Byler’s disease is a rare hereditary disease characterized by impaired transport of bile acids from liver cells, which leads to the rapid development of cirrhosis. The main clinical manifestations include jaundice staining of the skin and mucous membranes, itching, enlargement of the liver and spleen. Urine gets a dark shade, feces – light. The diagnosis is based on the detection of a genetic mutation (ATP8B1). The only radical treatment is surgical intervention (bypass surgery, liver transplantation). Conservative treatment (antipruritic, choleretic drugs, anti-cirrhotic therapy) is symptomatic.
K76 Other liver diseases
Byler’s disease (progressive familial intrahepatic cholestasis type I) was described in the descendants of Jacob Byler and has since been named after him. The first observation of this disease was made by pediatrician R. Clayton in 1965. According to various epidemiological data, the prevalence of pathology ranges from 1 in 50,000 to 1 in 100,000 newborns. However, to date, less than 200 clinical cases of Byler’s disease have been described. The greatest number of patients is noted among the Amish, an ethnically isolated group representing a special religious movement.
The development of Byler’s disease is caused by a mutation of the ATP8B1 gene located on chromosome 18 (locus 18q21-22). This gene is responsible for the synthesis of the enzyme P-type ATPase. This enzyme is located on the surface of hepatocytes. Its main function is to regulate the transport of ursodeoxycholic and henodeoxycholic acids from liver cells to the bile ducts. The type of hereditary transmission of pathology is autosomal recessive.
As a result of a genetic mutation, the activity of the P-type ATPase enzyme decreases sharply. Due to impaired transport into the ducts, bile acids (LC) begin to linger in hepatocytes, intrahepatic cholestasis occurs. As a result, the LC does not enter the intestinal lumen, so there is no important stage in digestion – the emulsification of fats.
The absorption of many nutrients, including fat-soluble vitamins (A, D, E, K), significantly worsens, which can lead to serious complications. Bile acids retained in hepatocytes have a high reactivity. The process of lipid peroxidation starts, which affects cell membranes, organelles, and the nucleus.
This leads to the death of liver cells, the proliferation of connective tissue. In view of the fact that these mechanisms occur almost from the period of the newborn, cirrhosis of the liver develops at a fairly early age. Pathoanatomic examination shows typical signs of biliary cirrhosis – cytoarchitectonics disorder, necrosis of hepatocytes, a large number of fibrous cords and nodes.
The first clinical signs that appear almost immediately after birth are jaundice and itching. Jaundice has a wave-like character, can regress independently. Relapses are often provoked by acute respiratory infections (ARI). Skin itching is often painful, intensifies at night. Multiple traces of scratching are visible on the skin.
The child becomes irritable, tearful, his sleep and appetite are disturbed. The liver and spleen are significantly enlarged (hepatosplenomegaly). The urine becomes dark, the feces lightens, up to the state of aholia. Due to impaired absorption of fats, the volume of the stool increases, fecal masses acquire an oily sheen, unformed character, are poorly washed off with water.
With the development of cirrhosis of the liver and portal hypertension, the abdomen increases even more in size due to the accumulation of fluid in the abdominal cavity (ascites). “extrahepatic signs” are attached – erythema palmar, vascular asterisks (telangiectasia) on the skin of the face and abdomen. The patient begins to lose weight, becomes weakened, sleep inversion occurs (insomnia during the day, drowsiness at night).
Rapidly developing intrahepatic cholestasis in Byler’s disease has a large number of adverse consequences. A violation of the absorption of nutrients leads to a lag in the child’s growth and physical development. Due to vitamin D deficiency, rickets, curvature of the spine occur in children, osteoporosis occurs in adults, which increases the risk of bone fractures.
Due to vitamin K deficiency, blood clotting processes are disrupted, nasal, gingival bleeding is possible. But the most serious complications, often leading to death, are associated with cirrhosis of the liver. These include hypersplenism, hepatic cell insufficiency, bleeding from esophageal veins, etc. Liver cancer (hepatocellular carcinoma) is also found in some patients.
Since Byler’s disease occurs mainly in children, pediatricians are engaged in the curation of patients. Adult patients are observed by gastroenterologists. A family history is of great importance: if one of the closest relatives has been diagnosed with Byler’s disease, then this pathology must be excluded. An additional examination is prescribed, including:
- Laboratory tests. With the development of hypersplenism against the background of liver cirrhosis, a decrease in the level of platelets, erythrocytes and hemoglobin is noted in the general blood test. In the biochemical analysis of blood in almost all patients, there is an increase in the concentration of direct bilirubin, hepatic transaminases (ALT, AST), alkaline phosphatase, a decrease in gamma-glutamyltranspeptidase, high-density lipoproteins and calcium.
- Ultrasound. Ultrasound of the abdominal organs in patients with formed cirrhosis reveals an increase in the liver, spleen, the presence of fluid, expansion and tortuosity of the portal and splenic veins.
- Genetic analysis. The polymerase chain reaction method reveals a mutation of the ATP8B1 gene of chromosome 18.
Differential diagnosis is carried out with diseases occurring with a pronounced cholestasis syndrome:
- primary sclerosing cholangitis;
- primary biliary cirrhosis;
- autoimmune hepatitis.
It is also necessary to distinguish Byler’s disease from other hereditary metabolic diseases affecting the liver and biliary tract – alpha-antitrypsin deficiency, Alazhil syndrome, etc.
All patients are subject to mandatory hospitalization in a hospital. There are currently no effective drugs that can achieve a cure for genetic pathology. Alcohol consumption is strictly prohibited. Patients with cirrhosis are recommended to limit the intake of protein and table salt. All conservative therapy is aimed at eliminating symptoms and correcting complications:
- Bile acid preparations. Ursodeoxycholic acid is prescribed in order to suppress the synthesis of endogenous bile acids and reduce the severity of cholestasis.
- Antipruritic drugs. To reduce the concentration of bile acids in the blood that cause painful skin itching, resins binding LC (cholestyramine) and inducers of microsomal liver enzymes (phenobarbital, rifampicin) are effective.
- Vitamins. In order to correct vitamin deficiency and associated complications (bleeding, osteoporosis), parenteral administration of vitamins D, K (cholecalciferol, phytomenadion) and oral forms of vitamins A, E (retinol, tocopherol) is prescribed. For the best therapeutic effect, calcium gluconate is added to vitamin D.
- Anti-cirrhotic therapy. To reduce the phenomena of ascites, albumin infusions and diuretic drugs (veroshpiron, furosemide) are prescribed. To reduce the severity of intoxication and encephalopathy, drugs binding ammonia (sodium benzoate, lactulose) are used.
Liver transplantation is considered the most radical method of treating Byler’s disease at the stage of cirrhosis formation. Transplantation allows prolonging the life of patients for 5-15 years. If it is impossible to perform a transplant, transjugular intrahepatic portosystemic bypass surgery is performed – the creation of a channel connecting the portal and hepatic veins. This operation reduces portal hypertension and thereby reduces the risk of life-threatening complications.
Prognosis and prevention
Byler’s disease is a serious disease with an unfavorable prognosis. Life expectancy in the vast majority of cases ranges from 2 to 15 years. There are data on patients who have lived up to 25-30 years. The most common cause of death of patients is gastrointestinal bleeding associated with esophageal varicose veins and vitamin K deficiency.
Less often, the fatal outcome is caused by hepatic encephalopathy and hepatic coma. The only effective method of primary prevention is considered to be prenatal diagnosis with termination of pregnancy. It is justified only if someone from close relatives of one of the parents was diagnosed with “Byler’s disease”.