Prof Raoul POUPON,Université Pierre et Marie Curie, AP-Hop de Paris, Service d’Hepatologie, Hôpital Saint-Antoine, Paris,France.
Primary biliary cirrhosis is a chronic inflammatory autoimmune disease that targets mainly cholangiocytes of the interlobular bile ducts. The condition affects primarily middle-aged women and is generally slowly progressive over a period of ten to twenty years. Inflammation and destruction of the bile ducts leads to decreased bile secretion, retention of toxic substances within the liver, fibrosis, cirrhosis and eventually liver failure requiring liver transplantation. The rate of progression varies greatly from one patient to another. PBC is characterized by the presence of a subset of antimitochondrial antibodies that react with the lipoyl domains of the –oxo-acid dehydrogenases in the mitochondria, the so-called M2 antigen, which are virtually diagnostic. Most patients with PBC are now diagnosed in the early stages of the disease and are treated with ursodeoxycholic acid (UDCA). The number of liver transplantations performed in this indication has been decreasing over the last two decades.
Key points about causation
- Due to a combination of multiple genetic factors (allelic variations of genes controlling the immune system) and environmental triggers (urinary tact infections, exposure to chemicals and toxin).
- T and B cell activation leads to autoimmunity against M2 antigen and causes small bile duct inflammation and destruction.
- Chronic cholestasis leads to biliary cirrhosis and liver failure.
Essential of Diagnosis
- Mainly elevation of serum alkaline phosphatase and gammaglutamyl transpeptidase.
- Antimitochondrial antibodies with M2 specificity
- Non suppurative destructive cholangitis at histology
Essentials of treament
- Ursodeoxycholic acid (13 to 15 mg/kg/day).
- In patients with suboptimal biochemical response to UDCA adjuvant therapy with budesonide or methotrexate possibly effective.
- Liver transplantation for end-stage disease or intractable symptoms.
Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that targets mainly cholangiocytes of the interlobular bile ducts. The condition affects primarily middle-aged women and is generally slowly progressive over a period of ten to twenty years. Inflammation and destruction of the bile ducts leads to decreased bile secretion, retention of toxic substances within the liver, fibrosis, cirrhosis and eventually liver failure requiring liver transplantation. The rate of progression varies greatly from one patient to another. PBC is characterized by the presence of a subset of antimitochondrial antibodies (AMA) that react with the lipoyl domains of the –oxo-acid dehydrogenases in the mitochondria, the so-called M2 antigen, which are virtually diagnostic. Most patients with PBC are now diagnosed in the early stages of the disease and are treated with ursodeoxycholic acid (UDCA). The number of liver transplantations performed in this indication has been decreasing over the last two decades.
The incidence and prevalence of PBC have been increasing over time. Most recent data in Europe, North America and Japan show an incidence of 2-4 per 100 000 population per year and point prevalence at 20 to 40 cases per 100 000. Geographic clustering is striking, suggesting genetic as well as environmental influences in its pathogenesis. Whether the higher rates of incidence and prevalence may reflect a true increase or an apparent increase due to a higher detection rate remains unknown.
Causes and Pathogenesis
PBC is thought to be a complex disease resulting from the combination of multiple genetic factors and superimposed environmental triggers. These factors may affect one or more components of the immune system and of the tissue that is targeted by the disease. The contribution of the genetic predisposition is evidenced by the familial clustering and the high degree to which monozygotic twins are concordant. The prevalence of PBC is 100 times higher in first-degree relatives than in the general population. Allelic variations in MHC class II (DR,DQ), components of the innate (C4*Q0,C4B*2,NRAMP1/SLC11A1, MBL,VDR) and of the adaptative (CTLA4, Il beta,TNF apha, IL12A, IL12RB2) immune system have been associated with PBC susceptibility. The genetic basis of variability in disease progression is poorly known. The French prospective study of genetic factors of PBC severity have suggested the role of variants of TNF alpha and SLCA2/AE2. Regarding environmental factors, mucosal infections, particularly urinary tract infections, cigarette smoking, toxin exposure have been consistently associated with PBC. The role of xenobiotics through covalent binding of 2-octynoic acid, a component of many chemicals to proteins is suggested by experimental studies. Smoking not only prediposes to disease may also accelerate its progression. The ratio of women to men with the disease is 10 to 1. This may be related to a higher incidence of X-chromosome monosomy in lymphoid cells.
Although a unified theory of PBC pathogenesis is not available, a paradigm can be proposed that considers pathobiological events leading to disease progression.
The preclinical phase is marked by autoimmunity and altered cholangiocyte homeostasis. Autoimmunity is manifested by M2 antibodies (M2Ab) that specifically react with the lipoyl domain of the E2 subunits of the 2-oxo-acid dehydrogenase complexes of the mitochondria. The T and B cells infiltrating the liver in PBC are specific for the M2 antigen. The M2 epitope is detectable in cholangiocytes undergoing apoptosis and at the luminal domain of the biliary cells of the small bile ducts. As opposed to other cell types, cholangiocytes undergoing apoptosis fail to bind glutathione to the lysine-lipoyl residue of the dehydrogenase and thereby fail to cleave the autoreactive epitope. Neighbouring cholangiocytes have the ability to phagocytose apoptotic cells and express the M2 epitope.This is a rational explanation for the tissue specificity of the autoimmune process.The mechanisms that could trigger cholangiocyte apoptosis are unknown but may involve mucosal IgA M2Ab, abnormal bile composition, altered endocrine or neuroendocrine mediated-regulation of metabolic and kinetic activity of cholangiocytes.
The early clinical phase is marked by inflammation and anicteric cholestasis. In this early stage, the non-ductopenic stage, inflammation is associated with similar rates of apoptosis and proliferation of the biliary cells. Cytolytic T cells, CD8, CD4 and NKT are attracted to the target cells by the release of chemokines. Killing is mediated mainly through activation of TNF, CD40 and Fas receptors. Under the pressure of this environment, cholangiocytes proliferate through mediators that include those of the cholinergic pathway and estrogens and their alpha receptors.
In many patients, inflammation spreads into the lobule leading to interface hepatitis.This process proceeds in two ways, the lymphocytic piecemeal necrosis similar to that found in autoimmune hepatitis and the biliary piecemeal necrosis which is marked by a striking increase in the number of ductular profiles associated with edema, neutrophil infiltration, periductular fibroplasia and hepatocellular death with features of cholate stasis.
Hepatocellular death triggers expansion of progenitor cells marked by the appearance of reactive ductules that secrete mediators that attract and activate fibroblasts. The limiting plates are thus progressively replaced by newly formed connective tissue. Interface hepatitis represents the turning point in the natural history of PBC. Its severity predicts the onset of cirrhosis.
Cholestasis is a hallmark of PBC. In the early non-ductopenic stage, cholestasis results from mediators and proinflammatory cytokines that inhibit canalicular and ductular bile secretion. UDCA has the ability to restore bile secretion at least in part because of its anti-inflammatory properties in the biliary tree.In later phases cholestasis is mainly due to the loss of bile ducts.
There are tree major forms of PBC.
The typical or classical form is represented by the slowly progressive decline of small bile ducts and parallel increase in liver fibrosis, leading to biliary cirrhosis over a period of 10 to 20 years. A second form that affects 10 to 20 % of patients is characterized by the fluctuating or persistent presence of features of autoimmune hepatitis. These patients have a more severe course, with early development of liver fibrosis and liver failure. A third form that affects 5 to 10% of patients is represented by the so-called premature ductopenic variant. Its hallmark is a very rapid onset of ductopenia and severe icteric cholestasis, progressing very quickly towards cirrhosis in less than five years.
PBC is currently diagnosed earlier in its clinical course. Half of the patients are asymptomatic at diagnosis. Fatigue and pruritus are early phase symptoms. Fatigue is a frequent complaint that is unrelated to disease severity and has a major impact on quality of life. Whether it is a specific symptom or not remains unknown. It is associated with cognitive and emotional dysfunction, depression, sensory and autonomic abnormalities as well as excessive day-time somnolence. About half of the patients have mild pruritus at diagnosis. It may be severe, particularly in the premature ductopenic variant, severely affecting quality of life. In some patients the diagnosis is made during the work-up of another autoimmune disease. In 5 to 10 % of the cases the diagnosis is made in the workup of cirrhosis. In the variant associated with features of autoimmune hepatitis the diagnosis may be made in a patient with seemingly acute hepatitis.
In the typical form, serum alkaline phosphatase and gamma-glutamyltranspeptidase are characteristically elevated, with only mild to moderate elevation of serum aminotransferases. In the premature ductopenic variant, cholestasis is quite severe and is associated with marked hypercholesterolemia affecting both HDL and LDL fractions. In patients with features of both autoimmune hepatitis and PBC, serum aminotrasferase levels may be markedly elevated and usually associated with marked IgG elevations. All forms of PBC are associated with increased IgM levels. Thrombocytopenia , polyclonal hyperglobulinemia and hyperbilirubinemia are indicators of cirrhosis. A prolonged INR and hypoalbuminemia usually occur in the terminal phase.
Ultrasound of the liver and biliary tree is mandatory in all patients presenting with liver abnormalities suggestive of PBC. If the the biliary system appears normal by ultrasound and the AMA is positive, no further radiologic examination of the bile ducts is necessary. If the diagnosis of PBC is uncertain cholangiography may be necessary.
The major hallmark of PBC is the presence of AMA in serum. AMA that react with the E2 component of pyruvate dehydrogenase are diagnostic of PBC. A variety of antinuclear antibodies are associated with PBC. Of these, those that react with the proteins of the pore complex (gp210, nucleoporin 62 ) and with the nuclear body protein (sp100) are specific.
Liver histologic examination is only indicated if AMA are negative or if the patient has the biochemical picture of atypical PBC or if superimposed co-morbidity is suspected. Nevertheless it shoud be emphasised that histology is necessary for prognostic evaluation and treatment strategy.
a) Specific therapy
All PBC patients with abnormal liver biochemistry should be considered for specific therapy.
UDCA, at the dose of 13 to 15mg/Kg/day, is currently considered the mainstay of therapy for PBC. Randomized, double-blinded, placebo-controlled trials have consistently shown that UDCA improves parameters of liver biochemistry including serum bilirubin, the major prognostic marker in PBC. UDCA delays the progression of fibrosis and of histological stage. A combined analysis of three randomized-controlled trials including 548 patients with PBC showed improved survival free of liver transplantation in patients with moderate to severe disease treated with UDCA at doses of 13 to 15 mg/kg/day for up to 4 years . Long-term observational studies from France, Spain and the Netherlands have shown that UDCA therapy is associated with an improvement in survival compared to that predicted by the Mayo model. Survival in UDCA-treated patients in stages 1 and 2 is similar to that in a control population . Some metaanalysis (but not all) including short-term trials with low doses of UDCA (less than 12mg/Kg/day) have questioned the efficacy of UDCA. However on the basis of all available data, it is currently recommended to treat PBC with UDCA using doses of at least 13 mg/kg/day and to start early. UDCA could be taken in divided doses or as a single dose.
Overall UDCA is extremely safe. Because UDCA is an acid it can lead to gastric discomfort, heartburn and symptomatic reflux. These symptoms are easily managed with proton pump inhibitors or by ingesting the bile acid at the end of meals. The majority of patients notice weight gain (3 Kg, on average). In patients with pruritus and frank cholestasis, UDCA may actually increase pruritus at the recommended dose; in these patients UDCA should be initiated at a lower dose (200-400 mg/day) and progressively increased to the recommended doseover 4 to 8 weeks.
The aim of UDCA therapy is to normalise serum bilirubin, alkaline phosphatase and aminotransferase levels at the end of the first year of therapy. In many patients this cannot be achieved. An optimal response to UDCA is defined when, after the first year of therapy, serum bilirubin is <1mg/dl, AST less 2 times the upper limit of normal, and alkaline phosphatase is < 3 times the upper limit of normal.. A decrease >50% in serum alkaline phosphatase has also been described as predictive of an excellent long-term prognosis. In a small subset of patients, the daily dose of 13-15 mg is not sufficient to achieve the best biochemical response. In these patients, measurement by HPLC-mass spectrometryof the blood or biliary enrichment in UDCA may be useful. In those with a low percentage of UDCA (less than 40%) a trial with daily doses up to 20mg/Kg/day is proposed to achieve a better response.
About 30 to 40% of our patients have a suboptimal response to UDCA. These patients need adjuvant therapy.
b) Adjuvant therapies
Glucocorticoids and methotrexate should be considered in patients with features of autoimmune hepatitis, severe interface hepatitis, abnormal serum bilirubin level or suboptimal response to UDCA
Preliminary studies in our patients indicate that patients with a suboptimal response to UDCA benefit from the combination of UDCA and glucocorticoids (prednisone or budesonide) in terms of survival without liver transplantation. Glucocorticoids, specifically budesonide, have been shown to provide added benefit in patients treated with UDCA, with greater biochemical and histological (inflammation and fibrosis) responses. Budesonide is given at a dose of 6 to 9 mg/day in non-cirrhotic patients. The drug is contraindicated in patients with cirrhosis.
Methotrexate has been shown to improve biochemical and histological results when added to UDCA in patients with an incomplete response to UDCA . However, in other studies methotrexate has been ineffective when used alone or in combination with UDCA. In a 10-year multicenter study, survival was the same in patients randomized to methotrexate plus UDCA as in randomized to colchicine plus UDCA, with a survival similar to that predicted by the Mayo model. However, one third of the patients had few signs of PBC after 10 years of treatment and no patient at a precirrhotic stage at enrollment progressed to cirrhosis. Methotrexate may cause interstitial pneumonitis similar to that seen in rheumatoid arthritis.
Many other drugs, colchicine, , cyclosporine, chlorambucil, penicillamine, azathioprine, mycophenolate mophetil, malotilate, thalidomide have been evaluated in PBC. They are either ineffective or toxic. None are effective in UDCA-treated patients at risk of developing cirrhosis and/or liver failure.
New medical therapeutic options
FXR is a major bile acid receptor that regulates the expression of genes involved in bile acid and lipid metabolism. It may also modulate innate immunity in the biliary tree and intestine. The FXR agonist, obeticholic acid, ameliorates liver biochemistries and reduces IgM levels in PBC. It is now assessed in phase 3 trials.
PPAR alpha agonists (bezafibrate, fenofibrate) are now recognized to have antiiflammatory and immunomodulatory properties in several experimental models of autoimmunity. Short-term administration of fibrates leads to marked improvement of liver biochemisties and immunoglobulins levels in PBC. Whether it could improve liver inflammation and fibrosis remains unknown.
c) Liver transplantation
Liver transplantation has greatly improved survival in patients with PBC. It is the only effective treatment for those with decompensated cirrhosis or liver failure. Patients the premature ductopenic variant of PBC do not respond to medical therapy and liver transplantation should be considered despite the absence of decompensated liver disease. PBC recurs in about 25% of patients at 5 years post-transplantation. Recurrence is more frequent in patients without a glucocorticoid and cyclosporin regimen. The utility of UDCA in this setting remains unknown.
d) Treatment of symptoms and complications
First line therapy is rifampicin at the daily dose of 300-600 mg/day in patients receiving UDCA. However the drug may induce hepatitis in some cases. Second line therapies include glucocorticoids, cholestyramine, sertraline and opiate antagonists. Plasmapheresis or biliary drainage may be successful when other treatments fail. In very rare patients resistant pruritus may be an indication for liver transplantation.
Modafinil, a drug approved for the treament of narcolepsy has been reported in open studies to provide significant improvement in fatigue in patients with PBC. The drug is used at a dose of up to 400 mg/day seems well tolerated and should be considered in patients with excessive fatigue and day-time somnolence.
UDCA induces an average 15-20 % decrease in total and LDL cholesterol after one year of therapy. Statins and fibrates are safe and effective in patients in whom LDL cholesterol is elevated despite UDCA..
A minority of patients with PBC develop presinusoidal portal hypertension before becoming cirrhotic. The management of portal hypertension in patients with PBC should follow the same guidelines as for patients with cirrhosis at large. Severe portal hypertension even without any other signs of decompensation is a good indication of liver transplantation. Osteopenia and osteoporosis
Osteopenia and osteoporosis affect up to 30% of patients with PBC patients. Current therapies include physical activity, calcium and vitamin D supplementation with the goal of achievingserum 25OH D3 levels > 30 ng/ml. Other therapies include biphosphonates or estrogen supplementation.
Sources of information for patients and doctors
 EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237-267.
 Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology 2009;50:291-308.
 Poupon R. Primary biliary cirrhosis : A 2010 update. J Hepatol 2010;52:745-58
 Poupon RE, Balkau B, Eschwege E, Poupon R, UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991;324:1548-1554.
 Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005;128:297-303.
 Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 2006;130:715-720.
 Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48:871-877.
 Poupon R. Autoimmune overlapping syndromes. Clin Liver Dis 2003;7:865-878.
 MacQuillan GC, Neuberger J. Liver transplantation for primary biliary cirrhosis. Clin Liver Dis 2003;7:941-956.
Workup and Management of the patient with PBC
1)The diagnosis is based on the 3 following criteria: a) cholestatic pattern of liver (elevated serum alkaline phosphatase and gammaglutamyltranspeptidase activities) ; b) presence of antimitochondrial antibodies with M2 specificity as confirmed by ELISA or immunoblotting; c) evidence of non suppurative destructive cholangitis (NSDC) at histology. Criteria a and b or c are sufficient for the diagnosis considering the high specificity of anti-M2 antibody and NSDC.
2) Patients with AMA and normal biochemical tests are at risk of developing true PBC. Patients with biochemical evidence of cholestasis but AMA negative may have PBC if portal inflammation and ductopenia are demonstrated at liver biopsy. The diagnosis is further supported in this setting if antinuclear antibodies against GP 210, Nucleoporin 62, sp100 giving nuclear-rim or nuclear –dot pattern are present. NSDC is highly suggestive of PBC but is not pathognomonic since it may be present in patients with autoimmune hepatitis, primary slerosing cholangitis, lymphoma and viral hepatitis C and E.
3) Mucosal infections especially recurrent urinary infections and cigarette smoking are two main risk factors for PBC and PBC progression. Infections should be treated or prevented; passive or active smoking should be avoided.
4) About 20% of the patients exhibit simultaneous or consecutive other autoimmune diseases, the most frequent being autoimmune hepatitis, CREST syndrome and/ or scleroderma and thyroiditis. Coeliac disease is not so frequent but should be recognized because of the beneficial effect of the gluten free diet.
5) First-degree relatives of patients with PBC are at high risk of PBC or other autoimmune diseases. The patients and their relatives should be informed and evaluated for these conditions.
6) While the pathogenesis of fatigue and pruritus is still unknown and their treatment empirical these two symptoms should be carefully analyzed and if possible quantified.
7) Next the attention should focus on the severity or potential severity of the disease.
a) Is there evidence of cirrhosis? Asymptomatic cirrhosis is probable if the following are present: splenomegaly, prothrombin index < 80%, serum albumin <38 g/L,-serum bilirubin> 2 mg/dl, platelet count i<150,000/microl. These patients should be screened for the presence of eosophageal varices and hepatocellular carcinoma.
b)Are there predictors of progression of PBC or poor response to UDCA? Fatigue and pruritus are in most cases not related to the severity of PBC and does not have major prognostic value. Serum bilirubin level is the best predictor of prognosis and of long-term response to UDCA treament. Patients with even mild elevation (more than 1mg/dl ) are at risk of developing extensive fibrosis or cirrhosis in the next ten years. Patients with high serum bilirubin level (more than 3mg/l), high serum alkaline phosphatase activity and cholesterol have usually severe ductopenia at presentation (the premature ductopenic variant of PBC) and will not respond to any medical therapy. These patients should be informed that liver transplantation is the only therapeutic alternative.
c) Is there evidence of features of autoimmune hepatitis ? Patients with criteria of both PBC and autoimmune hepatitis need treatment with both UDCA and glucocorticoids. High levels of serum bilirubin together with high ALT and IgG as well the presence of antiactine and anti SLA antibodies is very suggestive of this condition.
d) Liver biopsy is mandatory to fully evaluate the prognosis and to establish the best medical treatment. Given the risk of sampling error at least 10 portal tracts should be available. The individual lesions have to be graded. The METAVIR score can be used to assess both fibrosis and interface hepatitis (under the form of lymphocytic piecemeal necrosis). Presence and extent of the NSDC should be noted. Ductopenia should be quantified. However, in case of heavy portal inflammation this quantification may be difficult even with the use of cytokeratin histochemical staining. The presence and extent of biliary piece meal necrosis should be assessed. Nodular regenerative hyperplasia, sometimes present may indicate portal vascular damage by inflammatory cells. Presence of numerous fibrous septa, loss of more than 50% of the interlobular bile ducts, moderate to severe lymphocytic or biliary piecemeal necrosis are indices of severe prognosis . Patients with a high score of cholangitis activity (NSDC in more than 1/3 of portal tracts) and /or interface lymphocytic hepatitis may benefit from UDCA- budesonide or methotrexate combination. Patients with severe ductopenia and biliary interface hepatitis are usually fail to respond to any form of medical therapy.
8) Because the prognosis of PBC has improved over the past 2-3 decades, two associated conditions deserve particular attention. Hypercholesterolemia with increased LDL cholesterol is observed in about 20% of the patients. Accordingly the risk of cardiovascular disease should be evaluated and medical therapy proposed. Osteoporosis and osteopenia might be more frequent in PBC women than in a control population although this remains controversial. Nevertheless metabolic bone disease should be assessed and prevented particularly in those in whom glucocorticoids are considered.