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News Review

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HEPATITIS JOURNAL REVIEW:
A Bi-Monthly Publication of the Hepatitis Support Project

May 31 , 2006
Volume 3, Issue 8


Liz Highleyman

To download pdf version click here


In This Issue: Hepatitis C

Value of Repeat Biopsies

Long-Term Progression in Patients with Normal ALT

Factors Influencing ALT Level

Normal ALT in Coinfected Patients

Worse Outcomes in Coinfected Patients


Value of Repeat Biopsies
Biopsy remains the “gold standard” for assessing the degree of liver injury, but the optimal frequency of biopsies remains uncertain. An article in the April 2006 Journal of Gastroenterology suggests that the usual recommendation of every 3-5 years may not be often enough. S.T. Khouri and colleagues evaluated histological progression in 55 patients with untreated hepatitis C who received two liver biopsies at least one year apart (average 39 months). Initial biopsies showed low grades of fibrosis, but 93% of patients had evidence of necroinflammatory activity. At the second biopsy, 40% of patients showed progression of fibrosis and/or necroinflammation. Fibrosis progression was not associated with demographic factors such as age or gender, duration of infection, alcohol consumption, or ALT or AST levels. The authors concluded that, “No factor could be established at the first biopsy to predict which patients are at risk of progression.” They suggested that, “histologic reassessment between 3 and 5 years seems to be the only approach to document disease progression and establish treatment indication.” However, since 40% of patients already showed evidence of progression after an average of just over three years, more frequent biopsies may be needed to detect liver disease progression at the earliest stages - even more so for HIV/HCV coinfected patients, who typically experience more rapid progression.

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Long-Term Progression in Patients with Normal ALT
A normal ALT level has traditionally been thought of as an indicator of mild liver disease with a lower risk of progression. This assumption is controversial, however, since some patients with persistently normal ALT can develop severe liver disease; in Khouri’s study described above, for example, ALT did not predict fibrosis progression. The traditional view was supported by a study by M. Persico and colleagues published in the May 2006 Journal of Viral Hepatitis. The researchers followed 24 chronic hepatitis C patients with persistently normal ALT and 40 patients with elevated ALT for 10 years. The median histological stage was significantly higher among the patients with elevated ALT. Biopsies taken at baseline, five years, and 10 years revealed that patients with normal ALT typically did not show evidence of histological progression. While interferon-gamma production was similar in the two groups, those with elevated ALT had significantly greater proliferating hepatocyte activity. The authors concluded that their study “confirms that progression to cirrhosis is slow or absent” in patients with persistently normal ALT after a decade of follow-up.

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Factors Influencing ALT Level
In another ALT study, D. Prati and colleagues assessed viral and host metabolic factors influencing liver cell injury and ALT activity in patients with chronic hepatitis C; results were published in the April 2006 Journal of Hepatology. The analysis included more than 2800 participants enrolled in three phase III clinical trials of pegylated interferon alfa-2a (Pegasys) plus ribavirin; half achieved sustained virological response. In a comparison of 480 patients with normal ALT and 2386 with elevated ALT, patient gender, HCV genotype, HCV viral load, body mass index, and symptoms of the metabolic syndrome (high blood pressure, elevated blood glucose, and elevated cholesterol and triglycerides) were directly associated with increased ALT levels. Among patients with baseline elevated ALT who achieved SVR, ALT levels fell to 25 IU/L among men and 22 IU/L among women - about 30% of the traditional upper limit of normal. These data add to the growing evidence that liver injury in people with hepatitis C is linked with the metabolic syndrome and insulin resistance, although the mechanism remains poorly understood. The authors concluded that ALT levels in hepatitis C patients partially depend on the degree of metabolic dysfunction, which is the result of an interaction between HCV infection and individual characteristics. Therefore, they recommended, “treatment decisions should not be based on [ALT] level alone, but rather on global evaluation of the patient.”

In an accompanying editorial, S. Harrison discussed the growing epidemic of obesity, metabolic syndrome, and their relation to fatty liver disease. The increased rate of fatty liver disease means more people without viral hepatitis have above-normal ALT levels, complicating the use of ALT as an indicator of HCV-related liver disease. And in hepatitis C patients, elevated ALT may be associated with HCV, the metabolic syndrome, or both. Harrison suggested that using a revised definition of normal ALT - below 30 IU/L for men and 19 IU/L for women - “may allow for detection and treatment of hepatitis C patients earlier in their disease course, prior to development of advanced fibrosis.”

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Normal ALT in Coinfected Patients
Turning to HIV/HCV coinfection, the relation between ALT and liver disease progression in this population remains poorly understood. As reported in the April 15, 2006 Journal of Acquired Immune Deficiency Syndromes, S.A. Gonzalez and colleagues conducted a retrospective cross-sectional analysis of data from 89 consecutive HIV/HCV coinfected patients, as well as individuals with HCV alone, who underwent liver biopsy over a two-year period. Mean ALT levels and the overall proportion of patients with normal ALT (21% vs 18%) were similar in the coinfected and HCV monoinfected groups However, the coinfected patients had significantly more advanced fibrosis and necroinflammation. In the HCV monoinfected group, severe (grade 3 or 4) liver inflammation was less common among participants with normal ALT (5% vs 20%). But among the coinfected patients, the proportion with advanced necroinflammation was similar in individuals with normal or elevated ALT (32% vs 37%). ALT level was not significantly associated with the degree of liver fibrosis - not surprising, since elevated liver enzymes are a consequence of hepatocyte inflammation rather than over-production of scar tissue. The researchers concluded that, “In coinfected patients, normal ALT levels are not an indicator of mild necroinflammation and may not portend a more benign disease course.” They further suggested that in coinfected patients, “ALT levels may not provide adequate information regarding the extent of liver disease.”

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Worse Outcomes in Coinfected Patients
In other coinfection news, N.A. Merriman and colleagues reported in the April 2006 American Journal of Gastroenterology that HIV/HCV coinfected patients have more severe liver disease and higher mortality rates compared to people with either hepatitis C or HIV alone. The researchers analyzed records from 265 HCV/HIV coinfected, 251 HCV monoinfected, and 227 HIV monoinfected patients at the Philadelphia Veterans Affairs Medical Center. They found that coinfected patients had a significantly higher frequency of liver dysfunction - albumin level, platelet count, and prothrombin time - than the HCV-only or HIV-only groups (37%, 21%, and 20%, respectively), as well as higher mortality over three years (17%, 6%, and 9%, respectively). However, in accordance with several past studies, coinfection was not associated with worse HIV disease progression. In this study, the rate of death among coinfected patients was nearly twice as high for white patients compared with African-Americans (31% vs 15%), and whites died at a significantly younger average age (46 vs 52 years). However, this racial disparity in mortality was not seen in the HCV-only or HIV-only groups. The researchers could not explain this latter finding and called for further investigation.

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