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Primary Biliary Cholangitis (PBC)

(Primary Biliary Cirrhosis)

By

Tae Hoon Lee

, MD, Icahn School of Medicine at Mount Sinai

Reviewed/Revised Jan 2024
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Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, 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 , and liver failure. Patients usually are asymptomatic at presentation but may experience fatigue or have symptoms of cholestasis (eg, pruritus, steatorrhea) or cirrhosis (eg, 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 , ascites). Laboratory tests reveal cholestasis, increased IgM, and, characteristically, antimitochondrial antibody in the serum. Liver biopsy may be necessary for diagnosis and staging. Treatment includes ursodeoxycholic acid, obeticholic acid, bezafibrate, cholestyramine (for pruritus), supplementary fat-soluble vitamins, and, ultimately for advanced disease, 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 .

Etiology of Primary Biliary Cholangitis

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.

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 and insufficiently degraded. 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.

Symptoms and Signs of Primary Biliary Cholangitis

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 of Primary Biliary Cholangitis

  • Liver blood tests: Cholestasis with elevated alkaline phosphatase

  • Antimitochondrial antibody (AMA) or PBC-specific auto-antibodies (eg, sp100 or gp210) positivity

  • Liver biopsy: nonsuppurative destructive cholangitis and destruction of interlobular bile ducts

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, especially to confirm the presence of cirrhosis.

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).

Diagnosis reference

  • 1. Lindor KD, Bowlus CL, Boyer J, et al: Primary biliary cholangitis: 2018 Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 69(1):394-419, 2019. doi: 10.1002/hep.30145

Treatment of Primary Biliary Cholangitis

  • Arresting or reversing liver damage

  • Treating complications (chronic cholestasis and liver failure)

  • Sometimes liver transplantation

All alcohol use and hepatotoxic medications should be stopped. Ursodeoxycholic acid 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 (1 Treatment references Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... 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 ursodeoxycholic acid, or as a single agent in patients who 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 because it can cause liver failure.

For patients who do not respond adequately to ursodeoxycholic acid and do not have access to obeticholic acid, bezafibrate may be used in combination with ursodeoxycholic acid. Adding bezafibrate to ursodeoxycholic acid was evaluated in a phase 3 randomized trial for patients who did not have an adequate response to ursodeoxycholic acid alone (2 Treatment references Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more ). This combination showed a higher rate of complete biochemical response than that of ursodeoxycholic acid alone. Also, a retrospective study showed improved survival in patients given ursodeoxycholic acid in combination with bezafibrate compared with those who received ursodeoxycholic acid alone (3 Treatment references Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more ). However, bezafibrate is not available in the United States. Fenofibrate, another type of fibrate available in the United States, has not been as well-studied in this population, but it is still used because there are few medication options available. Fibrates can cause elevated aminotransferases and worsening renal function, which should be monitored. Also fibrates should be avoided in patients with decompensated cirrhosis.

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 medications should not be given simultaneously. Cholestyramine can also decrease absorption of various medications; if patients take any medication that could be affected, they should be told not to take the medication 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.

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). A long-term retrospective study of 785 patients in North America and Europe who had undergone liver transplantation for PBC reported patient survival rates of 90% at 5 years, 81% at 10 years, 70% at 15 years, and 53% at 20 years (4 Treatment references Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more ). 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.

Treatment references

  • 1. Lindor KD, Bowlus CL, Boyer J, et al: Primary biliary cholangitis: 2018 Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 69(1):394-419, 2019. doi: 10.1002/hep.30145

  • 2. Corpechot C, Chazouillères O, Rousseau A, et al: A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med 378(23):2171-2181, 2018. doi: 10.1056/NEJMoa1714519

  • 3. Tanaka A, Hirohara J, Nakano T, et al: Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis. J Hepatol 75(3):565-571, 2021. doi: 10.1016/j.jhep.2021.04.010

  • 4. Montano-Loza AJ, Hansen BE, Corpechot C, et al: Factors associated with recurrence of primary biliary cholangitis after liver transplantation and effects on graft and patient survival. Gastroenterology 156(1):96-107.e1, 2019. doi: 10.1053/j.gastro.2018.10.001. Epub 2018 Oct 6. Erratum in: Gastroenterology 158(1):288, 2020

Prognosis for Primary Biliary Cholangitis

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:

  • Rapid worsening of symptoms

  • Advanced histologic changes

  • Older patient age

  • Presence of edema

  • Presence of associated autoimmune disorders

  • Abnormalities in bilirubin, albumin, prothrombin time, or international normalized ratio (INR)

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

Key Points

  • Primary biliary cholangitis is a chronic, progressive cholestatic liver disorder that is caused by an autoimmune attack on small bile ducts and that occurs almost exclusively in women aged 35 to 70.

  • PBC typically progresses to a terminal stage over 15 to 20 years.

  • Suspect PBC if patients have unexplained elevated alkaline phosphatase and gamma-glutamyl transpeptidase but minimally abnormal aminotransferases, particularly if they have constitutional symptoms or manifestations of cholestasis (eg, pruritis, osteoporosis, vitamin D deficiency).

  • Measure IgM and antimitochondrial antibody, and do imaging (to rule out extrahepatic biliary obstruction). Consider liver biopsy.

  • Stop use of hepatotoxins (including alcohol), and treat with ursodeoxycholic acid, which may delay the need for transplantation. Obeticholic acid is the second-line treatment. Fibrate can be added to ursodeoxycholic acid. Obeticholic acid and fibrate should be avoided in decompensated cirrhosis.

  • Transplantation is indicated for decompensated liver disease (uncontrolled variceal bleeding, refractory ascites, intractable pruritus, hepatic encephalopathy).

Drugs Mentioned In This Article

Drug Name Select Trade
Actigall, Reltone, Urso 250, Urso Forte
OCALIVA
Locholest , Locholest Light, Prevalite , Questran, Questran Light
Antara, Fenoglide, Lipofen, Lofibra , Tricor, Triglide
Depade, ReVia, Vivitrol
Zoloft, Zoloft Concentrate, Zoloft Solution
Luminal, Sezaby
A Mulsin, Aquasol A, Dofsol-A
Calcidol, Calciferol, D3 Vitamin, DECARA, Deltalin, Dialyvite Vitamin D, Dialyvite Vitamin D3, Drisdol, D-Vita, Enfamil D-Vi-Sol, Ergo D, Fiber with Vitamin D3 Gummies Gluten-Free, Happy Sunshine Vitamin D3, MAXIMUM D3, PureMark Naturals Vitamin D, Replesta, Replesta Children's, Super Happy SUNSHINE Vitamin D3, Thera-D 2000, Thera-D 4000, Thera-D Rapid Repletion, THERA-D SPORT, UpSpring Baby Vitamin D, UpSpring Baby Vitamin D3, YumVs, YumVs Kids ZERO, YumVs ZERO
Alph-E-Mixed , AQUA-E, Aquasol E , Aquavite-E
Evista
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