Geoffrey C. Farrell

When assessing patients with chronic hepatitis B virus (HBV) infection, consider the state of viral replication, the immune response and whether viral mutations could be present, as well as evidence for liver disease or extrahepatic manifestations. In wild‐type infections, loss of hepatitis B e antigen (HBeAg), gain of anti‐HBe and disappearance of HBV DNA from serum indicate immunosuppression of viral replication, or ‘nonreplicative chronic HBV infection’. This ‘healthy carrier’ state must be distinguished from HBeAg‐negative chronic hepatitis B (CHB) resulting from precore and core promoter mutations. HBeAg‐negative CHB is common with genotypes D (Mediterranean region, south Asia) and C (north Asia) infections. Age, disease activity (alanine aminotransferase level) and severity (fibrosis stage, cirrhosis) influence treatment decisions. Following the marginal effectiveness of interferon and often temporary effectiveness of lamivudine due to drug resistance, treatment of CHB is entering a new era. Adefovir, entecavir, tenofovir, telbivudine and clevudine have equal or superior antiviral efficacy to lamivudine, whereas several agents are effective against lamivudine‐resistant HBV. Pegylated‐interferon (peginterferon) is superior to conventional interferon for obtaining sustained immunosuppression of HBV without drug resistance. Antiviral suppression of HBV replication for 2–5 years reverses hepatic fibrosis, prevents cirrhosis and, when cirrhosis is established, improves liver function, prevents hepatic decompensation and lowers the risk of liver cancer. Before embarking on immunosuppressive chemotherapy or organ transplantation in patients with chronic HBV infection, it is important to start antiviral therapy to prevent hepatitis flares. Antiviral therapy can be effective against membranous glomerulonephritis and polyarteritis nodosa caused by HBV. Further improvements in treatment of CHB are needed to prevent drug resistance and permanently suppress viral replication by eradicating viral templates or stimulating host immune responsiveness to HBV.

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution, and parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. NASH could be present in one third of NAFLD cases. Age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7- to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise. Pathogenic concepts for NAFLD/NASH must account for the strong links with overnutrition and underactivity, insulin resistance, and genetic factors. Lipotoxicity, oxidative stress, cytokines, and other proinflammatory mediators may each play a role in transition of steatosis to NASH. The present “gold standard” management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity. Whether achieved by “lifestyle adjustment” or anti-obesity surgery, this improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis. The same potential for “unwinding” fibrotic NASH is indicated by studies of the peroxisome proliferation activator receptor (PPAR)- γ agonist “glitazones,” but these agents may improve liver disease at the expense of worsening obesity. Future challenges are to approach NAFLD as a preventive public health initiative and to motivate affected persons to adopt a healthier lifestyle. (Hepatology 2006;43:S99-S112.)

Peroxisome proliferator‐activated receptor γ (PPARγ) has been implicated in the differentiation and growth inhibition of cancer cells. We examined the effects of PPARγ activation by troglitazone on hepatocellular carcinoma (HCC) cell growth, proliferation, and apoptosis in vitro and in vivo. We also studied relationships between PPARγ activation and cyclooxygenase‐2 (COX‐2) expression. Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST‐1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen (PCNA) Western blotting, and apoptosis by flow cytometry and TUNEL. Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored, and the effects of treatment with troglitazone were determined. In resected HCCs, PPARγ expression was less compared with the histologically normal surrounding liver. In cultures of Hep3B and Huh7 cells, basal expression of PPARγ was relatively low, but troglitazone caused dose‐dependent induction of PPARγ expression. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. Concomitant downregulation of PCNA and an increase in TUNEL staining, cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone. Troglitazone‐mediated PPARγ activation also suppressed COX‐2 expression and induced p27 in HCC cells. Administration of troglitazone to Huh7 tumor‐bearing mice significantly reduced tumor growth and caused tumor regression. In conclusion, collectively, these results indicate that PPARγ could be a regulator of cell survival and growth in HCC. PPARγ therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth.. (HEPATOLOGY 2006;43:134–143.)

Background/Aims: Refractoriness of some tumours to apoptosis has been related to over-expression of NF-κB, while NF-κB inhibition can promote apoptosis in several cell types. We compared NF-κB activation profiles between normal rat hepatocytes and ARL-6 rat hepatocellular carcinoma (HCC) cells exposed to hydrogen peroxide (H2O2), and examined whether NF-κB activation could explain the observed resistance to apoptosis of ARL-6 cells. We then infected ARL-6 cells with recombinant adenovirus containing mutant (non-degradable) I?B? (Adv-mI?B?), and examined whether this rendered ARL-6 cells more sensitive to oxidative stress-induced apoptosis. Methods: Cultured primary rat hepatocytes and ARL-6 cells were treated with graded doses of H2O2. To block NF-κB, ARL-6 cells were incubated with Adv-mIκBα for 24 h. Cytotoxicity, NF-κB activation, cell proliferation, and apoptosis were determined. Results: H2O2 induced more apoptosis in primary hepatocytes than ARL-6 cells, and the relative resistance of ARL-6 cells to H2O2-induced apoptosis was associated with more pronounced NF-κB activity. In ARL-6 cells, nuclear translocation of NF-κB took place within 2 h of administering H2O2 and remained prominent at 36 h. Adv-mI?B? sensitized ARL-6 cells to H2O2-induced apoptosis, but cell proliferation was minimally suppressed. Conclusions: Compared with normal hepatocytes, ARL-6 cells are refractory to apoptosis after exposure to H2O2, and this is associated with NF-κB activation. Conversely, NF-κB inhibition sensitises ARL-6 cells to H2O2-induced apoptosis. Sustained NF-?B activation in these HCC cells may protect them against apoptosis produced by oxidative stress.