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Current Issue

January - February, 2013

Vol. 12 Issue 1

On the cover: This figure showns a liver histology of a patient with massive hepatocellular necroses due to Halothane hepatitis.

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Use of acetylcysteine for non-acetaminophen-induced acute liver failure Ibrahim Sales, Amy L. Dzierba, Pamela L. Smithburger, Deanna Rowe, Sandra L. Kane-Gill Page 6-10

    The purpose of this review was to evaluate the effectiveness of acetylcysteine in the treatment of acute liver failure not related to acetaminophen. A search of MEDLINE April 2003 through May 2012 using the Pub- Med database was conducted using the keywords acetylcysteine and non-acetaminophen-induced acute liver failure or acetylcysteine and liver failure. All human case reports, case series, and research articles that discussed the use of acetylcysteine for non-acetaminophen induced liver failure were evaluated. A total of 263 articles were identified during this broad search with 11 articles included for review in this article; eight case reports, two retrospective trials, and one prospective, randomized, double-blind multicenter study. In conclusion, the data suggest marginal benefit of IV acetylcysteine in NAI-ALF with coma grades I-II; however, the routine use of acetylcysteine cannot be recommended. It may be considered in non-transplant centers while awaiting referral or when transplantation is not an option. Further studies are necessary to determine optimal dosing, duration, and criteria for patient selection.

  • Herbal hepatotoxicity and WHO global introspection method Rolf Teschke, Axel Eickhoff, Albrecht Wolff, Christian Frenzel, Johannes Schulze Page 11-21

    Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.

  • Hepatic venous pressure gradient measurement in pre-primary and primary prophylaxis of variceal hemorrhage Julio D. Vorobioff, Roberto J. Groszmann Page 22-29

    Pharmacological therapy of portal hypertensión can be accomplished according to different objectives. Among them, pre-primary prophylaxis aims to avoid / delay esophageal varices development while the target of primary prophylaxis is protection against first variceal bleeding. Hepatic venous pressure gradient (HVPG) measurement closely reflects portal pressure in most liver diseases whith predominant sinusoidal network involvement. Clinical-hemodynamic correlations have been demonstrated in both pre-primary and primary prophylatic therapy, allowing to establish HVPG measurement as a predictive parameter, not only regarding variceal growth and bled but also of liver disease evolution and other portal hypertensive related complications.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Safety and efficacy of treatment with pegylated interferon alpha-2a with ribavirin in chronic hepatitis C genotype 4 Juan José Urquijo, Moisés Diago, Jaume Boadas, Ramón Planas, Ricard Solá, Juan Angel del Olmo, Javier Crespo, José Carlos Erdozaín, María Dolores Antón, Carlos Arocena, Dolores Suarez, Josep Giné, Josep M. Barrera, Javier Gracia-Samaniego Page 30-35

    The hepatitis C virus (HCV) genotype is an important predictive outcome parameter for pegylated interferon plus ribavirin therapy. Most published therapeutic trials to date have enrolled mainly patients with HCV genotypes 1, 2 and 3. Limited studies have focused on genotype 4 patients, who have had a poor representation in pivotal trials. Our aim was to evaluate the efficacy and safety of treatment with standard dose pegylated interferon alfa-2a in combination with weight-based ribavirin in patients with chronic hepatitis C genotype 4. In this prospective observational study, 198 patients with HCV-4 were included in this study from February 2004 to August 2005,188 patients who received at least 1 dose of drugs were included in the ITT analysis and they were treated with pegylated interferon alfa-2a and ribavirin for 48 weeks. Baseline and demographic characteristics, response to treatment at weeks 12, 48 and 72, and the nature and frequency of adverse effects were analyzed. Virological response at week 12 was achieved in 144 patients (76.6%). Virological response at the end of treatment was present in 110 patients (58.5%). At week 72, 99 patients presented SVR (52.7%). The reported adverse events were similar to those found in the literature for treatments of similar dose and duration. In conclusion, combined treatment with pegylated interferon alfa-2a and ribavirin was well tolerated and effective in chronic hepatitis C genotype 4, yielding response rates between those reported for genotype 1 and those of genotypes 2-3.

  • Long-term follow-up of hepatitis C virus-positive patients with persistently normal serum transaminases Emanuele La Spada, Maurizio Soresi, Lydia Giannitrapani, Monica La Spada, Elisa Campagna, Antonino Terranova, Fabio Cartabellotta, Giuseppe Montalto Page 36-43

    Material and methods. This study prospectively evaluated the progression of liver disease in a group of anti-HCV-positive patients with persistently normal ALT levels (PNALT) who were HCV-RNA positive. Patients selected for this study were those who presented with PNALT according to the Italian Association for the Study of the Liver (AISF) criteria in the year 1995/96 and underwent liver biopsy. They were divided into two groups according to their ALT evolution. Forty-five patients were included in this study. Results. After a median follow-up time of 180 months twenty-five of them maintained PNALT, but two of these developed liver cirrhosis (LC) in a mean time of 174 and 202 months, respectively. Twenty patients had flares of ALT and three of them developed LC in a mean time of 162-178 months. Twelve of these patients underwent current antiviral treatment; six patients were SVR. At baseline, the 5 patients who progressed to LC had age and BMI significantly higher than patients without LC (P < 0.005 and P < 0.01, respectively). Grading (P < 0.006) and staging (P < 0.003) were also more severe at histology, while serum HDL-C levels were statistically lower (P < 0.002). Comparing patients with flares of transaminases with and without LC, we found a significant difference at baseline for age, BMI, HDL-C, grading and staging (P < 0.05; P < 0.01 and P < 0.003, respectively). Conclusion. In HCV-RNA positive patients associated with PNALT the grade of disease activity increased over the years in only half of patients and a higher degree of liver fibrosis at baseline was the major relevant factor for progression.

  • Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients Abdelfattah M. Attallah, Sanaa O. Abdallah, Ahmed A. Attallah, Mohamed M. Omran, Khaled Farid, Wesam A. Nasif, Gamal E. Shiha, Abdel-Aziz F. Abdel-Aziz, Nancy Rasafy, Yehia M. Shaker Page 44-53

    Background. Several noninvasive predictive models were developed to substitute liver biopsy for fibrosis assessment. Aim. To evaluate the diagnostic value of fibronectin which reflect extracellular matrix metabolism and standard liver functions tests which reflect alterations in hepatic functions. Material and methods. Chronic hepatitis C (CHC) patients (n = 145) were evaluated using ROC curves and stepwise multivariate discriminant analysis (MDA) and was validated in 180 additional patients. Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, albumin, complete blood count were estimated. Fibronectin concentration was determined using monoclonal antibody and ELISA. Results. A novel index named fibronectin discriminant score (FDS) based on fibronectin, APRI and albumin was developed. FDS produced areas under ROC curves (AUC) of 0.91 for significant fibrosis and 0.81 for advanced fibrosis. The FDS correctly classified 79% of the significant liver fibrosis patients (F2-F4) with 87% sensitivity and 75% specificity. The relative risk [odds ratio (OR)] of having significant liver fibrosis using the cut-off values determined by ROC curve analyses were 6.1 for fibronectin, 4.9 for APRI, and 4.2 for albumin. FDS predicted liver fibrosis with an OR of 16.8 for significant fibrosis and 8.6 for advanced fibrosis. The FDS had similar AUC and OR in the validation group to the estimation group without statistically significant difference. Conclusion. FDS predicted liver fibrosis with high degree of accuracy, potentially decreasing the number of liver biopsy required.

  • Liver fibrosis in young Egyptian beta-thalassemia major patients: relation to hepatitis C virus and compliance with chelation Mohsen S. Elalfy, Gamal Esmat, Randa M. Matter, Hesham E. Abdel-Aziz, Walid A. Massoud Page 54-61

    Background. The main causes of liver fibrosis in transfusion-dependent thalassemia major are hepatitis C virus (HCV) infection and hepatic iron overload. The study aimed to assess liver fibrosis in Egyptian adolescents and young adult poly-transfused beta thalassemia patients infected with HCV using liver FibroScan in relation to iron overload and Liver iron concentration (LIC). Material and methods. Fifty-one regularly transfused beta thalassemia patients above 12 years old were subjected to measurement of serum alanine transaminase (ALT), serum ferritin (SF), HCV (antibody and RNA), LIC assessed by hepatic R2* and transient elastography (TE) (FibroScan). FibroTest and liver biopsy were done to 25 patients. Results. Eighty two% of studied thalassemia patients were HCV antibody positive; 21(49%) of them were viremic (HCV RNA positive); median LIC was 12 mg/gm dry weight. There were strong positive correlation between the degree of liver stiffness and Ishak fibrosis score assessed in liver biopsy specimens (P = 0.002) and between FibroScan and FibroTest results (P < 0.001). Patients with HCV viremia showed significantly higher ALT, γ-glutamyl transpeptidase (GGT), SF, LIC and increased liver stiffness compared to patients with no viremia (P = 0.0001, 0.001, 0.012, 0.006 and 0.001) respectively. Liver cirrhosis (TE values > 12.5kPa) was encountered in 23.5% and variable degrees of liver fibrosis (TE values > 6-12.5 kPa) in 35% of studied thalassemic patients. Conclusion. Young beta thalassemia patients with active hepatitis C infection may have hepatic cirrhosis or fibrosis at young age when accompanied with hepatic siderosis. Non invasive Liver FibroScan and Fibro- Test were reliable methods to assess liver fibrosis in young thalassemic-patients.

  • Patients younger than forty years old with hepatitis C virus genotype-1 chronic infection had treatment responses similar to genotype-2 infection and not related to interleukin-28B polymorphism Chun-Yen Lin, I-Shyan Sheen, Wen-Juei Jeng, Chang-Wen Huang, Chien-Hao Huang, Ji-Yih Chen Page 62-69

    Background and rationale. Age is one of the predictors for sustained virological response (SVR) when treating chronic hepatitis C (CHC) patients with pegylated-interferon/ribavirin (PegIFN/RBV). However, the treatment responses of the young patients had not been analyzed before. Therefore, we conducted this study to investigate the treatment responses of CHC patients younger than 40 years old (y/o). Material and methods. We retrospectively analyzed our prospective cohort of genotype 1 (GT1)- and genotype 2 (GT2)-CHC patients who received 24-week PegIFN/RBV treatment. We divided these patients into two groups according to their age younger or older than 40 y/o. Clinical parameters including viral responses and single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) had been analyzed. Results. In GT1- CHC patients, the rapid, complete early viral response rates and the SVR rate were significantly higher in patients younger than 40 y/o. In GT-1 CHC patients younger than 40 y/o, the SVR rate was similar to the GT2-CHC patients, either with high or low baseline viral load. As for the SVR predictors, in CHC patients younger than 40 y/o, only BMI but not the genotype of HCV, not baseline viral load, and not IL28B SNP was the predictor. Conclusions. GT1-CHC patients younger than 40 y/o had SVR rate similar to GT2-CHC patients. The IL28B polymorphism had no impact on the SVR rate in these young GT1-CHC patients.

Non alcoholic fatty liver disease (NAFLD)
  • Utility of noninvasive methods for the characterization of nonalcoholic liver steatosis in the family practice. The “VARES” Italian multicenter study Ignazio Grattagliano, Enzo Ubaldi, Luigi Napoli, Carlo Fedele Marulli, Cristina Nebiacolombo, Carmelo Cottone, Piero Portincasa Page 70-77

    The diagnostic utilities of ultrasonography (US), fatty liver index (FLI) and an algorithm of nine serum markers (Fibromax) were evaluated in family practice to noninvasively characterize patients with nonalcoholic fatty liver disease (NAFLD). A multicenter study was conducted by enrolling 259 consecutively observed patients (age 51 ± 10 years) with clinical and ultrasonographic features of NAFLD . Patients had mild (16.2%), moderate (69.9%), or severe (13.9%) liver steatosis and 60.2% had hypertransaminasemia. The percent of patients with overweight, obesity, diabetes, hypertension, and dyslipidemia were 42.7%, 46.5% (4.2% severe obesity), 24.7%, 40.9%, and 56.4% , respectively. Lean patients (10.8%) had normal transaminases in two/ thirds of the cases. A multivariate logistic regression (including age > 50 yrs, BMI > 30 kg/m2, HOMA > 3, and hypertransaminasemia) identified 12.3% of patients at risk for steatohepatitis. With a sensitivity of 50% and specificity of 94.7%, Fibromax identified 34 patients (13.1%) with likely advanced fibrosis and found that over 28% of patients with moderate (ultrasonographic) steatosis were likely to be carrying severe steatosis. Steatotest score was significantly associated with BMI, waist circumference, ALT, triglycerides, and FLI. Fibrotest correlated only with ALT. FLI identified 73.4% of patients as likely to be carrying a fatty liver. In conclusion, NAFLD should be systematically searched and characterized in all patients with metabolic disturbances and cardiovascular risk. Asymptomatic subjects at risk also should be screened for NAFLD. Fibromax is a promising noninvasive diagnostic tool in family medicine for identifying patients at risk for NAFLD who require targeted follow-up.

Miscellaneous
  • Hepatitis C virus infection in patients with primary biliary cirrhosis Hsuan-Wei Chen, Hsin-Hung Huang, Ching-Huang Lai, Wei-En Chang, Yu-Lueng Shih, Wei-Kuo Chang, Tsai-Yuan Hsieh, Heng-Cheng Chu Page 78-84

    Background and aim. The aim of this study is to evaluate the role of hepatitis C virus (HCV) infection in patients with primary biliary cirrhosis (PBC). Material and methods. On the basis of a retrospective review of medical records, all patients consecutively diagnosed with PBC or HCV infection between 1999 and 2011 and who had a regular follow-up of at least 3 years were included in the study. Clinical characteristics, especially the severity of cirrhosis, were analyzed in PBC patients with HCV infection (PBC-HCV), PBC patients without HCV infection (PBC-only), and patients with only HCV infection (HCV-only). Results. A total of 76 patients with PBC, including 9 patients with HCV infection, were analyzed. Of the PBC-HCV patients, 7 (7/9, 77.8%) were women with a mean age of 55.11 ± 14.29 years. Age- and sex-matched PBC-only patients (n = 36) and HCV-only patients (n = 36) were used as control groups. In comparison to the PBC-only controls, PBC-HCV patients had a greater severity of cirrhosis based on Child-Pugh (p = 0.019) and Model for End-Stage Liver Disease (MELD) (p = 0.01) scores. However, no significant difference in the severity of cirrhosis was found between the PBC-HCV and HCV-only control patients (p = 0.94 in Child-Pugh scores; p = 0.64 in MELD scores). Conclusions. In PBC patients with concomitant HCV infection, aggressive management may be warranted in view of the associated more severe liver cirrhosis.

  • Impact of the severity of end-stage liver disease in cardiac structure and function Odilson Marcos Silvestre, Fernando Bacal, Danusa de Souza Ramos, Jose L. Andrade, Meive Furtado, Vincenzo Pugliese, Elisangela Belleti, Wellington Andraus, Flair José Carrilho, Luiz Augusto Carneiro D’Albuquerque, Alberto Queiroz Farias Page 85-91

    Background. The impact of end-stage liver disease (ESLD) in cardiac remodeling of patients with cirrhosis is unknown. Our aim was to correlate the severity of ESLD with morphologic and functional heart changes. Material and methods. 184 patients underwent a protocol providing data on the severity of ESLD and undergoing echocardiography to assess the diameters of the left atrium and right ventricle; the systolic and diastolic diameters of the left ventricle, interventricular septum, and posterior wall of the left ventricle; systolic pulmonary artery pressure; ejection fraction; and diastolic function. Severity of ESLD was assessed by the Model for End-Stage Liver Disease (MELD) score. Results. Left-atrial diameter (r = 0.323; IC 95% 0.190-0.455; p < 0.001), left-ventricular diastolic diameter (r = 0.177; IC 95% 0.033-0.320; p = 0.01) and systolic pulmonary artery pressure (r = 0.185; IC 95% 0.036-0.335; p = 0.02) significantly correlated with MELD score. Patients with MELD ≥ 16 had significantly higher left-atrial diameter and systolic pulmonary artery pressure, compared with patients with MELD scores < 16 points. Conclusions. Changes in cardiac structure and function correlate with the severity of ESLD.

  • High age and low sodium urine concentration are associated with poor survival in patients with hepatorenal syndrome Matthias Hinz, Alexander Wree, Christoph Jochum, Lars P. Bechmann, Fuat Saner, Alexander L. Gerbes, Guido Gerken, Ali Canbay Page 92-99

    Background. Combination therapy with terlipressin and albumin substitution is considered a widely accepted treatment regimen for patients with hepatorenal syndrome (HRS). However, only half of the patients respond to treatment and to date albumin substitution and terlipressin therapy are among the most expensive medical treatments available for patients with liver diseases. Thus, we aimed to identify clinical and etiological parameters to predict treatment response and overall mortality in patients with HRS. Material and methods. We retrospectively evaluated 21 patients, 13 male/8 female, aged 43-72 years with HRS. Four patients were transplanted after following combination treatment. Terlipressin was administered by continuous intravenous perfusion (2-6 mg/d) and albumin drips (50 mg) were given daily. Treatment response was defined by a decrease in serum creatinine level to ≤ 1.5 mg/dL or by a ≥ 50% reduction of the baseline concentration. Results. 57% of the patients responded to treatment, which was associated with improved survival at day 60, compared to non-responders. However, the overall mortality was not different between the two groups. Median age of 63 years was a significant negative predictor for therapy response. High baseline urinary sodium levels were of prognostic value for survival. The Model of End stage Liver Disease score (MELD score) did not correlate with therapy response. Conclusion. In conclusion high age is a predictor of non-response. Low urinary sodium before treatment is associated with poor survival. Terlipressin and albumin co-treatment is associated with increased two-months survival rate. This seemingly moderate extension in survival rate can, however, be decisive for obtaining liver transplantation.

  • Feasibility and reliability of the FibroScan S2 (pediatric) probe compared with the M probe for liver stiffness measurement in small adults with chronic liver disease Faruq Pradhan, Farah Ladak, Jenna Tracey, Pam Crotty, Robert P Myers Page 100-107

    Background. The success of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is influenced by anthropometric factors. In smaller adults, the M probe may fail due to narrow intercostal spaces and rib interference. We aimed to compare LSM using the FibroScan S2 (pediatric) probe with the M probe in small adults with chronic liver disease. Material and methods. In this prospective study, 41 liver disease patients and 18 controls with a thoracic perimeter ≤ 75 cm underwent LSM using the FibroScan M and S2 probes. TE failure was defined as no valid LSMs and unreliable examinations as < 10 valid LSMs, an interquartile range (IQR)/LSM > 30%, or success rate < 60%. Results. TE failure was not observed and reliability did not differ between the M and S2 probes (86% vs. 95%; P = 0.20). Liver stiffness measured using the M and S2 probes was highly correlated (ρ = 0.81; P < 0.0005) and median liver stiffness did not differ between probes (4.5 vs. 4.4 kPa; P = 0.10). However, in participants with a skin-capsular distance ≥ 15 mm, median liver stiffness was higher using the S2 probe (5.5 vs. 4.9 kPa; P = 0.008). When compared with validated liver stiffness cut-offs, the S2 probe would have overestimated the stage of fibrosis compared with the M probe in 10% of patients. Conclusions. The FibroScan S2 probe does not improve the feasibility of LSM in adults of smaller stature and may overestimate liver stiffness compared with the M probe. The FibroScan M probe should remain the preferred tool for LSM in small adults with chronic liver disease.

  • How to diagnose hepatic encephalopathy in the emergency department Felix Gundling, Edin Zelihic, Holger Seidl, Bernhard Haller, Andreas Umgelter, Wolfgang Schepp, Christoph Dodt Page 108-114

    Introduction. Blood ammonia-measurements are often performed in the emergency departments to diagnose or rule out hepatic encephalopathy (HE). However, the utility and correct interpretation of ammonia levels is a matter of discussion. At this end the present prospective study evaluated whether blood ammonia levels coincide with HE which was also established by the West Haven criteria and the critical flicker frequency, respectively. Material and methods. In 59 patients with known cirrhosis ammonia-levels were determined and patient were additionally categorized by the West-Haven criteria and were also evaluated psychophysiologically using the critical flicker frequency, CFF for the presence of HE. Results. When false positive and false negative results were collapsed the determination of blood ammonia levels alone resulted in 40.7% in a misdiagnoses of HE compared to the West-Haven criteria (24/59 when using West-Haven criteria, 95% confidence interval [CI], 28.1% to 54.3%) and 49.2% when compared with the results of the CFF (29/59, when using CFF, 95% CI, 35.9% to 62.5%). Discussion. Ammonia blood levels do not reliably detect HE and the determination of blood ammonia can not be regarded a useful screening test for HE. Its use as sole indicator for a HE in the Emergency Department may frequently result in frequent misinterpretations.

Basic studies

  • Therapeutic effects of granulocyte-colony stimulating factor on non-alcoholic hepatic steatosis in the rat Yi-Sun Song, Cheng-Hu Fang, Byung-Im So, Jun-Young Park, Dae Won Jun, Kyung-Soo Kim Page 115-122

    Background and rationale. Non-alcoholic hepatic steatosis refers to the accumulation of triglycerides in the liver in the absence of alcohol consumption. Granulocyte colony-stimulating factor (G-CSF) has been reported to be an effective treatment for a variety of liver diseases. We examined the possible therapeutic effects of G-CSF on non-alcoholic hepatic steatosis in rats. Material and methods. Thirty-week-old Otsuka Long Evans Tokushima Fatty (OLETF) rats received water containing 30% sucrose for 8 weeks to promote the development of non-alcoholic hepatic steatosis. After development of the model, the rats were injected with G-CSF (100 μg/kg/day) or saline for 5 days. Four weeks after this treatment, serum levels of glucose, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and free fatty acids (FFA) were measured. Histology was examined by hematoxylin and eosin (H-E) and periodic acid Schiff (PAS) staining, and levels of expression of hepatic lipogenic enzymes were determined by RT-PCR. Results. The G-CSF-treated rats displayed significantly fewer lipid droplets than the saline-treated rats (P < 0.01), and their levels of sterol regulatory element-binding protein (SREBP)-1c, fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) mRNAs were also lower (P < 0.01), as were their liver weight and serum levels of TG and FFA (P < 0.05). Conclusion. Our results indicate that G-CSF ameliorated non-alcoholic hepatic steatosis in the OLETF rat, and this therapeutic effect involved a reduction of SREBP-1c expression. Therefore, G-CSF deserves further study as a potential treatment for non-alcoholic hepatic steatosis.

  • Spondias pinnata stem bark extract lessens iron overloaded liver toxicity due to hemosiderosis in Swiss albino mice Bibhabasu Hazra, Rhitajit Sarkar, Nripendranath Mandal Page 123-129

    The present study was designed to evaluate the ameliorating effect of 70% methanol extract of Spondias pinnata (SPME) on iron overload induced liver injury. Iron overload was induced by intraperitoneal administration of iron-dextran into mice and resulting liver damage was manifested by significant rise in serum enzyme markers (ALT, AST, ALP and bilirubin) and reduction in liver antioxidants (SOD, CAT, GST and GSH). Hepatic iron, serum ferritin, lipid peroxidation, protein carbonyl and hydroxyproline contents were measured in response to the oral administration of SPME of different doses (50, 100 and 200 mg/kg body weight). In order to determine the efficiency as iron chelating drug, the release of iron from ferritin by SPME was further studied. Enhanced levels of antioxidant enzymes were detected in SPME treated mice. SPME produced a dose dependent inhibition of lipid peroxidation, protein oxidation, liver fibrosis; and levels of serum enzyme markers and ferritin were also reduced dose dependently. The liver iron content was also found to be less in SPME treated group compared to control group. The reductive release of ferritin iron was augmented significantly after dose dependent addition of SPME. The ameliorating effect of SPME on damaged liver was furthermore supported by the histopathological studies that showed improved histological appearances. In conclusion, the present results demonstrate the hepatoprotective efficiency of SPME in iron intoxicated mice, and hence possibly useful as iron chelating drug for iron overload diseases.

  • Evidence that estrogen receptors play a limited role in mediating enhanced recovery of bile flow in female rats in the acute phase of liver ischemia reperfusion injury Heleen A.H. de Vries, Fraukje A.M. Ponds, Vincent B. Nieuwenhuijs, Arthur Morphett, Robert T.A. Padbury, Greg J. Barritt Page 130-137

    Introduction. Female patients exhibit better survival and less hepatic damage from ischemia reperfusion (IR) injury following surgery. However, the effects of sex and estrogens on liver function in the acute phase of IR are not well understood. Objective. The aim was to investigate this question. Material and methods. A rat model of segmental hepatic ischemia was employed. Rats were pre-treated with the estrogen receptor antagonist ICI182,780 and/or the estrogen receptor agonist 17β-estradiol. Bile flow, blood concentrations of bilirubin and liver enzymes were measured, and liver histology was assessed. Results. Bile flow recovery immediately after the initiation of reperfusion was faster in females than in males. ICI182,780 reduced the rate of bile flow recovery in females but this reduction was not reversed by co-administration of 17 β-estradiol. In males, 17 β-estradiol alone did not enhance bile flow recovery. The changes in bile flow recovery observed under a given condition were correlated with small changes in blood liver enzymes and liver histology. Conclusions. Sex has a significant influence on the early recovery of liver function in the acute phase of IR injury. However, in female rats estrogen receptors play only a limited role in mediating enhanced recovery of liver function.

IMAGES IN HEPATOLOGY

  • Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin Nancy Aguilar-Olivos, María del Carmen Manzano-Robleda, Ylse Gutiérrez-Grobe, Fredy Chablé-Montero, Jorge Albores-Saavedra, Eric López-Méndez Page 138-141

    The differential diagnosis of fever of unknown origin (FUO) includes infectious, neoplastic, rheumaticinflammatory and miscellaneous diseases. We report the case of a 35-year-old man with FUO caused by Q fever. A liver biopsy showed the characteristic fibrin-ring lipogranulomas compatible with Q fever. The serologic tests confirmed the diagnosis of acute infection by Coxiella burnetii. The therapeutic response was excellent. In conclusion, we described a patient with acute Q fever and granulomatous hepatitis.

CASE REPORTS

  • Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: a closer look at the role of siderosis Joseph E. Maakaron, Maria Domenica Cappellini, Giovanna Graziadei, Jad Bou Ayache, Ali T. Taher Page 142-146

    Patients with thalassemia are often exposed to several risk factors for developing hepatocellular carcinoma (HCC) due to their repeated transfusions. However, even transfusion-independent patients with thalassemia intermedia (TI) can develop HCC, which is mainly attributed to a state of iron overload. We report here two cases and review the literature for the association between TI and HCC. Along with our cases, a total of 36 cases of HCC in thalassemic patients were reported in the literature. Of these, 22 (61%) were TI patients with 6 (27%) of them being hepatitis B and C negative. There was no consistency in their characteristics; therefore, we recommended screening thresholds for HCC in TI patients based on their total liver iron concentration (LIC).

  • Autoimmune hepatitis type-2 and Epstein-Barr virus infection in a toddler: art of facts or an artifact? Aglaia Zellos, Vana Spoulou, Eleftheria Roma-Giannikou, Ourania Karentzou, George N. Dalekos, Maria Theodoridou Page 147-151

    Epstein-Barr virus (EBV) can cause frequently asymptomatic (or anicteric) and self-limited hepatitis, while occasionally may result in considerable cholestatic hepatitis. Herein, we describe the case of a previously healthy toddler (26 month old girl) with prolonged cholestasis, elevated serum transaminases, EBV serology compatible with recent EBV infection and positive anti liver kidney microsomal antibody type 1 which is characteristic of new-onset autoimmune hepatitis type 2. Liver biopsy was also typical of autoimmune hepatitis as attested by the presence of portal inflammation with predominant T-lymphocytes and plasma cells and interface hepatitis. Persistent EBV-related hepatitis was excluded by the absence of viral inclusions and steatosis on liver specimens and negative liver EBV-PCR. In conclusion, our case strongly suggests that in children with prolonged cholestatic hepatitis, positive EBV serology cannot exclude the presence of other causes of liver disease. In this context, autoimmune hepatitis should be considered as an alternate diagnosis, particularly when there is specific liver-related autoantibody detection. In such conditions, liver biopsy seems mandatory in an attempt to achieve a correct and timely diagnosis of a potentially catastrophic disease as autoimmune hepatitis. Although some cases of autoimmune hepatitis type 1 following EBV infection have been reported in adults, to the best of our knowledge, the present case of autoimmune hepatitis type 2 after EBV infection represents the first case in children ever reported in the English literature.

  • Severe hepatitis induced by cyproterone acetate: role of corticosteroids. A case report Ludovico Abenavoli, Natasa Milic, Michel Beaugrand Page 152-155

    Cyproterone acetate (CPA) is an oral anti-androgen commonly used to treat advanced prostate cancer. A variety of hepatotoxic reactions has been reported with CPA. Here we describe a case of a male patient who developed severe drug-induced hepatotoxicity during the treatment with CPA. The case, presenting sub-acute hepatitis, was characterized by a rapid evolution of cirrhosis and a protracted activity during the period of a few months despite the treatment withdrawal and an apparent benefits of corticosteroids, suggesting their indication in life threatening cases.

  • First successful treatment of post-liver transplant hepatitis C fibrosing cholestatic hepatitis with boceprevir, peginterferon and ribavirin in a pre-transplant null responder Nawal Al Nahdi, Jo-Ann Ford, Erica D. Greanya, Jo-Ann Harrigan, Irene Tse, Urs P. Steinbrecher, Siegfried R. Erb, Eric M. Yoshida Page 156-160

    Fibrosing cholestatic hepatitis (FCH) is a less common but well-recognized severe complication of recurrent hepatitis C virus (HCV) infection post-liver transplant. This condition is fatal without successful treatment and to date; post-transplant antiviral interferon-based antiviral therapy has been associated with guarded success. The new era of protease inhibitors in the treatment of chronic HCV infection may alter the dismal outcome of this condition. To date, however, the experience with protease inhibitors in this condition is unreported. We report a post-liver transplant recipient with HCV associated FCH treated successfully with boceprevir, peginteferon and ribavirin for severe FCH. The patient was young woman who was a null responder pre-transplant to peginterferon and ribavirin. The peak serum bilirubin 391 μmol/L normalized to 15 μmol/L by week 8 of therapy. The pre-treatment HCV viral load of > 78 million IU/mL, decreased to 78 IU/mL at week 8 of therapy and was undetectable by week 12 and at the end of 48 week of treatment. 12 weeks post treatment, the HCV viral load remains undetectable. Significant anemia and neutropenia were encountered. Tacrolimus dosage titrated to trough levels, required marked reduction to 0.5 mg three times weekly. Despite the suboptimal peginterferon and ribavirin dosing, limited by adverse effects, full boceprevir dosing was maintained, with resolution of liver dysfunction. Boceprevir was obtained on compassionate grounds from the manufacturer before its licensure in Canada and this was the first use of boceprevir in the world for post-transplant FCH.

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