The Natural History of Primary Biliary Cirrhosis Mohamad H. Imam, MBBS1

Keith D. Lindor, MD2

1 Department of Internal Medicine, University of North Dakota, Fargo,

North Dakota 2 College of Health Solutions, Arizona State University, Phoenix, Arizona

Address for correspondence Keith D. Lindor, MD, College of Health Solutions, Arizona State University, Code: 3020, 550 N. 3rd Street, Phoenix, Arizona 85004 (e-mail: [email protected]).

Abstract Keywords

► primary biliary cirrhosis ► ursodeoxycholic acid ► liver transplantation

Our understanding of the natural history of primary biliary cirrhosis (PBC) has been evolving especially following the introduction of ursodeoxycholic acid (UDCA). A clearer understanding of disease pathophysiology and earlier diagnosis with increased prevalence of the disease worldwide has led to increased interest and improved outcomes in patients with PBC. In this article, the authors touch briefly on features of the disease and describe the natural history of PBC prior to and after the introduction of UDCA.

Primary biliary cirrhosis (PBC) is a slowly progressive chronic cholestatic liver disease characterized by nonsuppurative cholangitis of the bile ducts and primarily affecting middleaged women. The disease involves damage to the intrahepatic bile ducts culminating in liver fibrosis, cirrhosis, and possibly death. The rate of disease progression differs significantly between individual patients. The number of PBC patients needing liver transplants has decreased in North America unlike patients with primary sclerosing cholangitis (PSC).1 This can be best explained by medical advances leading to early disease diagnosis, which has led to earlier intervention and better outcomes for patients with PBC. Compared to outcomes experienced in the 1980s, significant changes in mortality rates from PBC have occurred, whereas the mortality rates of patients with PSC have remained unchanged.2 It is noteworthy that the natural history of PBC has changed dramatically following the introduction of ursodeoxycholic acid (UDCA). Poupon et al conducted the first open-label trial of UDCA at a dose of 12 to 15 mg/kg/d in patients with PBC in 1987 and successfully demonstrated a dramatic improvement in liver biochemistries in these patients with the use of UDCA.3

Epidemiology Over the past 30 years, the epidemiology of PBC has significantly changed, this is especially true in developed countries where the reported incidence of the disease has dramatically increased and patients with PBC have benefit-

Issue Theme Primary Biliary Cirrhosis; Guest Editor, Pietro Invernizzi, MD, PhD

ed from important health care resources, specifically liver transplantation.4 Primary biliary cirrhosis largely affects middle-aged women (30 to 65 years of age) from all racial groups; however, the disease may also occur in young women or men.5 Primary biliary cirrhosis is infrequently diagnosed in patients less than 25 years of age.6 However, the youngest described case of PBC was of a 12-year-old girl.7 The incidence of PBC in the United States is reported as 2.7 per 100,000 population per year, with a prevalence of 40.2 per 100,000.8 In the United Kingdom, a higher incidence is reported at 3.1 per 100,000 population per year and a prevalence of 25.1 per 100,000.9 In Iceland, similar overall incidence is reported at 2.0 to 2.5 cases per 100,000. Ageadjusted prevalence per 100,000 persons is reported as 65.4 for women and 12.1 for men.10

Pathophysiology Several hypotheses on the pathophysiology underlying PBC have been proposed. Evidence for autoimmunity playing a role includes the strong association with autoimmune extrahepatic disease impaired of B and T lymphocytes regulation, the presence of circulating autoantibodies in the serum, the development of liver granulomas, and finally abnormalities of the humoral and cellular immune systems.6,11,12 Environmental factors are also thought to play a role, although to a lesser extent.13 Evidence for this includes the effect of xenobiotics, urinary tract infections, and smoking on the

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DOI http://dx.doi.org/ 10.1055/s-0034-1383731. ISSN 0272-8087.

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Semin Liver Dis 2014;34:329–333.

The Natural History of Primary Biliary Cirrhosis

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development and progression of PBC.14,15 Recent evidence has shown a possible role for infiltration of bile ducts with mitochondrial protein-expressing inflammatory cells in the pathogenesis of bile duct lesions in PBC.16 Recently, it was identified that the risk of liver fibrosis in patients with PBC is increased in a dose-dependent fashion with smoking.17 Primary biliary cirrhosis is thought to be predisposed by genetic factors with several susceptibility loci for PBC being discovered recently. It is worth noting, that features of a genetic component to PBC is clearly reflected in the increased prevalence of PBC among one family, the high rate of concordance between identical twins and finally the presence of elevated antimitochondrial antibody (AMA) levels in family members of patients with PBC. The initiation phase, possibly through xenobiotics and molecular mimicry may then occur. Finally, a response to injury from the hepatocytes and cholangiocytes may lead to disease progression.

Natural History and Disease Progression In the era preceding the usage of UDCA, the natural history of PBC reflected a 10-year survival of 50% to 70% in patients who were asymptomatic and worse outcomes for symptomatic patients with a median survival of 5 to 8 years.11 Progression of the disease involves the development of fibrosis, cholestasis, ductopenia, and interface hepatitis. Symptomatic presentation often involves pruritus and fatigue.18 Antimitochondrial antibodies are found in the majority of PBC patients; however, 5% of PBC patients are AMA negative. A recent study found that bile duct damage around the portal areas in PBC patients with detectable AMA was milder as compared with AMA-negative patients.19 In AMA-positive patients, detection of the antibodies precedes the occurrence of symptoms or biochemical features of PBC. Moreover, follow-up of AMA-positive autoimmune hepatitis is helpful is detecting early-stage PBC.20 It is reported that the time from detection of AMA to development of PBC is around 6 years (range 1 to 19 years) in one study. It is worth noting that more than 90% of patients with AMA and no clinical features of PBC will not develop PBC.21 A recent study looked into the significance of AMA, antinuclear antibody- (ANA-) specific antibodies (anti-gp 210 and anti-sp 100) and antichromatin antibodies. Autoantibody positivity (except antichromatin) in addition to increased titers during follow-up was related to advanced disease. Moreover, lower anti-sp100 titers was accompanied with a lower Mayo risk score (p ¼ 0.025) and better response to UDCA (p ¼ 0.016).22 Poorer outcomes are noted in patients developing esophageal varices where 3-year survival following the first bleed is only around 46% and the overall 3-year survival following the development of varices is merely 59%. Reported liver failure following 5 years of disease follow-up in patients with PBC and varices is 15% to 20%. Following the introduction of UDCA, the natural history of PBC has changed dramatically. Responders to UDCA survive as long as age- and sex-matched healthy subjects.11 UrsodeoxSeminars in Liver Disease

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ycholic acid is the only approved medication by the Food and Drug Administration for patients with PBC. The American Association for the Study of Liver Diseases (AASLD) recommends use of UDCA in patients with PBC with an abnormal liver enzyme profile regardless of the histological stage. Liver transplantation is still required in a proportion of patients despite the use of UDCA; however, UDCA has been shown to delay the time to liver transplantation and in patients with PBC. Ursodeoxycholic acid does cause an improvement in transplant-free survival in patients with PBC. In a metaanalysis based in studies using adjusted doses such as a systematic review of seven randomized clinical trials involving 1,038 patients and their extended follow-up reported a decrease in the combined rates of death or liver transplantation (odds ratio [OR] ¼ 0.76, p ¼ 0.05) and the incidence of liver transplantation (OR ¼ 0.65, p ¼ 0.01), was reported. Following liver transplantation, UDCA compared with placebo has no effect on the rate of retransplantation, acute cellular rejection, and mortality related to allograft rejection.23 In PBC patients with features of autoimmune hepatitis, the combination therapy of UDCA and corticosteroids is more effective than UDCA alone.24 In patients with severe interface hepatitis, UDCA alone may not produce a biochemical response; hence, these patients often need supplementary treatment with immunosuppressants.25 A recent study concluded that Hispanics with PBC were more likely to display features of autoimmune hepatitis, had a decreased response to UDCA, and suffered from portal hypertension more commonly than non-Hispanic patients.26 Boberg et al studied at the cost and health consequences of treatment of PBC with UDCA and showed that PBC patients on UDCA compared with standard care had an increased life expectancy of 2.24 years and accumulated a lower lifetime treatment cost.27

Responders to Ursodeoxycholic Acid Greater than 25% to 30% of patients with PBC will show a complete response to UDCA.6 A recent study by Papastergiou et al determined that biochemical criteria at 1 year in early-stage PBC does not reflect with precision the therapeutic response to UDCA, but could reflect severity of the disease.28 A recent study by Carbone et al identified that male sex indicated a poorer response to UDCA therapy. Age at diagnosis also independently correlated with response to UDCA, patients presenting at a younger age were significantly more likely to be nonresponders and more likely to be symptomatic.29

Nonresponders to Ursodeoxycholic Acid Only one third of PBC patients may show no response to UDCA therapy. The absence of UDCA response following 1 year of treatment has been linked to increased risk of HCC.30 A recent study looking at rituximab for patients with an incomplete response to UDCA deduced that selective B-cell depletion was safe and led to a pronounced decrease in the production of autoantibodies, but did not have good biochemical efficacy.31 Alkaline phosphatase levels can normalize as fast as in 3 months in patients with PBC following bezafibrate and UDCA treatment.32

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The Natural History of Primary Biliary Cirrhosis

Imam, Lindor


Model name

Factors included



Mayo model

Age, bilirubin, albumin, prothrombin time, edema

Can predict short- and long-term survival and time for liver failure, hence allow for appropriate referral for liver transplantation

Does not involve response to therapy or time-dependent changes

MELD score

Bilirubin, creatinine, INR, dialysis (twice in last week)

Used to prioritize transplantation, adopted since 2002 for organ allocation to patients listed for liver transplantation in the United States

Does not take into account the degree of survival benefit after liver transplantation and less friendly to use than ChildPugh score at the bedside

Time-dependent Cox regression models

Age, bilirubin, albumin, ascites, gastrointestinal bleeding  histological variables

More accurate than the time-fixed models in predicting survival

Needs further validation, not used to prioritize transplantation


Bilirubin, albumin, PT, INR, ascites, hepatic encephalopathy

Easily calculated at the bedside

Does not entertain the cause of cirrhosis and the possibility of slowing of liver damage

Abbreviations: INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; PT, prothrombin time.

Primary Biliary Cirrhosis in Pregnancy Pregnant women with PBC are frequently symptomatic; however, in the pregnant population, exacerbations of PBC are less common during pregnancy and liver biochemistries are stable. Conversely, postpartum biochemical exacerbations are common.33

Complications Primary biliary cirrhosis encompasses several serious complications including portal hypertension and its associated development of varices, portal gastropathy, ascites, and he-

patic encephalopathy.11 Moreover, late-stage histologically advanced PBC is associated with increased development of hepatocellular carcinoma (HCC).6

Outcomes after Liver Transplantation Several predictive models for liver transplantation can be used in patients with PBC; ►Table 1 provides a summary of the most prominent models. In patients with PBC, survival of the graft and overall survival is superior when compared with other indications for liver transplantation. It is reported that 83%, 77%, and 69% of patients survive at 1, 5, and 10 years, respectively.34 Despite studies showing that fatigue in PBC

10 year survival of 50-70% (asymptomatic) Survival of 5-8 years (symptomatic) Untreated

Primary Biliary Cirrhosis UDCA



Survive as long as ageand sex-matched healthy subjects

Increased risk of HCC

Fig. 1 Summary of natural history in patients with primary biliary cirrhosis. HCC, hepatocellular carcinoma; UDCA, ursodeoxycholic acid.

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Table 1 Summary of predictive models for liver transplantation

The Natural History of Primary Biliary Cirrhosis

Imam, Lindor

improves following liver transplantation, a large number of patients do suffer from significant fatigue 2 years posttransplant.35

Recurrence following Transplantation 1982 marked the year at which recurrence was first described in PBC.36 Despite recurrence of PBC in 9% to 35% of patients,37–43 this recurrence rate is not associated with increased mortality or graft rejection. Granulomatous changes are the most pertinent histological feature for the diagnosis of recurrent PBC; this is especially important because in recurrent disease clinical and biochemical characteristics are often absent.44

12 Solis Herruzo JA, Solis Munoz P, Munoz Yague T. The pathogenesis





Summary The natural history of PBC has changed dramatically following the discovery of UDCA (►Fig. 1). Response to UDCA is predicted by age and sex where diagnosis of the disease at a younger age and male sex predict decreased response to UDCA. Antimitochondrial antibodies are the hallmark of this disease that primarily affects middle-aged women. Advances in clarifying the pathogenesis of PBC are underway and several mechanisms have already been proposed. In patients showing no response to UDCA, outcomes are often worse with an increased risk of HCC. Liver transplantation in patients with PBC has excellent outcomes and recurrence of the disease following transplantation is not associated with worse outcomes.






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The Natural History of Primary Biliary Cirrhosis

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The natural history of primary biliary cirrhosis.

Our understanding of the natural history of primary biliary cirrhosis (PBC) has been evolving especially following the introduction of ursodeoxycholic...
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