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Current Issue

May - June, 2015

Vol. 14 Issue 3

On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Diagnosis of liver nodules within and outside screening programs Massimo Colombo Page 304-309

    Evaluation of a liver nodule detected with ultrasound includes the recovery of a detailed medical history, a physical exam, appropriate contrast imaging examinations and, in selected cases, histopathology. In this setting, identification of liver disease accompanying a liver nodule helps distinction between benign nodules and metastatic malignant nodules from primary liver cancer, as recommended by scientific liver societies. Diagnostic algorithms for a liver nodule in patients with liver disease involve contrast CT scan, magnetic resonance imaging or contrast enhanced ultrasounds to show the typical neoplastic pattern of early arterial hyperenhancement wash-in followed by hypoenhancement in the late portal phase wash out. The flow charts developed by western societies utilize the discriminant criterion of tumor size i.e. the radiological diagnosis being endorsed in a nodule equal or greater than 1 cm whereas eastern societies rely on the recognition of a typical vascular pattern of the node, independently of size. Differential diagnosis should be obtained to differentiate liver related nodules like regenerative macronodules (more than 20% of the cases) and the less frequent intrahepatic cholangiocarcinoma (~2% of the cases) from liver disease unrelated nodules like hemangioma (~4%), neuroendocrine metastatic nodules (~1%) and focal nodular hyperplasia. In patients without liver disease, the most common liver nodules in the liver are hemangioma (~1.5%), focal nodular hyperplasia (0.03%) and hepatocellular adenoma (up to 0.004% in long term users of oral contraceptives). Optimization of management of patients with a liver nodule requires establishment of a multidisciplinary clinic.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • The fatigue impact scale for daily use in patients with hepatitis B virus and hepatitis C virus chronic infections Karine Miranda-Pettersen, Mychelle Morais-de-Jesus, Renato Daltro-Oliveira, Adriana Dantas Duarte Dias, Carlos Teles, Maria Isabel Schinoni, Ângela Miranda-Scippa, Raymundo Paraná, Lucas C. Quarantini Page 310-316

    Introduction. Fatigue is an important clinical finding in the hepatitis virus chronic infection. However, the absence of scales to measure fatigue, translated and validated for Brazilian Portuguese, prevents access to information essential in clarifying specific clinical conditions in this population. Aim. The aim of this study was to determine the psychometric properties of the fatigue impact scale for daily use (D-FIS), in Brazilian Portuguese, for patients with the hepatitis C virus (HCV) and hepatitis B virus (HBV) chronic infection. Material and methods. In this cross-sectional study, the authors evaluated the D-FIS in 101 outpatients, followed at the reference hospital. The Mini International Neuropsychiatric Interview Brazilian (MINI PLUS) was used to identify psychiatric disorders, and the Short Form Health Survey 36-item (SF-36) to evaluate the self-reported quality of life. We also examined the impact of fatigue on the quality of life of this group of patients. Results. Relevant psychometric D-FIS results were: floor effect proved to be 1%; skewness was 0.46; item homogeneity was 0.59 and SEM (SD = 8.51) was 2.4. The Cronbach’s alpha was 0.920 and item total correlation yielded coefficients ranging from 0.65 (item 1) to 0.85 (item 3). In a linear regression model, fatigue and depression influenced the self-reported quality of life. Conclusion. This study presents that the fatigue scale for daily use in Brazilian Portuguese can be considered a useful tool to verify the presence of fatigue in patients with the hepatitis viruses B and C.

  • Does hepatitis B virus coinfection have any impact on treatment outcome in hepatitis C patients on hemodialysis? Raul C. Wahle, Renata de Mello Perez, Christini Takemi Emori, Silvia N. de Oliveira Uehara, Patrícia da Silva Fucuta, Cristina Melo Rocha, Ana C. de Castro Amaral Feldner, Ivonete S. de Souza e Silva, Roberto J. Carvalho-Filho, Antônio E. Benedito Silva, Maria L. Gomes Ferraz Page 317-324

    Background. HBV/HCV coinfection is a common finding among hemodialysis patients. However, there is scarce information concerning the impact of HBV coinfection on the response to treatment of HCV-infected patients on hemodialysis. Aim. We aimed to compare the rate of sustained virologic response (SVR) to treatment with interferon-alfa (IFN) between hemodialysis patients with HBV/HCV coinfection and those with HCV-monoinfection. Material and methods. HCV-infected patients on hemodialysis treated with IFN were included. Patients coinfected by HBV/HCV were compared to HCV-monoinfected patients, regarding clinical and biochemical features and rates of SVR. Results. One hundred and eleven patients were treated. HBV/HCV coinfection was observed in 18/111 patients (16%). Coinfected patients were younger (p = 002), had more time on dialysis (p = 0.05) and showed a tendency to present a higher prevalence of septal fibrosis (p = 0.06). The analysis by intention to treat showed SVR of 56% among coinfected patients and 18% in HCV-monoinfected patients (p = 0.004). Conclusion. In conclusion, end-stage renal disease patients with HBV/HCV coinfection exhibit higher rate of SVR to HCV treatment than HCV-monoinfected patients. It is possible that factors related to the host immune response and viral interaction could explain the better response observed among coinfected patients.

  • HCV antiviral therapy in injection drug users: difficult to treat or easy to cure? Marcello Persico, Nicola Coppola, Valerio Rosato, Ludovico Abenavoli, Mario Masarone, Antonio De Luna Page 388-395

    Background and rationale of the study. Hepatitis C infection is very common among injection drug users(IDUs). In clinical practice there is reluctance to treat IDUs, because considered difficult-to-treat. Aim of this study was to evaluate the response to antiviral treatment in IDUs compared to non-IDUs. Main results. In this observational retrospective study, 204 non cirrhotic patients(112 IDUs, 92 non-IDUs) with chronic hepatitis C, treated with PEG-IFN and ribavirin in a tertiary centre for IDUs of Southern Italy from 2008 to 2011 were analyzed. Age, sex, genotype, steatosis, response to previous therapy, rapid(RVR), early(EVR), end-of-treatment(ETR), sustained(SVR) virological response were evaluated. IDUs were mainly young and males, with prevalence of genotype 3. A higher SVR rate in IDUs group compared to non-IDUs only in PerProtocol(PP) analysis (90% vs. 78,9% ;p = 0.04). On the contrary, in IntentionToTreat(ITT) analysis, no significant difference was relieved. A higher SVR rate at ITT analyses in naïve non-IDUs patients was found (76,13% vs. 90%, p = 0.021), but at PP analysis wasn’t confirmed. Treatment was well tolerated; a higher dropout rate was reported in IDUs (24 patients) compared to non-IDUs (2 patients). In order to exclude the effect of viral genotypes on SVR a genotype matched statistical analysis was done and no difference was found. Conclusions. IDUs naïve patients, due to young age and high prevalence of genotype 3, appear good candidates to dual antiviral therapy with high SVR rates. Dropout is the main non-response cause among these subjects, but through an optimal monitoring program with a multidisciplinary setting, their “difficult to treat” characteristics can be overcome.

Non alcoholic fatty liver disease (NAFLD)
  • Impact of H63D mutations, magnetic resonance and metabolic syndrome among outpatient referrals for elevated serum ferritin in the Basque Country Agustin Castiella, Eva Zapata, Leire Zubiaurre, Jose Ma. Alustiza, Ma. Dolores De Juan, Arantxa Iribarren, Jose I. Emparanza, Pedro Otazua Page 325-331

    Background and Aims. There are limited data on clinical and phenotypic characteristics of outpatients referred for hyperferritinemia (HF). To determine the causes of HF in outpatients referred to a secondary hospital. Material and methods. A prospective study of 132 consecutive patients with HF (> 200 μg/L, women; > 300 μg/L, men) was conducted from January-December 2010. Results. Mean age, 54.42 years (SD: 13.47, range: 23-83); body mass index (BMI), 28.80 (SD: 3.96, 17-39); ferritin (SF), 579.54 ng/mL (SD: 296.575, 206-1668); transferrin saturation (TSI), 43.87% (SD: 14.09, 12-95); iron (Fe), 134 μg/dL (SD: 49.68, 55-322); overweight: 48.31%, and obese: 40.44% (89%), and most patients were men (108/132). Regarding HFE mutations, H63D/H63D genotype and H63D allele frequencies were 17.5% (vs. 7.76% in controls); and 36% (31% in controls) respectively. While 63.6% consumed no alcohol, 18.1% consumed ≥ 60 g/day, the mean being 20.83 (SD: 33.95, 0-140). Overall, 6/132 (4.5%) patients were positive for B or C hepatitis. Mean LIC by MRI was 36.04 (SD: 32.78, 5-210), 53 patients having normal concentrations (< 36 μmol/g), 22 (33%) iron overload (37-80), and 4 (5%) high iron overload (> 80). Metabolic syndrome (MS) was detected in 44/80 men (55%) and 10/17 women (59%). In this group, the genotype frequency of the H63D/H63D mutation was significantly higher than in controls-21.56% vs. 7.76%- (p = 0.011); the H63D allelic frequency was 42.15% in MS group and 31% in controls (p = 0.027). Conclusion. The H63D/H63D genotype and H63D allele predispose individuals to HF and MS. MRI revealed iron overload in 33% of patients.

Liver transplantation
  • Risk factors for early repeat ERCP in liver transplantation patients with anastomotic biliary stricture James H. Tabibian, Mohit Girotra, Hsin-Chieh Yeh, Vikesh K. Singh, Patrick I. Okolo III, Andrew M. Cameron, Ahmet Gurakar Page 332-339

    Introduction. Anastomotic biliary strictures (ABS) are a significant clinical problem associated with decreased survival post-liver transplantation (LT). Contributing to the morbidity of ABS is the need for early (i.e. emergent or unplanned) repeat endoscopic retrograde cholangiopancreatographies (ER-ERCPs). Our aim was to determine clinical, operative, and endoscopic predictors of ER-ERCP in patients with ABS. Material and methods. Medical records of 559 patients who underwent LT at our institution from 2000-2012 were retrospectively reviewed for pertinent data. The primary endpoint was need for ER-ERCP. Seventeen potential predictors of ER-ERCP were assessed in bivariate analyses, and those with p < 0.20 were included in multivariate regression models. Results. Fifty-four LT patients developed ABS and underwent a total of 200 ERCPs, of which 40 met criteria for ER-ERCP. Predictors of ER-ERCP in bivariate analyses included balloon dilation within 3 months post-LT and donation after cardiac death (both p < 0.05). Balloon dilation within 3 months post-LT was also associated with shorter ER-ERCP-free survival (p = 0.02). Moreover, a significantly higher proportion (67%) of patients who underwent balloon dilation within 3 months post-LT subsequent experienced ≥ 1 ER-ERCP (p = 0.03), and those who experienced ≥ 1 ER-ERCP had lower stricture resolution rates at the end of endoscopic therapy compared to those who did not (79 vs. 97%, p = 0.02). In multivariate analyses, balloon dilation within 3 months post-LT was the strongest predictor of ER-ERCP (OR 3.8, 95% CI 1.7-8.6, p = 0.001). Conclusions. Balloon dilation of ABS within 3 months post-LT is associated with an increased risk of ER-ERCP, which itself is associated with lower ABS resolution rates. Prospective studies are needed to confirm these findings and their implications for endoscopic management and follow-up of post-LT ABS.

Miscellaneous
  • Serum ferritin is a biomarker for liver mortality in the Hemochromatosis and Iron Overload Screening Study Paul C. Adams, James C. Barton, Helen Guo, David Alter, Mark Speechley Page 340-345

    Background. We identified no reports of long-term follow-up of participants in hemochromatosis screening programs. We evaluated causes of death and survival in non-C282Y homozygous Canadian participants in the primary care-based hemochromatosis and iron overload screening (HEIRS) study. Material and methods. Initial screening (IS) included transferrin saturation (TS), serum ferritin (SF), HFE genotyping (C282Y, H63D), and health questionnaire responses. By definition, participants without C282Y or H63D had HFE wt/wt. We linked 20,306 Canadian participants to the Ontario Death Registry for dates and causes of death 9 y after IS. We computed Cox proportional hazards to identify factors with increased death risks and Kaplan-Meier curves to estimate survival of non-C282Y homozygous participants with SF ≤ 1,000 μg/L and > 1,000 μg/dL. Results. There were 19,052 evaluable participants (IS mean age 49 y; 60% women; 93 C282Y homozygotes). There were 988 deaths. Significantly increased hazard ratios for all-cause mortality were positively associated with TS, SF, men, and C282Y homozygosity, and liver disease, diabetes, and heart failure reports. Non-C282Y homozygous participants with SF > 1,000 μg/L had lower survival than those with SF ≤ 1,000 μg/L (p < 0.0001). Conclusions. Nine years after initial screening, non-C282Y homozygous participants and SF > 1,000 μg/L was associated with decreased survival.

  • Clinical characteristics, predictors, and survival among patients with hepatopulmonary syndrome Irfan Younis, Shahid Sarwar, Zeeshan Butt, Sheharyar Tanveer, Adnan Qaadir, Nauman Arif Jadoon Page 346-352

    Background. Hepatopulmonary syndrome (HPS) is a complication of advanced liver disease. The impact of HPS on survival is not clearly understood. Material and methods. A prospective study was carried out at Department of Medicine, King Edward Medical University Lahore from June 2011 to May 2012. Patients with cirrhosis of liver were evaluated for presence of HPS with arterial blood gas analysis and saline bubble echocardiography. All patients were followed for 6 months for complications and mortality. Cox regression analysis was done to evaluate role of HPS on patient survival. Results. 110 patients were included in the study. Twenty-nine patients (26%) had HPS. MELD score was significantly higher (p < 0.01) in patients with HPS (18.93 ± 3.51) as compared to that in patients without HPS (13.52 ± 3.3). Twenty two (75.9%) patients of Child class C, 5 (17.2%) patients of Child class B and 2 (6.9%) patients of Child class A had HPS (P 0.03). The clinical variables associated with presence of HPS were spider nevi, digital clubbing, dyspnea, and platypnea. HPS significantly increased mortality during six month follow up period (HR: 2.47, 95% CI: 1.10- 5.55). Child-Pugh and MELD scores were also associated with increased mortality. HPS was no longer associated with mortality when adjustment was done for age, gender, Child-Pugh, and MELD scores (HR: 0.44, 95% CI: 0.14-1.41). Both the Child-Pugh and MELD scores remained significantly associated with mortality in the multivariate survival analysis. Conclusions. HPS indicates advanced liver disease. HPS does not affect mortality when adjusted for severity of cirrhosis.

  • Exercise capacity of cirrhotic patients with hepatopulmonary syndrome José L. Faustini-Pereira, Lucas Homercher-Galant, Eduardo Garcia, Ajácio Bandeira de Mello Brandão, Claudio A. Marroni Page 353-360

    Introduction. Hepatopulmonary syndrome (HPS) is characterized by a clinical triad of liver disease and/or portal hypertension, intrapulmonary vascular dilatation and abnormal arterial oxygenation. These conditions can worsen muscle strength, exercise capacity and functionality in the affected population. Objective. The objective of this study was to compare exercise capacity, functional condition and respiratory muscle strength in cirrhotic patients diagnosed with HPS and cirrhotic patients without this diagnosis. Material and methods. This cross-sectional study used a convenience sample consisting of 178 patients (92 patients with HPS and 86 patients without HPS) with a diagnosis of liver cirrhosis caused by either alcohol consumption or the hepatitis C virus (HCV). Peak oxygen consumption (VO2 peak) was used to verify exercise capacity, the six-minute walk test (6MWT) was used to test functionality, and manovacuometry was used to evaluate the strength of the respiratory muscles. The Kolmogorov-Smirnov test and Student’s t-test were used for the statistical analysis. The data were analyzed using SPSS 16.00, and p < 0.05 was considered significant. Results. The group of patients with the diagnosis of HPS exhibited a lower VO2 peak (14.2 ± 2.3 vs. 17.6 ± 2.6, p < 0.001), shorter distance walked in the 6MWT (340.8 ± 50.9 vs. 416.5 ± 91.4, p < 0.001), lower maximal inspiratory pressure (-49.1 ± 9.8 vs. -74.2 ± 13.9, p = 0.001) and lower maximum expiratory pressure (60.1 ± 12.2 vs. 76.8 ± 14.7, p = 0.001). Conclusion. The group of cirrhotic patients diagnosed with HPS exhibited lower values for VO2 peak, distance walked in the 6MWT and respiratory muscle strength than the cirrhotic patients not diagnosed with HPS.

  • Safety and efficacy of angiographic occlusion of duodenal varices as an alternative to TIPS: review of 32 cases Alexander Copelan, Monzer Chehab, Purushottam Dixit, Mitchell S. Cappell Page 361-371

    Backgroud/rationale of study. Analyze safety and efficacy of angiographic-occlusion-with-sclerotherapy/ embolotherapy-without-transjugular-intrahepatic-portosystemic-shunt (TIPS) for duodenal varices. Although TIPS is considered the best intermediate-to-long term therapy after failed endoscopic therapy for bleeding varices, the options are not well-defined when TIPS is relatively contraindicated, with scant data on alternative therapies due to relative rarity of duodenal varices. Prior cases were identified by computerized literature search, supplemented by one illustrative case. Favorable clinical outcome after angiography defined as no rebleeding during follow-up, without major procedural complications. Results. Thirty-two cases of duodenal varices treated by angiographic-occlusion-with-sclerotherapy/embolotherapy- without-TIPS were analyzed. Patients averaged 59.5 ± 12.2 years old (female = 59%). Patients presented with melena-16, hematemesis & melena-5, large varices-5, growing varices-2, ruptured varices-1, and other- 3. Twenty-nine patients had cirrhosis; etiologies included: alcoholism-11, hepatitis C-11, primary biliary cirrhosis- 3, hepatitis B-2, Budd-Chiari-1, and idiopathic-1. Three patients did not have cirrhosis, including hepatic metastases from rectal cancer-1, Wilson’s disease-1, and chronic liver dysfunction-1. Thirty-one patients underwent esophagogastroduodenoscopy before therapeutic angiography, including fifteen undergoing endoscopic variceal therapy. Therapeutic angiographic techniques included balloon-occludedretrograde- transvenous-obliteration (BRTO) with sclerotherapy and/or embolization-21, DBOE (double-balloon-occluded-embolotherapy)-5, and other-6. Twenty-eight patients (87.5%; 95%-confidence interval: 69-100%) had favorable clinical outcomes after therapeutic angiography. Three patients were therapeutic failures: rebleeding at 0, 5, or 10 days after therapy. One major complication (Enterobacter sepsis) and one minor complication occurred. Conclusions. This work suggests that angiographic-occlusion-withsclerotherapy/ embolotherapy-without-TIPS is relatively effective (~90% hemostasis-rate), and relatively safe (3% major-complication-rate). This therapy may be a useful treatment option for duodenal varices when endoscopic therapy fails and TIPS is relatively contraindicated.

  • MELD score for prediction of survival after emergent TIPS for acute variceal hemorrhage: derivation and validation in a 101-patient cohort Leigh C. Casadaban, Ahmad Parvinian, Sean P. Zivin, Janesh Lakhoo, Jeet Minocha, M. Grace Knuttinen, Charles E. Ray Jr., James T. Bui, Ron C. Gaba Page 372-380

    Background and rationale for the study. The Model for End Stage Liver Disease (MELD) score has not been derived and validated for the emergent transjugular intrahepatic portosystemic shunt (TIPS) population. We sought to identify predictive factors for survival among emergent TIPS patients, and to substantiate MELD for outcomes prognostication in this population. Results. 101 patients with acute life threatening variceal hemorrhage underwent emergent TIPS (defined by failed endoscopic therapy for active bleeding, acute hemoglobin drop, ≥ 2-unit transfusion requirement, and/or vasopressor need) at between 1998-2013. Demographic, clinical, laboratory, and procedure parameters were analyzed for correlation with mortality using Cox proportional hazards regression to derive the prognostic value of MELD constituents. Area under receiver operator characteristic (AUROC) curves was used to assess the capability of MELD prediction of mortality. TIPS were created 119 ± 167 h after initial bleeding events. Hemodynamic success was achieved in 90%. Median final portosystemic pressure gradient was 8 mmHg. Variceal rebleeding incidence was 21%. The four original MELD components showed significant correlation with mortality on multivariate Cox regression: baseline bilirubin (regression coefficient 0.366), creatinine (0.621), international normalized ratio (1.111), and liver disease etiology (0.808), validating the MELD system for emergent cases. No other significant predictive parameters were identified. MELD was an excellent predictor of 90-day mortality in the emergent TIPS population (AUROC = 0.842, 95% CI 0.755-0.928). Conclusions. Based on independent derivation of prognostic constituents and confirmation of predictive accuracy, MELD is a valid and reliable metric for risk stratification and survival projection after emergent TIPS.

  • IFNL3 polymorphisms and HCV infection in patients with beta thalassemia Raffaella Origa, Giuseppe Marceddu, Fabrice Danjou, Luciana Perseu, Stefania Satta, Franca Rosa Demartis, Antonio Piga, Filomena Longo, Maria-Eliana Lai, Stefania Vacquer, Renzo Galanello Page 381-387

    Background and relationale for the study. Genome-wide association studies have identified host genetic variation to be critical for spontaneous clearance and treatment response in patients infected with hepatitis C virus. Recently, the role of the IFNL3 polymorphisms in influencing the spontaneous clearance of HCV, the response to interferon and the progression of liver fibrosis, was also demonstrated in patients with thalassemia major infected by genotype 1b. In the present study we retrospectively analyzed 368 anti-HCV positive patients with beta-thalassemia at two Italian major centers in Cagliari and Torino. Results. C/C variant of polymorphism rs12979860 was related to response to interferon treatment and, above all, to spontaneous clearance of the virus. However, the positive predictive power was stronger for viral persistence than spontaneous clearance and in such respect the TT allele was more predictive than CC. The methylation associated polymorphism rs4803221 had independent effects with respect to rs12979860 and the haplotype tagged by SNP rs12979860 and rs4803221 significantly could improve the viral clearance prediction in infected patients. Neither necroinflammation or bilirubin values in the chronic phase of the hepatitis C were related to IFNL3 polymorphisms. No relation among IFNL3 polymorphisms and fibrosis stage directly shown by the liver biopsy was found. Conclusions. Also in thalassemia the SNPs on chromosome 19q13 closely associates with spontaneous and treatment-induced HCV clearance. The viral clearance prediction is significantly improved by the haplotype tagged by SNP rs12979860 and rs4803221. Neither necroinflammation, bilirubin values or fibrosis stage seem to be related to IFNL3 polymorphisms.

Basic studies

  • Mycophenolic acid induces apoptosis of hepatic stellate cells in an in vitro model of HCV Jan Best, Andreas Zahn, Anja Beilfuß, Svenja Sydor, Christian Fingas, Jan-Peter Sowa, Olympia Anastasiou, Vito Cicinnati, Guido Gerken, Ali Canbay, Lars P. Bechmann Page 396-403

    Introduction. Hepatitis C virus (HCV) infection is an important risk factor for the development of liver fibrosis and progression to cirrhosis. Liver transplantation as terminal treatment option for liver disease requires life-long immunosuppression. However, immunomodulatory therapy may promote reinfection and renewed fibrogenesis. Immunosupressive agents may also affect the life cycle of hepatic stellate cells (HSC), the main source of extracellular matrix. We thus aimed to characterize the effects of three common immunosuppressive agents on HSC apoptosis with or without engulfment of HCV infected apoptotic bodies. Material and methods. LX2 cells were incubated with three different immunosuppressants (rapamycine, mycophenolic acid or cyclosporine A) and co-incubated for 24 and 48 h with apoptotic bodies (AB), produced from Huh7 cells or from Con1 cells (Huh7-cells containing a subgenomic HCV replicon). The engulfment of AB was confirmed by immunofluorescence staining. HSC viability, apoptosis rate and expression of profibrogenic and proapoptotic genes were quantified. Results. In LX2 cells that engulfed Con1 AB, the treatment with mycophenolic acid induced HSC apoptosis and reduced collagen 1alpha 1 expression compared to cylosporine A or rapamycine treatment. In conclusion mycophenolic acid is a potent inducer of HSC apoptosis and attenuates HSC activation and consecutively fibrogenesis in HCV infection. Translational studies will need to confirm these mono-culture results in vivo.

  • The ability of 17 beta-estradiol to attenuate intrahepatic vasoconstriction to endothelin-1 in female rats is lost in cirrhosis Hsin-Ling Ho, Fa-Yauh Lee, Shao-Jung Hsu, Sun-Sang Wang, I-Fang Hsin, Hui-Chun Huang, Jing-Yi Lee, Han-Chieh Lin, Shou-Dong Lee Page 404-413

    Background and rationale. The control of Endothelin-1 (ET-1)-mediated intrahepatic vasoconstriction in cirrhosis is beneficial for the alleviation of relevant complications. Cirrhosis is accompanied by hypogonadism and altered sex hormone status. Besides, sex hormones have vasoactive effects, but it is unknown if they influence vascular function in cirrhosis. This study aimed to investigate the roles of sex hormones in hepatic vascular reactions to ET-1 in cirrhosis. Liver cirrhosis was induced in Spraque-Dawley male and female rats with common bile duct ligation (BDL). Sham-operated (Sham) rats were controls. On the 43rd day after operations, intrahepatic vascular concentration-response curves to ET-1 were obtained with the following preincubatioins: 1) vehicle; 2) 17beta-estradiol; 3) progesterone; 4) testosterone. Livers from sham and BDL rats were dissected for real-time polymerase chain reaction analysis of estrogen, progesterone and testosterone receptors. Results. Compared with sham males perfused with vehicle, sham females presented higher perfusion pressure changes to ET-1 which was reversed only by 17beta-estradiol. In cirrhosis, compared with males, 17beta-estradiol no longer attenuated vascular responsiveness to ET-1 in females. In females, BDL rats had lower hepatic estrogen receptor ?(ER?) mRNA expression than that in sham rats. Conclusions. The sham females showed a stronger intrahepatic vascular constrictive effect to ET-1 than sham males, which could be reversed by 17beta-estradiol. However, the influence of 17beta-estradiol was lost in cirrhotic females, which may be attributed, at least partly, to intrahepatic ER? down-regulation in females with cirrhosis.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Cutaneous amyloidosis associated with autoimmune hepatitis-primary biliary cirrhosis overlap syndrome Emmanuel I. González-Moreno, Carlos R. Cámara-Lemarroy, David O. Borjas-Almaguer, Sylvia A. Martínez-Cabriales, Jonathan Paz-Delgadillo, Rodrigo Gutiérrez-Udave, Ana S. Ayala-Cortés, Jorge Ocampo-Candiani, Carlos A. Cortéz-Hernández, Héctor J. Maldonado-Garza Page 416-419

    Cutaneous amyloidosis is a rare disease characterized by the deposition of amyloid in the dermis. It can be primary or secondary, depending on associated diseases. It has been linked to various autoimmune diseases, including primary biliary cirrhosis. We present the case of a patient with an autoimmune hepatitis-primary biliary cirrhosis overlap syndrome with concomitant cutaneous amyloidosis, a very unusual association, and discuss similar cases and possible pathophysiological implications.

  • Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism Alessandro Federico, Ernesto Aitella, Dolores Sgambato, Alfonso Savoia, Fabio De Bartolomeis, Marcello Dallio, Eleonora Ruocco, Luciano Pezone, Ciro Abbondanza, Carmela Loguercio, Corrado Astarita Page 420-424

    The HCV protease inhibitor telaprevir associated with peginterferon–alpha and ribavirin, was widely used in the recent past as standard treatment in HCV genotype-1 infected patients. Telaprevir improves the sustained virology response rates, but at the same time increases the frequency of adverse cutaneous reactions. However, mechanisms through which telaprevir induces cutaneous lesions are not yet defined. A 50-year-old woman, affected by HCV genotype 1b, was admitted to our Department for a telaprevir-related severe cutaneous eruptions, eight weeks after starting a triple therapy (telaprevir associated with Peginterferon-alpha and ribavirin). Mechanisms of cutaneous reactions were investigated by skin tests with non-irritating concentrations of telaprevir and by activating in vitro T lymphocyte with different concentrations. Immediate and delayed responses to skin testing were negative, but the drug-induced lymphocytes activation was significantly higher as compared to patient’s baseline values and to parallel results obtained in three healthy subjects (p < 0.05). In conclusion, adverse cutaneous reactions of our patient were caused by a telaprevir-induced T-cell dependent immune mechanism.

  • Papillary in situ and intramucosal adenocarcinoma of the lower third of common bile duct. A report and review of the literature Eduardo E. Montalvo-Javé, Fredy Chablé-Montero, Liz N. Toapanta-Yanchapaxi, Fernando Rojas-Mendoza, Carlos López-Caballero, Mario L. Roca-Cabrera, Germán E. Mendoza-Barrera Page 425-429

    We report the case of a 37-year-old woman with no relevant medical history. She was admitted to the hospital for epigastric pain related with food intake for 4 days; the pain did not improve with symptomatic management. A laparoscopic cholecystectomy due to acute lithiasic cholecystitis was performed. However, after 4 days, postoperative painless jaundice was evident; thus, endoscopic retrograde cholangiopancreatography was performed, which revealed an amputation of intrapancreatic common bile duct, as well as secondary intra- and extrahepatic bile duct dilatation. Brushing of the distal portion of the common bile duct revealed a well-differentiated adenocarcinoma. Therefore, a Whipple procedure with pylorus preservation was performed. Pathologic diagnosis of a papillary in situ adenocarcinoma with two microscopic foci of microinvasion was established. The pathologic Tumor-Node-Metastasis (TNM) stage was pT1, pN0, pM0, R0. The patient is asymptomatic and disease-free 24 months after surgery. In general, adenocarcinomas of the extrahepatic bile ducts are uncommon and have a poor prognosis. However, symptomatic patients with early disease stages are even rarer and can be cured surgically.

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