AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic disease of the liver. The etiology 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 PBC. The term is controversial because cirrhosis only develops late in the course of the disease.

PBC 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.

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).

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 PBC and haplotype HLA-DR8 and, for some populations, HLA-DPB1.

The results of a controlled, interview-based study of 1032 patients were recently reported. This report noted that environmental factors, including infectious agents through urinary tract infections or chemicals contained in cigarette smoke, may induce PBC in genetically susceptible individuals, and exogenous estrogens may also contribute and may help explain the female predominance of the disease.

Frequency

United States

Although the epidemiology of this disease 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

PBC 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.

Mortality/Morbidity

For asymptomatic patients with antimitochondrial antibody (AMA)–positive findings, a normal biochemical liver profile, and histologic features that are compatible with PBC, 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.

Race

PBC is more common in Northern Europeans and is less common in populations of African descent.

Sex

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

Age

The disease 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.

CLINICAL

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History

Of patients with PBC, 25% are incidentally diagnosed during a routine blood evaluation.

• Fatigue (65%)
• • Fatigue is the first reported symptom. It can cause disability in some patients and has been associated with depression and obsessive-compulsive behavior. The etiology is unknown; however, a sleep abnormality, particularly excessive daytime somnolence, has been identified in a significant proportion of patients and has been associated with the degree of fatigue.
  • No correlation exists between this symptom and the stage of the liver disease, the height of the levels of liver enzymes, the Mayo model score, or the duration of therapy.
  • The etiology of fatigue is unclear; although some evidence suggests that abnormalities of the hypothalamic-pituitary-adrenal axis, decreased release of serotonin, and increased production of proinflammatory cytokines (ie, interleukin-1 [IL-1], interleukin-6 [IL-6], tumor necrosis factor-a [TNF-a]) may be responsible.
• Pruritus (55%)
• • According to estimates, 10% of patients experience severe pruritus.
  • The cause of this symptom is not known.
  • Pruritus appears unrelated to the deposition of bile acids in the skin.
  • Increased opioidergic tone (ie, increased production of endogenous opioid peptides, up-regulation of endogenous opioid receptors) appears to be the major mechanism. The height of the bilirubin level is proportionally related to the production of these peptides.
• Right upper quadrant discomfort occurs in 8-17% of patients.

Physical

Physical examination findings depend on the stage of the disease. In the early stages, examination findings are normal. As the disease advances, excoriations of the skin, xanthelasmata, or findings of cirrhosis may be present.

• Hepatomegaly (25%)
• Hyperpigmentation (25%)
• Splenomegaly (15%)
• Jaundice (10%)
• Xanthelasmata (10%) - In late stages of the disease
• Sicca syndrome (50-75%) - Xerophthalmia (ie, dry eyes), xerostomia (ie, dry mouth)
• Kayser-Fleischer rings (extremely rare)
• Stigmata of advanced liver disease (ie, cirrhosis) such as spider nevi, palmar erythema, ascites, temporal and proximal muscle wasting, and peripheral edema

Causes

PBC is a disease of unknown etiology, but various factors have been implicated as the causes of this illness.

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

DIFFERENTIALS

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Other Problems to be Considered

Drug-induced hepatotoxicity
Idiopathic adulthood ductopenia

WORKUP

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Lab Studies

• An elevation of the aminotransferases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be identified in most patients with PBC, but significant elevations of the alkaline phosphatase (ALP), g-glutamyl transpeptidase (GGTP), and immunoglobulin (mainly IgM) levels are usually the most prominent findings.
• Lipid levels and cholesterol levels may be increased, with an increased high-density lipoprotein (HDL) fraction. The latter finding explains why these patients do not have an increased risk for atherosclerosis.
• An increased erythrocyte sedimentation rate is another finding.
• As the disease progresses to cirrhosis, an elevated bilirubin level, a prolonged prothrombin time, and a decreased albumin level can be found. The increased bilirubin level is an ominous sign of disease progression, and liver transplantation must be considered.
• Thrombocytopenia is indicative of portal hypertension. Additionally, but not as commonly, abnormalities include elevated levels of ceruloplasmin, bile acids, and serum hyaluronate.
• The hallmark of this disease is the presence of antimitochondrial antibodies (AMAs) in the sera.
• • AMAs can be found in 90-95% of patients with PBC, and they have a specificity of 98% for this disease.
  • These antibodies target different components, mainly enzymes, in the mitochondria.
  • The presence of anti-M2, anti-M4, anti-M8, and anti-M9 has been associated with the severity of the disease. Patients with profile A (ie, only anti-M9) or profile B (ie, anti-M9 and/or anti-M2–positive by enzyme-linked immunosorbent assay [ELISA]) have a better disease course than patients with profile C (ie, anti-M2, anti-M4, and/or anti-M8–positive by ELISA) and profile D (ie, anti-M2, anti-M4, and/or anti-M8–positive by ELISA and complement-fixation test).
  • Antinuclear antibodies (ANAs) can be identified in 20-50% of patients with PBC.
  • Some patients have clinical, biochemical, and histological features of PBC, but their sera are negative for AMA. The diagnosis of autoimmune cholangitis has been used for these patients, but whether these patients represent the AMA-negative PBC group is a matter of debate. In terms of autoimmune markers, their profile is compatible with this type of autoimmune hepatitis (ie, high-titer ANA and/or SMA).
  • The natural history and associated autoimmune conditions in AMA-positive and AMA-negative PBC appear to be identical. A careful review of the liver biochemical pattern reveals cholestasis (ie, ALP and GGTP are elevated), and the liver biopsy findings are compatible with bile duct injury, ductopenia, cholestasis, and granulomas.

Imaging Studies

• Abdominal ultrasonography, CT scan, 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 patients are cirrhotic, findings compatible with portal hypertension (eg, nodular appearance of the liver, splenomegaly, intra-abdominal varices, ascites) can be observed. At this stage, follow-up imaging every 6 months with abdominal ultrasound is suggested for early detection of hepatic malignancy.

Procedures

• The diagnosis of the disease should be established or confirmed by performing a percutaneous or laparoscopic liver biopsy. This procedure also provides additional information about the stage of the disease and the patient's prognosis.
• In the late stages of the disease (ie, cirrhosis), an upper endoscopy study should be performed. If the patient has developed esophageal varices, prophylactic treatment (eg, beta-blockers, nitrates) can be initiated in an attempt to prevent variceal bleeding.

Histologic Findings

PBC is characterized by chronic, nonsuppurative, destructive cholangitis of the small interlobular bile ducts with a diameter of 40-80 mm. Early lesions signal damage of the basement membrane of the bile ducts and reactive hyperplasia of the epithelial lining. Lymphocytic and plasma cell infiltration, with eosinophilic condensation in the portal tracts, is another feature. Epithelioid aggregates or granulomas may be found around the bile ducts. Fibrosis and cirrhosis develop later.

Staging

Various staging systems have been developed, but the most prominent are those proposed by Ludwig et al and Scheuer.

• 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.

TREATMENT

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Medical Care

The goals of treatment are to slow the progression rate of the disease and to alleviate the symptoms (eg, pruritus, osteoporosis, sicca syndrome). Liver transplantation appears to be the only life-saving procedure.

• Ursodeoxycholic acid (UDCA) is the major medication used to slow the progression of the disease. Patients with early disease have clinical, biochemical, and histologic improvement. Reports suggest that UDCA delays the need for transplantation or delays death. The efficacy of this medication in late stages (ie, cirrhosis) is questionable. Patients who achieve biochemical response to UDCA after 1 year of treatment reportedly have a similar survival rate to the matched control population, and this observation might be used to identify the population of nonresponders who will require alternative or additional treatments.
• Immunosuppressive agents inhibit immune reactions that mediate the progression of the disease.
• Methotrexate: Results of various trials suggest improvement in biochemical and histological findings after treatment.
• Corticosteroids may alleviate symptoms and improve biochemical and histologic findings. Corticosteroid-induced osteoporosis is of great concern.
• Cyclosporine has some therapeutic potential.
• Colchicine has been used to limited effect.
• Antipruritic treatment
• • Pruritus is often refractory to medical therapy and significantly impacts patients' quality of life. Antihistamines are first-line agents to relieve pruritus in early stages and are the first line of medication for patients with mild-to-moderate pruritus. Use caution in patients with cirrhosis and signs of encephalopathy because antihistamines can further depress brain function.
  • Cholestyramine and colestipol are effective in sequestering bile salts in the enteric lumen. A 1- to 4-day delay is expected before the itching remits.
  • Rifampin can also be used, but the precise mechanism of action is unclear (may involve inhibition of bile acid uptake into hepatocytes and facilitation of excretion of dihydroxy and monohydroxy bile acids and toxic bile acids). Rifampin is used in patients whose conditions are not responding to cholestyramine.
  • Some evidence suggests that dronabinol (Marinol) can be used to good effect.
  • Plasmapheresis has also been implemented for patients with severe pruritus intractable to medical treatment. Results have been good.

Surgical Care

As the disease progresses to cirrhosis, an elevated bilirubin level, a prolonged prothrombin time, and a decreased albumin level can be found. The increased 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.

Activity

Increased activity is recommended, especially in postmenopausal women, to prevent osteoporosis.

MEDICATION

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The goals of treatment are to slow the progression rate of the disease and to alleviate the symptoms (eg, pruritus, osteoporosis, sicca syndrome). Liver transplantation appears to be the only life-saving procedure.

Drug Category: Bile acids

UDCA is the major medication used to slow the progression of the disease. Patients with early disease have clinical, biochemical, and histologic improvement. Reports suggest that UDCA delays the need for transplantation or delays death. The efficacy of this medication in late stages (ie, cirrhosis) is questionable.

Drug Category: Immunosuppressants

Inhibit key factors that mediate immune reactions.

Drug Name	Prednisolone (Delta-Cortef)
Description	May improve symptoms, biochemical findings, and histologic findings. Great concern exists about corticosteroid-induced osteoporosis.
Adult Dose	30 mg/d PO qd; progressively reduced over 8 wk to maintenance dose of 10 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin lesions
Interactions	Decreases effects of salicylates and toxoids (for immunizations); coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, carbamazepine, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Cyclosporine (Sandimmune, Neoral)
Description	Has some therapeutic potential.
Adult Dose	3 mg/kg/d PO divided bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UV-B radiation in psoriasis because it may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take orally

Drug Category: Anti-inflammatory agents

Decrease leukocyte motility and phagocytosis in inflammatory responses.

Drug Category: Antipruritics

Pruritus is often refractory to medical therapy and significantly impacts patients' quality of life. Antihistamines are first-line agents to relieve pruritus in early stages. Cholestyramine and colestipol are effective in sequestering bile salts in the enteric lumen. A 1- to 4-day delay is expected before itching remits.

Drug Name	Rifampin (Rifadin, Rimactane)
Description	Precise mechanism of action is unclear. May involve inhibition of bile acid uptake into hepatocytes and facilitation of excretion of dihydroxy and monohydroxy bile acids and toxic bile acids. Used in patients who are not responding to cholestyramine.
Adult Dose	300 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hepatitis
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia, which is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur; may cause reddish orange discoloration of tears, saliva, urine, and sweat; may permanently stain soft contact lenses

Drug Name	Colestipol (Colestid)
Description	Forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid–bound low-density lipoprotein cholesterol.
Adult Dose	Granules: 5-30 g/d PO qd or divided bid/qid; increase dose by 5 g at 1- to 2-mo intervals Tablets: 2-16 g/d initial dose PO; 2 g qd/bid; increase dose by 2 g at 1- to 2-mo intervals
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; complete biliary obstruction
Interactions	Decreases absorption of MTX, glipizide, imipramine, phenytoin, tolbutamide, niacin, clindamycin, NSAIDs, gemfibrozil, ursodiol, clofibrate, phenobarbital, warfarin, digitalis glycosides, propranolol, phenobarbital, hydrocortisone, and other drugs by inhibiting their absorption in the intestine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May be associated with increase in bleeding tendencies due to hypoprothrombinemia resulting from decrease in vitamin K absorption

Drug Category: Antihistamines

These agents are the first line of medication for patients with mild-to-moderate pruritus. Caution in patients with cirrhosis and signs of encephalopathy because antihistamines can further depress brain function.

FOLLOW-UP

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Complications

• Osteoporosis resulting from a decreased formation of bone has been found in a 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 half of patients with PBC. 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 PBC.
• 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 PBC.
• 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.

Prognosis

• The most reliable determinants of patient prognosis in PBC are the height of the serum bilirubin level and the Mayo risk score.
• • 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.

Patient Education

• For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article Cirrhosis.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Middle-aged women with pruritus and jaundice must be screened for PBC. Treatment with UDCA must be started, and periodic follow-up care should be scheduled.
• The level of hyperbilirubinemia and the Mayo risk score are of prognostic value.

MULTIMEDIA

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Media file 1:  This histological picture is compatible with primary biliary cirrhosis (PBC) stage II.
	View Full Size Image
Media type:  Histology

REFERENCES

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• Nakanuma Y, Tsuneyama K, Kono N, et al. Biliary epithelial expression of pyruvate dehydrogenase complex in primary biliary cirrhosis: an immunohistochemical and immunoelectron microscopic study. Hum Pathol. Jan 1995;26(1):92-8. [Medline].
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Article Last Updated: Aug 7, 2006