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Current Issue

March - April, 2013

Vol. 12 Issue 2

On the cover: Figure A. a and b: Contrast enhanced computerized tomography of abdomen showed ill - defined hypodense lesion with irregular margins (arrow) in segment VIII of right lobe of liver near hepatic vein confluence.

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Epidemiology of hepatocellular carcinoma in sub-Saharan Africa Michael C. Kew Page 173-182

    Published incidences of hepatocellular carcinoma in the Black population of sub-Saharan Africa underestimate the true incidence of the tumor because of the many instances in which hepatocellular carcinoma is either not definitively diagnosed or is not recorded in a cancer registry. Despite this, it is manifestly evident that the tumor occurs commonly and is a major cause of cancer deaths in Black African peoples living in the sub-continent, particularly in those living in rural areas. 46,000 new cases of hepatocellular carcinoma have been recorded to be diagnosed in sub-Saharan Africa each year, and age-standardized incidences of the tumor as high as 41.2/100,000 persons/year have been documented. The highest incidence of hepatocellular carcinoma has been recorded in Mozambique. The tumor occurs at a young age in rural dwelling and, to a lesser extent, urban dwelling Black Africans. It is also more common in men than women, particularly in the younger patients. Cirrhosis co-exists with hepatocellular carcinoma in about 60% of patients and is equally common in the two sexes. The tumor is not only common in the Black African population, it also carries an especially grave prognosis, with about 93% of the patients dying within 12 months of the onset of symptoms. Caucasians living in the sub-continent have a low incidence of hepatocellular carcinoma and it occurs at an older age.

  • S-adenosylmethionine metabolism and liver disease José M Mato, M Luz Martínez-Chantar, Shelly C Lu Page 183-189

    Methionine is an essential amino acid that is metabolized mainly by the liver where it is converted to Sadenosylmethionine (SAMe) by the enzyme methionine adenosyltransferase. Although all mammalian cells synthesize SAMe, the liver is where the bulk of SAMe is generated as it is the organ where about 50% of all dietary methionine is metabolized. SAMe is mainly needed for methylation of a large variety of substrates (DNA, proteins, lipids and many other small molecules) and polyamine synthesis, so if the concentration of SAMe falls below a certain level or rises too much the normal function of the liver will be also affected. There are physiological conditions that can affect the hepatic content of SAMe. Consequently, to control these fluctuations, the rate at which the liver both synthesizes and catabolizes SAMe is tightly regulated. In mice, failure to do this can lead to fatty liver disease and to the development of hepatocellular carcinoma (HCC). Therefore, maintaining SAMe homeostasis may be a therapeutic target in nonalcoholic steatohepatitis, alcoholic- and non-alcoholic liver cirrhosis, and for the chemoprevention of HCC formation.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Prediction of minimal residual viremia in HCV type 1 infected patients receiving interferon-based therapy Viola Knop, Gerlinde Teuber, Hartwig Klinker, Bernd Möller, Jens Rasenack, Holger Hinrichsen, Tilman Gerlach, Ulrich Spengler, Peter Buggisch, Konrad Neumann, Christoph Sarrazin, Stefan Zeuzem, Thomas Berg Page 190-198

    Introduction. Complete suppression of viral replication is crucial in chronic HCV treatment in order to prevent relapse and resistance development. We wanted to find out which factors influence the period from being already HCV RNA negative by bDNA assay (< 615 IU/mL) to become undetectable by the more sensitive TMA test (< 5.3 IU/mL). Material and methods. Evaluated were 433 HCV type 1-infected patients. All of them received 1.5 ug/kg Peg-IFNα-2b plus ribavirin for 18-48 weeks. bDNA was performed weekly during the first 8 weeks and thereafter at weeks 12, 24, and 48. Patients who became bDNA undetectable were addi- tionally analysed by TMA. Results. Of the 309 patients with on-treatment response (< 615 IU/mL), 289 also reached undetectable HCV RNA levels by TMA. Multivariate analysis revealed that viremia ≤ 400,000 IU/mL (p = 0.001), fast initial virologic decline (p = 0.004) and absence of fibrosis (p = 0.035) were independent predictors of an accelerated on-treatment response by TMA assay in already bDNA negative patients. bDNA negative patients becoming HCV RNA undetectable by TMA within the following 3 weeks had a frequency of relapse of 21%, whereas those showing TMA negativity after 3 weeks relapsed in 38% (p = 0.001). In RVR patients (bDNA < 615 IU/mL at week 4) the corresponding relapse rates were 15.3% vs. 37.5%, respectively (p = 0.003). Conclusion. Early viral kinetics, baseline viremia and fibrosis stage are important tools to predict persistent minimal viremia during interferon-based therapy. The data have implications for designing a more refined treatment strategy in HCV infection, even in the setting of protease inhibitor-based triple treatment.

  • Vitamin D deficiency and vitamin D therapy in chronic hepatitis C José M. Ladero, María J. Torrejón, Pilar Sánchez-Pobre, Avelina Suárez, Francisca Cuenca, Virginia de la Orden, María J. Devesa, María Rodrigo, Vicente Estrada, Gustavo López-Alonso, José A. Agúndez Page 199-204

    Background. Vitamin D has immunomodulatory properties, exerts an anti-hepatitis C virus (HCV) effect in vitro and improves response to interferon-based therapy in patients with chronic hepatitis C (CHC). Low serum levels of 25(OH) vitamin D [25(OH)D] are frequently found in CHC patients and seem to be related to more advanced stages of liver fibrosis. The study aims to establish the incidence of vitamin D deficiency in Spanish patients with CHC, its possible relation with features of liver damage and with the IL28B gene polymorphism, and the immediate effect of vitamin D therapy on CHC-related analytical variables. Materials and methods. Baseline serum 25(OH)D levels were measured in 108 consecutive CHC patients (60 men, age 54.3 ± 10.5 yrs). Results of transient elastography and of IL28B rs12979860C/T genotype were available in 89 and 95 patients, respectively. Forty one patients with insufficient levels of 25(OH)D received vitamin D supplements and were re-evaluated thereafter. Results. Deficiency of vitamin D (< 20 µg/dL) and suboptimal levels (20-30 µg/mL) were detected in 36.1% and 40.9% of patients, respectively. No relationships were found between 25(OH)D levels and biochemical liver tests, fibrosis stage and IL28B genotype. Vitamin D therapy normalized 25(OH)D levels in all treated patients, but did not modify significantly HCV-RNA serum levels or biochemical tests. Conclusions. Vitamin D deficiency is common in Spanish patients with CHC but it is related neither to biochemical and virological variables nor with the fibrosis stage and IL28B polymorphism. Vitamin D therapy has no immediate effect on HCV-RNA serum levels.

  • Efficacy and safety of entecavir and/or tenofovir in hepatitis B compensated and decompensated cirrhotic patients in clinical practice Mireia Miquel, Óscar Núñez, María Trapero-Marugán, Antonio Díaz-Sánchez, Miguel Jiménez, Juan Arenas, Antonio Palau Canós Page 205-212

    This study aimed to evaluate the efficacy and safety of entecavir and/or tenofovir in compensated (CC) or decompensated (DC) hepatitis B cirrhotic patients in real-life clinical practice. Of the 48 patients, included between April 2007 and March 2010, 12 were DC. The mean age was 55 ± 12.2 years, 85.4% were Caucasians and 8 patients were HBeAg positive. Mean viral load was 5.2 ± 1.9 log UI/mL. HBV-DNA undetectability at 3, 6, 12 and 24 months were 53.3%, 78.3%, 83.7% and 97.1%, respectively, similar in CC and DC. At 6 and 12 months, ≥ 80% of CC achieved ALT normalization, while only 42.9% and 71.4% in DC. After a median follow-up of 27.1 (0.7-45.3) months, 43 patients were Child Pugh Turcotte (CPT) class A (n = 39 at entry). In DC, progressive improvement in the MELD scores was observed: 12.73 (SD 4.5), 10.4 (SD 3.6) and 8.2 (SD 2.6), at baseline, 12 and 24 months, respectively. During follow-up, 7 patients died, 4 received liver transplantation and 5 developed hepatocellular carcinoma. In three out of four DC who died due to hepatic causes, these events occurred between the first 0.7 and 6.7 months, and all were CPT class C. Cumulative survival in CC vs. DC at 12 and 24 months were 94.4% vs. 66.7%, and 88.2% vs. 57.1%, respectively (log rank p = 0.03). No severe adverse events associated with entecavir or tenofovir were reported. In conclusion, in compensated and decompensated cirrhotic patients, entecavir and tenofovir were effective and well tolerated.

  • Prevalence and risk factors of isolated anti-HBc antibody and occult hepatitis B infection in hemodialysis patients: a nationwide study Hossein Keyvani, Shahram Agah, Ali Kabir, Seyed-Moayed Alavian Page 213-219

    Background. Recent studies have demonstrated that prevention of hepatitis B virus (HBV) transmission remains a challenge in hemodialysis (HD) patients. The aim of this study is to explore factors which increase the possibility of occult HBV (OHB) infection in patients under HD in Iran. Material and methods. Among 2188 cases who spent an average of 60.2 ± 61.1 months under HD, we selected 103 cases with isolated antihepatitis B virus core antibody (anti-HBc) and 231 controls without any HBV, hepatitis D virus (HDV) and hepatitis C virus (HCV) serologic markers. Socio-demographic data, past medical history, and clinical signs and symptoms were assessed. Results. The frequency of checking hepatitis B serologic markers was 15.3%. The rate of OHB infection in HD patients who were monitored for their HBV markers was 4.9%. Cases with isolated anti-HBc had significantly higher percentage of positive HBV DNA [odds ratio: OR (95% confidence interval: 95% CI) = 12.1 (1.4-105)], visual disturbances [OR (95% CI) = 1.8 (1.1-3.03)], history of diabetes mellitus [OR (95% CI) = 2.1 (1.3-3.5)], higher age, higher age when dialysis started and were mostly married, illiterate, disabled and retired. Diabetes mellitus was the only independent predictor of HBV DNA status in cases with isolated anti-HBc. Conclusion. In our region, OHB infection is prevalent among hemodialysis patients and displays a direct correlation with factors which are age related except diabetes mellitus. Thus, the presence of isolated anti-HBc should prompt the clinician to evaluate a possible OHB infection especially when it is detected in conjunction with a history of diabetes mellitus.

  • Single nucleotide polymorphisms in CXCR1 gene and its association with hepatitis B infected patients in Saudi Arabia Fahad N. Almajhdi, Mohammed Al-Ahdal, Ayman A. Abdo, Faisal M. Sanai, Mashael Al-Anazi, Nisreen Khalaf, Nisha A. Viswan, Hamad Al-Ashgar, Khalid Al-Kahtani, Hind Al-Humaidan, Riham Al-Swayeh, Zahid Hussain, Saud Alarifi, Majid Al-Okail, Ahmed Al-Qahtani Page 220-227

    Background/Aim. This study aims to investigate whether the SNPs of CXCR1 gene, could predict the likelihood of viral persistence and/or disease progression. Material and methods. We investigated the association of two different SNPs (rs2234671, and rs142978743) in 598 normal healthy controls and 662 HBV patients from a Saudi ethnic population. The HBV patients were categorized into inactive carriers (n = 428), active carriers (n = 162), cirrhosis (n = 54) and Cirrhosis-HCC (n = 18) sub-groups. Genetic variants in CXCR1 were determined by polymerase chain reaction (PCR)-based DNA direct sequencing. Results. The frequency of the risk allele ‘C’ for the SNP, rs2234671 was found to be insignificant when the patient group was compared to the uninfected control group, however, a significant distribution of the allele ‘C’ of rs2234671 was observed among active HBV carriers + cirrhosis + cirrhosis - HCC vs. inactive HBV carriers with an OR = 1.631 (95% C.I. 1.016-2.616) and p = 0.032. However, no significant association was observed for rs142978743 when the distribution of risk allele was analyzed among the different patient groups (i.e. inactive carriers, active carriers, cirrhosis and HCC). Furthermore, the most common haplotype, Haplo-1 (AG), was found to have an insignificant frequency distribution between HBV cases and controls, while the same haplotype was found to be significantly distributed when active carriers + cirrhosis + cirrhosis - HCC patients were compared to inactive HBV carriers with a frequency of 0.938 and p = 0.0315. Haplo-2 (AC) was also found to be significantly associated with a frequency of 0.058 and p = 0.0163. Conclusion. The CXCR1 polymorphism, rs2234671 was found to be associated with chronic HBV infection and may play a role in disease activity.

  • Response predictors and clinical benefits of hepatitis C retreatment with pegylated interferon and ribavirin in HIV/HCV coinfection Mario Peribañez-Gonzalez, Mariliza Henrique da Silva, Fernando Crivelenti Vilar, Ana Catharina Seixas-Santos Nastri, Paulo Abrão Ferreira, Roberto Focaccia, Maria Cássia Mendes Correa Page 228-235

    Background. Hepatitis C is a leading cause of mortality among HIV-infected individuals. Therefore, eradication of HCV in this population is a priority. There are scarce data regarding retreatment efficacy of HIV/ HCV coinfected patients. The aim of our study was to evaluate efficacy, predictors of response, and long term clinical benefits of sustained virological response (SVR) after hepatitis C retreatment in a population of HIV/HCV coinfected patients. Material and methods. We evaluated efficacy, safety, and clinical benefits of peginterferon(alfa-2a or alfa-2b) and ribavirin in a restrospective, observational, multicentric study, including 47 HIV/HCV coinfected patients, non-responders to previous treatment with conventional interferon alfa-2a and ribavirin. The primary endpoint of efficacy was SVR, defined as undetectable viral load 24 weeks after end of treatment. Death, liver disease progression, CD4 counts, and AIDS defining illness were the endpoints to access clinical benefits of treatment response. Results. In our analysis, 31.9% patients reached SVR. Genotypes 2/3 had a significant better SVR (66.7%) compared to genotypes 1/4 (33.3%) (p = 0.022). During follow-up, deaths (6.89%) and hepatic decompensation (28.6%) occurred only in the nonresponder group, while there were no cases of death or hepatic decompensation among the responder group(p = 0.037). Conclusion. Nearly one third of patients (mainly those with genotypes 2/3) reached SVR after hepatitis C retreatment in this group of HIV/HCV coinfected patients. SVR was protective against hepatic decompensation and death in a two-year follow-up period. Retreatment may be an effective and safe way to eradicate HCV until new anti-HCV drugs become available to this group of patients.

  • Serum level of soluble vascular cell adhesion molecule in patients with hepatocellular carcinoma and its association with severity of liver disease Antonio Díaz-Sánchez, Ana Matilla, Óscar Núñez, Diego Rincon, Raquel Lorente, Oreste Lo Iacono, Beatriz Merino, Ana Hernando, Rocio Campos, Gerardo Clemente, Rafael Banares Page 236-247

    Background. VCAM-1 (soluble vascular cell adhesion molecule-1) plays a role in liver angiogenesis. Hepatocellular carcinoma (HCC) has important angiogenic activity, so expression of VCAM-1 may be pathogenic. Aim. To assess the association between serum VCAM-1 (sVCAM-1) levels and features of tumour and liver disease in patients with and without HCC, and to study the influence of HCC treatment on sVCAM-1 levels. Material and methods. Concentrations in peripheral (sVCAM-1-P) and hepatic (sVCAM-1-H) veins were analysed using ELISA in 134 consecutive patients with chronic liver disease between May 2004 and February 2006, who underwent a splanchnic haemodynamic study. Of these patients, 58 had HCC. Results. sVCAM-1-P and sVCAM-1-H were well correlated in both groups. No association was found between sVCAM-1-H and tumour features. No differences were observed in sVCAM-1-H between HCC and non-HCC cirrhotic patients. There was a significant linear association between Child-Pugh stage and sVCAM-1-H in HCC-patients (Child-Pugh A [2,485 ± 1,294 ng/mL] vs. Child-Pugh B [3,408 ± 1,338 ng/mL] vs. Child-Pugh C [4,096 ± 862 ng/ mL]; p = 0.007). Seven non-cirrhotic HCC patients had a significantly lower sVCAM-1-H than cirrhotic HCC patients. Treatment of HCC leads to an increase in sVCAM-1-H levels although this was not associated with the necrosis response to treatment. Conclusions. sVCAM-1 levels are more closely associated with the severity of underlying liver disease than with the presence of HCC. sVCAM-1 levels are not associated with tumour features or invasiveness; therefore, sVCAM-1 does not seem to play an important role in the angiogenic processes of HCC.

  • Addition of pentoxifylline to pegylated interferon-alpha-2a and ribavirin improves sustained virological response to chronic hepatitis C virus: a randomized clinical trial Miguel Ángel Jiménez-Luévano, José Manuel Lerma-Díaz, Georgina Hernández-Flores, Miguel Ángel Jiménez-Partida, Alejandro Bravo-Cuellar Page 248-255

    Background and aim. The commonly accepted treatment for hepatitis C virus (HCV) infection, pegylated interferon alpha (PEG INF-alpha) and ribavirin, leads to 50-60% of sustained virological response (SVR). On the other hand, pentoxifylline (PTX) possesses antiviral and hepatoprotector properties. Aim. To investigate whether the addition of PTX to conventional hepatitis C treatment increases SVR. Material and methods. Seventy two patients of both genders were studied in a randomized fashion; the diagnosis of chronic HCV infection was made according to clinical and laboratory criteria and histopathologically classified according to METAVIR scoring system criteria. HCV viral load was tested by PCR, baseline, and after 6 months of treatment, as well as anti-HCV, anti-hepatitis B virus , and anti-human immunodeficiency virus antibodies by enzyme-linked immunosorbent assay. During 48 weeks, control group patients were treated with PEG INFalpha-2a plus ribavirin. PTX was administered to Experimental Group patients prior to the treatment. Results. Demographic data were similar in both groups. Experimental- and control-group subjects were at F2 and F3 states according to the METAVIR classification. The most common HCV genotypes were 1a and 1b (39% in the control group in each case, and 42% in the experimental group in each case). At the end of the study, hepatic enzymes and viral load decreased in both groups to similar values. SVR in the experimental group increased significantly (p < 0.05) when compared with standard therapy alone. Conclusion. Addition of PTX to conventional chronic hepatitis C treatment may increase the percentage of patients with SVR.

Non alcoholic fatty liver disease (NAFLD)
  • Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study Vincent Wai-Sun Wong, Grace Lai-Hung Wong, Angel Mei-Ling Chim, Winnie Chiu-Wing Chu, David Ka-Wai Yeung, Kevin Chi-To Li, Henry Lik-Yuen Chan Page 256-262

    Background. Probiotics have profound effect on nonalcoholic steatohepatitis (NASH) in animal models. We aimed to test the hypothesis that probiotics treatment was superior to usual care in reducing liver fat in NASH patients. Material and methods. Patients with histology-proven NASH were randomized to receive probiotics (n = 10) or usual care (n = 10) for 6 months. The Lepicol probiotic formula contained Lactobacillus plantarum, Lactobacillus deslbrueckii, Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum. The primary endpoint was change in intrahepatic triglyceride content (IHTG), as measured by proton-magnetic resonance spectroscopy, from baseline to month 6. Secondary endpoints included changes in liver biochemistry and metabolic profile. Results. IHTG decreased from 22.6 ± 8.2% to 14.9 ± 7.0% in the probiotic group (P = 0.034) but remained static in the usual care group (16.9 ± 6.1% to 16.0 ± 6.6%; P = 0.55). Six subjects in the probiotic group had IHTG reduced by more than 30% from baseline, compared to 2 subjects in the usual care group (P = 0.17). The probiotic group also had greater reduction in serum aspartate aminotransferase level (P = 0.008). On the other hand, the use of probiotics was not associated with changes in body mass index, waist circumference, glucose and lipid levels. Conclusions. Probiotics treatment may reduce liver fat and AST level in NASH patients. The therapeutic potential of probiotics in NASH should be tested in larger studies.

Hepatocellular Carcinoma (HCC)
  • Comparison of prognosis by viral etiology in patients with hepatocellular carcinoma after radiofrequency ablation Ping-Hsien Chen, Chiou Wei-Yu, Hung Yi-You, Su Hung-Hsu, Yi-Hong Chou, Teh-Ia Huo, Yi-Hsiang Huang, Wen-Chieh Wu, Yee Chao, Han-Chieh Lin, Jaw-Ching Wu Page 263-273

    Background. Radiofrequency ablation (RFA) has been performed as a first line curative treatment modality for patients with hepatocellular carcinoma (HCC) within the Milan criteria currently. However, prognosis of hepatitis B- and hepatitis C-related HCC after RFA remains debatable. This study aimed to assess the impact of viral etiology on the prognosis of HCC patients undergoing RFA. Material and methods. One hundred and ninety-two patients with positive serum HBV surface antigen (HBsAg) and negative serum antibody against HCV (anti-HCV) were enrolled as the B-HCC group and 165 patients with negative serum HBsAg and positive anti-HCV as the C-HCC group. Post-RFA prognoses were compared between the two groups using multivariate and propensity score matching analyses. Results. The B-HCC group had higher male-to-female ratio and better liver functional reserve than the C-HCC group. After a median follow-up of 23.0 ± 22.7 months, 55 patients died and 189 patients had tumor recurrence after RFA. The cumulative fiveyear survival rate was 75.9% and 69.5% in the B-HCC and C-HCC groups, respectively (p = 0.312), while the five-year recurrence-free survival rate was 19.0% and 26.6%, respectively (p = 0.490). After propensity-score matching, the B-HCC group still had comparable overall survival rate (p = 0.679) and recurrence-free survival rate (p = 0.689) to the C-HCC group. For 132 patients with Barcelona-Clinic Liver Cancer stage 0, the fiveyear overall survival and recurrence-free survival rates were also comparable between the two groups (p = 0.559 and p = 0.872, respectively). Conclusion. Viral etiology is not essential for determining outcome in HCC patients undergoing RFA.

Liver transplantation
  • Comparison of results of combined liver-kidney transplantation vs. isolated liver transplantation Victoria Aguilera, Isabel Ferrer, Marina Berenguer, Jairo Rivera, Ángel Rubín, Ángel Moya, Eugenia Pareja, Jaime Sánchez, Martín Prieto, José Mir Page 274-281

    Introduction. Combined liver-kidney transplantation (LKT) is the best therapeutic option for patients with end-stage liver and kidney disease. Objectives. To analyze baseline characteristics and clinical outcome of LKT compared to isolated liver transplantation (LT). Material and methods. The study included 16 LKT performed between 1998 and 2006 and 32 LT matched by age, sex, date and indication for transplantation. Demographic, pretransplant, post-transplant and survival variables were analyzed. Results. As planned by the study design, mean age, distribution by sex and indication for LT were similar between groups. The most common indication for LT was HCV- and/or alcohol-induced cirrhosis. The most common indication for KT was renal failure, in most cases secondary to glomerulonephritis. Twelve patients (69%) were on dialysis before LKT. Hepatocellular carcinoma and diabetes mellitus pre-transplantation were similar between groups. However pretransplant arterial hypertension (AHT) was higher in LKT than LT (50% vs. 19%; p = 0.02). In the post-transplant: reoperation due to bleeding, bacterial infections, liver rejection, AHT and median creatinine levels at 1st and 3rd years were similar in LKT and LT. In contrast, early post-transplant dialysis was higher in LKT than LT (31% vs. 3%; p = 0.01). Survival rates at 1st, 3rd, 5th and 7th years were similar in both groups (87.5%, 74%, 74% and 66% vs. 81%, 75%, 75% and 75% in LT and LKT, respectively). Conclusions. LKT is an effective therapeutic option in patients with end-stage liver and kidney disease. Most early and late complications and long-term survival are similar to those observed with LT.

  • A Canadian national retrospective chart review comparing the long term effect of cyclosporine vs. tacrolimus on clinical outcomes in patients with post-liver transplantation hepatitis C virus infection Eric M. Yoshida, Leslie B. Lilly, Paul J. Marotta, Andrew L. Mason, Marc Bilodeau, Marc Vaillancourt Page 282-293

    The transition from regular use of cyclosporine to the newer calcineurin-inhibitors, such as tacrolimus, has been suggested as a contributing factor to the “era effect” of worsening outcomes of post-transplant HCV recurrence. This retrospective medical chart review of 458 patients was undertaken to evaluate the role of immunosuppressant choice (cyclosporine vs. tacrolimus) in determining virologic response and clinical outcomes of post-liver transplant HCV infection recurrence. Our results showed that patients undergoing interferon-based treatment taking cyclosporine have significantly better odds (OR: 2.59, P = 0.043) of presenting a sustained viral response (66.7%) compared to tacrolimus (52.8%). This did not result in a significant effect on post-liver transplantation clinical events including HCV-related deaths, graft loss, fibrosing cholestatic hepatitis, hepatocellular carcinoma or graft rejection. Other variables, which showed a significant relationship with the achievement of sustained viral response included donor age (OR 0.96, P = 0.001) and HCV genotype 1 infection (OR 0.05, P < 0.001). The observed significant increase in the odds of acute/hyperacute (OR 6.49, P = 0.001) and chronic rejection (OR 10.45, P < 0.001) in the cyclosporine to tacrolimus switch group, accompanied by an increase in the odds of HCV-related death (OR 2.30, P < 0.047) compared to tacrolimus merits further study. A significant increase (P < 0.044) in new-onset diabetes mellitus with tacrolimus (28.3%) compared to cyclosporine (18.7%) was also observed. Pre-transplant diabetes mellitus was associated with a significantly increased likelihood of graft fibrosis (HR 1.95, P = 0.003).

Miscellaneous
  • Mean platelet volume is a useful indicator of systemic inflammation in cirrhotic patients with ascitic fluid infection Burak Suvak, Serkan Torun, Hakan Yildiz, Abdurrahim Sayilir, Yusuf Yesil, Adnan Tas, Yavuz Beyazit, Nurgül Sasmaz, Ertugrul Kayaçetin Page 294-300

    Aim. Ascitic fluid infection (AFI) consists primarily of two variants, namely, culture-negative neutrocytic ascites and spontaneous bacterial peritonitis (SBP). Mean platelet volume (MPV) has begun to be used as a simple and inexpensive indicator of inflammation in some diseases. We aimed to analyse whether platelet size alterations would be useful in predicting AFI in cirrhotic patients. Material and methods. A total of 135 patients with ascites due to cirrhosis and 55 control subjects were enrolled in this study. According to ascitic fluid analysis, 58 patients were considered to have AFI. MPV and inflammatory parameter values were determined for all study participants. The ability of MPV values to predict AFI in cirrhotic patients was analysed using receiver operator characteristic (ROC) curve analysis. Results. A statistically significant increase in MPV levels was observed in cirrhotic patients with AFI compared to cirrhotic patients without AFI and healthy controls (p < 0.001). A statistically significant increase was observed in the AFI group with respect to MPV, C-reactive protein (CRP) and white blood cell (WBC) levels. ROC curve analysis suggested that the optimum MPV level cut-off point for cirrhotic patients with AFI was 8.45, with a sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 70.7%, 67.5%, 75.4% and 62.1%, respectively (area under curve: 0.768). Conclusion. Our study shows that MPV is increased in cirrhotic patients with AFI. MPV measurement can considered to be an accurate diagnostic test in predicting AFI, possibly due to an ongoing systemic inflammatory response.

  • Intestinal mucosal proliferation, apoptosis and oxidative stress in patients with liver cirrhosis Stelios F. Assimakopoulos, Athanassios C. Tsamandas, Georgios I. Tsiaoussis, Elli Karatza, Dimitrios Zisimopoulos, Ioannis Maroulis, Eleni Kontogeorgou, Christos D. Georgiou, Chrisoula D. Scopa, Konstantinos C. Thomopoulos Page 301-307

    Background. Intestinal mucosal barrier dysfunction in liver cirrhosis and its implicated mechanisms is of great clinical importance because it is associated with the development of serious complications from diverse organs through promotion of systemic endotoxemia. Aim. The present study was designed to investigate whether enterocytes’ proliferation, apoptosis and intestinal oxidative stress are altered in the intestinal mucosa of patients with compensated and decompensated liver cirrhosis. Material and methods. Twelve healthy controls (group A) and twenty four cirrhotic patients at a compensated (n = 12, group B) or decompensated condition (n = 12, group C) were subjected to duodenal biopsy. In intestinal specimens mucosal apoptotic and mitotic activity and their ratio were recorded by means of morphological assessment and mucosal lipid hydroperoxides were measured. Plasma endotoxin concentration, an index of gut barrier function, was also determined. Results. Cirrhotic patients presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0.001), whilst endotoxemia was higher in decompensated disease (P < 0.05 vs. compensated cirrhosis). Intestinal mucosal mitotic count was significantly lower in patients with compensated and decompensated cirrhosis compared to controls (P < 0.01, respectively), whilst a trend towards increased apoptosis was recorded. The mitotic/apoptotic ratio was significantly reduced in groups B (P < 0.05) and C (P < 0.01) as compared to controls. Intestinal lipid peroxidation was significantly increased in decompensated cirrhotics (P < 0.001 vs. groups A and B). Conclusions. The present study demonstrates for the first time that human liver cirrhosis is associated with decreased intestinal mucosal proliferation and proliferation/apoptosis ratio even at early stages of cirrhosis and increased intestinal oxidative stress in advanced liver disease.

  • Focal nodular hyperplasia and hepatic regenerating nodules in pediatric oncology patients: how much invasive approach is necessary? Maria Debora De Pasquale, Lidia Monti, Maria Luisa D’Andrea, Maria Antonietta De Ioris, Aurora Castellano Page 308-314

    Introduction. Hepatic regenerating nodules (HRN) and focal nodular hyperplasia (FNH) are benign regenerating lesions of the liver that rarely occur in children. An increased incidence of these lesions is reported in children treated for cancer. Material and methods. Eight children who developed FNH and HRN after treatment for malignancies in the Oncology unit at the “Bambino Gesù” Pediatric Hospital in Rome, were retrospectively analyzed. Results. The lesions, considered in the differential diagnosis with metastatic relapse of the primitive disease, have been monitored with US or other available imaging techniques. Evolution of the lesions was observed in only 1 patient three years after the initial diagnosis of FNH. Conclusion. In conclusion serial monitoring with imaging techniques is sufficient to rule out liver metastasis and to monitor the evolution of the lesions. Surgery is suggested only in the case of complications.

Basic studies

  • A metal mixture induces transformation upon antioxidant depletion in a hepatic cell line Vicente Sánchez-Valle, Mahara Valverde, Leticia Carrizales, Jesus Mejía, Nahum Zepeta, Emilio Rojas Page 315-324

    Introduction. Metals are ubiquitous soil, air, and water pollutants. A mixture of arsenic cadmium and lead, in particular, has commonly been found in the vicinity of smelter areas. The mixture of As-Cd-Pb has been shown to be carcinogenic, and transforming potential and oxidative stress have been proposed as principal mechanisms involved in this process. The aim of this work was to explore the role of the antioxidant barrier in the establishment of cell transformation upon chronic exposure to a metal mixture containing 2 µM NaAsO 2 , 2 µM. CdCl 2 , and 5 µM Pb(C 2 H 3 O 2 ) 2 ·3H O in WRL-68 cells-a non-transformed human hepatic cell line. Material and methods. In this study, we used a WRL-68 cell model of human embryonic hepatic origin treated with antioxidant inhibitors (L-Buthionine-sulfoxamine and aminotriazole) to test the role of the antioxidant barrier in the establishment of cell transformation upon chronic exposure to a metal mixture of As-Cd-Pb (2 µM NaAsO 2 , 2 µM CdCl2 and 5 µM Pb(C 2 2 H 3 O 2 ) 2 ·3H O). We evaluated oxidative damage markers, including reactive oxygen species, lipid peroxidation, and genotoxicity, as well as antioxidant response markers, including glutathione concentration, catalase activity, and superoxide dismutase activity, wich promote morphological transformation, which can be quantified by foci formation. Results. As expected, we found an increase in the intracellular concentration of the metals after treatment with the metal mixture. In addition, treatment with the metal mixture in addition to inhibitors resulted in a large increase in the intracellular concentration of cadmium and lead. Our results describe the generation of reactive oxygen species, cytotoxicity, genotoxicity, and oxidative damage to macromolecules that occurred exclusively in cells that were morphologically transformed upon exposure to a metal mixture and antioxidant barrier inhibition. Conclusion. Our results show the importance of the antioxidant barrier role in the protection of cellular integrity and the transformation potential of this metal mixture via free radicals.

IMAGES IN HEPATOLOGY

  • Thoracic empyema due to migrated gallstones Rene Agustin Flores-Franco Page 325-326

    Hepatobiliary conditions should be considered in the differential diagnosis of right pleural effusion. Here we present the illustrative images of thoracic empyema due to migrated gallstones in a woman who was treated for laparoscopic cholecystectomy one year before. The gallstones were obtained unexpectedly during a thoracentesis with aid of an Abrams needle. This rare complication is discussed under current literature review.

CASE REPORTS

  • Abernethy malformation with multiple aneurysms: incidentally found in an adult woman with Caroli´s disease Kong Yalin, Zhang Hongyi, Liu Chengli, Wu Di, He Xiaojun, Xiao Mei, Zhao Gang, Zhang Hui Page 327-331

    Abernethy malformation is a rare anomaly with partial or complete congenital absence of the portal vein and subsequent development of extrahepatic portocaval shunts. We present the case of a 28-year-old woman who was incidentally diagnosed with type II Abernethy malformation and multiple aneurysms during an investigation for nonspecific abdominal pain and fever. The patient had been diagnosed with Caroli’s disease at the age of 10 and liver cirrhosis, portal hypertension a few years before. To the best of our knowledge, this is the first case reported with all such congenital anomalies associated together. Ultrasound, computed tomography, including three-dimensional reconstruction, and magnetic resonance imaging were performed which revealed a side-to-side shunt between the extrahepatic portal vein and the inferior vena cava, multiple aneurismal cystic dilation of the spleen artery and left renal artery, and extensive intrahepatic bile duct cysitic dilation with calculus formation. Etiology, clinical significance and management strategies with regard to these abnormalities are discussed.

  • Isolated granulomatous hepatitis-A histopathological surprise mimicking cholangiocarcinoma in ulcerative colitis Ashish Khandelwal, Ujjwal Gorsi, E. Celia Marginean, Demetri Papadatos, Uttam George Page 332-335

    A 63-yr-old woman, known case of ulcerative colitis, was diagnosed with sclerosing cholangitis 2 years back. She was admitted for investigation of abdominal discomfort, fatigue with elevated alkaline phosphatase and deranged liver function test. Imaging studies (computerised tomography and magnetic resonance imaging) demonstrated a normal biliary tree with focal hepatic lesion which was showing features of cholangiocarcinoma. Ultrasound guided biopsy of the lesion surprisingly revealed non caseating granulomata. Granulomatous hepatitis occurs in less than 1 percent of cases of inflammatory bowel disease. A clinical diagnosis of isolated granulomatous hepatitis was established as the lesion remained stable on follow up and no other cause for it was identified on further investigation. Although the differential diagnosis of focal hepatic lesion in patients with ulcerative colitis with sclerosing cholangitis is wide, granulomatous hepatitis presenting as focal mass lesion mimicking cholangiocarcinoma has never been described previously.

  • Hemorrhagic liver cyst rupture: An unusual life-threatening complication of hepatic cyst and literature review Yoann Marion, Christophe Brevart, Laurent Plard, Laurence Chiche Page 336-339

    Background & aims. Hemorrhagic rupture is an extremely rare complication of hepatic cyst. Its incidence, gravity and treatment modalities are inadequately covered in the literature. Material and methods. Based on a case report concerning a 37 year-old, 13-weeks pregnant woman, presenting with hemorrhagic shock subsequent to hemorrhagic rupture of a hepatic cyst and requiring urgent surgery, a review of the literature was conducted. Results. To date, 11 cases have been described in the literature. This complication is particularly serious with six cases of hemorrhagic shock, three of which led to death. In the majority of cases, urgent surgical treatment is required. Conclusions. Hepatic cysts are frequent benign tumors of the liver which are most often discovered fortuitously. Hemorrhagic rupture is the rarest associated complication, yet requires to be known for it is both serious and lethal and necessitates urgent surgical intervention.

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