Hepatitis: San Francisco Bay area

Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, Tobias H. · Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California 94304-1509, USA. · Clin Gastroenterol Hepatol. · Pubmed #18845489 No free full text.

Abstract: Chronic HBV infection is an important public health problem worldwide and in the United States. A treatment algorithm for the management of this disease, published previously by a panel of U.S. hepatologists, has been revised on the basis of new developments in the understanding of the disorder, the availability of more sensitive molecular diagnostic tests, and the licensure of new therapies. In addition, a better understanding of the advantages and disadvantages of new treatments has led to the development of strategies for reducing the rate of resistance associated with oral agents and optimizing treatment outcomes. This updated algorithm was based primarily on available evidence by using a systematic review of the literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to low or undetectable levels. Assays can now detect serum HBV DNA at levels as low as 10 IU/mL and should be used to establish a baseline level, monitor response to antiviral therapy, and survey for the development of drug resistance. Interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir are approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Although all of these agents can be used in selected patients, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir. Issues for consideration for therapy include efficacy, safety, rate of resistance, method of administration, and cost.

Anonymous00392, Yee HS, Currie SL, Darling JM, Wright TL. · Department of Veterans Affairs Hepatitis C Resource Center Program, San Francisco, California, USA. · Am J Gastroenterol. · Pubmed #17032203 No free full text.

Abstract: Chronic hepatitis C virus (HCV) infection affects approximately 1.3% of the general U.S. population and 5-10% of veterans who use Department of Veterans Affairs medical services. Chronic HCV is clearly linked to the development of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation. The consequences of HCV infection constitute a significant disease burden and demonstrate the need for effective medical care. Treatment of chronic HCV is aimed at slowing disease progression, preventing complications of cirrhosis, reducing the risk of HCC, and treating extrahepatic complications of the virus. As part of a comprehensive approach to HCV management, antiviral therapy with peginterferon alfa combined with ribavirin is the current standard of care. Antiviral therapy should be provided to those individuals who meet criteria for treatment and who are at greatest risk for progressive liver disease. Many of these patients may have comorbid medical and psychiatric conditions, which may worsen while on antiviral therapy. Current antiviral regimens are associated with significant adverse effects that can lead to noncompliance, dose reduction, and treatment discontinuation. To overcome these barriers and to address these issues, it has become crucial to facilitate a multidisciplinary team who can respond to and provide HCV-specific care and treatment. Screening for HCV, preventing transmission, delaying disease progression, ensuring appropriate antiviral therapy, and managing treatment-related adverse effects can improve patient quality of life, treatment adherence, and ultimately, improve patient outcomes.

Tien PC, Anonymous00369, Anonymous00370. · VAMC Infectious Disease Section, San Francisco, CA 94121, USA. · Am J Gastroenterol. · Pubmed #16181388 No free full text.

Abstract: Nearly 40% of human immunodeficiency virus- (HIV-) infected veterans on highly active antiretroviral therapy (HAART) in the United States are coinfected with hepatitis C virus (HCV). With the increased survival due to declining opportunistic infections as a result of HAART, HCV-associated liver disease has become a leading cause of death in HIV-infected individuals. HCV infection has been shown to lead to rapid progression of HCV-related liver disease in HIV infection. Results from recent clinical trials in HIV/HCV-coinfected patients show improved response rates using pegylated formulations of interferon plus ribavirin when compared to standard interferon plus ribavirin. However, the treatment of HCV in HIV/HCV-coinfected patients can be complicated by the hepatotoxic and myelosuppressive effects of HIV therapy and HIV infection itself. Prior to initiating HCV therapy, HIV therapy should be optimized by improving immune suppression and avoiding specific antiretroviral drugs that may cause hepatotoxicity and myelosuppression. In the event of treatment-related neutropenia or anemia during HCV therapy, the use of growth factors should be considered to maximize sustained virologic response to HCV therapy. In HIV/HCV-coinfected patients with end-stage liver disease, liver transplantation is being investigated and shows promise as a potential therapeutic option. With the recent advances in the treatment of HCV in HIV/HCV-coinfected individuals, all HIV/HCV-coinfected patients eligible for HCV treatment should be evaluated for HCV combination therapy with careful consideration of their HIV disease.

Keeffe EB, Kowdley KV. · Stanford University Medical Center, Palo Alto, CA · J Clin Gastroenterol. · Pubmed #15597022 No free full text.

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Gish RG. · Liver Transplant Program, California Pacific Medical Center, 2340 Clay Street, San Francisco, CA 94115, USA. · Gastroenterol Clin North Am. · Pubmed #15081104 No free full text.

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Ramachandran R, Kakar S. · Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA. · J Clin Pathol. · Pubmed #19474352 No free full text.

Abstract: The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. Acute hepatitis, with or without cholestasis, is the most common histological pattern of DILI, and drugs such as acetaminophen are the leading causes of acute liver failure. Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate can lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimmune hepatitis. Prolonged cholestasis and ductopenia resembling primary chronic biliary disease can occur. Drug-induced steatohepatitis is also an uncommon pattern, but is well described with drugs such as amiodarone and irinotecan. In the presence of risk factors such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine can precipitate or exacerbate steatohepatitis. Other observed patterns include granulomatous hepatitis, vascular injury (eg, sinusoidal obstruction syndrome), Ito cell lipidosis and neoplasms (eg, adenomas).

Bird BH, Ksiazek TG, Nichol ST, Maclachlan NJ. · Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. · J Am Vet Med Assoc. · Pubmed #19335238 No free full text.

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Nguyen MH, Keeffe EB. · Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA 94304, USA. · J Viral Hepat. · Pubmed #19236641 No free full text.

Abstract: SUMMARY: Chronic hepatitis B is a serious health problem worldwide with a substantial minority of patients experiencing premature death due to end-stage liver disease and/or hepatocellular carcinoma. Antiviral therapy may help prevent complications of chronic hepatitis B, and seven agents are currently approved in many countries. Of these agents, five are nucleos(t)ide analogs that all have a risk of antiviral drug resistance with long-term use. Efforts have been made in the recent years to prevent or to reduce the risk of viral resistance in patients treated with oral nucleos(t)ides as the majority of these patients will require therapy for 3-5 years or longer. One approach is to identify patients who would most likely develop antiviral resistance on long-term therapy using predictors obtainable early in the course of treatment, when intervention with new or additional therapy can be instituted. The most important predictors of treatment outcomes are serum HBV DNA levels at baseline and during the first 6 months of therapy. The purpose of this synopsis is to review the recent literature regarding the importance of serum HBV DNA levels in association with treatment outcomes in chronic hepatitis B, particularly the association of complete viral suppression early in the course of oral therapy with long-term treatment outcomes, particularly the incidence of antiviral drug resistance.

Deval J. · Roche Palo Alto LLC, Palo Alto, California 94304, USA. · Drugs. · Pubmed #19228073 No free full text.

Abstract: Over the past 20 years, nucleoside analogues have constituted an arsenal of choice in the fight against HIV, hepatitis B and C viruses, and herpesviruses. Classical antiviral nucleosides such as zidovudine act as obligate chain terminators. Once incorporated as monophosphates into the viral nucleic acid, they immediately block the progression of the polymerase as a result of their lack of a reactive 3'-hydroxyl (3'-OH) group. This review explores beyond the paradigm of obligate chain termination, from a structural and a mechanistic perspective, the strategy of inhibiting viral polymerases (RNA- and DNA-dependant) with nucleoside analogues containing a 3'-OH group. Depending on their mechanism of action, these molecules typically fall into the following three categories: (i) delayed chain terminators; (ii) pseudo-obligate chain terminators; or (iii) mutagenic nucleosides. Delayed chain terminators (i.e. penciclovir, cidofovir and entecavir) block the polymerase at an internal position within the viral nucleic acid, whereas R7128 and the 4'C substituted nucleosides do not permit subsequent incorporation events. Ribavirin, 5-hydroxydeoxycytidine and KP1461 are not chain terminators. Instead, they inhibit viral replication after mispairing with the template base, resulting in random mutations that are often lethal. Finally, brivudine, clevudine and other L-nucleosides have unique or yet to be defined mechanisms of inhibition.

Houghton M. · Epiphany Biosciences Inc., San Francisco, CA 94111, USA. · Liver Int. · Pubmed #19207970 No free full text.

Abstract: After nearly 6 years of intensive investigations between 1982 and 1988 in my laboratory at Chiron corporation, in which numerous molecular biological methods were used to investigate the viral aetiology of parenterally transmitted non-A, non-B viral hepatitis (NANBH), a single cDNA clone (5-1-1) was isolated that was shown to be derived from a new flavi-like virus, termed the hepatitis C virus (HCV). After screening hundreds of millions of bacterial cDNA clones derived from different liver and plasma samples obtained from experimentally infected chimpanzees, a single HCV clone was eventually isolated using a novel, blind immunoscreening method in which antibodies derived from a clinically diagnosed NANBH patient were used to identify a cDNA clone encoding an immunodominant epitope within HCV nonstructural protein 4. Its viral origin was demonstrated by its specific hybridization to a large single-stranded RNA molecule of approximately 10,000 nucleotides found only in NANBH-infected samples that shared distant sequence identity with flaviviruses. Further, HCV clone 5-1-1 was shown to be extrachromosomal and to encode an antigen eliciting antibody seroconversion only in NANBH-infected chimpanzees and humans. Subsequent work demonstrated that HCV was the principal cause of parenterally transmitted NANBH around the world, with an estimated 170 million global carriers and that blood screening tests detecting circulating HCV antibodies and viral RNA could effectively eradicate the transmission of transfusion-associated NANBH. Key viral-encoded enzymes essential to its life cycle are now the targets of vigorous, ongoing drug development activities, and the feasibility of successful vaccination strategies has been demonstrated using the valuable chimpanzee model, without which any progress on HCV would not have been possible. My colleagues and coworkers who made essential contributions to the discovery of HCV were George Kuo, who had his own laboratory at Chiron and who provided intellectual and practical input, Dan Bradley of the Centers for Disease Control and Prevention, who provided a large supply of well-characterized chimpanzee samples and knowledge of the NANBH field, and Qui-Lim Choo, in my own laboratory, who provided many years of outstandingly dedicated and precise molecular biology expertise.

Rook M, Rosenthal P. · Pediatric Gastroenterology, Hepatology and Nutrition, University of California San Francisco, 500 Parnassus Avenue, MU4E, Box 0136, San Francisco, CA 94143, USA. · Curr Gastroenterol Rep. · Pubmed #19166664 No free full text.

Abstract: The etiology of liver disease in childhood varies significantly from its etiology in the adult population. More children with complex diseases are surviving into adulthood, providing challenges to the primary care provider. Adults with pediatric liver disease differ in management, treatment, complications, and extrahepatic considerations. To provide these patients with an optimal transition into the adult health care system, the provider needs a comprehensive knowledge of the common causes of childhood liver disease and their implications and must understand the differences in caring for these patients. This review addresses some of the most common childhood liver diseases, their causes, presentation, evaluation, management, complications, and additional concerns.

Kim YI, Chung JW. · Division of Interventional Radiology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5642, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19090739 No free full text.

Abstract: There are various disorders involving the liver. They include metabolic diseases, hepatitis, liver cirrhosis and cancer, the latter of which may be the most serious. Delivery of therapeutic genes or drugs should be targeted to either one of the following cells in the liver: hepatocytes, Kupffer cells and tumor endothelial cells, or to the tumor cells themselves. To maximize the therapeutic effect and minimize systemic toxicity or nontarget injuries, the sufficient amount or dose of genes or drugs should be specifically delivered to a target, with minimal exposure in their active forms to nontarget cells. There are diverse strategies to improve selective delivery or targeting efficiency. In this article, we present potential new therapeutic strategies and clinical developments for liver cancer, with a focus on the progress in the localized delivery of therapeutic agents using image-guided procedures.

Benedetti NJ, Desser TS, Jeffrey RB. · Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305-5621, USA. · Ultrasound Q. · Pubmed #19060716 No free full text.

Abstract: Hepatic infections include pyogenic and amebic abscesses and fungal and parasitic diseases. Entry of the infectious organisms into the liver can occur by hematogenous spread via the portal vein or hepatic artery, ascension of the infection from the biliary tract, or from trauma. Worldwide, liver abscess is most often caused by Entamoeba histolytica, but in the developed world, pyogenic liver abscess is more common. Fungal infection is most often seen in immunosuppressed chemotherapy patients, whereas parasitic infections are seen in patients with recent travel to endemic areas of Asia, Africa, and South America. Imaging, and in particular ultrasound, plays a crucial role in following patients from treatment to resolution of disease.We review the ultrasound and computed tomographic findings and the clinical features that are characteristic of hepatic pyogenic abscess, amebic abscess, fungal infection, and parasitic infection.

Jamall IS, Yusuf S, Azhar M, Jamall S. · Risk-Based Decisions, Inc., 2033 Howe Avenue, Suite 240, Sacramento, California 95825, USA. · World J Gastroenterol. · Pubmed #19034963 links to  free full text

Abstract: Over the past decade, significant improvements have been made in the treatment of chronic hepatitis C (CHC), especially with the introduction of combined therapy using both interferon and ribavarin. The optimal dose and duration of treatment is still a matter of debate and, importantly, the efficacy of this combined treatment varies with the viral genotype responsible for infection. In general, patients infected with viral genotypes 2 or 3 more readily achieve a sustained viral response than those infected with viral genotype 1. The introduction of a pegylated version of interferon in the past decade has produced better clinical outcomes in patients infected with viral genotype 1. However, the published literature shows no improvement in clinical outcomes in patients infected with viral genotypes 2 or 3 when they are treated with pegylated interferon as opposed to non-pegylated interferon, both given in combination with ribavarin. This is significant because the cost of a 24-wk treatment with pegylated interferon in less-developed countries is between six and 30 times greater than that of treatment with interferon. Thus, clinicians need to carefully consider the cost-versus-benefit of using pegylated interferon to treat CHC, particularly when there is no evidence for clinically measurable benefits in patients with genotypes 2 and 3 infections.

Quan DJ. · Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, CA, USA. · Nephrol Nurs J. · Pubmed #18856082 No free full text.

Abstract: Chronic infection with hepatitis B virus can lead to liver disease, cirrhosis, and hepatocellular carcinoma. Treatment options include interferons and antiviral drugs. The interferons have immunomodulatory, antiproliferative, and antiviral effects. Nucleoside analogs, such as entecavir, lamivudine and telbivudine, and neucleotide analogs, such as adefovir and tenofovir, exhibit antiviral effects by inhibiting viral replication. Treatment is directed at suppressing viral replication and halting the progression of disease.

Delaney WE, Borroto-Esoda K. · Gilead Sciences, 333 Lakeside Dr. Foster City, CA 94404, USA. · Curr Opin Pharmacol. · Pubmed #18835366 No free full text.

Abstract: There are now five nucleoside/nucleotide analogs approved for the treatment of chronic hepatitis B (CHB) including three agents approved in the United States and/or European Union in the past three years. Each of these drugs has demonstrated short-term benefits in patients including histologic improvement, HBeAg seroconversion, suppression of hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT) normalization. However, long-term therapy is required in most patients and the five approved agents differ with respect to resistance profile and ability to achieve complete antiviral suppression. Lamivudine was the first approved agent, but its use leads to frequent antiviral resistance. Adefovir dipivoxil has a superior first line resistance profile and is fully active against lamivudine-resistant HBV. Newer agents including tenofovir disoproxil fumarate, entecavir, and telbivudine offer greater potency than lamivudine and adefovir dipivoxil. However, telbivudine resistance rates are comparatively high and both telbivudine and entecavir have decreased efficacy against lamivudine-resistant HBV. Tenofovir disoproxil fumarate, the most recently approved nucleotide (2008 in the European Union, and United States), is highly potent in both treatment-naïve and treatment-experienced patients. Overall, this class of compounds presents the opportunity to achieve complete antiviral suppression in the majority of patients, at least in the short-term. The challenge is how to best use these drugs long-term to minimize antiviral resistance and maintain maximal antiviral suppression, which is anticipated to make the greatest impact on limiting advanced complications of CHB.

Terrault NA. · Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco, CA 94143, USA. · Liver Transpl. · Pubmed #18825697 No free full text.

Abstract: 1. Pretransplant therapy, using a low-accelerating-dose regimen, is an option for patients with mildly decompensated liver disease and low laboratory Model for End-Stage Liver Disease scores. Achievement of an on-treatment virologic response is the goal of therapy. Preliminary data suggest that up to two-thirds of patients who become hepatitis C virus RNA-negative on treatment will be hepatitis C virus infection-free post-transplantation. 2. Effective prophylactic therapies are not available. Hepatitis C antibody therapy has been ineffective in preventing hepatitis C virus infection in studies to date. 3. Preemptive antiviral therapy started within weeks of transplantation is limited by tolerability, particularly in patients with high Model for End-Stage Liver Disease scores pre-transplantation. Rates of sustained virologic response vary from 8% to 39%. Histological benefits in virologic nonresponders have been demonstrated. 4. Posttransplant antiviral therapy in those with evidence of recurrent disease is the mainstay of management. A combination of pegylated interferon and ribavirin is the treatment of choice, and sustained virologic response is achieved with 48 weeks of treatment in approximately 30% of treated patients. Attainment of early loss of hepatitis C virus RNA is highly predictive of sustained virologic response. Histologic improvements are seen in responders. Survival is prolonged among those achieving a sustained virologic response. 5. Posttransplant antiviral therapy is limited by poor tolerability and the frequent need for dose reductions and/or discontinuation. Immunologic complications, including acute rejection, chronic rejection, and autoimmune-like hepatitis, occur in association with therapy, albeit at low rates. 6. Hepatitis C virus-infected liver transplant recipients represent an important patient population in need of new therapeutics options to prevent patient and graft losses due to recurrent hepatitis C virus disease.

Chakravarty EF. · Division fo Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, California 94304, USA. · Arthritis Rheum. · Pubmed #18821704 No free full text.

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Inductivo-Yu I, Bonacini M. · International Hepatology Scholar Program, California Pacific Medical Center, San Francisco, California 94115, USA. · Curr Drug Saf. · Pubmed #18690975 No free full text.

Abstract: With the advent of highly active antiretroviral therapy (HAART), the reduction in overall mortality and morbidity in HIV patients has been accompanied by the emergence of liver disease as a leading cause of death. Elevated liver enzymes may be due to HAART or to other risk factors, including hepatitis co-infection and alcohol use. The different components of HAART are each associated with different risks of liver toxicity. Most drugs are metabolized by cytochrome P450 enzymes in the liver, and this may be affected by liver disease. The mechanisms for drug-induced liver injury include dose-dependent toxicity, hypersensitivity reactions, idiosyncratic reactions, mitochondrial toxicity, and immune reconstitution. The diagnosis of drug-induced liver injury is exclusionary. Once diagnosed, management generally involves discontinuation of the offending drug(s). A number of studies in progress are investigating whether treatment of hepatitis co-infection can improve the tolerability of HAART.

Monto A, Currie S, Wright TL. · San Francisco Veterans Affairs Medical Center, CA, USA. · J Addict Dis. · Pubmed #18681191 No free full text.

Abstract: Liver disease is a major health problem for individuals with a history of injection drug use. This is mainly from the hepatitis C virus (HCV), with or without co-infection with HIV. HCV-associated liver disease takes decades to develop into cirrhosis, from which it can adversely affect health. HIV coinfection is among the factors that are often associated with liver disease progression, and efforts to understand liver disease progression in HIV-HCV coinfected patients remain important. Maintaining high CD4 counts and avoiding alcohol intake are associated with slower liver disease progression. Pegylated interferon and ribavirin combination therapy has the potential to clear HCV, which provides the strongest health benefit to patients affected by the virus, although this can be difficult to accomplish for many reasons. Steatosis, fat within the liver, may also have important pathological implications for liver disease related to HCV. Limiting liver disease progression in IDUs with hepatitis C may well be best accomplished through promoting their full utilization of health care.

Keeffe EB. · Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Trans Am Clin Climatol Assoc. · Pubmed #18528476 links to  free full text

Abstract: A number of studies have demonstrated that the acquisition of hepatitis A or hepatitis B in patients with chronic liver disease is associated with high rates of morbidity and mortality. Superimposition of acute hepatitis A in patients with chronic hepatitis C has been associated with a particularly high mortality rate, and chronic hepatitis B virus coinfection with hepatitis C virus is associated with an accelerated progression of chronic liver disease to cirrhosis, decompensated liver disease and hepatocellular carcinoma. With the availability of vaccines against hepatitis B and hepatitis A since 1981 and 1995, respectively, these are vaccine-preventable diseases. Studies have confirmed that hepatitis A and hepatitis B vaccines are safe and immunogenic in patients with mild to moderate chronic liver disease. However, hepatitis A and B vaccination is less effective in patients with advanced liver disease and after liver transplantation. These observations have led to the recommendation that patients undergo hepatitis A and B vaccination early in the natural history of their chronic liver disease. Vaccination rates are low in clinical practice, and public health and educational programs are needed to overcome barriers to facilitate timely implementation of these recommendations.

Ayoub WS, Keeffe EB. · Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA. · Aliment Pharmacol Ther. · Pubmed #18466358 No free full text.

Abstract: BACKGROUND: The long-term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma. AIM: To review the current treatment of chronic hepatitis B, with a focus on diagnosis and management of resistance and active management of suboptimal responses. METHODS: A systematic review of the literature, with a focus on recent guidelines, was undertaken. RESULTS: Among the six drugs licensed for the treatment of chronic hepatitis B in the US, the preferred agents in 2008 will include entecavir, peginterferon alfa-2a, possibly telbivudine, and tenofovir following licensure. When using an oral agent, a major focus of management is on the selection of a drug with high potency and low rate of resistance, and active on-treatment management to optimize therapy. Preventing the sequelae of antiviral drug resistance and appropriate management when resistance is initially detected are also the major focus of current management. The addition of an antiviral agent that is not cross-resistant is critical to restore suppression of viral replication. CONCLUSIONS: Newer agents and modified treatment strategies, especially using combination therapy, hold promise to optimize the management of patients with chronic hepatitis B by achieving the high potency and the lowest rate of resistance.

Sheikh MY, Choi J, Qadri I, Friedman JE, Sanyal AJ. · Division of Gastroenterology and Hepatology, University of California San Francisco Fresno Education Program, Community Regional Medical Center, Fresno, CA 93721, USA. · Hepatology. · Pubmed #18446789 No free full text.

Abstract: Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent fashion, thus contributing to steatosis, progression of fibrosis and resistance to interferon therapy. The molecular mechanisms in genotype 1 patients that lead to metabolic syndrome are still ambiguous. Based on our current understanding, HCV proteins associate with mitochondria and endoplasmic reticulum and promote oxidative stress. The latter mediates signals involving the p38 mitogen-activated protein kinase and activates nuclear factor kappa B. This transcription factor plays a key role in the expression of cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF-alpha inhibits the function of insulin receptor substrates and decreases the expression of the glucose transporter and lipoprotein lipase in peripheral tissues, which is responsible for the promotion of insulin resistance. Furthermore, reduced adiponectin levels, loss of adiponectin receptors, and decreased anti-inflammatory peroxisome proliferator-activated receptor alpha in the liver of HCV patients may contribute to reduced fatty acid oxidation, inflammation, and eventually lipotoxicity. This chain of events may be initiated by HCV-associated IR and provides a direction for future research in the areas of therapeutic intervention.

Strnad P, Stumptner C, Zatloukal K, Denk H. · Department of Internal Medicine I, University of Ulm, Robert-Koch-Strabe 8, 89081, Ulm, Germany. · Histochem Cell Biol. · Pubmed #18443813 links to  free full text

Abstract: Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising approximately 70 genes expressed in tissue specific manner. In addition to scaffolding function, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deficient animals exhibit a marked susceptibility to various toxic agents and Fas-induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with development of liver fibrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated K8/K18, chaperones and sequestosome1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non-alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transamidation of keratin 8 and p62 upregulation.

Jiang J, Torok N. · Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, USA. · Metab Syndr Relat Disord. · Pubmed #18370830 No free full text.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a major form of chronic liver disease in adults and children. It is one of the consequences of the current obesity epidemic, and can progress to nonalcoholic steatohepatitis (NASH), characterized by steatosis, inflammation, and progressive fibrosis, ultimately leading to cirrhosis and end-stage liver disease. The factors implicated in this progression are poorly understood. NASH is closely associated with obesity and the metabolic syndrome. Recent studies emphasize the role of insulin resistance, oxidative stress, lipid peroxidation, and cytokine release in the development of NASH. This review summarizes the current knowledge on the etiology and pathomechanism of NASH and the role of the metabolic syndrome in NASH development.