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November- December, 2018

Vol. 17 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

EDITORIALS

OPINIONS

  • The Evolving Role of Liver Biopsy in Non-alcoholic Fatty Liver Disease Juan Pablo Arab, Francisco Barrera, Marco Arrese Page 899-902

    Evaluation patients with nonalcoholic steatohepatitis (NASH) imply the need of appropriate assessment of disease severity (i.e. the presence of nonalcoholic steatohepatitis (NASH)) as well as of the disease stage (i.e. the extent of liver fibrosis). Liver biopsy (LB) is still considered the gold standard for diagnosing NASH as well as for establishing the degree of liver fibrosis. However, due to its invasive nature and costs, use of LB should be restricted to selected patients and, according guidelines and expert opinion, indicated in the following scenarios: a) when LB will guide treatment, b) to confirm or exclude NAFLD in patients with conflicting clinical data, c) to increase patient’s awareness about their disease, and improve engagement in their care and d) for inclusion in clinical trials. However, the role of LB in NAFLD is evolving since when new and costly therapeutic agents become available, LB will be eventually necessary to make clinical decisions. The use of non-invasive tools (NITs) to assess steatosis, NASH and hepatic fibrosis is useful to triage NAFLD patients and decide in whom perform a LB.

VIEWPOINTS

CONCISE REVIEW

  • Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy Karina González-Aldaco, Luis A. Torres-Reyes, Claudia Ojeda-Granados, Alexis José-Ábrego, Nora A. Fierro, Sonia Román Page 908-919

    Hepatitis C virus (HCV) is a lipid-enveloped virion particle that causes infection to the liver, and as part of its life cycle, it disrupts the host lipid metabolic machinery, particularly the cholesterol synthesis pathway. The innate immune response generated by liver resident immune cells is responsible for successful viral eradication. Unfortunately, most patients fail to eliminate HCV and progress to chronic infection. Chronic infection is associated with hepatic fat accumulation and inflammation that triggers fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Despite that the current direct-acting antiviral agents have increased the cure rate of HCV infection, viral genotype and the host genetic background influence both the immune response and lipid metabolism. In this context, recent evidence has shown that cholesterol and its derivatives such as oxysterols might modulate and potentialize the hepatic innate immune response generated against HCV. The impairment of the HCV life cycle modulated by serum cholesterol could be relevant for the clinical management of HCV-infected patients before and after treatment. Alongside, cholesterol levels are modulated either by genetic variations in IL28B, ApoE, and LDLR or by dietary components. Indeed, some nutrients such as unsaturated fatty acids have demonstrated to be effective against HCV replication. Thus, cholesterol modifications may be considered as a new adjuvant strategy for HCV infection therapy by providing a biochemical tool that guides treatment decisions, an improved treatment response and favoring viral clearance. Herein, the mechanisms by which cholesterol contributes to the immune response against HCV infection and how genetic and environmental factors may affect this role are reviewed.

  • An Argument for Vitamin D, A, and Zinc Monitoring in Cirrhosis Andree H. Koop, Omar Y. Mousa, Ly Elaine Pham, Juan E. Corral-Hurtado, Surakit Pungpapong, Andrew P. Keaveny Page 920-932

    Malnutrition is prevalent in cirrhosis. Vitamin and mineral deficiencies, including vitamin D, vitamin A, and zinc, are common and have been shown to correlate with survival. Our aim was to review the mechanisms of vitamin D, vitamin A, and zinc deficiencies in cirrhosis and the clinical assessment of affected patients, their outcomes based on the current literature, and management. This is a narrative review including the relevant literature for cirrhosis and vitamin D, vitamin A, and zinc deficiencies. Vitamin D deficiency has important effects in cirrhosis, regardless of the cause of chronic liver disease. These effects include associations with fibrosis and outcomes such as infections, hepatocellular carcinoma, and mortality. Vitamin A deficiency is associated with liver disease progression to cirrhosis and clinical decompensation, including occurrence of ascites or hepatic encephalopathy. Zinc deficiency can lead to hepatic encephalopathy and impaired immune function. Such deficiencies correlate with patient survival and disease severity. Caution should be applied when replacing vitamin D, vitamin A, and zinc to avoid toxicity. Identification and appropriate treatment of vitamin and mineral deficiencies in cirrhosis may reduce specific nutritional and cirrhosis-related adverse events. Routine monitoring of vitamin A, vitamin D and zinc levels in cirrhosis should be considered.

ORIGINAL ARTICLES

  • Effect of Proton Pump Inhibitors on Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis Tsung-Hsing Hung, Chih-Wei Tseng, Hsing-Feng Lee, Chih-Chun Tsai, Chen-Chi Tsai Page 933-939

    Introduction and aim. Spontaneous bacterial peritonitis (SBP) is a life-threatening infection in patients with cirrhosis. However, it is unknown whether patients with SBP and cirrhosis who do not have active gastrointestinal bleeding have a poorer prognosis if treated with proton pump inhibitors (PPI). Material and methods. We used the Taiwan National Health Insurance Database to identify 858 patients with SBP and cirrhosis who were administered PPIs and hospitalized between January 1, 2010, and December 31, 2013. One-to-two propensity score matching was performed to select a comparison group based on age, gender, and comorbidities. All patients obtained follow-up for 1 year. Results: The overall 30-day, 90-day, and 1-year mortality was 27.9%, 49.0%, and 73.7%, respectively, in the PPI group and 25.6%, 43.8%, and 67.2%, respectively, in the non-PPI group. After adjusting the Cox regression model for age, gender, and comorbidities, the hazard ratios for PPIs regarding 30-day, 30- to 90-day, and 90-day to 1-year mortality were 1.074 (95% CI 0.917-1.257, P = 0.377), 1.390 (95% CI 1.154-1.673, P = 0.001), and 1.297 (95% CI 1.099- 1.531, P = 0.002), respectively. Conclusions: PPIs did not increase the short-term mortality of patients with SBP and cirrosis who did not have active gastrointestinal bleeding, but PPIs increased the long-term mortality risk. For these patients, physicians should discontinue PPIs as early as possible.

  • The Effect of ICOS Polymorphism Interactions with HBV Mutations on HBV Subtype Infection Outcomes Xiao-Mei Song, Qing-Ling Li, Feng Guo, Hong Peng, Jin-Jun Guo Page 940-947

    Introduction and aim. Hepatitis B virus (HBV) infection remains a public health problem worldwide. In addition, HBV infection results are influenced by various virological, immunological, and genetic factors. Inducible T-cell costimulator (ICOS) polymorphisms involving chronic HBV infection have been confirmed in previous studies. This study was to explore the effects of ICOS single nucleotide polymorphisms in HBV subtypes and their interactions with viral mutations on HBV infection outcomes. Material and methods. A total of 1,636 Han Chinese individuals were recruited, including 47 asymptomatic HBV carriers (ASC), 353 chronic hepatitis B (CHB) patients, 327 HBV-related liver cirrhosis (LC) patients, 193 HBV-related hepatocellular carcinoma (HCC) patients, 464 patients with spontaneous recovery from HBV infection (SR), and 252 healthy controls (HC). DNA samples from these subjects were genotyped for four ICOS SNPs (rs11883722, rs10932029, rs1559931, and rs4675379). Direct sequencing was used to determine the HBV mutations in the enhancer II, basal core promoter, and pre-core regions. Results. We found that the genotype “TC” of ICOS rs10932029 SNP was associated with decreased HBV-related LC risk in the genotype C group. Additionally, the A1762T, G1764A and A1762T/G1764A mutations were associated with an increased risk of LC in the genotype C group. Further study indicated that interactions between ICOS rs10932029 genotype “TC” and A1762T or A1762T/G1764A mutations significantly decreased the LC risk in the genotype C group. Conclusion. The rs10932029 genotype “TC” might be an LC-protective factor for HBV genotype C infection. The interactions between the rs10932029 genotype “TC” and A1762T or A1762T/G1764A mutations could decrease the risk of LC.

  • Infection and Predictors of Outcome of Cirrhotic Patients after Emergency Care Hospital Admission Wajima Safi, Mayada Elnegouly, Raphael Schellnegger, Katrin Umgelter, Fabian Geisler, Wolfgang Reindl, Bernd Saugel, Alexander Hapfelmeier, Andreas Umgelter Page 948-958

    Introduction and aims. We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions. Material and methods. We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike’s Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account. Results. 218 patients were included. 71.2% were male, mean age was 61.1 ± 10.5 years. Mean MELD score was 16.2 ± 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 ± 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients. Conclusion. Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.

  • Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir ± Ribavirin for HCV in Brazilian Adults with Advanced Fibrosis Mario G. Pessôa, José V. Ramalho-Madruga, Katia Alves, Estevão P. Nunes, Hugo Cheinquer, Carlos E. Brandão-Mello, Maria C. Mendes-Correa, Maria L. Ferraz, Paulo R. A. Ferreira, Mário R. Álvares-da-Silva, Henrique S. Coelho, Evaldo S. Affonso-de-Araújo, Juvencio Furtado, Raymundo Paraná, Giovanni Silva, Sara A. Lari, Li Liu, Rakesh Tripathi, Tami Pilot-Matias, Daniel E. Cohen, Nancy S. Shulman, Ana Martinelli Page 959-968

    Introduction and aim. Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection. Material and methods. All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12). Results. The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event. Discussion. The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

  • Response to Loco-Regional Therapy Predicts Outcomes After Liver Transplantation for Combined Hepatocellular-Cholangiocarcinoma Samuel O. Antwi, Yacob Y. Habboush, Lori A. Chase, David D. Lee, Tushar Patel Page 969-979

    Introduction and aim. Combined hepatocellular-cholangiocarcinoma (HCC-CCA) is a rare liver malignancy distinct from either hepatocellular carcinoma (HCC) or cholangiocarcinoma. Liver transplantation (LT) is not recommended for HCC-CCA because of suboptimal outcomes. Non-invasive diagnosis of HCC-CCA is extremely challenging; thus, some HCC-CCAs are presumed as HCC on imaging and listed for LT with the correct diagnosis ultimately made on explant pathology. We compared HCC-CCA with HCC to determine the utility of response to pre-transplant loco-regional therapy (LRT) in predicting outcomes for HCC-CCA after LT as a potential means of identifying appropriate HCC-CCA patients for LT. Material and methods. Retrospective review of 19 patients with pathologically confirmed HCC-CCA were individually matched to 38 HCC patients (1:2) based on age, sex, and Milan criteria at listing was performed. The modified response evaluation criteria in solid tumors was used to categorize patients as responders or non-responders to pre-transplant LRT based on imaging performed before and after LRT. Overall survival (OS) and recurrence-free survival (RFS) were examined. Results. OS at 3 years post-transplant was 74% for HCC-CCA and 87% for HCC. RFS at 3 years was 74% for HCC-CCA, and 87% for HCC. Among responders to LRT, the 3-year OS was 92% for HCC-CCA and 88% for HCC; among non-responders, 3-year OS was 43% for HCC-CCA and 83% for HCC. Higher 3-year OS was observed among HCC-CCA responders (77%) compared with HCC-CCA non-responders (23%). Conclusions. OS was similarly high among responders to pre-transplant LRT irrespective of tumor type. Radiologic response to LRT could potentially be used to select appropriate HCC-CCA patients for LT if the findings are validated in independent studies.

  • Hepatoprotective Role of Thymol in Drug-Induced Gastric Ulcer Model Fatime Geyikoglu, Fatime Geyikoglu, Elif Gülcan Yilmaz, Huseyin Serkan Erol, Kubra Koc, Salim Cerig, Nihal Simsek Ozek, Ferhunde Aysin Page 980-991

    Introduction and aim. Indo is widely one of the non-steroidal anti-inflammatory drugs and one of the common toxic effects of this drug is hepatic failure. Thymol is a monoterpene phenol with many different pharmacological activities. However, up to now its hepatoprotective effects on Indo-induced gastric ulcer model in rats have not been explored yet. Material and methods. Thirty five Sprague-Dawley rats were divided into seven groups: control, ulcer control (30 mg/kg Indo), Indo + reference standard (50 mg/kg Rantidine), Indo + Thymol (75, 100, 250 and 500 mg/kg) groups. 10 minutes after the induction of ulcer with Indo; Thymol was orally administered to the rats. Liver function enzymes (AST, ALT and LDH) were measured from serum samples. TOS/TAC, TNF-&alpha and PGE2 levels, eNOS and Caspase-3 activity were assessed from tissue homogenate samples. In addition, histopathologic analysis on liver sections was performed. Results. Indo significantly increased the levels of hepatic enzymes, TNF-&alpha and eNOS, and caspase-3 activation, while decreased PGE2 levels. Furthermore, it induced oxidative stress as evidenced by elevated TOS and decreased TAC levels. However, Thymol treatment induced a significant improvement in these parameters, especially in 250 mg/kg dose. On the other hand, treatment with Thymol 500 mg/kg dramatically affected the parameters much worse than the Indo treated group. Conclusion. The findings of the current study demonstrated that Thymol administration significantly ameliorated liver injury due to Indo toxicity. This effect of Thymol (250 mg/kg) may be mediated by its anti-oxidative or anti-inflammatory effect, and up-regulation the synthesis of PGE2.

  • The -250G/A and -514C/T Polymorphisms in Hepatic Lipase Gene Promoter Confers an Increased Risk of Hepatocellular Carcinoma in a Chinese Population Chuan-Zhen Niu, Fu-Hua Zhang Zhang, Yan Li, Jing-Jing Liu, Cui-Xia Bao Page 992-1000

    Introduction and aim. Hepatocellular carcinoma (HCC) is a lethal malignancy, but the molecular mechanisms of hepatocarcinogenesis remain undefined. The present study aims to investigate the relationship between polymorphisms of the hepatic lipase (HL) gene promoters and risk of HCC. Material and methods. Totally, 279 HCC patients and 200 healthy individuals were enrolled. Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) was used to analyze the genotypes of HL gene. Logistic regression analysis was conducted to identify risk factors of HCC. Results. There was significant difference in the distribution of smoking history, drinking history, and family history of subjects between the case and control groups (all p < 0.05). Difference in the -250G/A (p = 0.011; OR = 1.61; 95%CI: 1.11-2.34) and -514C/T (p = 0.007; OR = 1.65; 95%CI: 1.14-2.38) genotypes and allele frequencies between two groups was significant. A higher risk of HCC was identified in those with polymorphisms in the - 250G/A (p = 0.007; OR = 1.45; 95%CI: 1.11-1.89) and -514C/T (p = 0.003; OR = 1.51; 95%CI: 1.15-2.00). Polymorphisms at - 250G/A (GA + AA) (p = 0.025; OR = 1.55; 95%CI: 1.06-2.28), -514C/T (CT + TT) (p = 0.021; OR = 1.57; 95%CI: 1.07-2.29), smoking history (p = 0.017; OR = 1.70; 95%CI: 1.10-2.63) and drinking history (p = 0.003; OR = 2.04; 95%CI: 1.27-3.27) were significantly related to the risk of HCC (all p < 0.05). Conclusion. The results obtained from this study indicated that polymorphisms of -250G/A and -514C/T in HL gene promoters were associated with the risk of HCC.

  • Drug-Drug Interactions in Hepatitis Patients: Do these Interactions Matter in Clinical Perspectives? Sidra Noor, Mohammad Ismail, Iqbal Haider, Faiza Khadim Page 1001-1011

    Introduction and aim. Hepatitis patients usually present with comorbidities and polypharmacy which increases risk of potential drug-drug interactions (pDDIs). We explored frequency, levels, predictors, and clinical relevance of pDDIs in hospitalized hepatitis patients. Material and methods. Retrospective cohort study was used. Clinical profiles of 413 hepatitis patients were reviewed for pDDIs using Micromedex-DrugReax. Frequency, levels and clinical relevance of pDDIs were reported. Logistic regression analysis was used to calculate odds-ratios for predictors. Results. Of total 413 patients, pDDIs were reported in 55.2%. Major-pDDIs were found in 35% patients. Total 660 pDDIs were identified, of which, 304 (46%) were of major-severity and 299 (45%) of moderateseverity. Patient’s profiles of top-10 major-pDDIs were presented with signs/symptoms such as fever, hepatomegaly, anorexia, jaundice, hypertension, tachycardia, bradycardia, & pedal edema; and abnormalities in labs such as electrolytes-level, alanine aminotransferase, blood urea nitrogen, bilirubin-level, & serum creatinine. Significant association was observed for the presence of pDDIs with > 9 prescribed medicines (p < 0.001), hospitalization of > 5 days (p = 0.03), and stroke as comorbidity (p = 0.05). Moreover, odds of exposure to major-pDDIs were significantly higher in patients taking > 9 prescribed medicines (p < 0.001), hospitalization of > 5 days (p = 0.002), and stroke as comorbidity (p = 0.002). Conclusion. We observed hepatitis patients presented with a considerable number of clinically relevant pDDIs. Attention should be given to widespread major-pDDIs and their potential adverse outcomes. Clinically relevant parameters, such as labs and signs/symptoms should be monitored particularly in high risk patients having polypharmacy, prolong hospitalization, and stroke as comorbidity.

  • MicroRNA Profile in Peripheral Blood Mononuclear Cells from Hepatitis B Virus Infected Patients Kangkang Yu, Qian Li, Ning Li Page 1012-1020

    Introduction and aim. The pathogenesis of hepatitis B virus (HBV)-related liver diseases remains not fully understood. Here, we aim to explore the potential roles of dysregulated miRNAs in chronic hepatitis B (CHB) and HBV-related acute-on-chronic liver failure (ACLF). Material and methods. MiRNA microarray was conducted in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors or patients with CHB or ACLF. Altered expression of miRNAs was further confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Finally, the differentially expressed miRNAs and their target genes were subjected to bioinformatics analysis. Results. The miRNA microarray identified 45 up-regulated and 62 down-regulated miRNAs with a fold change ≥ 1.5. Expression of eight miRNAs was validated using qRT-PCR analysis, which was consistent with miRNA microarray analysis. Bioinformatics analysis indicated that multiple biological processes and signaling pathways were affected by these miRNAs and a miRNA-gene regulatory network was generated with Cytoscape. Conclusion. The current study provided a global view of miRNA expression in PBMCs from CHB and ACLF patients. Functional analysis showed that multiple biological processes and signaling pathways were modulated by these miRNAs. These data provide intriguing insights into the molecular pathogenesis of HBVrelated liver diseases, which deserve further investigation.

  • Association of Interleukin-6 and Interleukin-1 Family Gene Polymorphisms in Autoimmune Hepatitis Azizollah Yousefi, Mehri Najafi, Farzaneh Motamed, Elham Mahmoudi, Alireza Zare Bidoki, Maryam Sadr, Farzaneh Rahmani, Fatemeh Farhmand, Ahmad Khodadad, Gholamhossein Fallahi, Nima Rezaei Page 1021-1025

    Introduction and aim. Autoimmune hepatitis (AIH) is an immune-mediated destruction of liver cells, in recognition of interface hepatitis, seropositivity for autoantibodies, and interface hepatitis in histology sections. Hepatocyte destruction in AIH is the direct result of CD4+ T-cell destruction. Yet, Th17 mediated immune attach and a diversity of cytokine networks, including pro-inflammatory cytokines such as Interleukin 1 (IL-1) and Interleukin 6 (IL-6), set the stage for the destructive liver damage. Material and method. Peripheral blood samples from 57 patients, with AIH, recruited from referrals to the main pediatric hospital in Tehran. Single nucleotide polymorphisms for the following cytokines genes, were evaluated through, polymerase chain reaction with sequencespecific primers (PCR-SSP) assay: IL-1a (C/T -889), IL-1α (C/T -511), IL-β (C/T +3962), IL-1 receptor (IL-1R; C/T Pst-I 1970), IL-1RA (C/T Mspa-I 11100), and IL-6 (C/G -174 and A/G nt565). Results. Significant higher frequency of genotype AA was detected in patients in IL-6 at position nt565 (15.8% in AIH patients vs. 2.9% in controls, p = 0.003). The haplotype GA of IL-6 at -174 and nt565, was significantly overrepresented in the AIH group, compared to (20.9% of AIH vs. 1.4% in controls p < 0.0001). Conclusion. Results of our study, indicate significant deviation toward high yield IL-6 polymorphisms, in AIH patients. These data could bring new insights in pathophysiology of disease, which could contribute to developing novel treatments for AIH.

  • Gene Therapy for Treatment of Chronic Hyperammonemia in a Rat Model of Hepatic Encephalopathy Plácido Espíritu-Ramírez, Nancy Y. Ortega-Balderas, Laura Sevilla-Tapia, Ana G. Montiel-Martínez, Ana R. Pastor-Flores, Laura A. Palomares, Miguel A. Torres-Vega Page 1026-1034

    Introduction and aim. Hepatic encephalopathy (HE), caused by hyperammonemia resulting from liver disease, is a spectrum of neuropsychiatric and motor disorders that can lead to death. Existing therapies are deficient and alternative treatments are needed. We have shown that gene therapy with a baculovirus vector containing the glutamine synthetase (Bac-GS) gene is efficient for reducing ammonia levels in an acute hyperammonemia rat model. However, the most common condition resulting from liver disease is chronic hyperammonemia. In this work, Bac-GS was evaluated in bile-duct ligated rats, a chronic liver disease model with hyperammonemia and some characteristics of Type C HE. Material and methods. Bac-GS was tested for mediating GS overexpression in HeLa cells and H9C2 myotubes. For determining the utility of Bac-GS for the reduction of ammonia levels in a chronic hyperammonemia animal model, four groups of rats were treated: control, sham, ligated with Bac-GS and ligated with Bac-GFP. Baculoviruses were injected i.m. 18 days post-surgery. Blood was drawn 2, 3 and 4 weeks post-surgery and plasma ammonia concentrations were quantified. Results. In protein lysates of cells and myotubes transduced with Bac-GS, a 44 kDa band corresponding to GS was detected. Significant results were obtained in the hyperammonemic bile-duct ligated rat model, as plasma ammonia was reduced to normal levels 3 days after treatment with Bac-GS. Furthermore, a transitory effect of Bac-GS was observed. Conclusion. Our results show that gene therapy by delivering GS is a promising alternative for treatment of hyperammonemia in acute-on-chronic liver failure patients with HE.

  • Association of Parity in Patients with Chronic Liver Disease Pegah Golabi, Sofie Fazel, Munkhzul Otgonsuren, Carey Escheik, Mehmet Sayiner, Zobair M. Younossi Page 1035-1041

    Introduction and aim. The impact of type of liver disease on parity rates hasn’t been described. Our aim was to assess the parity rates among women with CLD. Material and methods. The National Health and Nutrition Examination Survey-III (1988-1994) data were used to identify adult female participants with a diagnosis of CLD. Participants were asked about their reproductive health status. Parity was defined as having at least one live birth. Hepatic ultrasound, serologic, medical examination and clinical data were available to determine the presence and type of CLD. Body mass index (kg/m2) was divided into 3 categories (< 30; 30-35; 36+). Results. A total of 3,502 (865 NAFLD, 737 other CLD, 1,901 control) subjects were included. Patients with NAFLD were more likely to have at least one live birth than patients with other CLD and controls (77% in NAFLD vs. 72% in controls). Multivariate analysis revealed that presence of CLD other than NAFLD (OR: 0.46 [95% CI, 0.34-0.63]) and having a college or higher degree (OR: 0.48 [95% CI, 0.34-0.68]) were negatively associated while having low income (OR: 11.06 [95% CI, 6.86-17.82]) and being African American (OR: 3.93 [95% CI, 2.59-5.98]) were positively associated with having at least one live birth. Conclusions. This study revealed that patients with CLD other than NAFLD were less likely to have at least one live birth. NAFLD and obesity were associated with higher rates of live births which can potentially be explained by weight gain post live birth leading to obesity and its associated-NAFLD.

  • Thromboelastography Parameters in Patients with Acute on Chronic Liver Failure Sandeep Goyal, Shekhar Jadaun, Saurabh Kedia, Subrat Kumar-Acharya, Sharat Varma, Baibaswata Nayak, Bhaskar Thakur, Shalimar . Page 1042-1051

    Introduction and aim. Patients with acute on chronic liver failure (ACLF) have abnormal conventional coagulation tests- platelet count and international normalized ratio (INR). Thromboelastography (TEG) is a rapid, point-of-care assay, more comprehensive than platelet count and INR as it assesses for platelet adequacy (number and function), coagulation factors and clot retraction. The aim of the study was to evaluate the TEG parameters in patients with ACLF, chronic liver disease having acute decompensation (AD) and healthy subjects (HC). Material and methods. TEG parameters were assessed in patients with ACLF and AD within 24 h of admission. Consecutive patients were included in the study over 12 months. Healthy subjects were recruited as controls. Results. 179 patients were included- 68 ACLF, 53 AD and 58 HC. The mean values of INR in ACLF, AD and HC groups were 2.9 ± 1.4, 1.6 ± 0.4 and 1.1 ± 0.2; P < 0.001. Among TEG parameters - maximum amplitude (MA) was low in ACLF and AD patients as compared with HC (53.8 ± 15, 58.3 ± 13.9 mm and 67.2 ± 12.1 mm, respectively; P < 0.001). Lysis at 30 min (LY30) was high in ACLF patients, as compared to AD and HC (8.6 ± 14.1%, 5.0 ± 9.5% and 4.9 ± 9.8%, respectively; P = 0.060). There were no differences in r time, k time, and alpha angle between groups; normal in >90% patients. There was no difference in TEG parameters between different ACLF grades, whereas CCTs were more deranged with increasing grades of ACLF. Conclusion. Despite abnormal conventional coagulation tests, TEG parameters in ACLF patients are essentially normal, except reduced maximum amplitude. Future studies are needed to explore the utility of TEG in clinical management of ACLF patients.

  • Clinicopathological Distinction of Low-AFP-Secreting vs. High-AFP-Secreting Hepatocellular Carcinomas Ahmet Gurakar, Michelle Ma, Jacqueline Garonzik-Wang, Amy Kim, Robert A. Anders, Kiyoko Oshima, Christos Georgiades Page 1052-1066

    Introduction and aims. We aimed to investigate the clinical and pathological differences between low-AFP-secreting (AFP < 20 ng/mL) and high-AFP-secreting (AFP ≥ 20 ng/mL) hepatocellular carcinomas in patients who undergo liver transplant (LT). Material and methods. We evaluated 145 patients who underwent deceased donor LT for HCC from January 1, 2005 until August 1, 2015 at the Johns Hopkins Hospital. Results. Median pre-LT AFP in the entire cohort was 13 ng/mL (IQR 6-59). Using serum AFP cutoff of 20 ng/mL, 61 (42%) patients had high-AFP-secreting tumors and 84 (58%) had low-AFP-secreting tumors. Patients with high -AFP-secreting tumors had larger lesions (3 cm vs. 2.4 cm, p = 0.024), and were more likely to have microvascular-invasion (36.1% vs. 20.2%, p = 0.02) and poor-differentiation (18% vs. 4.8%, p = 0.01), and tumor recurrence following LT (28% vs. 6%, p < 0.001). The 1-year, 3-year, and 5-year recurrence-free survival for patients in the low-AFP-secreting group compared to the high-AFP-secreting group were 100%, 92%, 92% vs. 81.3%, 71.3%, 68.5% respectively (p = 0.0003). Conclusion. AFP is a suboptimal predictor of tumor recurrence following liver transplant in HCC patients. However, it can have some value in distinguishing more aggressive forms of HCC (high-AFP-secreting) that are associated with higher tumor recurrence. Novel tumor biomarkers are needed that can enhance predicting tumor recurrence following LT based on tumor biology.

CASE REPORTS

  • Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine? Marion Lepelley, Marion Allouchery, Jérôme Long, Dorothée Boucherle, Yves Ranchoup, François Le Marc’Hadour, Céline Villier, Nathalie Sturm Page 1067-1071

    Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

  • Improvement in Waldenström’s Macroglobulinemia after Successful Treatment of HCV with Direct-acting Antivirals Mattia Crespi, Maria Giulia Demarzo, Matteo Brunacci, Gaia Pellegatta, Fabio Ferrando, Alberto Ballestrero, Federica Grillo, Vincenzo Savarino, Edoardo G. Giannini Page 1072-1077

    Chronic hepatitis C (HCV) virus infection may be associated with several non-hepatic manifestations, mainly driven by chronic immune stimulation, such as mixed cryoglobulinemia and Non-Hodgkin’s Lymphoma. This association has been proved by several meta-analyses and some interventional studies demonstrating that antiviral treatment may be effective in inducing HCV-associated lymphoma regression. The recent advent of direct acting antivirals (DAAs) in the therapeutic armamentarium of HCV infection made possible treatment of patients with advanced liver disease. Here we report on a rare association of a cirrhotic patient with HCV and Waldenström’s Macroglobulinemia with severe cryoglobulinemia, who had already failed an interferon-based antiviral regimen, whose haematologic disease was ameliorated by HCV eradication following treatment with sofosbuvir and simeprevir with ribavirin, and where successful treatment was accompanied also by consistent improvement in liver function and parameters of portal hypertension.

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XXV ANNUAL MEETING OF THE LATIN AMERICAN ASSOCIATION FOR THE STUDY OF THE LIVER

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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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