Vol. 15 Issue 6
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
Due to virological, host and socio-economic factors, the clinical presentation and treatment of chronic hepatitis B (CHB) differs between developing and developed countries and may differ between one low-income country and another. National healthcare prevention and treatment policies, environmental factors, social habits and personal life-styles all influence HBV transmission and the clinical management and therapy of CHB. These factors can have a strong impact on the natural history of the disease and on Access to treatment and may eventually determine substantial changes in disease progression and the development of serious complications and hepatocellular carcinoma. In this review article, we analyze the clinical characteristics and access to antiviral treatment of CHB patients in low-income countries in Africa, Asia, Eastern Europe and Latin America.
Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases. Material and methods. A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223. Results. Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020). Conclusion. SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.
Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection. Material and methods. In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate. Results. Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (AEs) occurred in 9 black/AA and 6 Latino patients. Conclusion. SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% CIs were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.
Background and rationale for the study. The generation of people born before 1965 is a high-risk group for developing chronic hepatitis C virus (HCV) infection. Aim. To report the experience on single institution of HCV infection under birth-cohort or baby boomers effect. Material and methods. We used a cross-sectional design of consecutive subjects older than 18 years referred for serological evaluation for anti-HCV and detection of HCV RNA. Results. A total of 7,658 people were included. The global prevalence of HCV antibody was 4.5% (344/7658). The frequency with anti-HCV antibodies were 74 (10.9%), 158 (7.3%), and 112 (2.3%) for people born before 1945, 1945-1965, and 1966-1992, respectively (p < 0.01). The subjects HCV RNA-positive were 88.9%, 68.7%, and 44.4%, respectively (p < 0.001). The viral load was > 100,000 IU/mL in 74.4% of those positive for HCV RNA. Groups of older patients and anti-VHC, with year of birth before 1965, are more likely to show reactivity to HCV RNA and significant viral load (OR 10.0, CI 95% 4.8 to 20.1). Conclusion. We observed a high prevalence of unrecognized chronic HCV infection. The prevalence of HCV infection in people born before 1945 was twice the value of those born after 1965. Further studies are needed to determine the impact on health care services. Future work should focus on determining the appropriate model for the care of people at risk of chronic HCV.
Background and rationale. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of pediatric liver disease in western countries. Its prevalence in Indian subcontinent is not well studied. Material and methods. In a school based cross sectional study we have screened overweight and obese children in the age group of 11 to 15 years for NAFLD. Ultrasonography, elevated serum transaminases, fibroscan were used for defining NAFLD. Dietary habits, blood pressure, serum lipid profile, blood counts and insulin resistance were recorded. The relation of fibrosis 4 score, pediatric NAFLD fibrosis index, aspartate transaminases to platelet ratio index (APRI) with fibroscan was evaluated. Results. Out of 616 students screened 198 were overweight and obese. Hundred students and their parents gave informed consent for the further evaluation. The prevalence of NAFLD was 62% in overweight and obese children. Fatty liver was found in 50 % students on ultrasonography, liver stiffness (â¥ 6.1 Kilopascals) in 23% and raised alanine transaminase in 30%. Hypertension, dyslipidemia, diabetes mellitus and insulin resistance were seen in 6%, 18%, 2% and 66% students respectively. Systolic hypertension, serum triglyceride, aspartate transaminase, APRI was significantly higher in the NAFLD group. On binary logistic regression only systolic hypertension was an independent risk factor for NAFLD. Conclusion. In conclusion NAFLD is common in asymptomatic overweight and obese Indian children. Systolic hypertension is the only independent factor associated with NAFLD. Fibroscan has limited role for screening. We recommend screening for NAFLD in this high risk group with alanine transaminases and ultrasonography.
Background. Chemerin and retinol binding protein-4 (RBP-4) are adipokines which may play a role in the progression of NAFLD. It has been also suggested that cytokeratin-18 (CK-18) could be a marker of hepatocyte caspase-directed death while transgelin-2 production could reflect stage of liver fibrosis. The aim of this study was to evaluate the level of the above adipokines in sera of patients with NAFLD and determine the relation between the level of transgelin-2 and fibrosis-4 index (FIB-4). Material and methods. Ninety-five subjects included initially to the study were divided into four groups: (I) prediabetics, obese with NAFLD and metabolic syndrome (MS), (II) lean with NAFLD and without MS, (III) obese without NAFLD and MS, and (IV) healthy individuals. We determined the levels of chemerin, RBP-4, transgelin-2 and CK-18 fragments in sera of patients with NAFLD. Moreover, we examined if the levels of CK-18 fragments and transgelin-2 correlates with FIB4 value. Results. Chemerin and RBP-4 were highly expressed in sera of all NAFLD, especially in obese individuals. Chemerin level was also linked to MS. High level of serum CK-18 fragments and transgelin-2 did not correlate with obesity and MS, but seemed to correlate with progression of NAFLD to liver fibrosis. Conclusions. In conclusion, the production of the two adipokines, chemerin and RBP-4, is strongly associated with obesity in patients with NAFLD. Serum concentrations of CK-18 fragments and transgelin-2 correlate with the severity of NAFLD, but no with obesity.
Introduction and aim. Many transplant programs have expanded eligibility to include patients previously ineligible because of advanced age. Outcomes of simultaneous liver-kidney transplantation (SLK) in recipients with advanced age are not known. Material and methods. Data from patients undergoing transplantation between 2002 and 2015 were obtained from the UNOS Standard Analysis and Research file. Results. SLK recipients aged â¥ 65 years (N = 677), SLK recipients aged < 65 years (N = 4517), and recipients of liver transplant alone(LTA) aged â¥ 65 years(N = 8495) were compared. Recipient characteristics were similar between the SLK groups. Similar patient and graft survival were observed in SLK recipients aged â¥ 65 years compared to SLK recipients aged < 65 years and LTA recipients aged â¥ 65 years. Importantly, in a subgroup analysis, superior survival was seen in the SLK group aged â¥ 65 years compared to LTA recipients aged â¥ 65 years who underwent dialysis in the week prior to transplantation (p < 0.001). A prediction model of patient survival was developed for the SLK group aged â¥ 65 years with predictors including: age â¥ 70 years (3 points), calculated MELD score (-1 to 2 points), and recipient ventilator status at the time of SLK (4 points). The risk score predicted patient survival, with a significantly inferior survival seen in patients with a score â¥ 4 (p < 0.001). Conclusions. Age should not be used as a contraindication for SLK transplantation. The validated scoring system provides a guide for patient selection and can be used when evaluating elderly patients for SLK transplantation listing.
Introduction and aim. Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. It is primarily caused by hepatic cirrhosis or chronic viral hepatitis. Hepatic carcinogenesis is associated with increased oxidative stress. Thus, the aim of our study was to assess expression of the genes involved in the homeostasis of oxidative stress in patients with HCC. Material and methods. The study was performed on 32 patients with primary HCC (verified by liver histology in 29 patients) and 27 control subjects (in 11 subjects, liver histology was available either with no or minimal changes in the liver tissue). Gene expressions of heme oxygenase 1 (HMOX1), biliverdin reductase A/B (BLVRA/B), NADPH oxidase 2 (NOX2) and p22phox were analyzed in the liver and peripheral blood leukocytes (PBL) in the subjects. Results. Compared to controls, almost a 3 times higher mRNA level of BLVRA was detected in livers of HCC patients (p = 0.002); while those of BLVRB as well as HMOX1 were unchanged (p > 0.05). In accord with these results in the liver tissue, BLVRA mRNA levels in PBL were also significantly increased in HCC patients (p = 0.012). mRNA levels of NOX2 and p22phox in the liver tissue, although higher in HCC patients, did not differ significantly compared to control subjects (p > 0.05). Nevertheless, NOX2 mRNA level in PBL was significantly higher in HCC patients (p = 0.003). Conclusions. BLVRA mRNA levels in the liver as well as in PBL are significantly higher in HCC patients most likely as a feedback mechanism to control increased oxidative stress associated with HCC progression.
Background. Liver re-transplantation (re-OLT) remains the only feasible option for patients with graft failure following liver transplantation. Sparse resources and a growing waitlist mandate that available grafts are allocated properly. We studied the differences in patient demographics, characteristics, and survival for those listed for re-OLT in a region with prolonged wait times. Material and methods. We performed a single-center retrospective study, from 2005 to 2013, of adult candidates listed for liver re-OLT at a tertiary care center within United Network for Organ Sharing (UNOS) region 1. Results. Of the 48 patients listed for re-OLT, 1(2%) improved while waiting, 14(29%) died while waiting, and 33(69%) underwent re-OLT. Those re-transplanted represented 11% of the centerâs adult liver transplant volume during the same time period. Comparing those who died while waiting to those who achieved re-OLT, there was no significant difference in age (median 52 vs. 48 years, p=0.56) or MELD at second listing (median 29 vs. 26, p = 0.90). Waitlisted candidates who failed to achieve re-transplant died on average of 15.5 days (IQR 36 days) days after re-listing. Those re-transplanted achieved 3-year survival of 70% and there was no significant difference in 3-year survival of those re-transplanted within or beyond 90 days of first transplant (70% vs. 69.5%, p = 0.28). Conclusions. In conclusion, re-OLT is the only viable option for candidates with nonreversible liver graft failure. Inability to achieve re-OLT leads to nearly assured and expeditious death. Despite technical challenges, in experienced hands excellent long term survival following re-OLT can be achieved.
Background. The Rockall, Glasgow-Blatchford, and AIMS65 are useful and validated scoring systems for predicting the outcomes of patients with nonvariceal gastrointestinal bleeding. However, there are no validated evidence for using them to predict outcomes on variceal bleeding. The aim of this study was to evaluate and compare the prognostic accuracy of different nonvariceal bleeding scores with other liver-specific scoring systems in cirrhotic patients. Material and methods. A retrospective multicenter study that included 160 cirrhotic patients with acute variceal bleeding. The AUROCâs to predict in-hospital mortality, and rebleeding, were analyzed for each scoring system. Results. Overall in-hospital mortality occurred in 13% and in-hospital rebleeding in 12% of patients. The systems with the best AUROC value for predicting mortality were MELD (0.828; 95% CI 0.748-0.909), and AIMS65 (0.817; 95% CI 0.724-0.909). The best score systems for predicting rebleeding were Glasgow-Blatchford (0.756; 95% CI 0.640- 0.827), and Rockall (0.691; 95% CI 0.580-0.802). Conclusions. In addition to liver-specific scores, the AIMS65 score is accurate for predicting in-hospital mortality in cirrhotic patients with acute variceal bleeding. Other scoring systems might be useful for predicting significant clinical outcomes in these patients.
Background & Aims. It is unclear whether portal vein thrombosis (PVT) unrelated to malignancy is associated with reduced survival or it is an epiphenomenon of advanced cirrhosis. The objective of this study was to assess clinical outcome in cirrhotic patients with PVT not associated with malignancy and determine its prevalence. Material and methods. Retrospective search in one center from June 2011 to December 2014. Results. 169 patients, 55 women and 114 men, median age 54 (19-90) years. Thirteen had PVT (7.6%). None of the patients received anticoagulant treatment. The PVT group was younger (49 [25-62] vs. 55 [19-90] years p = 0.025). Child A patients were more frequent in PVT and Child C in Non-PVT. Median Model for End Stage Liver Disease (MELD) score was lower in PVT (12 [8-21] vs. 19 [7-51] p ? 0.001) p ? 0.001). There was no difference between upper gastrointestinal bleeding and spontaneous bacterial peritonitis in the groups. Encephalopathy grade 3-4 (4 [30.8%] vs. 73 [46.8%] p = 0,007) and large volume ascites (5 [38.5%] vs. 89 [57.1%] p= 0,012) was more common in non-PVT. Survival was better for PVT (16.5 ± 27.9 vs. 4.13 ± 12.2 months p = 0.005). Conclusions: We found that PVT itself does not lead to a worse prognosis. The most reliable predictor for clinical outcome remains the MELD score. The presence of PVT could be just an epiphenomenon and not a marker of advanced cirrhosis.
Background. Previous studies in high and low expressors has demonstrated that a variant in the GNPAT gene (D519G, Rs11558492, chromosome 1, exon 11) has been associated with severe iron overload in C282Y homozygotes for hemochromatosis. In this study, a GNPAT variant was assessed prospectively in patients referred for HFE testing over a range of serum ferritin levels. Material and methods. Consecutive patients sent for HFE testing were studied for the GNPAT variant using a TaqMan kit assay (Life Technologies, Burlington, ON). Serum ferritin and iron removed by phlebotomy was compared in C282Y homozygotes with and without the GNPAT variant. The frequency of the GNPAT variant in referred patients was compared to a control population of voluntary blood donors without HFE mutations. Results. There were 533 patients that had GNPAT analysis. The allele frequency for the GNPAT variant in C282Y homozygotes (n = 75) was 0.226 and in wild type control patients (n = 458) was 0.213 (p = .07). Forty-eight percent (of the C282Y homozygotes were heterozygous (n = 28) or homozygous (n = 8) for the GNPAT variant. The mean (log)ferritin and iron removed did not significantly differ between C282Y homozygous with GNPAT homozygotes, GNPAT heterozygotes, and without the GNPAT variant (p = 0.84). Conclusions. C282Y homozygotes referred for HFE testing commonly have a GNPAT variant. This GNPAT variant does not appear be a co-modifying gene affecting expression of HFE related hemochromatosis in this population. The GNPAT variant does not predict the severity of iron overload.
Background and rationale for the study. The purpose of this study was to assess the technical and clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) reduction for the management of TIPS-induced acute liver decompensation. Between August 2000 and November 2013, 347 patients underwent a TIPS procedure in the authors institution; 21/347 (6%) developed post-TIPS acute liver decompensation which was managed using a percutaneous shunt reduction technique. Patient demographics, laboratory tests before and after initial TIPS and TIPS reduction, procedural data and clinical follow-up data were analysed. Results. Twenty-one patients (mean age 63 years) who underwent an initial TIPS procedure for variceal bleeding (n = 7; 33%) or refractory ascites (n = 14; 67%) successfully underwent shunt reduction ten days (3-34 days) after the initial TIPS procedure. The portosystemic pressure gradient (PSPG) increased from 8 (3-17) mmHg before reduction to 12 (7-23) mmHg after shunt reduction. Survival at one and six months follow-up was 15 (71%) and 11 patients (52%), respectively. The international normalised ratio (INR) (1.7 vs. 1.5; p = 0.044) was significantly different after TIPS reduction in the non-survival group compared to the survival group. In conclusion, TIPS reduction for the management of TIPS-induced acute liver decompensation is technically feasible and is associated with a one and six-month mortality rate of 29% and 48%, respectively. Higher post-TIPS-reduction INR values may be associated with higher risk of early mortality.
Background. We previously identified miR-146b as being up-regulated during the development of hepatic fibrosis using deep sequencing technology and gene expression analysis. However, the roles and related mechanisms of miR-146b in hepatic stellate cells (HSCs), which are involved in fibrogenesis and fibrosis, have not been elucidated. Results. We report that miR-146b expression was increased in TGF-ß1-treated HSCs. TGF- ß1 enhanced α-SMA and COL1A1 protein expression in HSCs and stimulated proliferation of these cells compared with cells transfected with inhibitor NC. Conversely, miR-146b knock-down decreased α-SMA and COL1A1 expression and inhibited HSC proliferation. In addition, we found that miR-146b specifically regulated the translation of Krüppel-like factor 4 (KLF4) by targeting its 3' untranslated region. Forced expression of KLF4 inhibited TGF- ß1-induced enhancement of α-SMA and COL1A1 expression in HSCs, as well as proliferation of these cells. Moreover, miR-146b expression was negatively associated with KLF4 expression but positively associated with expression of α-SMA and COL1A1 during hepatic fibrosis. Conclusions. Our findings demonstrate the participation of miR-146b as a novel upstream effector of HSC activation via direct targeting of KLF4. Thus, targeted transfer of miR-146b into HSCs could be a useful strategy for the treatment of hepatic fibrosis.
Introduction and aim. Non-cirrhotic idiopathic portal hypertension (NCIPH), also known as hepatoportal sclerosis (HPS) is a disease of uncertain etiology. However, various pathophysiological mechanisms has been postulated, including chronic or recurrent infections and exposure to drugs or toxins. In this context, it appears to be of multifactorial etiology or resulting from a portal vascular endothelium aggression. It is important to consider whether the use of dietary supplements and herbs can trigger or contribute to the occurance of HPS. We report a possible association of HPS with the consumption of herbals and / or dietary supplements. Material and methods. We describe two cases of HPS in patients without known etiology causes associated with this disease. Results. Both patients were females who were diagnosed with HPS following the consumption of Herbalife® products and putative anorexigenic agents in the form herbals infusions. Image-based analysis and the assessment of the histopathological alterations found in the livers confirmed the diagnosis. The histopatological analysis of liver samples from both patients showed portal tracts enlarged by fibrosis with disappearance or reduction in the diameter of the portal vein branches. In many portal tracts, portal veins branches were replaced by aberrant thin-walled fendiforme vessels. The bile ducts and branches of the hepatic artery show normal aspects. Conclusion. After the exclusion of other etiologic factors and a comprehensive analysis of clinical history, consumption of Herbalife® products and anorexigenic agents was pointed-out as a puttative predisposing factor for the development of the disease.
Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support. Material and methods. We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed. Results. After MARS® procedure, patients' symptoms improved, as well as liver function tests, thus avoiding liver transplantation. Conclusion. Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.