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Current Issue

July - September, 2007

Vol. 6 Issue 3

On the cover: Official Journal of the Mexican Association of Hepatology

Annals of Hepatology

CONCISE REVIEW

  • Hepatopulmonary syndrome - Past to present Joye Varghese, Haseeb Ilias-basha, Ravishanker Dhanasekaran, Shivakumar Singh, Jayanthi Venkataraman Page 135-142

    Hepatopulmonary syndrome (HPS) is the one of the complication of liver cirrhosis with portal hypertension, irrespective of etiology, age and sex. It has also been observed in non cirrhotic portal hypertension and in acute hepatic conditions. Presence of hypoxemia or abnormal alveolar arterial oxygen tension with intrapulmonary vasodilation in liver cirrhosis is termed as HPS. Contrast echocardiogram is the better screening tool to demonstrate intrapulmonary shunt. Clinicians should be aware of other common chronic pulmonary and cardiac comorbid conditions, in particular COPD, tuberculosis, bronchial asthma and idiopathic pulmonary fibrosis, etc. which may coexist with HPS. There is no specific clinical finding to diagnose but digital clubbing, cyanosis, dyspnoea, platypnoea, and spider naevi are more common among cirrhosis with HPS. The presence of HPS independently worsens prognosis of cirrhosis. Even though number of mechanisms have been proposed to explain arterial hypoxemia in HPS, role of nitric oxide is the major one along with cytokines. Liver transplantation is the choice of treatment though mortality is comparatively high. There is no still effective recommended medical therapy to reverse this condition and anti cytokine/ nitric oxide inhibitors, etc are under preliminary stage.

  • MDR3 mutations associated with intrahepatic and gallbladder cholesterol cholelithiasis: an update Elvire Mbongo-Kama, Florence Harnois, Didier Mennecier, Eleonore Leclercq, Pascal Burnat, Franck Ceppa Page 143-149

    Background: The recurrent microlithiasis represents one of the most frequent clinical forms of lithiasis of the bile ducts. This affection is characterized by the presence of cholesterolic microgallstones on hepatic canaliculars, and belongs to a heterogeneous group of autosomal recessive liver disorders. Radiological diagnosis can be confirmed by analysis of MDR3 gene, coding a protein involved in physiologic translocation of phospholipids in bile. Discovery of MDR3 mutations is of particular interest, since normally associated with good effectiveness of medication by ursodesoxycholic acid. AIM: To review MDR3 mutations in humans associated with recurrent cholesterol microlithiasis and to suggest a practical approach for MDR3 gene analysis. Results: 48 mutations of MDR3 gene have been reported in humans to date, from which 43 (89.5%) in the coding region, and 5 splice site mutations have been associated to cholesterol cholelithiasis. 21 (43.8%) of the 43 precited mutations are located in only 8 exons on 28, near transmembrane or nucleotide binding domains of the protein. From the 22 remaining described mutations, 9 (18.8%) are restricted to exon 14. We suggest therefore to start analysis of MDR3 gene by screening exons 6, 7, 9, 10, 12, 14, 17, 23 and 24 with an appropriate protocol in this diagnosis associated with effective treatment. In conclusion such therapeutic orientation is valuable, since recurrent cholesterolic microlithiasis occurs relatively early in life, and by the fact that recurrence of symptoms may occur despite cholecystectomy, or shock-wave therapy.

ORIGINAL ARTICLES

  • Abnormal hepatic biochemistries and clinical liverdisease in patients with primary Sjögren´s syndrome Aldo J. Montaño-Loza, José Carlos Crispín-Acuña, José María Remes-Troche, Misael Uribe Page 150-155

    syndrome may present liver involvement. Our goals were to establish the prevalence of abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren’s syndrome and correlate their presence with other clinical and laboratory features. Methods: Ninety-five patients with diagnosis of primary Sjögren’s syndrome were studied. Data on gender, age, clinical features, liver biochemistries, tests of inflammation and autoimmunity, and concomitant diseases were collected. Results: Forty-two patients (44%) had abnormal hepatic biochemistries, and of these 19 patients (20%) had clinical liver disease. Patients with abnormal hepatic biochemistries had higher frequency of autoimmune hypotiroidism, arthritis, vasculitis, Raynaud’s phenomenon, higher sedimentation rate, and higher frequency of antinuclear and antimitochondrial antibodies than patients with normal liver biochemistries (P < 0.05 for each). Patients with clinical liver disease had higher frequency of arthritis, vasculitis, and higher frequency of antimitochondrial antibodies than patients without clinical liver disease (P < 0.05 for each). Twenty-one patients had diagnosis of a specific liver disease, such as hepatitis C virus infection (n = 11), autoimmune hepatitis (n = 2), primary biliary cirrhosis (n = 5), nonalcoholic fatty liver disease (n = 2), and hepatitis B virus infection (n = 1). In half of patients with liver involvement a definitive cause could not be identified. Conclusion: Liver involvement is frequently found in patients with primary Sjögren’s syndrome, and its presence is associated with clinical features of systemic disease, and markers of autoimmunity and inflammation. There may be a subgroup of patients with liver involvement secondary to primary Sjögren’s syndrome.

  • Geographical distribution of HCV genotypes in Mexico Juan Francisco Sánchez-Ávila, Elizabeth González, Victoria Vázquez, Susana Suárez, Misael Uribe Page 156-160

    Chronic hepatitis C (CHC) is the second cause of endstage liver disease in our country and one of the main indications of liver transplantation. Hepatitis C virus (HCV) genotype is the principal prognostic factor and the determinant of the therapeutic scheme. In our country few data exist regarding the prevalence of HCV infection and genotype distribution in the Mexican Republic has not been determined. The aim of this study was to characterize the prevalence of the different HCV genotypes and to explore their geographical distribution. Methods: Mexican patients with hepatitis C infection, detected throughout the country between 2003 and 2006, were included. All samples were analyzed by a central laboratory and Hepatitis C genotype was identified by Line Immuno Probe Assay in PCR positive samples (Versant® Line Probe Assay Quest Diagnostics Nichols Institute, San Juan Capistrano CA). Data were analyzed according to the four geographical areas in Mexico. Results: One thousand three hundred and ninety CHC patients were included. The most frequent genotype detected was genotype 1 (69%) followed by genotype 2 (21.4%) and genotype 3 (9.2%). Genotype 4 and 5 were infrequent. There was no subject infected with genotype 6. Genotype 1 and 2 exhibit very similar distribution in all geographical areas. Genotype 3 infected patients were more frequent in the North region (52%) compared with other areas: center-western (30%), center (17%), South-South east (1%) (p < 0.001). Conclusions: The most prevalent HCV genotype in Mexico is genotype 1. Geographical distribution of HCV genotypes in the four geographical areas in Mexico is not homogenous with a greater frequency of genotype 3 in the north region. This difference could be related to the global changes of risk factors for HCV infection.

  • Prevalence of non-alcoholic fatty liver disease: population based study Deepak Amarapurkar, Prafull Kamani, Nikhil Patel, Parijat Gupte, Pravin Kumar, Subhash Agal, Rajiv Baijal, Somesh Lala, Dinesh Chaudhary, Anjali Deshpande Page 161-163

    Background and aim: Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and liver transplantation in western countries. Increasing incidence of NAFLD has been well documented from Asian countries like Japan and China. Diabetes mellitus (DM), obesity, hyperinsulinemia are predisposing factors for NAFLD. There is increase in incidence of DM, obesity and insulin resistance in India in last two decades. Hence it is logical to expect increase in incidence of NAFLD in India. There is limited data on the prevalence of NAFLD from India. Majority of data comes from hospital based studies including small number of patients. Therefore this study was planned to estimate the prevalence of NAFLD in general population. Material and methods: Residents of two Railway colonies were evaluated on history, clinical examination, anthropometric measurements, biochemical tests and abdominal ultrasound. Results: 1,168 participants were evaluated. Persons with any amount of alcohol consumption, HBs Ag positive, Anti HCV positive, persons with other known liver diseases and taking medications causing liver disease were excluded. Prevalence of NAFLD on ultrasound was 16.6%. Out of 730 subjects above the age of 20 years (341 male 384 female 389) mean age 39.08 ± 12.3 years, 4% had diabetes, 57% had central obesity. Prevalence of NAFLD based on the ultrasound above 20 years of age was 18.9%. NAFLD was more prevalent in male than female (24.6% vs 13.6%, p < 0.001). Risk factors associated with NAFLD were age more than 40 years, male gender, central obesity, high BMR > 25, elevated fasting blood sugar, raised AST and ALT. Conclusion: Prevalence of NAFLD in Indian population is comparable to the west.

  • Evaluation of gallbladder motility: comparison of two-dimensional and three-dimensional ultrasonography Susanne Stads, Niels G. Venneman, Robert C.H. Scheffer, Melvin Samsom, Karel J. van Erpecum Page 164-169

    Since impaired gallbladder emptying contributes to gallstone formation, the evaluation of gallbladder motility requires accurate methodology. Recently developed 3-dimensional ultrasonography may take into account various gallbladder shapes more accurately than conventional 2-dimensional ultrasonography. Therefore, volumes of water-filled balloons of various sizes were determined in vitro by 2-dimensional ultrasonography with the sum of cylinders method and by 3-dimensional ultrasonography. Also, in 15 gallstone patients and 6 healthy volunteers, fasting gallbladder volumes and postprandial motility were determined by both methods. Volumes of water-filled balloons as measured by both methods correlated strongly with true volumes (R= 0.93 for 2-dimensional and R = 0.98 for 3- dimensional ultrasonography). Gallbladder volumes measured by both methods were also correlated (R = 0.66, P < 0.001). In gallstone patients, 3-dimensional ultrasonography yielded smaller gallbladder volumes than 2-dimensional ultrasonography (P = 0.007), but not in healthy subjects. With both methods, gallstone patients exhibited decreased postprandial gallbladder motility compared to healthy subjects. In conclusion, gallbladder volume measurements by 3-dimensional and 2-dimensional ultrasonography are strongly correlated. Nevertheless, in gallstone patients, gallbladder volumes by 3-dimensional ultrasonography tend to be smaller than by 2-dimensional ultrasonography, possibly due to interference of gallstones with the volume measurement.

  • Angiogenesis in chronic liver disease Anjali D. Amarapurkar, Deepak N. Amarapurkar, _ Vibhav, Nikhil D. Patel Page 170-173

    inflammation and fibrosis. As a consequence angiogenesis leading to new vasculature may have prognostic value in disease progression. Interfering with angiogenesis may be a potential target to avoid progression of liver disease. Hence we planned to evaluate the CD34 and vascular endothelial growth factor (VEGF), the markers for angiogenesis in chronic liver disease. Method: Liver biopsies from 79 patients of chronic liver disease and 21 cases of HCC (M: F = 4:1, age range 22 to 80) were stained for routine HE, CD 34 and VEGF immunostaining (Dako Corp & Santa Cruz respectively). Etiologies of chronic liver disease were alcoholic liver disease, HBV, HCV infection, NAFLD, autoimmune liver disease, and cryptogenic liver disease. Thirty biopsies from normal liver obtained at autopsy were taken as controls. Expressions of CD 34 and VEGF were compared with the stage of fibrosis. Results: Out of 79 patients, angiogenesis was seen in 45.5% cases of chronic liver disease. None of the case with normal liver histology was CD 34 or VEGF positive. No significant correlation of angiogenesis was found between any etiologies of chronic liver disease. CD 34 was positive in 18/21 (85.7%) cases of hepatocellular carcinoma. CD 34 and VEGF positivity was 20.9% and 46.5% in stage 1 and 2 fibrosis while it was 75% and 80% in stage 3 and 4 fibrosis respectively. VEGF appeared more common as compared to CD 34 in early fibrosis. Conclusion: Angiogenesis was present in 45.5% cases of chronic liver disease. It was proportional to the increase in stage of fibrosis. Expression of VEGF was commonly found in early stages of fibrosis. Hence, therapeutic strategies of inhibiting VEGF expression may be of importance in preventing the progression of chronic liver disease in its early stage.

  • Antiviral therapy: Inhibition of Hepatitis C Virus expression by RNA interference directed against the NS5B region of the Viral Genome Laura Trejo-Ávila, Regina Elizondo-González, Karina del C. Trujillo-Murillo, Pablo Karina del C., Cristina Rodríguez-Padilla, Ana María Rivas-Estilla Page 174-180

    health problem with 170 million chronically infected people throughout the world. Currently, the only treatment available consists of a combination of pegylated interferon (INF-α) and ribavirin, but only half of the patients treated show a sufficient antiviral response. Thus there is a great need for the development of new treatments for HCV infections. RNA interference (RNAi) represents a new promising approach to develop effective antiviral drugs and has been extremely effective against HCV gene expression in short-term cell culture. Our aim was to determine the effect of RNAi directed against the NS5B-HCV region on HCV expression in a human hepatoma cell line that expresses HCV-subgenomic replicon (Huh7 HCV replicon cells). Methods: We transfected Huh7 HCV replicon cells with different concentrations of RNAi (100-200 nM) targeting the NS5B region of the viral genome. 2-6 days post-transfection HCV-RNA was quantified by semiquantitative and real-time RT-PCR, and HCV NS5B protein levels were assayed by western blot. Cell viability was also quantified by MTT assay. Results: Our results indicate that the NS5B-siRNAs used in this study can specifically inhibit HCV-RNA replication and protein expression (more than 90%) compared to control cells. Conclusions: Synthetic siRNA against NS5BHCV inhibited HCV replication and viral proteins levels and thereby becomes a powerful strategy to combat hepatitis C virus.

EDITORIAL

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Fatal hepatitis C associated fibrosing cholestatic hepatitis as a complication of cyclophosphamide and corticosteroid treatment of active glomerulonephritis Faisal Saleh, Hin Hin Ko, Jennifer E. Davis, Wichian Apiratpracha, James J. Powell, Siegfried R. Erb, Eric M. Yoshida Page 186-189

    Fibrosing cholestatic hepatitis (FCH) is an aggressive and usually fatal form of viral hepatitis in immunocompromised patients. It is characterized by progressive cholestasis leading to hepatic failure, and a characteristic histopathological features including: periportal fibrosis, ballooning degeneration of hepatocytes, cholestasis, with minimal inflammation. FCH has been reported almost exclusively in heavily immunosuppressed organ transplant recipients or patients with AIDS. This case report describes a previously immunocompetent patient with previously stable chronic hepatitis C who developed fibrosing cholestatic hepatitis after receiving cyclophosphamide and corticosteroids for active glomerulonephritis.

  • Spontaneous rupture of a giant non parasitic hepatic cyst presenting as an acute surgical abdomen Nikolaos S. Salemis, Epameinondas Georgoulis, Stavros Gourgiotis, Efstathios Tsohataridis Page 190-193

    Spontaneous rupture of a non parasitic hepatic cyst is an extremely rare occurrence. A 50 -year- old male, was admitted with typical clinical manifestations of acute surgical abdomen. At exploratory laparotomy, a giant ruptured non parasitic cyst occupying the entire left liver lobe was found, along with a large amount of free intraperitoneal fluid. The cyst was widely unroofed very close to the liver parenchyma. The patient had an uneventful postoperative course and was discharged six days later. The clinical presentation, diagnostic evaluation and surgical management of this extremely rare clinical entity are discussed, along with a review of the literature. This case, which according to our best knowledge is the fourth reported in the literature, highlights the considerable risk of serious complications associated with the presence of a large symptomatic nonparasitic hepatic cyst. Prophylactic treatment should be considered in all these cases.

LIVER NEWS ELSEWHERE

  • Worldwide mortality from cirrhosis Nahum Méndez-Sánchez, Antonio R. Villa, Daniel Zamora-Valdés, Daniela Morales-Espinosa, Misael Uribe Page 194-195

    Background/Aims: Cirrhosis mortality has registered large changes over the last few decades. Aim: To report worldwide mortality due to cirrhosis over the period 1980-2002. Methods: Age-standardized (world standard) cirrhosis mortality rates per 100,000 were computed for 41 countries worldwide over the period 1980-2002 using data from WHO mortality database. Results: In the early 1980s, the highest rates were in Mexico, Chile (around 55/100,000 men and 14/100,000 women), France, Italy, Portugal, Austria, Hungary and Romania (around 30-35/100,000 men and 10-15/ 100,000 women). Mortality from cirrhosis has been steadily declining in most countries worldwide since the mid or late 1970s (annual percent change, APC, between -5% and -1.5% in the last decade only for both sexes). In southern Europe, rates in the early 2000s were less than halved compared to earlier decades. In contrast, rates have been rising in Eastern European countries to reach extremely high values in the mid 1990s, and declined only thereafter. In the UK rates were still steadily rising (APC around +7% in men and +3% in women from England and Wales, and +9% in men and +7% in women from Scotland). Conclusions: Mortality from cirrhosis shows favourable trends in most countries of the world, following the reduction in alcohol consumption and hepatitis B and C virus infection. The steady upward trends observed over more recent calendar periods in the UK and central and eastern European countries are attributed to the persistent increase in the prevalence of alcohol consumption. Abstract published under the permision of the editor of J Hepatol

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