Symptoms and signs are similar to those of Addison's disease. Distinctive clinical and general laboratory signs include the absence of hyperpigmentation, relatively normal levels of electrolytes and blood urea; Hyponatremia, if it occurs, is a consequence of dilution.

In patients with panhypopituitarism, suppression of thyroid and sexual functions and hypoglycemia are observed; with secondary adrenal insufficiency, accompanied by severe symptoms, coma may develop. Adrenal crisis is most likely in patients receiving treatment for replacement of the function of one endocrine gland, especially when treated with thyroxine without replacing hydrocortisone.

Tests to differentiate between primary and secondary adrenal insufficiency are discussed when describing Addison's disease. Patients with confirmed secondary adrenal insufficiency should undergo CT or MRI of the brain to detect pituitary tumor or atrophy. The adequacy of the hypothalamic-pituitary-adrenal connection during long-term treatment with glucocorticoids can be determined using an intravenous injection of 250 mcg of a synthetic analogue of ACTH. After 30 minutes, plasma cortisol levels should be greater than 20 mcg/dL (>552 nmol/L). The gold standard for testing the HPA axis is the insulin stress test, which induces hypoglycemia and increased cortisol levels.

The corticoliberin test (CRH) can be used to differentiate between hypothalamic and pituitary variants, but is rarely used in clinical practice. After administration of corticoliberin at a dose of 100 mcg (or 1 mcg/kg) intravenously, the normal reaction is an increase in plasma ACTH levels by 30-40 pg/ml; Patients with hypothalamic insufficiency usually develop a response, but those with pituitary insufficiency do not.

Catad_tema Diseases of the endocrine system - articles

Primary adrenal insufficiency. Clinical recommendations.

Primary adrenal insufficiency

ICD 10: E27.1, E27.2, E27.4, E27.8, E27.9

Year of approval (revision frequency): 2016 (reviewed every 5 years)

ID: KR524

Professional associations:

Approved

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

Agreed

Scientific Council of the Ministry of Health Russian Federation __ __________201_

Glucocorticoids

Cortisol

Mineralocorticoids

Aldosterone

Addison's disease

Adrenalectomy

Corticotropin releasing hormone

Adrenal cortex

Cortisol

Adrenocorticotropic hormone

Adrenoleukodystrophy

Hydrocortisone

Fludrocortisone

List of abbreviations

UI – adrenal insufficiency

CFI - chronic adrenal insufficiency

PNF – primary adrenal insufficiency

CRH – corticotropin releasing hormone

ACTH – adrenocorticotropic hormone

PRA – plasma renin activity

VCFA - very long chain fatty acids

APS – autoimmune polyendocrine syndrome

CAI – congenital dysfunction of the adrenal cortex

Terms and Definitions

Steroidogenesis– the process of synthesis of steroid hormones (in the adrenal glands and gonads) from cholesterol.

Glucocorticoids e – hormone synthesized in the adrenal cortex (cortisol).

Mineralocorticoid– a hormone synthesized in the adrenal cortex (aldosterone).

Monogenic disease– a hereditary disease caused by mutations in one gene.

Adrenalectomy– surgical removal of the adrenal gland (unilateral) or adrenal glands (bilateral).

1. Brief information

1.1. Definition

Adrenal insufficiency (AI)– a syndrome caused by a deficiency in the synthesis and secretion of cortisol in the adrenal cortex.

1.2. Etiology and pathogenesis

In most cases (but not all), glucocorticoid (cortisol) deficiency is combined with mineralocorticoid (aldosterone) deficiency. Without replacement therapy, adrenal insufficiency is a fatal disease. A patient suffering from chronic primary adrenal insufficiency (CPI) requires ongoing replacement therapy with glucocorticoids (and, in most cases, mineralocoricoids).

Chronic PUI is an etiologically heterogeneous disease. Damage to the adrenal glands can develop as a result of exposure to external factors - hemorrhage (more often in children under 1 year), infectious (tuberculosis), tumor (lymphoma, metastases), adrenalectomy (for adrenal tumors, Cushing's disease). In children, the most common cause of POI is one of hereditary diseases accompanied by impaired embryogenesis, destruction of the adrenal glands or defects in steroidogenesis

Etiology of primary CIU (Table 1)

Table 1. Etiology of PUI

Nosology
HEREDITARY VARIANTS
Congenital dysfunction of the adrenal cortex (7 options)	CYP11A1 3bGDM, CYP17, CYP21, CYP11B1, POR
Autoimmune isolated NI	Polygenic inheritance (predisposing alleles of the HLA-DQ, HLA-DR systems)
	Polygenic inheritance
	MC2R, MRAP, MCM4, NNT, STAR, ALADIN
	DAX gene, X chromosome deletion
Allgrove syndrome (Triple A)
Smith-Lemli-Opitz syndrome
IMAGe syndrome	Unknown
Kearns-Sayre syndrome	Mitochondrial DNA defects
OPTIONS PURCHASED
Bilateral adrenalectomy Hemorrhage into the adrenal glands Metastatic or tumor lesion of the adrenal glands (lymphoma, etc.) Infectious lesion of the adrenal glands (septicopyemia, tuberculosis)	No genetic nature

1.4. Coding according to ICD – 10

E27.1 – Primary adrenal insufficiency;

E27.2 – Addison's crisis;

E27.4 – Other and unspecified adrenal insufficiency;

E27.8 – Other specified adrenal disorders;

E27.9 – Disease of the adrenal glands, unspecified.

1.5. Classification

Depending on the level of damage in the hypothalamic-pituitary-adrenal system, NN can be primary, which is caused by the pathology of the adrenal glands themselves, and central - secondary (associated with reduced secretion of adrenocorticotropic hormone (ACTH) of the pituitary gland) or tertiary (associated with impaired secretion of corticotropin-releasing hormone). hormone (CRH) in the hypothalamus).

1.6. Clinical picture

Insufficiency of glucocorticoids (cortisol) is manifested by weakness, fatigue, decreased appetite and weight loss, fainting, convulsions with loss of consciousness. Convulsive syndrome is caused by low blood glucose levels (hypoglycemia) and often develops after a long night break in eating.

Mineralocorticoid (aldosterone) deficiency is manifested by nausea, increased need for salt, vomiting, repeated and not bringing relief, leading to dehydration, which is commonly called “salt-wasting crises.” Symptoms usually sharply intensify against the background of other diseases, high fever, and stressful situations.

Almost all symptoms of cortisol and aldosterone deficiency are nonspecific, that is, they can be a sign of diseases of other organs and systems ( gastrointestinal tract, central nervous system and etc).

The most specific manifestations of primary adrenal insufficiency are hyperpigmentation of the skin and/or mucous membranes and an increased need for salt. Often people around you first notice hyperpigmentation on open areas of the body (face, hands). The maximum manifestations of hyperpigmentation are observed on the skin of the external genitalia, axillary areas, knees, elbows, and the nipples, navel, perianal area and scars at the site of skin damage are also pigmented. Areas of hyperpigmentation may be on the mucous membranes of the oral cavity.

With central forms of hypocortisolism there is never hyperpigmentation, because ACTH levels are always low. Secondary and tertiary adrenal insufficiency is not characterized by a deficiency of mineralocorticoids (aldosterone), therefore, such patients will not have symptoms of salt loss. The remaining clinical signs are common to primary, secondary and tertiary adrenal insufficiency

2. Diagnostics

2.1.Complaints and anamnesis

Complaints:

• convulsive syndrome
• skin hyperpigmentation
• attacks of hypoglycemia (loss of consciousness, trembling, sweating)
• constant weakness
• increased fatigue
• loss of appetite, weight loss
• repeated vomiting, nausea, diarrhea due to illness, high fever, stress
• craving for salty foods

Anamnesis data

• The patient has a disease, one of the components of which may be adrenal insufficiency
• Having close relatives suffering from hereditary forms of chronic adrenal insufficiency

Patients without any clinical manifestations CNN, but having a disease of which CNN may be a component, as well as relatives with a hereditary form of CNN, should be considered a high-risk group for the development of CNN. In this case, genetic counseling, specific examination, including genetic diagnosis and/or clarifying diagnostics for the presence of latent subclinical congenital disorder are necessary.

Determining the specific nosological form of adrenal insufficiency makes it possible to predict the course of the disease, the likelihood of the occurrence of pathology in other organs and systems, and determine the patient’s treatment tactics. Establishing a genetic defect in hereditary forms of hypocortisolism makes it possible to determine the risk of having sick children in the patient’s family, to carry out prenatal diagnosis, and in some cases, prenatal treatment of the fetus.

2.2. Physical examination

Upon examination, the following symptoms have diagnostic significance:

• hyperpigmentation of the skin and mucous membranes (local or diffuse);
• pale or grayish skin tone;
• low blood pressure;
• underweight or sudden weight loss.

None of the clinical manifestations is a strictly specific criterion for diagnosing CNN and requires laboratory confirmation.

2.3. Laboratory diagnostics

• At the first stage of the examination, it is recommended to analyze the following laboratory parameters:

1. Serum cortisol level (at 8.00)
2. ACTH level in blood plasma (at 8.00)
3. Serum glucose
4. Serum potassium level
5. Serum sodium level
6. Plasma renin (plasma renin activity)

A comment: Blood sampling for hormonal studies is carried out in the morning at 8-9.00 on an empty stomach. In a hospital setting, blood sampling to measure renin, ARP is carried out lying down; after a night's sleep, the patient should not take a vertical position until blood sampling or lie down for 2 hours before the blood sampling procedure. If it is impossible to take blood while lying down, other standards are used to assess the renin index.

• It is recommended that the first diagnostic step is to determine the level of basal cortisol and ACTH in the blood.

Comments: Blood for research must be taken early in the morning at 6.00-9.00 hours, which corresponds to the physiological peak of glucocorticoid secretion

Simultaneously with a low level of cortisol in primary adrenal insufficiency, a high level of ACTH in plasma is determined. This study requires the doctor to follow the rules for blood sampling: sampling time in the early morning hours, the sample is taken into a cold tube with EDTA; the tube must be delivered to the laboratory for testing within several hours. With significantly elevated level ACTH (more than 150 pg/ml) and cortisol levels less than 500 nmol/l can be diagnosed as primary adrenal insufficiency.

Table 3. Estimation of basal cortisol levels.

• In case of probable and doubtful results of cortisol levels, diagnostic tests are recommended

Comments: If the patient is receiving glucocorticoid therapy, then the study of basal cortisol and ACTH levels is not reliable. In this case, they proceed to stage II of diagnosis using stimulation tests.

If the ACTH level is less than 150 pg/ml and the cortisol level is less than 500 nmol/l, an additional stimulation test with synacthen is required

Algorithm for conducting a test with short-acting ACTH:

Initially, blood is taken to determine cortisol, after which 250 mcg of tetracosactide (a synthetic analogue of ACTH) in 5 ml of saline is injected intravenously, the infusion duration is 2 minutes. Then, after 30 and 60 minutes, blood is taken to re-determine cortisol.

Normally, the cortisol level upon stimulation exceeds 500 nmol/l. With primary adrenal insufficiency, the response to stimulation is absent or reduced, the rise in cortisol is less than 500 nmol/l.

In the absence of short-acting ACTH drugs, it is possible to conduct a similar test with a long-acting ACTH drug (Sinacthen-depot). After intramuscular administration of 1 ml of Synacthen (1 mg), blood is taken to determine cortisol after 10-12 and 24 hours. The results are assessed similarly to the short-acting ACTH test.

A cortisol release in response to ACTH administration of more than 500 nmol/l allows us to clearly exclude primary adrenal insufficiency, however, it does not exclude the possibility of secondary adrenal insufficiency. To diagnose central hypocortisolism, an insulin test, a metyrapone test, and a corticotropin-releasing hormone stimulation test are used.

Lack of adequate cortisol release (more than 500 nmol/l) in response to ACTH administration can also be observed in patients with congenital forms of central hypocortisolism, while the basal ACTH level will be normal or reduced.

• Determination of steroidogenesis metabolites in 24-hour urine (17-hydroxycorticosteroids) is not informative and is not recommended for diagnosing NN.

Comments:Studying the level of free cortisol in saliva and 24-hour urine can also be used to diagnose NN and in in some cases has a number of technical advantages (for example, non-invasiveness when collecting material).

• It is recommended to study the levels of potassium, sodium, and renin, which are the main indicators of the presence of muralocorticoid deficiency.

Comments: Laboratory confirmation of mineralocorticoid deficiency is electrolyte disturbances - hyponatremia, hyperkalemia and hormonal studies - increased plasma renin activity (renin).

In some cases, to exclude mineralocorticoid deficiency, a test with furosemide is indicated. This test is based on the fact that normally hypovolemia caused by furosemide stimulates the secretion of aldosterone. In patients with mineralocorticoid deficiency, adequate aldosterone release does not occur. However, in our practice this test is not widely used and is not recommended routinely to exclude mineralocorticoid deficiency.

2.4.Instrumental diagnostics

No specific instrumental diagnostics have been developed.

2.5. Differential diagnosis

Algorithm for differential diagnosis of primary CIU

In order to determine the nosological form of CNN, it is necessary to evaluate:

1. Age of manifestation of adrenal insufficiency
2. Presence of glucocorticoid and mineralocorticoid components
3. Family history
4. Presence of other clinical components

In the absence of additional clinical components that suggest the etiology of CIU, it is necessary:

1. All boys with the onset of CLI after the age of three years should undergo a study of VLCFA (very long chain fatty acids) to exclude X-linked adrenoleukodystrophy
2. For patients of both sexes with the onset of the disease after the age of three years, conduct a study of antibodies to 21-hydroxylase
3. Conduct genetic studies to identify mutations in known genes responsible for the development of adrenal insufficiency

Table 2. Hereditary variants of primary CNN.

Primary CNN (age of manifestation)	Additional clinical signs
After 3 years	Chronic mucocutaneous candidiasis Hypoparathyroidism Minor components (alopecia, autoimmune hepatitis, diabetes, autoimmune thyroiditis, hypogonadism, dental hypoplasia, etc.)	Autoimmune polyglandular syndrome type 1
	Autoimmune thyroiditis Graves' disease Diabetes mellitus type 1	Autoimmune polyglandular syndrome type 2
	Decreased vision, hearing, behavior disorder Changes on MRI of the brain (foci of demyelination) Gait disturbance, weakness in legs Hypergonadotropic hypogonadism	X-linked adrenoleukodystrophy
	Normal mineralocorticoid function	Familial isolated glucocorticoid deficiency	MC2R, MRAP, MCM4, NNT, STAR
	Violation of the formation of external genitalia	Congenital dysfunction of the adrenal cortex	CYP11A1 3bGDM, CYP17, CYP21, CYP11B1, POR,
	Achalasia cardia Alacrymia Neurological disorders Hyperkeratosis of the soles	Allgrove syndrome (Triple A)
	Malformations of the kidneys, heart Microcephaly, Hypospadias	Smith-Lemli-Opitz syndrome
	Hypogonadotropic hypogonadism Duchenne muscular dystrophy Transcarbamylase deficiency	Congenital X-linked adrenal hypoplasia	DAX gene, X chromosome deletion
	Intrauterine growth restriction Metaphyseal dysplasia Anomalies of the development of the genitourinary system	IMAGe syndrome

3. Treatment

The main goals of treatment for PUI are:

1. Select the regimen and dose of glucocorticoids so that they best correspond to the physiological and circadian rhythm of cortisol
2. Avoid the development of adrenal crisis
3. Avoid chronic overdose and its long-term undesirable effects (osteoporosis, increased cardiovascular risks, metabolic syndrome)
4. Improve the patient’s quality of life by ensuring his psychosocial adaptation

• Hydrocortisone therapy is recommended.

Comments:Hydrocortisone 8 - 10 mg/m2/day, 3 times dose; Cortisone – acetate 10-12 mg/m2/day 3 times; Prednisolone 2-3 mg/m2/day (possible for individual needs, but not recommended, 2 times dose

With the addition of intercurrent diseases, stress (psychological or severe physical exercise) increase the dose of glucocorticoids 2-3 times during the acute phase of the disease or when exposed to stress. In the future, it is recommended to return to the usual replacement dose that the patient took before the illness.

• Patient and family education recommended

Comments: A key role in the treatment of NN is played by teaching the patient and his parents (or guardians) the basic principles of replacement therapy and behavior in unusual and acute situations.

Basic rules that every patient (or parent), as well as his immediate environment, should know:

• Increase the dose of Cortef 2-3 times in a stressful situation, when infectious diseases with a temperature above 38
• Have an emergency kit in your home and camping first aid kit - hydrocortisone for intramuscular (or intravenous) administration. Be able to give the patient or accompanying person, if necessary (sharp deterioration in condition, vomiting, loss of consciousness, convulsions), an intramuscular injection before arrival medical care.

• For the treatment of acute adrenal crisis it is recommended:

• Administration of hydrocortisone 25 – 50 mg IM (on its own, before hospitalization)
• Administration of hydrocortisone 100 mg/m(2) - bolus
• Infusion of NaCl 0.9% + glucose 5-10% 450-500 ml/m(2) – 1 hour, then 2-3 l/m(2)/day
• Infusion therapy with hydrocortisone 100 - 200 mg/m2/day, intravenous drip – 1-2 days
• Monitoring the levels of potassium, sodium, glucose, blood pressure, heart rate - every 2 hours
• Normalization of the condition, potassium, sodium
• transition to intramuscular administration of hydrocortisone with a gradual reduction and transition to oral medications
• Prescribing cortineff at a dose of hydrocortisone<50 мг/сут

4. Rehabilitation

Specific rehabilitation measures have not been developed.

5. Prevention and clinical observation

Monitoring a patient with PUI

1. Monitoring the adequacy of replacement therapy once every 6 months includes

• study of potassium, sodium
• plasma renin activity (PRA)
• examination by an endocrinologist once every 6 months with an assessment of the dynamics of height and weight, blood pressure, complaints, analysis of the causes of acute conditions (if any have occurred over the past period since the previous examination).

1. Examination taking into account the cause of PUI to identify new components of the syndrome or correct already prescribed therapy for additional components together with other specialists

Examples:

• For X-linked adrenoleukodystrophy: MRI of the brain once every 6 months, consultation with a neurologist – once every 6 months
• For autoimmune polyglandular syndromes or isolated autoimmune PUI: study of ionized calcium, phosphorus, TSH, fT4, ALT, AST, glucose, clinical blood test, as well as other studies - as indicated.
• In case of DAX-1 gene defects: monitoring the dynamics of sexual development for timely prescription of replacement therapy with sex steroids.

Patients with rare hereditary variants of PUI should be observed not only at their place of residence, but also in specialized medical centers with experience in monitoring patients with rare endocrine pathologies.

6. Additional information affecting the course and outcome of the disease

By the time of planned surgical treatment, the child must have clinical and laboratory compensation for glucocorticoids and mineralocorticoids.

1. Minimally invasive procedures(dental procedures less than 1 hour, diagnostic - skin biopsy, etc.) , as well as stressful situations (exams, olympiads, etc.)

The dose of Cortineff is doubled 2 hours before the procedure once, the dose of Cortineff does not change

1. “Minor” interventions (diagnostic procedures, including colonoscopy, tooth extraction and other dental procedures lasting more than 1 hour)

Day before intervention – baseline dose of Cortef and Cortineff

In the morning before the intervention - hydrocortisone suspension (solu-cortef) for a weight up to 15 kg - 12.5 mg, for a weight over 15 kg - 25 mg (25 mg/m(2)) or a “double” dose of cortef

After the intervention - if enteral nutrition is possible - tablet drugs - Cortef at a double dose, Cortineff at the same dose, control of potassium, sodium, glucose.

The next day - return to the base dose

1. Surgical treatment with endotracheal anesthesia (moderate complexity)

(cholecystectomy, hysterectomy, surgery on the external genitalia, etc.)

• Day before surgery:

The evening dose is doubled. If oral administration is not possible, intramuscular administration of hydrocortisone (solu-cortef) at the rate of: children up to 15 kg - 12.5 mg, over 15 kg - 25 mg (25 mg/m(2))

• On the day of surgery:

Morning - hydrocortisone (solu-cortef) IM 12.5 - 25 mg

• During surgery

Intravenous drip during surgery - 50 mg/m(2) or 25 mg for children under 15 kg, 50 mg for children over 15 kg (administration rate based on blood pressure)

• After surgery - hydrocortisone (solu-cortef) IM 12.5 - 25 mg (25 mg/m(2)) - every 6 hours, if you feel unwell, low blood pressure, the dose can be increased by 50-100%. Control of potassium, sodium, glucose.
• 1st day after surgery: In the absence of complications, absence of vomiting, switch to tablet drugs in a dose increased by 2-3 times from the base dose: Cortef (3 times a day), Cortineff at the usual dose
• From the 2nd day, in the absence of complications, gradually reduce the dose to the standard dose over 3-5 days

1. Surgical treatment with endotracheal anesthesia (severe)

(cardiac surgery, liver surgery, brain surgery, colonectomy, etc.)

The day before surgery - double dose of Cortef, in the evening - 25-50 mg of hydrocortisone (solu-Cortef)

On the day of surgery – 100-200 mg (150 mg/m(2)) of hydrocortisone per day (25-50 mg every 6 hours)

1st day after surgery - 100 mg per day IM (or 100-150 mg per m 2 body surface area) (25-50 mg every 6 hours)

Criteria for assessing the quality of medical care

Treatment with glucocorticoids (hydrocortisone) intramuscularly or intravenously during a crisis of adrenal insufficiency

The level of potassium, sodium, glucose, cortisol in the blood was determined

The level of ACTH (adrenocorticotropic hormone) in the blood was determined

Determination of very long chain fatty acids (VLCFA) in the blood of a boy over three years old with primary adrenal insufficiency of unknown etiology was performed.

	Quality criterion	Type of criterion (event-based, time-based, result-based)
	event-based
	event-based
	event-based
	event-based

Bibliography

1. Orlova E.M., Kareva M.A. "Primary adrenal insufficiency in children: clinical options, diagnosis, treatment." Methodological manual for doctors 2008
2. Handbook of a pediatric endocrinologist/Dedov II, Peterkova VA, Shiryaeva TYu, Bezlepkina OB, Kareva MA, Kuraeva, Nagaeva EV, Orlova EM, Strebkova NA. – M: Littera, 2011 – 528 p.
3. Pediatric Adrenal Diseases Workshop, Turin, May 2010 Ghizzoni L. (Turin) Cappa M. Chrousos G.P. Loche S. Maghnie M, Karger, 2011
4. Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, Falorni A, Gan EH, Hulting AL, Kasperlik-Zaluska A, K?mpe O, L?v?s K, Meyer G, Pearce SH. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014 Feb;275(2):104-15
5. Grossman A, Johannsson G, Quinkler M, Zelissen P. Therapy of endocrine disease: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe. Eur J Endocrinol. 2013 Oct 21;169(6):R165-75
6. Horn MA, Erichsen MM, Wolff AS, M?nsson JE, Husebye ES, Tallaksen CM, Skjeldal OH.

Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease. Clin Endocrinol (Oxf). 2013 Sep;79(3):316-20

1. Meyer G, Hackemann A, Penna-Martinez M, Badenhoop K. What affects the quality of life in autoimmune Addison's disease? Horm Metab Res. 2013 Feb;45(2):92-5
2. Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012 Aug 13;7:5
3. Meimaridou E, Hughes CR, Kowalczyk J, Chan LF, Clark AJ, Metherell LA ACTH resistance: genes and mechanisms. Endocr Dev. 2013;24:57-

Appendix A1. Composition of the working group

EAT. Orlova, M.A. Kareva, M.A. Melikyan, N.A. Strebkova, I.S. Chugunov, I.V. Kopylova, V.A. Peterkova,

For final revision and quality control, the recommendations will be re-analyzed by members of the working group in order to assess that all comments and comments from experts have been taken into account, and the risk of systematic errors in the development of recommendations is minimized.

Methods used to collect/select evidence:

Search in electronic databases.

Description of methods used to collect/select evidence:

Methods used to assess the quality and strength of evidence:

Expert Consensus

Methods used to analyze evidence:

Reviews of published meta-analyses;

Systematic reviews with evidence tables.

Description of methods used to analyze evidence:

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The outcome of the study influences the level of evidence assigned to the publication, which in turn influences the strength of the recommendations resulting from it.

The assessment process, of course, can also be affected by a subjective factor. To minimize potential bias, each study was assessed independently, i.e., by at least two independent members of the working group. Any differences in assessments were discussed by the whole group as a whole.

Evidence tables:

Evidence tables were completed by members of the working group.

Methods used to formulate recommendations:

	Description
	Strong arguments for using this method
	Compelling arguments for using this method
	Weak arguments for using this method
	Weak arguments against this method
	Strong arguments against using this method
Level of evidence
	Supported by more than one randomized controlled trial
	Supported by more than one non-randomized clinical trial; several analytical studies from more than one center;
	Confirmed by expert opinion, clinical experience, descriptive studies, expert panels;

Good Practice Points (GPPs)

Economic analysis:

No cost analysis was performed and pharmacoeconomics publications were not reviewed.

External expert assessment.

Internal expert assessment.

These draft recommendations were reviewed by independent experts who were asked to comment primarily on the extent to which the interpretation of the evidence underlying the recommendations is understandable.

Comments were received from primary care physicians and local pediatricians regarding the clarity of the recommendations and their assessment of the importance of the recommendations as a working tool for daily practice.

The preliminary version will also be sent to a non-medical reviewer for comments from a patient perspective.

Appendix A3. Related documents

The procedure for providing medical care to the adult population in the field of “endocrinology” (approved by Order of the Ministry of Health of Russia dated November 12, 2012 N 899n)

Appendix B: Patient Information

Adrenal insufficiency crisis

Symptoms of adrenal crisis:

• Nausea, vomiting, diarrhea
• Sharp weakness
• Dizziness
• Loss of consciousness
• Convulsions

What to do?

1. Give an IM injection of hydrocortisone as quickly as possible
2. Call an ambulance

• Always have an “emergency kit” with you (hydrocortisone ampoule or injection syringe)
• Carry an identification bracelet (or badge, card) indicating that you are receiving hydrocortisone

Emergency kit

Rule! Should ALWAYS be with you !!!

1. Ampoule with hydrocortisone
2. Syringe for intramuscular injections 2 ml (Attention: insulin syringes are not suitable!!)
3. Alcohol wipe
4. Patch

How to make an intramuscular injection correctly?

Intramuscular injection technique

Step 1. Place the bottle on a horizontal surface (table), press the yellow cap on top. The solvent will pour into the container with the powder, then shake the bottle until the powder is completely dissolved.

Step 2. Remove the syringe from the package

Step 3. Remove the protective “circle” on the yellow cap of the bottle, pierce the rubber cap with a needle and draw 2 ml of solution into the syringe.

Step 4. Free the area for injection from clothing on the body - the outer upper quadrant of the buttock, thigh (outer surface), shoulder (as indicated in the picture). If possible, quickly wipe the injection site with an alcohol wipe.

Step 5. Insert the needle into? length

Step 6: Push the plunger all the way down

Step 7: Quickly pull out the needle

Step 8: Apply the patch to the injection site

Adrenal insufficiency is one of the most serious diseases that affects the endocrine system and leads to serious consequences for the body. Most often, the disease occurs in women after 30 years of age and is characterized by a decrease in the synthesis of hormones by the adrenal cortex due to destructive changes in the body.

Endocrine glands, consisting of a cortex and medulla, the activity of which is regulated by the pituitary gland and hypothalamus. In the human body, they are responsible for the synthesis of glucocorticoids, mineralocorticoids and sex hormones - androgens. Doctors call a decrease in the level of synthesized hormones adrenal insufficiency. Depending on the level at which the lesion occurred, leading to hypocortisolism, primary, secondary and tertiary forms of the disease are distinguished.

In ICD-10, adrenal insufficiency is coded E27 (Other adrenal disorders).

A rare tertiary deficiency is caused by a decrease in the production of corticoliberin, with congenital or acquired pathology of the hypothalamus.

The secondary form is caused by a decrease in the production of ACTH in a special endocrine gland - the pituitary gland. The reasons leading to insufficient hormone production can be congenital (hypopituitarism) or acquired during life (trauma, tumors, infections, hemorrhage).

Primary failure is the most common variant of the disease, occurring when 80% of the gland structure is destroyed. Doctors include factors that provoke the development of this pathology:

1. Idiopathic cortical atrophy. At the same time, specific antibodies to 21-hydroxylase are formed in the body of a sick person, which also affect normal cells of the endocrine gland. More than 50% of patients also have other autoimmune pathologies such as thyroiditis.
2. Adrenoleukodystrophy, Allegrove syndrome and other congenital pathologies.
3. Tuberculosis of the adrenal cortex, combined with tuberculosis of the lungs.
4. Hemochromatosis, scleroderma, blastomycosis and syphilis.
5. Tumors and metastases malignant neoplasms of other localizations (breast cancer, lung cancer).
6. Therapy with cytostatics and long-term use of glucocorticoid hormones which leads to withdrawal syndrome.
7. Necrosis, hemorrhage, condition after removal of the gland.

Important! There is also a special form of the disease called false adrenal insufficiency. Its appearance is associated with a violation of the sensitivity of receptors to steroid hormones.

Symptoms

Chronic insufficiency of the adrenal cortex is clinically manifested when most of the gland is affected.

As a result of disturbances in the exchange of mineral salts and fluids, characteristic symptoms appear:

• Darkening of the skin, visually reminiscent of a tan. In the early stages of the disease, the skin of the face, neck, and palms acquires a bronze tint. This color also appears in skin folds or in places of natural pigmentation (the area around the nipples, genitals).
• Occasionally, with an autoimmune form of the pathology, white, depigmented areas - vitiligo - are noted against the background of darkening of the skin.
• Weight loss due to loss of muscle mass, increased fatigue, exercise intolerance.
• Arterial hypotension, frequent dizziness, loss of consciousness.
• Loss of appetite, nausea, vomiting.
• Disturbance of the gastrointestinal tract - diarrhea, pain in the abdominal area, constipation.
• Decreased concentration, memory impairment.
• Irritability, mood swings.

Important! One of the important characteristic signs that allows one to suspect pathology in the early stages is the patients’ increased craving for salty foods, up to the desire to consume pure salt.

Diagnostic methods

Symptoms of the disease are nonspecific and vary widely depending on the form and stage of the disease, as well as on the individual characteristics of the patient.

For diagnostic purposes, doctors use the following methods:

1. A thorough visual examination, which can detect areas of skin pigmentation, determine body weight, and record blood pressure levels. In patients without concomitant hypertension, the figures are determined to be 90/60 mm. rt. Art.
2. A blood test that records anemia and eosinoilia. Biochemical studies that help determine hypoglycemia and low sodium levels.
3. Determination of the content of adrenal hormones in urine.
4. Stimulation test with ACTH, allowing to differentiate primary and secondary forms of the disease, tests with water load.
5. Ultrasound examination of the kidneys and adrenal glands.
6. Computed tomography, MRI - allow us to identify and clarify the localization of tumors of the adrenal glands and pituitary tumors.
7. Determination of the level of antibodies to 21-hydrocylase.

Important! Clinical manifestations are nonspecific and are recorded in many other diseases, such as neurocirculatory dystonia, malignant neoplasms, pellagra, liver cirrhosis, poisoning with heavy metal salts. At the first appearance of unpleasant symptoms, it is important to immediately consult a doctor for diagnosis and selection of effective treatment.

Treatment

The choice of treatment method depends on the form of adrenal insufficiency. Therapy should be aimed at eliminating the cause of the disease and replacing corticosteroid deficiency.

To eliminate symptoms, use:

1. Elimination of the cause of the emerging pathology - therapy with anti-tuberculosis drugs, treatment of syphilis, resection of tumors, radiation therapy for tumors in the pituitary gland or hypothalamus.
2. Lifelong replacement therapy in case of irreversible changes in the primary form. It is carried out with corticosteroids and mineralocorticoids. Patients are prescribed hydrocortisone, prednisolone, DOXA.
3. In case of secondary adrenal insufficiency, the secretion of aldosterone is preserved, so only glucocorticoids (prednisolone) are used for treatment.
4. Several times a year, women are prescribed courses of anabolic steroids - Nandrolone.

Patients are treated on an outpatient basis. The effectiveness of the prescribed therapy is assessed by improvements in clinical indicators - establishment of normal blood pressure levels, weight gain, disappearance of weakness, return of appetite.

Also, in addition to the main therapy, you can use traditional methods, more about which in this video.

With adrenal insufficiency, it is important to follow a correct lifestyle to avoid worsening the condition and decompensation of the disease. For patients on hormone replacement therapy, it is important to:

• Strictly follow medical prescriptions, do not reduce or cancel hormonal medications on your own, even if you feel better.
• Follow a specialized diet with a high salt content and rich in protein foods.
• Avoid smoking, drinking alcohol, and do not use sleeping pills.
• Limit intense physical activity and avoid stress.

Important! With timely treatment and correctly selected hormonal replacement therapy, the prognosis is favorable. Most patients achieve stable compensation and improved quality of life.

First of all cortisol. This pathological the condition was first described British therapist Thomas Addison in his publication of the year, entitled Constitutional and local consequences of adrenal cortex disease.

Classification Addison's disease can occur due to primary adrenal insufficiency(in which the adrenal cortex itself is affected or poorly functioning), or secondary adrenal insufficiency, in which the anterior lobe pituitary gland does not produce enough adrenocorticotropic hormone(ACTH) for adequate stimulation of the adrenal cortex. Etiology and pathogenesis Addison's disease can occur with any damage to the adrenal cortex or pituitary gland, leading to decreased production of cortisol or aldosterone. Thus, Addison's disease can occur with tuberculosis of the adrenal glands, damage to the adrenal cortex by chemical agents (for example, cloditan), non-hormone-producing adrenal tumors that destroy healthy tissue, etc. Symptoms Addison's disease usually develops slowly over several months or years, and symptoms may go unnoticed or not appear until stress or illness occurs that dramatically increases the need. body V glucocorticoids. The most common symptoms of Addison's disease are: Chronic fatigue, gradually worsening over time; Muscle weakness; Weight loss and appetite ; Nausea , vomit , diarrhea , pain V stomach ; low blood pressure, which decreases further when standing (orthostatic hypotension); Hyperpigmentation of the skin in patches in areas exposed to sunlight, known as Addison's melasma; Dysphoria, irritability, short temper, dissatisfaction with everything; Attraction to salt and salty food, thirst, drinking plenty of fluids; Hypoglycemia, low level glucose V blood ; U women menses become irregular or disappear, men develops impotence ; Tetany(especially after using milk) due to excess phosphates ; Paresthesia and disturbances in the sensitivity of the limbs, sometimes up to paralysis, due to excess potassium ; Increased quantity eosinophils in blood; Hypovolemia(decrease in circulating blood volume); Dehydration(dehydration); Tremor(shaking hands, head); Tachycardia(cardiopalmus); Anxiety, anxiety, internal tension; Dysphagia(swallowing disorders). Addisonian crisis In some cases, symptoms of Addison's disease can occur unexpectedly quickly. This condition of acute adrenal insufficiency is called “Addisonian crisis” and is extremely dangerous and threatening. life sick with a condition. Any spicy disease , blood loss , injury, surgery or infection may aggravate existing adrenal insufficiency, which may lead to Addisonian crisis. Addisonian crises are most common in patients with Addison's disease who are undiagnosed or untreated, or who receive inappropriately small, insufficient doses of corticosteroids, or in those whose glucocorticoid dose is not temporarily increased due to illness, stress, surgery, etc. In previously diagnosed and adequately treated patients, Addisonian crisis can occur as a result of abrupt cessation of corticosteroid treatment or a sharp reduction in their dose, or when the body's need for glucocorticoids increases (surgery, infections, stress, injury, shock). Addisonian crisis can also occur in patients who do not have Addison's disease, but who are receiving or have recently received long-term treatment with glucocorticoids for other diseases ( inflammatory , allergic , autoimmune etc.) with a sharp reduction in dose or sudden withdrawal of glucocorticoids, as well as with an increase in the body’s need for glucocorticoids. The reason for this is the suppression of secretion by exogenous glucocorticoids ACTH and endogenous glucocorticoids, gradually developing functional atrophy adrenal cortex with long-term glucocorticoid treatment, as well as decreased sensitivity receptors tissues to glucocorticoids (desensitization) during therapy with supraphysiological doses, which leads to the patient’s dependence on the entry of exogenous glucocorticoids into the body (“steroid dependence”). Symptoms of Addisonian crisis Sudden severe pain in the legs, lower back, or abdomen; Severe vomiting, diarrhea, leading to dehydration and the development of shock; a sharp decrease in blood pressure; Spicy psychosis or confusion, delirium ; Hyponatremia, hyperkalemia, hypercalcemia, hyperphosphatemia; Brown plaque on the tongue and teeth due to hemolysis and development of deficiency gland. Prevalence The prevalence of Addison's disease in the human population is estimated to be approximately 1:100,000 of the population. Some research and information sites believe that the prevalence of Addison's disease is underestimated and that a more realistic estimate is 1:25,000-1:16,600 population Determining the exact number of patients with adrenal insufficiency is problematic at best, since many patients with relatively mild symptoms never seek medical attention and remain undiagnosed. ) Addison's disease can develop in people of any gender, any ethnicity, and at any age. However, the onset of the disease is most typical in adults between 30 and 50 years of age. Some studies suggest that women are slightly more likely than men to develop Addison's disease, and it tends to be more severe in women. Studies have not found any association between ethnic origin and the incidence of Addison's disease. Heredity There are several different causes that can lead to the development of Addison's disease, and some of them have a hereditary component. The most common cause of Addison's disease in USA and countries Western Europe- autoimmune destruction of the adrenal cortex. The tendency to develop this autoimmune aggression against the tissues of one's own adrenal glands is most likely inherited as a complex genetic defect. This means that for the development of such a condition, an “orchestra” of several different genes is needed, interacting with as yet unidentified environmental factors. Bibliography National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NIH Publication No. 04–3054: Addison's disease. Endocrine and Metabolic Diseases Information Service. National Institute for Health (June 2004). Retrieved June 7, 2006. Neuroimmunology, The Medical School, University of Birmingham - Abid R Karim, Birmingham UK Links Addison’s Disease Research Today - monthly online journal summarizing recent primary literature on Addison’s disease Support groups for those suffering from Addison's disease Addison's Disease Self Help Group (ADSHG) - UK support group Australian Addison's Disease Association - Australian support and information group Nederlandse Vereniging voor Addison en Cushing Patiënten - Dutch support and information group with information and documentation in English Encyclopedic Dictionary of Psychology and Pedagogy SYNATRIAL BLOCK- honey Sinatrial block (SB) is a pathological slowing or complete cessation of impulse transmission from the sinoatrial to the atrium and ventricular node. In ECG leads from the body surface, the electrical activity of the sinoatrial node... ... Directory of diseases Article instructions. The text of this article almost completely repeats the instructions for use of the drug provided by its manufacturer. This violates the rule against instructions in encyclopedia articles. Also... Wikipedia Active ingredient ›› Dexamethasone* (Dexamethasone*) Latin name Dexaven ATX: ›› H02AB02 Dexamethasone Pharmacological group: Glucocorticoids Nosological classification (ICD 10) ›› C81 Hodgkin’s disease [lymphogranulomatosis] ›› C85… … Active ingredient ›› Methylprednisolone* (Methylprednisolone*) Latin name Lemod ATX: ›› H02AB04 Methylprednisolone Pharmacological group: Glucocorticoids Nosological classification (ICD 10) ›› A16 Tuberculosis of the respiratory system, not... ... Dictionary of medicines I Addison's disease (morbus Addisoni; Th. Addison, English doctor, 1793 1860; synonym bronze disease) a disease caused by bilateral damage to the adrenal cortex and a complete cessation or significant decrease in the formation... ... Medical encyclopedia Active ingredient ›› Dexamethasone* (Dexamethasone*) Latin name Dexason ATX: ›› H02AB02 Dexamethasone Pharmacological group: Glucocorticoids Nosological classification (ICD 10) ›› A41 Other septicemia ›› C81 C96 Malignant… … Dictionary of medicines