Response to Ursodeoxycholic Acid May Be Assessed Earlier to Allow Second-Line Therapy in Patients with Unresponsive Primary Biliary Cholangitis.

BACKGROUND: Response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has been traditionally assessed 1 to 2 years after treatment initiation. With the development of new drugs, some patients may benefit from an earlier introduction of second-line therapies. AIMS: This study aims to identify whether well-validated response criteria could correctly identify individuals likely to benefit from add-on second-line therapy at 6 months. METHODS: Analysis of a multicenter retrospective cohort which included only patients with clear-cut PBC. RESULTS: 206 patients with PBC (96.6% women; mean age 54 ± 12 years) were included. Kappa concordance was substantial for Toronto (0.67), Rotterdam (0.65), Paris 1 (0.63) and 2 (0.63) criteria at 6 and 12 months, whereas Barcelona (0.47) and POISE trial (0.59) criteria exhibited moderate agreement. Non-response rates to UDCA was not statistically different when assessed either at 6 or 12 months using Toronto, Rotterdam or Paris 2 criteria. Those differences were even smaller or absent in those subjects with advanced PBC. Mean baseline alkaline phosphatase was 2.73 ± 1.95 times the upper limit of normal (× ULN) among responders versus 5.05 ± 3.08 × ULN in non-responders (p < 0.001). CONCLUSIONS: After 6 months of treatment with UDCA, the absence of response by different criteria could properly identify patients who could benefit from early addition of second-line therapies, especially in patients with advanced disease or high baseline liver enzymes levels.

Clinical features and treatment outcomes of primary biliary cholangitis in a highly admixed population.

INTRODUCTION AND OBJECTIVES: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. MATERIAL AND METHODS: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. RESULTS: 562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates. CONCLUSIONS: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization.

Anti-mitochondrial Antibody-Negative Primary Biliary Cholangitis Is Part of the Same Spectrum of Classical Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. AIMS: The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. METHODS: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. RESULTS: A total of 464 subjects (95.4% females, mean age 56 ± 5 years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11 years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12 years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378 mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7 mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4 mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34 to 62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. CONCLUSIONS: AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.

Fibrates for the Treatment of Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid: An Exploratory Study.

Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC. Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria. Results: In total, 27 patients (100% women, mean age 48.9 ± 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39-76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria. Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients.

UPDATE OF THE BRAZILIAN SOCIETY OF HEPATOLOGY RECOMMENDATIONS FOR DIAGNOSIS AND MANAGEMENT OF AUTOIMMUNE DISEASES OF THE LIVER.

New data concerning the management of autoimmune liver diseases have emerged since the last single-topic meeting sponsored by the Brazilian Society of Hepatology to draw recommendations about the diagnosis and treatment of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), overlap syndromes of AIH, PBC and PSC and specific complications and topics concerning AIH and cholestatic liver diseases. This manuscript updates those previous recommendations according to the best evidence available in the literature up to now. The same panel of experts that took part in the first consensus document reviewed all recommendations, which were subsequently scrutinized by all members of the Brazilian Society of Hepatology using a web-based approach. The new recommendations are presented herein.

Endoscopic Management of Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) remains a rare but potentially devastating chronic, cholestatic liver disease. PSC causes obstruction of intra- and/or extra-hepatic bile ducts by inflammation and fibrosis, leading to biliary obstruction, cirrhosis and portal hypertension with all associated sequelae. The most dreaded consequence of PSC is cholangiocarcinoma, occurring in 10-20% of patients with PSC, and with population-based estimates of a 398-fold increased risk of cholangiocarcinoma in patients with PSC compared to the general population. We use the 4-D approach to endoscopic evaluation and management of PSC based on currently available evidence. After laboratory testing with liver chemistries and high-quality cross-sectional imaging with MRCP, the first D is Dominant stricture diagnosis and evaluation. Second, Dilation of strictures found during ERCP is performed using balloon dilation to as many segments as possible. Third, Dysplasia and cholangiocarcinoma diagnosis is performed by separated brushings for conventional cytology and fluorescence in situ hybridization (FISH), and consideration for direct cholangioscopy with SpyGlass™. Fourt and finally, Dosing of antibiotics is critical to prevent peri-procedural cholangitis. The aim of this review article is to explore endoscopic tools and techniques for the diagnosis and management of PSC and provide a practical approach for clinicians.

Fibrates for Primary Biliary Cholangitis: What's All the Hype?

Ursodeoxycholic acid is the first-line therapy for primary biliary cholangitis. However, a subset of patients fail to show biochemical response. For these patients, adjuvant therapies are warranted. Obeticholic acid was conditionally approved as a second-line drug. Evidence is building up in favor of fibrates, which are available for off-label use.

Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver

ABSTRACT In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.

RESUMO Para definir as recomendações baseadas em evidências científicas sobre o diagnóstico e tratamento das doenças autoimnus do fígado, a Sociedade Brasileira de Hepatologia organizou em Outubro de 2014, encontro monotemático em São Paulo. Um Comitê organizador de sete investigadores foi selecionado pela Diretoria da Sociedade para organizar a agenda científica, assim como para selecionar vinte debatedores para fazer uma revisão sistemática e apresentar tópicos relacionados à hepatite autoimune, colangite esclerosante primária, cirrose biliar primária e suas síndromes de superposição (overlap). O texto inicial do submetidoo a apreciação e aprovação da Sociedade Brasileira de Hepatologia através de consulta a todos associados através da home page da Sociedade, O trabalho apresentado representa a versão final do trabalho original, devidamente revisado e organizado em tópicos, segundo as recomendações da Sociedade Brasileira de Hepatologia.

Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver.

In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.

Effect of ethnicity on liver transplant for hepatocellular carcinoma.

OBJECTIVES: The incidence of hepatocellular carcinoma associated with nonalcoholic fatty liver disease is increasing. We sought to compare tumor characteristics and outcomes after a liver transplant according to the cause of liver disease and ethnicity. MATERIALS AND METHODS: We retrospectively evaluated patients with hepatocellular carcinoma (292, 23%) out of all the liver transplant recipients (N=1266) at the University of Miami between 2000 and 2010. Liver disease was caused by hepatitis C virus in 221 patients (76%), nonalcoholic fatty liver disease in 19 patients (6.5%), hepatitis B virus in 20 patients (7%), alcohol in 44 patients (15%), and other in 18 patients (6%). The median age was 57 years (range, 17 to 77 y), 218 were men (75%), 270 were white (92%), and 92 were Hispanic (31.5%). RESULTS: Patients with hepatocellular carcinoma and nonalcoholic fatty liver disease were more likely to be older (64 vs 57; P = .0006), Hispanic (58% vs 30%; P = .018); nonsmokers (89% vs 65%; P = .041), diabetic (84% vs 26% P < .0001), hypertensive (63% vs 27%; P = .003), and using statins (32% vs 4%; P = .0004) compared with hepatocellular carcinoma without nonalcoholic fatty liver disease. Diabetes, hypertension, and nonalcoholic fatty liver disease are significantly more common in Hispanics than in non-Hispanic persons with hepatocellular carcinoma. In persons without hepatocellular carcinoma, the proportion of Hispanics was similar between those with (n=84) and those without (n=1182) nonalcoholic fatty liver disease. Hispanic ethnicity was not associated with worse tumor behavior or overall survival. CONCLUSIONS: Patients transplanted for hepatocellular carcinoma and nonalcoholic fatty liver disease were older, and were more frequently Hispanic than were persons with hepatocellular carcinoma and without [corrected] nonalcoholic fatty liver disease. Hispanic ethnicity may be a risk factor for hepatocellular carcinoma.

High frequency of genotype D and spontaneous hepatitis B virus genomic mutations among Haitians in a multiethnic North American population.

GOALS/BACKGROUND: The importance of hepatitis B virus (HBV) genotype and mutations has been increasingly recognized. We aimed to determine HBV genotype, precore (PC), and basal core promoter region (BCP) mutations in a HBV multiethnic South Florida population. STUDY: Samples from 213 patients were tested for HBV-DNA using Abbott RealTime HBV IUO assay, and for mutations using INNO-LiPA assay. RESULTS: Patients were predominantly male (67%); 61 (31%) were African American, 60 (28%) Hispanic, 37 (17%) Haitian, 27 (19%) white non-Hispanic, and 14 (6.6%) Asian. Genotype A was found in 101 (69%), D in 25 (17%), F in 9 (6%), G in 7 (5%), C and E in 6 (4%) each, B in 4 (3%), and H in 2 (1%) patients. Mixed genotypes were detected in 11 patients. Genotype A was more prevalent in all ethnicities except for Asian. Among hepatitis B e antigen (HBeAg)-negative patients (59%), BCP, PC, and combined BCP/PC mutations were found in 30 (37.5%), 13 (16.3%), and 14 (17.5%), respectively. Genotype D was associated with higher frequency of HBeAg-negative status [18/24 (75%) vs. 62/121 (51%) P=0.03] and mutations [16/19 (84%) vs. 40/67 (60%) P=0.04] compared with others. Genotype A was negatively associated with mutations [26/31 (84%) vs. 30/55 (55%), P=0.009]. PC mutations were more common in genotype D (14/19, 73%) compared with genotype A (7/54, 13%, P<0.0001). One-hundred percent and 79% of Asians and Haitians had spontaneous mutations, respectively. All Haitians with genotype D had PC mutations and 3 (50%) had BCP/PC. CONCLUSIONS: The present study shows that HBeAg-negative status and spontaneous mutations were more common with genotype D; the presence of genotype D in Haitians was always associated with spontaneous mutations.

Ethnicity predicts metabolic syndrome after liver transplant.

PURPOSE: Post-transplant metabolic syndrome (PTMS) is associated with important causes of morbidity and mortality in solid organ transplant recipients. Our aim was to investigate predictors of PTMS in liver transplant (LT) recipients. METHODS: We randomly selected 343 adults (>18 years of age) from a large cohort of 1,262 ethnically diverse patients who received LTs during 2000-2010. RESULTS: Of 343 patients included, 68.2 % were male, with a mean age of 54 ± 10 years, 87 % White, and 31 % Hispanic. Prior to LTs, 6.2 % were on lipid-lowering agents and 24.5 % had BMI ≥ 30 (mean 26.9 ± 5 kg/m(2)). More Hispanics had diabetes before LTs compared to non-Hispanics (p = 0.037). Among those with follow-up of >6 months (n = 304) after LTs, the proportion of patients with diabetes and hypertension increased from 21.9 to 27 % (p < 0.0001), and from 11.5 to 51.6 % (p < 0.0001), respectively. Cholesterol levels increased from 150 ± 115 to 167 ± 70 (p < 0.0001). BMI remained unchanged. PTMS developed in 41 (13.5 %) and cardiovascular events in 31 (10.2 %) patients. Hispanics had higher risk of developing PTMS compared to non-Hispanics (OR 2.30, 95 % CI 1.18-4.49). Survival was not affected by PTMS (p = 0.3), ethnicity (p = 0.52), or nonalcoholic steatohepatitis as the etiology of liver disease (p = 0.50). CONCLUSIONS: More Hispanics had diabetes before LTs (29 to 18 %, p < 0.05) and were more prone to developing PTMS after LTs compared to non-Hispanics.