Cholelithiasis: Clinical Guidelines

List of Abbreviations

MA – malformations

MABT – malformations of the biliary tract

ATC – Anatomical Therapeutic Chemical classification

AC – acalculous cholecystitis

BS – biliary sludge

BT – biliary tract

NAG – ATC group "Other analgesics and antipyretics"

DHBSG – dynamic hepatobiliary scintigraphy

SOD – sphincter of Oddi dysfunction

BD – bile ducts

BA – bile acids

CHL - cholelithiasis

GB - gallbladder

HDL – high-density lipoproteins

LDL - low-density lipoproteins

VLDL - very low-density lipoproteins

medicamentos – medications

LDH – lactate dehydrogenase

PT – physical therapy

MRI – magnetic resonance imaging

MRCP - magnetic resonance cholangiopancreatography

NSAIDs – ATX group "Non-steroidal anti-inflammatory and antirheumatic products"

TG – triglycerides

UDCA – ursodeoxycholic acid**

US – ultrasound examination

PL – phospholipids

Chol – cholesterol

ERCP – endoscopic retrograde cholangiopancreatography

Terms and Definitions

Cholelithiasis (CHL) is a dystrophic and dysmetabolic disease of the hepatobiliary system caused by impaired cholesterol and/or bilirubin metabolism and characterized by the formation of calculi in the biliary tract.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Cholelithiasis (CHL) is a dystrophic and dysmetabolic disease of the hepatobiliary system caused by impaired cholesterol and/or bilirubin metabolism and characterized by the formation of calculi in the biliary tract.

When stones form in the gallbladder, it is referred to as "cholecystolithiasis"; in the common bile duct, as "choledocholithiasis"; and in the intrahepatic ducts, as "intrahepatic cholelithiasis".

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

Cholelithiasis in both adults and children is a multifactorial disease. [6,7,13,16,17]

The cause of stone formation is an excessive concentration of bile.

There are two main types of stones [4,6,7,16]:

1. Cholesterol stones. Their cholesterol content is >50%. They also contain bile pigments, calcium salts, and a matrix consisting of mucus glycoproteins. The stones are usually large and single.

2. Pigment stones. They consist predominantly of calcium bilirubinate and complexes of calcium and mucus glycoproteins. In turn, they are divided into 2 subtypes: a) black stones (consisting predominantly of calcium bilirubinate, usually multiple, <5 mm in size). Their cholesterol content is <20%. The formation of black stones is most characteristic of hemolysis and liver cirrhosis; b) brown stones (consisting of calcium salts of unconjugated bilirubin, mucin glycoproteins, cholesterol, calcium palmitate, and stearate; soft, layered, radiolucent). Their cholesterol content is 20-50%. Inclusions of bacterial components may be found in the core of the stone.

Among the various causal factors contributing to the development of CHL in childhood, nutritional disorders are of no small importance. The risk of calculus formation in the biliary tract increases significantly even at an early age, even with relatively minor nutritional disorders. It is no coincidence that a balanced diet, including breastfeeding, is the cornerstone for preventing the development of CHL in children. Natural feeding helps reduce the risk of hyperlipidemia, hyperinsulinemia, and obesity. Taurine, contained in human milk, improves lipid absorption, increases bile acid secretion, reduces cholesterol secretion, and also has a protective effect against the formation of cholesterol stones [6, 7, 16]. CHL occurs in 20% of children with obesity and metabolic syndrome. An elevated fasting insulin level (a marker of insulin resistance [IR], the main criterion of MS) is a risk factor for CHL. The risk of developing CHL in children with DM increases by 3 times. [30,31].

Of particular importance is the impairment of the detoxification function of the microbial flora of the digestive tract. The overgrowth of anaerobic bacteria, caused by the physiological immaturity of the digestive tract in childhood, disrupts bile acid metabolism. The latter are metabolized not to tertiary (ursodeoxycholic), but to secondary bile acid (deoxycholic). Deoxycholic acid, upon absorption, returns to the liver. Its excess contributes to the formation of pigment gallstones [1,6,7,14,16].

One cannot underestimate the adverse effects of xenobiotics, medications, biologically active substances, and the deteriorating quality of drinking water, which contributes to the accumulation in the body of heavy metal salts and organic and inorganic substances that directly or indirectly affect various organs and systems, including the liver and biliary tract [6,7,16].

In children, impaired cholesterologenesis is often caused not by excessive hepatic cholesterol (Chol) production, but by impaired its utilization from the intestine. This is facilitated by various dyskinetic disorders of the digestive tract, as well as impaired absorption of individual food components - proteins, fats, and carbohydrates. Changes in cavitary and membrane digestion processes lead to the saturation of bile with cholesterol even when its normal production in the liver occurs [1,2,6,7,10,16].

The formation of cholesterol gallstones is promoted by impaired cholesterol transport (Fig. 1).

Fig. 1 - Pathogenesis of cholesterol lithiasis.

The necessary conditions for stone formation are [4,6,16]:

1. Supersaturation of bile with Chol. This is a necessary, but not sufficient condition for stone formation. In most cases, the time bile spends in the GB is not long enough for the precipitation and growth of Chol crystals.

2. Nucleation of Chol monohydrate crystals. Nucleation is promoted by mucins and non-mucin glycoproteins (in particular, immunoglobulins), while apolipoproteins A-I, A-II, and certain other glycoproteins inhibit it. Nucleation of the Chol monohydrate crystal and its growth occurs in the mucin gel layer. The coalescence of vesicles forms liquid crystals, which then turn into solid crystals. Further growth occurs due to the sedimentation of Chol-supersaturated lamellar structures and vesicles.

3. Decreased GB motility – due to reduced sensitivity to cholecystokinin and/or autonomic neuropathy. In many patients with CHL, GB motility is reduced.

The formation of pigment stones is more often observed in individuals of Asian descent, in chronic hemolysis, bacterial contamination of the biliary tract, diseases involving the ileum (in particular, Crohn's disease), cystic fibrosis, liver cirrhosis, and Gilbert syndrome.

In biliary tract infections, under the influence of bacterial ß-glucuronidase, bilirubin is deconjugated, becomes insoluble, and is incorporated into stones. In hemolysis, the excretion of conjugated bilirubin into bile increases, after which it undergoes deconjugation in the biliary tract under the influence of endogenous glucuronidase. The formation of pigment stones is also promoted by impaired function of the GB epithelium in maintaining bile pH and forming bilirubin salts, as well as the production of phospholipase A by bacteria, which catalyzes the hydrolysis of bile PLs to lysolecithin and fatty acids involved in the formation of the pigment stone matrix [4,12].

Main risk factors for the development of CHL in childhood [4,6,16, 21]:

1) Age. The incidence of CHL clearly correlates with age (more frequent in adolescence).

2) Female sex. The risk of developing CHL in women is 2-3 times higher, which is associated with the effect of estrogens on lithogenic potential.

3) A family history of CHL (increases the risk by 4-5 times).

4) Overweight and obesity. Among children with metabolic syndrome, CHL is detected in 20% of cases.

5) Diabetes mellitus (increases the risk by 3 times).

6) Liver diseases (cirrhosis) (increases the risk by 10 times).

7) Use of medications that affect cholesterol concentration in bile, biliary motility, or are capable of crystallization in bile (ceftriaxone**).

8) Rapid weight loss (probability of developing CHL >30%).

9) Lesions of the terminal ileum (Crohn's disease).

10) Prolonged (more than 4 weeks) parenteral nutrition.

11) Congenital microspherocytosis and sickle cell anemia.

Rarer causes also predisposing to the development of CHL include: primary sclerosing cholangitis, Wilson disease (hepatolenticular degeneration), urolithiasis, congenital nephrotic syndrome, hypothyroidism, Down syndrome, cystic fibrosis, and Gaucher disease [83]

The mechanisms of gallstone formation in the presence of certain risk factors for CHL are presented in Table 1 [4].

Table 1 - Factors predisposing to gallstone formation.

One of the factors in stone formation is an altered ratio of cholesterol, phospholipids, and bile acids due to hereditary features in the activity of enzymes controlling the synthesis and transport of these components (Table 2) [4].

Table 2 - Changes in the ratio of cholesterol, phospholipids, and bile acids in bile in the presence of genetic alterations in the activity of enzymes controlling cholesterol metabolism and transport.

Genetic predisposition to cholelithiasis.

Currently, the genetic determinism of cholelithiasis is recognized by both domestic and foreign researchers. A relationship with the inheritance of a specific HLA genotype has been identified. The risk group for stone formation includes children carrying HLA antigens: (Ag) B12 and/or B18, in combination with antigens of the CW4; A9; A11; A19 loci. If a child has a single locus B antigen (B12 or B18), the risk of developing the disease is 30%; with a combination of these antigens, it increases to 70%. In addition, cholelithiasis in children shows a persistent tendency of maternal-line inheritance with a recessive inheritance pattern. For genetically determined factors to manifest as disease, the presence of promoters—factors that trigger the manifestation of cholelithiasis—is necessary [1, 6, 16].

It should be noted that in each specific case, the process of gallstone formation is slow, and pathophysiological disturbances consist of supersaturation of bile with sediment.

It should be noted that there are no significant sex differences in the heritability of cholelithiasis. It has been established that genetic predisposition accounts for 25% of the total risk of gallstone formation [84]. Using a mouse model, it was described that the Lith1 and Lith2 genes may play a role in gallbladder stone formation: the Lith1 gene is involved in hepatic cholesterol hypersecretion, and the Lith2 gene regulates bile flow. In humans, the functional analogues of the murine Lith1 and Lith2 genes are the ABCG5 and ABCG8 genes, which show significant expression in hepatocytes and intestinal cells [85]. Gallbladder stones are increasingly common in children. The genetic cause of prevalent lithiasis in children remains unknown. However, it has been shown that the p.D19H variant in the ABCG8 gene and, to a lesser extent, the p.V1296V rs217434 variant in the NPC1L1 gene increase the risk of gallbladder stone formation in children and adults. The predisposition to cholesterol stone formation is associated with impaired cholesterol metabolism resulting from its accelerated transport or reduced intestinal absorption combined with increased synthesis [86]. It was previously reported that microRNA-223 plays an important role in hepatic cholesterol homeostasis. However, its role in regulating biliary cholesterol secretion and gallstone formation remains insufficiently studied. It is known that microRNAs (miRNAs) regulate gene expression. It has been shown that microRNA-223 (miRNA-223) can prevent gallstone formation in mice fed a lithogenic diet by directly targeting the ABCG5 and ABCG8 genes. To date, no studies have been published evaluating the effect of microRNA-223 (miRNA-223) on the development of cholelithiasis in humans [87].

It is known that cholelithiasis is associated with increased biliary cholesterol secretion and low serum phytosterol levels. Nissinen et al. determined the ABCG8 gene D19H polymorphism, serum cholesterol, non-cholesterol sterols, and lipids in 66 children who developed cholelithiasis later in life and in 126 control children. In the first group, 22.7% of patients carried the lithogenic D19H variant of the ABCG8 gene and had decreased phytosterol levels, whereas in the control group this percentage was 19.0%. According to this study, low phytosterol levels in childhood contributed to the onset of cholelithiasis in adults who were carriers of the D19H risk variant of the ABCG8 gene. Furthermore, the rs41279633 and rs2174340 variants of the NPC1L1 gene had a minor effect on non-cholesterol sterols [88].

Low-phospholipid associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, remains poorly understood. In one study, the ABCB4 gene was analyzed, showing that pathogenic variants in the ABCB4 gene can lead to low-phospholipid associated cholelithiasis (LPAC) - a hypophospholipid-associated cholelithiasis defined by the presence of symptomatic and recurrent cholelithiasis (including after cholecystectomy) in young patients with evidence of intrahepatic micro- or macrolithiasis, or common bile duct lithiasis based on liver ultrasound [89].

Pathogenic variants in the ABCB4 gene can also lead to other phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, and intrahepatic cholestasis of pregnancy. In a retrospective analysis of 26 pediatric patients with pathogenic variants in the ABCB4 gene, cholelithiasis was diagnosed in 15% of patients, while in adults this rate was higher (67% of patients) [90].

In another study involving 35 children with idiopathic cholelithiasis meeting the clinical criteria for low-phospholipid associated cholelithiasis (LPAC) syndrome (OMIM #600803), a potentially pathogenic variant c.2318G>T of the ABCB4 gene was detected in only one case. This phenomenon may be explained by sexual immaturity preventing the manifestation of LPAC [91].

The etiology of gallstones may involve a deficiency of the NTCP protein, which is encoded by the SLC10A1 gene, and bile acid metabolism disorders caused by NTCP deficiency predispose to gallstone formation [92].

Studies have also identified pathogenic variants in the ATP8B1, ABCB11, ABCB4, and TJP2 genes as a cause of cholestasis. Multifactorial analysis showed that pruritus was a major factor associated with the presence of pathogenic variants in these genes. Pathogenic variants in genes responsible for PFIC (progressive familial intrahepatic cholestasis) can be observed in a significant number of cases in both children and adults with cryptogenic cholestasis, including in the heterozygous state. The presence of this condition should always be suspected, especially in the presence of pruritus [93].

Patients with cholesterol stones showed decreased levels of plant sterols (campesterol and sitosterol) and increased levels of cholesterol precursors not only compared to healthy individuals but also compared to children with pigment stones, which explains the higher cholesterol content in cholelithiasis [94].

In another study, children with cholesterol stones had a low rate of cholesterol absorption and preserved cholesterol metabolism homeostasis. The black pigment stone group was characterized by impaired cholesterol metabolism and accumulation of cholestanol, campesterol, and sitosterol in serum and stones, indicating their involvement in the pathogenesis [95].

Relatively low levels of phytosterols and cholestanol were observed in children who developed gallstones in adulthood, which can be used as a prognostic marker for the development of cholelithiasis [96].

Cholangitis and chronic cholecystitis in children are most commonly associated with cholelithiasis, but can also occur without it. The initiating factor is believed to be bile sludge, often consisting of cholesterol crystals and/or calcium bilirubinate, which promotes stone formation and inflammation. These processes lead to chronic obstruction, decreased contractility, and biliary stasis, which further contributes to inflammation of the gallbladder wall and bile ducts. Biliary stasis can also promote bacterial overgrowth, usually Escherichia coli and enterococci, which can irritate the mucosa and intensify the inflammatory response.

Chronic acalculous cholecystitis is less studied, but it can result from functional insufficiency of the gallbladder, leading to spasm and the inability to properly empty the gallbladder contents, causing chronic biliary stasis [105].

1.3 Epidemiology of the Disease or Condition

Gallstone disease is characterized by a fairly high prevalence in countries with a Western lifestyle (Europe, North America, Russia): this disease is recorded with a frequency of 10-20%. Such a high frequency, in addition to the important contribution of genetic factors, is explained by dietary characteristics with the consumption of large amounts of simple carbohydrates. In Africa, Asian countries, and Japan, the prevalence of gallstone disease is lower at 3.5-5% [4].

The male-to-female morbidity ratio is 1:3. In recent decades, there has been an increase in the frequency of gallstone disease in children and adolescents, which is associated with the increased availability of ultrasound examination [19, 26, 27]. There are no official statistics on the prevalence of gallstone disease in the general pediatric population of Russia. Gallstone disease in children is rare: the prevalence is 0.13-0.22% [25]. Children with obesity are more frequently affected [21, 22, 23].

Among children under 7 years of age, boys are affected 2 times more often than girls. At the age of 7 to 9 years, the male-to-female ratio becomes 1:1, at 10-12 years – 1:2, and in adolescence – 1:3 [6, 16].

The epidemiology of chronic cholecystitis and cholangitis in children has not been studied in detail; nevertheless, according to available data, these conditions in children predominantly occur in association with gallstone disease [97, 98, 105].

1.4 Features of Coding the Disease or Condition

Gallstone disease [cholelithiasis] (K80):

K80.0 — Calculus of gallbladder with acute cholecystitis

K80.1 — Calculus of gallbladder with other cholecystitis

K80.2 — Calculus of gallbladder without cholecystitis

K80.3 — Calculus of bile duct with cholangitis

K80.4 — Calculus of bile duct with cholecystitis

K80.5 — Calculus of bile duct without cholangitis or cholecystitis

K80.8 — Other forms of cholelithiasis

K81.1 – Chronic cholecystitis

K82.8 – Other specified diseases of gallbladder

K83.0 – Cholangitis

K83.8 – Other specified diseases of biliary tract

K83.9 – Disease of biliary tract, unspecified

1.5 Classification of the disease or condition

There is no universally accepted classification for children. The classification adopted by the Congress of the Scientific Society of Gastroenterologists of Russia in 2002 may be used, which distinguishes 4 stages of the disease (Table 3) [1,6,13,16].

Table 3 - Classification of cholelithiasis.

Stage I – initial, or pre-calculous:

• thick, heterogeneous bile;

• formation of biliary sludge (BS) with microcolits;

• formation of biliary sludge with putty-like bile (PLB);

• formation of biliary sludge with microcolits and putty-like bile.

Stage II – gallstone formation:

• localization;

• number of calculi;

• composition;

• clinical course.

Stage III – stage of chronic recurrent calculous cholecystitis.

Stage IV – stage of complications.

1.6 Clinical presentation of the disease or condition

In children, several variants of the clinical picture of cholelithiasis can be distinguished [6,7,16]:

• latent course (asymptomatic gallstone carriage);

• painful form with typical biliary colic;

• dyspeptic form;

• masking other diseases.

Asymptomatic gallstone carriage is implied when calculi in the gallbladder (ducts) are an incidental diagnostic finding in asymptomatic children. This clinical stage of cholelithiasis can last from several months to several years and accounts for 80%.

The painful form deserves special attention in children, in whom an "acute abdomen" attack resembles biliary colic in the character of its clinical manifestations. In most cases, the attack is accompanied by reflexive vomiting, and in rare cases, by icterus of the sclera and skin, and acholic stools. Yellowish discoloration of the skin and visible mucous membranes is not typical for children with cholelithiasis. If they appear, impaired bile passage can be suspected, and with the simultaneous presence of acholic stools and dark urine – obstructive jaundice. Attacks of typical biliary colic occur in 0.5–0.7% of children with cholelithiasis.

The pain is preceded by fatty food intake or physical exertion. Early pain occurs immediately after dietary indiscretions and is paroxysmal in nature. It is usually associated with impaired bile passage into the duodenum due to concomitant developmental anomalies, as well as dysfunctions of the digestive system sphincters. Late pain, conversely, tends to be dull and aching, and is mainly caused by concomitant diseases of the upper gastrointestinal tract (gastroduodenitis, peptic ulcer disease, etc.) [6,7,16, 20].

The dyspeptic form is the most frequent clinical manifestation of cholelithiasis in childhood. The variety of dyspeptic manifestations in cholelithiasis can be explained by the features of autonomic dysfunctions. The most frequent clinical manifestations of vagotonia in children with cholelithiasis include: headache, predisposition to allergic reactions, skin marbling, pronounced vascular pattern, diffuse red dermographism, intolerance to stuffy rooms, motion sickness, hyperhidrosis, sinus arrhythmia with a tendency to bradycardia, nausea, hyperventilation, and tissue pastosity. Among sympathicotonic signs, the following predominate: pallor and dryness of the skin, predisposition to tachycardia, white or pink dermographism, palpitations, and restless sleep. Virtually all children experience impaired activity of the digestive tract sphincter apparatus in the form of duodenogastric and gastroesophageal refluxes, which are combined with diseases of the esophagus, stomach, and duodenum. All of this accounts for the variety and non-specificity of dyspeptic manifestations in children with gallstone disease.

Thus, the clinical picture of gallstone disease in children lacks the characteristic symptoms observed in adults during exacerbations of calculous cholecystitis [16, 19, 20].

Cholangitis and chronic cholecystitis may have no clinical manifestations or may present with recurrent acute episodes of obstruction. Due to the increasing incidence of cholelithiasis and the disproportionately high need for surgical intervention in the pediatric population, cholecystitis should be considered in the differential diagnosis of a child with jaundice or right upper quadrant abdominal pain.

Calculous cholecystitis usually occurs in children with a pre-existing systemic disease and therefore may be masked by other conditions and the use of analgesic therapy. The possibility of cholecystitis should be considered in diagnostics if the child has a systemic infection and multiple risk factors [97,98, 105, 106].

In the presence of signs of primary sclerosing cholangitis, which may be one of the extraintestinal manifestations of inflammatory bowel diseases, see the relevant clinical guidelines.

2. Diagnostics, medical indications and contraindications for diagnostic methods

In 95% of cases, cholelithiasis in children is asymptomatic. Chronic cholecystitis and/or cholangitis in most cases manifest with acute and/or chronic pain.

An important symptom is periodically occurring pain in the right hypochondrium.

Yellowish discoloration of the skin indicates a complication of cholelithiasis—choledocholithiasis.

The main diagnostic criterion for cholelithiasis is the detection of calculi during ultrasound examination of the gallbladder and bile ducts.

2.1 Complaints and Anamnesis

Symptoms in children with cholelithiasis at the stage of formed gallstones are not as typical as in adults. This is due to the fact that the presence of calculi in the biliary tract in children is not accompanied by an acute inflammatory process in the gallbladder that causes the classic symptoms of calculous cholecystitis/cholangitis.

When taking the history of present illness, it is necessary to pay attention to:

- the presence of pain, its cause, frequency of attacks, duration and intensity, relationship with food intake (spicy, fatty, fried food);

- localization of pain, its radiation, intensity, and character;

- presence of nausea, vomiting and its character, whether vomiting brought relief;

- changes in stool character (acholic stools, bowel dysfunction, constipation, diarrhea, flatulence).

A history of fever, pale stools, dark urine, jaundice, and skin pruritus is characteristic of cholelithiasis complications. When taking the medical history, it is necessary to pay attention to the combination of cholelithiasis with obesity, diabetes mellitus, etc. A hereditary predisposition should be investigated.

2.2 Physical Examination

When examining the patient, the general condition should be assessed: general appearance, skin color (pallor, cyanosis, jaundice), and changes in the color of mucous membranes (scleral icterus).

Special attention is paid to the examination of the abdomen, its protrusion, retraction, and the degree of participation of the abdominal wall in the act of respiration. Intensification or appearance of pain during abdominal straining or coughing is noted. Superficial palpation reveals muscle guarding and hyperesthesia zones.

During abdominal palpation, special attention is paid to palpating the liver and gallbladder. Before palpating the liver, its percussive borders are determined, then the lower edge of the liver is examined, a possible increase in the size of the gallbladder is established, and the presence of "point" and "gallbladder" symptoms (Murphy's sign) is assessed.

At the same time, the diagnostic value of the so-called "point" symptoms (Jonáš, Riedel, Lyakhovitsky, Kharitonov, etc.) in childhood is low. "Gallbladder" symptoms such as Grekov-Ortner, Kerley (Kera), and Mussy are also rarely detected. Hepatomegaly is likewise not typical for children with cholelithiasis. A moderate percussive enlargement and palpatoric protrusion (by 1-2 cm) of the liver edge along the right midclavicular line is possible in case of impaired bile outflow [6,7,16].

2.3 Laboratory Diagnostics

In the absence of cholelithiasis complications, chronic cholecystitis, and cholangitis, no significant deviations from the norm are observed in laboratory tests. Changes may be caused by diseases frequently comorbid with cholelithiasis.

(LoE – C, GoR – 5)

Comment: the test is performed during initial diagnosis and in case of suspected cholangitis and choledocholithiasis; during dynamic monitoring, the frequency is determined individually.

The test is part of a general therapeutic blood biochemistry panel.

(GoR – C, LoE – 5)

Comments: Pigment stone formation is more frequently observed in chronic hemolysis, bacterial contamination of the biliary tract, diseases affecting the ileum (in particular, Crohn's disease), cystic fibrosis (mucoviscidosis), liver cirrhosis, and Gilbert's syndrome.

The test is performed during initial diagnosis and in case of suspected cholangitis and choledocholithiasis, and subsequently during dynamic monitoring; the frequency is determined individually.

The test is part of a general therapeutic blood biochemistry panel.

(UCSR – C, UDS – 5)

Comment: Biochemical parameters may have certain diagnostic value when clarifying the composition of gallstones: if changes in the lipid complex are registered, the calculi are more likely to be cholesterol stones; if signs indicative of cholestasis are detected, bilirubin calculi are more frequently identified.

The level of total blood cholesterol (study of blood cholesterol level) in children with cholelithiasis is at the upper limit of age norms and/or slightly exceeds it. Blood triglyceride levels change to a greater extent (study of blood triglyceride levels). Total lipid levels decrease, while triglycerides, on the contrary, increase. Children with cholelithiasis show an increase in total lipids, as well as low-density lipoproteins (LDL) (study of low-density lipoprotein cholesterol level) and very low-density lipoproteins (VLDL) (study of blood lipoprotein levels). A simultaneous increase in triglycerides, unesterified fatty acids, and phospholipids indicates a pronounced disorder of bile acid metabolism.

Of decisive importance for calculus formation is not so much the level of total cholesterol itself, but dyslipoproteinemia—an increase in the LDL and VLDL fractions and a decrease in the high-density lipoprotein (HDL) fraction. Dyslipidemia and elevated insulin levels may be a manifestation of metabolic syndrome in obese children.

The test is performed during initial diagnosis—selectively, when cholesterol stones are suspected (study of blood cholesterol level), and in doubtful cases additionally—study of low-density lipoprotein cholesterol level, blood lipoprotein levels, high-density lipoprotein cholesterol level, blood triglycerides. In dynamic monitoring, tests are performed as needed, with the frequency determined individually.

(UCSR – C, UDS – 4)

2.4 Instrumental Diagnostics

(UCSR – C, UDS – 4)

Comments: Complex ultrasound examination of the abdominal organs is a screening method for detecting gallstones in the biliary system and assessing the structure of the gallbladder. Ultrasound assesses the structure of the gallbladder, its contents, the presence of calculi, the size and contents of the common bile duct (choledochus), and the state of the pancreas.

The examination can be performed during dynamic monitoring; the frequency is determined individually.

In the presence of calculi, functional tests evaluating the contractile function of the gallbladder are not performed due to the lack of diagnostic significance and the potential risk of complications [38].

(UCSR – C, UDS – 4)

Comments: MRCP and endoscopic ultrasound (endosonography of the pancreatobiliary zone) are indicated if ultrasound does not detect stones in the bile ducts, but there are indirect signs of choledocholithiasis (dilation of the common bile duct diameter, elevated alanine aminotransferase and aspartate aminotransferase activity, blood free and conjugated bilirubin level testing, blood alkaline phosphatase activity determination, blood gamma-glutamyl transferase activity determination) [40, 41],

In children, MRCP is preferred in most cases as a less invasive examination [107].

• Depending on the indications, dynamic hepatobiliary scintigraphy is recommended—determining the functional capacity of the liver, gallbladder, and sphincters of the biliary system during cystic duct obstruction to diagnose a "non-functioning" gallbladder [4, 6, 7, 9, 10, 16, 20, 29].

(LoE – C, GoR – 5)

Comments: The diagnostic algorithm in children with cholelithiasis is represented by a set of introscanning studies that complement each other in diagnostic value. To choose the therapeutic strategy, all three examinations can be performed if necessary.

Hepatobiliary scintigraphy, due to the continuous recording of the kinetics of bile labeled with a radiopharmaceutical throughout the entire study, makes it possible to assess its passage through the bile ducts, gallbladder, and intestines, and further characterize the anatomical and functional features of the biliary system (cholecystitis, gallbladder shape anomalies and dyskinesia, Sphincter of Oddi dysfunction, duodenal dyskinesia, etc.). If the scintigraphic picture is ambiguous, for more precise anatomical visualization of the radiopharmaceutical accumulation site during dynamic hepatobiliary scintigraphy, the study may be supplemented by single-photon emission computed tomography of the hepatobiliary system (SPECT) (including using, for example, a single-photon emission computed tomography/computed tomography system, or, for example, a combined single-photon emission computed tomography/computed tomography (SPECT/CT) system (SPECT/CT)), which can increase the diagnostic value of the performed study [4, 6, 7, 9, 10, 16, 20, 29, 36, 39, 100, 101, 102,].

SPECT or SPECT/CT can be performed as an additional examination to any radioisotope method (hepatobiliary scintigraphy) without additional administration of a radiopharmaceutical, i.e., within the framework of a single study.

• To assess gallbladder function in order to determine treatment strategy (the possibility of litholytic therapy), oral cholecystography and cholangiography (oral cholecystography) is recommended, which allows for assessing the storage capacity of the gallbladder, clarifying the number, size, and buoyancy of stones, as well as the state of the cystic duct [42].

(UCSR – C, UDS – 4)

2.5 Other Procedures

(GoR – C, LoE – 5)

Comments: although plain abdominal radiography is not routinely used for the diagnosis of cholelithiasis, this examination can also detect radiopaque calculi in the right upper quadrant.

It is believed that the greater or lesser radiopacity of a stone depends on its calcium content. Predominantly cholesterol stones are either not visible at all on a plain radiograph or are visualized as a blurred, indistinct shadow. Calcium bilirubinate stones and mixed (cholesterol-pigment-lime) stones, on the contrary, are clearly visible on the radiograph.

(GoR – C, LoE – 5)

Comments: Computed tomography makes it possible to visualize even small calculi (predominantly calcium ones) up to 1–2 mm in diameter. However, "soft" calculi without calcium content are visualized only after contrast administration. If the calculus size is greater than 5 mm, its structure can be described. A more informative examination method is spiral computed tomography of the abdominal cavity with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction (MSCT), which is one of the most accurate visualization methods. It is indicated to clarify the nature of the gallbladder wall lesion and its relationship with surrounding organs in order to exclude a tumor process.

2.5.1 Differential Diagnosis

Cholelithiasis is differentiated from esophagitis, gastritis, gastroduodenitis, chronic pancreatitis, chronic duodenal obstruction, etc.

Particular difficulties arise when children present with an "acute" abdomen picture. In such cases, cholelithiasis is differentiated from acute appendicitis, hiatal hernia strangulation, gastric and duodenal ulcers, as well as volvulus, intestinal obstruction, and, in girls, gynecological diseases (adnexitis, ovarian cyst torsion, etc.).

Differential diagnostic workup is carried out with urinary system diseases (pyelonephritis, cystitis, urolithiasis, etc.), as well as with space-occupying lesions of the abdominal cavity and retroperitoneal space, including malignant ones [6, 7, 16].

Due to the fact that in children cholelithiasis may be one of the manifestations of congenital, hereditary pathology or infectious/parasitic diseases, additional examinations may be required to clarify the cause of cholelithiasis. In particular, these may include hemolytic anemia, parasitic and bacterial infections, as well as various genetic diseases such as low phospholipid-associated cholelithiasis (LPAC) (ABCB4 deficiency), Caroli syndrome, Gilbert syndrome, cystic fibrosis, and myotonic dystrophy.

Cholecystitis in children should be differentiated from cholangitis, gallbladder rupture, renal colic, gastritis, pleurisy, hepatitis, liver abscess, abdominal space-occupying lesions, pyelonephritis, irritable bowel syndrome [106].

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

Management tactics for patients with cholelithiasis should be differentiated depending on the presence or absence of symptoms. There are two main approaches to the treatment of cholelithiasis in children: surgical and conservative.

Surgical treatment is indicated for children with characteristic symptoms and/or complications of cholelithiasis. In cases of asymptomatic cholelithiasis, a watchful waiting strategy (observation) or conservative treatment is possible (if the stones are radiolucent).

Conservative therapy is aimed at relieving pain syndrome and dissolving stones.

Medical treatment may be prescribed in case of refusal of surgical treatment or in the presence of contraindications to surgery [43, 44].

3.1 Conservative Treatment

The goal of conservative treatment is to dissolve stones, reduce the risk of cholelithiasis complications, and relieve pain syndrome.

Hospitalization is indicated in case of exacerbation of cholelithiasis.

Relief of pain syndrome

There are no clear criteria for the duration of pain relief. It is carried out until symptoms resolve or early cholecystectomy is performed (if indicated).

• For the relief of pain syndrome in biliary colic and calculous cholecystitis, analgesic therapy is recommended as first-line therapy [36, 45].

(UCSR – C, UDS – 4)

Comment: nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) and/or "other analgesics and antipyretics" (OAA) and/or antispasmodic agents of various pharmacological groups are most commonly used. According to meta-analysis data, in adult patients with biliary colic and cholecystitis, the analgesic effect of NSAIDs and OAAs is superior to that of antispasmodics and comparable to opioids (narcotic analgesics) [45]. "Standard" NSAIDs (non-selective) and OAAs have age restrictions: for example, metamizole sodium (contraindicated under 3 months of age or body weight under 5 kg; ibuprofen**: from 3 months in suspension and rectal forms, from 6 years in tablets; paracetamol** in the form of an infusion solution may be prescribed from 1 month.

According to studies in adults, opioids (narcotic analgesics) are used as second-line therapy for pain relief in colic and calculous cholecystitis associated with cholelithiasis when NSAIDs/OAAs and antispasmodics are ineffective [36, 38].

(LoE – C, GoR – 5)

Comment: The main drugs for relieving acute abdominal pain attacks in cholelithiasis are antispasmodic agents. It is advisable to use these drugs (with a short time to achieve maximum serum concentration): according to the ATC classification, drugs for functional gastrointestinal disorders - other synthetic anticholinergics (hyoscine butylbromide - over 6 years old, platyphylline**) and papaverine and its derivatives (phosphodiesterase inhibitors for parenteral administration) (drotaverine** in tablets (40 mg), for children from 6 years of age)

Litholytic agents

• Litholytic therapy is recommended for children with asymptomatic cholelithiasis, as well as in cases where, despite symptoms, the patient or their legal representatives refuse surgical treatment, with the aim of dissolving/reducing the size of gallstones [36, 44, 49].

(UCSR – C, UDS – 4)

Comment: The prescription of litholytic agents (drugs for the treatment of biliary tract diseases) is justified only in the presence of cholesterol stones and preserved gallbladder function [38, 50].

Before prescribing litholytic therapy, the patient and parents (guardians) should be informed that even with proper patient selection, treatment success is achieved in only 7.2% - 30.8% of cases [43, 51]. Following stone dissolution, long-term anti-relapse therapy is required [38].

(UCSR – C, UDS – 4)

Comment: To achieve success in litholytic therapy, it is recommended to observe a number of mandatory conditions:

• Absence of an inflammatory process in the biliary system;

• Early initiation of therapy (before signs of stone calcification appear);

• The size of the calculus should not exceed 10 mm, and in the presence of small stones, they should not occupy more than ½ of the gallbladder volume;

• Treatment is continuous and should continue for at least 6–12 months;

• UDCA** is prescribed at a dosage of 10 mg/kg per day for stone dissolution; in the presence of signs of cholangitis, the dose may be higher – 12–15 mg/kg/day in 2–3 divided doses – for a long time (up to 6–12 months according to the instructions) (the drug is approved for use in children in the oral suspension dosage form – from 1 month, capsules – from 3 years, film-coated tablets – from 6 years).

• Adherence to a diet enriched with dietary fiber (for preventive purposes, see the corresponding section);

• Long-term maintenance therapy – at half the dose once at night to prevent recurrence of stone formation [52].

UDCA** does not act on HMG-CoA reductase, but induces the formation of a liquid crystalline mesophase on the surface of calculi in the gallbladder. These liquid crystals gradually detach from the stone surface and are then dispersed in the solution.

• Ultrasound monitoring of the efficacy of litholytic therapy is advisable no more frequently than once every 6–10 months. This time interval is due to two factors:

1. slow rate of stone dissolution (approximately 1 mm per month) [53];

2. dissolution of large stones occurs from the inside out (while the outer calcium-containing shell and the stone diameter may remain unchanged for a considerable time). In this case, the stone may "disappear" as soon as its outer shell disintegrates [38].

• If 12 months after the initiation of treatment, ultrasound of the gallbladder shows that the stone size remains unchanged or increases, litholytic therapy is recommended to be discontinued due to lack of efficacy [1, 6, 7, 16, 19, 20].

(UCSR – C, UDS – 4)

Medical Nutrition Therapy

• Children with cholelithiasis are recommended to follow a frequent, small-meal feeding regimen (5–6 times a day) to improve biliary motility [37].

(UCSR – C, UDS – 4)

Comment: fractional meals help normalize pressure in the duodenum, stimulate and regulate biliary motility, and improve gallbladder emptying [20].

Carbonated water, smoked and fried foods, and spices are excluded from the diet, as they can cause spasm of the sphincter of Oddi.

3.2 Surgical Treatment

Children with cholelithiasis presenting with characteristic symptoms and/or complications (cholecystitis, choledocholithiasis, cholangitis, pancreatitis) are indicated for surgical treatment [20, 40, 44, 49].

Every 10 days of delay in surgical treatment increases the risk of recurrent symptoms and complications (choledocholithiasis and pancreatitis) by 5% (p = 0.0004) [49].

Patient management tactics and indications for surgical treatment are decided jointly with a pediatric surgeon. Preference in choosing surgical treatment should be given to minimally invasive methods [21].

The timing for cholecystectomy in children with symptomatic cholelithiasis depends on the presence or absence of complications. Currently, there are no clear criteria for determining the timing of cholecystectomy in children [36.]

• Prior to surgical intervention, children with cholelithiasis are recommended to undergo a comprehensive ultrasound examination of the abdominal organs and laboratory tests assessing liver function and cholestasis markers (determination of blood alkaline phosphatase activity, blood gamma-glutamyl transferase activity, free and conjugated bilirubin levels in the blood, conjugated bilirubin level in the blood, unconjugated bilirubin level in the blood, blood aspartate aminotransferase activity, blood alanine aminotransferase activity) to rule out choledocholithiasis. Signs of gallstones in the bile ducts include: jaundice, severe pain syndrome, elevated liver panel parameters, pancreatitis, and an increased diameter of the common bile duct and/or intrahepatic ducts on ultrasound [55, 56, 57].

(LetER – C, LORQ-5)

Comment:

The absence of common bile duct dilation with normal liver panel parameters effectively rules out choledocholithiasis with high probability [58, 59].

Comment: the sensitivity of ultrasound for detecting stones in the common bile duct is lower than in the gallbladder, being approximately 73%–80% when performed by an experienced specialist [57, 60]. If doubts regarding the presence or absence of choledocholithiasis persist after ultrasound, MRCP or endoscopic ultrasound (EUS) is advisable. MRCP and EUS are not always available and are significantly more expensive. The sensitivity of these diagnostic methods is 93% and 95%, and the specificity is 96% and 97%, respectively [61].

(UCSR – C, UDS – 4)

Comment: if technical difficulties arise during laparoscopic surgery (e.g., multiple adhesions obstructing proper exposure of the gallbladder, uncontrollable bleeding, unclear anatomy, or bile leakage), the pediatric surgeon must convert to an open cholecystectomy.

• If choledocholithiasis is detected, endoscopic or surgical decompression of the bile ducts is recommended for therapeutic purposes and to prevent complications [36, 41].

(UCSR – C, UDS – 4)

Comment: the choice of decompression method depends on the experience of the pediatric surgeon and endoscopist, as well as the availability of appropriate equipment. Whenever possible, endoscopic retrograde cholangiopancreatography (ERCP) with papillosphincterotomy should be preferred. If ERCP is not feasible, surgical intervention is performed [41]. In the presence of cholangitis, ERCP should be performed within 72 hours of diagnosis. In severe cases, within 12 hours [32, 39].

Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services", includes the following services: Endoscopic retrograde papillosphincterotomy,

• In children under 3 years of age with cholelithiasis, surgical treatment is recommended only in the presence of recurrent abdominal pain. Spontaneous dissolution of calculi is possible at this age [16, 17].

(GoR – C, LoE – 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are 3 stages of rehabilitation treatment: clinical, outpatient clinic, and sanatorium-resort stage. Non-pharmacological treatment methods involve the combined use of various therapeutic techniques, among which an important place is given to a therapeutic regimen and diet therapy; preformed physical factors, sanatorium-resort treatment (including balneotherapy and climatotherapy), therapeutic exercise (kinesiotherapy), reflexology, and psychocorrection methods can also be selectively prescribed. These methods have a low level of evidence. The techniques are prescribed by a physical therapy physician [6, 7, 16].

The use of physical factors, sanatorium-resort treatment, therapeutic exercise, massage or kinesiotherapy, and psychocorrection can be prescribed according to indications after successful litholytic therapy; in asymptomatic cases, they are prescribed with caution, and in frequently recurring chronic calculous cholecystitis, they are contraindicated.

(LoE – C, GoR – 5)

Comments:

Sanatorium-resort treatment includes differentiated motor regimens, climatotherapy, medical nutrition, and balneotherapy using mineral waters for internal and external use. Contraindications to sanatorium-resort treatment include cholelithiasis with frequent and prolonged severe attacks accompanied by impaired bile outflow or signs of active infection (fever, etc.), and gallbladder empyema.

Sanatorium-resort institutions under the jurisdiction of the Ministry of Health of the Russian Federation admit children aged 4 to 14 years inclusive, including those accompanied by a legal representative, and children aged 15 to 18 years unaccompanied. If a sanatorium-resort institution has a department for children, children aged 7 to 14 years inclusive are admitted without being accompanied by a legal representative, unless the need for accompaniment is due to medical indications [Letter of the Ministry of Health and Social Development of the Russian Federation No. 14-5/10/2-4265 dated May 29, 2009, "On Sending Children for Sanatorium-Resort Treatment to Sanatorium-Resort Institutions under the Jurisdiction of the Ministry of Health and Social Development of Russia"].

(Level of Evidence C, Grade of Recommendation 5)

Comment: Climatotherapy in a resort setting is carried out starting with regimen I (gentle, weak). In the warm months of the year, a transfer to regimen II (gentle-toning) is possible after 3-5 days.

(Level of Evidence C, Grade of Recommendation 5

Comment: thalassotherapy is carried out according to regimen I (mainly for preschool children and those with autonomic regulation disorders) and regimen II (for school-age children). In the summer months, thalassotherapy according to regimen I is carried out when the sea water temperature is not lower than 22 ºC (after a preliminary 3-5 day adaptation with rubbing down with sea water at 23-24 ºC and the first dip at a water temperature of 23-24 ºC), daily, for a course of 15-20 baths. According to regimen II, thalassotherapy is carried out when the sea water temperature is not lower than 21 ºC, taking into account the water temperature – from 3 to 7-8 min.

(Level of Evidence C, Grade of Recommendation 5)

Comment: For internal intake, low- or medium-mineralized mineral waters are used at the rate of 3-5 ml per 1 kg of the child's body weight (i.e., children aged 6-10 years are prescribed up to 100 ml per intake, and at 11-14 years - up to 200 ml), 3 times a day, 30 minutes before meals throughout the entire period of stay in the sanatorium.

(Level of Evidence C, Grade of Recommendation 5)

Comment: Mineral baths are prescribed according to the traditional method: temperature 37°C, duration 5-8 minutes for children 7-10 years old and 8-12 minutes for 11-14 years old, for a course of 6-8 procedures for the younger age group and 8-10 for the older group.

Therapeutic exercise and medical massage

(GoR – C, LoE – 5)

Comment: physical activity also contributes to the normalization of body weight, which is also a prevention of cholelithiasis [29.].

Morning hygienic gymnastics, therapeutic gymnastics (individual or small-group), and dosed walking are performed [75 ].

The tasks of therapeutic exercise include, among other things, a general tonic effect, improvement of blood circulation in the abdominal cavity, training of abdominal and diaphragmatic breathing, strengthening of the abdominal muscles, ligamentous apparatus, and muscles of the abdominal organs, improvement of bile outflow and excretion through exercises that tone the biliary tract (exercises lying on the back, stomach, standing on all fours, standing: moderate torso bends, turns, and circular movements). Classes are held in the morning before breakfast and in the afternoon 1.5–2 hours after meals; the duration of classes is 20–30 minutes. Exercises are performed with a large amplitude of movements. Diaphragmatic breathing (abdominal breathing) is widely used, which promotes gallbladder emptying and strengthens the abdominal muscles. Therapeutic exercise is prescribed in the amount of 10 procedures, every other day.

Psychotherapy

(Level of Evidence – C, Grade of Recommendation – 5).

Comments: Treatment method options include music therapy, neurolinguistic programming, biofeedback (BFB), etc. [103, 104].

4.1 Rehabilitation of Children Undergoing Cholecystectomy

The principles of rehabilitation in the postoperative period are measures aimed at:

• preventing the recurrence of gallstone formation,

• normalizing the processes of bile formation and bile excretion,

• preventing postcholecystectomy syndrome.

(GoR – C, LoE – 5)

5. Prevention and Dispensary Observation

5.1 Prevention

Prevention focuses on reducing the LDL percentile and triglycerides and increasing the HDL percentile, which is usually achieved through lifestyle changes, primarily diet adherence (diet for liver and biliary tract diseases), optimal physical activity, and medical litholytic treatment.

Primary, secondary, and tertiary prevention are distinguished.

Primary prevention is understood as the formation and maintenance of a so-called healthy lifestyle. This includes promoting breastfeeding and a balanced diet for older children. Great importance is attached to plant or dietary fibers, which are considered natural enterosorbents. Other factors are also crucial—strict adherence to sanitary and hygienic rules, the so-called "dirty hands" problem, which leads to an increased risk of digestive system diseases. The expediency and necessity of creating adequate conditions for children at home and at school are driven by the fact that patients with cholelithiasis, as well as those with other gastroenterological diseases, frequently exhibit neurovegetative and psychoemotional disorders.

Secondary prevention involves measures and methods that allow for the detection of cholelithiasis at early stages, i.e., identifying risk factors for gallstone formation: family history, metabolic disorders, developmental anomalies of the biliary tract, etc.

Tertiary prevention aims to prevent the worsening of the disease after its detection. The set of measures is determined by the nature of the disease. For instance, the presence of viral hepatitis in a patient with cholelithiasis requires the adjustment of therapeutic tactics with the use of systemic antiviral drugs.

5.2 Patient Management

Initial diagnosis and selection of therapy for cholelithiasis in children can be carried out both in outpatient clinics and in a specialized gastroenterological hospital or department (or a pediatric department with appropriate specialists); patients with a mild course may also be hospitalized in a day care unit.

In outpatient settings, upon suspicion or detection of cholelithiasis, primary care pediatricians should refer patients for a consultation with a gastroenterologist.

The frequency of visits for a patient with cholelithiasis is determined individually, depending on the clinical course and dynamics of the disease. On average, follow-up examinations for children with cholelithiasis should be conducted every 6–12 months (or more frequently if indicated), including a comprehensive abdominal ultrasound and a general clinical biochemical blood test. Therapy is adjusted as necessary.

When managing a patient who has undergone cholecystectomy, follow-up (dispensary observation) is carried out for 2 years with quarterly comprehensive abdominal ultrasound and, if necessary, a general clinical biochemical blood test. Therapy is adjusted as necessary.

Children and adolescents with cholelithiasis are classified under health group III. Prior to surgical intervention, they are monitored every 3–6 months by a pediatrician and a gastroenterologist; procedures include a comprehensive abdominal ultrasound and, if necessary, a general clinical biochemical blood test.

In all cases, the age-related features of cholelithiasis should be kept in mind. In asymptomatic gallstone carriers under 3 years of age and in adolescence, medical therapy should be preferred, and surgical treatment should be performed only in the presence of recurring pain syndrome.

6. Organization of Medical Care

• Indications for hospitalization in a medical organization [19, 20, 28].

Emergency hospitalization:

- Severe pain syndrome

- Presence of peritoneal irritation signs

- Obstructive jaundice

- High body temperature

- Presence of intoxication symptoms

Elective hospitalization:

- History of repeated attacks of hepatic (biliary) colic;

- Presence of concomitant chronic pancreatitis;

- Decreased gallbladder contractility;

- Presence of complications

• Indications for discharging a patient from a medical organization:

Absence of signs of exacerbation, complications, or other manifestations requiring inpatient treatment;

The organization of dietary nutrition for patients during inpatient treatment in medical organizations is carried out in accordance with Appendix 3 of the Order of the Russian Ministry of Health dated September 23, 2020, No. 1008n "On Approval of the Procedure for Providing Patients with Therapeutic Nutrition"

Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition"

7. Additional Information

7.1 Complications

Inadequate therapy for cholelithiasis, prolonged lack of medical treatment, or untimely specialized care may lead to complications such as stone impaction, common bile duct obstruction, acute cholecystitis, pancreatitis, gallbladder fistula, obstructive jaundice, peritonitis, and perforation.

7.2 Outcomes and Prognosis

These depend on the child's age, disease duration, and the cause of gallstone formation. In infants and young children, cholesterol stones dissolve rapidly and practically do not recur. Bilirubin concretions caused by hemolytic jaundice, congenital heart defects, or hypoparathyroidism are practically insoluble. The prognosis in these cases is complicated by the need for surgery against the background of a severe underlying disease. In cases of successful gallstone litholysis and laparoscopic cholecystectomy, stone recurrence is rare. Postcholecystectomy syndrome does not develop. Children lead a normal lifestyle and return to sports, and an active lifestyle is indicated for them. All this improves the prognosis. In adolescence, medical treatment is generally successful [6, 7, 16].

Special attention should be paid to asymptomatic gallstone carriage. Observation of children has shown that over a period of 2 to 5 years, the clinical picture of cholelithiasis changes: dull aching abdominal pain appears, followed by dyspeptic disorders such as heartburn, nausea, constipation, and flatulence; some children experience paroxysmal pain. In other words, asymptomatic gallstone carriage is nothing other than a latent course of cholelithiasis, which sooner or later is accompanied by the manifestation of pain. The prognosis in asymptomatic gallstone carriage depends on the quality of dispensary observation and compliance with the scheduled control visits to the pediatrician or gastroenterologist [6, 7, 16].

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of primary health care for children with cholelithiasis (ICD-10 codes: K80)

Criteria for assessing the quality of specialized medical care for children with cholelithiasis (ICD-10 codes: K80)

References

Appendix A1. Working Group Composition

Baranov A.A., Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Chief Freelance Pediatrician of the Russian Ministry of Health, Professor at the Department of Pediatrics and Pediatric Rheumatology of the N.F. Filatov Clinical Institute of Children's Health of the Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University)

Namazova-Baranova L.S., Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatrists of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Chief Freelance Pediatric Specialist in Preventive Medicine of the Russian Ministry of Health

Averkina N.A. – Cand. Sci. (Med.), Chief Specialist of the Central Research Institute for Health Information and Applications of the Russian Ministry of Health, gastroenterologist, pediatrician at the pediatric consultative and diagnostic department of the Shumakov National Medical Research Center of Transplantology and Artificial Organs, member of the Union of Pediatrists of Russia

Apkhanova T.V., Doctor of Medical Sciences, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health

Vishnyova E.A., Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Deputy Head for Scientific Work at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, member of the Union of Pediatrists of Russia

Volynets G.V., Doctor of Medical Sciences, Head of the Department of Gastroenterology, Veltischev Research Institute of Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University, Professor at the Department of Innovative Pediatrics and Pediatric Surgery of the Faculty of Additional Professional Education of the Pirogov Russian National Research Medical University, member of the Euro-Asian Society of Infectious Diseases, member of the Association of Pediatric Gastroenterologists, Hepatologists and Nutritionists of Russia, member of the Union of Pediatrists of Russia

Gorelov A.V., Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor, Deputy Director for Scientific Work at the Central Research Institute of Epidemiology of Rospotrebnadzor, Doctor of Medical Sciences, Professor at the Department of Childhood Diseases of the Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University)

Gundobina O.S., Cand. Sci. (Med.), Leading Research Fellow, gastroenterologist at the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the Russian Academy of Sciences, member of the Union of Pediatrists of Russia

Efimenko N.V., Doctor of Medical Sciences, Professor, Deputy General Director for Scientific Work – Head of the Pyatigorsk Research Institute of Balneology, branch of the North Caucasus Federal Research and Clinical Center of the Federal Medical-Biological Agency of Russia, Pyatigorsk

Zalikhin D.V., PhD, Pediatric Surgeon at the Department of Emergency and Purulent Surgery, Filatov Children's City Clinical Hospital of the Moscow Healthcare Department, Member of the Association of Pediatric Surgeons of Russia

Zokirov N.Z., DSc, Head of the Department, Academy of Postgraduate Education under the FSBI FRC FSB of Russia, FSBI "Children and Adolescents FRC of the FMBA of Russia", Member of the Union of Pediatrists of Russia

Kaitukova E.V. – PhD, Deputy Head for Medical Operations - Head of the Consultative and Diagnostic Center for Children, Gastroenterologist, Leading Research Scientist at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Member of the Union of Pediatrists of Russia

Komarova E.V. – DSc, Deputy Head for Expertise in Innovative Treatment and Rehabilitation Methods, Gastroenterologist, Chief Research Scientist at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Member of the Union of Pediatrists of Russia

Konchugova T.V., DSc, Professor, Chief Research Scientist at the Department of Physiotherapy and Reflexology, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of Russia

Novikova V.P. – DSc, Professor, Head of the Department of Propaedeutics of Childhood Diseases, Head of the Laboratory of Medical and Social Problems in Pediatrics, Research Center of Saint Petersburg State Pediatric Medical University

Podkamenev A.V. – DSc, Saint Petersburg State Pediatric Medical University, Associate Professor / Professor at the Department of Pediatric Surgical Diseases named after Academician G.A. Bairov

Potapov A.S. – DSc, Professor, Head of the Center for Inflammatory Bowel Diseases in Children, Head of the Gastroenterology Department, National Medical Research Center of Children's Health of the Ministry of Health of Russia; Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University), Member of the Union of Pediatrists of Russia

Razumovsky A.Yu. – Corresponding Member of the RAS, DSc, Professor, Head of the Department of Pediatric Surgery, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Head of the Russian Association of Pediatric Surgeons

Revunenkov G.V. – PhD, Leading Research Scientist, Head of the Department of Innovative Diagnostic Research Methods, Ultrasound Diagnostics Physician, Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the RAS, Member of the Union of Pediatrists of Russia

Selimzyanova L.R. – PhD, Leading Research Scientist, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Member of the Union of Pediatrists of Russia, Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists

Sichinava I.V., DSc, Professor at the Department of Childhood Diseases, Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Union of Pediatrists of Russia, Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists

Smirnov A.N., DSc, Professor, Head of the Department of Emergency and Purulent Surgery, Pediatric Surgeon at Filatov Children's City Clinical Hospital of the Moscow Healthcare Department, Professor at the Department of Pediatric Surgery, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Russian Association of Pediatric Surgeons

Smirnova O.Ya. – Medical Geneticist, Senior Research Scientist at the Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists

Strokova T.V. – DSc, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Clinic of the Federal Research Center of Nutrition and Biotechnology, Head of the Department of Gastroenterology and Dietology, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University)

Surkov A.N., DSc, Head of the Pediatric Gastroenterology Department for Inpatients, Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Member of the Union of Pediatrists of Russia

Sytkov V.V., PhD, Associate Professor at the A.V. Mazurin Department of Gastroenterology and Dietology; Associate Professor at the Department of Pediatric Surgery, N.A. Semashko Scientific Research Institute of Clinical Medicine, Russian University of Medicine of the Ministry of Health of Russia; Coloproctologist, Pediatric Surgeon, Surgical Department of the Federal Scientific and Clinical Center for Children and Adolescents of the Federal Medical-Biological Agency, Member of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists

Tepaev R.F. – DSc, Head of the Anesthesiology and Intensive Care Service, Bashlyeva Children's City Clinical Hospital, Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

Tkachenko M.A., PhD, Pediatrician, Gastroenterologist, Chief Freelance Gastroenterologist of the Healthcare Committee of the Leningrad Region, Associate Professor at the Department of Outpatient Pediatrics named after Academician A.F. Tur, Saint Petersburg State Pediatric Medical University

Khavkin A.I. – DSc, Professor, Head of the Moscow Regional Center of Gastroenterology and Hepatology, Chief Research Scientist at the Department of Gastroenterology, Research Institute of Childhood of the Moscow Region, Chairman of the Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists

Kharitonova L.A., DSc, Professor (participation in the initial version of the document)

Khodova T.V., DSc, Head of the N.K. Krupskaya Children's Sanatorium, North-Caucasian Federal Research and Clinical Center of the FMBA of Russia

Kholostova V.V., DSc, Pediatric Surgeon at the Department of Emergency and Purulent Surgery, Filatov Children's City Clinical Hospital of the Moscow Healthcare Department, Member of the Russian Association of Pediatric Surgeons

Yudina T.M., PhD, Member of the Union of Pediatrists of Russia (participation in the initial version of the document)

Yablokova E.A., PhD, Associate Professor at the Department of Childhood Diseases, Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Union of Pediatrists of Russia

Yakovlev M.Yu., DSc, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of Russia

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

Pediatricians

Gastroenterologists

General practitioners (family physicians)

Surgeons

Pediatric surgeons

Ultrasound diagnostics physicians

Medical university students enrolled in residency and postgraduate programs

Table 1.Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2.Levels of Evidence (LoE) grading scale for prevention, treatment and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3.Grades of Recommendation (GoR) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Methods used for evidence collection/selection: search in electronic databases.

Description of methods used to assess the quality and strength of evidence: the evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. Search depth: 5 years.

Methods used to assess the quality and strength of evidence:

1. expert consensus;

2. significance assessment in accordance with the rating scale.

Methods used for evidence analysis:

1. reviews of published meta-analyses;

2. systematic reviews with evidence tables.

Description of methods used for evidence analysis

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations.

To minimize potential bias, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If a consensus could not be reached, an independent expert was involved.

Evidence tables: compiled by the authors of the clinical guidelines.

Methods used to formulate the recommendations: expert consensus.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not reviewed.

Recommendation validation method

1. External expert review.

2. Internal expert review.

Description of the recommendation validation method

The draft of these recommendations was reviewed by independent experts who were primarily asked to comment on how comprehensible the interpretation of the evidence underlying the recommendations is.

All comments received from the experts were thoroughly systematized and discussed by the members of the working group (authors of the recommendations). Each item was discussed individually.

Consultation and peer review

The draft recommendations were reviewed by independent experts who were primarily asked to comment on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Key recommendations

The grades of recommendations based on the corresponding levels of evidence are provided throughout the text of the recommendations.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. On approval of the procedure for providing pediatric care (Order of the Ministry of Health of the Russian Federation No. 366n dated April 16, 2012)

2. "On approval of the Procedure for providing medical care to the population in the profile 'gastroenterology'"; Order of the Russian Ministry of Health No. 906n dated November 12, 2012

3. "On Approval of the Procedure for Providing Medical Care in the Profile 'Pediatric Surgery'", Order of the Russian Ministry of Health No. 562n dated October 31, 2012. Drug information: https://grls.rosminzdrav.ru/

Other regulatory legal documents used in the development of the clinical guidelines:

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

2. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

3. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers."

4. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

5. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Public Health Protection in the Russian Federation' regarding Clinical Guidelines".

6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of the Information Included in Clinical Guidelines", Order of the Russian Ministry of Health No. 617n dated June 23, 2020.

7. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On approval of the nomenclature of medical services."

8. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019, "On classifications and criteria used in the implementation of medical and social expertise of citizens by federal state institutions of medical and social expertise" (comes into force on January 1, 2020);

9. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Forms for Medicinal Products, the Procedure for Issuing Said Forms, Their Accounting, and Storage"

10. Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition"

Appendix A3.1 Examples of Diagnoses

• Cholelithiasis: multiple radiolucent gallbladder calculi less than 2 cm in size; recurrent biliary pain.

• Cholelithiasis: radiolucent gallbladder calculi less than 1 cm in size, multiple. Complication: Biliary colic (date of resolution).

• Cholelithiasis, asymptomatic stone carriage : single gallbladder calculus 5 mm in size.

Appendix A3.2 Explanation of notes

** – a medicinal product included in the Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on June 9, 2023) <On Approval of the List of Vital and Essential Drugs, as well as Lists of Drugs for Medical Use and the Minimum Assortment of Drugs Required for the Provision of Medical Care>

# - The use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use (off-label) is carried out by decision of the medical commission subject to the signed informed voluntary consent (pursuant to Federal Law No. 323-FZ of November 21, 2011, as amended).

Appendix B. Physician Action Algorithms

Algorithm for the management of children with cholelithiasis [36]

Appendix C. Patient Information

Cholelithiasis - is the formation of hard deposits of cholesterol or calcium salts (gallstones) in the gallbladder or adjacent bile ducts.

In children, the presence of stones is usually not accompanied by any clinical manifestations. However, some patients experience symptoms such as nausea and intense, unrelenting pain in the upper middle and upper right abdomen. In some cases, severe pain may occur paroxysmally and be accompanied by fever.

Cholelithiasis is one of the most common diseases. On average globally, every fifth woman and every tenth man have gallstones. Gallstone formation occurs when the chemical balance of bile components is disrupted, leading to the initial formation of small solid particles ("flakes") in the bile, from which larger gallstones subsequently form. Gallstones can vary in size; they can be rounded and smooth or irregular in shape with multiple facets. The number of stones also varies, ranging from one to hundreds. Cholesterol stones and pigment stones (in conditions with elevated bilirubin levels) are also distinguished.

Complications of cholelithiasis include: obstruction of the cystic duct or common bile duct by a gallstone, acute and chronic inflammation of the gallbladder, acute inflammation of the pancreas caused by obstruction of the pancreatic duct, and inflammation of the biliary tract.

Many gallstones, especially those that do not cause symptoms, are discovered incidentally during diagnostic procedures including ultrasound examinations (ultrasound) and computed tomography ordered for other reasons. If gallstones are suspected, the doctor may order additional tests, which usually include: a general (clinical) blood count and general therapeutic biochemical blood test, comprehensive abdominal ultrasound, and—according to indications—computed tomography and other tests if clinically necessary.

The presence of gallstones in the gallbladder not accompanied by symptoms of an "acute abdomen" does not require immediate surgical intervention. Treatment is indicated, the main method of which in children is medical dissolution of gallstones. This treatment can be quite prolonged (up to 2 years). During the first 5 years after successful stone dissolution, the recurrence rate is approximately 10% per year, after which this figure begins to gradually decrease.

However, successful stone dissolution cannot completely prevent the recurrence of stone formation. To monitor the stone formation process, periodic follow-up ultrasounds are required after the completion of treatment.

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

Not applicable