Hepatology highlights
Authors: Harvey J. Alter
Journal: Hepatology (2004)

Because there was a stepwise increase in the odds ratio for fibrosis with each level of alcohol intake, the authors conclude that even light alcohol intake may be playing a role in fibrosis development and that their study size of 800 “…may be inadequate to demonstrate a subtle effect of low amounts of alcohol on fibrosis.” I think this is a very cautious interpretation of their data. One could also reasonably conclude that low amounts of alcohol are probably not detrimental to HCV-infected patients and that one drink a day may have more cardiac benefit than it has fibrogenic detriment, as consistent with the NIH consensus statement. I'll drink to that. (See HEPATOLOGY 2004;39:826–834.) SARS has captured the headlines for its lethal respiratory consequences, but other organ disease has not been prominent except as a terminal event. Now Chau et al. report three cases of hepatitis in which SARS-associated coronavirus (SARS CoV) has been found in liver tissue by PCR. SARS CoV is an enveloped, single-stranded, positive-sense RNA virus that replicates in the cytoplasm of infected cells, features common to HCV. More than 8,000 persons have developed the SARS syndrome, predominantly in Asia, and the fatality rate is about 10%, increasing in the elderly. I was not aware that 60% of SARS patients have elevated ALT levels; these have been difficult to interpret because of multiple potentially hepatotoxic agents, including antibiotics, ribavirin, and protease inhibitors, that are used to treat these patients. In the 3 patients reported, ALT peaked at 493, 475, and 941 IU/L. Bilirubin and coagulation factors were normal, and there was no lactic acidosis. Liver biopsy showed ballooning, acidophilic bodies, and mild to moderate lobular lymphocytic infiltration. Importantly, there was no granuloma, eosinophilic infiltration, cholestasis, fibrosis, fibrin deposition, giant mitochondria, or microvesicular or macrovesicular steatosis. The most striking finding was a large number of cells in mitosis, readily seen by both light and electron microscopy. The hyperproliferative state was also shown by immunohistochemical stains for the proliferative antigen Ki-67; 0.5% to11.4% of nuclei were positive for Ki-67. The conspicuous mitosis seemed out of proportion to the extent of liver damage. All 3 patients had evidence for apoptosis, the presumed mechanism of liver damage. RT-PCR for SARS-CoV was positive in the liver but not in the serum, so the hepatic localization was not a matter of serum contamination. Viral particles were not seen in the liver. All 3 patients recovered completely from their liver disease. The SARS CoV is quite distinct from other coronaviruses, but a group 2 coronavirus has been shown to cause liver disease in mice and to induce similar pathologic changes. I normally would not highlight Case Reports, but SARS is a hot topic, and confirmed SARS-associated acute hepatitis is a novel observation I find intriguing. Now that it has been reported, can other cases be SARS behind? (See HEPATOLOGY 2004;39:302–310.) The nearly 100% infection of HCV-naïve liver in the HCV-transplant setting has always served as prima facie evidence for extrahepatic sites of HCV replication. Many studies have detected HCV RNA in peripheral blood mononuclear cells (PBMC), and some have demonstrated low-level replication based on the finding of negative-strand replicative intermediates. Ducoulombier and coworkers carry this a step farther by examining the HCV quasispecies in various PBMC compartments. The findings are quite interesting, not because the researchers found HCV in several PBMC compartments, but because they found differences in the HCV quasispecies composition between the plasma and PMBC and among different PBMC compartments. HCV RNA was found in 11 out of 11 CD 19+ B cells, in 10 out of 11 CD 14+ monocytes, and in 4 out of 8 CD8+ T effector cells, but in no CD4+ T helper cells. By cloning and sequencing to detect quasispecies variation in HVR1 and determining the ratio of nonsynonymous to synonymous (dN/dS) sequence changes and by phylogenetic tree analysis, they found significantly different sequences between HCV in plasma and at least one cellular compartment in all cases; B cells and monocytes were the main PBMC subsets involved in HCV compartmentalization, and the variants harbored by B cells and monocytes were always different from each other. By measuring IgG-bound versus free HCV, they showed that compartmentalization to cells was not simply binding of HCV complexes through Fc receptors. Overall, the authors conclude, “differences in dN/dS ratios between compartments, together with the statistically significant compartmentalization of HCV variants, may point to autonomous HCV replication in blood B lymphocytes and/or monocytes.” Evidence from this and other studies suggests that these cell-compartmentalized variants replicate slowly and contribute little to the plasma viral load. These data suggest that distinct HCV variants within PBMC are under less immune pressure and not only might play a role in HCV persistence, but also might represent a quiet harbor of slowly replicating forms biding their time to sail into the next available liver. (See HEPATOLOGY 2004;39:817–825.) Tired of knockout mice? Then try some knockins, now available at knockoff prices. Wang et al. generated two HBV gene knockin transgenic mouse lines containing the complete genes of HBsAg and HBx, each inserted into the same p21 locus. Between the ages of 15 and 24 months, 53% of male HBsAg heterozygotes and 72% of male HBsAg homozygotes developed HCC; no female mice developed HCC within that time. In the HBx knockins, 62% of males and 44% of females developed HCC. None of the wild-type controls developed HCC. In gene array analysis, expression of the estrogen receptor ER-β was extremely elevated only in the liver tumors of male HBsAg transgenic mice, fitting with the male-female HCC disparity noted above and suggesting that the ER-β-signaling pathway might be involved in the male preponderance observed during the development of HBsAg-related HCC in humans. These data also suggest that ER-β-specific ligands may be excellent targets for new HCC treatment modalities. This study of knockins is a knockout. (See HEPATOLOGY 2004;39:318–324.) What are we to make of this? It would be logical to think that viral integration precedes oncogene activation, which in turn incites tumor evolution and growth. This sequence may indeed be correct in some cases, but it appears that early, small tumors frequently lack both WHV integration and N-myc rearrangement. Hence, these phenomena may not be the initiators of tumorogenesis, but rather the outcome and then perpetuator of the process. In essence, integration and N-myc oncogene rearrangements may be vitally important, but not a sine qua non of tumor formation. However, cells with viral integrations and oncogene activation probably have a selective advantage and then clonally expand so that as the tumor grows and becomes more dysplastic, the proportion of tumor nodules harboring these facilitative events markedly increases. Can these events in woodchuck HCC be directly translated to human HCC? Yes and no. In humans, HBV DNA integrations are randomly distributed throughout the genome and are less frequently associated with specific growth regulatory genes, and clearly HCC is a much less common outcome in neonatally infected children than in experimentally infected woodchucks. In humans, perhaps only when the random integration hits the right oncogenic site does the opportunity for clonally selective, neoplastic growth occur. In addition, tumorogenesis is not unidimensional, and in a proportion of cases, other mechanisms may prevail in the pathogenesis of both woodchuck and human HCC. (See HEPATOLOGY 2004;39:1008–1016.) A meta-analysis of 1,013 patients from 3 randomized trials showed that peginterferon-α2a monotherapy significantly reduced fibrosis compared with conventional IFN-α2a monotherapy and that this effect was seen in sustained viral responders and not in nonresponders (odds ratio 1.61). Patients with BMI <30kg/m2 and high baseline ALT had the greatest probability of histological improvement. This outcome counters previous claims that IFN has long-term benefit even in the absence of viral clearance. (See HEPATOLOGY 2004;39:333–342.) Bräu et al. examined whether a 16-week delay in administration of ribavirin in HIV/HCV-coinfected patients receiving conventional IFN had benefit compared with those receiving ribavirin at initiation of therapy. Overall, SVR was low in both groups (11.3% vs. 5.6%) and not significantly different. The low SVR reflects the suboptimal treatment (absence of pegylation), frequent ribavirin dose reductions, the coexistence of HIV, and the high rate of discontinued therapy (51%). Not unexpectedly, patients on ribavirin had more anemia in the first 16 weeks, exaggerated in those receiving AZT. HIV infection improved during therapy for HCV. No severe adverse effects due to HIV-HCV drug interactions were noted. Since therapies have advanced since this study was initiated, its relevance is diminished, and this is always the problem in complex long-term clinical trials in a field that is rapidly evolving. (See HEPATOLOGY 2004;39:989–998.)