List of Abbreviations
AD – autosomal dominant
AR – autosomal recessive
ATP – adenosine triphosphate
ADP – adenosine diphosphate
ACTH – adrenocorticotropic hormone
IV – intravenous
IM – intramuscular
CHI – congenital hyperinsulinism
CHD – congenital heart disease
G-1-P – glucose-1-phosphate
G-6-P – glucose-6-phosphate
GDH – glutamate dehydrogenase
GDM – gestational diabetes mellitus
GTP – guanosine triphosphate
DR – diazoxide-resistant
DS – diazoxide-sensitive
GI – gastrointestinal tract
IUGR – intrauterine growth restriction
IGF-1 – insulin-like growth factor 1
CT – computed tomography
LDH – lactate dehydrogenase
MCT1 – monocarboxylate transporter 1
MRI – magnetic resonance imaging
MODY (Maturity-Onset Diabetes of the Young) – maturity-onset diabetes of the young
IGT – impaired glucose tolerance
PI – pancreatic index
SC – subcutaneous
PET – positron emission tomography
DM – diabetes mellitus
FT4 – free thyroxine
GH – growth hormone
TSH – thyroid-stimulating hormone
US – ultrasound examination
ECHO-CG – echocardiography
18F-DOPA – 18F-L-dihydroxyphenylalanine
Terms and Definitions
Diazoxide-sensitive variant of congenital hyperinsulinism is a variant where diazoxide therapy allows achieving euglycemia in a patient
Diazoxide-resistant variant of congenital hyperinsulinism is a variant where diazoxide therapy at maximum doses for a period of at least 6 days does not allow achieving euglycemia in a patient
Protein-induced form of congenital hyperinsulinism is a form of the disease in which episodes of hypoglycemia are triggered by protein intake
Physically-induced form of congenital hyperinsulinism is a form of the disease in which episodes of hypoglycemia are triggered by physical exertion
Focal form of congenital hyperinsulinism – is a histological form of the disease in which inadequate increased insulin secretion is carried out by a limited area of the pancreas, while the rest of the organ retains normal function
Diffuse form of congenital hyperinsulinism – is a histological form of the disease in which inadequate increased insulin secretion is carried out by the beta cells of the entire pancreatic tissue
Atypical form of congenital hyperinsulinism is a non-focal histological form of the disease in which inadequate increased insulin secretion is carried out by beta cells located chaotically among normal pancreatic beta cells
Imprinting is a genetic phenomenon in which the expression of certain genes depends on which parent the alleles were inherited from
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Congenital hyperinsulinism (CHI) is a group of diseases characterized by inadequate hypersecretion of insulin by the pancreatic beta cells, leading to the development of hypoglycemia [1].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The most common cause of CHI is pathogenic mutations in genes involved in the regulation of insulin secretion. Currently, 14 such genes have been described. In addition, there are syndromic disorders whose symptom complex may include hyperinsulinemic hypoglycemia. A separate group consists of transient hyperinsulinemic hypoglycemia of newborns, developing as a complication of the perinatal period or as a consequence of intrauterine growth restriction [2]. Hyperinsulinemic hypoglycemia after gastrointestinal surgery has also been described.
The specific genetic mutation determines the unique pathway of CHI development. Below are the main links whose impairment activates insulin production or action, subsequently leading to hypoglycemia.
The glucose-dependent mechanism of insulin secretion is a complex multistep process controlled by various hormonal and enzymatic systems. Normally, glucose enters beta cells via facilitated diffusion, where it undergoes the first stage of glycolysis with the help of the enzyme glucokinase [3]. As a result of the first phosphorylation reaction, an active glucose metabolite — glucose-6-phosphate (G-6-P) — is formed. Leucine is also one of the stimulators of insulin secretion. Glucose and leucine activate the intracellular Krebs cycle, resulting in the synthesis of adenosine triphosphate (ATP). An increase in ATP levels and an increase in the ATP/adenosine diphosphate (ADP) ratio triggers a cascade of reactions: ATP-dependent K+ channels are inhibited, membrane depolarization and the opening of voltage-gated Ca++ channels occur, and the intracellular concentration of Ca++ increases, which in turn stimulates insulin exocytosis (Figure 1).
When blood glucose levels decrease, its intracellular metabolism becomes less intense, leading to a decrease in the ATP/ADP ratio. The latter mediates the opening of ATP-dependent K+ channels and the closing of voltage-gated Ca++ channels, thereby blocking insulin secretion.
The most common cause of CHI is inactivating mutations in the KCNJ11 and ABCC8 genes encoding ATP-dependent K+ channels [4,5]. Both autosomal recessive and autosomal dominant mutations of these genes have been described. Thus, a situation is formed in which the aforementioned channels become non-functional regardless of the glycemia level. As a consequence, the beta cell membrane is in a depolarized state, which entails excessive influx of Ca++ into the cell and insulin hypersecretion.
The second most common cause of CHI is activating autosomal dominant mutations in the GLUD1 gene. This gene encodes glutamate dehydrogenase, which is necessary for the conversion of glutamate into alpha-ketoglutarate and ammonium. An increase in alpha-ketoglutarate leads to an increase in ATP and the aforementioned cascade of reactions. Patients with a mutation in the GLUD1 gene experience hypoglycemia both on an empty stomach and after protein intake. The latter is explained by the fact that any protein food contains the amino acid leucine, which activates glutamate dehydrogenase [6].
Groups of patients with CHI caused by mutations in the GCK, HADH, HNF4A, HNF1A, SLC16A1, UCP2, HK1, PGM1, PMM2, CACNA1D, FOXA2 genes have also been described. It is important to note that in more than 30% of cases, the molecular genetic variant of CHI cannot be established [4,5]. Genetic variants of CHI and their main clinical characteristics are presented in Table 1.
1.3 Epidemiology of the Disease or Condition
The incidence of CHI is 1:30,000 to 1:50,000 live births in the general population and 1:2,500 in closed populations with a high percentage of consanguineous marriages [19]. In the Russian Federation, the incidence of this disease corresponds approximately to 1:50,000 [19].
1.4 Features of Coding the Disease or Condition
E15 — Nondiabetic hypoglycemic coma
E16.1 — Other forms of hypoglycemia
E16.2 — Hypoglycemia, unspecified
E16.8 — Other specified disorders of internal secretion of pancreas
E16.9 — Disorder of internal secretion of pancreas, unspecified
Examples:
E16.1 - Congenital hyperinsulinism, diazoxide-sensitive course.
E16.1 - Congenital hyperinsulinism, diazoxide-resistant course, diffuse form. Condition after subtotal pancreatectomy (06/05/2017). Complications: psychomotor retardation.
E16.1 - Beckwith-Wiedemann syndrome: congenital hyperinsulinism, omphalocele, macroglossia.
Table 1. Genetic variants of monogenic forms of CHI and their clinical characteristics
1.5 Classification of the disease or condition
CHI is a heterogeneous disease both etiologically and in terms of clinical course and diversity of morphological forms.
Classification of congenital hyperinsulinism [1,4,15,20].
1. By disease duration:
- Transient CHI.
- Persistent CHI.
2. Etiological variants:
- Monogenic forms: mutations in genes involved in the regulation of insulin secretion: KCNJ11, ABCC8, GCK, GLUD1, HADH, HNF4A, HNF1A, SLC16A1, UCP2, HK1, PGM1, PMM2, CACNA1D, FOXA2.
- Syndromic forms:
Beckwith-Wiedemann syndrome;
Sotos syndrome;
Kabuki syndrome;
Turner syndrome;
congenital disorders of glycosylation, etc.
- Secondary CHI due to complications of the intrauterine and perinatal periods (birth asphyxia, diabetic fetopathy, small for gestational age, intrauterine sepsis).
3. By hypoglycemia trigger:
- Protein-induced CHI.
- Exercise-induced CHI.
4. By response to diazoxide therapy:
- Diazoxide-responsive form.
- Diazoxide-resistant form.
5. By histological form:
- Diffuse CHI.
- Focal CHI.
- Atypical CHI.
1.6 Clinical presentation of the disease or condition
As a rule, CHI manifests in the first days or weeks of life and presents with severe, persistent hypoglycemia requiring extremely high intravenous (IV) infusion rates of dextrose** solution for correction. However, milder forms with a late onset (up to three years of age) and a mild course are also encountered. Typically, hypoglycemia in CHI occurs in the fasting state, although in some forms hyperinsulinemia can be triggered by food intake. Newborns with CHI are frequently large for gestational age [10,21,22].
Clinical manifestations of hypoglycemia are nonspecific and are divided into adrenergic and neuroglycopenic. The former include tearfulness, irritability, and excessive sweating. Neuroglycopenic symptoms manifest as decreased concentration, weakness, refusal to feed, drowsiness, and impaired consciousness. In more than half of cases, the onset of CHI presents with seizures in children; newborns may also exhibit respiratory disorders up to and including apnea. It is worth noting that patients may also feel well and maintain normal activity levels despite hypoglycemia. This phenomenon is attributed to the body's adaptation to persistent hypoglycemia.
Characteristic facial features and comorbid conditions are observed in patients with syndromic forms of the disease.
Beckwith-Wiedemann syndrome: macrosomia, hemihyperplasia, macroglossia, umbilical hernia, omphalocele, earlobe creases, development of embryonal tumors [23,67].
Kabuki syndrome: Kabuki make-up facies, intellectual disability, skeletal anomalies, cardiovascular malformations [24,25].
Sotos syndrome: abnormal facial features (long narrow face, prominent forehead, small pointed chin), overgrowth (gigantism), skeletal anomalies, mental retardation [26].
Turner syndrome with ring X chromosome: short stature, hypergonadotropic hypogonadism, cardiovascular malformations [27].
Congenital disorders of glycosylation: multiorgan disorders, redistribution of subcutaneous adipose tissue with fat pads on the palms and soles [28].
Persistent hypoglycemia leads to irreversible brain cell damage. Patients may experience the following complications: psychomotor and speech development delay, epilepsy, visual impairments, cerebral palsy, swallowing disorders [4,29].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Timely diagnosis of the disease helps reduce the risk of neurological complications from CHI. The main criterion for diagnosing CHI is an unsuppressed insulin level (blood insulin > 1.25 µIU/mL, C-peptide > 0.5 ng/mL) in the presence of hypoketotic (blood 3-hydroxybutyrate < 1.8 mmol/L) hypoglycemia (blood glucose < 2.8 mmol/L) [30–32]. Common difficulties in establishing the diagnosis include the nonspecific clinical picture of hypoglycemia, initial misdiagnosis of epilepsy in the presence of seizures without glycemic monitoring, as well as the necessity to assess insulin levels exclusively during hypoglycemia and without accounting for laboratory reference ranges.
2.1 Complaints and Anamnesis
It is recommended: taking a medical history in patients with clinical manifestations of hypoglycemia [19,30,32]
Characteristic symptoms of CHI include:
• convulsive syndrome (focal/generalized seizures);
• muscular hypotonia (in the neonatal period);
• loss of consciousness, depressed consciousness, lethargy;
• respiratory disorders: apnea, bradypnea (typical of the neonatal period);
• increased appetite, progressive weight gain;
• in older children, episodes of aggression and inappropriate behavior during fasting may occur.
When taking the medical history, it is necessary to clarify:
• perinatal history (presence of asphyxia, intrauterine infection);
• pregnancy course features (maternal gestational diabetes);
• anthropometric parameters at birth;
• presence of close relatives suffering from hypoglycemic syndrome, data on early infant mortality in the family;
• history of consanguineous marriage;
• age of onset of the first symptoms of hypoglycemia.
LoR CLoE 5 Level of Recommendation C (Level of Evidence – 5)
It is recommended: calculating the glucose requirement (a set of assessments during transfusion and infusion therapy) in patients with clinical manifestations of hypoglycemia receiving intravenous glucose infusions [19,30–34].
An additional diagnostic criterion for CHI is a high glucose utilization rate (> 8 mg/kg/min) required to maintain normal blood glucose levels (> 3.5 mmol/L).
Standard formulas are used for calculation:
IV Glucose (mg/kg/min) = (% glucose solution × mL/kg/day) / 144
or
IV Glucose (mg/kg/min) = (% glucose solution × mL/h) / 6.0 × kg
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.2 Physical Examination
It is recommended: to perform a physical examination in all patients with clinical manifestations of hypoglycemia [19,30–34].
During the examination, attention should be paid to:
• dysmorphic stigmata (typical of syndromic CHI forms);
• anthropometric data (macrosomia or microcephaly may be detected);
• the child's psychomotor development (delay is possible);
• condition of the retina and optic disc (blindness is a complication of severe neonatal hypoglycemia);
• presence of congenital heart defects, renal anomalies (typical of syndromic CHI forms).
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.3 Laboratory Diagnostics
It is recommended: performing regular blood glucose tests every 2–3 hours before meals in patients with clinical signs of hypoglycemia [19,30–34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Recommended: regular blood glucose testing, which can be performed using a portable blood glucose meter or continuous glucose monitoring. It is recommended to assess the glycemic profile in this manner for at least 1–3 days [66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: when monitoring blood glucose levels, it is important to determine when and how often the patient develops hypoglycemia: whether this occurs on an empty stomach or after meals, clarify after which foods this happens more frequently, how long after a meal, and whether there is a relationship between hypoglycemia and physical activity [33,34]. Continuous glucose monitoring systems have certain limitations in the first months of life and can only be used as additional monitoring rather than for diagnosis.
Recommended: confirmation of congenital hyperinsulinism diagnosis solely based on laboratory criteria (not earlier than 3 days of life, which minimizes false results that may be associated with the adaptation period). For diagnosis, the presence of the primary criterion (insulin level, C-peptide level, and glucose level) and one or more of the 4 additional criteria is mandatory [19,31–35].
Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)
Diagnostic criteria (evaluated not earlier than 3 days of life)
Primary diagnostic criterion (during hypoglycemia of less than 2.8 mmol/L) | |
|---|---|
Insulin level C-peptide level | greater than 1.25 µIU/mL greater than 0.5 ng/mL (= greater than 0.17 nmol/L) |
Additional criteria | |
1. Ketone bodies (3-hydroxybutyrate) during hypoglycemia (less than 2.8 mmol/L) | less than 1.8 mmol/L |
2. Glucose utilization rate to maintain euglycemia | greater than 8 mg/kg/min for newborns greater than 3 mg/kg/min for children over 1 year of age |
3. Response to #glucagon** administration (at a dose of 0.05 mg/kg, but not exceeding 1 mg intravenously, intramuscularly, subcutaneously, single dose) | rise in glycemia by ≥ 1.7 mmol/L from baseline |
4. Decreased level of free fatty acids in blood plasma | less than 1.7 mmol/L |
Recommended: performing provocation tests if studies were not conducted during spontaneous hypoglycemia [30–34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Provocation tests
Recommended: performing a diagnostic fasting test (testing blood glucose, blood insulin, blood C-peptide, and blood or urine ketones at the end of the fasting period or upon reaching hypoglycemia and/or ketonemia greater than 1.8 mmol/L) [30–35].
The fasting test is the "gold standard" for the diagnosis of CHI.
The duration of the fasting period depends on the child's age and weight. Currently, there are no standardized protocols for this diagnostic test in children. It is recommended to use the following time intervals:
- children aged 3 days to 30 days weighing less than 3 kg: 2.5–3 hours;
- children aged 3 days to 30 days weighing more than 3 kg: 3.5–4 hours;
- children aged 1–3 months: 6 hours;
- children aged 3–12 months: 8 hours;
- children aged 1–2 years: 12 hours;
- children aged 2 years and older: 18 hours.
During the test, monitoring of general well-being and blood glucose levels should be carried out for all patients, and control of ketonemia is also desirable. In newborns requiring intravenous dextrose** infusion, glycemic monitoring is necessary every 30 minutes; in older children, glucose levels can be measured every 60 minutes. Ketonemia control should be performed at least once every 6 hours.
The test is terminated:
- if glycemia is less than 3.0 mmol/L, or
- ketonemia is greater than 1.5 mmol/L, or
- marked deterioration of the child's condition.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the fasting test should be performed only in a hospital setting, under the supervision of qualified medical personnel, and only when venous access is available. If the child is receiving a dextrose** infusion, abruptly stopping it is not recommended: a gradual reduction in the infusion rate is necessary (by 2–5 mL/h every 15 minutes). In newborns with CHI, hypoglycemia can develop rapidly with minimal clinical manifestations; therefore, before the test, a 10% dextrose** solution for bolus administration must be prepared, as well as #glucagon**, the administration of which may be necessary in the event of loss of venous access.
Recommended: performing a #glucagon** test (blood glucose testing after #glucagon** administration) as an additional confirmatory diagnostic method at the end of the fasting test. The patient is administered #glucagon** subcutaneously or intravenously at a dose of 0.05 mg/kg (not exceeding 1 mg). Blood glucose is evaluated at 5, 10, 15, and 30 minutes. An increase in glycemia of more than 1.7 mmol/L indicates a diagnosis of CHI [30–35].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: after the #glucagon** test, rebound hypoglycemia may occur in patients 60–90 minutes later. In case of a pronounced increase in ketone bodies during hypoglycemia, the administration of #glucagon** is inappropriate.
Recommended: performing a protein tolerance test (blood glucose testing, blood insulin testing, blood C-peptide testing after protein intake) in patients with suspected postprandial hypoglycemia based on history [19,30–34].
The test is preferably performed after a 3–6 hour fasting period (if possible). Protein formula is calculated as 1 g of protein per 1 kg of weight, administered orally. Capillary glycemia is tested before the test, and then at 30, 60, 90, and 120 minutes. Venous blood is sampled at the same time points to determine insulin, C-peptide, and glucose levels.
The test is stopped in case of hypoglycemia less than 3.0 mmol/L or after 120 minutes.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: precautions are the same as for the fasting test. In children with protein-sensitive CHI, extremely severe hypoglycemia requiring continuous intravenous dextrose** infusion may develop during this test [19,30–34].
Recommended: performing a glucose tolerance test (blood glucose testing after dextrose** solution intake) in patients with suspected postprandial hypoglycemia based on history [30–35].
The test is preferably performed after a 3–6 hour fasting period (if possible). The dextrose** solution is calculated using the formula of 1.75 g per 1 kg of weight, administered orally. Glycemia levels are tested initially, and then at 30, 60, 90, 120, 150, and 180 minutes.
The test is stopped in case of hypoglycemia less than 3.0 mmol/L or after 180 minutes, after which venous blood glycemia and insulin levels are tested.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Recommended: for the differential diagnosis of CHI and other conditions accompanied by hypoglycemia, testing additional parameters [19,30–32]:
Test material | Parameter |
|---|---|
Venous blood | • Blood potassium level testing, blood sodium level testing • Blood alanine aminotransferase, aspartate aminotransferase, cholesterol, and total protein testing • Blood cortisol, growth hormone, insulin-like growth factor-1, TSH, and free thyroxine testing |
Capillary blood | • Blood lactic acid (lactate) testing • Blood ammonia testing* • Comprehensive determination of amino acid and acylcarnitine concentrations in blood by tandem mass spectrometry * |
Urine | • Comprehensive determination of organic acid content in urine by tandem mass spectrometry |
* - the sample can be taken from either venous or capillary blood.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: normally, in a child with declining glycemia, insulin and C-peptide should not be detectable in the blood, and ketone bodies should adequately rise, reflecting the normal physiology of gluconeogenesis and glycogenolysis. In CHI during hypoglycemia, insulin has detectable values (i.e., greater than 1.25 µIU/mL), as does C-peptide (greater than 0.5 ng/mL), although formally it may not exceed laboratory reference ranges. Simultaneous testing of C-peptide levels is necessary to exclude iatrogenic hypoglycemia. In the case of sharply elevated insulin levels and undetectable C-peptide levels, iatrogenic insulin administration can be suspected, and blood drug screening by tandem mass spectrometry (identifying hypoglycemic agents) helps exclude the use of oral hypoglycemic drugs. Cortisol levels in patients with CHI can often be relatively low (less than 250 nmol/L), which should not be regarded as adrenal insufficiency [19].
To exclude other potential causes of hypoglycemia (including glycogen storage disorders), testing for free and conjugated bilirubin and alkaline phosphatase in the blood is useful.
Recommended: molecular genetic testing for all patients with CHI, except for children with obvious clinical signs of a transient disease course (small for gestational age, birth asphyxia, etc.). It is recommended to test genes responsible for the development of CHI (KCNJ11, ABCC8, GLUD1, etc.); in addition, specific NGS panels of genes responsible for the development of CHI and/or whole-exome sequencing may be used [19,34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the choice of genetic testing methodology depends on the laboratory's capabilities. The interpretation of genetic test results should be performed by a geneticist and/or pediatric endocrinologist, taking into account all disease characteristics (inheritance pattern, clinical picture, treatment sensitivity, etc.). The inheritance pattern of mutations in ATP-sensitive potassium channel genes determines the morphological form of the disease. It is advisable to perform simultaneous blood collection from both the child and both parents for further verification. The absence of mutations does not rule out a diagnosis of CHI [1,4]. In the presence of characteristic dysmorphic features suggesting a particular syndromic variant of CHI, a geneticist consultation and molecular genetic testing of the corresponding gene are required [1,4,28,34].
2.4 Instrumental Diagnostics
Recommended instrumental diagnostic methods for the differential diagnosis of focal and diffuse forms of CHI. Positron emission tomography with 18F-L-dihydroxyphenylalanine (18F-DOPA PET) is the only diagnostic method that allows visualization of the insulin hypersecretion focus in children with confirmed CHI [34,36-40]. This study is performed in patients with a diazoxide-resistant disease course. 18F-DOPA PET can only be used for the differential diagnosis of focal and diffuse forms (the sensitivity of 18F-DOPA PET ranges from 88 to 94 %, and the specificity is 100 %) [34,36-40]. If the focal form of CHI is confirmed, resection of the insulin hypersecretion area with preservation of normally functioning pancreatic tissue is possible. In the diffuse form of the disease, the options considered are either continuing medical therapy with second- and third-line drugs or performing a subtotal pancreatectomy with the removal of up to 95-98 % of the tissue [34,36-40].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
Comment 1: when preparing patients for the procedure, therapy with insulinostatic drugs (diazoxide, #octreotide**, glucagon**) should be discontinued at least 48 hours before 18F-DOPA PET. Euglycemia is maintained using intravenous infusion of a dextrose** solution. The study is performed under medical sedation. PET data are recorded over a series of time intervals. For objective evaluation, the pancreatic index (PI) is used, which is the ratio of standardized 18F-DOPA uptake levels in different parts of the pancreas, along with visual assessment obtained in 3D reconstruction mode.
Result interpretation: if the PI is less than 1.3 and there is a visually uniform 18F-DOPA uptake, a diffuse form of the disease is more likely; if the PI is greater than 1.5 and there is a visual local increase in 18F-DOPA uptake, a focal form of CHI is more likely. With a PI in the range of 1.3–1.5, 18F-DOPA uptake should be regarded as corresponding to a non-focal, likely atypical form.
The uptake of the 18F-DOPA isotope by beta cells in the diffuse form of CHI will be practically identical to that in a healthy child.
Comment 2: in accordance with Article 13, Clause 5.6 of Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicines", radiopharmaceutical medicinal products manufactured directly by medical organizations in the manner established by the authorized federal executive body are not subject to state registration.
Not recommended are diagnostic methods such as ultrasound, MRI, contrast-enhanced CT, and #fludeoxyglucose [18F] PET, as they do not allow differential diagnosis between the diffuse and focal forms of the disease [32,36-40].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
2.5 Other Procedures
Recommended: urgent intraoperative pathomorphological examination of pancreatic tissue for all patients with confirmed CHI undergoing surgical intervention.
Result interpretation: The diffuse form is established in the presence of a relatively uniform distribution of islets of Langerhans, giant nuclei in 10 % of the beta cells of the endocrine islets, and an increased volume of beta-cell cytoplasm [41]. The focal form of the disease is established in the presence of a focus of confluent islets of Langerhans with a small number of beta cells with giant nuclei and a relatively normal morphological picture of the pancreatic tissue outside the focus [42,43].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comment 1: methodology for performing urgent intraoperative pathomorphological examination: pancreatic tissue taken from foci suspicious for pathology and at the margins of resected areas is stained with hematoxylin and eosin, and its morphological characteristics are evaluated. Depending on the results obtained, the extent of resection may be expanded, with repeated sampling of tissue samples bordering the resected areas, until the border of healthy pancreatic tissue is reached.
Comment 2: this examination of pancreatic tissue must be performed by an experienced specialist.
Recommended: histological examination of pancreatic biopsy material for all patients with confirmed CHI undergoing surgical intervention [19,41-43].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Result of histological examination interpretation: Diffuse form is established in the presence of a relatively uniform distribution of islets of Langerhans, giant nuclei in 10 % of the beta cells of the endocrine islets, and an increased volume of beta-cell cytoplasm [41]. Focal form of the disease is established in the presence of a focus of confluent islets of Langerhans with a small number of beta cells with giant nuclei and a relatively normal morphological picture of the pancreatic tissue outside the focus [42,43]. If the histological picture does not correspond to the two aforementioned forms, an atypical form is diagnosed.
Comment 1: methodology for histological examination of pancreatic biopsy material: pancreatic tissue is stained with hematoxylin and eosin, and immunohistochemical testing is performed using at least 1 of the following antibodies: insulin, Isl1, Nkx2.2, chromogranin A, or type 1 dopamine receptors. In this case, all resected pancreatic tissue undergoes histological examination, whereas only areas suspicious for pathological changes undergo immunohistochemical testing.
Comment 2: histological examination of pancreatic biopsy material must be performed by an experienced specialist. In the absence of pathological changes in the resected pancreatic tissue combined with a recurrence of congenital hyperinsulinism symptoms in the patient, a repeat 18F-DOPA PET-CT is indicated to rule out the presence of congenital hyperinsulinism foci that were not removed during surgery.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
The main objective of CHI treatment is to achieve sustained euglycemia against the background of a normal feeding regimen. It is worth noting that this effect is by no means always achieved, and in such cases, dietary manipulations are possible, such as using carbohydrate-enriched formulas, adding cornstarch to food, and in some situations, gastrostomy to allow continuous nighttime feeding [15,19,22,30,32,33,35].
Given the characteristic of CHI, in which hypoglycemia is hypoketotic, any decrease in blood sugar levels in childhood, even if asymptomatic, can lead to severe neurological complications [19,29]. When monitoring children with CHI, it is recommended to maintain glycemia levels in the range of 3.9–5.6 mmol/L regardless of meal times [34].
3.1 Emergency care for hyperinsulinemic hypoglycemia
Recommended: for emergency care in case of hyperinsulinemic hypoglycemia:
- If the child is conscious and able to drink and eat – 10 % #dextrose solution** (5-15 ml), then feed, establish frequent small meals [30,32,66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
- If hypoglycemia persists or if the child is unconscious:
Recommended: if venous access is available, intravenous administration of 10 % dextrose** solution at 1 ml/kg as a bolus (slowly over 3 min), then establish continuous intravenous infusion of 10 % dextrose** solution at a rate of 3 ml/kg/hour, increasing the rate and/or concentration of the glucose solution according to glycemia levels [30-34,66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Recommended: if venous access is unavailable, administering glucagon** at 0.1 mg/kg (maximum 1 mg) subcutaneously or intramuscularly [30-34,66].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: rebound hypoglycemia may occur with glucagon** administration. As a rule, it develops 60-120 minutes after the injection. Frequent blood glucose monitoring is required after administering glucagon** [19,30-34].
3.2 Infusion therapy with dextrose solution**
Recommended: in the presence of persistent hypoglycemia, initiate continuous intravenous infusion of dextrose**. Initially, it is recommended to use 10% dextrose** and administer it at a rate of 3 ml/kg/h. Adjustment of the rate and concentration of the administered solution should be carried out based on blood glucose levels. Blood glucose monitoring must be performed at least every 3 hours (before feedings). Target blood glucose values are 3.9-5.6 mmol/L [32].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: it should be borne in mind that during CHI, the glucose utilization rate can reach extremely high values (15-20 mg/kg/min); a highly concentrated dextrose** solution (20% or more) may be required to achieve euglycemia. If the solution concentration is more than 12.5%, placement of a central venous catheter is recommended. IMPORTANT! The volume of infusion therapy with dextrose** solutions and the concentration of drugs are determined exclusively by blood glucose levels. Target blood glucose levels for CHI are 3.9-5.6 mmol/L [32,44].
3.3 Medical therapy for CHI
Recommended: using diazoxide as the first-line drug. Children receiving a large volume of dextrose infusion** (more than 200 ml/kg/day) should start treatment with #octreotide** preparations at a starting dose of 5-10 mcg/kg/day, maximum 20 mcg/kg/day, dividing the daily dose into 4 subcutaneous injections and/or with glucagon** [30,32,35,45].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
The main drugs used to treat CHI are given in Table 2 of Appendix A3. Combinations of drugs may be used in the absence of contraindications.
The criterion for the effectiveness of conservative treatment is the ability to achieve stable euglycemia (> 3.5-4 mmol/L) while discontinuing intravenous administration of dextrose** and glucagon**. An additional criterion is the child's ability to tolerate the minimum safe fasting interval appropriate for their age/weight.
Recommended: performing a follow-up fasting test (blood glucose test, blood insulin test, blood C-peptide test upon reaching the standard fasting interval or upon the development of hypoglycemia) during therapy. In the presence of drug-induced compensation, there is an adequate increase in ketone body levels and suppression of insulin secretion during the prolonged fasting interval [4,19,30,32,35].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3.3.1 First-line conservative therapy. Diazoxide.
Recommended to use diazoxide as the first-line therapy for congenital hyperinsulinism [30-34]. The starting dose is 5 mg/kg/day for children with normal or large birth weight and 3 mg/kg/day for infants with intrauterine growth restriction. It is administered orally 2-4 times a day in equal doses. Diazoxide has a cumulative effect. The efficacy of the drug should be assessed no earlier than 3 days after the start of its administration. If there is no effect, the dose may be gradually increased up to a maximum of 20 mg/kg/day. Diazoxide resistance can be diagnosed if there is no effect from maximum therapeutic doses and no earlier than 6 days from the start of treatment. The effective therapeutic dose is selected individually and averages 6-10 mg/kg/day during the first 3 years of life. In older children, the dose does not depend on weight and averages 100-150 mg/day.
The main side effects of diazoxide therapy are:
⮚ Fluid retention in the body; therefore, preventative prescription of diuretics is indicated for all patients. In case of large infusion volumes (more than 200 ml/kg/day), it is advisable to add glucagon** to the infusion prior to starting diazoxide therapy, which will reduce the volume of the administered dextrose** solution and avoid edema.
⮚ Dyspepsia, anorexia, regurgitation, vomiting. These side effects are dose-dependent and in some cases transient. In case of pronounced dysphagia and food refusal, it is advisable to initiate tube feeding.
⮚ Acute pulmonary hypertension is a rare and formidable complication. It is most frequently described in patients with congenital heart disease and intrauterine growth restriction. Echocardiography is indicated for all children before starting therapy and 3-5 days after initiating treatment. In case of acute pulmonary hypertension, diazoxide must be discontinued.
⮚ Hypertrichosis. This side effect manifests within the first 6-12 months of starting therapy. It is dose-dependent and reversible. Diazoxide does not affect androgen secretion, so the phenomena of hypertrichosis do not require additional hormonal evaluation. When used in adolescent children (especially girls), symptoms of hypertrichosis can cause psychological difficulties and lead to decreased compliance.
⮚ Hyperuricemia. More common in older patients. In some cases, it may require discontinuation of therapy.
⮚ Thrombocytopenic purpura. Extremely rare. Requires discontinuation of the drug. After platelet counts normalize, a repeated trial of diazoxide therapy with a change of manufacturer may be considered.
⮚ Leukopenia. Rare. Subclinical in nature. Does not require specific monitoring.
⮚ Hyperglycemia and ketoacidosis. May occur with overdose. In addition, these phenomena can be triggered by acute respiratory viral infections or other infections in patients receiving an adequate dose of diazoxide. Children with CHI are shown more frequent monitoring of blood/urine glucose and ketones during infectious diseases. In case of significant hyperglycemia (greater than 8 on an empty stomach and greater than 10 after meals) and/or ketosis, diazoxide should be discontinued for the duration of the infection [19,32,35,45-50].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: the duration of treatment depends on the form of the disease. If there is reason to assume a transient course (patients with low birth weight for gestational age, Beckwith-Wiedemann syndrome, etc.), a trial discontinuation of treatment is possible after 3-6-12 months (see section "Dynamic Monitoring").
As a diuretic in case of fluid retention, it is preferable to use #hydrochlorothiazide preparations, which have a potentiating effect on diazoxide, during infusion therapy and in the presence of fluid retention syndrome in patients without infusion therapy.
3.3.2 Second-line conservative therapy. Somatostatin and its analogues.
Recommended: therapy with #octreotide** preparations in the absence of an effect from diazoxide or its intolerance. #Octreotide** in patients with CHI is prescribed at a starting dose of 3 mcg/kg/day as divided subcutaneous injections every 6 hours or as a continuous subcutaneous infusion (using an insulin pump). If there is no effect, the dose may be gradually increased. The maximum therapeutic dose is 20 mcg/kg/day [19,30,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Recommended: when using #octreotide**, its continuous subcutaneous administration is recommended, which allows achieving a stable concentration of the drug in the blood and minimizing glycemic variability during the day [19,32,56].
GPP CLE 4Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of Evidence – 4)
Recommended: in patients with the diffuse form and a good response to #octreotide**, switching to long-acting somatostatin therapy (ATX Group Somatostatin and its analogues H01CB) (including #Lanreotide** preparations at a starting dose of 30-35 mg once every 28 days), which significantly improves the quality of life of patients [19,32,52,57].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Among the side effects, the most common are:
⮚ Dyspepsia, diarrhea, steatorrhea, colic.
Recommended: prescribing enzyme preparations in age-appropriate dosages for children over 3 years of age per instructions [19,32,58].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
⮚ Cholelithiasis. More typical for older patients. Rarely occurs in infants in the first year of life.
Recommended: performing follow-up abdominal ultrasound examinations (comprehensive) once every 12 months [19,32,54].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
⮚ Acute necrotizing enterocolitis. A rare and fatal complication. Described only in children in the first days and weeks of life. #Octreotide** is contraindicated in children with a history of necrotizing enterocolitis (NEC) [53,55].
⮚ Decreased growth rate, suppression of growth hormone secretion.
Recommended: regular height measurement, determination of blood insulin-like growth factor 1 during long-term use of #octreotide** [54].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
⮚ Hypothyroxinemia. In rare cases, it may be observed with the use of high doses (15-20 mcg/kg) of #octreotide** [19,32,54].
Recommended: dynamic follow-up determination of blood thyroid-stimulating hormone (TSH) levels and serum free thyroxine (FT4) levels [19,52,54,56,57].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comment: #octreotide** is characterized by tachyphylaxis. In most cases, an increase in glycemia levels is observed at the start of therapy; however, within 1–3 days, the need for infusion therapy may resume.
Surgical treatment of CHI
It is recommended to perform surgical treatment for focal forms in the scope of partial pancreatic resection with the removal of the pathological focus [19,32,58-60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comment: the outcome of the surgery is complete remission of congenital hyperinsulinism.
It is recommended to perform surgical treatment for diffuse pharmacoresistant forms in the scope of subtotal pancreatectomy (95–98%). In diffuse forms, partial resection (70–80%) is possible, which does not achieve a complete cure, but in the postoperative period can be controlled by medications that reduce insulin secretion (diazoxide, #octreotide** in doses specified for the therapy of congenital hyperinsulinism (see above)). The scope of surgical intervention for the diffuse form should be discussed collectively in each specific case [19,32,58-60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comment 1: surgical outcome – in the first years after surgical treatment: euglycemia (50–60%), hypoglycemia (30–40%), diabetes mellitus (10%–20%); in long-term follow-up of more than 10 years – diabetes mellitus up to 95%, exocrine insufficiency [32,58-60].
Comment 2: operations can be performed using either an open (laparotomic) or laparoscopic approach [61]. The surgery must be performed by an experienced surgeon. During the surgery, it is indicated to perform urgent intraoperative pathomorphological examination for additional verification of the morphological form and assessment of the radicality of surgical treatment in the focal form.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
It is recommended to have follow-up by a neurologist, ophthalmologist, and medical speech therapist for all children with congenital hyperinsulinism (given the high risks of neurological complications in patients with neonatal hyperinsulinemic hypoglycemia). The scope and duration of rehabilitation measures are determined by the degree of hypoglycemic CNS damage and are set by the neurologist [19,32,62,63].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
5. Prevention and Dispensary Observation
It is recommended to regularly examine children with congenital hyperinsulinism to assess disease compensation and treatment efficacy. Many researchers have noted that the course of congenital hyperinsulinism becomes milder with age, and in some cases, even complete remission is possible. This primarily applies to children with transient variants (consequences of perinatal asphyxia, syndromic forms of congenital hyperinsulinism). Therapy may be discontinued in such patients within the first 3–12 months of life [2,19,30,64].
Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)
Follow-up care for children with transient mild forms of congenital hyperinsulinism (consequences of intrauterine growth restriction, perinatal asphyxia, syndromic forms):
It is recommended to carry out the following measures:
1. Consultations with specialist physicians at least:
- Consultation with a pediatric endocrinologist – once every 3 months.
- Consultation with a neurologist – once every 3 months.
- Consultation with a pediatrician – once every 3 months.
- Consultation with an ophthalmologist – once every 6 months.
2. Laboratory tests:
- Blood glucose testing every 3 hours for 2–3 days during therapy – once every 3 months.
- Fasting test (blood glucose test, blood insulin test, blood C-peptide test, blood 3-hydroxybutyrate test upon reaching the standard fasting interval or during hypoglycemia) during therapy – at least once every 6 months [19,30,32,65].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to trial discontinuation of diazoxide therapy in the event of a sustained absence of hypoglycemia and a minimal therapeutic dose of the drug (less than 3 mg/kg/day).
3–4 days after complete discontinuation, the child undergoes a fasting test (blood glucose test, blood insulin test, blood C-peptide test, blood ketone bodies test upon reaching the age-appropriate fasting interval or during hypoglycemia).
In the absence of data supporting hyperinsulinism, there is no need for further treatment in such patients [19,30,32,64].
Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)
Follow-up care for children with persistent pharmacosensitive forms of congenital hyperinsulinism:
It is recommended to undergo a comprehensive examination with a frequency of at least once every 3 months in the first year of life, then at least once every 6 months up to 3 years of age, and then (in case of compensation) – at least once a year in the following scope [19,32,65]:
1. Consultations with specialist physicians:
- Consultation with a pediatric endocrinologist;
- Consultation with a neurologist;
- Consultation with a pediatrician;
- Consultation with an ophthalmologist with ophthalmoscopy;
- Consultation with a medical speech therapist.
2. Laboratory tests for patients receiving diazoxide:
- Blood glucose testing every 3 hours for 2–3 days during therapy;
- Control fasting test (blood glucose test, blood insulin test, blood C-peptide test upon reaching the standard fasting interval or during hypoglycemia, blood ketone bodies test) during therapy;
- Complete blood count (CBC) with differential.
- Determination of blood potassium, sodium, and uric acid levels.
2.1. Laboratory tests for patients receiving therapy with somatostatin and its analogues (ATX group: Somatostatin and its analogues H01CB):
- Blood glucose testing every 3 hours for 2–3 days during therapy;
- Control fasting test (blood glucose test, blood insulin test, blood C-peptide test upon reaching the standard fasting interval or during hypoglycemia, blood ketone bodies test) during therapy;
- Complete blood count (CBC) with differential;
- Determination of blood alanine aminotransferase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase levels;
- Blood thyroid-stimulating hormone (TSH) test, free thyroxine test, and insulin-like growth factor 1 (IGF-1) level test.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: drug dose adjustments should be primarily based on glycemic parameters and examination results, rather than being calculated solely.
During puberty, disease decompensation and reduced drug compliance may occur, which requires closer monitoring of children and, in some cases, psychological support.
3. Instrumental examinations:
- Abdominal ultrasound (comprehensive) (for patients receiving therapy with somatostatin and its analogues (ATX group: Somatostatin and its analogues H01CB));
- Brain MRI (per the recommendation of a neurologist and/or ophthalmologist);
- Echocardiography (for patients receiving diazoxide therapy, at least once a year);
- Electroencephalography (per the recommendation of a neurologist).
Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)
Follow-up care for children after subtotal pancreatectomy [32,68,69]:
It is recommended to undergo examination at least once every 3 months in the first year of life, then at least once every 6 months up to 3 years of age, and then (in case of compensation) – at least once a year, in the following scope:
1. Consultations with specialist physicians:
- Consultation with a pediatric endocrinologist;
- Consultation with a gastroenterologist;
- Consultation with a pediatrician.
2. Laboratory tests – a comprehensive examination for the development of insulin-dependent diabetes mellitus (blood glucose level test, glycated hemoglobin (HbA1c) test, glucose tolerance test) and assessment of exocrine pancreatic function (coprological examination, fecal pancreatic elastase-1 activity determination).
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
6. Organization of Medical Care
Indications for hospitalization in a medical organization:
1) newly diagnosed hypoglycemia in a child for the purpose of examination and diagnosis clarification;
2) hypoglycemia in patients with congenital hyperinsulinism accompanied by seizures/loss of consciousness for acute management and selection/adjustment of therapy;
3) surgical treatment of congenital hyperinsulinism;
4) planned hospitalization of patients with congenital hyperinsulinism for control tests to adjust ongoing therapy.
Indications for patient discharge from a medical organization:
1) presence of clinical, laboratory, and pharmacological compensation based on examination results;
2) presence of clinical and laboratory remission of the disease based on examination results.
7. Additional Information
No additional information available.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1. | Continuous glucose monitoring was performed over 24 hours in patients with suspected congenital hyperinsulinism. | Yes/no |
2. | A fasting test was performed (blood glucose test, blood insulin test, blood C-peptide test, blood or urine ketone test at the end of the fasting interval or upon reaching hypoglycemia and/or ketonemia > 1.8 mmol/L) when congenital hyperinsulinism was suspected. | Yes/no |
3. | Infusion therapy with dextrose solution** was performed to achieve euglycemia in patients with newly diagnosed congenital hyperinsulinism. | Yes/no |
4. | Specific insulinostatic therapy (diazoxide and/or drugs from the somatostatin and its analogues group and/or glucagon**) has been prescribed to patients with a confirmed diagnosis of congenital hyperinsulinism. | Yes/no |
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Appendix A1. Working Group Composition
DIRECTORS
Valentina Aleksandrovna Peterkova – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Director of the Institute of Pediatric Endocrinology at the Academician I. I. Dedov National Medical Research Center for Endocrinology of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology at the Institute of Higher and Continuing Professional Education of the Academician I. I. Dedov National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Russian Ministry of Health.
Olga B. Bezlepkina – MD, PhD, Professor, Deputy Director of the Center – Director of the Institute of Pediatric Endocrinology, 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, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
TEXT AUTHORS:
Anna V. Bolmasova – PhD in Medical Sciences, Senior Research Fellow at the Department of Hereditary Diseases and Early-Age Endocrinopathies, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Eda A. Yanar – PhD in Medical Sciences, Research Fellow at the Department of Hereditary Diseases and Early-Age Endocrinopathies, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Irina L. Nikitina – MD, PhD, Head of the Research Laboratory of Pediatric Endocrinology, Scientific Advisor of Pediatric Department No. 2, Head of the Department of Children's Diseases at the Institute of Medical Education of the Almazov Centre, Member of the Profile Commission on Pediatric Endocrinology of the Russian Ministry of Health.
Anna A. Kolodkina – PhD in 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.
Sofia M. Mikhalina – Pediatric Endocrinologist at 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.
EXPERTS:
Irina L. Alimova – MD, PhD, Professor, Head of the Department of Hospital Pediatrics with a Course in Neonatology of Continuing Professional Education, Smolensk State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Smolensk Region.
Elena B. Bashnina – MD, PhD, 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.
Nina V. Bolotova – MD, PhD, Professor at the Department of Propaedeutics of Children's Diseases, Pediatric Endocrinology and Diabetology, Saratov State Medical University named after V.I. Razumovsky of the Russian Ministry of Health.
Galina A. Galkina – MD, PhD, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics of the 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.
Liliya V. Ditkovskaya – PhD in Medical Sciences, Associate Professor, Associate Professor at the Department of Children's Diseases named after Professor I.M. Vorontsov, Faculty of Postgraduate and Continuing Professional Education, Pediatric Endocrinologist at the Clinic of Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.
Aleksey V. Kiyaev – MD, PhD, 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.
Tatyana V. Kovalenko – MD, PhD, Professor, Head of the Department of Pediatrics and Neonatology, Izhevsk State Medical Academy of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Republic of Udmurtia.
Irina B. Kostrova – 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 – MD, PhD, Professor at the Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Privolzhsky (Volga) Federal District.
Elena V. Nagaeva – MD, PhD, Head of the Department of Thyroidology, Somatic and Reproductive Development Disorders, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Elena E. Petryaykina – MD, PhD, 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.
Galina N. Svetlova – PhD in Medical Sciences, Deputy Chief Physician, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Pediatric Endocrinologist.
Tatyana E. Taranushenko – MD, PhD, Head of the Department of Pediatrics, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Krasnoyarsk Krai, Chief freelance pediatric endocrinologist of the Siberian Federal District.
Elena B. Khramova – MD, PhD, Professor, Head of the Department of Children's Diseases, Pediatric Faculty, Tyumen State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Health Department of the Tyumen Region.
Igor S. Chugunov – PhD in 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.
Conflict of interest: the authors of the clinical guidelines declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Methods used for collecting/selecting evidence: electronic database search.
Description of methods used for evidence collection/selection: publications included in the Cochrane Library, EMBASE, MEDLINE, and PubMed databases served as the evidence base for the guidelines. The search depth was 15 years.
Methods used for assessing the quality and strength of evidence: expert consensus; significance assessment in accordance with a rating scheme.
Methods used to analyze evidence: reviews of published clinical trials and systematic reviews.
Target audience for these clinical guidelines:
Pediatric endocrinologists;
Pediatricians;
Neonatologists.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for grading levels of clinical persuasiveness of recommendations (LCPR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
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.
The decision to update is made by the Russian Ministry of Health based on proposals submitted by non-profit medical professional organizations. The formulated proposals must take into account the results of a comprehensive assessment of drugs and medical devices, as well as the results of clinical approbation.
Appendix A3. Reference Materials
Current instructions for medicinal products mentioned in the clinical guidelines are available at http://grls.rosminzdrav.ru
Order of the Ministry of Health of the Russian Federation No. 583n dated October 29, 2024, "On Approval of the Procedure for Providing Medical Care in the Profile of 'Pediatric Endocrinology'".
Table 2.
Appendix B. Physician Action Algorithms
Algorithm for the management of patients with congenital hyperinsulinism, taking into account clinical and genetic features
Appendix C. Patient Information
Parents/guardians of all patients with CHI must be proficient in blood glucose testing using a portable glucometer. Clear instructions must be provided regarding the frequency of glycemic measurements and target blood sugar levels.
Parents should be informed about the potential clinical manifestations of hypoglycemia in children of different ages.
The home medicine cabinet must store hyperglycemic agents for emergency use:
- Dextrose** solution (10%), which can be administered orally, is used if the child has hypoglycemia and is conscious. It is important to warn parents against attempting parenteral administration of glucose solution on their own, as intramuscular injections of highly concentrated solutions can lead to local complications.
- Dextrose** tablets (for oral use), used if the child has hypoglycemia and is conscious.
- Glucagon** solution for intramuscular or subcutaneous injection. Can be used in severe hypoglycemia with loss of consciousness. Training in reconstitution and injection techniques is required.
Upon admission of the child to kindergarten or school, it is necessary to inform the teacher/educator/nurse about their condition and the methods for treating hypoglycemic states.
Parents should be informed that in the event of intercurrent illnesses accompanied by diarrhea, vomiting, and food refusal, hypoglycemia may worsen and develop even during ongoing treatment. If such conditions develop, hospitalization for supportive infusion therapy with dextrose** solutions may be indicated for children with CHI.
All patients with CHI are advised to wear a medical ID bracelet indicating their name, emergency medical care recommendations, and a trusted contact's phone number.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Specific questionnaires have not been developed and are not used.