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May - June, 2013

Vol. 12 Issue 3

On the cover: Abdominal ultrasound showed multiple small hyperechoic foci (Figure A, arrows). The cholangiogram showed trifurcation of the hilus and confirmed dilatation of the bile ducts (Figure B, arrowheads).



  • Probiotics in non-alcoholic fatty liver disease: which and when Ludovico Abenavoli, Emidio Scarpellini, Samir Rouabhia, Clara Balsano, Francesco Luzza Page 357-363

    Non-alcoholic fatty liver disease (NAFLD) is a common and serious disease. Literature reports the central role of the gut-liver axis in the pathogenesis of NAFLD, and recently suggests that the microbiota is a casual factor of the disease, involved in the interactions between intestinal lumen and liver. Probiotic are commensal bacteria, able to modulate the microbiota with benefits for the health of humans. Several data suggest a range of potentially beneficial medicinal uses for probiotics, in particular in NAFLD patients. However, the species with higher efficacy in this disease are not identified. The present review focuses on the role of gut-liver axis in the pathogenesis, and on the potential therapeutic role of probiotics in the managing of NAFLD.


Clinical Studies

Viral Hepatitis
  • The efficacy and safety of nucleos(t)ide analogues in the treatment of HBV-related acute-on-chronic liver failure: a meta-analysis Yu Shi, Jianqin He, Wei Wu, Jianrong Huang, Yida Yang, Jifang Sheng, Liang Yu, Zhi Chen, Hongyu Jia Page 364-372

    Introduction. The application of nucleos(t)ide analogues in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) has not yet been widely accepted. Therefore, we conducted a meta-analysis of prospective and retrospective studies to examine the efficacy and safety of nucleos(t)ide analogues in treating HBV-related ACLF. Material and methods. Two independent reviewers identified eligible studies through electronic, and manual searches, and contact with experts. Three-month mortality was defined as the primary efficacy measure. ACLF reactivation and HBV DNA inhibition were secondary efficacy measures. Quantitative meta-analyses were performed to compare differences between nucleos(t)ide analogue and control groups. Results. Five eligible studies were identified. Antiviral treatment with nucleos(t)ide analogues led to significant reduction of HBV DNA [HBV DNA reduction > 2 log: 70.4 vs. 29%, RR = 2.29, 95%CI (1.49, 3.53), P < 0.01]. ACLF patients receiving nucleos(t)ide analogue had significantly lower 3-month mortality [44.8 vs. 73.3%, RR = 0.68, 95%CI (0.54, 0.84), P < 0.01] as well as incidence of reactivation [1.80 vs. 18.4%, RR = 0.11, 95%CI (0.03, 0.43), P < 0.01] compared to those who did not. There was no significant difference in the prognosis of patients treated with entecavir or lamivudine [36.4 vs. 40.5%, RR = 0.77, 95%CI (0.45, 1.32), P = 0.35]. No drug-related adverse events were reported during follow-up. Conclusion. Our findings suggest that nucleos(t)ide analogue treatment reduces short-term mortality as well as reactivation of HBV-related ACLF patients. Nucleos(t)ide analogues are well-tolerated during therapy, and suggestive evidence indicates that entecavir and lamivudine confer comparable short-term benefits in these patients. However, further studies are needed to clarify these observations.

  • Analysis of hepatitis C virus (HCV) RNA load in platelets of HCV-monoinfected patients receiving antiviral therapy Márcia Paschoal do Espírito-Santo, Carlos Eduardo Brandão-Mello, Vanessa Alves Marques, Elisabeth Lampe, Adilson José De Almeida Page 373-379

    Introduction. Detection of hepatitis C virus (HCV) has been reported in extrahepatic sites such as peripheral blood mononuclear cells and platelets. Quantitation of HCV-RNA in platelets from patients under antiviral therapy has not been reported. Material and methods. HCV-RNA levels in paired serum and platelet samples of 17 chronically HCV-infected patients were determined at baseline, week 12, end-of-treatment, and 24 weeks after completion of treatment with pegylated interferon plus ribavirin. Quantitation of HCV-RNA load was performed using COBAS® TaqMan® HCV Test v 2.0 (lower limit of detection, 25 IU/mL). The cohort predominantly consisted of female (59%) with a mean age of 50.7 ± 10.0 years. Results. Measure- ments of HCV-RNA in relation to different timepoints of therapy revealed baseline viral load was most frequently detected in higher levels in serum than in platelets (5.6 x 10 4 IU/mL vs. 379.0 IU/mL; p = 0.0002), a trend also demonstrated in most samples throughout the study. HCV-RNA was also found at low levels (< 25.0-314.0 UI/mL) persistently in platelets of three patients who have lost detectable HCV-RNA in serum during antiviral therapy, resulting in virological relapse. Conclusion. HCV-RNA levels are most frequently detected in higher levels in serum than in platelets, independent of timepoint of antiviral therapy. Further studies with an increase in size of the samples are needed to better evaluate whether or not patients who presented HCV-RNA at low levels in platelets after having lost detectable HCV-RNA in serum during antiviral therapy are at increased risk of relapse of HCV infection during follow-up evaluation.

  • Patient adherence to antiviral treatment for chronic hepatitis B and C: a systematic review Faydra I. Lieveld, Lotte G. van Vlerken, Peter D. Siersema, Karel J van Erpecum Page 380-391

    Introduction. Poor adherence to treatment for various chronic diseases is a frequent phenomenon. Current guidelines for the treatment of chronic hepatitis B (HBV) and hepatitis C (HCV) recommend optimal adherence, since it has been suggested that poor adherence is associated with an increased risk of virological failure. We aimed to give an overview of studies exploring adherence to combination treatment (PEG-interferon plus ribavirin) for HCV and nucleos(t)ide analogues for HBV. Material and methods. A systematic review was conducted using the databases PubMed, Embase, Cochrane Library and Web of Knowledge. Search terms included “adherence” or “compliance” combined with “hepatitis B”, “hepatitis C” or “viral hepatitis”. Results. The final selection included 19 studies (13 HCV, 6 HBV). Large differences in patient numbers and adherence assessment methods were found between the various studies. For HCV mean adherence varied from 27 to 97%, whereas the proportion of patients with ≥ 80% adherence varied from 27 to 96%. Mean adherence reported in HBV studies ranged from 81 to 99%, with 66 to 92% of patients being 100% adherent. For both HCV and HBV studies, the highest adherence rates were reported in studies using self-report whereas lower adherence rates were reported in studies using pharmacy claims. Poor adherence to treatment was associated with an increased risk of virological failure. Conclusion. Non-adherence to treatment in chronic viral hepatitis is not a frequent phenomenon. However, given the increased risk of virological failure in poorly adherent patients, clinicians should routinely address adherence issues in all patients treated for chronic viral hepatitis.

  • Poor response to hepatitis C treatment in elderly patients Ivonete Silva, Roberto Carvalho Filho, Ana Cristina Feldner, Iandra Zaros, Antonio Eduardo Silva, Maria Lucia Ferraz Page 392-398

    Introduction. Treatment of genotype 1 chronic hepatitis C in elderly patients has been associated with low rates of a sustained virological response (SVR), but the reasons are unclear. Objective. To determine the SVR rate in patients ≥ 60 years with genotype 1 chronic hepatitis C treated with Peg-IFN and ribavirin, and to identify risk factors related to treatment response in this specific group of patients. Material and methods. Patients were divided into < 60 years (non-elderly) and ≥60 years (elderly) and were compared regarding clinical, laboratory and histological characteristics and response to treatment. Results. A total of 231 patients were included in the study. The elderly group (n=89) presented a predominance of women, more advanced hepatic disease, higher glucose, cholesterol and LDL levels, lower hemoglobin levels, and a larger proportion of overweight subjects. The SVR rate was lower (25 vs. 46%) and anemia, ribavirin dose reduction and use of filgrastim and erythropoietin were more frequent in elderly patients. Negative predictive factors of SVR in the whole group (n = 231) were glucose ≥ 100 mg/dL and age ≥ 60 years. In the elderly group, only pretreatment variables (lower serum glucose and higher hemoglobin levels) were associated with SVR. Conclusion. The SVR rate was low in elderly patients. However, this poor response was not due to poor tolerance, but mainly to pretreatment conditions. Among elderly patients, the best candidates for hepatitis C treatment are those with elevated pretreatment hemoglobin levels and adequate glycemic control.

  • Impact of sustained virologic response on quality of life in chronic HVC carriers Renato Daltro-Oliveira, Mychelle Morais-de-Jesus, Karine Miranda Pettersen, Raymundo Paraná, Lucas C. Quarantini Page 399-407

    Introduction. It is known that patients with chronic hepatitis C have a lower health-related quality of life (HRQOL) than the general population and evidence suggests that the hepatitis C virus (HCV) could exert direct neuropathic action on HRQOL. From this perspective, the virus clearance should be accompanied by improvement in HRQOL. Thus, we sought to review systematically the evidence in the literature and perform a meta-analysis of HRQOL changes caused by sustained virologic response (SVR). Material and methods. The PubMed was searched using the keywords Hepatitis C, Quality of Life and Therapy. The reviewers came to a consensus on articles that were selected to full reading and those that should be included in the study and a meta-analysis was performed of mean change difference between responders and non-responders. Results. Eleven studies were included in the systematic review and four in the metaanalysis. Of these, nine studies showed more favorable outcome for responders, and they had a better outcome even in studies that evaluated only cirrhotic patients, previous non-responders, relapsers, patients in first treatment and patients unaware of treatment response. Moreover, the meta-analysis showed that the general health and vitality domains had statistically significant mean change difference between responders and non-responders, presenting a summary effect of 6.3 (CI 95% 2.5-10.0) and 7.8 (CI 95% 3.4- 12.1) respectively. Conclusion. There is evidence indicating that SVR is accompanied by an improvement in HRQOL and patients reaching SVR have clinically relevant improvement in domains of general health and vitality.

  • Differential expression of transforming growth factor- β 1 and HBx enhances hepatitis B virus replication and augments host immune cytokines and chemokines Fahad N Almajhdi, Ahmed Y. Al-Qudari, Zahid Hussain Page 408-415

    Background/Aims. This study investigated how HBV replication and host immune response are effected by reduced expression of TGF-β1 and HBx. Material and methods. Short interfering RNA (siRNA) knockdown technology has been used to examine the role of TGF-β1 in hepatitis B virus replication. The siTGF-β1 has been transfected along with 1.3mer HBV x-null to investigate the knockdown effect of TGF-β1 on HBV replication and host immune factors. Results. In this study, we found that diminished expression of TGF-β1 and increased expression of HBx enhances HBV replication several folds. The differential expression of TGF-β1 and HBx also stimulated transcriptional viral replicative intermediate (pgRNA) and secretion of core and ‘e’ antigen at translational level. Consequently, several cytokines such as IL-2, IL-8 and chemokine monocyte-chemoattractant protein (MCP-1) were increased significantly in response to stimulation of HBV replication. In contrast, TNF-α and RANTES mRNA expression increased insignificantly in response to enhanced HBV replication. Conclusions. We concluded that reduced expression of TGF-β1 together with HBx expression stimulate HBV replication and immune response, although the underlying mechanism of stimulation most likely differs.

Non alcoholic fatty liver disease (NAFLD)
Hepatocellular Carcinoma (HCC)
  • The effect of celecoxib on the development of diethylnitrosamine-induced liver tumors in rats Larissa Widholzer Galant, Angelo Alves de Mattos, Eduardo Menti, Fabiana Borba Valiatti, Ângelo Zambam De Mattos, Marilene Porawski, Antônio Hartmann, Cláudia Ramos Rhoden Page 425-433

    Background/aims. Hepatocellular carcinoma is one of the most commonly diagnosed malignant tumors in the world, and it typically has a poor prognosis. Extensive studies have examined the effects of non steroidal anti-inflammatory drugs selective to COX-2 on the chemoprevention of various tumors. The objective of this study is to observe the effect of celecoxib on the development of liver tumors in rats. Material and methods. Hepatocellular carcinoma was induced in a group of 75 rats with the carcinogen diethylnitrosamine. The animals were divided into 5 groups. Three groups received various doses of celecoxib, one group received indomethacin, and a control group received no non-steroidal selective anti-inflammatory drugs. Results. The experimental model was considered to be successful because 78% of the rats in the control group developed liver tumors. The number of neoplastic lesions was similar among the celecoxib, indomethacin and control groups, although the nodule diameter of the lesions was smaller in the celecoxib group. Better results were observed in animals that received celecoxib at doses of 6 and 9 mg/kg/ day; 4 rats in these groups did not show any neoplastic histological lesions, and a greater proportion of the nodules in the other animals in these groups were benign than in the groups that did not use celecoxib. Conclusions. These results suggest that celecoxib may play a role in modifying the natural history of hepatocellular carcinoma development.

Liver transplantation
  • Impact of creatinine values on MELD scores in male and female candidates for liver transplantation Guilherme Mariante-Neto, Caroline P. Marroni, Alfeu de Medeiros Fleck Junior, Cláudio Augusto Marroni, Maria Lúcia Zanotelli, Guido Cantisani, Ajácio B. M. Brandão Page 434-439

    Introduction. A systematic bias against women, resulting from the use of creatinine as a measure of renal function, has been identified in Model for End-stage Liver Disease (MELD)-based liver allocation. Correction of this bias by calculation of female creatinine levels using the Modification of Diet in Renal Disease (MDRD) formula has been suggested. Material and methods. A cohort of 639 cirrhotic candidates for first-time liver transplantation was studied. Creatinine levels were corrected for gender using the MDRD formula. The accuracy of MELD, with or without creatinine correction, to predict 3- and 6-month mortality after inclusion in a transplant waiting list was estimated. Results. Women exhibited significantly lower creatinine levels, glomerular filtration rate, and MELD scores than men. After creatinine correction, female MELD scores had a mean increase of 1.1 points. Creatinine correction yielded an increase of 3 points in the MELD score in 15.2% of patients, 2 points in 22.4%, and 1 point in 17.6% of patients. The likelihood of death at 3 and 6 months after enrollment in the transplant waiting list was similar in males and females and the likelihood of receiving a transplant, as assessed by Kaplan-Meier survival curves, was also similar in males and females. Conclusion. The survival or the likelihood of receiving a transplant while on the waiting list were similar in men and women in both pre- and post-MELD eras and creatinine correction did not increase the accuracy of the MELD score in estimating 3- and 6-month mortality in female candidates for liver transplantation.

  • Impact of MELD score implementation on liver allocation: experience at a Brazilian center Adriana Gonçalves da Silva Machado, Alfeu de Medeiros Fleck Jr., Cláudio Marroni, Maria Lúcia Zanotelli, Guido Cantisani, Ajácio Bandeira de Mello Brandão Page 440-447

    Introduction. Model for end-stage liver disease (MELD) is an accurate predictor of mortality in patients with cirrhosis, and has been used on liver allocation in Brazil since 2006. However, its impact on organ allocation, waiting list and post-transplant mortality is still poorly characterized. This study aimed to assess the impact of implementation of the MELD system on liver allocation and mortality after liver transplantation (LT) in Southern Brazil. Material and methods. Adult patients with chronic liver disease on the waiting list for primary deceased-donor LT were divided into two cohorts (pre- and post-MELD implementation) according to the date of waiting list placement. Disease severity, as assessed by MELD score at placement, was similar in both cohorts. Patients were followed for at least 18 months to assess the outcomes of interest (death/LT). Results. Higher MELD scores correlated with waiting list mortality, which increased 20% with each additional point (HR 1.2; 95%CI 1.14-2.26; p < 0.001). Waiting list mortality was 30.9% before and 21.7% after MELD implementation (nonsignificant). Transplant rate increased after MELD implementation (52 vs. 40%, p = 0.002). After excluding patients with hepatocellular carcinoma, mean MELD scores at LT were significantly higher in the MELD era (p < 0.01). There was no significant correlation between MELD scores at LT and post-LT survival. During 18-month follow-up, post-LT mortality rate was 25.4% before and 20% after MELD implementation (nonsignificant). Conclusion. MELD implementation was associated with a reduction in waiting list mortality. Although sicker patients received LT in the MELD era, post-transplant survival was similar in both periods.

  • Serum natremia affects health-related quality of life in patients with liver cirrhosis: a prospective, single centre study Ewa Wunsch, Grzegorz Naprawa, Dorota Koziarska, Malgorzata Milkiewicz, Przemyslaw Nowacki, Piotr Milkiewicz Page 448-455

    Introduction. Hyponatremia is associated with high mortality and predicts hepatic encephalopathy but its effect on health-related quality of life remains to be established. Material and methods. In this study we prospectively analyzed the relationship between hyponatremia, clinical features and quality of life in a cohort of 116 patients with cirrhosis. Chronic Liver Disease Questionnaire and Medical Outcomes Study 36- Item Short Form Health Survey were performed to assess quality of life. Evaluation of hepatic encephalopathy included West-Haven criteria, Psychometric Hepatic Encephalopathy Score and Critical Flicker Frequency analysis. Severity of liver disease was assessed with Child–Pugh score and MELD. Univariate and multivariate analysis were implemented to evaluate the influence of analyzed factors on quality of life. Results. Multivariate analysis has identified serum natremia, Psychometric Hepatic Encephalopathy Score, Critical Flicker Frequency and severity of liver disease measured with MELD and Child-Pugh score as independent factors affecting quality of life in patients with cirrhosis. West Heaven criteria failed to show the relationship with quality of life in analyzed subjects. Serum kalemia showed correlation with neither quality of life, hepatic encephalopathy nor severity of the disease. Conclusion. In patients with cirrhosis serum natremia along with severity of liver disease and hepatic encephalopathy exerts a significant effect on patients’ quality of life.

  • IGF-I and IGFBP-3 serum levels in patients hospitalized for complications of liver cirrhosis Marcelo Fernando Ronsoni, César Lazzarotto, Leonardo Fayad, Mariana Costa Silva, Christiane Lourenço Nogueira, Maria Luiza Bazzo, Janaína Luz Narciso-Schiavon, Esther Buzaglo Dantas-Corrêa, Leonardo de Lucca Schiavon Page 456-463

    Background. IGF-I and IGFBP-3 are part of IGF system and, due to their predominantly hepatic synthesis, they seem to correlate with hepatic dysfunction intensity. Aims. To investigate the significance of IGF-I and IGFBP-3 in patients with decompensated liver disease. Material and methods. Cross-sectional study that included cirrhotic patients admitted to hospital due to complications of the disease, in whom IGF-I and IGFBP-3 serum levels were measured by chemiluminescence. Results. Seventy-four subjects with a mean age of 53.1 ± 11.6 years were included in the study, 73% were males. IGF-I levels were positively correlated with IGFBP-3 and albumin, and negatively correlated with Child-Pugh, MELD, creatinine, INR and aPTT ratio. IGFBP-3 levels were positively correlated with IGF-I and albumin, and negatively correlated with Child-Pugh, MELD, creatinine, INR, total bilirubin and aPTT ratio. Significantly lower scores of IGF-I and IGFBP-3 were observed in patients with higher MELD values and higher Child-Pugh classes (P < 0.05). Conclusions. In cirrhotic patients admitted to hospital due to complications of the disease, IGF-I and IGFBP-3 serum levels were associated with variables related to liver dysfunction and to more advanced liver disease. The levels of these markers seem to undergo little influence from other clinical and laboratory variables, therefore mainly reflecting hepatic functional status.

  • Transjugular intrahepatic portosystemic shunt is associated with significant changes in mitral inflow parameters Radek Pudil, Rudolf Praus, Petr Hulek, Vaclav Safka, Tomas Fejfar, Martina Vasatova, Vaclav Jirkovsky Page 464-470

    Introduction. Liver cirrhosis is associated with hyperdynamic circulation which can result in heart failure. Transjugular intrahepatic portosystemic shunt (TIPS) due to increase of cardiac output is a stressful stimulus for cardiovascular system. Therefore, new methods for early detection of heart failure are needed. Transmitral flow is a marker of diastolic dysfunction. Aim. To analyze short- and long-term effect of TIPS procedure on transmitral flow. Material and methods. 55 patients (38 men and 17 women, 55.6 ± 8.9 years) with liver cirrhosis treated with TIPS were enrolled in the study. Echocardiography was performed before, 24 h, 7, 30 and 180 days after the procedure. During 6 month follow up 22 patients died. Results. Left ventricle end-diastolic diameter was increasing during the follow-up [baseline: 47 (44.7-51.2) mm, day 7: 50 (46.5-51.3) mm, p < 0.05; day 30: 49.5 (46.7-55.2) mm, p < 0.01; 6 months: 52.5 (48.3-55.2) mm, p < 0.01)]. The peak early filling velocity (E) was significantly increasing [before: 75.5 (60.5-87.3) cm/s, 24 h: 88 (74.3 109.7), p < 0.01; day 7: 89 (81.5-105) p < 0.01; 1 month: 94 (82.7-108.5) p < 0.01; 6 month: 91 (80.1-120.2) p < 0.01]. Peak late atrial filling velocity (A) significantly increased within 24 h after the procedure: 85.1 (76.2-99.5) vs. 91.2 (81.5-104.5) cm/s, p < 0.05. The E/A ratio was increasing during the follow up (baseline: 0.88, 24 h after: 0.89, 1 week: 1.0, 30 days: 1.13, 6 month: 1.06 p < 0.01). Conclusion. Hemodynamic changes following TIPS procedure can be monitored using echocardiography. Transmitral flow analysis can serve as a useful tool for evaluating of diastolic function in these patients.

  • Association of amino acid imbalance with the severity of liver fibrosis and esophageal varices Hirayuki Enomoto, Yoshiyuki Sakai, Nobuhiro Aizawa, Yoshinori Iwata, Hironori Tanaka, Naoto Ikeda, Kunihiro Hasegawa, Kazunori Yoh, Tomoyuki Takashima, Kazunari Iwata, Masaki Saito, Hiroyasu Imanishi, Hiroko Iijima, Shuhei Nishiguchi Page 471-478

    Background. The relationships between the metabolic parameters and the endoscopic findings of esophageal varices have been poorly investigated. We investigated the association of the branched-chain amino acids to tyrosine ratio (BTR) with the severity of liver fibrosis and esophageal varices. Material and methods. We studied hepatitis C virus (HCV)-positive chronic liver disease patients who had undergone liver biopsy (n = 149). The relationship between the BTR values and the liver fibrotic stage was investigated. We also studied whether the BTR value was associated with the presence and bleeding risk of varices in patients with HCV-related compensated cirrhosis. Results. The mean values of the BTR decreased with the progression of the fibrosis (METAVIR score: F0-1: 6.40 ± 1.19; F2: 5.85 ± 1.33; F3: 5.24 ± 0.97, F4: 4.78 ± 1.14). In the 58 patients with HCV- related compensated cirrhosis, the mean values of the BTR decreased with the severity of varices (patients without varices: 5.01 ± 1.15, patients with a low-risk varices: 4.42 ± 1.06, patients with a high-risk varices: 3.86 ± 1.02). The BTR value was significantly lower in the patients with varices than in those without varices (4.17 ± 1.07 vs. 5.01 ± 1.15, P < 0.01). The BTR value was also significantly lower in the patients with a high risk of hemorrhage than in those with a low risk (3.86 ± 1.02 vs. 4.78 ± 1.14, P < 0.01). Furthermore, the BTR value was the most significantly different parameter, with the smallest P-value among all the factors examined, including the platelet count and albumin level. Conclusion. A decreased BTR value was found to be associated with the progression of liver fibrosis and severity of varices.

Basic studies

  • PGE2 induces MUC2 and MUC5AC expression in human intrahepatic biliary epithelial cells via EP4/p38MAPK activation Yang Li, Junmin Song, Hong Yu, Shuodong Wu Page 479-486

    Background. MUC2 and MUC5AC overproduction is considered to be associated with hepatolithiasis and related to inflammation. However, mechanisms underlying MUC upregulation under inflammatory stimulation in human intrahepatic biliary epithelial cells (HIBECs) are not completely understood. Material and Methods. Expression of MUC2 and MUC5AC mRNA in HIBECs was detected by real-time PCR. Expression of COX-2, EP4, and phosphorylated ERK, JNK and p38MAPK protein was detected by Western blot. Concentrations of PGE2, IL-1â and TNF-á in cell culture supernatants were measured using the Quantikine Elisa kit. Results. COX-2 expression as well as PGE2 production in HIBECs was upregulated significantly by LPS, which was completely blocked by either TLR4 antagonist or NFêB inhibitor. Selective COX-2 inhibitor suppressed LPS-induced MUC2 and MUC5AC mRNA expression remarkably. Exogenous PGE2 increased MUC2 and MUC5AC mRNA expression in a dosage-dependent manner independent of IL-1â and TNF-á. PGE2 receptor EP4 agonist elevated MUC2 and MUC5AC expression, whereas EP4 antagonist had the opposite effect. Expression of phosphorylated p38MAPK was upregulated by exogenous PGE2, and p38MAPK inhibitor reduced MUC2 and MUC5AC expression in HIBECs. In addition, it was found that levels of PGE2, MUC2 and MUC5AC in bile samples from the hepatic ducts affected by intrahepatic stones were significantly higher than those from the unaffected hepatic ducts of patients with hepatolithiasis. Conclusions. Our findings indicate that PGE2 induces MUC2 and MUC5AC expression in HIBECs via EP4-p38MAPK signaling.



  • Heap of stones: An unusual cause for biliary colic and elevated liver function tests Henning Wittenburg, Volker Keim, Albrecht Hoffmeister Page 493-494

    A 40-year old woman presented with symptomatic intrahepatic gallstones in one liver segment only four years after cholecystectomy for cholelithiasis. Multiple small, yellow and round calculi were completely removed from the intrahepatic bile ducts via ERCP. The young age of the patient, recurrence of gallstones after cholecystectomy and intrahepatic gallstones suggested a subtype of the low-phospholipid associated cholelithiasis syndrome, a monogenic form of cholesterol cholelithiasis due to variations of the ABCB4 gene that encodes the canalicular phospholipid transporter MDR3.


  • Hepatic carcinosarcoma: clinicopathologic features and a review of the literature Yang-Sheng Lin, Tao-Yeuan Wang, Jiunn-Chang Lin, Horng -Yuan Wang, Kuei-Fang Chou, Shou-Chuan Shih, Ming-Jen Chen Page 495-500

    Hepatic carcinosarcoma (HCS) is defined as a malignant tumor containing an intimate mixture of carcinomatous and sarcomatous elements. Here, we report the case of a 72-year-old man who developed HCS froman otherwise normal liver. The patient had no history of alcohol abuse or hepatitis B or C infection. An enhanced abdominal CT scan revealed a 9-cm heterogeneous tumor, with enhancement during the arterial phase and delayed wash-out in the latter phases. Also, a marked elevation in alpha-fetoprotein level (15,164 ng/mL; normal range, < 10 ng/mL) was noted. He underwent resection of liver segments V and VI under a pre-operative diagnosis of atypical hepatocellular carcinoma (HCC). The diagnosis of HCS was made based on thorough pathologic examination with a panel of immunohistochemical staining. Following surgery, the patient made an uneventful recovery, and at present, 16 months post-surgery, he remains well with no evidence of tumor recurrence. In conclusion, pre-operative diagnosis of HCS is difficult and radical resection in the early stage is encouraged to improve the prognosis of these patients.

  • Liver failure unmasks celiac disease in a child Abdulrahman Al-Hussaini, Amna Basheer, Albert J. Czaja Page 501-505

    Background. Liver involvement in celiac disease (CD) varies from asymptomatic mild non-specific hepatitis to liver failure. Here we report the first child with liver failure due to a sclerosing cholangitis associated with CD. Case report. An 11 year old girl presented with fatigability for 1 year and jaundice and abdominal distension for 3 weeks. On examination, the growth parameters were below 3rd percentile; she had splenomegaly and severe ascites. Liver function tests revealed elevated liver enzymes (ALT 84 U/L, total bilirubin 98.7 μmol/L, and direct 58.3 μmol/L, gamma-glutamyltransferase 111 U/L, INR 2.7, and albumin 16 g/L). Extensive investigations excluded infectious, metabolic, structural, and endocrine causes of chronic liver disease. Because of the short stature and anemia, CD was suspected, and serological evaluation revealed increased IgA antibodies to tissue transglutaminase (385 units; normal, 0-20 units). Histopathological examination of small intestinal biopsies showed total villous atrophy consistent with celiac disease. Liver biopsy showed bridging fibrosis, portal tract expansion by lymphocytes, plasma cells, and neutrophils, bile ductular proliferation, and periductular fibrosis. Magnetic resonance cholangiography revealed beading and narrowing appearance of intra- and extrahepatic bile ducts. The histopathological and imaging findings are diagnostic of sclerosing cholangitis. The child was initiated on ursodeoxycholic acid, gluten free diet for life, and steroid that was tapered over 3 months. At 3 month follow up, liver function tests completely normalized. Conclusion. CD is a potentially treatable cause of liver failure. All patients with severe unexplained liver disease should undergo serological screening for CD.



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