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September - October, 2014

Vol. 13 Issue 5

On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Probiotics and synbiotics may improve liver aminotransferases levels in non-alcoholic fatty liver disease patients Caroline Buss, Cristiane Valle-Tovo, Suellen Miozzo, Angelo Alves de Mattos Page 482-488

    Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of liver diseases ranging from simple steatosis to steatohepatitis (NASH). Alterations in intestinal microbiota and inflammatory response may play a key role in disease progression and development of complications in liver diseases, mainly in cirrhosis and NASH. The aim of this study was to perform a systematic review on randomized clinical trials (RCTs) testing probiotics, prebiotics or both (synbiotics) in the treatment of NAFLD in adult patients. After the screening process, 9 full-text articles were included in the review and 6 studies were excluded. Three randomized controlled trials were finally included in the qualitative synthesis. All patients in all the 3 studies were randomized to receive different formulations of probiotics, synbiotics or placebo. Reductions in aminotransferases were observed in the treated group in 2 of the studies. However, in one study reductions were also detected in the control group. In conclusion, the available evidence precludes, for the moment, recommendations on the use of pre and probiotics in clinical practice.

  • Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease Zhang Wenfeng, Wu Yakun, Mu Di, Gong Jianping, Wu Chuanxin, Huang Chun Page 489-495

    Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of liver metabolic damage and is related to insulin resistance and genetic susceptibility. Inflammation mediated by Kupffer cells (KCs) is of critical importance to the development of NAFLD. The primary role of KCs in NAFLD is considered to be the perturbation of the C-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) pathways as a result of lipopolysaccharide (LPS) recognition by Toll-like receptor 4 (TLR4). Simultaneously, the activation of NF-κB, as mediated by oxidative and endoplasmic reticulum (ER) stress and free fatty acid (FFA) or free cholesterol (FC) crystal formation, heavily relies on NF-κB regulatory factors and TLR4. Additionally, the imbalance of certain pro-inflammatory cytokines and chemokines released by innate immunity is deemed to promote the steatosis of hepatocytes. In conclusion, this review indicates that the inflammatory and oxidative stress of KCs play a significant role in the development of NAFLD.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Updating the knowledge of hepatitis E: new variants and higher prevalence of anti-HEV in Argentina María S. Munné, Nancy R. Altabert, Lucio O. Otegui M., Sara N. Vladimirsky, Rita Moreiro, María P. Espul, Carlos Espul, Abelardo Manzur, Sonia S. Soto, Leonardo S. Brajterman, Jorge E. González Page 496-502

    Introduction. Hepatitis E is a disease of global distribution, with significant morbidity and mortality, whose scope and burden continue to emerge in low endemic countries. Material and methods. In 2012, we studied the prevalence of anti-HEV antibodies in 202 adult serum samples. We also analyzed samples from 143 patients with acute non-A-C hepatitis from January 2011 to December 2013. Acute HEV infections were diagnosed with anti-HEV IgM and/or HEV RNA. HEV RNA was also investigated in 94 swine fecal samples. HEV RNA was sequenced and characterized. Results. We found higher values of prevalence than those previously reported in the 1990s. The overall prevalence of anti-HEV IgG antibodies was 15.4%. The prevalence was 10.6% in the 123 adults voluntarily screened on World Hepatitis Day 2012 in Buenos Aires city and 14.8, 16.7 and 35.7% respectively in the smaller groups of healthcare workers, blood donors and HIV-positive patients from different regions of the country. Nine acute HEV infections were diagnosed in the three years analyzed. We characterized new human variants of subgenotype 3a and 3i. New subgenotype 3i variants were found in swine from two distant provinces closely related to the human ones. Conclusions. These results enlarge the knowledge of HEV and contribute with new information. However, higher values of prevalence found in small groups need to be confirmed in larger studies. Many aspects of the spectrum of the disease and the reservoirs and routes of transmission are still unknown and thus deserve additional research.

  • Treatment of chronic hepatitis C genotype 1 early responders with 36 week pegylated interferon and ribavirin therapy Ajit Sood, Vandana Midha, Omesh Goyal Page 503-509

    Introduction. Standard treatment for patients with chronic hepatitis C genotype 1 (CHC G-1) infection includes pegylated interferon plus ribavirin (PEG-RBV) for 48 weeks. Shorter treatment regimen would be more acceptable due to lower cost and fewer side-effects. We aimed to compare the efficacy of 36 week PEG-RBV therapy with standard 48 week therapy in CHC G-1 patients who achieve complete early virological response (cEVR). Material and methods. Consecutive treatment-naïve patients with CHC G-1 were treated with pegylated interferon a2b (1.5 μg/kg/week) or α2a (180 μg/week) and weight based ribavirin. Patients who achieved cEVR at 12 weeks [undetectable HCV RNA irrespective of RVR (rapid virological response)] were randomized into- group A (48 weeks therapy) and group B (36 weeks therapy). Primary end-point was achievement of sustained virological response (SVR) at 24 weeks of follow up. Results. Out of the total 166 patients started on treatment, 112 (69.3%) achieved cEVR, and were randomized into group A (n = 59) and group B (n = 53). Fifty-five (93.2%) patients in group A and 50 (94.3%) in group B completed therapy. The overall SVR rate in group A was 79.6% (47/59) and group B was 84.9% (45/53)(p = 0.622). SVR rates in the two groups were comparable in all patient sub-groups according to factors like viral load (≤ or > 400,000 IU/mL), RVR (achieved/not achieved), age (≤ or > 40 years), body mass index(≤ or > 27) and cirrhosis (present/absent). Conclusion. In CHC G-1 patients who achieve cEVR, 36 weeks PEG-RBV therapy is as effective as standard 48 weeks therapy, irrespective of other host or virological factors.

  • Hepatitis E virus exposure in pregnant women in rural Durango, Mexico Cosme Alvarado-Esquivel, Luis F. Sánchez-Anguiano, Jesús Hernández-Tinoco Page 510-517

    Background and Aim. Hepatitis E virus (HEV) infection represents a risk for mortality in pregnant women. The seroepidemiology of HEV infection in rural pregnant women in the Americas is largely unknown. The aim of the study was to determine the seroepidemiology of anti-HEV IgG antibodies in rural pregnant women in Durango, Mexico. Materials and methods. The presence of anti-HEV IgG antibodies was determined in 439 pregnant women in rural Durango, Mexico using an enzyme-linked immunoassay. Seroprevalence association with socio-demographic, clinical and behavioral characteristics of the women was also investigated. Results. Twenty five (5.7%; 95% CI: 3.88-8.27) of the 439 women (mean age: 24.53 ± 6.1 years) had anti-HEV antibodies. Multivariate analysis showed that HEV seropositivity was associated with increasing age (OR = 1.11; 95% CI: 1.03-1.20; P = 0.004), consumption of unpasteurized cow milk (OR = 5.37; 95% CI: 1.17- 24.63; P = 0.03), and overcrowding at home (OR = 2.36; 95% CI: 1.13-4.92; P = 0.02). In contrast, the variables educational level, occupation, socio-economic status, foreign travel, consumption of untreated water and raw or undercooked meat, and raising animals did not show associations with HEV seropositivity. Exposure to HEV was associated with the number of deliveries but not with the number of cesarean sections or miscarriages. Conclusions. This is the first report of seroprevalence and contributing factors for HEV infection in rural pregnant women in the Americas, and of an association of the consumption of unpasteurized cow milk with HEV exposure. Results of this study should be useful for designing optimal preventive measures against HEV infection.

  • Promotor methylation: Does it affect response to therapy in chronic Hepatitis C (G4) or fibrosis? Abdel-Rahman N. Zekri, Ahmed M. Raafat, Suzan Elmasry, Abeer A. Bahnassy, Yasmin Saad, Hamed A. Dabaon, Mohamed El-Kassas, Hend I. Shousha, Auhood A. Nassar, Mohamed Ale EL-Dosouky, Nehal Hussein Page 518 -524

    Background and aim. DNA methylation plays a critical role in the control of important cellular processes. The present study assessed the impact of promoter methylation (PM) of some genes on the antiviral response to antiviral therapy and it’s relation to the presence of fibrosis in HCV-4 infected patients from Egypt. Material and methods. Clinical, laboratory and histopathological data of 53 HCV-4 infected patients who were subjected to combined antiviral therapy were collected; patients were classified according to their response to treatment and the fibrosis status. The methylation profiles of the studied groups were determined using the following genes: APC, P14ARF, P73, DAPK, RASSF1A, and O6MGMT in patients’ plasma. Results. O6MGMT and P73 showed the highest methylation frequencies (64.2 and 50.9%) while P14 showed the lowest frequency (34%). Sustained virological response (SVR) was 54.7%with no significant difference in clinico-pathological or laboratory features between the studied groups. PM of O6MGM was significantly higher in non-responders (p value 0.045) while DAPK showed high methylation levels in responders with no significance (p value: 0.09) andPM of RASSF1A was significantly related to mild fibrosis (p value: 0.019). No significant relations were reported between PM of any of the studied genes and patients’features. Conclusion. PM of some Tumor Suppressor genes increases in chronic active HCV-4. However, only 06MGMT can be used as a predictor of antiviral response and RASSF1A as a marker of marked fibrosis in this small set of patients. An extended study, including more patients is required to validate the results of this preliminary study.

Liver transplantation
  • Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience Nabiha Faisal, Eric M. Yoshida, Marc Bilodeau, Philip Wong, Mang Ma, Kelly W. Burak, Bandar Al-Judaibi, Eberhard L. Renner, Leslie B. Lilly Page 525-532

    Introduction. Hepatitis C (HCV) continues to be the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for recurrent HCV in Genotype 1 (G1) LT recipients have been disappointing (30-40%). Experience with triple therapy using protease inhibitors (PI) boceprevir (BOC), telaprevir (TVR) in these patients has been limited. Material and methods. This national multicenter retrospective study included 76 patients (64 male, mean age 57 ± 6 years), treated for G1 HCV recurrence with either BOC (n = 41) or TVR (n = 35), who were non-responders or relapsers (n = 54), treatment naïve (n = 22) or had fibrosing cholestatic HCV (n = 3). 53 patients were on cyclosporine, 22 on tacrolimus and one patient on prednisone alone. Results. On treatment virologic response was observed in 84% (64/76), 83% in BOC and 85% in TVR group. A higher week 4 response after starting triple therapy (RVR) was noted in TVR group 25/35 (81%) as compared to BOC group 26/41 (63%); p value = 0.02. The end of treatment response was 78% and 75% in BOC and TVR group, respectively. SVR 12 weeks after treatment discontinuation was observed in 59.5% (22/37); 58.3% in the BOC group and 61.5% in TVR group. Treatment was discontinued early in 23 patients (serious adverse effects n = 19, treatment failure n = 4). Infections occurred in 5 patients with 2 deaths (all in BOC). Anemia was the most common side effect (n = 55, 72%) requiring erythropoietin and RBV dose reduction. In the BOC group, cyclosporine dose reduction was 2.2 ± 1.0 fold and 8.6 ± 2.4 fold with tacrolimus. In TVR group, dose reduction was 3.0 ± 1.4 with cyclosporine and 12 ± 5.7 fold with tacrolimus. Conclusions. PI-based triple therapy appears more effective in producing HCV-RNA clearance than dual therapy. Tolerability is a serious issue and drug-drug interactions are manageable with close monitoring.

Miscellaneous
  • Survey of health status, nutrition and geography of food selection of chronic liver disease patients Timothy Leslie, Lisa Pawloski, Jillian Kallman-Price, Carey Escheik, Noreen Hossain, Yun Fang, Lynn H. Gerber, Zobair M. Younossi Page 533-540

    Background. Obesity, a complex disease determined both by genetic and environmental factors, is strongly associated with NAFLD, and has been demonstrated to have a negative impact on HCV and other chronic liver diseases (CLD). Rationale. This study assessed the association between type and location of food sources and chronic liver disease (CLD) using Geographic Information Systems (GIS). Results. CLD patients completed surveys [267 subjects, 56.5% female, age 55.8 ± 12.0, type of CLD: 36.5% hepatitis C (HCV), 19.9% hepatitis B (HBV), 19.9% non-alcoholic fatty liver disease (NAFLD); primary food source (PFS): 80.8% grocery store, secondary: 26.2% bulk food store, tertiary: 20.5% restaurants; fresh food (FF): 83%, pre-packaged (PP) 8.7%, already prepared (AP) 8.3%]. FF consumers had significantly fewer UEH servings/month (p = 0.030) and lived further away from convenience stores (1.69 vs. 0.95 km, p = 0.0001). Stepwise regression reveals the lowest FF consumers were NAFLD patients, subjects with UEH or restaurants and ethnic food stores as their PFS (R = 0.557, p = 0.0001). Eating already-packaged foods and utilizing restaurants or ethnic food stores as the PFS positively correlated with NAFLD (R = 0.546, p = 0.0001). Conclusions. Environmental food source measures, including type and density, should be included when examining areas hyper-saturated with a variety of food options. In hyper-saturated food environments, NAFLD patients consume more prepared food and less FF. CLD patients with UEH also eat significantly more prepared food and frequent restaurants and ethnic food stores as their PFS.

  • Ultra-sensitive procalcitonin may help rule out bacterial infections in patients with cirrhosis Sebastián Marciano, Leila Haddad, Alfredo P. Martínez, María L. Posadas, Federico Piñero, Gonzalo J. Mora, Laura N. Guerrero, Ezequiel Ridruejo, Oscar G. Mandó, Diego H. Giunta, Adrián C. Gadano Page 541-547

    Background. Bacterial infections are frequent complications in patients with cirrhosis. Since they are associated with poor outcomes, antibiotics are frequently over-prescribed. Surrogate markers of bacterial infections, like procalcitonin, are needed to better discriminate between infected and not infected patients. Aims. To evaluated the diagnostic accuracy of an ultra-sensitive procalcitonin assay for the diagnosis of bacterial infections in patients with cirrhosis. Material and methods. In a single-center prospective study, we determined the basal levels of procalcitonin in 106 episodes of admissions to the emergency department in 84 cirrhotic patients. Patients were classified as infected or not infected by two independent hepatologists blinded to the procalcitonin result. Results. The prevalence of bacterial infection was 28% (29 episodes). The median procalcitonin was significantly higher in the infected group than in the not infected group (0.45 vs. 0.061 ng/mL, p < 0.001). The diagnostic accuracy of procalcitonin for bacterial infection estimated by the ROC curve was 0.95 (CI: 95%, 0.91-0.99). When selecting a cutoff value of 0.098 ng/mL a sensitivity of 97% and a negative predictive value 98% were found. Conclusions. The use of an ultra-sensitive procalcitonin assay identifies patients with cirrhosis at very low risk of bacterial infections.

  • Heparin-induced thrombocytopenia testing is over-utilized in cirrhosis & correlates with poor clinical outcomes Karlyn Martin, Leila Kia, Neehar D. Parikh, Laura Kulik, Brandon McMahon Page 548-554

    Introduction. Heparin-induced thrombocytopenia (HIT) is a serious complication seen in hospitalized, medically-ill patients. Evaluation for HIT using a commercially-available ELISA-based test has become increasingly common; however, it does have a high false positive rate. Implications of HIT testing in patients with cirrhosis have not yet been reported. Material and methods. We conducted a single-institution, retrospective review of all patients with cirrhosis admitted over a 29-month period. The student’s t-test and the χ2 test were used for comparisons. We performed a stratified survival analysis using Kaplan-Meier and log rank testing. Results. A total of 1,305 patients had a HIT Ab sent during the study period. Of these patients, 106 had cirrhosis and were included in the study. Eighteen (17%) of the patients with cirrhosis were HIT Ab positive and four of the eighteen had a positive Serotonin Release Assay (SRA) confirmatory test. No difference was found in platelet nadir, thrombotic rate, length of stay, and patient survival between patients with positive HIT Ab and negative HIT Ab testing. No consistent treatment was used among patients who were HIT Ab positive, despite hematology service consultation. Patients who were HIT Ab negative were more likely to have undergone liver transplantation compared to those who were positive (27 vs. 5.5%, respectively; p = 0.048). Conclusion. Our data suggest that HIT Ab testing is over-used in patients with cirrhosis and is poorly predictive of outcomes. With a poor positive predictive value, HIT testing may add unnecessary complexity to an already complicated patient population.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Minimally invasive treatment of Mirizzi’s syndrome: is there a safe way? Report of a case series Giuseppe Piccinni, Andrea Sciusco, Giuseppe M. De Luca, Angela Gurrado, Alessandro Pasculli, Mario Testini Page 558-564

    Mirizzi’s syndrome (MS) is a rare complication of the inveterate biliary lithiasis. Diagnostic and therapeutic standardization is still missing, especially since laparoscopic cholecystectomy has become the gold standard approach for symptomatic cholelithiasis. Our study is a retrospective analysis based on a case-series. It considered 370 cholecystectomies performed from 2006 to 2011. We selected 11 patients affected by MS (2.97%). We divided them according to Csendes’ classification. Endoscopic Retrograde Cholangio-Pancreatography (ERCP) was used for biliary drainage when the patient suffered jaundice and/or cholangitis and,preoperatively, to confirm the suspicion of MS obtained through Magnetic Resonance Cholangio-Pancreatography (MRCP). We found it useful to exploit nasobiliary drainage (NBD) for intra-operative check of the biliary tree. In all 5 patients of the type 1 group MS was discovered intraoperatively and treated with Laparoscopic Sub-total Cholecystectomy (LSC). One patient suffered from biliary leakage, solved with NBD positioning. The type 2 group was made up of 2 women and 1 man. All of them were preoperatively submitted to ERCP and NBD positioning. Two underwent LSC and one was converted to laparotomy. The type 3 was represented by a 63-year-old woman suffering from recurrent cholangitis. She was submitted to MRCP,ERCP and then underwent LSC. The 2 patients affected by type 4 underwent open biliary reconstruction. In conclusion, every attempt should be made to identify MS prior to LCS since it will allow NBD insertion by ERCP. Once LCS is initiated, if MS is identified intra-operatively, we can provide the most practical surgical options.

  • Antimitochondrial antibody serocoversion post-liver transplant during hepatitis C treatment with peginterferon α, ribavirin and telaprevir Vladimir Marquez-Azalgara, Trana Hussaini, Siegfried R. Erb, Eric M. Yoshida Page 565-567

    Pegylated interferon alpha (PEG-IFN α), a key component of chronic hepatitis C therapy, has been linked to the development of auto-antibodies and autoimmune disease. We report the first case of antimitochondrial antibody (AMA) seroconversion during PEG-INF α based therapy after liver.1-4 transplantation. A fiftyseven year-old man five months after liver transplantation was initiated on hepatitis C triple therapy with PEG-INF α, ribavirin and telaprevir. He had failed previous PEG-IFN α and ribavirin 12 years pre-transplant and his AMA remained negative pre-transplant. After twelve weeks of antiviral therapy, he developed elevated liver enzyme tests associated with an AMA seroconversion to seropositivity. A liver biopsy failed to show histological evidence of primary biliary cirrhosis or graft rejection. He was initiated on urseodeoxycholic acid with subsequent improvement of his liver enzymes. This case demonstrates that despite adequate immunosuppression, AMA seroconversion may occur post-transplant during interferon-based therapy. As AMA seroconversion did not occur during the pre-transplant PEG-IFN therapy, we speculate that donor allograft antigens in combination with PEG-IFN may have been a factor in the post-transplant seroconversion.

  • Juvenile hemochromatosis associated with heterozygosity for novel hemojuvelin mutations and with unknown cofactors Serena Pelusi, Raffaela Rametta, Claudia Della Corte, Riccardo Congia, Paola Dongiovanni, Edoardo A. Pulixi, Silvia Fargion, Anna L. Fracanzani, Valerio Nobili, Luca Valenti Page 568-571

    Background & Aims. Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder characterized by severe early-onset iron overload, caused by mutations in hemojuvelin (HJV), hepcidin (HAMP), or a combination of genes regulating iron metabolism. Here we describe two JH cases associated with simple heterozygosity for novel HJV mutations and unknown genetic factors. Case 1: A 12 year-old male from Central Italy with beta-thalassemia trait, increased aminotransferases, ferritin 9035 ng/ml and transferrin saturation 84%, massive hepatocellular siderosis and hepatic bridging fibrosis. Case 2: A 12 year-old female from Northern Italy with ferritin 467 ng/ml, transferrin saturation 87-95%, and moderate hepatic iron overload. Material and methods. Direct sequencing of hemochromatosis genes (HFE-TfR2-HJV-HAMP-FPN-1) was performed in the children and siblings. Results. In case 1, we detected heterozygosity for a novel HJV mutation (g.3659_3660insG), which was inherited together with the beta thalassemia trait from the father,who (as well as the mother) had normal iron parameters. In case 2, we detected another novel HJV mutation (g.2297delC) in heterozygosity, which was inherited from the mother, affected by mild iron deficiency. The father had normal iron stores. Both mutations are frameshifts determining premature stop codons. No other disease causing variant was detected. Conclusion. Although beta-thalassemia trait was a possible cofactor of iron overload in case 1, iron overload cannot be explained by simple heterozygosity for HJV mutations in both cases. Other genetic factors should be investigated, and further studies are needed to understand genotype-phenotype correlations in JH.

LETTER TO EDITOR

LIVER NEWS ELSEWHERE

XXIII ANNUAL MEETING OF THE LATIN AMERICAN ASSOCIATION FOR THE STUDY OF THE LIVER AND THE NATIONAL CONGRESS OF THE MEXICAN ASSOCIATION OF HEPATOLOGY

The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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