Prof. Raoul Poupon
UPMC Univ Paris 06, UMRS_893, CdR Saint-Antoine, F-75012, Paris, France
INSERM, UMRS_893, CdR Saint-Antoine, F-75012, Paris, France
AP-HP, Hôpital Saint-Antoine, Service d’Hépatologie & Centre de Référence des Maladies Inflammatoires des Voies Biliaires, F-75012, Paris, France
Primary biliary cholangitis (primary biliary cirrhosis) (PBC) is a chronic inflammatory autoimmune disease that affects mainly the biliary cells lining the small bile ducts of the liver. As many other autoimmune disorders PBC occurs mostly women. Its peak incidence occurs in the fifth decade of life, and it is uncommon in persons under 25 years of age. From a clinical standpoint PBC is defined empirically as a syndrome characterized by chronic cholestasis and autoantibodies directed mainly against the E2 subunits of pyruvate dehydrogenase complex of mitochondria. Histologically the typical lesion is the so-called non-suppurative destructive cholangitis (NSDC) often associated with ductopenia and inflammation extending beyond the portal tracts into the surrounding parenchyma. Spreading of the inflammatory process into the lobule is associated with hepatocellular destruction and manifested either under the form of lymphocytic piecemeal necrosis or biliary piecemeal necrosis. As the result of hepatocellular death the limiting plates are progressively replaced by newly formed connective tissue making fibrous septa linking adjacent portal tracts and leading eventually to cirrhosis. The severity of this pathological process and its rate of progression are highly variable from one patient to another.
There are 3 major forms of the disease. The typical form is represented by the slowly progressive decline of patent small bile ducts and progressive parallel increase in liver fibrosis leading to biliary cirrhosis over a period of 10 to 20 years. A second form that affects about 15 to 20 % of the patients is characterized by the fluctuating or persistent presence of the features of autoimmune hepatitis (1). 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 the patients is represented by the so-called premature ductopenic variant (2). Its hallmark is a very rapid onset of ductopenia and severe cholestasis progressing very quickly towards cirrhosis in less than 5 years.
Diagnosis and evaluation of the patient with PBC
The diagnosis of PBC is generally easy. The diagnosis is based on the 3 following criteria: a) abnormal biochemical tests with preferential elevation of serum alkaline phosphatase and gammaglutamyltranspeptidase activities) ; presence of antimitochondrial antibodies with M2 (AMA) specificity as confirmed by ELISA or immunoblotting; c) evidence of NSDC at histology.
Criteria a and b or c are sufficient for the diagnosis considering the high specificity of anti-M2 antibody and NSDC. 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. In some patients AMA appear during the follow-up of these patients. 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.
The evaluation of the patient is of considerable importance for the prognosis and treatment.
Mucosal infections especially recurrent urinary infections and cigarette smoking are two main risk factors of PBC (3, 4). Infections should be treated or prevented; passive or active smoking should be avoided.
About 30% of the patients exhibit simultaneous or consecutive other autoimmune diseases, the most frequent being autoimmune hepatitis, CREST syndrome and/ or sleroderma and thyroiditis. Sicca symptoms are sought by direct questioning. They include xerostomia but also dental caries, gum infection and tracheobronchitis. Celiac disease is not so frequent but should be recognized because of the beneficial effect of the gluten free diet.
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.
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.
Next the attention should focus on the severity or potential severity of the disease.
Is there evidence of cirrhosis? Asymptomatic cirrhosis is probable if splenomegaly is disclosed, if prothrombin index is lower than 80%, if serum albumin is lower than 38 g/L, if serum bilirubin is more than 2 mg/dl, if the platelet count is les than 150000/microl. In these patients eosophageal varices should be evaluated and treated if of large size. The cirrhotic patients are at risk of developing hepatocellular carcinoma and as such need to be regularly investigated by imaging techniques.
Is there evidence of indices of severity and predictors of poor response to ursodeoxycholic acid (UDCA) therapy apart cirrhosis? 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 even with 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.
Is there evidence of features of autoimmune hepatitis ? Patients with both the criteria of PBC and autoimmune hepatitis need to be given both UDCA and glucocorticoids. High levels of serum bilirubin together with high ALTand IgG as well the presence of antiactine and anti SLA antibodies is very suggestive of this condition. HLA DR3 and DR4 could be another marker of this PBC variant.
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. We used the Metavir score 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 i.e, the mixture of ductular proliferation, macrophages, polymorphonuclears and fibroplasia 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 (5, 6).
Because the prognosis of PBC is far better than 2 or 3 decades ago 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 possibly 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 in particular in those at risk of receiving glucocorticoids.
Specific therapy for PBC
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-control 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 (7-10). 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 (11). Long-term observational studies from France, Spain and the Netherlands (6, 12-14) have shown that UDCA therapy provides a better survival than that predicted by the Mayo model. The survival rate of UDCA treated patients in stage 1 and 2 is similar to that in a control population (6). 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. I recommend one dose in the morning, the other in the evening, and both at meals. In some active patients the compliance seems better with a single dose. Because UDCA is an acid it could produce in some patients gastric discomfort, burning sensation and symptomatic reflux. These symptoms are easily managed with proton pump inhibitors or by ingesting the bile acid at the end of meals.
Overall UDCA is extremely safe. The majority of the patients note a weight gain (2 Kg, on average). This weight gain may be more significant in the patients who have stopped smoking. In patients with pruritus and frank cholestasis, UDCA may increase pruritus if given at the dose of 13-15 mg/Kg/day. In these patients I recommend to start UDCA therapy at a low dose (200-4OO) mg/day and to progressively increase the daily dosage over a period of 4 to 8 weeks.
The aim of UDCA therapy is to provide the normalisation of the serum bilirubin, alkaline phosphatase and ALT or AST levels at the end of the first year of therapy. In many patients this could not be achieved. We define the optimal response to UDCA when serum bilirubin is less than 1mg/dl and AST less than two times the upper limit of normal, and alkaline phosphatase less than 3 times the upper limit of normal at the end of the first year of therapy. Indeed the patients with these criteria have a normal life expectancy without liver transplantation (15). Others (13) have observed that patients with a decline of serum alkaline phosphatase of more 50% achieved 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 the patients who do respond adequately we measure by LC-MS the blood and biliary enrichment in UDCA. 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 40% of our patients have a suboptimal response to UDCA. These patients need an adjuvant therapy.
Patients with features of autoimmune hepatitis, severe interface hepatitis, abnormal serum bilirubin level or suboptimal response to UDCA -as defined above- deserve trials with adjuvant therapies. Currently glucocorticoids (prednisone or budesonide) and methothrexate could be considered for these patients.
The rationale for the use of glucocorticoids is based on the following arguments. Glucocorticoids and specificically budesonide have been shown to provide benefit in patients treated by UDCA (16-18). Combination of both affords better biochemical response and better histological response in terms of inflammation and fibrosis. Budesonide is given at 6 to 9 mg/day in non-cirrhotic patients. The drug is contraindicated in patients with cirrhosis. 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.
Methotrexate improved biochemical test results and liver histological findings when it was added to UDCA in patients who had an incomplete response to UDCA (19). However other studies found no efficacy of methotrexate was used alone or in combination with UDCA. In a 10-year study, survival was the same in patients taking methotrexate and UDCA as in those taking colchicine and UDCA and survival was similar to that predicted by the Mayo model. However, one third of the patients had few signs of PBC after 10 years of treatment (20). No patient who was in the precirhotic stage at baseline showed progression to cirrhosis. Methotrexate may cause interstitial pneumonitis similar to that seen in rheumatoid arthritis.
Several drugs, colchicine, bezafibrate, ciclosporine, chlorambucil, penicillamine azathioprine, mycophenolate mophetil, malotilate, thalidomide have been evaluated in PBC. Many of them are either ineffective or toxic. None of them have been shown to be effective in UDCA treated patients at risk of development of cirrhosis or liver failure as defined above.
Orthopic 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. The patients who present with the features of the premature ductopenic variant of PBC do not respond to any medical therapy and despite the absence of any decompensation draws a major benefit from liver transplantation. PBC recurs in about 25% of patients at 5 years. Recurrence is more frequent in patients without a glucocorticoid and ciclosporin regimen. The beneficial long-term effect of UDCA in this setting remains unknown.
Treatment of symptoms and complications
The 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, and opioids antagonists. Plasmapheresis or biliary drainage may be successful when other treaments fail. In very rare patients resistant pruritus may be an indication for liver transplantation
Fatigue is a frequent complaint in PBC. The symptom is unrelated to the severity of the disease. Whether it is a specific symptom or not remains unknown. Fatigue has a major impact on the quality of life of PBC patients. It is associated with cognitive and emotional dysfunction, depression, sensory and autonomic abnormalities (21, 22). It is also associated with excessive day-time somnolence (23). Modafinil, a drug approved for the treament of narcolepsy have been reported in open studies to provide significant benefit in PBC patients with fatigue (24, 25). The drug used at a dose up to 400 mg /day seems well tolerated and in our experience very effective in those with excessive fatigue and day-time somnolence.
UDCA induces an average 15-20 % falls in total and LDL cholesterol at one year of therapy. Statins and ezetimibe are safe and effective in those who still have increased LDL cholesterol.
A minority of patients with PBC develop presinusoidal portal hypertension before becoming cirrhotic. The management of portal hypertension in patients with PBC should be as for all cirrhotic patients. Severe portal hypertension even without any other sign of decompensation is a good indication of liver transplantation. Liver transplantation should be preferred to TIPS.
Osteopenia and osteoporosis.
Current treatments for osteopenia and osteoporosis that affect up to 30% of PBC patients included physical activity, calcium and vitamin D supplementation in order to achieve at least 30 ng/ml of serum 25OH D3, biphosphonates or estrogens supplementation.
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2. Vleggaar FP, van Buuren HR, Zondervan PE, ten Kate FJ, Hop WC. Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant. Gut 2001;49:276-281.
3. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005;42:1194-1202.
4. Zein CO, Beatty K, Post AB, Logan L, Debanne S, McCullough AJ. Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment. Hepatology 2006;44:1564-1571.
5. Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology 2002;122:652-658.
6. 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.
7. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000;32:1196-1199.
8. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, Berenguer J, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol 2000;32:561-566.
9. Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis. Hepatology 1999;29:644-647.
10. Poupon RE, Lindor KD, Pares A, Chazouilleres O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003;39:12-16.
11. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113:884-890.
12. Poupon RE, Bonnand AM, Chretien Y, Poupon R. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology 1999;29:1668-1671.
13. 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.
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17. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, Ackermann H, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999;117:918-925.
18. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, Farkkila M. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005;41:747-752.
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22. Poupon RE, Chretien Y, Chazouilleres O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cirrhosis. Hepatology 2004;40:489-494.
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25. Jones DE, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther 2007;25:471-476.