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members of a cohort of 1,667 hepatitis C virus (HCV)-infected injection drug users (IDUs) were selected for liver biopsy procedure after stratification based on 2 consecutive serum alanine transaminase (ALT) levels. Liver histology, which could be fully evaluated for 207 subjects, was classified by using the modified Ishak scores. At the time of biopsy, the median age of subjects was 41.3 years and the median estimated duration of HCV infection was 20.7 years; 94% were African American; 78% men; 31% were human immunodeficiency virus (HIV) seropositive; and 76% had HCV genotype 1a or 1b. Total modified histologic activity index (MHAI) scores ranged from 0 to 9, and 26.6% had a total MHAI score of 5 or greater. Persons with a total MHAI score of 5 or greater were more likely to be HIV infected (P ‫؍‬ .04). Higher fibrosis, indicated by Ishak modified fibrosis scores of 3 to 6, was present in 10.1% of subjects and was found more often in those older than 46 years of age (the highest quartile) (P < .01). Both fibrosis scores of 3 or greater and total scores of 5 or greater were associated with elevated ALT, aspartate transaminase (AST), and ␥-glutamyl transpeptidase (GGT) levels (P < .01). When serial values were considered, the results of liver enzyme testing could reduce the probability of an IDU having a fibrosis score of 3 or greater from 10% to 3%. In conclusion, these data indicate that severe liver disease is uncommon in this urban, HCV-infected IDU cohort, especially in younger persons and those with repeatedly normal liver enzymes. (HEPATOLOGY 2002;35:1247-1255

Although most hepatitis C virus (HCV) infections are acquired by injection drug use, prospective data on the progression of liver fibrosis are sparse. Baseline liver biopsies were obtained (1996-1998) on a random sample of 210 out of 1667 HCV-positive injection drug users (IDUs). Subjects were followed biannually, with a second biopsy offered to those eligible. Paired biopsies were scored 0 to 6 (modified Ishak score), significant fibrosis was defined as score 3 or greater, and progression of fibrosis was defined as an increase 2 or more units or clinical evidence of end-stage liver disease. Predictive values of blood markers [FibroSURE, aspartate aminotransferase-to-platelet-ratio index (APRI) and alanine aminotransferase (ALT)] were assessed for detection of contemporaneous and future liver fibrosis. Among 119 prospectively followed IDUs, 96% were African American; 97% HCV genotype 1a/b; 27% HIV-infected, and median age was 42 years. Most (90.7%) did not have significant liver fibrosis at first biopsy. Although predictive value for detecting insignificant fibrosis at first biopsy was greater than 95% for FibroSURE, APRI, and ALT, specificities were 88.9%, 72.7%, and 72.7%, respectively. After 4.2 years median follow-up, 21% had progression of fibrosis, which was significantly associated with serum level of HCV RNA and ALT. No serological test had predictive value greater than 40% for contemporaneous or future significant fibrosis. Even initial biopsy result had only a 30.4% value for predicting future significant fibrosis. In conclusion, significant liver fibrosis and progression were detected in some, but not most, IDUs in this cohort. In this setting with low fibrosis prevalence, FibroSURE, ALT, and APRI tests predict insignificant fibrosis; however, further work is needed to find noninvasive markers of significant liver fibrosis. (HEPATOLOGY 2006;43: 788-795.)

Serum alanine transaminase (ALT) levels are used to select hepatitis C virus (HCV)-infected patients for treatment and liver biopsy. However, the natural history of these measurements is poorly understood. To examine the hypothesis that ALT levels vary over time in HCV-infected patients, serial serum ALT levels were prospectively measured in a No test uniformly predicts which individuals will have persistent infection, develop cirrhosis, or respond to therapy, although viral load, HCV genotype, liver histology, and serum transaminases have been studied. [4][5][6][7] Long-term elevation in serum transaminases, especially alanine transaminase (ALT), was once the principal indication of persistent HCV infection, formerly called non-A, non-B hepatitis. However, up to 30% of HCV infections persist without detectable ALT elevation. 8-10 Serum ALT has also been correlated with the degree of histological inflammation in the liver. However, histologically mild disease has been recognized in individuals with elevated ALT values, and histologically advanced disease has been demonstrated in individuals with normal or minimally elevated ALT measurements. 11,12 In addition, ALT normalization 8 to 12 weeks after interferon therapy predicts the ultimate response in some, but not all, individuals. 13,14 These limitations notwithstanding, serum transaminase measurements are inexpensive, safely obtained, and readily available, and continue to be widely used in the management of HCV infection. For example, a recent NIH Consensus Panel recommended that individuals with normal ALT levels not receive interferon therapy for HCV infection. 15 In addition, in a recent survey of 1,249 gastroenterologists and hepatologists, the result of a single ALT determination dramatically affected the frequency with which liver biopsies were performed. 16 Different estimates of the value of liver enzyme testing may derive from limitations of existing studies. Almost all existing studies are based in liver disease clinics, though it is estimated that fewer than 10% of HCV-infected individuals are followed in this setting. In addition to the referral bias of liver disease clinic-based studies, cross-sectional studies cannot evaluate ALT trends, and most prospective studies include few participants. Moreover, many HCV-infected individuals followed in clinical centers have received treatment, making natural history studies impossible. In this investigation, the temporal trends and demographic correlates of liver enzymes were prospectively assessed among a large cohort of almost entirely untreated HCV-infected individuals in the community. PATIENTS AND METHODSPopulation and Study Design. Since 1989, a cohort of former and current injection drug users in the AIDS Linked to the Intravenous Experience (ALIVE) study has been followed semiannually at Johns Hopkins University (Baltimore, MD). 17 Using a historical prospective study design, HCV infection in this group was evaluated at enrollment and at subsequent visits using a second-generation enzyme immunoassa...

Cytokines, such as TNF alpha, modulate the behavior of many cells by regulating the expression of a wide array of genes. When a cytokine binds to its receptor on the cell surface, the receptor becomes activated and activates signal transduction cascades. These cascades typically involve a series of phosphorylation reactions that lead to sequential activation of various kinases. The targets of these kinases include DNA binding proteins that regulate the transcription of target genes. The activity of DNA binding proteins, such as c-Jun and NF-kappa B, titrates the transcriptional activity of cytokine-regulated genes. Both acute and chronic alcohol consumption of ethanol increase hepatic expression of TNF alpha. After acute ethanol consumption, this is associated with increased induction of several TNF-dependent regenerative events, including the activation of c-Jun and increased binding activity of NF-kappa B. However, chronic consumption of ethanol appears to impede TNF alpha signaling in the liver because it attenuates the increases in c-JUN activity and NF-kappa B binding, which normally follow partial hepatectomy. These results suggest that one mechanism by which ethanol influences liver cell behavior is by influencing local expression of TNF alpha and changing the activity of TNF-regulated transcription factors.

The liver has tremendous regenerative capacity. This distinguishes it from other vital organs (e.g. the brain, heart and lungs) that cannot replace functional tissue once it has been destroyed. Although hepatocytes rarely proliferate in the healthy adult liver, virtually all surviving hepatocytes replicate at least once after 70% partial hepatectomy. Therefore, partial liver resection has been used to characterize mechanisms that regulate liver regeneration. Residual hepatocytes up-regulate both proliferative and liver-specific gene expression in order to preserve tissue specific function. In addition, hepatocyte proliferation is tightly co-ordinated to complement regenerative responses in hepatic non-parenchymal cells (e.g. endothelia, biliary epithelia, stellate and Kupffer cells), so that the entire organ can be reconstituted within days. Studies with neutralizing antibodies to tumour necrosis factor-alpha (TNF) clearly demonstrate that, after partial hepatectomy, TNF promotes liver cell proliferation. The present review focuses on the regulation of the hepatocyte proliferative response by pro-inflammatory cytokines.

The use of renal allografts from HCV + donors for HCV + recipients shortens the waiting time for these patients, with no short-term differences in renal and liver function, graft loss, or patient survival.

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