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Current Issue

January - February, 2016

Vol. 15 Issue 1

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

EDITORIAL

CONCISE REVIEW

  • The role of zinc in liver cirrhosis Kurt Grüngreiff, Dirk Reinhold, Heiner Wedemeyer Page 7-16

    Zinc is an essential trace element playing fundamental roles in cellular metabolism. It acts mostly by binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Zinc is critical to a large number of structural proteins, enzymatic processes, and transcription factors. Zinc deficiency can result in a spectrum of clinical manifestations, such as poor of appetite, loss of body hair, altered taste and smell, testicular atrophy, cerebral and immune dysfunction, and diminished drug elimination capacity. These are common symptoms in patients with chronic liver diseases, especially liver cirrhosis. The liver is the main organ responsible for the zinc metabolism which can be affected by liver diseases. On the other hand, zinc deficiency may alter hepatocyte functions and also immune responses in inflammatory liver diseases. Liver cirrhosis represents the most advanced stage of chronic liver diseases and is the common outcome of chronic liver injury. It is associated with energy malnutrition, with numerous metabolic disorders, such as hypoalbuminemia, with imbalance between branched-chain amino acids and aromatic amino acids, and with reduced zinc serum concentrations. All these processes can influence the clinical outcome of patients, such ascites, hepatic encephalopathy and hepatocellular carcinoma. In the present review, we summarize the emerging evidence on the pitoval role of zinc in the pathogenesis of liver cirrhosis.

  • Hepatitis C virus strategies to evade the specific-T cell response: a possible mission favoring its persistence Jorge F. Quarleri, José R. Oubiña Page 17-26

    Hepatitis C virus (HCV) is a small, enveloped RNA virus. The number of HCV-infected individuals worldwide is estimated to be approximately 200 million. The vast majority of HCV infections persist, with up to 80% of all cases leading to chronic hepatitis associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma. The interaction between HCV and the host have a pivotal role in viral fitness, persistence, pathogenicity, and disease progression. The control of HCV infection requires both effective innate and adaptive immune responses. The HCV clearance during acute infection is associated with an early induction of the innate and a delayed initiation of the adaptive immune responses. However, in the vast majority of acute HCV infections, these responses are overcome and the virus persistence almost inexorably occurs. Recently, several host- and virus-related mechanisms responsible for the failure of both the innate and the adaptive immune responses have been recognized. Among the latter, the wide range of escape mutations to evade the specific-T-and B-cell responses as well as the T cell anergy and the CD8+ T cell exhaustion together with the interference with its function after prolonged virus exposure hold a pivotal role. Other HCV strategies include the modification or manipulation of molecules playing key roles in the induction of the interferon response and its induced effector proteins. In this review, we attempt to gain insights on the main T cell immune evasion strategies used by the virus in order to favor its persistence.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Biochemical non-invasive assessment of liver fibrosis cannot replace biopsy in HIV-HCV coinfected patients Dimas A. Kliemann, Fernando H. Wolff, Cristiane V. Tovo, Paulo R. Alencastro, Maria L.R. Ikeda, Ajácio B.M. Brandão, Nêmora Barcellos, Sandra C. Fuchs Page 27-32

    Background and rationale. The liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis. However, this method presents limitations. In addition, the non-invasive evaluation of liver fibrosis is a challenge. The aim of this study was to validate the fibrosis cirrhosis index (FCI) index in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, and compare to AST/ALT ratio (AAR), AST to platelet ratio index (APRI) and FIB-4 scores, as a tool for the assessment of liver fibrosis in coinfected patients. Material and methods. Retrospective cross sectional study including 92 HIV-HCV coinfected patients evaluated in two reference centers for HIV treatment in the Public Health System in Southern Brazil. Patients who underwent liver biopsy for any indication and had concomitant laboratory data in the 3 months prior to liver biopsy, to allow the calculation of studied noninvasive markers (AAR, APRI, FIB-4 and FCI) were included. Results. APRI < 0.5 presents the higher specificity to detect no or minimal fibrosis, whereas APRI > 1.5 presents the best negative predictive value and FCI > 1.25 the best specificity to detect significant fibrosis. The values of noninvasive markers for each Metavir fibrosis stage showed statistically significant differences only for APRI. In conclusion, until better noninvasive markers for liver fibrosis are developed and validated for HIV-HCV coinfected patients, noninvasive serum markers should be used carefully in this population.

  • Hepatitis E virus serum antibodies and RNA prevalence in patients evaluated for heart and kidney transplantation Alberto Unzueta, Riccardo Valdez, Yu-Hui H. Chang, Yvonne M. Desmarteau, Raymond L. Heilman, Robert L. Scott, David D. Douglas, Jorge Rakela Page 33-40

    Background. Acute hepatitis E virus (HEV) infection in solid organ transplant recipients is rare, but can cause severe hepatic and extrahepatic complications. We sought to identify the pretransplant prevalence of HEV infection in heart and kidney candidates and any associated risk factors for infection. Material and methods. Stored frozen serum from patients undergoing evaluation for transplant was tested for HEV immunoglobulin G (IgG) antibodies and HEV RNA. All patients were seen at Mayo Clinic Hospital, Phoenix, Arizona, with 333 patients evaluated for heart (n = 132) or kidney (n = 201) transplant. HEV IgG antibodies (anti-HEV IgG) were measured by enzyme-linked immunosorbent assay, and HEV RNA by a noncommercial nucleic acid amplification assay. Results. The prevalence of anti-HEV IgG was 11.4% (15/132) for heart transplant candidates and 8.5% (17/201) for kidney transplant candidates, with an overall seroprevalence of 9.6% (32/333). None of the patients tested positive for HEV RNA in the serum. On multivariable analysis, age older than 60 years was associated with HEV infection (adjusted odds ratio, 3.34; 95% CI, 1.54-7.24; P = 0.002). Conclusions. We conclude that there was no evidence of acute HEV infection in this pretransplant population and that older age seems to be associated with positive anti-HEV IgG.

Liver transplantation
  • Risk factors for and management of ischemic-type biliary lesions following orthotopic liver transplantation: A single center experience Tao Jiang, Chuanyun Li, Binwei Duan, Yuan Liu, Lu Wang, Shichun Lu Page 41-46

    Introduction. Biliary complications can cause morbidity, graft loss, and mortality after liver transplantation. The most troublesome biliary complications are ischemic-type biliary lesions (ITBL), which occur since transplants can now be performed after the donor has undergone circulatory death. The exact origin of this type of biliary complication remains unknown. Material and methods. A total of 528 patients were retrospectively analyzed following liver transplantation after excluding 30 patients with primary sclerosing cholangitis and those lost to follow-up from January 2007 to January 2014. The incidence of and risk factors for ITBL were evaluated. Results. Cold ischemia time (CIT) (P = 0.042) and warm ischemia time (WIT) (P = 0.006) were found to be independent risk factors for the development of ITBL. Use of the cytochrome P450 (CYP) 3A5 genotype assay to guide individualization of immunosuppressive medications resulted in significantly fewer ITBL (P = 0.027. Autoimmune hepatitis might be a risk factor for ITBL, as determined using univariate analysis (P = 0.047). Conclusions. Efforts should be taken to minimize risk factors associated with ITBL, such as CIT and WIT. The CYP3A5 genotype assay should be used to guide selection of immunosuppressive therapy in an effort to reduce the occurrence of ITBL.

  • Intrapulmonary vascular dilation in children with chronic liver diseases: pre- and post-liver transplantation Anant Khositseth, Suporn Treepongkaruna, Khemika Khemakanok, Sumate Teeraratkul, Vichai Pansrimangkorn, Chollasak Thirapattaraphan, Surasak Leelaudomlipi Page 47-52

    Background and study aims. Chronic liver disease (CLD) can cause hepatopulmonary syndrome (HPS), defined as triad of liver disease, hypoxemia, and intrapulmonary vascular dilation (IPVD). The aim of this study was to determine the evidence of IPVD in a cohort of pediatric patients with CLD pre- and post-liver transplantation (LT). Material and methods. All pediatric patients with CLD listed for LT were studied. Pulse oxygen saturation (SpO2), technetium-99m–labeled macroaggregated albumin (99mTc- MAA) perfusión scan (positive test: uptake of the isotope ≥ 6% in the brain), and echocardiography with saline bubble test (SBT) were performed. SBT was re-evaluated at 3-6 months after LT. Grading of SBT included grade 0 (no bubble), I (1-9 bubbles), grade II (10-20 bubbles), and grade III (> 20 bubbles). Results. Eighteen patients, median age 22.5 months (8-108), were enrolled. Most had biliary atresia (77.8%). Pre-LT, all patients had SpO2 of 100% and none had positive 99mTc- MAA perfusion scan. Two patients (11%) had negative SBT (grade 0), 1 (5.5%) had grade I, 3 (16.5%) had grade II, and 12 (67%) had grade III, respectively. Post-LT SBT became negative in all survivors (n = 16), (p = 0.0001). Conclusions. Most cirrhotic children in this cohort study had evidence of IPVD by positive SBT. However, none of these met the criteria for diagnosis of HPS. This evidence of IPVD subsided after LT.

  • Early allograft dysfunction after liver transplantation: an intermediate outcome measure for targeted improvements David D. Lee, Kristopher P. Croome, Jefree A. Shalev, Kaitlyn R. Musto, Meenu Sharma, Andrew P. Keaveny, C. Burcin Taner Page 53-60

    Background. The term early allograft dysfunction (EAD) identifies liver transplant (LT) allografts with initial poor function and portends poor allograft and patient survival. Aims of this study are to use EAD as an intermediate outcome measure in a large single center cohort and identify donor, recipient and peri-operative risk factors. Material and methods. In 1950 consecutive primary LT, donor, recipient and peri-operative data were collected. EAD was defined by the presence of one or more of the following: total bilirubin ≥ 10 mg/dL (171 μmol/L) or, INR ≥ 1.6 on day 7, and ALT/AST > 2,000 IU/L within the first 7 days. Results. The incidence of EAD was 26.5%. 1-, 3-, and 5-year allograft and patient survival for patients who developed EAD were significantly inferior to those who did not (P < 0.01 at all time points). Multivariate analysis demonstrated associations in the development of EAD with recipient pre-operative ventilator status, donation after cardiac death allografts, donor age, allograft size, degree of steatosis, operative time and intra-operative transfusion requirements (all P < 0.01). Patients with EAD had a significantly longer hospitalization at 20.9 ± 38.9 days (median: 9; range: 4-446) compared with 10.7 ± 13.5 days (median: 7; range: 3-231) in patients with no EAD (P < 0.01). Conclusions. This is the largest single center experience demonstrating incidence of EAD and identifying factors associated with development of EAD. EAD is a useful intermediate outcome measure for allograft and patient survival. Balancing recipient pretransplant conditions, donor risk factors and intra-operative conditions are necessary for avoiding EAD.

Hepatocellular Carcinoma (HCC)
  • Hepatocellular carcinoma <= 4 cm treated with radiofrequency ablation with or without percutaneous ethanol injection Fuyan Shi, Zhijun Tan, Hongqing An, Xiaoli Wang, Yongyong Xu, Suzhen Wang Page 61-70

    Background. To compare the survival of Chinese cirrhotic patients with hepatocellular carcinoma (HCC) ≤ 4 cm who underwent radiofrequency ablation (RFA) alone or a combination of RFA with percutaneous etanol injection (PEI). Material and methods. Retrospective analysis was performed for 681 cases with HCC ≤ 4 cm who were treated with RFA alone or RFA combined with PEI (RFA + PEI) between 2004 and 2011. Results. As a result, 180 patients in each group were selected after propensity score matching (PSM). Higher overall survival (OS) and recurrence-free survival (RFS) rates were achieved by RFA + PEI compared with RFA alone (P = 0.019 and 0.009, respectively). The 1-, 3-, and 5-year cumulative OS rates were 78.0, 44.4, and 30.1% for patients in RFA group and 88.2, 58.0, and 41.1% for patients in RFA + PEI group, respectively. Besides, the 1-, 3-, and 5-year cumulative RFS rates were 77.0, 43.8, and 29.2% in RFA group, and 87.9, 57.6, and 38.4% in RFA + PEI group, respectively. The local recurrence, complete ablation and five-year mortality showed no distinct differences between RFA and RFA + PEI groups in three subgroups classified with tumor size. Moreover, Cox regression multivariate analysis results showed that sex and treatment approach were significantly related to OS, whereas sex, status of HBsAg, local recurrence, and number of tumor nodule were related to RFS. Conclusion. Therefore, the combination of RFA and PEI yielded better OS and RFS rates than RFA alone for Chinese patients with HCC ≤ 4 cm.

  • Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma Kanlayanee Sawanyawisuth, Nattawat Tantapotinan, Ratthaphol Kraiklang, Anucha Puapairoj, Chaisiri Wongkham Page 71-81

    Background and aim. Trophoblast cell surface antigen 2 (TROP2) or tumor-associated calcium signal transducer 2 (TACSTD2) is a 36-kDa type I transmembrane glycoprotein and exerts dual functions as an oncogene and tumor suppressor in cancer cells. In this study, we investigated the expression and functions of TROP2 in liver fluke-associated cholangiocarcinoma (CCA). Material and methods. TROP2 expression in 85 CCA tissues was detected by using immunohistochemistry. The methylation status of TROP2 promoter was studied in 15 matched pairs of normal and CCA formalin fixed paraffin embedded (FFPE) tissues using the bisulfite genomic sequencing (BGS) method. The functions of TROP2 on cancer cell behavior were investigated using siRNA in CCA cell lines. Proliferation, migration and invasion assays were performed. A PCR array was used to evaluate the impact of TROP2 knockdown on the gene expression profiles. Results. TROP2 was highly expressed in all normal bile duct epithelia, but significantly down-regulated in CCA cells. Sixty percent of CCA revealed promoter hypermethylation compared to the corresponding adjacent normal tissues. TROP2 knockdown significantly enhanced the proliferation and migration in CCA cell lines, and altered the expressions of MARCK, EMP1 and FILIP1L. Conclusion. We provide new evidence that TROP2 is epigenetically down-regulated and operates as a negative regulator of cell proliferation and migration in liver fluke-associated CCA.

  • Treatment allocation in hepatocellular carcinoma: Assessment of the BCLC algorithm Mandy Richani, Philippe Kolly, Marina Knoepfli, Evelyn Herrmann, Martin Zweifel, Hendrik von Tengg-Kobligk, Daniel Candinas, Jean-François Dufour Page 82-90

    Background and aims. The Barcelona Clinic Liver Cancer (BCLC) staging system is the algorithm most widely used to manage patients with hepatocellular carcinoma (HCC). We aimed to investigate the extent to which the BCLC recommendations effectively guide clinical practice and assess the reasons for any deviation from the recommendations. Material and methods. The first-line treatments assigned to patients included in the prospective Bern HCC cohort were analyzed. Results. Among 223 patients included in the cohort, 116 were not treated according to the BCLC algorithm. Eighty percent of the patients in BCLC stage 0 (very early HCC) and 60% of the patients in BCLC stage A (early HCC) received recommended curative treatment. Only 29% of the BCLC stage B patients (intermediate HCC) and 33% of the BCLC stage C patients (advanced HCC) were treated according to the algorithm. Eighty-nine percent of the BCLC stage D patients (terminal HCC) were treated with best supportive care, as recommended. In 98 patients (44%) the performance status was disregarded in the stage assignment. Conclusion. The management of HCC in clinical practice frequently deviates from the BCLC recommendations. Most of the curative therapy options, which have well-defined selection criteria, were allocated according to the recommendations, while the majority of the palliative therapy options were assigned to patients with tumor stages not aligned with the recommendations. The only parameter which is subjective in the algorithm, the performance status, is also the least respected.

Miscellaneous
  • The mystery of the Hawaii liver disease cluster in summer 2013: A pragmatic and clinical approach to solve the problem Rolf Teschke, Alexander Schwarzenboeck, Christian Frenzel, Johannes Schulze, Axel Eickhoff, Albrecht Wolff Page 91-109

    Background and aim. In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis. Material and methods. To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions. Results. We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster. Conclusions. Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.

Basic studies

  • Hypothermia is better than ischemic preconditioning for preventing early hepatic ischemia/reperfusion in rats Larisse Longo, Leila Xavier Sinigaglia-Fratta, Giovana R. Weber, Andrea Janz-Moreira, Nélson A. Kretzmann, Tomaz de J.M. Grezzana-Filho, Norma Possa-Marroni, Carlos O. Corso, Carlos T. Schmidt-Cerski, Themis Reverbel-da-Silveira, Mário R. Álvares-da-Silva, Jorge L. dos-Santos Page 110-120

    Background. Topical hypothermia (TH) and ischemic preconditioning (IPC) are used to decrease I/R injury. The efficacy of isolated or combined use of TH and IPC in the liver regarding inflammation and cytoprotection in early ischemia/reperfusion (I/R) injury needs to be evaluated. Material and methods. Wistar rats underwent 70% liver ischemia for 90 min followed by 120 min of reperfusion. Livers of animals allocated in the sham, normothermic ischemia (NI), IPC, TH, and TH+IPC groups were collected for molecular analyses by ELISA and Western blot, aiming to compare proinflammatory, anti-inflammatory, and antioxidant profiles. Results. Compared with NI, TH presented decreased tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-12 concentrations and increased IL-10 levels. TH animals displayed lower inducible nitric oxide synthase (iNOS) and higher endothelial nitric oxide synthase (eNOS) expressions. NAD(P)H-quinone oxidoreductase-1(NQO1) expression was also lower with TH. Isolated IPC and NI were similar regarding all these markers. TH+IPC was associated with decreased IL-12 concentration and reduced iNOS and NQO1 expressions, similarly to isolated TH. Expression of Kelch-like ECH-associated protein (Keap)-1 was increased and expression of nuclear and cytosolic nuclear erythroid 2-related factor 2 (Nrf2) was decreased with TH+IPC vs. NI. Conclusion. TH was the most effective method of protection against early I/R injury. Isolated IPC entailed triggering of second-line antioxidant defense enzymes. Combined TH+IPC seemed to confer no additional advantage over isolated TH in relation to the inflammatory process, but had the advantage of completely avoid second-line antioxidant defense enzymes.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Acute liver failure associated with Garcinia cambogia use Rebecca Corey, K. Tuesday Werner, Andrew Singer, Adyr Moss, Maxwell Smith, Jessica Noelting, Jorge Rakela Page 123-126

    Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed.

  • Direct intrahepatic portocaval shunt for treatment of portal thrombosis and Budd-Chiari syndrome Mark R. Pedersen, Peter Molloy, David Wood, Anil Seetharam Page 127-130

    Budd-Chiari syndrome (BCS) refers to hepatic venous outflow obstruction that in severe cases can lead to acute liver failure prompting consideration of revascularization or transplantation. Here, a 22 year old female with angiographically proven BCS secondary to JAK2/V617F positive Polycythemia vera on therapeutic warfarin presented with acute liver failure (ALF). Imaging revealed a new, near complete thrombotic occlusion of the main portal vein with extension into the superior mesenteric vein. An emergent direct intrahepatic portocaval shunt (DIPS) was created and liver function promptly normalized. She has been maintained on rivaroxaban since that time. Serial assessment over 1 year demonstrated continued shunt patency and improved flow in the mesenteric vasculature on ultrasound as well as normal liver function. DIPS is a viable alternative in the treatment of ALF from BCS when standard recanalization is not feasible. Improved blood flow may also improve portal/mesenteric clot burden. While further investigation is needed, new targeted anticoagulants may be viable as a long term anticoagulation strategy.

  • Liver transplantation utilizing a severely fractured graft: every organ counts Zhi Ven Fong, Madhukar S. Patel, Heidi Yeh, James F. Markmann, Parsia A. Vagefi Page 131-134

    In our current era where shortage of liver grafts is commonplace, utilization of traumatic liver grafts may represent an opportunity to expand the organ donor pool without compromising graft survival. However, data on liver transplantation using a fractured liver allograft is scarce, with only small case series and reports found in the literature. In this report, we describe our experience with utilizing a liver graft with grade IV hepatic fracture for transplantation. At 12 months follow up, the recipient has excellent graft function and has regained an excellent quality of life. We demonstrated that the ability to safely use a fractured liver graft represents an additional avenue for expansion of the deceased donor population, especially in regions with prolonged waitlist times.

LETTER TO EDITOR

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