2.2 Cholestatic liver diseases

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Cholestasis means the accumulation of bile components in the liver cells, namely bile salts and possibly also bilirubin (bilirubinostasis).

Chronic cholestasis can be triggered by intrahepatic diseases. This can involve pathologies directly of the bile duct tree, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4 cholangiopathy. It can also be indirect, as a result of cirrhosis. Intrahepatic cholestasis can also be triggered by congenital conditions that are associated with impaired bile duct transport. These conditions are very rare.

Chronic cholestasis results in a deficiency of bile components in the small intestine. A decrease in bile salts can lead to malabsorption of fats, resulting in steatorrhea and a deficiency of fat-soluble vitamins. Acute cholestasis is caused by an obstruction of the large bile ducts. This can lead to painful jaundice, which is mainly caused by choledocholithiasis, or painless jaundice, usually due to malignancy. This is accompanied by dark urine and pale stools. Cholestasis is accompanied by a build-up of bile components in the blood, which causes itching. There can also be an increase in bilirubin, which leads to jaundice (icterus).

The bilirubin increase in cholestasis consists of a combination of unconjugated (indirect) and conjugated (direct) bilirubin. An exclusive increase in unconjugated bilirubin occurs in hemolysis, in which there is an excessive production of bilirubin, which can no longer be conjugated. It also occurs in Gilbert's syndrome. This is characterized by an isolated increase in unconjugated bilirubin, without an increase in the other liver tests. This is a genetic conjugation disorder of bilirubin, which does not give rise to any disease picture and can be detected by searching for a single-gene mutation.

Itching (pruritus) is a typical feature of cholestatic liver disease. This complication is very difficult to treat. Reasons for treatment are nocturnal itching and scratching lesions. The treatment of pruritus consists of anti-itch lotions and colestyramine, a resin that binds bile salts in the intestines and therefore must be given four hours apart from taking other medication. It works mainly for mild forms of itching. Rifampicin is usually prescribed, but this can cause hepatotoxicity in about 5% of patients. In case of jaundice it leads to vitamin K deficiency. Itching can sometimes be an indication for liver transplantation. There is no place for antihistamines because they are not effective here and can only increase fatigue.

Bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators. 

Treatment of hepatocytes with bile acids did not directly cause cell toxicity but increased the expression of numerous proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and other proteins that influence immune cell levels and function. Up-regulation of several of these genes in hepatocytes and in the liver after bile duct ligation required early growth response factor-1, but not farnesoid X receptor. In addition, early growth response factor-1 was up-regulated in the livers of patients with cholestasis and correlated with levels of inflammatory mediators. These data demonstrate that Toll-like receptor 4 is not required for the initiation of acute inflammation during cholestasis. In contrast, bile acids directly activate a signaling network in hepatocytes that promotes hepatic inflammation during cholestasis. 

During obstructive cholestasis, increased concentrations of bile acids activate ERK1/2 in hepatocytes, which up-regulates early growth response factor 1, a key regulator of proinflammatory cytokines, such as macrophage inflammatory protein 2 (MIP-2), which, in turn, exacerbates cholestatic liver injury. Previous studies have indicated that IL-17A contributes to hepatic inflammation during obstructive cholestasis, suggesting that bile acids and IL-17A may interact to regulate hepatic inflammatory responses.

Bile acids act as triggers of the IL-23/IL-17A axis and suggest that IL-17A promotes hepatic inflammation during cholestasis by synergistically enhancing bile acideinduced production of proinflammatory cytokines by hepatocytes.

Typically presents in middle-aged women with chronic cholestasis, pruritus, and positive anti-mitochondrial factors.

Primary biliary cholangitis (PBC, formerly called primary biliary cirrhosis) is a rare, potentially life-threatening liver disease. The disease primarily affects women between the ages of 50 and 70 at diagnosis, but can also occur in younger women and men.

This involves progressive destruction of the small interlobular bile ducts in the portal fields. This subsequently leads to increased concentrations of bile acids in the liver cells, later to liver fibrosis and finally to biliary cirrhosis. This damage would be chemically caused by cholangiocytes excreting insufficient bicarbonate. Bicarbonate protects bile ducts from damage.

The disease is characterized by fatigue (80%) and pruritus (50%). It can be associated with other organ pathology, such as sicca syndrome, arthralgia and autoimmune thyroiditis.

Serious clinical complications occur in these patients in approximately 15% of cases respectively. After 5 to 10 years this can increase to 30%. However, this evolution is very variable and after 20 to 30 years patients can still show few symptoms.

Risk groups for a more aggressive course are young women and men. The level of alkaline phosphatases is one of the best independent predictors of the patient's prognosis.

The diagnosis is made on the basis of the increase in alkaline phosphatases and gamma-GT, together with the increase in IgM immunoglobulins and autoantibodies against mitochondria (anti-mitochondrial factors > 1/40). A distinction is made between an anti-mitochondrial positive and negative form. The latter is rather rare. The antibodies anti-sp100 and anti-gp210 are also very suggestive of PBC. The biopsy is suggestive.

In case of severe fatigue the following diseases should be excluded:

- hypothyroidism;

- celiac disease;

- pernicious anemia.

There is an effective treatment, namely ursodeoxycholic acid 13-15 mg/kg/day. About one third of patients do not respond to this therapy. As second-line therapy obeticholic acid and fibrates are used today.

Chronic cholestasis can cause osteopenia in middle-aged women, who are already at increased risk for osteoporosis. These patients should receive calcium and vitamin D supplements.

Presents as chronic cholestasis, especially in young men, associated with chronic inflammatory bowel disease.

It is a rare disease. This involves chronic inflammation of the large hepatic bile ducts, as well as the intrahepatic bile ducts. This causes fibrosis and biliary strictures.

The disease occurs mainly in young men. More than 70% of patients with PSC have inflammatory bowel diseases, such as ulcerative colitis.

The diagnosis is made on the basis of a chronic increase in alkaline phosphatases and gamma-GT. An MRI scan of the bile ducts, or MRCP, typically shows stenosis and small pearl-shaped dilatations. The liver biopsy is also suggestive.

The disease is mainly complicated by recurrent cholangitis. Approximately 8% of patients develop cholangiocarcinoma (1% per year). Isolated short strictures are suspicious for cholangiocarcinoma and patients have an increased risk of gallbladder cancer.

The disease can slowly progress to an end-stage of biliary cirrhosis. Since these patients can be transplanted systematically, the main causes of death are now not so much liver failure, but colorectal and hepatobiliary tumors (including gall bladder tumors).

There are 2 types of PSC:

- large duct PSC, the most common form;

- small duct PSC, in which there are no abnormalities of the extrahepatic bile ducts.

A distinction must be made with the rarer forms of sclerosing cholangitis, such as ICU cholangiopathy or biliary strictures after liver transplantation, due to ischemia of the bile ducts. There is no recognized therapy for PSC. Biochemical improvements are noted with ursodeoxycholic acid. In cholangitis, endoscopic balloon dilations of the stenosis in the choledochus should be performed. In case of recurrent cholangitis and liver decompensation, PSC is an indication for liver transplantation.

Presents as pseudotumors of the bile ducts.

IgG4-associated cholangiopathy belongs to the IgG4-induced system pathology. It occurs mainly in older men, with a history of exposure to solvents. It usually presents as a cause of painless jaundice. Another manifestation is IgG4-associated pancreatitis. In 75% of cases, there is a serum IgG4 value four times above the normal value. On MRCP, there are long thickenings of the choledochus with narrowing. The differential diagnosis must be made with PSC and cholangiocarcinoma. It can present as a tumor of the bile ducts (pseudotumor).

The current treatment consists of prednisolone, combined with azathioprine. This is given for at least 12 weeks. Relapse is frequent, which results in lifelong treatment in some patients.

There may be an overlap between AIH and PBC or AIH and PSC. The conditions may co-occur or one form may evolve into the other: from autoimmune hepatitis in childhood to primary sclerosing cholangitis in adulthood. These variants are treated with corticosteroids-azathioprine and ursodeoxycholic acid.

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