Primary Biliary Cholangitis (PBC)

Primary biliary cholangitis (PBC) is the most common liver disease associated with chronic cholestasis in adults. Most (95%) cases occur in women aged 35 to 70. PBC also clusters in families. A genetic predisposition, perhaps involving the X chromosome, probably contributes. There may be an inherited abnormality of immune regulation.

An autoimmune mechanism has been implicated; antibodies to antigens located on the inner mitochondrial membranes occur in > 95% of cases. These antimitochondrial antibody (AMA), the serologic hallmarks of PBC, are not cytotoxic and are not involved in bile duct damage.

PBC is associated with other autoimmune disorders, such as systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more , Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes ... read more , CREST syndrome (also known as limited scleroderma Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more ), and autoimmune thyroiditis.

T cells attack the small bile ducts. CD4 and CD8 T lymphocytes directly target biliary epithelial cells. The trigger for the immunologic attack on bile ducts is unknown. Exposure to foreign antigens, such as an infectious (bacterial or viral) or toxic agent, may be the instigating event. These foreign antigens might be structurally similar to endogenous proteins (molecular mimicry); then the subsequent immunologic reaction would be autoimmune and self-perpetuating. Destruction and loss of bile ducts lead to impaired bile formation and secretion (cholestasis). Retained toxic materials such as bile acids then cause further damage, particularly to hepatocytes. Chronic cholestasis thus leads to liver cell inflammation and scarring in the periportal areas. Eventually, hepatic inflammation decreases as hepatic fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more progresses to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more .

AMA -negative PBC is characterized by autoantibodies, such as antinuclear antibodies (ANAs), anti–smooth muscle antibodies, or both and has a clinical course and response to treatment that are similar to those of PBC. However, AMA is absent.

About half of patients present without symptoms. Symptoms or signs may develop during any stage of the disease and may include fatigue or reflect cholestasis (and the resulting fat malabsorption, which may lead to vitamin deficiencies and osteoporosis), hepatocellular dysfunction, or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more .

Symptoms usually develop insidiously. Pruritus, fatigue, and dry mouth and eyes are the initial symptoms in > 50% of patients and can precede other symptoms by months or years. Other initial manifestations include right upper quadrant discomfort (10%); an enlarged, firm, nontender liver (25%); splenomegaly (15%); hyperpigmentation (25%); xanthelasmas (10%); and jaundice (10%). Eventually, all the features and complications of cirrhosis occur. Peripheral neuropathy and other autoimmune disorders associated with primary biliary cholangitis may also develop.

Diagnosis is confirmed if 2 of the previous 3 criteria are present.

In asymptomatic patients, primary biliary cholangitis (PBC) is detected incidentally when liver tests detect abnormalities, typically elevated levels of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT). PBC is suspected in middle-aged women with classic symptoms (eg, unexplained pruritus, fatigue, right upper quadrant discomfort, jaundice) or laboratory results suggesting cholestatic liver disease: elevated alkaline phosphatase (usually higher than 1.5 times the normal range) and GGT but minimally abnormal aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], usually less than 5 times normal ranges). Serum bilirubin is usually normal in the early stages; elevation indicates disease progression and a worsening prognosis.

If PBC is suspected, liver tests and tests to measure serum IgM (increased in PBC) and AMA should be done. Enzyme-linked immunosorbent assay (ELISA) tests are 95% sensitive and 98% specific for PBC; false-positive results can occur in autoimmune hepatitis (type 1). Other autoantibodies (eg, antinuclear antibodies [ANAs], anti–smooth muscle antibodies, rheumatoid factor) may be present. Extrahepatic biliary obstruction should be ruled out. Ultrasonography is often done first, but ultimately MRCP and sometimes endoscopic retrograde cholangiopancreatography (ERCP) are necessary. Liver biopsy Liver Biopsy Liver biopsy provides histologic information about liver structure and evidence of liver injury (type and degree, any fibrosis); this information can be essential not only to diagnosis but also... read more is required to confirm AMA-negative PBC. Liver biopsy helps to rule out other cholestatic diagnoses (drug-induced liver disease, sarcoidosis, PBC, biliary obstruction, autoimmune hepatitis) or coexisting liver diseases are suspected (autoimmune hepatitis or nonalcoholic steatohepatitis). Liver biopsy may detect pathognomonic bile duct lesions, even in early stages. As PBC progresses, it becomes morphologically indistinguishable from other forms of cirrhosis. Liver biopsy also helps stage PBC.

Some PBC patients have overlapping features with autoimmune hepatitis (ALT more than 5 times the normal range, IgG more than 2 times the normal range, positive anti-smooth muscle antibody, and moderate to severe interface hepatitis in liver biopsy).

Usually, PBC progresses to terminal stages over 15 to 20 years, although the rate of progression varies. PBC may not diminish quality of life for many years. Patients who present without symptoms tend to develop symptoms over 2 to 7 years but may not do so for 10 to 15 years. Once symptoms develop, median life expectancy is 10 years. Predictors of rapid progression include the following:

The prognosis is ominous when pruritus disappears, xanthomas shrink, jaundice develops, and serum cholesterol decreases.

All alcohol use and hepatotoxic drugs should be stopped. Ursodeoxycholic acid (13 to 15 mg/kg orally once a day) decreases liver damage, prolongs survival, and delays the need for liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more . About 40% of patients do not have biochemical improvement after ≥ 12 months (alkaline phosphatase less than 1.5 to 2 times the normal range and normalization of total bilirubin); they may have advanced disease and require liver transplantation in a few years. Obeticholic acid is used in addition to ursodeoxycholic acid for patients who do not adequately respond to, or as a single agent if patients cannot tolerate ursodeoxycholic acid. If patients have decompensated cirrhosis, a prior decompensation event, or compensated cirrhosis with evidence of portal hypertension, obeticholic acid is contraindicated since it can cause liver failure.

Pruritus may be controlled with cholestyramine 4 to 16 g/day. This anionic-binding drug binds bile salts and thus may aggravate fat malabsorption. If cholestyramine is taken long-term, supplements of fat-soluble vitamins should be considered. Cholestyramine can decrease absorption of ursodeoxycholic acid, so these drugs should not be given simultaneously. Cholestyramine can also decrease absorption of various drugs; if patients take any drug that could be affected, they should be told not to take the drug within 1 hour before or 4 hours after taking cholestyramine. Pruritus can be one of the common side effects of obeticholic acid, resulting in treatment discontinuation.

Some patients with pruritus respond to ursodeoxycholic acid and ultraviolet light; others may warrant a trial of rifampicin, naltrexone, sertraline, phenobarbital, or antihistamine.

Patients with fat malabsorption due to bile salt deficiency should be treated with vitamin A, D, E, and K supplements. For osteoporosis, weight-bearing exercises, bisphosphonates, or raloxifene may be needed in addition to calcium and vitamin D supplements. In later stages, portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more or complications of cirrhosis Complications Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more require treatment.

Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more has excellent results. The general indication is decompensated liver disease (uncontrolled variceal bleeding, refractory ascites, intractable pruritus, and hepatic encephalopathy). Survival rates after liver transplantation are > 90% at 1 year, > 80% at 5 years, and > 65% at 10 years. Antimitochondrial antibodies tend to persist after transplantation. Primary biliary cholangitis recurs in 15% of patients in the first few years and in > 30% by 10 years. Recurrent PBC after liver transplantation appears to have a benign course. Cirrhosis rarely occurs.

AMA-negative PBC has similar treatment response to ursodeoxycholic acid.