Primary chronic adrenal insufficiency: clinical guidelines

List of Abbreviations

ACTH – adrenocorticotropic hormone

AR – autosomal recessive

AD – autosomal dominant

ALT – alanine aminotransferase

AST – aspartate aminotransferase

APS – autoimmune polyglandular syndrome

IV – intravenous

i.m. – intramuscularly

IUGR – intrauterine growth restriction

CRH – corticotropin-releasing hormone

X-L – X-linked

PCAI – primary chronic adrenal insufficiency

DSD – disorders of sex development

CNS – central nervous system

Terms and Definitions

Primary chronic adrenal insufficiency (PCAI, Addison's disease) is a syndrome caused by impaired synthesis and secretion of cortisol and/or aldosterone, which may be caused by direct adrenal damage, congenital malformations, or, rarely, adrenocorticotropic hormone unresponsiveness.

Secondary adrenal insufficiency is a syndrome manifested by decreased cortisol synthesis due to impaired synthesis and secretion of adrenocorticotropic hormone.

Adrenal crisis (salt-wasting crisis, adrenal insufficiency crisis) is a life-threatening condition characterized by acute cardiovascular failure and severe electrolyte disturbances associated with glucocorticoid and mineralocorticoid deficiency, presenting with hypotension, hypovolemia, shock, and varying degrees of impaired consciousness.

Orphan disease: rare diseases with a prevalence of no more than 10 per 100,000 population.

Adrenalectomy: surgical removal of one or both adrenal glands.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Adrenal insufficiency, or hypocortisolism, is a pathological condition caused by decreased cortisol secretion, which may also be accompanied by mineralocorticoid and adrenal androgen deficiency [1].

Primary adrenal insufficiency (PCAI, Addison's disease) is caused directly by pathology of the adrenal glands themselves rather than by impaired hypothalamic-pituitary regulation. In primary adrenal insufficiency, along with glucocorticoid deficiency, mineralocorticoid and adrenal androgen deficiency develops in the majority of cases. Secondary and tertiary adrenal insufficiency are caused by impaired secretion of adrenocorticotropic hormone by the pituitary gland and corticotropin-releasing hormone (CRH) by the hypothalamus [1].

Adrenal crisis (salt-wasting crisis, adrenal insufficiency crisis) is a life-threatening condition characterized by acute cardiovascular failure and severe electrolyte disturbances associated with gluco- and mineralocorticoid deficiency, presenting with hypotension, hypovolemia, shock, and varying degrees of impaired consciousness [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

PCAI is a heterogeneous group of diseases caused by various factors and having different pathogenesis [1,2]:

- impaired embryonic development and formation of the adrenal glands due to genetic defects;

- hereditary disorders of adrenal steroidogenesis;

- hereditary resistance to the action of adrenocorticotropic hormone;

- destruction of adrenal tissue due to infectious, neoplastic, autoimmune processes, infiltrative diseases (e.g., hemochromatosis), metabolic disorders (e.g., X-linked adrenoleukodystrophy), or adrenal hemorrhage;

- adrenalectomy: surgical removal of the adrenal glands due to other diseases;

- use of certain medications.

A detailed classification of AI with indication of etiology is presented in Table 1 [3].

1.3 Epidemiology of the Disease or Condition

There are no data on the prevalence of AI among children in Russia. All diseases accompanied by PCAI in childhood are classified as orphan diseases.

1.4 Features of Coding the Disease or Condition

E27.1 Primary adrenocortical insufficiency (Addison's disease, autoimmune adrenalitis)

E27.2 Addisonian crisis (adrenal crisis)

E27.3 Drug-induced adrenocortical insufficiency

E27.4 Other and unspecified adrenocortical insufficiency (adrenal hemorrhage, infarction; adrenocortical insufficiency NOS; hypoaldosteronism)

E35.1 Disorders of adrenal glands in diseases classified elsewhere (Addison's disease of tuberculous etiology (A18.7), Waterhouse-Friderichsen syndrome (meningococcal) (A39.1))

E89.6 Postprocedural hypofunction of adrenal cortex (medulla)

1.5 Classification of the disease or condition

PCAI is subdivided into hereditary and acquired forms. Acquired PCAI includes adrenal insufficiency due to adrenal destruction (oncological diseases, hemorrhages, infectious adrenal diseases [tuberculous, fungal]), autoimmune inflammation, adrenalectomy, and as a side effect of certain medications (mitotane**, ketoconazole**, levothyroxine sodium**, and a number of other drugs that can affect steroid hormone metabolism) [1–3].

The classification of hereditary forms of PCAI is presented in Table 1.

Table 1. Hereditary forms of primary adrenal insufficiency (T. Kirkgoz, T. Guran, 2018 with additions)

1.6 Clinical presentation of the disease or condition

The main symptoms of the disease can be divided into two groups, depending on the pathogenesis. Given that individual patients may present with isolated glucocorticoid or isolated mineralocorticoid deficiency, it is important to separately outline the clinical manifestations for these conditions [4–6].

1. Manifestations of glucocorticoid deficiency [1–9]:

• weakness and increased fatigue

• nausea, vomiting

• headaches, especially in the mornings

• abdominal pain

• hyponatremia

• hyperpigmentation of the skin (especially over joints and in areas of increased friction from clothing), mucous membranes (gum margins, tongue, palate)

• weight loss, drastic decrease in appetite

2. Manifestations of mineralocorticoid deficiency [1–9]:

• dizziness, headaches

• very pronounced craving for salt and salty foods

• nausea, vomiting

• signs of dehydration

• hypotension

• hyponatremia and hyperkalemia

• lethargy

Patients may also exhibit manifestations of impaired androgen synthesis:

1. Manifestations of androgen excess in congenital adrenal hyperplasia (21-hydroxylase deficiency, 11-beta-hydroxylase deficiency): disorders of external genitalia development (virilization in female patients), precocious isosexual puberty in boys and heterosexual puberty in girls, accelerated early growth, advanced bone age resulting in short final stature, hirsutism, voice deepening, menstrual irregularities, uterine hypoplasia. The severity of these clinical manifestations depends on the degree of enzyme deficiency, as well as disease compensation during therapy and treatment adherence.

2. Manifestations of androgen deficiency [2,3,8,10]:

- in certain steroidogenesis disorders in the adrenals (e.g., StAR protein defect): disorders of sex development (feminization in male patients), hypogonadism;

- in all other cases: mildly expressed or absent axillary and pubic hair growth (mainly in female patients, whereas in male patients these manifestations are masked by testicular testosterone production).

Clinical manifestations of adrenal crisis (acute adrenal insufficiency) [1–3,6,11]:

- repeated vomiting, often projectile, diarrhea, abdominal pain (may mimic clinical signs of an "acute abdomen"), fever, marked weight loss, anorexia;

- hyponatremia (with or without hyperkalemia), hypoglycemia, metabolic acidosis, possible hypercalcemia;

- hypotension or hypovolemic shock;

- delirium, syncopal episodes, generalized seizures.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Primary adrenal insufficiency is characterized by nonspecific clinical manifestations, which can lead to diagnostic and treatment errors [1–5].

Primary adrenal insufficiency (PAI) can be suspected in patients presenting with the above clinical manifestations, but it can only be diagnosed based on laboratory test results. It is also possible to suspect PAI in an asymptomatic patient based on medical history, if the patient has a previously established diagnosis that may include PAI as a component, or has relatives with hereditary forms of PAI [1–5].

Glucocorticoid deficiency can be established under any of the following conditions [1,4,7,12]:

1. Total blood cortisol level less than 140 nmol/L in the presence of elevated blood adrenocorticotropic hormone levels exceeding twice the upper limit of normal in the early morning hours;

2. Total blood cortisol level less than 500 nmol/L during an adrenocorticotropic hormone (ACTH) (H01AA) stimulation test.

A total blood cortisol level between 140 and 500 nmol/L requires confirmation using an adrenocorticotropic hormone (ACTH) (H01AA) stimulation test. A total blood cortisol level greater than 500 nmol/L under any conditions makes the presence of PAI unlikely [1,4,7,12].

Mineralocorticoid deficiency can be established based on elevated renin levels (plasma renin activity) combined with low or normal (inappropriately normal relative to the elevated renin level) blood aldosterone levels, along with electrolyte disturbances (hyponatremia, hyperkalemia). Electrolyte disturbances or their minimal changes may be absent at the onset of the disease [1,4,7,12].

2.1 Complaints and Anamnesis

Comments: manifestations of PAI are nonspecific, but the combination of these manifestations with certain laboratory findings (hypoglycemia, hyponatremia, hyperkalemia) and progressive clinical deterioration makes PAI probable and necessitates evaluation to rule out PAI.

Comments: PAI in childhood is typically a hereditary disease, and familial cases are not uncommon. Moreover, in hereditary forms of PAI, the disease may manifest not at birth, but later in life, and even in adulthood. In some situations, a genetic defect can be identified in a patient before the appearance of any clinical picture, for example, during the screening of a patient due to an established hereditary disease in their relatives (parents, siblings, male relatives—depending on the inheritance pattern of the disease). Detecting a known pathogenic genetic variant in a patient will require periodic screening for PAI. Often in such cases, the diagnosis can be established at a pre-clinical or subclinical stage, and the development of severe, life-threatening conditions can be prevented through the timely initiation of hormone replacement therapy. Which family members need to be evaluated depends on the specific nosological form and its inheritance pattern (see Table 1).

2.2 Physical Examination

Comments: upon physical examination, the following symptoms have diagnostic value:

• skin and mucosal hyperpigmentation (local or diffuse);

• skin pallor or grayish tint;

• decreased skin turgor;

• decreased blood pressure;

• body weight deficit or rapid weight loss.

None of the clinical manifestations are strictly specific criteria for the diagnosis of chronic adrenal insufficiency and require laboratory confirmation.

2.3 Laboratory Diagnostics

To establish the diagnosis of primary chronic adrenal insufficiency (PCAI), the clinical picture alone is insufficient; mandatory laboratory confirmation is required.

1. Blood adrenocorticotropic hormone (ACTH) level testing;

2. Blood total cortisol level testing;

3. Blood renin level testing or determination of plasma renin activity;

4. Blood aldosterone level testing;

5. Blood potassium level testing;

6. Blood sodium level testing;

7. Assaying blood glucose levels.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: testing blood levels of adrenocorticotropic hormone and total cortisol makes it possible to diagnose the presence of adrenal insufficiency (specifically, glucocorticoid deficiency) and perform differential diagnosis between primary and secondary adrenal insufficiency. In PCAI, there will be an elevated adrenocorticotropic hormone level with a low or inappropriately low total cortisol level in the blood, whereas in secondary adrenal insufficiency, the blood adrenocorticotropic hormone level will be low-normal or decreased. Blood glucose testing will reveal hypoglycemia, which is characteristic of glucocorticoid deficiency. An elevated renin level, with a low or inappropriately elevated aldosterone level in the blood, makes it possible to diagnose mineralocorticoid deficiency. A decrease in blood sodium levels may indicate a deficiency of both glucocorticoids and mineralocorticoids, while an increase in blood potassium levels indicates the presence of mineralocorticoid deficiency.

Comments: taking into account the circadian rhythm characteristics of adrenocorticotropic hormone and cortisol secretion, testing blood adrenocorticotropic hormone and total cortisol levels must be performed in the morning hours—the hours of their maximum secretion. It is also necessary to take into account the biological rhythms of the given patient, age, and to clarify information about possible time zone changes by the patient over the past few days.

Comments: a blood adrenocorticotropic hormone level greater than 66 pmol/L exerts a maximal stimulating effect on glucocorticoid synthesis. A blood total cortisol level less than 138 nmol/L when blood adrenocorticotropic hormone is above these values confirms that the adrenal cortex is unable to adequately respond to adrenocorticotropic hormone stimulation. An elevation in blood adrenocorticotropic hormone against the background of normal blood total cortisol values may also indicate the onset of PCAI development and requires a follow-up examination of the patient.

Comments: in the vast majority of cases, there is no need to perform stimulation tests to diagnose PCAI, and the disease is diagnosed based on a decreased blood cortisol level and an elevated blood ACTH level. In patients with borderline total blood cortisol levels from 140 to 500 nmol/L and a slight elevation in ACTH, performing an ACTH analogue test or, if unavailable, an insulin tolerance test is recommended.

Insulin stimulation test protocol:

1. Take a blood sample to determine the blood total cortisol level prior to drug administration.

2. Administer #soluble insulin [human genetically engineered]** IV bolus at a dose of 0.1 IU/kg.

3. Take blood samples to determine blood total cortisol levels every 15 minutes for 2 hours.

4. A drop in blood glucose below 2.2 mmol/l is an indicator of a correctly performed test.

5. Continuous monitoring of the patient's condition and capillary blood glucose testing using a glucometer are necessary for timely management of severe hypoglycemia symptoms.

If the blood total cortisol level rises above 500 nmol/L, PCAI is ruled out. If there is no increase in blood total cortisol or an inadequate increase (less than 500 nmol/L), PCAI is confirmed.

Comments: an elevated blood renin level, the absence of an adequate increase in blood aldosterone level relative to blood renin (or its decrease) along with electrolyte disturbances (hyponatremia, hyperkalemia) makes it possible to establish mineralocorticoid deficiency.

Comments: the choice of study method and the gene to be tested depends on the age of disease manifestation, the patient's gender, clinical picture, and family history (see Table 1).

2.4 Instrumental Diagnostics

2.5 Other Procedures

None provided.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Main goals of PCAI treatment:

1. Select a glucocorticoid regimen and dosage so that they correspond as closely as possible to the physiological and circadian rhythm of cortisol.

2. Avoid the development of adrenal insufficiency crisis (addisonian crisis).

3. Avoid chronic overdosage and its long-term adverse effects (osteoporosis, increased cardiovascular risks, metabolic syndrome).

4. Improve the patient's quality of life by ensuring their psychosocial adaptation.

3.1 Pharmacotherapy of PCAI

Comments: Patients presenting with an acute severe condition suspected of adrenal crisis (the clinical presentation of adrenal crisis is described in detail in Section 1.6 "Clinical presentation of the disease...") must be initiated on glucocorticoid therapy prior to diagnosis for vital indications. A blood sample must be drawn to measure total serum cortisol and adrenocorticotropic hormone levels prior to the initial administration of glucocorticoids. If findings are inconclusive or blood collection prior to glucocorticoid administration is not feasible, diagnostic workup may be performed later once the patient's condition has stabilized, by temporarily discontinuing or reducing the glucocorticoid dose.

Comments: Oral hydrocortisone** tablets are the drug of choice in pediatric practice. Prescribing oral prednisolone** and dexamethasone** in pediatric practice is discouraged, particularly in children with open growth plates, due to the high risk of overdose with these drugs and their negative impact on patient growth.

Comment: it must be borne in mind that in the body, cortisone is activated by the hepatic enzyme type 1 11-beta-hydroxysteroid dehydrogenase, the activity of which is variable in childhood, and the pharmacokinetics of this drug may be unpredictable.

Comments: most forms of PAI feature mineralocorticoid deficiency. The only available mineralocorticoid medication is fludrocortisone** oral tablets.

Comments: in newborns and infants in the first year of life, mineralocorticoid requirements are at their peak, and for full compensation, infants need 1–2 grams of sodium chloride added to their food to ensure an adequate dietary sodium intake.

Comments: one of the significant causes of death in patients with PAI is adrenal crisis. Therefore, educating patients and their relatives on issues related to PAI management and adrenal crisis prevention is extremely important.

3.2 Management of Adrenal Insufficiency Crisis

Comments: all patients presenting with the clinical picture of an adrenal crisis must have a blood sample drawn to assess blood sodium, potassium, and glucose levels if the patient has a previously established diagnosis of primary adrenal insufficiency. If the patient does not have a previously established diagnosis of PAI, a blood sample must be drawn to measure adrenocorticotropic hormone and total serum cortisol levels prior to initiating glucocorticoid administration. If rapid blood collection is not feasible, therapy must be initiated immediately (if the patient is not yet in a healthcare facility). All patients require continuous monitoring of pulse, blood pressure, electrocardiogram recording, and blood potassium and sodium testing every 2 hours.

- if blood glucose is below 3.5 mmol/L, administer 10% dextrose** solution IV bolus at 2 mg/kg. Recheck blood glucose in 15 minutes and repeat 10% dextrose** IV bolus if necessary;

- in case of shock or moderate/severe dehydration, administer 0.9% sodium chloride** solution IV bolus at 10 ml/kg. Repeat if necessary. Measure blood electrolytes immediately;

- subsequent maintenance infusion therapy: 0.9% sodium chloride** solution or 5% dextrose** solution in consultation with an anesthesiologist-intensivist.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the use of prednisolone** and dexamethasone** is inappropriate in adrenal crisis; however, in the absence of hydrocortisone** preparations, due to the necessity of performing emergency interventions to manage a life-threatening condition, other glucocorticoids—prednisolone** and dexamethasone**—may be used at doses equivalent to hydrocortisone**.

Comment: receiving stress doses of hydrocortisone** is often sufficient to cover the mineralocorticoid effect of fludrocortisone**, making the use of this drug unnecessary against the background of parenteral stress doses of hydrocortisone**. Fludrocortisone** is resumed once the patient is able to take oral medications.

3.3 Prevention of Adrenal Crisis

Comments: if body temperature rises above 38℃, in other acute and stressful conditions, patients with PAI need a 2–3-fold increase in the daily dose of hydrocortisone**; in case of severe hyperthermia, a 3-fold increase in the hydrocortisone** dose. If body temperature is below 38℃ or there is no fever, it is necessary to be guided by the patient's well-being: if weakness and poor well-being develop, it is recommended to increase the daily dose of hydrocortisone** by 2–3 times. A 2–3-fold increase in the hydrocortisone** dose is possible under the action of other stress factors – invasive and non-invasive medical procedures, severe emotional stress.

Comment: parenteral administration of hydrocortisone** will allow time to seek specialized medical care during this period. If poor well-being or vomiting persists after 6 hours, repeat the administration of hydrocortisone**.

3.4 Dietary Therapy

Diet therapy is not provided.

3.5 Anesthesia

Special pain management methods are not provided.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation measures have not been developed.

5. Prevention and Dispensary Observation

1. Examination data – growth rate, body weight dynamics, blood pressure, assessment of skin and mucous membranes, assessment of well-being;

2. Blood renin level test (or plasma renin activity determination), blood potassium and sodium levels tests.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: regular examination by a pediatric endocrinologist or pediatrician is necessary to adjust therapy. Glucocorticoid therapy is selected based on the patient's well-being, body weight dynamics, and growth rate. Fludrocortisone** dose adjustment is carried out based on the results of peripheral blood pressure measurement, blood sodium, potassium, and renin levels (or plasma renin activity determination).

Comments: when adjusting glucocorticoid doses in PAI, it is necessary to focus primarily on the patient's well-being, weight gain rate, and growth rate. Glucocorticoid deficiency will manifest as lack of weight gain, weakness, lethargy, and hypoglycemic states. Glucocorticoid excess will manifest as rapid Cushingoid weight gain, decreased growth rate, and elevated blood pressure.

Comments: for fludrocortisone** dose titration, clinical evaluation of the patient's condition is important (salt craving, postural hypotension, inadequate weight gain in fludrocortisone** deficiency, and hypertension, edema in fludrocortisone** excess). It is also necessary to be guided by the results of blood sodium and potassium levels tests, blood renin level test, or plasma renin activity determination.

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1. Emergency hospitalization of children in a hospital with signs of an adrenal crisis to clarify the diagnosis and carry out emergency measures to relieve the crisis;

2. Emergency hospitalization of children in a hospital with a diagnosed PAI upon the occurrence of an adrenal crisis;

3. Elective hospitalization in a hospital or day hospital of children with suspected PAI if it is impossible to perform the primary examination in full on an outpatient basis, including children from risk groups for the development of PAI (patients with hereditary syndromes in which PAI may develop);

4. Elective hospitalization in a hospital or day hospital of children with a diagnosed PAI if it is impossible to perform dynamic examination in full on an outpatient basis.

Indications for discharge of a patient from a medical organization:

1. In case of emergency hospitalization of a child with an adrenal insufficiency crisis, discharge from the hospital is carried out after the crisis of adrenal insufficiency is relieved and the child is transferred to oral medications;

2. In case of hospitalization of a child with suspected PAI, discharge of the patient from the hospital or day hospital is carried out after clarifying the diagnosis and determining the treatment tactics;

3. In case of hospitalization of a child with a diagnosed PAI for dynamic examination and therapy adjustment, the patient can be discharged after completing the scope of examination and treatment adjustment provided for by clinical guidelines.

7. Additional Information

Performing invasive interventions under general anesthesia in patients with PAI requires switching to parenteral forms of hydrocortisone** or administration of stress doses of hydrocortisone** [75,79,80,87].

In the postoperative period, it is possible to continue i.v. infusion at the doses indicated above or switch to i.v. bolus or i.m. administration of hydrocortisone** at 1–2 mg/kg every 6 hours [75,79,80] [87].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Peterkova Valentina Aleksandrovna - Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Director of the Institute of Pediatric Endocrinology at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology at the Institute of Higher and Additional Professional Education of the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Russian Ministry of Health.

Bezlepkina Olga Borisovna - Doctor of Medical Sciences, Professor, Deputy Director of the Center - Director of the Institute of Pediatric Endocrinology at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Professor at the Department of Pediatric Endocrinology and Diabetology of the Institute of Higher and Additional Professional Education at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

TEXT AUTHORS:

Sozaeva Leila Salikhovna - Candidate of Medical Sciences, Senior Researcher at the Department of Endocrine System Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Chugunov Igor Sergeevich - Candidate of Medical Sciences, Head of the Pediatric Department of Endocrine System Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health,

Kolodkina Anna Aleksandrovna - Candidate of Medical Sciences, Head of the Department of Hereditary Diseases and Early-Age Endocrinopathies, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Kalinchenko Natalia Yuryevna - Candidate of Medical Sciences, Senior Researcher at the Department of Endocrine System Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Enikeeva Sofya Rustemovna - Researcher at the Department of Endocrine System Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Kopylova Irina Aleksandrovna - Candidate of Medical Sciences, Senior Researcher at the Department of Endocrine System Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

EXPERTS

Bashnina Elena Borisovna — Doctor of Medical Sciences, Professor at the Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov, Chief freelance pediatric endocrinologist of the North-Western Federal District.

Galkina Galina Aleksandrovna — Doctor of Medical Sciences, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Rostov Region, Chief freelance pediatric endocrinologist of the Southern Federal District.

Kiyaev Alexey Vasilievich — Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief freelance pediatric endocrinologist of the Sverdlovsk Region, Chief freelance pediatric endocrinologist of the Ural Federal District.

Kostrova Irina Borisovna - Head of the Pediatric Endocrinology Department, Children's Republican Clinical Hospital named after N.M. Kuraev, Chief freelance pediatric endocrinologist of the Republic of Dagestan, Chief freelance pediatric endocrinologist of the North Caucasian Federal District.

Oleg A. Malievsky – D.Sc. in Medicine, Professor at the Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Volga Federal District.

Petryaikina Elena Efimovna - Doctor of Medical Sciences, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of Moscow, Chief freelance pediatric endocrinologist of the Central Federal District.

Samsonova Lyubov Nikolaevna — Doctor of Medical Sciences, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Taranushenko Tatyana Evgenevna - Doctor of Medical Sciences, Head of the Department of Pediatrics at the Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voйно-Yasenetsky of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of Krasnoyarsk Krai, Chief freelance pediatric endocrinologist of the Siberian Federal District.

Conflict of interest: the authors of the clinical guidelines declare no conflict of interest. For the final editing and quality control, the guidelines were re-evaluated by the working group members, who concluded that all comments and feedback from experts had been taken into account, and the risk of bias in the development of the guidelines was minimized.

Appendix A2. Methodology for Developing Clinical Guidelines

The guidelines presented herein are based on a systematic literature review performed by the group members. Articles published up to 2024 were submitted for review. The experts within the group reviewed these data as well as selected articles with the highest level of evidence.

Target audience for these clinical guidelines:

1. pediatric endocrinologist

2. pediatrician

3. anesthesiologist-resuscitologist

Table 11. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 12. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 13. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Order of the Ministry of Health of the Russian Federation No. 863n dated November 9, 2012 "On approval of the standard of primary health care for children with chronic adrenal insufficiency" (Registered with the Ministry of Justice of Russia on March 18, 2013, No. 27732).

Up-to-date instructions for medical product use can be found on the official website of the Ministry of Health of the Russian Federation http://grls.rosminzdrav.ru/Default.aspx (http://grls.rosminzdrav.ru/Default.aspx).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Adrenal glands – what are they?

The adrenal glands are two small triangular "lumps" weighing only about 10 g, located ABOVE the kidneys, which is why they are called ADRENAL glands. Every person has them.

What are the adrenal glands for?

The adrenal glands are endocrine glands that produce substances essential for the body – hormones.

The inner ("medulla") part of the adrenal gland produces adrenaline.

The outer part, called the "adrenal cortex", produces corticosteroids (cortisol, aldosterone, and androgens):

• CORTISOL is a hormone that helps properly utilize energy stores in the body (glucose, proteins, fats) and regulates the function of every cell in your body. In addition, cortisol helps a person cope with stress and infections, providing strength and energy.

• ALDOSTERONE is another hormone produced by the adrenal glands. It controls the water, potassium, and sodium balance in your body to ensure the proper functioning of the heart, kidneys, and all other organs, and maintains normal blood pressure.

• ANDROGENS are male sex hormones produced in small amounts by the adrenal glands.

What is adrenal insufficiency?

Adrenal insufficiency means the body lacks enough cortisol. Often, aldosterone is also deficient. A person cannot survive without cortisol and aldosterone. When cortisol is lacking, a person becomes weak, loses appetite, lacks the energy to play, work, study, or sometimes even walk:

• If there is a shortage of aldosterone, salt (sodium) starts leaving the body along with water. People begin to consume more salt in their food to make up for the deficiency. Parents often say about children that they "eat salt straight from the salt shaker."

Symptoms of so-called "salt wasting" can include vomiting, diarrhea, and dehydration. Doctors refer to this condition as an "addisonian crisis".

Symptoms of adrenal insufficiency

• Darkening of the skin (tanning, "bronze skin", dark elbows and knees)

• Unusually rapid fatigability and excessive tiredness

• Dizziness

• Very low blood pressure

• Nausea, vomiting

• Diarrhea

• Poor appetite

• Abdominal pain

• Muscle weakness

• Unexplained weight loss

• Craving for salty foods

• Depression

• Low blood glucose levels

If such symptoms appear, you should immediately inform your doctor, who will help determine if this is related to adrenal insufficiency and prescribe examination and treatment.

Why do the adrenal glands malfunction?

There are many reasons why the adrenal glands stop producing enough cortisol and aldosterone.

• Congenital inherited adrenal disorders (congenital adrenal hyperplasia, congenital adrenal hypoplasia, adrenoleukodystrophy, and other rarer causes).

In children, adrenal insufficiency most often manifests as a result of a genetic defect. A malfunction occurs in the "cortisol and aldosterone production factory" located in the adrenal glands. This "factory" is called steroidogenesis. It employs many helpers (enzymes) that "assemble" hormones from the necessary components.

If any of the helper enzymes do not work, or if the necessary parts are missing, the required hormones cannot be produced in the proper quantities.

This is what is called "adrenocortical hormone deficiency" or "adrenal insufficiency".

• Autoimmune adrenal insufficiency, or Addison's disease

This type of adrenal insufficiency occurs in both children and adults. In these cases, the "hormone production factory" in the adrenal glands has simply broken down. This can be caused by an autoimmune process, resulting in the production of "autoantibodies"—substances mistakenly produced by one's own immune system against its own adrenal glands. Genes are responsible for this once again. Sometimes, much less frequently, the adrenal glands are destroyed as a result of hemorrhage, infection (such as tuberculosis), or tumors.

• Surgical removal of the adrenal glands (adrenalectomy)

Sometimes surgeons have to remove both adrenal glands to treat another, more dangerous disease.

• Pituitary disorders

The adrenal glands can also malfunction due to pituitary diseases. The pituitary gland produces adrenocorticotropic hormone, which is important for the adrenal glands and stimulates their function. If, as a result of pituitary diseases, adrenocorticotropic hormone is insufficient, the "healthy" adrenal glands do not receive the "command from above" and stop producing cortisol. Doctors call this "secondary adrenal insufficiency."

Almost always, to establish the exact cause of the disease, it is necessary to perform complex blood tests on the patient: genetic testing—searching for "defects" (mutations) in genes—and/or testing for specific autoantibodies in the blood.

How to live when the adrenal glands do not work?

There are medications that completely replace the missing hormones—glucocorticoids. This treatment is called "replacement therapy."

Your pediatric endocrinologist will recommend the doses, regimen, and specific medications to use (how many times a day and at what time).

You must ALWAYS take your medications at the prescribed time. Missing doses can be very dangerous for you. If you do accidentally miss a dose, take it later or take two doses at the same time.

In case of a sharp deterioration in condition—severe weakness, nausea, fainting, seizures, loss of consciousness, and repeated vomiting—administer hydrocortisone suspension** 50–100 mg intramuscularly for children over 5 years old (50 mg for children under 5 years old) while waiting for the ambulance team to arrive.

If you are facing a surgical intervention (operation), consult your doctor. Dose adjustment depends on the severity of the surgery.

I must carry an information card, bracelet, or badge stating that I suffer from adrenal insufficiency and am receiving replacement therapy (see below for details).

Why is it necessary to carry medical identification items?

• This is essential so that people and doctors who come to your aid in an emergency situation can quickly determine what needs to be done.

• During a crisis, you may lose consciousness, so it is extremely crucial that bystanders accidentally nearby know that you are receiving hydrocortisone (glucocorticoid) replacement therapy. If something unexpected happens and you are unable to communicate that you need hydrocortisone, you may not receive timely medical care, which can be life-threatening.

What forms can identification items take?

Bracelets, pendants, cards, badges.

What information should they contain?

1. First and Last Name.

2. If I am unconscious or experiencing seizures, vomiting, diarrhea, or delirium, I URGENTLY need to receive a glucocorticoid injection. Your attending physician will advise you on the specific medication and dosage. Delay can be life-threatening!

3. Contact phone number for family or physician.

Vaccination

Adrenal insufficiency is not a contraindication for vaccination. Often, children and adults suffering from adrenal insufficiency are denied vaccination on the grounds that their condition may worsen. There is no basis for this claim. The likelihood of a crisis developing is much higher against the background of an acute infectious disease.

On the day of vaccination, in case of feeling unwell, the glucocorticoid dose should be doubled, and then immediately returned to the usual dose once you feel well.

Sports

Adrenal insufficiency is not a contraindication for playing sports. A person who regularly takes the prescribed replacement therapy can play sports just like a healthy person. Standard physical activity (school physical education, backyard sports games) does not require an additional dose of medication. If physical exertion is very high or, for example, competitions are coming up, the glucocorticoid dose must be doubled for that period.

It must be taken into account that excessively traumatic or extreme sports create a higher risk of an acute situation for any person.

Adrenal crisis

Symptoms of an adrenal crisis:

• Nausea, vomiting, diarrhea

• Severe weakness

• Dizziness

• Loss of consciousness

• Seizures

WHAT TO DO?

What are the potential complications from long-term medication use?

Complications from ongoing lifelong glucocorticoid and mineralocorticoid replacement therapy are minimal.

As we have already explained, a person cannot live without cortisol. Replacement therapy aims to supply the body with the missing hormones. The doses selected for each patient with adrenal insufficiency are as close to physiological as possible (meaning the daily dose is roughly equal to the amount of hormone a person's body normally produces each day).

A short-term dose increase during illness or stress causes no harm.

Prolonged incorrect administration and significantly overestimated doses of medications will, of course, lead to side effects—growth retardation, weight gain, elevated blood pressure, increased bone fragility (i.e., reduced bone mineral density), cataracts, and diabetes mellitus. These can be avoided by taking medications correctly and regularly consulting a pediatric endocrinologist.

Glucocorticoid medications can irritate the gastric mucosa, causing gastritis. We recommend taking tablets after meals or washing them down with milk or kissel.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.