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Current Issue

October - December, 2010

Vol. 9 Issue 4

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




Clinical Studies

  • Liver transplantation for T3 lesions has higher waiting list mortality but similar survival compared to T1 and T2 lesions Timothy M. Schmitt, Sean C. Kumer, Neeral Shah, Curtis K. Argo, Patrick G. Northup Page 390-396

    Background. Restrictive staging criteria for liver transplant (LT) patients with HCC in the U.S. have resulted in favorable long-term recurrence-free survival, but these criteria exclude a subgroup of patients who, despite tumor size beyond T2 stage, demonstrate an acceptable outcome. The aim of this study was to assess the waiting list and post-transplant mortality of patients with HCC tumors greater than Milan T2 stage. Methods. The U.S. OPTN standard transplant dataset was analyzed for patients with a diagnosis of HCC who were listed for liver transplantation between February 2002 and 2008. Those patients with Milan T3 stage tumors were compared to patients with T1 and T2 lesions. Multivariate survival models were developed to investigate independent predictors of death or tumor recurrence post-transplant. Results. 7,391 patients with HCC were identified. 351 (4.75%) had T3 lesions. Compared to non-T3 patients, total tumor burden was greater and total alpha-fetoprotein (AFP) was higher in the T3 patients. T3 patients also were more likely to receive pretransplant locoregional therapy. There were no significant differences between T3 patients and non-T3 patients in demographic variables or physiologic MELD score at the time of transplant, waiting time, or donor risk index. Waiting list mortality was increased for T3 patients compared to non-T3 and tumor progression while waiting was higher. Independent predictors of waiting list mortality included physiologic MELD score at the time of listing, total tumor burden, and serum AFP. There was significant regional variation in the utilization of exceptions for T3 patients and UNOS regions 4, 9, and 10 performed a higher percentage of their transplants in T3 patients compared to other regions. There was no difference in post transplant survival between T3 and non-T3 patients. Independent predictors of post-transplant mortality included physiologic MELD score at the time of transplant, recipient age, and donor risk index. In patients with T3 tumors, total tumor burden was not an independent predictor of post transplant survival. Conclusions. Patients who are listed for liver transplantation with Milan stage T3 HCC have higher waiting list mortality but have similar post-transplant survival compared to patients with T1 and T2 HCC.

  • Prevalence and factors associated with the presence of Abnormal Function Liver Tests in patients with ulcerative colitis Jesús K. Yamamoto-Furusho, Magdalena Sánchez-Osorio, Misael Uribe Page 397-401

    Aim. To investigate the prevalence of abnormal function liver tests and risk factors associated with their development in Mexican patients with UC. Methods. A total of 200 patients with confirmed diagnosis of UC were evaluated prospectively during a one year period from January 1, 2007 to December 31, 2008. Results. A total of 94 females and 106 males patients with UC were analyzed. The age at diagnosis was 31.4 ± 13.2 years and the mean of disease duration was 6.7 ± 5.2 years. We found a high prevalence of abnormal function livers tests in 40% of UC patients. The pattern of abnormal function liver test was hepatitis in 70%, cholestatic (20%) and mixed (10%). The most common cause of abnormal function liver test was transient elevation in 50 patients (63%) followed by fatty liver disease (11.2%), primary sclerosing cholangitis (6.3%), drug-toxicity (6%) and others (13.5%) including chronic hepatitis C, total parenteral nutrition, granulomatous and ischemic hepatitis. In the multivariate logistic regression model, active disease, colectomy and abdominal sepsis were factors that persisted associated with the development of abnormal liver tests in UC patients. Conclusion. A high prevalence of abnormal function liver tests (40%) was found in Mexican UC patients is likely to be related to active disease, colectomy and the presence of sepsis.

  • Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens† Ylse Gutierrez Grobe, Guadalupe Ponciano-Rodríguez, Martha H. Ramos, Misael Uribe, Nahum Méndez-Sánchez Page 402-409

    Background & Aim. Non alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. Population studies have demonstrated that men and posmenopausal women have higher prevalence of NAFLD. The aim was to investigate the prevalence of NAFLD in premenopausal, posmenopausal and polycystic ovary syndrome (PCOS) women. Methods. A cross sectional study carried out at University Hospital in Mexico City from January 2009 to November 2009. One hundred ninety seven women who agreed to participate were divided into groups, comprising 93 with NAFLD and without NAFLD. Anthropometric, metabolic and biochemical variables were measured. Serum estradiol and cortisol concentrations were determined and compared between the groups. Results. Of the 197 patients, 93(47.2%) had NAFLD and 104 (52.8%) did not have NAFLD. The prevalence of NAFLD in premenopausal, postmenopausal and PCOS patients was 32.2, 57.9, and 62%, respectively. Age, BMI, hip to waist ratio, fasting glucose, HOMA –IR, and insulin were significantly higher in NAFLD patients. Women without NAFLD had significantly higher levels of serum estradiol (100 ± 95.4) compared with NAFLD patients (55.5 ± 66.6) p = 0.001. By group with and without NAFLD: premenopausal (55.44±93.3 vs. 128.56 ± 109.22), posmenopausal (44.98 ± 51.41 vs. 42.72 ± 51.48) and PCOS women (64.9 ± 53.3 vs. 101.36 ± 80.89) had significantly different hormone profile. Conclusion. These results suggest that NAFLD is more prevalent in postmenopausal and women with PCOS than those premenopausal ones. The estrogens may have a protective effect of against NAFLD in women.

  • Synergistic Effect of Celecoxib on 5-fluorouracil-induced Apoptosis in Hepatocellular Carcinoma Patients Ahmad R. Bassiouny, Amira Zaky, Hashem M. Neenaa Page 410-418

    Background. Cyclooxygenase-2 (COX-2) enzyme over expression is reported in many human HCC cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with HCC. COX-2 is often increased and involved in drug resistance and poor prognosis. Method. Between January 2001 and December 2007, 15 patients with MDR-positive-HCC from 34 HCC patients based on tissue and serum liver of glypican-3 and fitting the preset eligibility criteria, were treated with a combination regimen with intravenous infusion of (5-FU) 750 mg once per week, 100mg/day cyclophosphamide (Endoxan) and 400 mg/day celecoxib taken orally in divided doses, while the rest of the patients received only 5-FU and Endoxan. Twenty-one patients (62%) had liver disease associated with hepatitis C virus (HCV) and 5 patients with hepatitis B virus (62%). Results. We found that celecoxib reduced P-glycoprotein with activation of caspase-3 and marked regression of tumor sizes. Sera angiogenic factors (VEGF & bFGF) levels measurement in HCC patients indicated that, the sera levels of both angiogenic factors were reduced significantly (p < 0.05) after treatment. Based on the tumor markers AFP & Glypican-3, 11 of the patients had a PR (11/15), including 3 patients who had normalization of AFP, and four patients had CR (4/15). Conclusions. These data suggest that the combination of 5-FU, Endoxan and Celecoxib is highly effective palliative regimen for patients with HCC with good performance status (score £ 3). The study suggests a framework for Celecoxib-based combination treatment of HCC.

  • Fatigue and depressive symptoms associated with chronic viral hepatitis patients’ health-related quality of life (HRQOL) Katerina Karaivazoglou, Gregoris Iconomou, Christos Triantos, Thomas Hyphantis, Konstantinos Thomopoulos, Maria Lagadinou, Charalambos Gogos, Chryssoula Labropoulou-Karatza, Konstantinos Assimakopoulos Page 419-427

    Background and rationale. It is well established that chronic viral hepatitis (CVH) negatively affects patients ’ health-related quality of life (HRQOL). The aim of the present study was to assess the extent to which fatigue and depressive symptoms are associated with CVH patients’ HRQOL. Methods. Eighty-four adult CVH outpatients [45 with hepatitis B virus (HBV) and 39 with hepatitis C virus (HCV) infection] participated in the study. The Short Form-36 Health Survey (SF-36), the Beck Depression Inventory-II (BDI-II) and the Fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia Scale (FACT-F) were used to assess HRQOL, depression and fatigue, respectively. Results. All aspects of HRQOL perceived by CVH patients were significantly impaired compared to the general population, as a comparison with Greek population- based normative data revealed. HBV patients presented similar HRQOL with HCV patients. Clinical parameters including infection activity, fibrosis stage or inflammation grade, as well as depressive symptoms and fatigue were found to be significantly associated with HRQOL. Multivariate analyses showed that older age (p <0.001) and higher fatigue scores (p <0.001) were the variables most closely associated with the physical HRQOL, whereas higher rates on depressive symptoms (p <0.0005) and fatigue (p <0.020) scales were the variables most closely associated with the mental HRQOL. Conclusions. In conclusion, CVH is associated with impaired HRQOL. Fatigue and impaired psychological functioning is associated with diminished HRQOL in CHV, independent of the disease etiology. Consequently, management of fatigue and depressive symptoms should be considered a priority, in order to improve HRQOL in CVH patients.

  • Liver diseases in Mexico and their associated mortality trends from 2000 to 2007: A retrospective study of the nation and the federal states Nahum Méndez-Sánchez, Elsy García-Villegas, Beatriz Merino-Zeferino, Soledad Ochoa-Cruz, Antonio R. Villa, Herlinda Madrigal, Ramón A. Kobashi-Margáin, Ylse Gutiérrez-Grobe, Norberto Chávez-Tapia, Guadalupe Ponciano-Rodríguez, _ Misael Uribe Page 428-438

    Introduction. Liver disease is a major health issue in Mexico. Although several studies have been performed to analyze the impact of liver diseases on the Mexican population, none has compared the prevalence and impact of liver disease between states within Mexico. AIM: To analyze trends in mortality associated with liver diseases from 2000 to 2007 at the national and state levels. Methods. Data was obtained from the Ministry of Health (number of deaths) and the National Population Council (CONAPO) (population at risk) and mortality rates were analyzed using statistical software. Results. Mortality due to viral hepatitis, liver tumors, and cirrhosis increased over the study period. Alcohol-related mortality decreased but was still the main cause of liver-related deaths. Viral hepatitis infection occurred predominantly in the northern states and liver tumors occurred predominantly in the central region. Alcohol-related deaths were elevated along the Pacific shoreline and deaths associated with cirrhosis occurred mainly in the central and southern states. Conclusion. Incidence of liver-related mortality has increased and will continue to do so in the future.

  • G308A polymorphism of TNF-alpha gene is associated with insulin resistance and histological changes in non alcoholic fatty liver disease patients Rocio Aller, Daniel Antonio de Luis, Olatz Izaola, Manuel González Sagrado, Rosa Conde, Tomas Alvarez Gago, David Pacheco, Jose Manuel González, María Concepcion Velasco Page 439-444

    Some studies have pointed to a role of TNF-alpha in pathogenesis of non alcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the influence of G308A polymorphism TNF alpha gene on the histological changes, insulin resistance and TNF-alpha levels in overweight patients. A population of 66 patients with NAFLD was recruited in a cross sectional study. A biochemical analysis of serum was measured. Genotype of TNF alpha gene G308A was studied. Fifteen patients (22.7%) had the genotype G308A (mutant type group) and 51 patients (77.3%) G308G (wild type group). Patients with mutant type group presented more moderate-severe portal inflammation (86.7%) in liver biopsy compared to patient with wild genotype (19.7%). Mutant type group had more moderate-severe fibrosis (73.3%) than wild type group (51.3%). The multivariate analysis adjusted by age, sex, BMI and genotype with the dependent variable (fibrosis) showed that HOMA remained in the model, with an increase of the probability to develop fibrosis of 1.78 (CI95%:1.06-3.2) and develop moderate-severe inflammation of 1.45 (CI95%:1.02-2.1) with each increase of one unit on HOMA levels. In conclusion, Patients with mutant genotype have more frequently moderatesevere portal inflammation and fibrosis than wild type genotype.


Basic studies

  • The preventive effect of low molecular weight heparin on CCL4-induced necrosis and apoptosis in rat liver Aysel Kukner, Fatma Tore, Tülin Firat, E. Hakan Terzi, Hakan Oner, Yasemin H Balaban, Candan Ozogul Page 445-454

    Introduction. Heparin having anti-inflammatory and anti-fibrotic properties may have therapeutic effect on liver injury. The present study investigated the effect of low molecular weight heparin (Enoxaparin) on carbon tetrachloride (CCl4) induced hepatic necrosis and apoptosis in rats. Material and methods. Thirty male rats were divided into 5 groups. Group I: Control; Group II: Olive oil dissolved CCl4 at dose of 1 mL/kg, ip, twice per week; Group III: CCl4 and Enoxaparin at dose of 180 IU/kg, sc, daily; Group IV: Enoxaparin; Group V: Olive oil at dose of 1 mL, ip, twice per week. The liver histology at the forth week was examined by haematoxylin-eosin, Masson’s trichrome, Toluidine blue and Periodic acid schiff stains. Proliferative and apoptotic activities were assessed semi-quantitatively by proliferating cell nuclear antigen (PCNA) and caspase- 3 immune staining and TUNEL method. Semi-quantitative values formulated by the equation HSCORE = åPi (i+1) including both distribution and intensity of staining. Additionally, nidogen and a-smooth muscle actin were labeled by immunohistochemistry. Results. CCl4 group had marked hepatocelluar necrosis around the vena centralis and increased inflammatory cells and mast cells. Hepatocytes showed deposition of lipid droplets, decrease in glycogen, apoptosis, and picnotic or enlarged nuclei. Enoxaparin reduced necrosis, apoptosis, and number of mast cells but had no effect on lipid droplets in hepatocytes. HSCORE’s of caspase-3 and PCNA were also significantly decreased by administration. Conclusion. Enoxaparin have beneficial effects against necrosis as well as apoptosis at the early stage of CCL4 induced liver injury.



  • Anaplastic large cell lymphoma presenting as acute liver failure: A report of two cases with review of literature Uma Nahar Saikia, Nidhi Sharma, Ajay Duseja, Ashish Bhalla, Kusum Joshi Page 457-461

    Primary hepatic anaplastic large cell lymphoma (ALCL) of the liver is a rare entity. We present here two cases of primary hepatic anaplastic large cell lymphoma (ALCL) of the null-cell type. Both the cases had jaundice with “B” symptoms and hepatomegaly. The serum billirubin and liver enzymes were raised in both cases. The liver showed sinusoidal infiltration by atypical lymphoid cells with marked nuclear pleomorphism, dispersed chromatin and prominent nucleoli in both the cases. These cells were positive for CD30, negative for CD3, CD20 and EMA, and diagnosed as ALCL of the null-cell type. We hereby report these cases with the review of literature on primary hepatic ALCLwith their possible etio-pathogenesis & diagnostic clues which may help in timely diagnosis & management in such cases.

  • Fatal rhinocerebral mucormycosis under the shade of hepatic encephalopathy Hilmi Ataseven, Ilhami Yüksel, Selcan Gültuna, Seyfettin Köklü, Serkan Uysal, Ömer Basar, Nurgül Sasmaz Page 462-464

    Mucormycosis is an acutely fatal infection that occurs in immuncompromised patients. Cirrhosis is an acquired immune deficiency state and those patients are more prone to develop opportunistic infections. A 42-years-old cirrhotic man was admitted to our gastroenterology clinic with hepatic encephalopathy. Although he recovered from encephalopathy with supportive measurements, he developed paresthesia on the face. He was diagnosed with rhinocerebral mucormycosis and antifungal therapy was administered. Surgical treatment couldn’t be performed because of his bleeding diathesis and poor general condition. He succumbed on the 12th day of his admission.

  • Clear cell hepatocellular carcinoma arising 25 years after the successful treatment of an infantile hepatoblastoma Jeffrey Basile, Stephen Caldwell, Norris Nolan, Christopher Hammerle Page 465-467

    Primary liver tumors in children are rare with hepatoblastoma (HB) being the most common malignancy. Clear cell carcinoma, a variant of hepatocellular carcinoma (HCC), is another rare tumor of the liver that tends to affect adults. We describe the diagnosis and management of the only known documented case of a primary clear cell HCC arising twenty-five years after the patient was successfully treated with chemotherapy and surgical resection for a malignant HB as an infant. While some evidence has shown a genetic link between HB and various types of HCC, other research has shown distinct chromosomal alterations and molecular mechanisms unique to both. Further knowledge of liver tumorigenesis will help elucidate the complicated genetic, molecular, and environmental factors involved in the development of these two rare hepatic malignancies.

  • Recurrent idiopathic acute hepatitis-associated aplastic anemia/pancytopenia fourteen years after initial episode Nawal Al Nahdi, Holly Wiesinger, Heather Sutherland, Eric M. Yoshida Page 468-470

    Aplastic anemia following viral hepatitis is a condition well recognized in the medical literature. Although hepatitis-associated aplastic anemia is an uncommon syndrome, there are several reports in the literature describing such cases. In these reports, aplastic anemia generally occurs following a viral infection, including parvovirus B19, but may also be idiopathic. The etiology of both the hepatic injury and the bone marrow failure is speculated to be immune-mediated. We report a patient who suffered acute idiopathic hepatitis and severe pancytopenia fourteen years after a similar episode in childhood. This is only the second case report of acute hepatitis in association with bone marrow failure and aplastic anemia in childhood with sudden recurrence many years later in adulthood.



  • Lysophosphatidic acid and atotaxin in patients with cholestasis and pruritus: Fine biology, anticipated discernment Nora V. Bergasa Page 475-479

    Background & aims. Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons. Methods. Cytosolic free calcium ([Ca(2+)] (i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)] (i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. Results. Transient increases in neuronal [Ca(2+)] (i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)] (i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP vs. pregnant controls (P < 0.0001) and cholestatic patients with vs. without pruritus (P < 0.0001). Autotaxin activity correlated with intensity of pruritus (P < 0.0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or muopioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. Conclusions. We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.



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

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