Epstein-Barr virus belongs to the herpesvirus family (herpes type 4) and is the most common and highly contagious viral infection.

According to statistics, up to 60% of children and almost 100% of adults are infected with this virus. Epstein-Barr virus is transmitted by airborne droplets(during kissing), contact-household (common household items), less often through blood (transmissible) and from mother to fetus (vertical path).

The source of infection is only humans, most often these are patients with latent and asymptomatic forms. Epstein-Barr virus enters the body through the upper respiratory tract, from where it penetrates into lymphoid tissue, causing damage to the lymph nodes, tonsils, liver and spleen.

What diseases does it cause?

The Epstein-Barr virus is dangerous not so much because of its acute infection of humans, but because of its tendency to cause tumor processes. Unified classification of viral Epstein-Barr infection(VIEB) does not exist, the following is proposed for use in practical medicine:

• by time of infection - congenital and acquired;
• according to the form of the disease - typical (infectious mononucleosis) and atypical: erased, asymptomatic, damage to internal organs;
• according to the severity of the flow - mild, medium degree and heavy;
• according to the duration of the course - acute, protracted, chronic;
• by activity phase – active and inactive;
• complications;
• mixed (mixed) infection - most often observed in combination with cytomegalovirus infection.

Diseases caused by the Epstein-Barr virus:

• Filatov's disease (infectious mononucleosis);
• Hodgkin's disease (lymphogranulomatosis);
• chronic fatigue syndrome;
• malignant formation of the nasopharynx;
• lymphomas, including Burkitt's lymphoma;
• general immune deficiency;
• systemic hepatitis;
• brain damage and spinal cord(multiple sclerosis);
• tumors of the stomach and intestines, salivary glands;
• hairy leukoplakia oral cavity and others.

Symptoms of Epstein-Barr virus

Acute infection (AVIEB)

CVIEB is infectious mononucleosis.

The incubation period ranges from 2 days to 2 months, with an average of 5-20 days.

The disease begins gradually, with a prodromal period: the patient complains of malaise, increased fatigue, sore throat.

Body temperature is slightly elevated or within normal limits. After a few days, the temperature rises to 39-40°C, and intoxication syndrome occurs.

The main symptom of acute viral infection Epstein-Barr is a polyadenopathy. Mainly the anterior and posterior cervical muscles increase The lymph nodes, as well as occipital, submandibular, supraclavicular, subclavian, axillary, ulnar, femoral and inguinal lymph nodes. Their sizes reach 0.5-2 cm in diameter, they are doughy to the touch, moderately or slightly painful, and are not fused to each other and the surrounding tissues. The skin over them does not change. The maximum severity of polyadenopathy is diagnosed on days 5-7 of illness, and after 2 weeks the lymph nodes begin to shrink.

The palatine tonsils are also involved in the process, which is manifested by signs of tonsillitis, the process is accompanied by impaired nasal breathing, a nasal voice, and the presence of purulent discharge on the back wall throats.

Enlarged spleen (splenomegaly) is one of the late signs, To normal sizes the spleen returns after 2-3 weeks of illness, less often after 2 months.

Enlarged liver (hepatomegaly) is less common. In some cases, mild jaundice and darkening of the urine are observed.

At acute infection rarely suffers from Epstein-Barr virus nervous system. Possible development serous meningitis, sometimes meningoencephalitis, encephalomyelitis, polyradiculoneuritis, but all processes end in complete regression of focal lesions.

There is also a rash, which can be different. These may be spots, papules, roseola, dots or hemorrhages. Exanthema lasts about 10 days.

Chronic Epstein-Barr virus infection

CIVEB is characterized by a long duration and periodic relapses of the disease.

Patients complain of general fatigue, weakness, increased sweating. Pain in muscles and joints, exanthema, persistent cough in the form of grunting, impaired nasal breathing.

Headaches, discomfort in the right hypochondrium, and mental disorders in the form of emotional lability and depression, weakening of memory and attention, decreased mental abilities and sleep disturbances.

There is generalized lymphadenopathy, hypertrophy of the pharyngeal and palatine tonsils, enlargement of the liver and spleen. Often to chronic infection Epstein-Barr virus is associated with bacteria and fungi (genital herpes and herpes lips, thrush, inflammatory processes digestive tract and respiratory system).

Diagnostics

The diagnosis of acute and chronic Epstein-Barr infection is made on the basis of complaints clinical manifestations and laboratory data:

• < 20 Ед/мл - отрицательно;
• > 40 U/ml - positive;
• 20 - 40 U/ml – doubtful*.

• < 20 Ед/мл - отрицательно;
• > 20 U/ml – positive*.

according to independent laboratory Invitro

5. DNA diagnostics

Using the polymerase chain reaction (PCR) method, the presence of Epstein-Barr virus DNA is determined in various biological materials(saliva, cerebrospinal fluid, smears from the mucous membranes of the upper respiratory tract, biopsies of internal organs).

6. If indicated, other studies and consultations

Consultation with an ENT doctor and immunologist, radiography chest And paranasal sinuses nose, ultrasound of the abdominal cavity, assessment of the blood coagulation system, consultation with an oncologist and hematologist.

Treatment of Epstein-Barr virus infection

There is no specific treatment for Epstein-Barr virus infection. Treatment is carried out by an infectious disease specialist (for acute and chronic infections) or an oncologist for the development of tumor-like neoplasms.

All patients, especially those with infectious mononucleosis are hospitalized. An appropriate diet and rest are prescribed for the development of hepatitis.

Actively used various groups antiviral drugs: isoprinosine, valtrex, acyclovir, arbidol, viferon, intramuscular interferons (reaferon-EC, roferon).

If necessary, antibiotics (tetracycline, sumamed, cefazolin) are included in therapy - for example, for a sore throat with extensive plaque, a course of 7-10 days.

Immunoglobulins are also prescribed intravenously (intraglobin, pentaglobin), complex vitamins(sanasol, alphabet), antiallergic drugs (tavegil, fenkarol).

Correction of immunity is carried out by prescribing immunomodulators (lykopid, derinat), cytokines (leukinferon), biological stimulants (actovegin, solcoseryl).

Relief various symptoms diseases are treated with antipyretics (paracetamol) when the temperature rises, for coughs - antitussives (libexin, mucaltin), for difficulties with nasal breathing, nasal drops (nasivin, adrianol) and so on.

The duration of treatment depends on the severity and form (acute or chronic) of the disease and can range from 2-3 weeks to several months.

Complications and prognosis

Complications of acute and chronic Epstein-Barr virus infection:

• peritonsillitis;
• respiratory failure (swelling of the tonsils and soft tissues of the oropharynx);
• hepatitis;
• splenic rupture;
• thrombocytopenic purpura;
• liver failure;

The prognosis for acute infection with the Epstein-Barr virus is favorable. In other cases, the prognosis depends on the severity and duration of the disease, the presence of complications and the development of tumors.

DRAFT PROTOCOL

DIFFERENTIAL DIAGNOSTICS AND TREATMENT OF SYNDROME

CHOLESTASIS IN NEWBORN CHILDREN

Introduction

One of the most frequent violations metabolism detected during the neonatal period is an increase in the concentration of bilirubin in the blood serum. When its level is more than 68 µmol/l, newborns develop jaundice skin and sclera. Hyperbilirubinemia in the first days of life can be caused by both physiological and pathological reasons and therefore always demands special attention. Increasing intensity of jaundice, its greenish tint along with gradual increase the size of the liver, a change in its consistency from elastic to dense, the appearance of acholia of stool and dark urine, indicates a violation of the excretory function of the hepatobiliary system - neonatal cholestasis. Laboratory confirmation This syndrome is caused by an increase in the direct fraction of bilirubin by more than 15-20% of the total level, an increase in the concentrations of cholesterol, beta-lipoproteins (β-LPD), bile acids (BA), as well as the level of alkaline phosphatase (ALP) and gamma-glutamine transferase enzymes (GGT).

The causes of cholestasis syndrome during the neonatal period may be the morphofunctional characteristics of the liver and bile ducts, which are characterized high level synthesis of bile acids and the immaturity of their hepatic-intestinal circulation. In addition, already in the first month of life, the first clinical signs may be detected, indicating pathology of the liver and bile ducts, manifesting in the form of cholestasis syndrome.

Over the past 20 years, our understanding of the basis and pathophysiology of many liver diseases has increased significantly. Introduction of new approaches to diagnosis and treatment, accumulated clinical experience made it possible to establish a number of new nosological forms, which until recently were designated by the term idiopathic neonatal hepatitis. Considering that the effectiveness of treatment congenital diseases liver depends on the timing of its onset, the problem becomes especially important early diagnosis.

The formation of neonatal cholestasis can be caused by diseases of the hepatobiliary system, as well as a combination of nonspecific pathological factors perinatal period, i.e. have extrahepatic origin.

Regardless of the etiology of cholestasis, therapy for this category of patients involves prescribing therapeutic nutrition, additional administration fat-soluble vitamins, as well as the use of the choleretic drug ursodeoxycholic acid. In the case of cholestasis caused by extrahepatic causes (transient), during treatment, positive dynamics and gradual relief of the pathological condition are noted. In case of diseases of the liver and biliary system, in order to clarify the cause and timely prescribe etiopathogenetic therapy, children need an in-depth examination in a specialized department.

Neonatal cholestasis due to extrahepatic causes.

In the structure of extrahepatic causes of the formation of neonatal cholestasis, the leading place is occupied by conditions accompanied by the development of hypoxia or ischemia of the hepatobiliary system, hypoperfusion gastrointestinal tract, persistent hypoglycemia, metabolic acidosis and congestive cardiovascular failure .

Disorders of the excretory function of the hepatobiliary system can be detected in children with hemolytic disease newborns against the background of a significant increase in bilirubin concentration. In this case, there is a change in the colloidal properties of bile and an increase in its viscosity. In some cases, bilirubin can have a direct toxic effect on hepatocyte membranes and cell mitochondria. An important place is occupied by systemic and localized bacterial infections. The synthesis and excretion of a complex cascade of inflammatory mediators by Kupffer cells, as well as hepatocytes and sinusoidal endothelial cells, has a direct impact on the formation and excretion of bile. Therapeutic measures carried out by a newborn in an intensive care unit and intensive care, include potentially hepatotoxic medicines, total parenteral nutrition, which also contribute to the disorder functional state hepatobiliary system. The development of cholestasis is more often observed in premature newborns with the simultaneous effect of several pathological and iatrogenic factors on liver function and the condition of the bile ducts. These changes are based on varying degrees severity of destructive changes in the bile ducts, impaired permeability of hepatocyte membranes and intercellular connections, which in most cases are reversible with timely therapy. A characteristic feature of neonatal cholestasis caused by extrahepatic causes is its dependence on severity and duration pathological conditions perinatal period and the action of iatrogenic factors. As you improve general condition child and resolution of the underlying disease, in most cases there is a gradual decrease in cholestasis. However, its residual effects can persist for a long time, up to 6-8 months of life. The diagnosis of neonatal cholestasis, which is a complication of severe extrahepatic pathology, is established by identifying factors predisposing to its development and excluding diseases of the hepatobiliary system.

Therapy in these cases includes adequate treatment underlying disease, limiting the use of potentially hepatotoxic drugs and blood products. The prescription of pathogenetically based choleretic therapy with the drug ursodeoxycholic acid (Ursofalk-suspension), at a dose of 15-20 mg/kg/day, is indicated. Using most others choleretic drugs containing primary bile acids (cholenzyme, flamin, allochol and others) has limitations in the neonatal period, since at this age their high formation is characteristic with the manifestation of a toxic effect.

Diseases of the liver and bile ducts, manifested by cholestasis syndrome in newborns and children early age(Table 1).

Table 1

Diseases of the liver and bile ducts, manifested by cholestasis syndrome in newborns and young children

Extrahepatic cholestasis

Atresia of the extrahepatic bile ducts

Common bile duct cyst

- "Bile plugs" and/or bile duct stones

Compression of the common bile duct

Intrahepatic cholestasis

1.Progressive familial intrahepatic cholestasis (PFIC)

Type 1 (Byler's disease)

Type 11 (Byler syndrome)

Type 111 (MDR3 gene deficiency)

2. Benign familial intrahepatic cholestasis

3. Metabolic disorders

Alpha-1 antitrypsin deficiency

Galactosemia

Fructosemia

Tyrosinemia

Impaired synthesis of bile acids due to enzyme deficiency

Peroxisomal deficiency (Zellweiger syndrome),

Neonatal hemochromatosis

Niemann-Pick disease type C

Mitochondrial deficiency

4.AND infectious diseases (viral, bacterial, caused by protozoa)

5.Endocrine disorders

Hypopituitarism

Hypothyroidism

6. Chromosomal disorders

Trisomy 13, 17 or 18 chromosomes

7. Cholestasis associated with complete parenteral nutrition

8. Cholestasis caused toxic effect medicines

9. Others

Alagille syndrome

Nonsyndromic form of hypoplasia of intrahepatic gallbladder

Perinatal sclerosing cholangitis

Idiopathic neonatal hepatitis

Depending on the level of damage to the hepatobiliary system, it is customary to distinguish diseases manifested by extrahepatic and intrahepatic cholestasis, the differential diagnosis between which is based on a combination of three signs: persistence of stool acholia, blood GGT level and visualization of the gallbladder during fasting ultrasound. (table 2)

Table 2.

Differential diagnosis between extrahepatic and intrahepatic cholestasis in newborns.

Type of cholestasis

Indicators:

Extrahepatic

Cholestasis

Intrahepatic cholestasis

Persistence of stool acholia

Constant

Fickle

Blood GGT level

Visualization of the gastrointestinal tract with ultrasound

Not rendered

Visualized

GGT - gamma glutamine transferase, GLP - gallbladder, Ultrasound – ultrasound examination.

Extrahepatic cholestasis.

The constant nature of stool acholia, an increase in the serum level of the HGG enzyme, as well as the lack of visualization of the gallbladder during ultrasound on an empty stomach is characteristic feature extrahepatic cholestasis, the causes of which at this age may be:

1. Atresia of the extrahepatic bile ducts

2. Common bile duct cyst

3. “Bile plugs” and/or stones of the common bile duct.

Most common cause extrahepatic cholestasis and neonatal cholestasis in general is extrahepatic bile duct atresia (EBDA), the characteristic feature of which is:

1. In most cases, children with AVHD are born full-term with anthropometric indicators corresponding to the physiological norm.

2. Jaundice appears on days 2-3 of life, i.e., on normal days physiological jaundice deadlines. Approximately two thirds of patients have “ light gap"- a decrease in the intensity of jaundice by the end of 1-2 weeks of life, followed by a gradual increase and the appearance of a greenish tint of jaundice by the end of 1 month.

3. Acholia of stool is the earliest and most constant clinical sign disease, its appearance is often preceded by the passage of meconium.

4. Characteristic of ARLD is the absence of hepatomegaly at birth, followed by an increase in the size of the liver and a change in its consistency from elastic to dense during the first 2 months of life.

5. By the age of 1 month of life, development is possible hemorrhagic syndrome(bleeding from the mucous membranes of the gastrointestinal tract, umbilical wound, intracranial hemorrhage) caused by vitamin K deficiency dependent blood clotting factors (PTI or PTV) as a result of disruption of the absorption of vitamin K in the intestine.

6. By the age of 1-2 months of life, as a rule, a weight deficit is formed, the severity of which depends on the type of feeding the child.

7. The earliest laboratory sign The disease is caused by an increase in bilirubin due to the direct fraction in the blood serum, which is more than 20% of the level of total bilirubin.

8. Characterized by an increase in other biochemical markers of cholestasis (gamma-glutamine transferase (GGT), β-lipoproteins, cholesterol, alkaline phosphatase, bile acids, etc.), the severity of which increases over time from a minimal increase during the first 2-3 weeks of life to a significant increase by 2-3 months.

9. Cytolysis enzymes (ALT, AST) increase moderately, and, as a rule, delayed. In most cases, during the first 2-3 weeks after birth, these indicators remain within normal limits and then gradually increase.

10. Indicators reflecting the protein-synthetic function of the liver (albumin, fibrinogen, PTI, etc.), on early stages diseases do not change.

11. Informative method visualization of the hepatobiliary system is an ultrasound, during which the gallbladder on an empty stomach is not visualized or is detected in the form of a “hyperechoic strand”. In some cases, with bile duct atresia, dilatation of the intrahepatic bile ducts is detected, less often - cysts in the porta hepatis and polysplenia.

12. Hepatobiliary scintigraphy, retrograde cholecystocholangiography (RCCP), magnetic resonance imaging (MRI) and liver biopsy have additional diagnostic value. With hepatobiliary scintigraphy, which has a fairly high sensitivity and specificity in patients with AVHD, there is a lack of radioisotope substance entry into the intestine along with satisfactory absorption and storage function of the liver. Carrying out RCP has a number of technical limitations in children in the first months of life.

13. Morphological study Liver biopsy shows varying degrees of bile clots, bile duct proliferation, portal edema, and fibrosis.

The diagnosis of galactosemia is based on high content galactose in the blood serum, reducing substances in the urine, deficiency of the enzyme galactose-1-phosphate uridyl transferase in erythrocytes, leukocytes and hepatocytes. Genetic testing for a specific locus is also possible.

The main method of treatment is a diet with a complete exclusion of galactose and lactose (Pregestimil, Nutramigen, AL110 and others). Timely initiation of therapeutic nutrition leads to complete recovery of the patient. It is advisable to monitor the effectiveness of therapeutic nutrition by determining the level of galactose - 1 - phosphate in red blood cells. An increase in this metabolite to 3 mg/dL is considered acceptable.

With timely administration of therapeutic nutrition, the prognosis is favorable. Described rare cases development of liver cirrhosis and/or hepatocellular carcinoma. There may also be a low intellectual index with impairment of abstract thinking, speech and visual perception, muscle hypotonia, tremor, ataxia and mental retardation. In addition, cases of violation reproductive function in women with the formation of hypergonadotropic hypogonadism.

Endocrine disorders. Cholestasis syndrome is one of the manifestations of hypothyroidism or hypopituitarism, which have typical clinical and laboratory manifestations . Low levels of relevant hormones confirm the diagnosis. Congenital endocrine disorders serve as an indication for hormone replacement therapy.

Toxic effect of drugs. In most cases, with cholestasis caused by the toxic effects of drugs, there is an indication of the use of a potentially hepatotoxic drug, which has a certain value in diagnosis. Potentially hepatotoxic drugs may include some antibiotics (tetracycline, erythromycin, lincomycin, novobiocin, clavulanic acid, ampicillin, chloramphenicol, gentamicin, 1st generation cephalosporins, thienam), diuretics (Lasix), non-steroidal anti-inflammatory drugs (indomethecin), nitrofurans (furagin, 5 -nok), sulfonamide drugs, anticonvulsants and antipsychotics. Treatment of toxic liver damage includes exclusion of potentially hepatotoxic drugs, choleretic and syndromic therapy.

Long-term total parenteral nutrition. Cholestasis due to long-term total parenteral nutrition (TPN) can be diagnosed in neonates receiving TPN for more than 2 weeks and in older children for more than 3-4 weeks. After the start of enteral nutrition, signs of cholestasis decrease. The most effective etiopathogenetic treatment in this case is the maximum early start enteral nutrition, as well as choleretic therapy.

Idiopathic neonatal hepatitis. The diagnosis of idiopathic neonatal hepatitis is established after excluding all known reasons development of cholestasis syndrome and detection of giant cell transformation of hepatocytes during histological examination of liver biopsy.

A characteristic feature of diseases with predominant damage to the intrahepatic bile ducts, as well as a-1-antitrypsin deficiency, is the satisfactory state of health of patients and the absence of pathological changes in other organs and systems (Table 3). Deficiency of a-1-antitrypsin during the first month of life manifests itself as cholestasis syndrome, whereas pathological changes on the part of the lungs develop much later, after 3-5 years of life. Diagnostic value has low serum levels of alpha-1-antitrypsin and alpha-1-globulin.

Alagille syndrome is conditionally classified in this subgroup. It is characterized by anomalies and/or malformations of other organs, but in most cases they do not have clinical significance. Diagnosis of Alagille syndrome is based on identifying characteristic features phenotype and 2 or more typical anomalies and/or malformations of other organs:

1. Identification of signs of intrauterine hypotrophy (weight-height indicator for full-term newborns, correspondence of birth weight to gestational age in case of premature birth).

2. Identification of phenotypic features (wide, protruding forehead, hypoplasia of the middle third of the face, deep-set, widely spaced eyes (hypertelorism), long straight nose with a thickening at the tip, protruding chin, rare dermatoglyphics, etc.)

3. ECHO-CG (peripheral stenosis or hypoplasia of the pulmonary artery)

4. Consultation with an Ophthalmologist (posterior or anterior embryotoxon)

5. X-ray of the spine - direct projection (split of the vertebral bodies in the form of a “butterfly”.

Less often when this syndrome There are anomalies of the urinary system and other organs.

To confirm the diagnosis, a puncture biopsy of the liver is performed, which reveals hypoplasia of the intrahepatic bile ducts. There is no etiopathogenetic treatment for this syndrome. When cirrhosis of the liver develops and there are no gross heart or kidney defects, the only radical method The treatment is liver transplantation.

PVC 3 types

(MDR3 gene deficiency)

Lack of phospholipids in bile

PFIC type 3 - progressive familial intrahepatic cholestasis, MDR3 gene - multidrug resistance gene, g. n. – bile ducts.

Detection of hypoplasia of the intrahepatic bile ducts (in the absence of signs characteristic of Alagille syndrome) indicates a non-syndromic form of hypoplasia of the intrahepatic bile ducts. Detection of bile duct proliferation requires additional retrograde or percutaneous cholangiography. Deformation of the bile ducts revealed by cholangiography in combination with proliferation of the bile ducts during histological examination of a liver biopsy allows us to establish the diagnosis of perinatal sclerosing cholangitis. The absence of changes in this study indicates progressive familial intrahepatic cholestasis (PFIC) type 3, confirmed by the absence of phospholipids in the bile.

Symptomatic treatment of cholestasis syndrome

Symptomatic treatment is aimed at preventing and treating complications of long-term cholestasis syndrome and emerging liver cirrhosis

For all diseases manifested by cholestasis syndrome, with the exception of atresia of the extrahepatic bile ducts, cysts of the common bile duct and impaired synthesis of bile acids due to fermentopathy, choleretic therapy with the drug ursodeoxycholic acid (Ursofalk) is indicated. The use of other choleretic drugs has limitations in children in the first months of life, since many of them (cholenzym, flamin and others) contain dried large bile cattle and, consequently, primary fatty acids, the formation of which at this age is already large. Ursodeoxycholic acid (UDCA) is a non-toxic tertiary bile acid (BA), normally contained in human bile in small quantities (no more than 5% of the total bile acid pool). It is more polar and hydrophilic compared to other FAs. These properties determine practically complete absence toxicity of this compound, as well as its high cholekinetic activity. Range therapeutic action UDCA includes several main mechanisms:

1. UDCA forms mixed micelles with non-polar hydrophobic FAs, which significantly reduces their toxicity potential and enhances their exocytosis by activating calcium-dependent alpha-protein kinase.

2. UDCA induces choleresis rich in bicarbonates, which leads to an increase in the passage of bile and stimulates the excretion of toxic FAs and bilirubin.

3. Nonpolar dimers of this FA are integrated into the inner layer of hepatocyte membranes, stabilizing their structure.

4. UDCA has the ability to reduce the absorption of toxic and lipophilic FAs and other components of bile in the ileum.

5. UDCA reduces the expression of major histocompatibility complex antigens (HLA class 1 on hepatocytes and HLA class 2 on bile duct epithelial cells), which determine the activation of cytotoxic T lymphocytes.

Ursodeoxycholic acid preparations are prescribed at a rate of 15-20 mg/kg/day. If effectiveness is insufficient, the dose may be increased to 30 mg/kg/day. When conducting long-term treatment for more than 1-2 months, a maintenance dose of 10 mg/kg/day is used.

To ensure a normal growth rate, such children require an increase in protein and calorie load compared to healthy children, as well as the content of medium chain triglycerides (MCTs) in the diet. Wherein an important condition is a balanced diet. This can be achieved by using special therapeutic diet. If this does not lead to the desired effect, nutrition is administered through a nasogastric tube or partial parenteral nutrition is provided.

If breast milk is available and there are no contraindications to its use in a child, enzyme preparations should be prescribed (Creon - 1 thousand units/kg/day) or a combination breast milk with a medicinal mixture containing MCT.

With absence breastfeeding, children's need for basic food ingredients can be achieved using nutritional therapy containing MCTs or partial parenteral nutrition.

The amount of MCT required for children with cholestasis syndrome (50-60%) is contained in the Humana medicinal mixture, MCT, as well as in mixtures based on protein hydrolysates (Pregestimil, Alfare, etc.). The use of the latter is not entirely justified in this category of patients, since in most cases they do not have protein absorption disorders or allergies to it, and these mixtures have a significantly worse taste and more high cost. Our experience of using the Humana mixture, MCT in children with chronic progressive liver diseases indicates its good tolerability and a significant improvement in the nutritional status of patients.

An important component of nutrition are fat-soluble vitamins and microelements, the deficiency of which is observed in all patients with long-term cholestasis syndrome. Recommended Doses fat-soluble vitamins and microelements are presented in table 6 .

Table 6.

with cholestasis syndrome.

Name:

Dose:

Route of administration:

Multiplicity:

Vitamin D

30000 – 60000 IU

*5.000 – 8.000 IU

1 time/month

1 time/day

Vitamin A

25000 – 50000 IU

*5.000-20.000 IU

1 time/month

1 time/day

Vitamin E

*25 IU/kg/day

peros(tocopherol polyethylene glycol 1000 succinate)

1 time/2 weeks

Vitamin K (vicasol)

1 mg/kg (max – 10 mg)

1 time/1-2 weeks.

1 time/day

Zinc (zinc sulfate)

1 time/day

*in the absence of monitoring the level of vitamins in the blood, preference should be given to oral route introduction.

** based on the calculation of elemental Ca, ratio Ca/P = 2.

Majority chronic diseases liver, manifested by cholestasis syndrome, are accompanied by skin itching, significantly affecting the quality of life of patients. Exist different methods, reducing itchy skin. This medications with different mechanisms of action (cholesteramine, rifampicin, ursofalk, heptral, etc.), phototherapy, plasmapheresis and biliary diversion surgery. Products that affect the skin receptor apparatus are also used, such as menthol oil, lanolin, warm baths, etc.

Complications of liver cirrhosis are portal hypertension, hepatorenal and hepatopulmonary syndromes, bacterial peritonitis and/or cholangitis, as well as hepatic encephalopathy. Treatment portal hypertension includes salt restriction, use of diuretics, replenishment of albumin levels in the blood, and severe cases- paracentesis. Dilated veins of the esophagus and stomach are an indication for the use of H2 blockers and, in some cases, sclerotherapy. The formation of hepatorenal and hepatopulmonary syndromes is absolute indication for liver transplantation. In case of bacterial complications, it is carried out antibacterial therapy. The appearance of signs of encephalopathy serves as the basis for prescribing a diet low in protein and the use of lactulose preparations (Duphalac, etc.).

Thus, neonatal cholestasis is one of early signs wide range diseases of the liver and bile ducts, and may also have extrahepatic origin. The effectiveness of treatment of many hereditary and congenital diseases of the hepatobiliary system depends on the timing of its onset, and therefore determines the need for their early diagnosis. Algorithm differential diagnosis provides an optimal list of studies necessary to establish a diagnosis in the shortest possible time.

-- [Page 5] --

Most significant indicator we consider the level of bilirubin, the normalization of which is a prognostically favorable sign, indicating high probability easy option course of the disease and the absence of indications for LT throughout life. Regardless of the course, the formation of liver cirrhosis is not typical for Alagille syndrome, while the indications for LT are complications of long-term cholestasis, which significantly impair the child’s quality of life. It should be especially emphasized that any surgical intervention on the biliary system in this syndrome significantly worsens the child’s condition and contributes to the formation of biliary cirrhosis, which was shown in 3 children in our study.

15 children with Byler's disease aged from 10 days to 6 years were also dynamically examined. Byler's disease is always an indication for LT. Optimal timing its implementation is determined by the appearance of pathological conditions that impair the quality of life or signs of biliary cirrhosis. In our study, the timing of LT varied from 9 months to 8 years. In all cases, the indications were determined in a timely manner and the operation was performed effectively. A high risk of development has been established oncological diseases hepatobiliary system, which were identified in 4 children (27%), at an average age of 2.2+0.5 years: hepatocellular carcinoma in 3 and cholangiocarcinoma in one patient. The results obtained determined the need to recommend ultrasound monitoring and dynamic determination of the level of a-AF during the observation of children with Byler's disease.

In order to identify pathognomonic morphological changes and determine indications for liver biopsy, the results of histological examination at various diseases hepatobiliary system. In children with BA, cholestasis, proliferation of the bile ducts and fibrosis have been established to varying degrees of severity (Table 4).

Table 4. Main morphological changes in the liver in children with biliary atresia depending on age.

Histological features	Children with biliary atresia
	1.0+0.5 months life n-10	2.0+0.5 months life n-9	3.0+0.5 months life n-11
Inflammatory activity according to Knodel (points)	3,7+1,5	2,8+1,5*	4,1+2,4*
Periportal and bridging necrosis	8/10	6/9	7/11
Intralobular degeneration and focal necrosis	8/10	7/9	8/11
Portal inflammation	10/10	9/9	11/11
Degree of fibrosis severity according to Desmet, points	1,7+0,4	1,8+0,5*	2,6+1,1*
Porto-portal fibrosis	6/101	7/92	5/11
Fibrous septa	1/10	1/9	4/11
Cirrhosis	0/10	0/9	2/11
Bile duct proliferation	10/10	9/9	11/11
Degree of severity of cholestasis:
Intracellular	10/10	9/9	11/11
In bile capillaries	8/10	9/9	6/11
In the bile ducts	8/10	7/9	7/11

* R< 0,05, 1 – у 3-х детей 1 группы и 2 - у 1-го пациента 2 группы гистологические признаки фиброза в препаратах отсутствовали.

All had inflammatory changes of low or minimal Knodel activity. The severity of cholestasis and proliferation of the bile ducts was minimally expressed at 1 month and increased significantly by 3 months of life. Similar patterns have been identified in the dynamics of fibrosis formation. A direct relationship was revealed between the severity of morphological changes and the age of the child (r-0.92, p<0,05). Суммарная активность воспаления по Кнодель у детей гр.1 была выше по сравнению с больными гр. 2 и ниже чем у детей гр 3, однако статистически значимых отличий не выявлено. У детей гр.2 степень выраженности воспаления была достоверно ниже, чем у детей гр.3 (р<0,05). Вместе с тем, следует отметить невысокую суммарную оценку воспаления по Кнодель у всех обследованных больных, соответствующую низкой или очень низкой гистологической степени активности.

An inverse relationship was found between the activity of the serum level of the GGT enzyme and the severity of fibrosis according to the Desmet scale in children older than 1 month of life (r-0.93, p<0,05), что позволяет говорить о диагностической ценности данного биохимического показателя (рис 4).

Fig.4. The relationship between the severity of fibrosis (in Desmet scores) and the serum level of the GGT enzyme in children with biliary atresia (r -0.93, p<0,05).

An increase in GGT by less than 10 times with a high probability indicates a significant degree (3-4 points on the Desmet scale) of the severity of fibrotic changes in the liver tissue. It was not possible to identify other clinical and laboratory parameters that reliably reflect the degree of morphological changes in BA. For diseases manifested by intrahepatic cholestasis, in order to clarify the diagnosis, a morphological study of liver biopsy was carried out on 35 children aged 1 to 4 months of life. Of these, 9 children had Bayler's disease, 11 children had Alagille syndrome, 4 children had a non-syndromic form of bile duct hypoplasia, 4 children had PFIC type 3, 3 children had a-1-AT deficiency, two had neonatal hemochromatosis, and two had galactosemia. All children had cholestasis, minimal or low degree of inflammation activity according to Knodel and fibrotic changes. The maximum severity of fibrosis is described in type 3 PFIC (3.75+0.5 points), significantly different from children with Byler's disease (1.5+0.5 points) and Alagille syndrome (1.3+0.5 points) (R<0,05). Характерным гистологическим признаком синдрома Алажиля является гипоплазия внутрипеченочных желчных протоков. Во всех исследованиях отношение внутрипеченочных желчных протоков к портальным трактам было меньше 0,6. Кроме того, единичные желчные протоки, которые определялись в препаратах, в большинстве случаев оказывались аномальными (рис 5). Типичным для болезни Байлера является внутриклеточное скопление крупных гранул желчи «желчи Байлера» наряду со значительным увеличением размеров гепатоцитов, выявленное у всех детей (рис 5). Характерным проявлением неонатального гемохроматоза служит внутриклеточное скопление железа (рис 5), дефицита а-1-АТ - ПАС-позитивные включения.

Ab
V

Env. according to Van Gieson Okr. hematoxylin and eosin, Env. according to Perls

Fig 5. Abnormal bile duct in Alagille syndrome (a), intracellular accumulation of bile clumps– “Byler’s bile” in Byler’s disease (b), Intracellular accumulation of iron in neonatal hemochromatosis (c).

In order to study the role of viral infections in the genesis of diseases of the hepatobiliary system, we conducted a study of the DNA of viruses of the Herpes family and hepatitis B and C viruses using PCR in liver biopsies and in blood. In parallel, a histological examination of the liver biopsy was carried out. The study included a patient with generalized CMV infection, one of the manifestations of which was hepatitis. In liver biopsy, CMV DNA was detected in the majority of children with BA and in a patient with a generalized form of CMV (Table 5). In other diseases with known etiopathogenesis, this virus was detected only in 2 children.

Table 5. Frequency of detection of CMV DNA in liver biopsy of children with diseases of the hepatobiliary system.

Diagnosis	Liver biopsy	blood
BA	27 / 30	5 / 30
PSVH types 1-3	1 / 7	0 / 7
Alagille syndrome	1 / 5	0 / 5
PSC	0 / 2	0 / 2
Neonatal hemochromatosis	0 / 2	0 / 2
Other	0 / 3	0 / 3
CMV hepatitis.	1 / 1	1 / 1

It is known that jaundice syndrome in children is represented by a variety of conditions. And if hemolytic, hepatitis and, less common in childhood, mechanical (surgical = subhepatic) jaundice are well known to pediatricians and are taken into account in differential diagnosis, then the so-called familial forms (functional hyperbilirubinemic syndromes) are more often described in the casuistry section. But as the structure of morbidity changes, hereditary syndromes come to the fore. Patients with functional hyperbilirubinemic conditions, primarily children, are observed for a long time (according to our data, from 6 months to 3 years or more) with initially erroneous diagnoses (hepatitis, etc.). Meanwhile, remembering a disease means diagnosing it by 50%.

In this regard, we decided to summarize the literature data and the results of our own observations.

In terms of time of manifestation and severity of manifestations, one of the first places is occupied by Crigler-Nayyar syndrome.

Crigler-Nayyar syndrome type I is a congenital familial non-hemolytic jaundice with kernicterus resulting from the complete absence of uridine diphosphate glucoronyl transferase (UDPGT) with normal liver functions and no signs of hemolysis or Rh conflict.

The pathogenesis of the disease lies in the absence or sharp decrease in the activity of UDPGT, as a result of which the serum level of unconjugated fat-soluble bilirubin significantly increases. It binds to albumin and diffuses across the placental and blood-brain barriers (the latter only in newborns). The binding (a kind of buffer, compensatory capacity) of albumin decreases and, accordingly, the clinical course of the syndrome worsens with hypoalbuminemia, acidosis, an increase in the concentration of organic ions, the administration of heparin, salicylates, sulfonamides, and the consumption of free fatty acids. The penetration of unbound, unconjugated bilirubin into cells and mitochondria leads to a blockade of oxidative-phosphorylation reactions, especially in the hypothalamus, caudate nucleus, subcortical nuclei, and cerebellum.

Clinically, jaundice is noted. Unconjugated bilirubin can reach a concentration of 400-450 mg/l. Fecal urobilinogen does not exceed 100 mg/l. Kernicterus is manifested by bilirubin encephalopathy in the form of hypotension, lethargy, as well as a sharp depression or even absence of the sucking reflex, neurogenic and metabolic hypotrophy, opisthotonus, and spasticity. The use of phenobarbital or glutethemide - inducers of microsomal enzymes - does not give positive results. Functional liver tests (isolation of indocyanine green, bromosulfthalein), as well as cholangiography, liver histology and hematological findings do not add anything significant to the overall clinical picture. The prognosis of the disease is very poor, patients rarely live more than 18 months.

Differential diagnosis (DD) is carried out with Gilbert-Meulengracht, Dabin-Jones, Rotor, Lucy-Driscoll syndromes, kernicterus of newborns of any other etiology, congenital cirrhosis of the liver and hepatitis, atresia of the biliary ducts or small intestine ().

The course of Crigler-Nayyar syndrome type II is much more favorable. Its definition almost exactly repeats Crigler-Nayyar syndrome type I (congenital familial non-hemolytic jaundice with kernicterus with normal liver functions), with the only difference that UDFGT is present, although the enzyme activity is significantly reduced. The level of unconjugated bilirubin can fluctuate between 60-250 mg/l, fecal urobilinogen - 200-800 mg/l. The effect of phototherapy and microsomal enzyme inducers is good. Jaundice rarely reaches the nuclear stage, patients live up to 50 years or more, but in a separate period, especially with delayed treatment, cases of deafness, choreoathetosis, neuromuscular and personality abnormalities, and dental hypoplasia are common.

In terms of frequency among congenital familial functional bilirubinemias, Gilbert's syndrome ranks first. Our experience of working in multidisciplinary - pediatric and therapeutic - clinics has shown that in each of them about 10 - 20 cases of the syndrome are identified per year. But the true frequency is apparently higher, since the diagnosis of the disease is based mainly on clinical data and a functional test with fasting, and “clinical mildness” does not attract the doctor’s attention. Thus, S. D. Podymova believes that at least 1–5% of the population have Gilbert’s syndrome. Having observed such patients, we came to the conclusion that the syndrome is associated with generalized connective tissue dysplasia (especially often like Marfan and Ehlers-Danlos syndromes).

The pathogenesis of the syndrome is ambiguous. A slight decrease in the activity of UDFGT is detected (by 10 - 30% compared to the norm), but the main significance is given to the disruption of the uptake of bilirubin by hepatocytes. The latter is associated with an abnormality in membrane permeability and a defect in intracellular transport proteins. This heterogeneity in bilirubin clearance is also reflected by the variability of test substrates such as bromosulfthalein and indocyanine green.

Clinically, the syndrome is characterized by subictericity of varying degrees of severity. More often this is expressed in icterus of the sclera, dull yellowness of the skin, especially the face, sometimes partial yellowing of the feet and palms, armpits and nasolabial triangle. Patients often complain of general weakness, depression, poor sleep, and difficulty concentrating. The effect of hunger on increasing serum bilirubin levels is also known for healthy people, but is significantly pronounced in Gilbert's syndrome. In order to identify it, a fasting test is carried out. Within 48 hours, the patient receives food with an energy value of 400 kcal/day. On the day the test starts, in the morning on an empty stomach and 2 days later, serum bilirubin is determined. When it rises by 50 - 100%, the test is considered positive.

Recently, many experts have completely identified it with Meulengracht syndrome, considering them as one condition - Gilbert-Meulengracht syndrome - and defining it as a benign familial constitutional hiberbilirubinemia resulting from abnormal liver enzymes. Family history is of great importance for the diagnosis (slight jaundice in the patient’s family members). The clinical picture is manifested by intermittent mild jaundice, never accompanied by nuclear jaundice. Jaundice increases with fasting, as mentioned above, physical overload, surgical interventions, alcohol consumption, and infectious diseases. Patients are concerned about nausea, a feeling of fullness in the stomach, heaviness in the epigastrium, pain in the right hypochondrium, constipation or dyspepsia. Almost half of the patients have latent hemolysis (a risk group for cholelithiasis!). Along with the already mentioned neurological disorders, within the framework of general connective tissue dysplasia characteristic of these patients, such manifestations as flaming and pigmented nevi, pigmentation of the eyelids, bradycardia and arterial hypotension are also described. The use of microsomal enzyme inducers is very effective. The prognosis is good. The diagnosis is based on clinical examination and laboratory functional tests. Histological findings (see table) are nonspecific and are not always detected. Therefore, in view of the general non-severe condition of the patients, a puncture biopsy of the liver is hardly justified (remember that the risk of examination should not exceed the risk of an unidentified diagnosis and that previously patients died from the disease, later from treatment, and now from examination).

DD is carried out with all types of unconjugated bilirubinemia, Crigler-Nayjar syndrome type II, hemolytic anemia, shunt hyperbilirubinemia (ineffective hematopoiesis with intramedullary formation of a significant amount of bilirubin = thalassemia, pernicious anemia), posthepatic persistent hyperbilirubinemia.

Dubin-Jones syndrome is a familial disorder of the excretion of conjugated bilirubin into the bile ducts, combined with pigment deposition in the liver cells and moderate enlargement of the liver (“chocolate liver”). There is no violation of glucuronidation. The pathogenesis consists of insufficient transport of conjugated bilirubin into and out of the hepatocyte. Bilirubin enters the blood, its level in the blood rises, and then it is intensively excreted through the kidneys. The disease can debut at any age (different gene penetrance?), but often manifests itself after taking hormonal contraceptives or during pregnancy.

Clinically, VV manifests itself in recurrent periods of jaundice of varying severity, but, as a rule, is not accompanied by itching; the increase in the size of the liver and then the spleen is moderate. Liver function tests are not changed or changed slightly, but there is a slow release of contrast into the gallbladder, an increase in the level of coproporphyrin I and a decrease in the level of coproporphyrin III in the urine. Histologically, melanin-like pigment ranging from yellow-brown to black is deposited in liver ribosomes. Kupffer cells remain free, and the connective tissue does not grow.

DD is carried out with all forms of conjugated and unconjugated hyperbilirubinemia with jaundice: Gilbert-Meulengracht, Rotor, Caroli syndromes (cystic dilatation of intrahepatic bile ducts), hepatitis, primary biliary cirrhosis, cholestasis, Zieve syndrome (symptom complex). Zieve syndrome is a symptom complex with hemolytic anemia, hyperlipidemia and jaundice that develops in patients with excessive alcohol consumption. It is caused by an increased content of C16- and C18-fatty acids in the erythrocyte membrane with a decrease in the content of long-chain unsaturated acids. The provoking factor for the destruction of red blood cells is often alcohol consumption, after which hemolysis and hyperlipidemia develop. Clinically, the syndrome manifests itself mainly after alcoholic excesses and is accompanied by increasing pain in the right hypochondrium and/or epigastrium, fever, nausea, vomiting, loss of appetite, an increase in the size of the liver, and often the spleen. In laboratory tests - increased activity of transaminases, alkaline phosphatase, gamma-glutamyltransferase, anemia with manifest or latent hemolysis, hypercholesterolemia and/or hypertriglyceridemia. Histologically - alcoholic fatty degeneration of the liver with or without cirrhosis.

A form of Dubin-Jones syndrome (or an independent nosological unit?) is Burk syndrome. In this case, lipochromic hepatosis is also detected, but WITHOUT jaundice, although WITH SIGNIFICANT hepatosplenomegaly.

Rotor syndrome is an idiopathic familial benign hyperbilirubinemia with an adequate increase in conjugated and unconjugated bilirubin.

The pathogenesis consists of impaired uptake of unconjugated bilirubin by hepatocytes, changes in its glucuronidation and excretion, followed by reflux of bilirubin into the blood.

Clinically, the syndrome is manifested by chronic jaundice (or subicterus) of the skin and mucous membranes. At the same time, its intensity fluctuates; an increase in the size of the liver and spleen is not observed. The histological picture of the liver under light microscopy is not changed, under electron microscopy - mitochondria of various sizes, in phagolysosomes - pigment bodies in the form of lattice-shaped inclusions.

Diagnoses of posthepatic benign hyperbilirubinemia and physiological jaundice of newborns, postprandial jaundice (long-term consumption of large amounts of refractory fats), as prognostically favorable, are based on the principle of excluding more severe variants of hyperbilirubinemia. It can be assumed that such conditions are associated with subtle enzymatic abnormalities or abnormalities in the development of the gallbladder (constrictions, kinks, especially in the siphon area, narrowing of the common bile duct, leading to increased pressure in the bile ducts and excessive load on the hepatocyte).

Familial benign recurrent cholestasis = Aagenes syndrome = Summerskill-Tigstruppa = Norwegian cholestasis = cholestasis with lymphedema. The very abundance of synonyms indicates the rarity of the syndrome: each newly described case is presented to the authors as a discovery. Because it is rarely found in the literature, it is difficult to determine its true prevalence. It is mainly known from descriptions of Scandinavian authors. The pathogenesis probably involves hypoplasia of the lymphatic vessels of the liver and other organs.

Clinically, the syndrome manifests itself as cholestasis (the most sensitive and specific enzyme of cholestasis is leucine aminopeptidase) already in the neonatal period. Then cholestasis decreases on its own, recurring in adults. Lymphedema develops slowly. Hepatomegaly and liver dysfunction are typical. Histologically, it is expressed as intrahepatic cholestasis with giant cell transformation.

Chronic cholestasis is accompanied by a deficiency of fat-soluble vitamins. Vitamin E deficiency leads to progressive cerebellospinal degeneration (Permutter syndrome).

DD of Aagenes syndrome is carried out with all syndromes of cholestasis and congenital lymphedema (Milroy, Wever-Smith syndromes).

Malignant familial cholestasis (Byler's disease = Clayton-Uberg syndrome). In the vast majority of cases, it appears in the 1st year of life. Initially, cholestasis (jaundice) resolves on its own after a few weeks or months. Then the intensity of jaundice increases, and painful itching occurs. The liver and spleen are significantly enlarged. As a result of damage to the liver parenchyma, hemorrhagic syndrome occurs. Echographically, the liver looks dense, resembles cirrhotic, and thick stagnation is observed in the lumen of the gallbladder. The prognosis is bad.

DD is performed with all cholestasis syndromes and Alagille syndrome.

Lucy-Driscoll syndrome is an autosomal recessively inherited rare condition manifested by massive hyperbilirubinemia, which develops in all children born to the same mother with this disease in the first four days of their life.

The pathogenesis lies in the presence of a factor - an inhibitor of bilirubin conjugation in the blood and urine of the mother and postnatally in the blood and urine of children. The serum of such mothers inhibits in vitro bilirubin conjugation 5-7 times more strongly than the serum of women who are not conductors of this syndrome. A similar factor is probably represented by a steroid, but it has not yet been identified. The clinical picture corresponds to severe hyperbilirubinemia up to kernicterus.

DD is carried out with Crigler-Nayjar syndrome types I and II, novobiocin jaundice, estrogen jaundice (transient jaundice of infants fed breast milk) and oxytocin jaundice.

Treatment of familial functional hyperbilirubinemia is carried out according to the following principles:

• excretion of conjugated bilirubin (increased diuresis, activated carbon as an adsorbent of bilirubin in the intestine);
• binding of already circulating bilirubin in the blood (introduction of albumin at a dose of 1 g/kg body weight for 1 hour). It is especially advisable to administer albumin before replacement blood transfusion;
• destruction of bilirubin fixed in tissues, thereby releasing receptors, peripheral receptors that can bind new portions of bilirubin, preventing its penetration through the blood-brain barrier. This is achieved through phototherapy. The maximum effect is observed at a wavelength of 450 nm. Blue light lamps are more effective, but they make it difficult to observe your baby's skin. The photo source is placed at a distance of 40 - 45 cm above the body (the procedure is carried out only in an incubator with temperature control). The child's eyes must be protected. The photodegradation of bilirubin is enhanced by riboflavin, which is a chromophore even in intracellular concentration. The required duration of phototherapy is also reduced with the addition of cholestyramine, although this drug is less physiological than riboflavin. Phototherapy is much more effective when simultaneously conducting sessions of oxygen barotherapy, since oxygen enhances the decomposition of bilirubin;
• for syndromes caused by a decrease in the activity of UDFGT (for example, Crigler-Nayyar type 11), the appointment of inducers of microsomal enzymes: phenobarbital up to 5 mg/kg per day, and after 12 years and glutethimide. The use of cytochromes seems promising;
• the desire to avoid provoking factors (infection, overload), drugs that compete with glucoronidation or displace bilirubin from its connection with albumin (oral contraceptives, sulfonamides, heparin, salicylates). Conditions accompanied by increased permeability of the blood-brain barrier (acidosis) should be avoided;
• use of sufficient water load (prevention of bile thickening syndrome);
• in the presence of plasma glucuronidation inhibitors transmitted in mother's milk, warming the milk at 56°C for 15 minutes;
• the use of additional doses of fat-soluble vitamins and microelements;
• in critical cases - exchange blood transfusion.

Thus, thoughtful interpretation of the symptoms of hyperbilirubinemia, early diagnosis, comprehensive treatment, and careful follow-up will improve the prognosis of familial hyperbilirubinemia.

Literature

1. Alazhil D., Odevre M. Diseases of the liver and biliary tract in children. M.: Medicine, 1982. - 486 p.
2. Asoyan A. V. The use of hyperbaric oxygenation in the complex treatment of hyperbilirubinemia in newborns with hemolytic disease. Author's abstract. dis... Ph.D. M., 1985. - 24 p.
3. Hasan Abu Jabal. Chronic gastroduodenitis in children against the background of connective tissue dysplasia. Author's abstract. dis... Ph.D. M., 1997. - 24 p.
4. Imambaev S.E. Echography in the diagnosis of diseases of the biliary system in children. Author's abstract. dis... Ph.D. M., 1986. - 24 p.
5. Podymova S. D. Liver diseases. M.: Medicine, 1993. - 544 p.
6. Emery A., Rimoin D. (Ed.) Principles and practice of medical Genetics. London, Vv. 1, 2. - 1983.
7. Leiber B. Die klinischen Syndrome. Muenchen. — 1990.
8. Moelbert E., Marx R. Elektronenmikroskopiesche Untersuchungen am Lebergewebe beim Rotor-Syndrom. Acta hepato-splenoloy, 1966. - 13. - ss. 160 - 175.

DEFINITION

A hereditary disease based on a violation of the excretion of bile acids through the canalicular membrane of the hepatocyte. It was first described in children, descendants of Jacob Byler, and has since been named after him.

ICDC CODE 76.8 - Other specified liver diseases.

ETIOLOGY

Progressive familial intrahepatic cholestasis is a consequence of a genetically determined disruption of the structure of the hepatocyte canalicular membrane. It has an autosomal recessive type of inheritance and includes three main types: type 1 (Bailer's disease), type II (Bailer's syndrome), type III (MDR3 gene deficiency). Types I and II are based on impaired excretion of bile acids, while type III is caused by impaired excretion of phospholipids.

The gene responsible for the development of the disease is localized in the region of the long arm of chromosome 18 (18q21), with a length of 7 cM in the interval between markers D18S69 and D18S64.

PATHOGENESIS

Byler's disease is based on a deficiency of the membrane-bound enzyme, P-type ATPase, which plays a key role in the transport of fat-soluble compounds and bile acids through the canalicular membrane of the hepatocyte. As a result of this defect, primary bile acids accumulate in liver cells and have a damaging effect on them, promoting their destruction (trigger factor of apoptosis). On the other hand, primary bile acids do not enter the bile system and, therefore, the intestines, which leads to disruption of the absorption of fats and fat-soluble vitamins.

CLINICAL PICTURE

The appearance of the first signs of cholestasis in most cases is noted during the neonatal period, less often at the age of 1-10 months of life. Cases of gastrointestinal and intracranial bleeding that preceded the appearance of other clinical signs of the disease have also been described. Characterized by jaundice, moderate hepatomegaly, inconsistent acholia of stool and dark urine. A typical sign of Byler's disease is itchy skin, which appears within the first three months of life. The child's lag in physical development and the presence of signs of deficiency of fat-soluble vitamins (rachitic changes and osteopenia, muscle hypotonia, dry skin and mucous membranes, dullness and brittleness of nails and hair, ophthalmoplegia, petechial rash and/or bleeding of mucous membranes) are also characteristic of this disease. Cholestasis syndrome in Byler's disease has a wave-like course. Factors contributing to the increase in clinical and laboratory signs of cholestasis are infectious diseases of the upper respiratory tract and other intercurrent diseases.

DIAGNOSTICS

Prenatal

These genetic markers of chromosome 18 can also be used for prenatal diagnosis of the disease and genetic counseling.

Physical examination

It is necessary to evaluate the color of the skin and sclera, the size of the liver and spleen, the color of stool and urine. Children older than three months of age may have itchy skin.

Laboratory research

Low levels of GGT and serum cholesterol along with an increase in other markers of cholestasis, including alkaline phosphatase, direct fraction of bilirubin and bile acids.

Characterized by an increase in cytolysis enzymes and no changes in the protein-synthetic function of the liver.

An increase in PT or a decrease in the prothrombin index is often noted, the genesis of which is associated with impaired absorption of vitamin K in the intestine.

To clarify the diagnosis of Byler's disease, it is possible to carry out molecular genetic testing of a specific locus of the long arm of chromosome 18 (18q21), with a length of 7 cM in the interval between markers D18S69 and D18S64.

Instrumental studies

When performing a puncture biopsy of the liver, the presence of predominantly intracellular cholestasis is noted. Secondarily, a rearrangement of hepatocytes occurs, forming tubular structures, pseudotubules and the formation of biliary cirrhosis of the liver. Electron microscopy detects bile in the form of coarse granules ("Byler's bile") in hepatocytes and intrahepatic bile canaliculi.

Differential diagnosis

Carry out with other liver diseases manifested by intrahepatic cholestasis with low levels of the GGT enzyme (Zellweiger syndrome, impaired synthesis of bile acids due to fermentopathy).

Consultation with a clinical geneticist is indicated.

TREATMENT

Treatment Goals

Correction of complications of long-term cholestasis.

Non-drug treatment

Drug treatment

Ursodeoxycholic acid at a dose of 20-30 mg/(kg/day) in 2 doses - constantly. Fat-soluble vitamins, macro- and microelements (see treatment of ARVP). In older children, with the development of skin itching, the following drugs are used: cholesterol at a dose of 4-16 g/day, rifampicin 10 mg/kg/day) and others, phototherapy, plasmapheresis. They also use products that affect the skin's receptor apparatus, such as menthol oil, lanolin, warm baths, etc.

Surgery

With the development of pathological conditions that impair the patient’s quality of life (skin itching, retardation in physical development, changes caused by a deficiency of fat-soluble vitamins), liver transplantation is performed.

Further management

Drug treatment is carried out continuously. Dynamic outpatient examination once every 1-2 months or as indicated.

Without liver transplantation, the prognosis of the disease is unfavorable. Patients die between the ages of 2 and 15 years. Some patients have been described with a life expectancy of up to 25 years. In addition, as the disease progresses, cancer of the liver and biliary system may develop.

Progressive familial intrahepatic cholestasis type II (Byler syndrome)

DEFINITION

A hereditary disease based on a violation of the excretion of predominantly one primary bile acid (chenodeoxycholic acid) through the canalicular membrane of the hepatocyte, associated with the absence of P-glycoprotein on its surface.

ICD-K76.8 CODE - other specified liver diseases.

EPIDEMIOLOGY

The disease occurs in isolated populations in the Middle East. Greenland and Sweden.

ETIOLOGY

The gene responsible for the development of this disease is localized on chromosome 2 (2q24). This gene has a molecular structure similar to that of the gene responsible for the development of type I progressive familial intrahepatic cholestasis, and therefore it is designated “sister”. The basis of progressive familial intrahepatic cholestasis type II is a violation of the excretion of predominantly chenodeoxycholic acid through the canalicular membrane of the hepatocyte, associated with the absence of P-glycoprotein on its surface.

PATHOGENESIS

Does not differ from type 1 progressive familial intrahepatic cholestasis.

CLINICAL PICTURE

DIAGNOSTICS

Prenatal

These genetic markers of chromosome 2 can be used for prenatal diagnosis of the disease and genetic counseling.

Physical examination

See Progressive familial intrahepatic cholestasis type I.

Laboratory research

See Progressive familial intrahepatic cholestasis type I.

Differential diagnosis

Conducted with other liver diseases manifested by intrahepatic cholestasis with low levels of the GGT enzyme. Consultation with a clinical geneticist is indicated.

Etiopathogenetic.

Treatment goals: correction of complications of long-term cholestasis.

Non-drug treatment

Medical nutrition with a high content of medium chain triglycerides.

Drug treatment

See Progressive familial intrahepatic cholestasis type I.

Surgery

See Progressive familial intrahepatic cholestasis type I.

Further management

See Progressive familial intrahepatic cholestasis type I.

See Progressive familial intrahepatic cholestasis type I.