Vol. 4 Issue 3
On the cover: Official Journal of the Mexican Association of Hepatology
A major challenge in the field of hepatology is the fight against hepatitis C that affects more than 150 million people world-wide. Despite the enormous improvement that has been achieved in the therapy of chronic hepatitis C over the last decade, there is an urgent medical need for new therapeutic approaches. This review focuses on the optimization of the current standard therapy of hepatitis C and future treatment directions beyond pegylated interferon alpha and ribavirin.
Chronic hepatitis C virus (HCV) infection is very common among HIV-positive patients who were infected through intravenous drugs use or contaminated blood products (e.g., hemophiliacs). An increase in liver-related deaths among HIV-positive subjects co-infected with HCV has been acknowledged over the last years. HIV infection has a negative impact on the natural history of chronic hepatitis C, accelerating the progression of liver fibrosis. Moreover, interactions between anti-HIV and anti-HCV drugs are of concern, and a lower response to anti-HCV therapy limits its benefit in the HIV/HCV-coinfected population. Regarding treatment monitoring, the stopping rule at week 12 recommended for HCV-monoinfected individuals, seems to be equally valid in HIV-infected patients. This finding is of great value, since it allows to offer treatment in the absence of contraindication (e.g., low CD4 counts, alcohol abuse, etc), discontinuing it as soon as at 12 weeks after initiation when no chances of cure are anticipated, saving costs and deleterious side effects. There are important barriers to HCV treatment in HIV/HCV-coinfected patients, which are necessary to be addressed in order to increase the eligibility and applicability of HCV therapy in this population. In addition, strategies aimed to improve tolerance of the HCV medication with adequate support as well as to enhance the response to current available therapies, including individualized tailoring of drug dosages and length of treatment, should be pursuit to enhance the rate of treatment success. Finally, new anti-HCV drugs currently under development are eagerly awaited for the growing number of HCV/HIV-coinfected patients non-responders or relapsers to the current therapy.
Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic, progressive destruction of small intrahepatic bile duct with portal inflammation and ultimately fibrosis, leading to liver failure in the absence of treatment. The serologic hallmark of PBC is the presence of autoantibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex (PDC). Current theories on the pathogenesis of PBC favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. Like other better characterized autoimmune diseases, there appears to be a genetic susceptibility and a triggering event that initiates the autoimmune attack on bile duct cells. DRB1*0801 and DRB1*0803 are the major susceptibility alleles among Northern European and Japanese populations, respectively. The generation of immune responsiveness to self-antigen can result in pathogenic autoimmune damage of the intrahepatic biliary epithelial cells mediated by both humoral and cellular immune responses. The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. Human and animal studies have suggested that the induction of an antibody response reactive with self-antigen may result from a number of different priming events. Among the events demonstrated to induce an antibody response cross-reactive with self-PDC are exposures to bacterial PDC or retroviral proteins or xenobiotics or microchimerism. The diversity of the potential events giving rise to antibody responses cross-reactive with PDC, which could promote subsequent T-cell tolerance breakdown, suggests the intriguing possibility that PBC could represent a condition with a common final pathway but with multiple triggers able to induce a B-cell response cross-reactive with self- PDC. There are important questions about the pathogenesis of PBC which remain unanswered.
Progression of liver disease in chronic hepatitis C depends on several factors related to the host, virus and the environment which deserves further investigations. 120 candidates for blood donation with hepatitis C virus were divided into three groups according to alcohol intake: abstainers41, light drinkers36 and heavy drinkers43. Liver histopathology alterations, namely architectural staging, periportal and lobular inflammation as well as portal inflammatory infiltrate were graded from 0 to 4 and afterwards divided into light (0 to 2) and severe (3 to 4). There were more drinkers among men (83.5%) than among women (41.5%). Regarding the three groups, mild periportal inflammation was significantly related with abstainers and light drinkers groups whereas severe periportal inflammation was more predominant in heavy drinkers (p = 0.033). When we compared mild with severe histopathological alterations older age was significantly (p = 0.004) associated with severe fibrosis, periportal inflammation and portal inflammatory infiltrate. In relation to enzyme levels a significant difference in fibrosis and lobular activity was found for ALT, AST and GGT. Only AST was a marker of greater portal inflammatory infiltrate. Additionally, platelets were significantly lower in severe fibrosis and in periportal inflammation. Logistic regression analysis identified AST and platelets as independent predictors for severe fibrosis. In conclusion, a correlation was found between alcohol consumption and periportal inflammation. Fibrosis correlated with age, high enzymes levels and low platelets. AST and platelets were the best predictors for severe fibrosis.
Most iatrogenic bile duct injuries are recognized in the early postoperative period (first 48 hours). These patients usually have additional complications such as a suboptimal hydroelectrolitic status, subhepatic collections, external biliary fistula and malnutrition. In these circumstances, besides the elevation of bilirrubin and transaminases associated with the injury, hypoalbuminemia is frequently encountered. The timing for repair is decided according to the condition of each patient. We report the impact of preoperative abnormal low serum albumin levels on the results of biliary tract reconstruction after a iatrogenic biliary lesion. Method: Patients who underwent biliary reconstruction in our center from 1998 to 2002 were analyzed. Only patients with complex injuries (Strasberg E, Bismuth III-IV, Stewart-Way III) were included. Major postoperative complications were recorded and correlated with preoperative liver function tests. Results: Seventy seven patients were analyzed. In 41 cases, the injury was a consequence of a laparoscopic operation. All patients were treated by a Roux-en-Y hepatojejunostomy. No operative mortality was recorded. The most frequent postoperative complications were postoperative biliary fistula (8/77-9%, p < 0.017) and subhepatic collections (9/77-9%, p < 0.39). All fistulae closed spontaneously and the subhepatic collections were drained. Overall, complications were more common in the group with hypoalbuminemia (p < 0.002). Conclusion: Early repair is indicated if there is no systemic contraindication (sepsis, multiple organic failure, electrolytic imbalance). Abnormalities in the liver function tests, particularly a low serum albumin, should not delay the operation. Although significantly more postoperative complications are observed in an early repair, long-term results are comparable to those of an elective repair.
Objective: To evaluate the frequency of hepatobiliary diseases and the clinical manifestations in patients with HIV treated with non highly active anti-retroviral therapy. Methods: Seven hundred clinical records of patients with HIV infection who entered the Instituto Nacional de Ciencias Médicas y de la Nutrición Salvador Zubirán from January 1987 to December 1996 were reviewed. All patients with alterations associated to hepatobiliary disease and/or liver function tests derangement throughout the clinical development of their disease were included. Demographic variables, date of diagnosis and clinical stage of the disease, as well as the presentation forms, diagnostic approach and image studies were analyzed. Results: One hundred and sixtyone patients (22.8%) with hepatobiliary manifestations were found. The average time between the HIV diagnosis and the presentation of hepatic manifestations was 2-12 years. The majority of patients 124/161 (77%) did not show clinical signs of liver damage. The diagnostic suspicion was established by the presence of alkaline phosphatase above normal in 29% and alkaline phosphatase plus aminotransferases above normal in 45%. Hepatomegaly and jaundice were present in 18% and 4% of the patients, respectively. The most frequent ultrasonographic diagnosis were hepatomegaly (40%) and steatosis (30%). Liver biopsies were performed in 85 (51%) of the patients. The main histologic diagnoses were granulomatous hepatitis (29%), steatosis plus granulomatous hepatitis (19.5%), and steatosis alone (14.6%). Microorganisms were isolated in 27.9% being the most frequent Mycobacterium tuberculosis (26.6%), Histoplasma capsulatum (20%), Cytomegalovirus (13.3%), and Mycobacterium avium intracellulare (11%). The HBsAg was positive in 21 of the 69 patients (30.4%). Conclusions: The clinical presentation was asymptomatic in most of cases and the main etiology could be explained by the presence of associated infections, granulomatoses and liver steatosis.
Background: Gallbladder carcinoma (GBC) is a frequent neoplasm in Hispanic and native American populations. GBC is preceded by gallstones, chronic cholecystitis and dysplastic changes of the gallbladder epithelium. The knowledge of the molecular events involved in its pathogenesis is scarce. Aims: We investigated the role of TP53 inactivation in the sequential pathogenesis of GBC. Methods: Invasive tumor-, dysplastic- and histologically normal GB epithelial- cells were obtained from archival formalinfixed tissues from GBC and GB from gallstone patients without GBC. Normal GB epithelia from 5 non-gallstone specimens were also studied. DNA extracted was examined for loss of heterozygosity (LOH) using 2 microsatellite markers and for TP53 mutations at exons 5 to 8. Results: GBCs demonstrated a high frequency of LOH (81%) and mutation (67%), and both abnormalities indicating gene inactivation were detected in 52%. Similar frequency of Original Article TP53 Abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma§ Mauricio Moreno;1 Fernando Pimentel;2 Adi F Gazdar;3 Ignacio I. Wistuba;4 Juan F. Miquel1 TP53 abnormalities and gene inactivation (38%) were detected in their accompanying normal and dysplastic epithelia. Noteworthy, one third of normal and dysplastic epithelia obtained from GBs of gallstone patients without GBC demonstrated either TP53 allele loss or mutation, but gene inactivation was less frequent (11%). Most mutations affected exons 5 and 7, and they were more frequently missense point mutations. The same TP53 mutation was detected in only a subset (27%) of comparisons between non-malignant epithelia adjacent to GBCs, indicating that TP53 mutation occurs independently at several epithelial foci. Conclusions: These findings indicate that TP53 abnormalities are early and frequent events in the pathogenesis of GBC, starting from chronic cholecystitis.
Background: Percutaneous ethanol injection has been successfully used for hepatocelular carcinomas (HCC) smaller than 5 cm in size. For larger lesions large volume ethanol injection has not been well explored. Aim: Evaluate the results of intraoperative Ultrasonographic- guided large volume ethanol injection for HCC larger than 4 cm in size. Patients and methods: Ten patients were candidates for this treatment between June 1999 and July 2003. A retrospective review of the clinical files was performed. Absolute ethanol, average of 100 mL (range 80-120 mL) was administered intraoperatively. Follow-up evaluation included alpha-fetoprotein (AFP) and ultrasound or computed tomography. Results: There were six women and four men, the median age was 62 years (range 56-80). The median lesion size was 8 cm (range 4-15 cm). Hepatitis C liver cirrhosis was the most common associated chronic liver disease (70%). A significant reduction of AFP levels after treatment was observed (Initial 966 ng/dL, post treatment levels: 42 ng/dL) US and CT scan showed tumor necrosis. Morbidity was 40%. No operative mortality was recorded. The one and four year survival rate was 60% and 20%. Conclusion: Intraoperative US-guided large volume ethanol injection is a safe palliative therapy for cirrhotic patients with HCC lesions greater than 5 cm in size. The impact on survival should be compared in a controlled double blind study.
Little information exists in the international scientific or medical literature about the hepatic manifestations and complications of Epstein-Barr virus (EBV). The aim of this study was to describe a series of patients with hepatic manifestations of EBV infection. Our sample population was a series of patients whose hepatic dysfunction was correlated with a documented EBV infection. Serum concentrations of IgG and IgM antibodies against the EBV viral capsid antigen (anti- EBV VCA IgG), EBV early antigen, and EBV nuclear antigen (EBV-EBNA), and heterophilic antibodies were determined. The expression of latent membrane protein (LMP 1) was also evaluated in each patient. RESULTS. The study included nine patients (six men, three women) with a mean age of 43.5 years. Five patients presented with recent clinical pictures suggestive of acute EBV infection. Five patients began with a cholestatic pattern. Two patients required liver biopsies. Those liver biopsies showed positive immunohistochemical staining for LPM 1. No fatalities were attributed to EBV infection. In conclusion, the bilirubin levels of patients with acute EBV infection differed from those reported in the medical literature. EBV infection should be considered in the differential diagnosis of patients with liver abnormalities or diverse hepatic manifestations, increased levels of aminotransferases, or a transitory cholestatic pattern with a favorable outcome.