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Cholestasis
Last reviewed: 12.07.2025
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Cholestasis is stagnation and reduction of bile flow into the duodenum due to a violation of its excretion due to a pathological process in any area from the hepatocyte to the Vater's papilla. Long-term cholestasis leads to the development of biliary cirrhosis of the liver over 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, established in the presence of regenerated nodes in the liver and such signs of cirrhosis as hepatic encephalopathy or fluid retention in the body.
Functionally, cholestasis means a decrease in the tubular flow of bile, 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 retention in the blood of components normally excreted in bile. The concentration of bile acids in the blood serum increases. Clinical signs include skin itching (not always), increased levels of alkaline phosphatase (biliary isoenzyme), and GGT in the serum.
Causes of Cholestasis
Obstruction of bile flow may occur at any level, from the intrahepatic ducts to the ampulla of Vater. Causes of intrahepatic cholestasis include hepatitis, drug toxicity, and alcoholic liver disease. Rarer causes include primary biliary cirrhosis, cholestasis of pregnancy, and metastatic cancer.
Extrahepatic causes of cholestasis include common bile duct stones and pancreatic cancer. Less common causes include common bile duct strictures (usually related to previous surgery), duct cancer, pancreatitis, pancreatic pseudocyst, and sclerosing cholangitis.
How does cholestasis develop?
The mechanisms of cholestasis are complex, even with mechanical obstruction. The pathophysiological mechanisms reflect the absence of bile constituents (most importantly bilirubin, bile salts, and lipids) in the intestine and their reabsorption, which leads to their entry into the systemic circulation. The stool is often discolored due to the low intake of bilirubin into the intestine. The absence of bile salts can lead to malabsorption, causing steatorrhea and deficiency of fat-soluble vitamins (especially A, K, and D); vitamin K deficiency can lead to decreased prothrombin levels. In long-term cholestasis, concomitant malabsorption of vitamin D and calcium can cause osteoporosis or osteomalacia.
Impaired bilirubin passage results in mixed hyperbilirubinemia. Some conjugated bilirubin enters the urine, giving it a dark color. High levels of bile salts circulating in the blood may be responsible for pruritus. Increased cholesterol and phospholipid levels result in hyperlipidemia despite fat malabsorption (this is facilitated by increased synthesis in the liver and decreased esterification of cholesterol in the blood plasma); triglyceride levels do not change significantly. Lipids circulate in the blood as a special, atypical, low-density lipoprotein called lipoprotein X.
Non-cholestatic conjugated hyperbilirubinemia
Bilirubin metabolism disorders causing conjugated hyperbilirubinemia without cholestasis are asymptomatic and without complications, except for jaundice. Unlike unconjugated hyperbilirubinemia in Gilbert's syndrome, bilirubin may appear in the urine. Aminotransferase and alkaline phosphatase levels remain within normal limits. No treatment is required.
Dubin-Johnson syndrome
This rare autosomal recessive disorder results in defective excretion of bilirubin glucuronide. The disease is usually diagnosed by liver biopsy; the liver is heavily pigmented as a result of intracellular accumulation of a melanin-like substance, but the liver is otherwise histologically normal.
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Rotor syndrome
This is a rare disorder that has a clinical presentation similar to Dubin-Johnson syndrome, but liver pigmentation is not observed, although other subtle metabolic differences are present.
Unconjugated hyperbilirubinemia is a disorder of bilirubin metabolism, consisting of its increased synthesis or impaired conjugation.
Hemolysis
Hemolysis of red blood cells is the most common and clinically important cause of increased bilirubin synthesis. Although a healthy liver can bind excess bilirubin, hemolysis can lead to an uncontrolled increase in bilirubin. However, even with extensive hemolysis, serum bilirubin rarely reaches values greater than 5 mg/dL (> 86 μmol/L). However, hemolysis associated with liver disease can cause significant increases in bilirubin levels; in these cases, ductal excretion of bile is also impaired, sometimes leading to conjugated hyperbilirubinemia.
Gilbert's syndrome
Gilbert's syndrome is thought to be an asymptomatic disorder with mild unconjugated hyperbilirubinemia throughout life; it may be mistaken for chronic hepatitis or other liver diseases. Gilbert's syndrome occurs in 5% of the population. There is a family history, but a clear inheritance pattern is difficult to establish.
The pathogenesis includes a complex of complex disorders of bilirubin metabolism in the liver. In this case, the activity of glucuronyl transferase is reduced, although not as significantly as in type II Crigler-Najjar syndrome. Many patients also have slightly accelerated 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 discovered incidentally in young adults when elevated bilirubin levels are found, which typically range between 2 and 5 mg/dL (34-86 µmol/L) and tend to increase with fasting and stress.
Gilbert's syndrome should be differentiated from hepatitis by examining bilirubin fractions, which demonstrate a predominance of unconjugated bilirubin, normal liver function tests, and absence of bilirubin in the urine. The absence of anemia and reticulocytosis helps to exclude hemolysis. No specific treatment is required.
Crigler-Najjar syndrome
This is a rare, inherited syndrome due to deficiency of the enzyme glucuronyl transferase. Patients with autosomal recessive type I (complete) disease have marked hyperbilirubinemia. They usually die of kernicterus by 1 year of age but may survive into adulthood. Treatment includes ultraviolet irradiation and liver transplantation. Patients with autosomal dominant type II (partial) disease (which has variable penetrance) have less severe hyperbilirubinemia [< 20 mg/dL (< 342 μmol/L)]. They usually survive into adulthood without neurologic impairment. Phenobarbital (1.5-2.0 mg/kg orally 3 times daily) may be effective because it induces hepatocyte microsomal enzymes.
Primary shunting hyperbilirubinemia is a rare familial benign condition associated with overproduction of early labeled bilirubin.
What's bothering you?
Classification of cholestasis
Cholestasis is divided into extra- and intrahepatic, as well as acute and chronic.
Extrahepatic cholestasis occurs with mechanical obstruction of the bile ducts, usually outside the liver; however, obstruction by hilar cholangiocarcinoma invading the main intrahepatic ducts may also be included in this group. The most common cause of extrahepatic cholestasis is a common bile duct stone; other causes include pancreatic and ampulla cancer, benign ductal strictures, and cholangiocarcinoma.
Diagnosis of cholestasis
Evaluation is based on history, physical examination, and diagnostic tests. Differential diagnosis between intrahepatic and extrahepatic causes is of great importance.
Cholestasis results in jaundice, dark urine, discolored stools, and generalized pruritus. If cholestasis is chronic, increased bleeding (due to vitamin K malabsorption) or bone pain (due to osteoporosis due to vitamin D and calcium malabsorption) may develop. Abdominal pain and constitutional symptoms (eg, anorexia, vomiting, fever) reflect the underlying cause and are not manifestations of cholestasis itself. Evidence of hepatitis due to alcohol abuse or medications that may cause cholestasis suggests intrahepatic cholestasis. Bilateral colic or pain typical of pancreatic disease (eg, pancreatic cancer) suggests extrahepatic cholestasis.
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Physical examination
Chronic cholestasis may be accompanied by dark pigmentation of the skin, excoriations (due to itching), or lipid deposits (xanthelasma or xanthomas). Signs of chronic hepatocellular disease (eg, spider veins, splenomegaly, ascites) suggest intrahepatic cholestasis. Symptoms of cholecystitis suggest extrahepatic cholestasis.
Laboratory research
Regardless of the etiology, the characteristic increase in alkaline phosphatase levels reflects increased synthesis rather than decreased excretion. Aminotransferase levels are usually moderately elevated. Bilirubin levels vary. In order to clarify the cause of an elevated alkaline phosphatase level, provided that other liver tests are within normal limits, it is necessary to determine the level of gamma-glutamyl transpeptidase (GGT). If liver failure is suspected, it is necessary to determine the PT (usually INR is used). Unfortunately, neither the level of alkaline phosphatase and GGT, nor the level of bilirubin reflect the cause of cholestasis.
Other laboratory tests may sometimes help to clarify the cause of cholestasis. Elevated aminotransferases suggest hepatocellular abnormalities, but they are often elevated in extrahepatic cholestasis, especially in acute common bile duct obstruction by a stone. Elevated serum amylase is nonspecific but suggests complete common bile duct obstruction. Correction of prolonged PT or INR after vitamin K administration suggests extrahepatic obstruction, but this may also occur in hepatocellular abnormalities. Detection of antimitochondrial antibodies is definitive in primary biliary cirrhosis.
Instrumental studies of the biliary tract are mandatory. Ultrasonography, CT, and MRI can reveal dilation of the common bile duct, which usually occurs several hours after the onset of symptoms of mechanical obstruction. The results of these studies can establish the underlying cause of obstruction; in general, gallstones are well diagnosed by ultrasonography, and pancreatic lesions by CT. Ultrasound is usually preferred due to its lower cost and the absence of ionizing radiation. If ultrasonography reveals extrahepatic obstruction but not its cause, a more informative study is indicated, usually endoscopic or magnetic resonance cholangiopancreatography (ERCP, MRCP). Diagnostic laparoscopy or laparotomy is rarely used, only in case of progression of extrahepatic obstruction and when it is impossible to establish the cause by other instrumental methods. Liver biopsy is indicated if intrahepatic cholestasis is suspected, if the diagnosis is not established by noninvasive diagnostic methods. Since this manipulation involves damage to the biliary tree, which may lead to peritonitis, dilation of the biliary tract must be excluded before biopsy (using ultrasonography or CT).
What do need to examine?
Treatment of cholestasis
Extrahepatic biliary obstruction requires mechanical decompression. In other cases, treatment of the underlying cause, manifestations, and complications (eg, vitamin malabsorption) is necessary.
Decompression of the biliary tract usually requires laparotomy, endoscopy (eg, to remove duct stones), or placement of stents and drainage for strictures and partial obstruction. For obstruction by inoperable malignancy, a stent is usually placed transhepatically or endoscopically to ensure adequate drainage.
Pruritus usually resolves with removal of the underlying cause of cholestasis or with cholestyramine 2-8 g orally twice daily. Cholestyramine binds bile salts in the intestine. However, cholestyramine is ineffective in complete biliary obstruction. If hepatocellular dysfunction is not severe, hypoprothrombinemia is usually compensated for by vitamin K supplementation. Calcium and vitamin D supplementation, with or without a bisphosphonate, only slightly slow the progression of osteoporosis in long-standing and irreversible cholestasis. Vitamin A supplementation prevents deficiency, and symptoms of severe steatorrhea can be minimized by replacing dietary fat with (medium-chain) triglycerides.