Cholestasis

Cholestasis is a stagnation and a decrease in the intake of bile in the 12 duodenum as a result of a violation of its excretion due to a pathological process at any site from the hepatocyte to the father nipple. Prolonged cholestasis leads to the development of biliary cirrhosis of the liver for several months or years. The formation of cirrhosis is not accompanied by sharp changes in the clinical picture. The diagnosis of biliary cirrhosis is morphological, it is established in the presence of regenerating nodes in the liver and such signs of cirrhosis as hepatic encephalopathy or fluid retention in the body.

Functionally, cholestasis means a decrease in tubular bile flow, hepatic excretion of water and organic anions (bilirubin, bile acids).

Morphologically, cholestasis means the accumulation of bile in hepatocytes and bile ducts.

Clinically, cholestasis means a delay in the blood of components normally excreted in bile. Increases the concentration of bile acids in the blood serum. Clinical signs are itchy skin (not always), an increase in the level of alkaline phosphatase (biliary isoenzyme), GGTP in serum.

[1], [2], [3], [4], [5], [6], [7], [8]

Causes of cholestasis

Violation of the passage of bile can be observed at any level, from the intrahepatic ducts to the ampule of the Fater's nipple. The causes of intrahepatic cholestasis include hepatitis, toxic effects of drugs and alcoholic liver disease. Rarer causes include primary biliary cirrhosis, pregnant cholestasis and metastatic cancer.

Extrahepatic causes of cholestasis include concrements of the common bile duct and pancreatic cancer. Less common are strictures of the common bile duct (usually associated with a previous operation), ductal cancer, pancreatitis, pancreatic pseudocyst and sclerosing cholangitis.

Causes of cholestasis

[9], [10]

How does cholestasis develop?

Mechanisms for the development of cholestasis are complex, even with mechanical obstruction. Pathophysiological mechanisms reflect the absence of bile elements (most importantly - bilirubin, bile salts and lipids) in the intestines and back absorption, which leads to their entry into the systemic bloodstream. The chair is most often discolored because of the small intake of bilirubin into the intestine. The absence of bile salts can lead to malabsorption, causing steatoreju and deficiency of fat-soluble vitamins (especially A, K and D); Vitamin K deficiency can lead to a decrease in the level of prothrombin. With prolonged course of cholestasis, concomitant malabsorption of vitamin D and calcium can cause osteoporosis or osteomalacia.

Violation of the passage of bilirubin leads to the development of mixed hyperbilirubinemia. A certain amount of conjugated bilirubin enters the urine and gives it a dark color. With the high level of bile acid salts circulating in the blood, the appearance of pruritus is probably associated. An increase in the level of cholesterol and phospholipids leads to hyperlipidemia, despite malabsorption of fat (this is facilitated by an increase in the synthesis in the liver and a decrease in the esterification of cholesterol in the blood plasma); a significant change in the level of triglycerides does not occur. Lipids circulate in the blood as a special, atypical, low-density lipoprotein, called lipoprotein X.

Pathogenesis of cholestasis

Noncholestatic conjugated hyperbilirubinemia

Disturbances of bilirubin metabolism that cause conjugated hyperbilirubinemia without cholestasis occur without clinical symptoms and complications, with the exception of jaundice. Unlike unconjugated hyperbilirubinemia in the Gilbert syndrome, bilirubin can appear in the urine. The levels of aminotransferases and alkaline phosphatase remain within normal limits. Treatment is not required.

Symptoms of cholestasis

Dubin-Johnson Syndrome

This rare autosomal recessive disease leads to impaired glucoronide excretion of bilirubin. The disease is usually diagnosed with a liver biopsy; while the liver is significantly pigmented as a result of intracellular accumulation of a melanin-like substance, but otherwise the histological structure of the liver is normal.

[11], [12], [13], [14], [15], [16], [17]

Rotor Syndrome

This is a rare disease that proceeds clinically like Dubin-Johnson syndrome, but liver pigmentation is not noted, although there are other subtle metabolic differences.

Unconjugated hyperbilirubinemia is a violation of bilirubin metabolism, which consists in its increased synthesis or disruption of conjugation.

Hemolysis

Hemolysis of erythrocytes is the most frequent and clinically important reason for the increased synthesis of bilirubin. Despite the fact that a healthy liver can bind excess bilirubin, hemolysis can lead to its uncontrolled increase. However, even with intensive hemolysis, serum bilirubin rarely reaches values greater than 5 mg / dl (> 86 μmol / L). At the same time, hemolysis against liver disease can cause a significant increase in the level of bilirubin; in these cases, ductal bile excretion is also impaired, leading in some cases to conjugated hyperbilirubinemia.

Gilbert's Syndrome

Gilbert's syndrome is presumably a disease with asymptomatic course and moderate unconjugated hyperbilirubinemia throughout life; it can be taken for chronic hepatitis or other liver diseases. Gilbert syndrome occurs in 5% of the population. A family history is traced, but it is difficult to establish a clear picture of inheritance.

Pathogenesis involves a complex of complex disturbances in the metabolism of bilirubin in the liver. At the same time, the activity of glucuronyltransferase is reduced, although not as significantly as in type II of the Kriegler-Nayar syndrome. Many patients also slightly accelerated the destruction of red blood cells, but this does not explain hyperbilirubinemia. The histological structure of the liver is within normal limits.

Gilbert's syndrome is most often found by chance in young people when an increased level of bilirubin is found, which usually ranges between 2 and 5 mg / dL (34-86 μmol / L) and tends to increase with fasting and stress.

Gilbert's syndrome should be differentiated from hepatitis by examining the bilirubin fractions, which show the predominance of unbound bilirubin, normal indices of functional hepatic tests and the absence of bilirubin in the urine. The absence of anemia and reticulocytosis allows to exclude hemolysis. Special treatment is not required.

The Kriegler-Nayar Syndrome

This is a rare, inherited syndrome, associated with a deficiency of the enzyme glucuronyltransferase. In patients with autosomal recessive I type (complete) disease, pronounced hyperbilirubinemia is observed. They usually die from bilirubin encephalopathy at the age of 1 year, but can live to adulthood. Treatment includes UFO and liver transplantation. In patients with autosomal dominant type II (partial) disease (which has variable penetrance), hyperbilirubinemia is less expressed [<20 mg / dL (<342 μmol / L)]. They tend to live to adulthood without neurological disorders. Phenobarbital (1.5-2.0 mg / kg orally 3 times a day) can be effective, inducing microsomal enzymes of hepatocytes.

Primary bypass giperbilirubinemia. This is a rare family benign condition associated with hyperproduction of early labeled bilirubin.

Classification of cholestasis

Cholestasis is divided into extra- and intrahepatic, as well as acute and chronic.

Extrahepatic cholestasis develops with mechanical obstruction of the bile ducts, usually outside the liver; at the same time, obstruction in the cholangiocarcinoma of the liver gates that germinate the main intrahepatic ducts can also be attributed to this group. The most common cause of extrahepatic cholestasis is the stone of the common bile duct; Other causes include pancreatic cancer and fatal nipple, benign duct strictures and cholangiocarcinoma.

[18], [19], [20], [21], [22], [23], [24]

Diagnosis of cholestasis

The evaluation is based on anamnesis, physical examination and diagnostic tests. It seems very important differential diagnostics between the intra-hepatic and extrahepatic causes.

Cholestasis leads to jaundice, darkening of urine, discoloration of the stool and generalized skin itching. If cholestasis has a chronic course, increased bleeding may occur (due to malabsorption of vitamin K) or bone pain (due to osteoporosis due to malabsorption of vitamin D and calcium). Abdominal pain and general symptoms (eg, anorexia, vomiting, fever) reflect the underlying cause, and do not directly manifest as cholestasis. Signs of hepatitis due to alcohol abuse or taking potentially dangerous from the point of view of the development of cholestasis drugs presume the presence of intrahepatic cholestasis. Hepatic colic or pain, typical of pancreatic diseases (eg, pancreatic cancer), involves extrahepatic cholestasis.

[25], [26], [27], [28], [29], [30]

Physical examination

In chronic course of cholestasis, dark pigmentation of the skin, excoriation (due to itching) or skin deposits of lipids (xanthelasm or xanthoma) can be observed. Symptoms of chronic hepatocellular diseases (for example, spider veins, splenomegaly, ascites) indicate the presence of intrahepatic cholestasis. Symptoms of cholecystitis suggest extrahepatic cholestasis.

Laboratory research

Regardless of the etiology, a characteristic increase in the level of alkaline phosphatase reflects a higher degree of its synthesis than a decrease in excretion. Aminotransferase levels usually increase moderately. The level of bilirubin varies. In order to clarify the cause of increased alkaline phosphatase, provided that other hepatic tests are within normal limits, it is necessary to determine the level of gamma glutamyltranspeptidase (GGT). If there is a suspicion of a liver failure, it is necessary to define PV (MHO is usually used). Unfortunately, neither the level of alkaline phosphatase and GGT nor the level of bilirubin does not reflect the cause of cholestasis.

Sometimes other laboratory tests help in clarifying the cause of cholestasis. An increase in the level of aminotransferases suggests hepatocellular disorders, but their increase is often observed even with extrahepatic cholestasis, especially in cases of acute obstruction of the common bile duct with a stone. A high level of serum amylase is a nonspecific index, but suggests complete obstruction of the common bile duct. Correction of prolonged PV or MHO after intake of vitamin K suggests extrahepatic obstruction, but this can be observed in hepatocellular disorders. The detection of antimitochondrial antibodies specifically indicates primary biliary cirrhosis of the liver.

Instrumental studies of the biliary tract are mandatory. Ultrasonography, CT and MRI reveal the dilatation of the common bile duct, which usually occurs a few hours after the onset of symptoms of mechanical obstruction. The results of these studies can establish the main cause of obstruction; in general, gallstones are well diagnosed in ultrasonography, and pancreatic damage - with CT. Ultrasound is usually more preferred because of the lower cost and the lack of ionizing radiation. If an extrahepatic obstruction is established in ultrasonography, but not its cause, a more informative study, usually endoscopic or magnetic resonance cholangiopancreatography (ERCPG, MRCPG), is shown. Diagnostic laparoscopy or laparotomy is rarely used, only in case of progression of extrahepatic obstruction and if it is impossible to establish the cause by other instrumental methods. A liver biopsy is indicated if there is a suspicion of intrahepatic cholestasis if the diagnosis is not established by non-invasive diagnostic methods. Since this manipulation involves damage to the biliary tree, which can lead to peritonitis, biopsy should be preceded by dilatation of the biliary tract (ultrasonography or CT).

Diagnosis of cholestasis

Treatment of cholestasis

Extrahepatic biliary obstruction requires mechanical decompression. In other cases it is necessary to treat the underlying cause, manifestations and complications (for example, malabsorption of vitamins).

Decompression of the biliary tract usually requires laparotomy, endoscopy (for example, for the removal of duct stones) or the installation of walls and drainage with stricture and partial obstruction. When an inoperable malignant neoplasm is obstructed, the stent is usually installed transhepatically or endoscopically to ensure adequate drainage.

Treatment of cholestasis

Cutaneous itching usually disappears after elimination of the main cause of cholestasis or when taking cholestyramine in a dose of 2-8 g orally 2 times a day. Cholestyramine binds bile salts in the intestine. However, cholestyramine is ineffective with complete biliary obstruction. If hepatocellular disorders are not expressed, hypoprothrombinemia is usually compensated by the use of vitamin K preparations. The addition of calcium and vitamin D preparations, with or without a bisphosphonate, only slightly slows the progression of osteoporosis in the long-term and irreversible course of cholestasis. The addition of vitamin A prevents its deficiency, and the symptoms of severe steatorrhea can be minimized by replacing edible fat (medium chain) triglycerides.