

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