Primary Biliary Cholangitis (Primary Biliary Cirrhosis)

Updated: Jun 03, 2016
  • Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF; Chief Editor: BS Anand, MD  more...
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Overview

Practice Essentials

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic disease of the liver, presumably autoimmune in nature, that leads to progressive cholestasis and often end-stage liver disease (see the image below). The name change reflects the fact that cirrhosis occurs only in the late stage and therefore does not correctly identify patients with early-stage disease. [1]

PBC is most frequently a disease of women and occurs between the fourth and sixth decades of life.

This histologic picture is compatible with stage 2 This histologic picture is compatible with stage 2 primary biliary cholangitis.

Signs and symptoms

Of patients with PBC, 25% are incidentally diagnosed during a routine blood evaluation. Symptoms of PBC include the following:

  • Fatigue (65% of patients): The first reported symptom
  • Pruritus (55%)
  • Right upper quadrant discomfort (8-17%)

Physical examination findings depend on the stage of the disease. In the early stages, examination findings are normal. As the disease advances, the following signs may be noted:

  • Hepatomegaly (25%)
  • Hyperpigmentation (25%)
  • Splenomegaly (15%)
  • Jaundice (10%)
  • Xanthomas and Xanthelasmas (10%): In late stages of the disease
  • Sicca syndrome (50-75%): Xerophthalmia (ie, dry eyes), xerostomia (ie, dry mouth)
  • Kayser-Fleischer rings (extremely rare)

In patients with advanced disease, findings may include the following stigmata of cirrhosis:

  • Spider nevi
  • Palmar erythema
  • Ascites
  • Temporal and proximal muscle wasting
  • Peripheral edema

See Clinical Presentation for more detail.

Diagnosis

Abnormalities on laboratory studies include the following:

  • Significant elevations of the alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGTP), and immunoglobulin levels (mainly IgM): Usually the most prominent findings
  • Elevation of the aminotransferases alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
  • Increased lipid and cholesterol levels, with an increased HDL fraction
  • Increased erythrocyte sedimentation rate
  • Elevated bilirubin level, prolonged prothrombin time, and decreased albumin level: Indicate progression of disease to cirrhosis
  • Thrombocytopenia: Indicates portal hypertension
  • Antinuclear antibodies (ANAs): Can be identified in 20-50% of patients with PBC

Less common abnormalities include elevated levels of the following:

  • Ceruloplasmin
  • Bile acids
  • Serum hyaluronate

The hallmark of PBC is the presence of antimitochondrial antibodies (AMAs) in serum. AMAs can be found in 90-95% of patients with PBC, and they have a specificity of 98% for this disease. Four AMA profiles occur:

  • Profile A: Positive for anti-M9 only
  • Profile B: Anti-M9 and/or anti-M2–positive by ELISA
  • Profile C: Anti-M2, anti-M4, and/or anti-M8–positive by ELISA
  • Profile D: Anti-M2, anti-M4, and/or anti-M8–positive by ELISA and complement-fixation test

Patients with profile A or B have a better disease course than patients with profile C or D.

Some patients have clinical, biochemical, and histologic features of PBC, but their sera are negative for AMA. The diagnosis of autoimmune cholangitis has been used for these patients.

Imaging studies

  • Abdominal ultrasonography, CT scanning, or MRI are important to exclude biliary obstruction
  • Nonspecific findings include increased echogenicity of the liver parenchyma and findings compatible with portal hypertension
  • Portal lymphadenopathy can be recognized in approximately 15% of these patients

Once cirrhosis develops, findings compatible with portal hypertension can be observed, including the following:

  • Nodular appearance of the liver
  • Splenomegaly
  • Intra-abdominal varices
  • Ascites

In patients with cirrhosis, follow-up imaging every 6 months with abdominal ultrasonography is suggested for early detection of hepatic malignancy.

Staging

  • Stage 1 (portal stage of Ludwig): Portal inflammation, bile duct abnormalities, or both are present
  • Stage 2 (periportal stage): Periportal fibrosis is present, with or without periportal inflammation or prominent enlargement of the portal tracts with seemingly intact, newly formed limiting plates
  • Stage 3 (septal stage): Septal fibrosis with active inflammatory, passive paucicellular septa, or both are present
  • Stage 4 (cirrhosis): Nodules with various degrees of inflammation are present

See Workup for more detail.

Management

Pharmacologic treatment of PBC is as follows:

  • Ursodeoxycholic acid (UDCA) is the major medication used to slow the progression of the disease
  • Obeticholic acid may be considered in combination with UDCA in adults with an inadequate response to UDCA for at least 1 year or as monotherapy in adults unable to tolerate UDCA
  • Methotrexate may produce improvement in biochemical and histologic findings
  • Corticosteroids may alleviate symptoms and improve biochemical and histologic findings
  • Cyclosporine has some therapeutic potential
  • Colchicine has been used with limited effect

Pruritus is often refractory to medical therapy and significantly impacts patients' quality of life. Antipruritic treatment is as follows:

  • Antihistamines are first-line agents for patients with mild-to-moderate pruritus, but can further depress brain function in patients with cirrhosis and signs of encephalopathy
  • Cholestyramine and colestipol sequester bile salts in the enteric lumen; a 1- to 4-day delay is expected before the itching remits
  • Rifampin can also be used for pruritus unresponsive to cholestyramine
  • Dronabinol (Marinol) use is supported by some evidence
  • Plasmapheresis may be effective in patients with severe pruritus intractable to medical treatment

In patients with cirrhosis, an elevated bilirubin level is an ominous sign of disease progression, and liver transplantation must be considered. Liver transplantation appears to be the only life-saving procedure.

See Treatment and Medication for more detail.

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Background

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic and progressive cholestatic disease of the liver. The name change reflects the fact that cirrhosis occurs only in the late stage and therefore does not correctly identify patients with early-stage disease. [1] The etiology of this disease is unknown, although it is presumed to be autoimmune in nature. The major pathology of this disease is a destruction of the small-to-medium bile ducts, which leads to progressive cholestasis and often end-stage liver disease.

In 1851, Addison and Gull described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. In 1950, Ahrens and colleagues named this disease primary biliary cirrhosis. [2]  As noted above, the term is controversial because cirrhosis only develops late in the course of the disease; therefore primary biliary cholangitis is preferred.

Primary biliary cholangitis is most frequently a disease of women and occurs between the fourth and sixth decades of life. The symptoms may strongly affect patients' quality of life and may induce incapacitation. Various therapeutic approaches have been implemented with variable results; in selected candidates, liver transplantation is the only treatment option for the terminal stages of the disease. After the procedure, the disease has a relatively high recurrence rate despite immunosuppressive therapy.

The image below demonstrates the histologic appearance of stage 2 primary biliary cholangitis.

This histologic picture is compatible with stage 2 This histologic picture is compatible with stage 2 primary biliary cholangitis.

For patient education resources, see the Digestive Disorders Center and the Infections Center, as well as Cirrhosis.

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Pathophysiology

The exact mechanism of the liver damage is unknown, although evidence indicates that it can be of autoimmune origin. The data supporting this hypothesis are as follows: (1) abnormalities of the humoral and cellular immune systems (ie, elevated serum levels of immunoglobulins, mainly immunoglobulin M [IgM]), (2) multiple circulating autoantibodies, (3) granulomas in the liver and regional lymph nodes, (4) impaired regulation of both B and T lymphocytes, and (5) the association of this disease with a variety of autoimmune-mediated diseases (eg, autoimmune thyroiditis; keratoconjunctivitis sicca; scleroderma; calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia [CREST] syndrome). [3]

A continuous destruction of small and medium bile ducts occurs, which is mediated by activated CD4 and CD8 lymphocytes. As a result, chronic cholestasis is the prominent clinical and laboratory finding. Once destroyed, it is well established that regeneration of bile ducts is either not possible or inefficient.

Subsequent to the loss of the intrahepatic bile ducts, a disruption of the normal bile flow occurs with retention and deposition of toxic substances, which are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and the hepatocytes. In addition, increased expression of the HLA class II antigens in the liver occurs, rendering hepatocytes and bile duct epithelial cells more susceptible to activated T lymphocytes and perhaps exacerbating immunologically mediated cytotoxicity. An association has been suggested between primary biliary cholangitis and haplotype HLA-DR8 and, for some populations, HLA-DPB1.

In a controlled, interview-based study of 1032 patients, Gershwin et al noted that in genetically susceptible persons, environmental factors, including chemicals found in cigarette smoke and infectious agents introduced through urinary tract infections, may induce primary biliary cholangitis. The authors stated that exogenous estrogens may also contribute to the disease's development and that this may help to explain why the disease occurs more frequently in females than in males. [4, 5]

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Etiology

Primary biliary cholangitis is a disease of unknown etiology, but various factors have been implicated as the causes of this illness, such as the following:

  • Genetic factors: First-degree relatives have a 570- to 1000-fold increased chance of developing primary biliary cholangitis. The presence of an inherited abnormality of immune regulation has been proposed.
  • Infection with organisms of the family Enterobacteriaceae: Cross-reactivity between antigens on the bacterial wall and the mitochondria has been postulated. Patients with primary biliary cholangitis present with an increased incidence of gram-negative urinary tract infections.
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Epidemiology

United States statistics

Although the epidemiology of primary biliary cholangitis has not been studied systematically, the published prevalence is 65.4 cases for women and 12.1 cases for men (40.2 cases overall) per 100,000 population. The incidence of the disease has been estimated as 4.5 cases for women and 0.7 cases for men (2.7 cases overall) per 100,000 population.

International statistics

Primary biliary cholangitis is reported to be more prevalent in the United Kingdom and Scandinavia. The prevalence of the disease has been estimated as 24 cases per 100,000 population in Newcastle, United Kingdom; 12.9 cases per 100,000 population in Northeast England; 1.9 cases per 100,000 population in Victoria, Australia; 2.2 cases per 100,000 population in Ontario, Canada; 2.7 cases per 100,000 population in Estonia; 9.2 cases per 100,000 in Malmö, Sweden; and 15.1 cases per 100,000 population in Umea, Sweden.

Race-, sex-, and age-related demographics

Primary biliary cholangitis is more common in Northern Europeans and is less common in populations of African descent.

Women account for 75-90% of patients with primary biliary cholangitis. Males who are affected have a disease course similar to that of females; however, men appear to be more likely to develop hepatocellular carcinoma.

Primary biliary cholangitis mostly affects middle-aged women, with a mean age of 39 years. Onset usually occurs in persons aged 30-65 years. However, patients as young as 22 years and as old as 93 years at the time of diagnosis have been reported.

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Prognosis

The most reliable determinants of patient prognosis in primary biliary cholangitis are the height of the serum bilirubin level and the Mayo risk score.

Note the following:

  • Published reports indicate that, when serum bilirubin values are constantly above 2, the mean survival rate is 4.1 years.
  • When bilirubin levels are constantly above 6 mg/dL, the mean survival rate is 2.1 years.
  • When bilirubin levels are constantly above 10 mg/dL, the mean survival rate is 1.4 years.
  • The Mayo risk score is calculated as follows: R = 0.871 log e (bilirubin in mg/dL) + (–2.53) log e (albumin in g/dL) + 0.039 age in years + 2.38 log e (prothrombin time in seconds) + 0.859 (edema score of 0, 0.5, or 1)
  • A report reassessed the Mayo risk score, taking into consideration other factors found to be important in the timing of transplantation in patients with chronic cholestatic liver disease. Neither the height of the serum bilirubin level nor the Mayo risk score are invalidated by UDCA therapy. Treatment with UDCA before liver transplantation does not alter the posttransplantation outcome.

Björnsson et al determined that fatigue levels may be a prognostic indicator for primary biliary cholangitis.12Bjornsson E, Kalaitzakis E, Neuhauser M, et al. Fatigue measurements in patients with primary biliary cholangitis and the risk of mortality during follow-up. Liver Int. Among 208 patients with the disease (16 males, 192 females, median age 59 years), the investigators recorded an overall baseline score of 28 on the fatigue impact scale (FIS). The score at follow-up (median 5 years)—at which time 186 patients were still alive, including 5 who had undergone liver transplantation—was 25. Specific baseline FIS scores were as follows:

  • Survivors (nontransplantation): 27 (12-43)
  • Nonsurvivors: 36 (12-72)
  • Patients who underwent liver transplantation: 99 (41-102)

In their report, Björnsson et al suggested that high fatigue levels can aid in predictions of liver-related mortality or liver transplantation need in patients with primary biliary cholangitis.

Age [hazard ratio (HR) 1.1 (confidence interval (CI) 1.0-1.2)] and aspartate aminotransferase [HR 2.0 (CI 1.3-3.0)] were independently associated with decreased survival on multivariate analysis. FIS scores over 40 [HR 9.6 (CI 2.3-39.7)] and bilirubin [HR 4.8 (CI 2.8-8.2)] were independently associated with a poor outcome in patients who underwent Tx or had a liver-related death.

Mortality and morbidity

For asymptomatic patients with antimitochondrial antibody (AMA)–positive findings, a normal biochemical liver profile, and histologic features that are compatible with primary biliary cholangitis, the progression of the disease is relatively slow; however, the patient life expectancy is not identical to that of the general population. Of these patients, 40-67% develop symptomatic disease in approximately 5-7 years. Once they develop symptoms (mainly cholestasis) and remain untreated, the median patient survival duration ranges from 5.5-12 years. Generally, the median survival duration from the time of diagnosis is 7.5 years for patients who are symptomatic and 16 years for patients who are asymptomatic.

Significant changes in the mortality rate have been noticed since the early 1980s with an increase in the age of death. This might be a consequence of treatment. [6]

Complications

The following complications may arise in patients with primary biliary cholangitis:

  • Osteoporosis resulting from a decreased formation of bone has been found in one third of patients.
  • Fat-soluble vitamin deficiency is a rare complication that is present in patients with long-standing hyperbilirubinemia.
  • Hypercholesterolemia and hyperlipidemia have been identified in 85% of patients.
  • Esophageal motility problems can occasionally occur, with asymptomatic or symptomatic reflux causing esophagitis and, possibly, stricture. This is more common in patients with CREST syndrome.
  • Patients with jaundice can develop steatorrhea. This complication results from the decreased excretion of bile acids. Mild pancreatic insufficiency has also been reported.
  • Renal tubular acidosis can be observed in approximately one half of patients with primary biliary cholangitis. Copper deposition in the renal tubules or an autoimmune phenomenon might be the mechanism for this complication.
  • Hypothyroidism has been noted in 20% of patients with primary biliary cholangitis.
  • Hepatocellular carcinoma can develop, with an overall incidence of approximately 6% (4.1% in women; 20% in men with advanced disease).
  • Asymptomatic bacteriuria has been found in 35% of patients with primary biliary cholangitis.
  • Autoimmune thrombocytopenia and hypoglycemia with insulin receptor autoantibodies may occur.
  • Transverse myelitis and necrotizing myelopathy caused by vasculitis may occur.
  • Xanthomatous peripheral neuropathy may occur.
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