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Current Issue

April - June, 2009

Vol. 8 Issue 2

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

In Memoriam

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Non-invasive assessment of fibrosis in non-alcoholic fatty liver disease (NAFLD) Francesco Vizzutti, Umberto Arena, Valerio Nobili, Roberto Tarquini, Marco Trappoliere, Giacomo Laffi, Fabio Marra, Massimo Pinzani Page 89-94

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children and adolescents. The resulting increase in the number of patients with NAFLD is expected to translate into increased numbers of patients with liver cirrhosis, and hepatocellular carcinoma. In this context, it is particularly important to identify patients at risk for progressive chronic liver disease. Currently, liver biopsy is the gold standard to diagnose non-alcoholic steatohepatitis (NASH) and to establish the presence and stage of fibrosis. Due to the remarkable increase in the prevalence of NAFLD and the concomitant efforts in developing novel therapies for patients with NASH, non-invasive, simple, reproducible, and reliable noninvasive methodologies are needed. This paper provides a concise overview of the role of non-invasive diagnostic tools for the determination of presence and extent of fibrosis in NAFLD patients, with particular emphasis on the methods currently available in clinical practice.

  • Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress Abraham Lemberg, Maria Alejandra Fernández Page 95-102

    This review addresses recent and not so recent works that emphasize on the mechanisms by which liver damage can induce encephalopathy. Hepatic encephalopathy constitutes an intriguing complication in severe liver acute and chronic disease, whose pathophysiology is still not completely understood. In this pathology, alterations in normal brain function are associated with morphological and functional impairments of astrocytes and neurons. A wide spectrum of psychoneurological symptoms has been described and the anatomical substratum is usually associated with brain edema and intracranial hypertension, as well as with changes in the function of brain cells. An increase in blood ammonia, toxic to the brain, depends on the activity of the enzyme glutamine synthetase, the glutamine/glutamate cycle and the brain capacity to eliminate toxic substances. When the concentration of the excitotoxic neurotransmitter glutamate is increased, it acts as a toxic agent, especially when its specific transporters are altered and its uptake is decreased. Glutamine has also been recently considered a toxic substance when its concentration is high, and consequently contributes to brain edema. Finally, the formation of reactive oxygen species, basically produced by mitochondria, influence with their toxic action on membrane lipids, proteins and DNA. In conclusion we suggest that at least these four elements are involved directly in the mechanism of hepatic encephalopathy.

  • Current and future treatment options for HCV Bernd Kronenberger, Stefan Zeuzem Page 103-112

    Aim of antiviral therapy of patients with chronic hepatitis C is the sustained elimination of the hepatitis C virus (HCV). The standard of care (SOC) is peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks in patients infected with HCV genotype 1 or 2/3, respectively. Overall, approximately half of the patients can be cured by SOC. Based on baseline viral load and the speed of virologic response during treatment, individualization of treatment duration is possible. However, this approach is not sufficient to substantially improve the sustained virologic response (SVR) rates. This goal can be achieved with new HCV specific inhibitors against the NS3/4A polymerase and the NS5B polymerase. Recent trials reported SVR rates in the order of 67-69% and 67-75% for the combination of SOC with the protease inhibitors telaprevir and boceprevir, respectively, in patients with HCV genotype 1 infection. Several new HCV specific inhibitors such as protease inhibitors, nucleoside and non-nucleoside polymerase inhibitors as well as non HCV specific compounds with anti-HCV activity such as cyclophilin inhibitors, silibinin, and nitazoxanide are currently in clinical evaluation. The review describes recent developments and discusses limitations posed by resistance development and drug toxicity.

ORIGINAL ARTICLES

  • Prevalence of hepatitis C virus infection in patients with cardiomyopathy Vijaya Boyella, Ikenna Onyebueke, Najabh Farraj, Suzette Graham-Hill, Cherif El Younis, Nora V. Bergasa Page 113-115

    Chronic hepatitis C can be associated with extrahepatic manifestations; thus, we explored the association of this viral infection with dilated cardiomyopathy in a group of sixty-three patients with a cardiac ejection fraction of less than 40% determined by an echocardiogram in a prospective study. Two of the forty-one patients with non-ischemic cardiomyopathy (4.8%) had serum antibodies to the hepatitis C virus and one of those had hepatitis C virus RNA (2.4%) in serum, consistent with chronic hepatitis C. One of the 22 patients with ischemic cardiomyopathy (4.5%) had serum antibodies to the hepatitis C virus but the hepatitis C virus RNA was not detected in their serum, consistent with prior infection but not chronic hepatitis C. In this study, chronic hepatitis C was not prevalent in the group of patients, although the only patient with chronic hepatitis C had non-ischemic cardiomyopathy. As a genetic predisposition to develop cardiomyopathy secondary to chronic hepatitis C has been suggested to be relevant in this type of complication, studies that include different racial and ethnic groups are warranted, as treatment of the hepatitis may lead to resolution of the cardiomyopathy.

  • Common SPINK-1 mutations do not predispose to the development of non-alcoholic fatty liver disease Nevin Oruc, Omer Ozutemiz, Ulus Salih Akarca, Afig Berdeli, Galip Ersoz, Fulya Gunsar, Zeki Karasu, Tankut Ilter, Yucel Batur Page 116-119

    Background: Non-alcoholic fatty liver disease (NAFLD) is common in obese and diabetics. Serine protease inhibitor Kazal-1 (SPINK-1) protein is highly expressed in the liver and adipose tissue of diabetic and obese suggesting its role in NAFLD. SPINK-1 also behaves as an acute phase reactant protein. Some genetic factors including the genetic variations in SPINK-1 protein have been linked to chronic pancreatitis and diabetes. We therefore hypothesized that SPINK-1 mutations might be a risk factor for the development of NAFLD. Methods: Liver biopsy proven fifty NAFLD cases (20 steatohepatitis, 30 diffuse fatty liver disease and 44 healthy controls were included to the study. Liver function tests were measured. Body mass index was calculated. Insulin resistance was determined by using a homeostasis model assessment (HOMA-IR). Ultrasound evaluation was performed for each subject. Common genetic mutations in the third exon of SPINK-1 gene were analyzed by direct sequencing method. Results: We found two cases with a SNP at N34S location in NAFLD group (allele frequency %4). One subject with diffuse fatty liver disease and other with liver cirrhosis due to NAFLD had N34S mutation. No SNPs were detected in healthy controls. In conclusions, in limited number of patients SPINK-1 mutations were not considered as a risk factor alone for NAFLD development.

  • Incidence and prognostic factors associated with biliary atresia in western India Saket R. Sanghai, Ira Shah, Sushmita Bhatnagar, Anuradha Murthy Page 120-122

    Aim: To estimate the incidence of Biliary Atresia(BA) amongst Neonatal Cholestatic Syndromes (NCS) and determine prognostic factors in BA patients who have undergone Kasai's portoenterostomy. Study design- Retrospective analysis. Setting- Pediatric Hepatobiliary Clinic at B.J. Wadia Children's Hospital, Mumbai. Methods and materials: 32 patients diagnosed with BA referred to the clinic from May 2005 to July 2007 were included in the study. All patients underwent a detailed history, clinical examination and were tested for Liver function tests (LFT), USG abdomen, Liver biopsy, intra-operative cholangiogram and CMV tests. Patients were followed up for a period of 1 month to 7 years post operatively and complications such as cholangitis, progress to liver cell failure and cirrhosis was noted. Results: Incidence of BA amongst NCS (n = 88) was 36.4%. 8 patients of BA (25%) were lost to follow up. Out of the remaining, 10 (41.7%) improved and 14 (58.3%) did not improve. The mean age of presentation was 89 + 55.8days. 1 patient (25%) out of 4 with bile duct size of < 100 microns showed an improvement whereas 3 (37.5%) out 8 patients with bile duct size 100-200 microns showed improvement and 4 (50%) with bile duct size of > 200 microns had improvement post Kasai surgery. Those with bile duct sizes > 200 microns had better prognosis than those with sizes 100- 200 microns (Odd's ratio = 1.8) and < 100 microns (Odd's ratio = 3). 12 patients (50%) were operated before 3 months of age and 50% of them responded to surgery. The remaining 12 patients were operated after 3 months of age and only 33% showed any improvement. (Odd's ratio = 2). Other parameters like SGOT (P = 0.598), SGPT (p = 0.901), total Bilirubin (p = 0.349), Direct Bilirubin (p = 0.429), Alkaline Phosphatase (p = 0.605) and GGTP (p = 0.480), cirrhosis (p = 0.417), degree of fibrosis (p = 0.384), degree of inflammation (p = 0.964) and Cholangitis (P = 0.388) had no effect on the outcome. Conclusion: Biliary Atresia is a common cause of NCS in India. Children with Bile duct size > 200 microns have a good prognosis. Portoenterostomy before 3 months of age has a better outcome.

  • Adipokines in a group of mexican patients with nonalcoholic steatohepatitis Linda E. Muñoz, Paula Cordero, Liliana Torres, Alma Y. Sauceda, Juan P. Flores, Jose J. Segura Page 123-128

    Introduction: Leptin has been implicated in the pathogenesis of nonalcoholic steatohepatitis. It has also been suggested that adiponectin plays an important role in the transition from fatty liver disease to nonalcoholic steatohepatitis. Objective: To evaluate whether leptin and adiponectin levels are related to the degree of necroinflammatory activity and fibrosis in patients with nonalcoholic steatohepatitis. Methods: Leptin and adiponectin levels were determined in 52 patients with nonalcoholic steatohepatitis and in 49 controls by enzyme- linked immunosorbent analysis. Results: Median (interquartile range) leptin levels were higher in patients with nonalcoholic steatohepatitis than in the controls (5.75 (12.3) ng mL–1 and 2.80 (2.40) ng mL–1, respectively; P = 0.0035). Adiponectin levels were lower in patients with nonalcoholic steatohepatitis than in the controls (6.55 (5.05) g mL–1 and 9.30 (6.70) mg L–1, respectively; P = 0.0218). Leptin levels were lower in overweight patients than in obese patients (2.25 (6.73) and 8.0 (16.0) ng mL–1, respectively; P = 0.0025). The amount of necroinflammatory activity observed in liver biopsies correlated positively with the amount of fibrosis (P < 0.0001). Increased lactate dehydrogenase correlated with increased fibrosis in patients with nonalcoholic steatohepatitis (P = 0.0012). Necroinflammatory activity correlated with adiponectin, -glutamyltranspeptidase, the quantitative insulin-sensitivity check index, and ferritin (P < 0.05). Risk factors for nonalcoholic steatohepatitis in the logistic regression analysis were leptin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and - glutamyltranspeptidase (P < 0.0001). Only lactate dehydrogenase (P = 0.0012) was significantly associated with advanced fibrosis on logistic regression analysis. Conclusions: Lactate dehydrogenase was associated with fibrosis and advanced fibrosis. Leptin was associated with nonalcoholic steatohepatitis but not with fibrosis or necroinflammatory activity. Adiponectin was related to necroinflammatory activity. Risk factors for nonalcoholic steatohepatitis were leptin and liver enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and -glutamyltranspeptidase).

  • Subzero nonfreezing storage of rat hepatocytes using UW solution and 1,4-butanediol. II- functional testing on rewarming and gene expression of urea cycle enzymes Edgardo E. Guibert, Luciana L. Almada, María E. Mamprin, Cristina Bellarosa, María Dolores Pizarro, Claudio Tiribelli, Joaquín V. Rodríguez Page 129-133

    In the present study we have analyzed the viability and metabolic competence of isolated rat hepatocytes subjected first, to subzero nonfreezing storage (up to 120 h at -4 ºC) in modified University of Wisconsin (UW) solution with 8% 1,4-butanediol, and then to a normothermic rewarming step (KHR media, 37 ºC, up to 120 min, carbogen atmosphere). Results were compared with hepatocytes stored up to 120 h at 0ºC in modified UW solution and with freshly isolated hepatic cells. We have found that only cell suspensions stored in subzero nonfreezing conditions were able to finish the rewarming period with a viability comparable with the control group. Also, we have investigated the enzyme activities and the relative expression at messenger RNAs levels of two of the Urea cycle (UC) enzymes: Carbamyl phosphate synthetase I (CPSI) and ornithine transcarbamylase (OTC), during 60 min of rewarming. Results were compared with the ammonium removal efficiency of the three groups. In conclusion: These data indicated that hepatocytes preserved under cold or subzero conditions up to 120 h followed by 60 min of rewarming, maintain UC enzymes at levels similar to freshly isolated hepatocytes, allowing their use in bioartificial liver devices.

  • Role of ursodeoxycholic acid in prevention of hepatotoxicity caused by amoxicillin-clavulanic acid in rats Gamal A. El-Sherbiny, Ashraf Taye, Ihab T. Abdel-Raheem Page 134-140

    Incidence of hepatotoxicity caused by the broad spectrum antibiotic combination amoxicillin-clavulanic acid (Co-amoxyclav) has been increasingly recognized and the mechanism of this toxicity remains undefined. On the other hand, Ursodeoxycholic acid (UDCA) has been suggested as efficient antioxidant therapy in various liver diseases. Therefore, the present study was designed to elucidate the possible role of oxidative stress in hepatotoxicity induced by Co-amoxyclav and the putative protective role of UDCA in rats. Effects of amoxicillin (Amox; 50 mg/kg, orally, 21 d) or clavulanic acid (Clav; 10 mg/kg, orally, 21 d) and their combined administration on the biochemical liver parameters, reduced glutathione (GSH), lipid peroxidation measured as hepatic malondialdehyde (MDA) levels. In addition, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) production in liver homogenate were also evaluated. On the other hand, the protective effects of pretreatment with UDCA (20 mg/kg, orally, 21 d) on these parameters were also evaluated. Our results show that pretreatment with UDCA reduced the liver parameters that were enhanced by single or combined administration of Amox and/or Clav such as serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and serum bilirubin levels. Moreover, pretreatment with UDCA normalized the GSH level and inhibited the elevation in hepatic MDA concentration. The enhanced MPO activity and ROS production in liver homogenate of rats treated with Clav or Co-amoxyclav were also normalized by UDCA pretreatment. In conclusion, the present data suggest that UDCA acts as effective hepatoprotective agent against liver dysfunction caused by Co-amoxyclav and this effect is related to its antioxidant properties.

  • Pharmacokinetics of acemetacin and its active metabolite indomethacin in rats during acute hepatic damage and liver regeneration Aracely E. Chávez-Piña, Liliana Favari, Gilberto Castañed Hernández Page 141-147

    Background and aim: The pharmacokinetics of acemetacin, a non-steroidal anti-inflammatory drug which is biotransformed to indomethacin by hepatic first-pass effect, was examined during the necrotic and regeneration phases resulting from acute hepatitis induced by carbon tetrachloride (CCl4). Material and methods: Acute hepatitis was induced by oral CCl4 administration to male Wistar rats. On days 0, 1 and 3 after the insult, liver histological analysis was performed, biochemical markers of liver damage and regeneration were measured, and the pharmacokinetics of oral acemetacin and of its active metabolite, indomethacin, were determined. Results: One day after CCl4 administration, liver necrosis was apparent and there was an increase in the circulating levels of indicators of liver damage and regeneration with regard to control conditions. Acemetacin bioavailability was increased, although not in a statistically significant manner. On the other hand, indomethacin bioavailability was significantly reduced. By day 3, histological analysis revealed liver recovery, although not complete, while biochemical indicators of hepatic damage had reverted either totally or partially. Markers of liver regeneration were still increased. Bioavailability acemetacin and indomethacin was comparable to control values. In conclusion: Indomethacin bioavailability after oral administration of its precursor, acemetacin, is significantly reduced by acute hepatitis produced by CCl4. Pharmacokinetic alterations, as liver damage, are reversible, but do not require complete liver regeneration to return to basal conditions.

EDITORIAL

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Portal venous gas. Report of three cases José-Luis Martínez, Jorge González-Acosta Page 151-155

    When portal venous gas (PVG) is found, it is usually considered an ominous sign. It is now more frequently found because of the improvement in imaging studies, mainly through computed tomography (CT). It was first related primarily to mesenteric ischemia. However, it is now identified in other conditions and the prognosis is not related to the presence in itself of PVG, but to the nature and severity of the underlying condition or disease that causes it. Next, we report three patients with portal venous gas that were seen at our surgical department. All the patients presented acute abdominal pain and during their diagnostic studies, portal venous gas was identified. Intestinal ischemia was diagnosed in two of them, who underwent an exploratory laparotomy, one of them died within 24 hours. In the other patient, the pain subsided and was treated medically and the recovery was uneventful. In conclusion: the most important factor related to portal venous gas is the disease that caused it. The most common cause of PVG is mesenteric ischemia, so every effort should be made to rule it out, as the prognosis is related to an early diagnosis and almost all patients require surgery. Other causes had been reported and conservative treatment could be used in selected cases.

  • Congenital choledochal cyst in an infant with cystic fibrosis Parviz Tabatabaie, Gholam-Hossein Fallahi, Fatemeh Farahmand, Kambiz Eftekhari, Maedeh Ahmadi, Faezeh Ahmadi, Fatemeh Bazvand, Nima Rezaei Page 156-157

    Congenital choledochal cyst is malformation of the biliary ductal system, which rarely occur. We describe here a 4-month old boy, who was referred to our center with respiratory distress and low level consciousness. In physical examination, a mass was detected in right upper quadrant of abdomen. Sonographic examination indicated a cystic structure representing the choledochal cyst. Further evaluation confirmed the diagnosis of cystic fibrosis in this patient. Although choledochal cyst is considered as a rare disease, it is the most frequent malformation of the extrahepatic biliary ducts, which easily could be misdiagnosed.

  • The use of sildenafil to treat portopulmonary hypertension prior to liver transplantation Ian S.H Cadden, Erica D. Greanya, Siegfried R. Erb, Charles H. Scudamore, Eric M. Yoshida Page 158-161

    Portopulmonary hypertension (PPH) is an infrequent, but well-recognized complication of liver cirrhosis. PPH in those with end-stage liver disease has a significant impact on per-operative and intra-operative mortality, with liver transplantation being contraindicated in those individuals with mean pulmonary artery pressure exceeding 50 mmHg. Vasodilatory therapy is the mainstay of pharmacotherapy for PPH, although the evidence of benefit is largely extrapolated from the pulmonary hypertension literature. We report the use of the phosphodiesterase inhibitor, sildenafil, in a patient with end stage liver disease and PPH, with a pulmonary artery pressure before transplantation of 75 mmHg, to reduce pulmonary artery pressure prior to a successful liver transplant.

  • Acute liver failure due to white phosphorus ingestion Oscar Santos, Juan-Carlos Restrepo, Lina Velásquez, Jaime Castaño, Gonzalo Correa, Elsy Sepúlveda, Nora Yepes, Sergio Hoyos, Carlos Guzmán, Germán Osorio, Andres Cardenas Page 162-165

    Background: White phosphorus is chemical compound available in military ammunition as well as in explosive powder of recreational use. This latter form is commonly found in Latin America and Asia as a main ingredient of gunpowder used to make street firecrackers. Small firecrackers may be ingested accidentally or used as a toxic agent in suicidal attempts which may cause of acute liver failure and death; however the clinical features, incidence and outcome are poorly described in the literature. Methods: We describe three cases of white phosphorus intoxication with acute liver failure secondary to the consumption of firecrackers. In two cases, ingestion occurred secondary to suicidal attempts and in one, ingestion occurred by accident. In one case, liver injury improved with supportive care, in the other, the patient required liver transplantation and the third case had a fatal outcome. Conclusions: Clinicians providing care of patients with acute hepatitis of unclear etiology should be aware that the ingestion of firecrackers containing white phosphorus might cause acute liver failure that may require liver transplantation.

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