Jian Shi, Cheng Wu, Yong Lin, Yue-Xiang Chen, Liang Zhu, Wei-fen Xie
Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials.
Am J Gastroenterol. 2006 Jul;101(7):1529-38. doi: 10.1111/j.1572-0241.2006.00634.x.
Abstract/Text
OBJECTIVES: The effect of ursodeoxycholic acid (UDCA) treatment on survival and liver histological progression of primary biliary cirrhosis (PBC) remains uncertain. The aim of this study is to assess the long-term efficacy of mid-dose UDCA treatment for PBC.
METHODS: Electronic databases including Medline, Embase, Cochrane controlled trials register, Science Citation Index, and PUBMED (updated to Nov 2005), and manual bibliographical searches were conducted. A meta-analysis of all long-term randomized controlled trials (RCTs) comparing mid-dose UDCA with placebo or no treatment was performed.
RESULTS: Seven RCTs and six reports of their extended follow-up including 1,038 patients were assessed. UDCA could significantly improve liver biochemistry, but had no effect on pruritus and fatigue. UDCA could delay the progression of PBC, especially for early-stage patients. Meta-analysis of the seven RCTs including their extended follow-up showed a significant reduction of the incidence of liver transplantation (OR 0.65, p = 0.01), and a marginally significant reduction of the rate of death or liver transplantation (fixed-effect model: OR 0.76, p = 0.05; random-effect model: OR 0.77, p = 0.3) in the UDCA group, except death (OR 1.01, p = 1). In the sensitivity analyses, which included studies administrating placebo as control, long-term studies (> or = 48 months), or large size studies (total number of patients > or = 100), we all found long-term treatment with UDCA could significantly reduce the incidence of liver transplantation, and death or liver transplantation.
CONCLUSIONS: Long-term treatment with mid-dose UDCA can improve liver biochemistry and survival free of liver transplantation in patients with PBC. In addition, UDCA therapy can delay the histological progression in the early-stage patients.
Luigi Muratori, Alessandro Granito, Paolo Muratori, Georgios Pappas, Francesco B Bianchi
Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value.
Clin Liver Dis. 2008 May;12(2):261-76; vii. doi: 10.1016/j.cld.2008.02.009.
Abstract/Text
Antimitochondrial antibodies (AMA) are the serologic cornerstone in the diagnosis of primary biliary cirrhosis (PBC), even if they are not detectable in a proportion of patients, notwithstanding the most sensitive and sophisticated technologies used. To fill in the serologic gap in AMA-negative PBC, there is sound evidence to consider antinuclear antibody (ANA) patterns, such as anti-multiple nuclear dots and anti-membranous/rim-like, as PBC-specific surrogate hallmarks of the disease, and their detection can be considered virtually diagnostic. Furthermore, particular ANA specificities, such as anti-gp210, anti-p62, anticentromere antibodies, and anti-dsDNA, may provide additional diagnostic and prognostic information.
Keith D Lindor, M Eric Gershwin, Raoul Poupon, Marshall Kaplan, Nora V Bergasa, E Jenny Heathcote, American Association for Study of Liver Diseases
Primary biliary cirrhosis.
Hepatology. 2009 Jul;50(1):291-308. doi: 10.1002/hep.22906.
Abstract/Text
Anna Cavazza, Llorenç Caballería, Annarosa Floreani, Fabio Farinati, Miquel Bruguera, Diego Caroli, Albert Parés
Incidence, risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: comparative analysis from two centers.
Hepatology. 2009 Oct;50(4):1162-8. doi: 10.1002/hep.23095.
Abstract/Text
UNLABELLED: The limited information and divergent results on the prevalence, incidence, and risk factors for hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) may be due to the low prevalence of the disease and geographical and environmental differences. Therefore, we analyzed the incidence, prevalence, survival, and risk factors for HCC in patients with PBC from two European centers (389 from Barcelona, Spain, and 327 from Padova, Italy) followed up for 9.3 +/- 6.5 years. Gender, age, smoking habit, alcohol consumption, presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies (anti-HCV), and advanced histological stage (III-IV) were evaluated as risk factors for tumor development. Twenty-four patients (13 from Barcelona and 11 from Padova) developed HCC. The prevalence of HCC was similar in Barcelona (3.34%) and Padova (3.36%). The incidence was 0.35 and 0.37 per 100 patient-years, respectively. Male gender, age >52 years, smoking habit, alcohol >40 g/day, HBsAg, and anti-HCV were not associated with HCC. Advanced histological stage was the only factor associated with the development of HCC (odds ratio [OR]: 5.80, 95% confidence interval [CI]: 2.34-14.38, P < 0.001). When analyzing the two series separately, male gender was associated with higher likelihood of HCC in Padova (OR: 8.09, 95% CI: 1.93-33.8, P < 0.01). The median survival after the diagnosis of HCC was 36 months.
CONCLUSION: The prevalence and incidence of HCC is similar in Spain and Italy and the advanced histological stage is the only risk factor associated with the development of HCC in PBC. The slight disparities observed between the two series might be explained by patient features on diagnosis of liver disease.
廣原淳子：原発性胆汁性肝硬変全国調査（第28報）．厚生労働科学研究補助金，難治性疾患克服事業報告書．2008．.
廣原淳子：原発性胆汁性肝硬変全国調査（第29報）．厚生労働科学研究補助金，難治性疾患克服事業報告書．2009．.
廣原淳子：原発性胆汁性肝硬変全国調査（第31報）．厚生労働科学研究補助金，難治性疾患克服事業報告書．2011．.
厚生労働省難治性疾患政策研究事業「難治性の肝・胆道疾患に関する調査研究」班：原発性胆汁性胆管炎（PBC）の診療ガイドライン（2017年）.
European Association for the Study of the Liver
EASL Clinical Practice Guidelines: management of cholestatic liver diseases.
J Hepatol. 2009 Aug;51(2):237-67. doi: 10.1016/j.jhep.2009.04.009. Epub 2009 Jun 6.
Abstract/Text
J Goulis, G Leandro, A K Burroughs
Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.
Lancet. 1999 Sep 25;354(9184):1053-60. doi: 10.1016/S0140-6736(98)11293-X.
Abstract/Text
BACKGROUND: Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, but its effect on disease progression and survival is uncertain. The aim of this study was to clarify the efficacy of UDCA in primary biliary cirrhosis.
METHODS: A systematic review, including the use of meta-analysis, was done for the randomised and switch-over phases of trials comparing UDCA with placebo, obtained from Medline and Embase databases, and from manual searches derived from review articles and abstracts of major international meetings. All trials had more than a mean of 6 months' follow-up and only included patients with primary biliary cirrhosis (PBC) according to established diagnostic criteria.
FINDINGS: 17 relevant articles were identified: 11 randomised controlled trials, including 1272 patients, and six reports of the switch-over phases. UCDA had a favourable effect on liver biochemistry in most of the studies but not on symptoms or the progression of histological stage; two studies did not assess survival, liver transplantation, or complications of liver disease. Meta-analysis showed no difference between UDCA and placebo in the incidence of death (odds ratio 1.21, 95% CI 0.71-2.04), liver related death (0.72, 0.22-2.32), liver transplantation (1.27, 0.78-2.07), death or liver transplantation (1.26, 0.87-1.82), and in the development of complications of liver disease (1.11, 0.64-1.92). With the primary end point defined by the authors (a combined end point in three studies, and death or liver transplantation in the others) an odds ratio of 1.53 (0.97-2.42) was obtained. Assessment of the switch-over phases, during which there was a longer follow-up, did not change the results of the meta-analysis.
INTERPRETATION: Published randomised controlled trials of UDCA do not show evidence of therapeutic benefit in PBC and its use as standard therapy needs to be re-examined.
Yan Gong, Zhi Bi Huang, Erik Christensen, Christian Gluud
Ursodeoxycholic acid for primary biliary cirrhosis.
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD000551. doi: 10.1002/14651858.CD000551.pub2. Epub 2008 Jul 16.
Abstract/Text
BACKGROUND: Primary biliary cirrhosis is an uncommon autoimmune liver disease with unknown aetiology. Ursodeoxycholic acid (UDCA) has been used for primary biliary cirrhosis, but the effects remain controversial.
OBJECTIVES: To evaluate the benefits and harms of UDCA on patients with primary biliary cirrhosis against placebo or no intervention.
SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library, MEDLINE, EMBASE, SCI-EXPANDED, The Chinese Biomedical CD Database, LILACS, and the references of identified studies. The last search was performed in January 2007.
SELECTION CRITERIA: Randomised clinical trials evaluating UDCA versus placebo or no intervention in patients with primary biliary cirrhosis.
DATA COLLECTION AND ANALYSIS: The primary outcomes were mortality and mortality or liver transplantation. Binary outcomes were reported as odds ratio (OR) or relative risk (RR) and continuous outcomes as weighted mean difference, all with 95% confidence intervals (CI). Meta-regression was used to investigate the associations between UDCA effects and quality of the trial, UDCA dose, trial duration, and patient's severity of primary biliary cirrhosis. We also used Bayesian meta-analytic approach to estimate the UDCA effect as sensitivity analysis.
MAIN RESULTS: Sixteen randomised clinical trials evaluating UDCA against placebo or no intervention were identified. Data from three trials have been updated. Nearly half of the trials had high risk of bias. The combined results demonstrated no significant effects favouring UDCA on mortality (OR 0.97, 95% CI 0.67 to 1.42) and mortality or liver transplantation (RR 0.92, 95% CI 0.71 to 1.21). The findings were supported by the Bayesian meta-analyses. UDCA did not improve pruritus, fatigue, autoimmune conditions, liver histology, or portal pressure. UDCA seemed to improve biochemical variables, like serum bilirubin, ascites, and jaundice, but the findings were based on few trials with sparse data. The use of UDCA is significantly associated with adverse events, mainly weight gain.
AUTHORS' CONCLUSIONS: This systematic review did not demonstrate any benefit of UDCA on mortality and mortality or liver transplantation of patients with primary biliary cirrhosis. The few beneficial effects could not be due to random errors or outcome reporting bias.
戸田剛太郎他：ウルソデオキシコール酸（UR-PBC錠）の原発性胆汁性肝硬変に対する臨床評価 用量設定試験。肝胆膵 1998;37(3）: 443-460.
Christophe Corpechot, Olivier Chazouillères, Alexandra Rousseau, Antonia Le Gruyer, François Habersetzer, Philippe Mathurin, Odile Goria, Pascal Potier, Anne Minello, Christine Silvain, Armand Abergel, Maryline Debette-Gratien, Dominique Larrey, Olivier Roux, Jean-Pierre Bronowicki, Jérôme Boursier, Victor de Ledinghen, Alexandra Heurgue-Berlot, Eric Nguyen-Khac, Fabien Zoulim, Isabelle Ollivier-Hourmand, Jean-Pierre Zarski, Gisèle Nkontchou, Sara Lemoinne, Lydie Humbert, Dominique Rainteau, Guillaume Lefèvre, Luc de Chaisemartin, Sylvie Chollet-Martin, Farid Gaouar, Farid-Hakeem Admane, Tabassome Simon, Raoul Poupon
A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.
N Engl J Med. 2018 Jun 7;378(23):2171-2181. doi: 10.1056/NEJMoa1714519.
Abstract/Text
BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition.
METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months.
RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group.
CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).
Akira Honda, Atsushi Tanaka, Tetsuji Kaneko, Atsumasa Komori, Masanori Abe, Mie Inao, Tadashi Namisaki, Naoaki Hashimoto, Kazuhito Kawata, Atsushi Takahashi, Masashi Ninomiya, Jong-Hon Kang, Mie Arakawa, Satoshi Yamagiwa, Satoru Joshita, Takeji Umemura, Ken Sato, Akira Kaneko, Kentaro Kikuchi, Jun Itakura, Takako Nomura, Keisuke Kakisaka, Hideki Fujii, Norifumi Kawada, Yasuhiro Takikawa, Tsutomu Masaki, Hiromasa Ohira, Satoshi Mochida, Hitoshi Yoshiji, Satoshi Iimuro, Yasushi Matsuzaki, Hajime Takikawa, Japan PBC Study Group
Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis.
Hepatology. 2019 Dec;70(6):2035-2046. doi: 10.1002/hep.30552. Epub 2019 Apr 12.
Abstract/Text
In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.
© 2019 by the American Association for the Study of Liver Diseases.
Atsushi Tanaka, Junko Hirohara, Toshiaki Nakano, Kosuke Matsumoto, Olivier Chazouillères, Hajime Takikawa, Bettina E Hansen, Fabrice Carrat, Christophe Corpechot
Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis.
J Hepatol. 2021 Sep;75(3):565-571. doi: 10.1016/j.jhep.2021.04.010. Epub 2021 Apr 18.
Abstract/Text
BACKGROUND & AIMS: A beneficial effect of bezafibrate (BZF) on symptoms and biochemical features of primary biliary cholangitis (PBC) has been reported in patients with an incomplete response to ursodeoxycholic acid (UDCA), but long-term effects on survival remain unknown. In Japan, BZF has been used as a de facto second-line therapy for PBC since 2000. Herein, we compared the survival rates between patients treated with and those without BZF in a large nationwide Japanese PBC cohort.
METHODS: All consecutively registered patients of this cohort who started UDCA therapy from 2000 onwards and had a follow-up ≥1 year were included. Association between BZF exposure and mortality or need for liver transplantation (LT) was assessed using time-dependent, multivariable-and propensity score-adjusted Cox proportional hazards models. Clinical benefit was quantified using the number needed to treat (NNT).
RESULTS: Of 3,908 eligible patients, 3,162 (81%) received UDCA only and 746 (19%) UDCA and BZF over 17,360 and 3,932 patient-years, respectively. During follow-up, 183 deaths (89 liver-related) and 21 LT were registered. Exposure to combination therapy was associated with a significant decrease in all-cause and liver-related mortality or need for LT (adjusted hazard ratios: 0.3253, 95% CI 0.1936-0.5466 and 0.2748, 95% CI 0.1336-0.5655, respectively; p <0.001 for both). This association was consistent across various risk groups at baseline. The NNTs with combination therapy to prevent 1 additional death or LT over 5, 10, and 15 years were 29 (95% CI 22-46), 14 (10-22), and 8 (6-15), respectively.
CONCLUSIONS: In a large retrospective cohort study of treatment effects in patients with PBC, the addition of BZF to UDCA was associated with improved prognosis.
LAY SUMMARY: The long-term efficacy of bezafibrate (BZF) on liver transplantation (LT) - free survival in patients with PBC and an incomplete response to ursodeoxycholic acid (UDCA) remains to be determined. In this Japanese nationwide retrospective cohort study, the use of UDCA-BZF combination therapy, compared to UDCA alone, was associated with a lower risk of all-cause and liver-related mortality or need for LT. These results indicate that BZF is so far the only drug in PBC to have demonstrated efficacy in improving symptoms, biochemical markers, and long-term outcomes.
Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
S K Goh, S E Gull, G J Alexander
Pregnancy in primary biliary cirrhosis complicated by portal hypertension: report of a case and review of the literature.
BJOG. 2001 Jul;108(7):760-2.
Abstract/Text
J Palma, H Reyes, J Ribalta, I Hernández, L Sandoval, R Almuna, J Liepins, F Lira, M Sedano, O Silva, D Tohá, J J Silva
Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo.
J Hepatol. 1997 Dec;27(6):1022-8.
Abstract/Text
BACKGROUND/AIMS: Intense pruritus and the risk of stillbirths and premature deliveries justify the search for an effective pharmacologic treatment of intrahepatic cholestasis of pregnancy. This study was designed to test the efficacy of ursodeoxycholic acid in maternal pruritus, the biochemical abnormalities and the outcome of pregnancy, in patients with intrahepatic cholestasis of pregnancy of early onset.
METHODS: Pregnant patients hospitalized in a secondary case-referral center with intense pruritus and abnormal serum levels of bile salts and aminotransferases, detected before week 33 of pregnancy, were randomly assigned to receive ursodeoxycholic acid, 1 g per day orally, or an identical placebo, until delivery, in a double-blind study. A 3-week trial period was chosen to compare drug and placebo effects. The follow-up was extended for 3 months after delivery.
RESULTS: Twenty-four patients entered the trial; eight had deliveries before 2 weeks of treatment and one dropped out. The study was then completed in 15 patients: eight received ursodeoxycholic acid and seven placebo. No adverse effects were detected in the mothers or in their babies. After 3 weeks of treatment, patients receiving ursodeoxycholic acid (mean daily dose 16 mg/kg body weight) had a significant improvement in pruritus (p<0.02), in serum bilirubin (0.36+/-0.19 mg/dl (mean+/-SD) versus 0.95+/-0.48 in patients receiving placebo, p<0.01), in aspartate aminotransferase (52+/-42 IU/l vs 98+/-44, p<0.05) and in alanine aminotransferase (54+/-50 IU/l vs 229+/-154, p<0.01); serum total bile salts also tended to be lower in patients receiving ursodeoxycholic acid (26.3+/-33.7 micromol/l vs 55.0+/-44.8, p N.S.). Deliveries occurred at or near term in all mothers who received ursodeoxycholic acid (mean week of pregnancy: 38), while they occurred before week 36 of pregnancy in five patients who received placebo, including one stillbirth. All babies born alive had birth weights adequate for gestational age and they were thriving normally 3 months after delivery.
CONCLUSIONS: Ursodeoxycholic acid is effective and safe in patients with intrahepatic cholestasis of pregnancy of early onset, attenuating pruritus and correcting some biochemical abnormalities in the mothers. Relevant aspects of fetal outcome were also improved in patients receiving ursodeoxycholic acid compared to placebo.
Olivier Chazouillères, Dominique Wendum, Lawrence Serfaty, Olivier Rosmorduc, Raoul Poupon
Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome.
J Hepatol. 2006 Feb;44(2):400-6. doi: 10.1016/j.jhep.2005.10.017. Epub 2005 Nov 15.
Abstract/Text
BACKGROUND/AIMS: Whether primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue.
METHODS: Seventeen patients with simultaneous form of strictly defined overlap were followed for 7.5 years. First-line treatment was UDCA alone (UDCA) in 11 and combination of immunosuppressors and UDCA (UDCA + IS) in 6.
RESULTS: Characteristics at presentation were not significantly different between the 2 groups. In the UDCA + IS group (f-up 7.3 years), biochemical response in terms of AIH features (ALT<2ULN and IgG < 16 g/L) was achieved in 4/6 and fibrosis did not progress. In the UDCA group, biochemical response was observed in three patients together with stable or decreased fibrosis (f-up 4.5 years) whereas the eight others were non-responders with increased fibrosis in four (f-up 1.6 years). Seven of these eight patients subsequently received combined therapy for 3 years. Biochemical response was obtained in 6/7 and no further increase of fibrosis was demonstrated. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P = 0.04).
CONCLUSIONS: Combination of UDCA and immunosuppressors appears to be the best therapeutic option for strictly defined PBC-AIH overlap syndrome.
A W Lohse, K H zum Büschenfelde, B Franz, S Kanzler, G Gerken, H P Dienes
Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals.
Hepatology. 1999 Apr;29(4):1078-84. doi: 10.1002/hep.510290409.
Abstract/Text
Some patients with autoimmune liver disease present with a clinical and/or histological picture showing characteristic findings of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Various names, mostly overlap syndrome, have been used to describe these cases, which have thus far not been more closely characterized. The aim of this study was the comparison of 20 patients with overlapping features to representative patients considered suffering from typical AIH or typical PBC (20 patients in each group). We found these patients to indeed show a very mixed picture of both conditions biochemically, serologically, and histologically. However, closer analysis suggested that all of these patients were primarily suffering from PBC as all of them had at least either bile duct destruction on histology or anti-M2 positive antimitochondrial antibodies (AMA). We suggest that these PBC patients because of their genetic susceptibility, evidenced by the AIH-characteristic histocompatibility leukocyte antigen (HLA) type B8, DR3, or DR4, developed a more hepatitic picture. Response to immunosuppressive therapy was excellent. We propose that the name "overlap syndrome" be abandoned for "PBC, hepatitic form." These observations not only have pathophysiological implications, but also suggest that therapy of PBC should be guided by the degree of biochemical and histological hepatic involvement.
K V Menon, P Angulo, S Weston, E R Dickson, K D Lindor
Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.
J Hepatol. 2001 Sep;35(3):316-23.
Abstract/Text
BACKGROUND/AIMS: To identify indicators of osteoporosis and to determine the rate of bone loss in patients with primary biliary cirrhosis (PBC).
METHODS: Bone mineral density of the lumbar spine and hip was measured at annual intervals over 7 years of follow-up in 176 patients with PBC.
RESULTS: Osteoporosis (t-score below -2.5) was found in 20% of patients and occurred 32.1 times more frequently in patients with PBC than expected. Patients with histologic stage 3 or 4 disease had a 5.4-fold increased risk of osteoporosis compared to patients with stage 1 or 2. Age, body mass index, advanced stage (3 or 4), and history of fractures were the only independent indicators of osteoporosis. After 3 years of follow up, the rate of bone loss in patients with stage 1 or 2 increased and equaled that seen in patients with stage 3 or 4. Serum bilirubin level was the only variable independently associated with the rate of bone loss over time.
CONCLUSIONS: Severity of the liver disease contributes significantly to the severity of bone disease in PBC. PBC patients who are older, thinner and have more advanced liver disease may have the most benefit from bone density measurements and treatment for their osteoporosis.
Alberto Benetti, Andrea Crosignani, Massimo Varenna, Cristina Squarcia Giussani, Mariangela Allocca, Massimo Zuin, Mauro Podda, Pier Maria Battezzati
Primary biliary cirrhosis is not an additional risk factor for bone loss in women receiving regular calcium and vitamin D supplementation: a controlled longitudinal study.
J Clin Gastroenterol. 2008 Mar;42(3):306-11. doi: 10.1097/01.mcg.0000248017.31386.39.
Abstract/Text
BACKGROUND AND GOALS: Alterations in bone metabolism in primary biliary cirrhosis (PBC) are generally considered to be highly prevalent and severe, but no data are available from prospective studies with adequate control groups. The aims of this study were: (1) to measure changes in bone mineral density (BMD) over time; (2) to correlate the degree of bone loss with the severity of liver disease; and (3) to characterize bone disease in PBC patients receiving regular calcium and vitamin D supplementation.
STUDY: We enrolled 118 women with PBC (mean age+/-SD: 56+/-11 y; 72% postmenopausal; 43% with cirrhosis), and measured BMD (lumbar spine, DXA-Hologic) at entry and serially over the following 5 years. The controls were 472 healthy women selected from a large observational group matched for age and menopausal status (mean age+/-SD: 55+/-10 y; 73% postmenopausal).
RESULTS: Mean BMD was 0.851+/-0.142 g/cm2 in the PBC group and 0.857+/-0.158 g/cm2 in the control group; the prevalence of osteoporosis was 28% and 29%, respectively. BMD significantly correlated with age and postmenopausal status, but not with liver cirrhosis or serum bilirubin levels. The biochemical markers of bone turnover were high in about 50% of the patients. The yearly bone loss in the PBC group was 0.008 g/cm2 (95% confidence interval: 0.014-0.003) similar to that calculated in the control group.
CONCLUSIONS: Among patients with PBC, the prevalence of osteoporosis and the yearly rate of BMD loss are similar to those observed in the general population, and are not associated with the severity of liver disease.
Nuria Guañabens, Albert Parés, Inmaculada Ros, Luisa Alvarez, Francesca Pons, Llorenç Caballería, Ana Monegal, M Jesus Martínez de Osaba, Merce Roca, Pilar Peris, Juan Rodés
Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.
Am J Gastroenterol. 2003 Oct;98(10):2268-74. doi: 10.1111/j.1572-0241.2003.07639.x.
Abstract/Text
OBJECTIVES: Osteopenia increases the morbidity of primary biliary cirrhosis (PBC). In this study, we have compared two bisphosphonates, alendronate and cyclical etidronate, that inhibit osteoclast-mediated bone resorption and have examined their effects on bone mass in patients with this disease.
METHODS: A total of 32 women with PBC were randomly assigned to receive alendronate (10 mg/day) or etidronate (400 mg/day) for 14 days every 3 months. Bone mineral density of the lumbar spine and proximal femur were measured initially and every 6 months. Bone fractures and markers of bone mineral metabolism were also evaluated.
RESULTS: Sixteen patients were allocated to each group, which were comparable with respect to the severity of PBC and osteopenia. Thirteen patients in each group completed the 2-yr trial. Both treatments increased bone mineral density after 2 yr, although the increase at the lumbar spine and at the proximal femur was significantly higher in patients receiving alendronate than in patients on etidronate. This higher effect of alendronate paralleled with changes in the biochemical markers of bone turnover. No patient developed new vertebral fractures, but new peripheral fractures were detected in two patients on alendronate and in one on etidronate. There were no serious adverse effects. Neither treatment impaired liver function or cholestasis.
CONCLUSIONS: Alendronate effectively increases bone mass and has greater antiresorptive power than etidronate in patients with primary biliary cirrhosis, and is associated with minor or no side effects.
Karen F Murray, Robert L Carithers, AASLD
AASLD practice guidelines: Evaluation of the patient for liver transplantation.
Hepatology. 2005 Jun;41(6):1407-32. doi: 10.1002/hep.20704.
Abstract/Text
