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November- December, 2014

Vol. 13 Issue 6

On the cover: Figure A. Abdominal CT scan revealed multiple hypodense lesions in the liver. Figure B. Biopsy of one of the lesions showed heptocytes with enlarged and dark smudge cells

HEPATOLOGY HIGHLIGHTS

EDITORIAL

CONCISE REVIEW

  • Role of SERPINB3 in hepatocellular carcinoma Patrizia Pontisso Page 722-727

    SERPINB3 (formerly known as squamous cell carcinoma antigen-1 or SCCA1) is a member of the family of serine-protease inhibitors. SERPINB3 protects cells from oxidative stress conditions, but in chronic liver damage this serpin may lead to hepatocellular carcinoma through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition and decrease of desmosomal junctions, cell proliferation and invasiveness. SERPINB3 may also contribute to tumor cell resistance to anti-neoplastic drugs through its binding to the respiratory Complex I, protecting cells from the pro-oxidant action of chemotherapeutic agents. Mechanisms of tumor growth promotion induced by SERPINB3 include the inhibition of intratumor infiltration of natural killer cells, up-regulation of Myc oncogene and the recent identification of this serpin as a Ras-responsive factor. In the liver SERPINB3 and SERPINBB4 isoforms (known as squamous cell carcinoma antigen or SCCA) are undetectable in normal hepatocytes, but their expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma. High SERPINB3 levels have been recently detected in HCC tissue of patients with early tumor recurrence after surgical resection. In serum SERPINB3/4 isoforms (or SCCA) are detectable bound to IgMs (SCCA-IgM) in the majority of HCV infected patients with HCC and in patients with cirrhosis their levels and/or the progressive increase have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM was predictive of HCC prognosis, since low levels of this biomarker were able to identify HCC patients with long overall and progression-free survival.

  • Cholesterol cholelithiasis in pregnant women: pathogenesis, prevention and treatment Ornella de Bari, Tony Y. Wang, Min Liu, Chang-Nyol Paik, Piero Portincasa, David Q.-H. Wang Page 728-745

    Epidemiological and clinical studies have found that gallstone prevalence is twice as high in women as in men at all ages in every population studied. Hormonal changes occurring during pregnancy put women at higher risk. The incidence rates of biliary sludge (a precursor to gallstones) and gallstones are up to 30 and 12%, respectively, during pregnancy and postpartum, and 1-3% of pregnant women undergo cholecystectomy due to clinical symptoms or complications within the first year postpartum. Increased estrogen levels during pregnancy induce significant metabolic changes in the hepatobiliary system, including the formation of cholesterol-supersaturated bile and sluggish gallbladder motility, two factors enhancing cholelithogenesis. The therapeutic approaches are conservative during pregnancy because of the controversial frequency of biliary disorders. In the majority of pregnant women, biliary sludge and gallstones tend to dissolve spontaneously after parturition. In some situations, however, the conditions persist and require costly therapeutic interventions. When necessary, invasive procedures such as laparoscopic cholecystectomy are relatively well tolerated, preferably during the second trimester of pregnancy or postpartum. Although laparoscopic operation is recommended for its safety, the use of drugs such as ursodeoxycholic acid (UDCA) and the novel lipid-lowering compound, ezetimibe would also be considered. In this paper, we systematically review the incidence and natural history of pregnancy-related biliary sludge and gallstone formation and carefully discuss the molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation during pregnancy. We also summarize recent progress in the necessary strategies recommended for the prevention and the treatment of gallstones in pregnant women.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Hepatitis C virus infection in patients and family members attending two primary care clinics in Puebla, Mexico Aurelio López-Colombo, Daniel Meléndez-Mena, Virginia Sedeño-Monge, José R. Camacho-Hernández, Eduardo Vázquez-Cruz, Eduardo R. Morales-Hernández, Francisca Sosa-Jurado, Luis Márquez-Domínguez, Gerardo Santos-López Page 746-752

    Background. Approximately 180 million persons (~2.8%) globally are estimated to be infected by hepatitis C virus (HCV). HCV prevalence in Mexico has been estimated to be between 1.2 and 1.4%. The aim of present work was to determine the prevalence of HCV infection in patients and family members attending two primary care clinics in Puebla, Mexico. Material and methods. Patients and their accompanying family members in two clinics were invited to participate in this study between May and September 2010. Results. A total of 10,214 persons were included in the study; 120 (1.17%) persons were anti-HCV reactive. Of the reactive subjects, detection of viral RNA was determined in 114 subjects and 36 were positive (31%). The more frequent risk factors were having a family history of cirrhosis (33.1%) and having a blood transfusion prior to 1995 (29%). After a multiple logistic regression analysis only transfusion prior to 1995 resulted significant to HCV transmission (p = 0.004). The overall detected HCV genotypes were as follows: 1a (29%), 1b (48.5%), 2/2b (12.8%), and 3a (6.5%). Conclusion. The HCV prevalence in this population is in agreement with previous studies in other regions of Mexico.

  • Survival of hepatitis C-infected haemophilia patients is predicted by presence of cirrhosis but not by anti-viral treatment Yaakov Maor, Jonathan M. Schapiro, Dalia Bashari, Uri Martinowitz Page 753-761

    Background/Purpose. Hepatitis C (HCV) is a major cause of morbidity and mortality in haemophilia patients who received clotting factor concentrates before the availability of virus-inactivated factors in the mid- 1980s. Recently, it has been suggested that anti-HCV treated patients, particularly those achieving a sustained virological response (SVR) have an improved outcome. We sought to examine the survival of treated and untreated HCV-infected haemophilia patients. Material and methods. We studied overall and liver-related survival of patients with haemophilia and other congenital bleeding disorders between 2000 and 2010. The outcome was compared in 3 sub-groups: HCV mono-infected (N = 127), HCV/HIV co-infected (N = 28), and patients with either HCV-antibodies negative or persistent HCV RNA-negative (referred to as non-infected) (N = 45). Sixty-two (40%) (HCV and HCV/HIV) patients underwent anti-HCV treatment with an SVR rate of 40.3%. Results. Overall and liver-related 10-year survival were: 82.1 and 89.3%, 95.3 and 99.2 and 100% for HCV/HIV co-infected, HCV mono-infected and non-infected haemophilia patients, respectively (p = 0.015 and 0.023 for comparisons of HCV/HIV vs. HCV; p = 0.003 for comparison of HCV/HIV and non-infected). One HCV mono-infected and 3 co-infected patients died of end-stage liver disease (2 underwent liver transplantation). There was no survival benefit from anti-HCV treatment or from attaining of an SVR. Only clinically suspected cirrhosis remained as an independent predictor of survival. Conclusion. The prognosis of haemophilia patients who acquired HCV/HIV co-infection is worse than that of HCV mono-infected or non-infected or haemophiliacs. This is mainly due to liver-related mortality. Anti-HCV treatment or SVR had no observable impact on survival rate.

  • Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital Sandro C. Ferreira, Silvana G. F. Chachá, Fernanda F. Souza, Andreza C. Teixeira, Rodrigo C. Santana, Márcia G. Villanova, Sérgio Zucoloto, Leandra N. Ramalho, Gleici S. C. Perdoná, Alfonso D. C. Passos, Ana L. C. Martinelli Page 762-770

    Introduction. Few studies have evaluated the factors involved in the spontaneous HBsAg seroclearance in patients with chronic hepatitis B (HBV) followed up on a long-term basis from areas with a low prevalence of HBV infection. We aimed to determine the rate of spontaneous HBsAg seroclearance and the factors related to it in patients with chronic HBV infection followed up at the Hepatitis Outpatient Clinic of HCFMRP from 1992-2008. Materials and methods. A total of 548 patients with chronic HBV infection (366 with chronic hepatitis B and 182 inactive carriers) were followed for 15 years and 9 months with an annual measurement of HBV-DNA, ALT, AST and GGT (average of 4 annual determinations) and serology (HBsAg, HBeAg, Anti-HBeAg and Anti-HBsAg). Results. Spontaneous HBsAg seroclearance occurred in 40 patients (7.3%) with a mean age of 46.0 ± 14.4 years, corresponding to an annual rate of 0.7%.The factors related to spontaneous HBsAg seroclearance were inactive carrier status (67.5 vs. 32.5%, p = 0.000191) and age of more than 40 years (p = 0.0007). There was no difference in the rate of spontaneous HBsAg seroclearance when comparing males and females (p = 0.383). Patients with spontaneous HBsAg seroclearance did not progress to more severe forms of the disease during follow-up. Conclusion. Spontaneous HBsAg seroclearance has a favorable long-term prognosis in patients with chronic HBV infection. HBsAg seroclearance occurred at rates compatible with low prevalence areas and was associated with low serum HBV-DNA levels and an age older than 40 years.

  • HBsAg expression of liver correlates with histological activities and viral replication in chronic hepatitis B Pin-Nan Cheng, Yen-Cheng Chiu, Hung-Wen Tsai, Ru-Hsueh Wang, Hung-Chih Chiu, I-Chin Wu, Ting-Tsung Chang Page 771-780

    Introduction. The intrahepatic hepatitis B surface antigens (HBsAg) expression is related to disease pro- gression of chronic hepatitis B. We examined the features of intrahepatic HBsAg expression. Material and methods. A total of 181 patients with e antigen positive chronic hepatitis B were enrolled. Patterns and semi-quantitative measurement of intrahepatic HBsAg expression were analyzed. The association of intrahepatic hepatitis HBsAg expression with clinical, viral, and histological characteristics was evaluated. Results. Higher necroinflammation grade and greater fibrosis stage accompanied with lower serum HBV DNA and HBsAg levels were observed in patients with type II ground glass hepatocytes and 2+/3+ scales of intrahepatic HBsAg expression. Basal core promoter T1762/A1764 mutations were strongly associated with the pattern of type II ground glass hepatocytes expression (P < 0.001) and higher level of HBsAg expression (9.3 ± 8.0% vs. 4.3 ± 5.0%, P = 0.008). In multivariate analysis, basal core promoter mutations (Odds ratio: 6.356, 95% confidence interval: 1.204 ~ 33.356, P = 0.029) was associated with 2+/3+ scale of HBsAg expression. Conclusion. Both pattern and levels of intrahepatic HBsAg expression were associated with severity of liver disease in e antigen positive chronic hepatitis B. Strong relationship between intrahepatic HBsAg expression and basal core promoter 1762/A1764 mutations indicated that HBsAg expression may be the histological manifestation of hepatitis B virus genomic evolution under host immune surveillance.

Liver transplantation
  • D-MELD does not predict post-liver transplantation survival: a single-center experience from Brazil Ane M. Costabeber, Lívia C. Lionço, Cláudio Marroni, Maria L. Zanotelli, Guido Cantisani, Ajácio Brandão Page 781-787

    Background. The D-MELD score was designed to prevent donor-recipient matches with a high risk of unfavorable outcome. The main objective of the present study was to assess the predictive value of the DMELD score for 1-month and 3-month post-transplant mortality in a cohort of patients who underwent deceased-donor liver transplantation in Southern Brazil. Material and methods. A cohort study was conducted. Receiver operating characteristic c-statistics were used to determine the ability of the D-MELD score to predict mortality. The Kaplan-Meier method was used to analyze survival as a function of time regarding D-MELD scores, and the Cox model was employed to assess the association between D-MELD and mortality. Results. Most recipients were male, with a mean age of 54.3 ± 9.6 years (n = 233 transplants). Mean donor age was 44.9 ± 16.8 years (19.3% of donors were aged ≥ 60 years). Mean MELD and D-MELD scores were 16.3 ± 7.1 and 733.1 ± 437.8 respectively. Overall survival at 1 and 3 months was 83.6%. The c-sta- tistic value for 1- and 3-month mortality was < 0.5 for the D-MELD. Analysis of Kaplan-Meier curves for groups with D-MELD scores < 1,600 and ≥ 1,600 did not show statistically significant differences in survival (p = 0.722). Conclusion. D-MELD scores were unable to predict survival in this cohort of Brazilian liver transplant recipients.

Hepatocellular Carcinoma (HCC)
  • The role of Interleukin 28B gene polymorphism in Turkish patients with hepatocellular carcinoma Hikmet Akkiz, Sedef Kuran, Ersin Akgöllü, Oguz Üsküdar, Aynur Bekar, Süleyman Bayram Page 788-795

    Background and aim. Multiple risk factors lead to hepatocellular carcinoma (HCC) including viral infections, mutation and single nucleotide polymorphisms (SNPs). Interleukin 28B (IL28B) gene rs12979860 polymor- phism has been shown to be associated with HCC in the different populations, but its association with HCC has not been investigated in the Turkish population. We investigated whether the rs12979860 polymorphism of IL28B gene affects the risk of HCC. Material and method. We performed genotyping analysis using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a hospital-based case-control study of 187 confirmed HCC patients and 208 healthy subjects (cancer and viral infection negative) in the Turkish population. Results. The allele and genotype analysis showed no significant differences between the risk of HCC and IL28B gene rs12979860 polymorphism (OR = 1.10; 95% 0.59-2.08 P = 0.76 for genotype). However, in the HBV-related HCC subgroup, the TT genotype increased a 1.46-fold the risk of developing HCC, but not statistically significant (OR = 1.46; 95% 0.71-2.97 P = 0.30). Furthermore, no significant differences were found between clinical findings, and sex in comparison with the IL28B genotypes in HCC group (P > 0.05). Conclusion. Our results suggest, for the first time, that no significant association were found between IL28B rs12979860 genotypes with the risk of developing HCC in Turkish patients. Further independent investigations are required to clarify the possible role of IL28B gene rs12979860 polymorphism on the risk of developing HCC in a larger series and also in patients of different ethnic origins.

  • m-RECIST at 1 month and Child A are survival predictors after percutaneous ethanol injection of hepatocellular carcinoma Mauricio F. Silva, Flair J. Carrilho, Denise C. Paranaguá-Vezozzo, Luciana T. Campos, Lucas S. Nacif, Marcio A. Diniz, Alberto Q. Farias, Venancio A.F. Alves, Luis A. C. D’Alburquerque, Suzane K. Ono Page 769-802

    Background and aims. Percutaneous ethanol injection (PEI) is a well-established therapeutic option in pa- tients with cirrhosis and hepatocellular carcinoma (HCC). The modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) are an important tool for the assessment of HCC response to therapy. The aim was to evaluate whether HCC response according to the m-RECIST criteria could be an effective predictor of long-term survival in Barcelona Clinic Liver Cancer (BCLC) stage 0 and A HCC patients undergoing PEI. Material and methods. 79 patients were followed-up for median time of 26.8 months. HCC diagnosis was based on the current guidelines of the American Association for Study of the Liver Diseases (AASLD) and European Association for Study of the Liver (EASL). Patient survival was calculated from the first PEI session to the end of the follow-up. Results. The 1-, 3-, and 5-year overall survival rates were 79, 48 and 37%, respectively. In the multivariate analysis, Child-Pugh-Turcotte (CPT) (p = 0.022) and the response to m-RECIST criteria (p = 0.016) were associated with patient survival. CPT A patients who achieved Complete Response (CR) 1 month after PEI presented a 5-year survival rate of 55%. By contrast, the worst scenario, the group with CPT B but without CR had a 5-year survival rate of 9%, while the group with either CPT A or CR as a survival predictor had a 5-year survival rate of 31%. In conclusion, in BCLC stage 0 and A HCC-patients, m-RECIST at 1 month and Child A may predict survival rates after PEI.

Miscellaneous
  • Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension Hans-Jürgen Seyfarth, Nadine Favreau, Carsten Tennert, Claudia Ruffert, Michael Halank, Hubert Wirtz, Joachim Mössner, Jonas Rosendahl, Peter Kovacs, Henning Wittenburg Page 803-809

    Background. Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. Material and methods. PH patients with (n = 23) or without (n = 25) an increase of alanine-aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. Results. Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). Conclusion. Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.

  • Recreational physical activity is inversely associated with asymptomatic gallstones in adult Mexican women Santiago Henao-Morán, Edgar Denova-Gutiérrez, Segundo Morán, Ximena Duque, Katia Gallegos-Carrillo, Nayeli Macías, Jorge Salmerón Page 810-818

    Background and rationale. Epidemiologic research suggests that physical activity (PA) reduces the risk of chronic diseases including gallstones. Objective. This study explores the association between recreational physical activity (RPA) and risk of asymptomatic gallstones (AG) in adult Mexican women. Material and methods. We performed a cross-sectional analysis of women from the Health Workers Cohort Study. The study population included Mexican women aged 17-94 years, with no history of gallstone (GS) or cholecystectomy. A self-administered questionnaire was used to collect information on weight change, gynecological health history, cholesterol-lowering medications and diuretics, history of diabetes mellitus type 2 (DM2), PA and diet. PA was calculated in minutes/day, minutes/week and Metabolic Equivalents (METs)/week. Gallstone diagnosis was performed using real-time ultrasonography. The association between RPA and risk of AG was evaluated using multivariate logistic regression models. Results. Of the 4,953 women involved in the study, 12.3% were diagnosed with AG. The participants with AG were significantly older, had a higher body mass index, and had a higher prevalence of DM2 than those without AG. The participants with > 30 min/day of RPA had lower odds of AG (OR = 0.80; 95% CI: 0.65-0.97; P = 0.03), regardless of other known risk factors for gallstone disease. Furthermore, we observed an inverse relationship between RPA time and AG risk, especially in women doing more than 150 min a week of RPA (OR = 0.76; 95%CI: 0.610.95; P = 0.02). Conclusion. These findings support the hypothesis that RPA may protect against AG, although further prospective investigations are needed to confirm this association.

  • The risk of carcinogenesis in congenital choledochal cyst patients: an analysis of 214 cases Xiao-dong He, Lei Wang, Wei Liu, Qi Liu, Qiang Qu, Bing-lu Li, Tao Hong Page 819-826

    Background. Choledochal cysts are most common in Asian populations. In addition, the incidence of biliary tract malignancies from choledochal cysts is increasing, but the risk of carcinogenesis is still unclear. Material and methods. Clinical data from 214 congenital choledochal cyst cases from 1968 to 2013 were retrospectively analyzed. Results. Todani type I was more common (139, 65.0%) than type IVa (53, 24.8%) or type V (17, 7.9%) in these choledochal cyst patients. Biliary tract malignant tumors occurred in the gallbladder (2, 13.3%), common bile duct (10, 66.7%), and intrahepatic bile duct (3, 20%) in 15 patients (7.0%), including one patient in whom malignant transformation occurred in the intrahepatic bile duct in a type IVa patient 15 years after extrahepatic cyst resection. An age at symptom onset ≥ 60 years was a risk factor (p < 0.001), while an initial complete surgery was a protective factor for carcinogenesis (p = 0.001). Conclusions. Choledochal cysts should be removed once diagnosed because of an increased risk of malignant transformation with increasing age. Complete cyst removal is necessary for the first surgical treatment. Additional hepatectomy should be considered for type IVa choledochal cysts because cholangiocarcinoma can arise from the intrahepatic bile duct years after the extrahepatic cyst excision.

IMAGES IN HEPATOLOGY

  • Adenovirus hepatitis presenting as tumoral lesions in an immunocompromised patient Juan Putra, Arief A. Suriawinata Page 827-829

    A 59-year-old man with T-cell prolymphocytic leukemia on alemtuzumab presented with neutropenic fever, intermittent nausea, and multiple ill-defined low attenuation foci in the liver on abdominal computed tomography scan which were suspicious for metastatic disease. Histological examination revealed the diagno- sis of adenovirus hepatitis. Patient responded well to cidofovir. Adenovirus hepatitis is a rare but important entity to be considered by the clinicians, radiologists, and pathologists. Timely diagnosis and appropriate management are essential to improve the prognosis of adenovirus hepatitis in immunocompromised patients.

CASE REPORTS

  • Dislodgement of variceal bands after esophageal balloon tamponade for variceal bleeding Estela Mogrovejo, Palaniappan Manickam, Gregg Polidori, Mitchell S. Cappell Page 832-837

    A 43-year-old male with alcoholic cirrhosis underwent EGD for hematemesis which revealed bleeding, grade II, lower esophageal varices that were endoscopically ligated with 6 bands. All the bands remained attached to varices at the completion of EGD. Despite apparent initial hemostasis, balloon tamponade was performed one hour later for suspected continued bleeding. Due to suspected continuing bleeding, EGD was repeated 4 h after initial EGD, and 3 h after balloon tamponade. This EGD revealed the esophageal varices; none of the bands remaining on esophageal mucosa; multiple mucosal stigmata likely from trauma at initial site of variceal bands before dislodgement; and 3 dislodged bands in gastric body, duodenal bulb, or descending duodenum. The patient expired 17 h thereafter from hypovolemic shock. This single report may suggest an apparently novel, balloon tamponade complication: dislodgement of previously placed, endoscopic bands. The proposed pathophysiology is release of bands by stretching entrapped, esophageal mucosa during esophageal balloon tamponade. This complication, if confirmed, might render balloon tamponade a less desirable option very soon after band ligation.

  • Bone metastases as the initial presentation of hepatocellular carcinoma. Two case reports and a literature review Jose M. Ruiz-Morales, Rita Dorantes-Heredia, Fredy Chablé-Montero, Sara Vazquez-Manjarrez, Nahum Méndez-Sánchez, Daniel Motola-Kuba Page 838-842

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is the fifth most com- mon cancer in the world; its incidence has been increasing in recent years. Extrahepatic spread is present at the time of diagnosis in only about 5 to 15% of patients. Skeletal metastasis of HCC occurs less frequently compared with other cancers and is considered a rare primary form of presentation. We report two cases of unsuspected HCC presenting with multiple bone lesions as the initial presentation. The first patient was a 76-year-old man with symptoms of fatigue and back pain. The PET-CT revealed the hypercaptant bone lesions and a liver lesion. The pathology report showed that the metastases were positive for the hepatic marker HEPAR-1, indicating that they had originated from the HCC. The second patient was a 56year-old man. He presented to the emergency department for right shoulder pain and weakness of the entire right arm with no history of trauma. During hospitalization, the patient became quadriplegic. MRI revealed osseous blastic lesions in the cervical vertebrae and right shoulder. A CT-guided biopsy was performed in the cervical lesion and showed poorly differentiated carcinoma. Immunohistochemistry staining was positive for HEPAR-1. In conclusion, this cases show an unusual presentation of HCC with skeletal metastasis.

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