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ALT & Biopsy Predict Outcome
  Normal aminotransferases and mild liver histology in patients with hepatitis C predict a more favorable natural history
Commentary by Jules Levin: This study was done in HCV monoinfected patients. Progression is reported to be accelerated in HIV/HCV coinfected patients so the results of the study and recommendations bby the authors based on the study may not be completely applicable to coinfected patients. The authors support using ALT as a measure of monitoring disease progression and say "patients with normal aminotransferase levels and mild liver histology can safely defer treatment". It's important to add that studies show that a percentage of patients, perhaps 12-20%, with normal ALT can have more advanced liver disease on biopsy. Coinfected patients may be more prone to have normal ALT but more advanced disease because HIV can accelerate HCV. Therefore, liver biopsy plays an important and perhaps indispensible role in assessing a patient's liver disease stage and in recommending when to begin therapy.
Chronic hepatitis C is estimated to affect 170 million persons worldwide and at least 2.7 million in the United States. Chronic infection with hepatitis C virus (HCV) is now the major cause of chronic hepatitis in the western world and the single major reason for liver transplantation in the United States.
However, not all cases of chronic hepatitis C are progressive or lead to the serious complications of cirrhosis or hepatocellular carcinoma. Indeed, natural history studies suggest that only 5%-20% of persons develop cirrhosis during the first 20 years of HCV infection and that some patients remain asymptomatic and without significant liver disease for many decades, if not for life. In assessing patients and recommending therapy, knowledge of the natural history and prognosis of the disease is important, particularly because current therapies are expensive, difficult to tolerate, and limited in efficacy. In patients with mild disease, it is frequently best to advise delaying therapy, particularly because advances in efficacy and tolerability of therapeutic regimens are likely to continue to occur.
In an attempt to better define the natural history and prognostic factors in chronic hepatitis C, we evaluated liver histology from all patients who underwent 2 or more liver biopsies who were seen at the Clinical Center of the National Institutes of Health over a 20-year period. Hepatic fibrosis was used as the primary marker for disease progression.
Assessment of fibrosis
Liver biopsy specimens were read and scored under code by a hepatic pathologist (D.E.K.) using a modification of the histology activity index (HAI) for grading of inflammation and necrosis20,21 and the Ishak fibrosis score for staging of fibrosis. The necroinflammatory components of the HAI include periportal inflammation and necrosis (0-10), lobular inflammation and necrosis (0-4), and portal inflammation (0-4). Instead of the HAI fibrosis score (0-4), the Ishak score was used, which stages fibrosis from 0-6 (1-2, portal fibrotic expansion; 3-4, bridging fibrosis; 5-6, cirrhosis). Steatosis was scored based on the proportion of hepatocytes with fat (1+, 25%; 2+, 26%-50%; 3+, 51%-75%; 4+, 76%).
To validate the adequacy of the biopsy, we recorded the number of portal tracts in each biopsy. The mean number of portal tracts in the initial biopsy was 21 (range, 4-51; median, 20). Similarly, the mean number of portal tracts in the second biopsy was 19 (range, 5-42; median, 18). Less than 10% of biopsies had <10 portal tracts, the number generally used to define an adequate biopsy. Worsening of fibrosis was defined as a 1-point increase and improvement as a 1-point decrease in Ishak score. The rate of fibrosis progression was assessed in 2 ways. First (longitudinal analysis), the difference in fibrosis scores between the first and second (or last) liver biopsies was divided by the duration of time between the biopsies and expressed as fibrosis units per year. Second (cross-sectional analysis), the fibrosis score of the initial liver biopsy was divided by the estimated duration of infection, which was based on risk factor assessment and history of exposure. For patients whose only risk factor was transfusion of blood or blood products, the date of transfusion was used to date onset of infection. For patients whose exposure was injection drug use or use of cocaine, the year of first drug use was used. For patients with a specific and convincing single parenteral exposure, such as a needle-stick accident, the date of the event was used to estimate the duration of infection.
HCV RNA was measured by the Roche Monitor kit version 1.1 (Roche Molecular Diagnostics, Indianapolis, IN).23 Genotyping of HCV was performed using a commercial line-probe hybridization assay.24
Chronic hepatitis C virus (HCV) is now the major cause of chronic hepatitis in the Western world and the single major reason for liver transplantation in the United States. While patients with aggressive disease often develop irreversible cirrhosis and end-stage liver disease, some patients remain asymptomatic and without significant liver disease for many decades, if not for life. Because current therapies are costly, have many adverse effects, and are limited in efficacy, prognostic indicators of disease progression would greatly help in advising patients on their therapeutic options. In patients with mild disease, for instance, it may be better to advise delaying therapy, because of the continued advances in efficacy and tolerability of therapeutic regimens. To address this issue, this study attempted to define the natural history and prognostic factors in chronic hepatitis C. Liver histology from 123 patients of the Clinical Center of the National Institutes of Health with 2 or more liver biopsies were assessed to attempt to better define the natural history and prognostic factors in chronic hepatitis C. Hepatic fibrosis was used as the primary marker for disease progression. The study showed that 39% of patients had progression of fibrosis scores, 37% exhibited no change, and 24% improved. The best predictors of progression of fibrosis in chronic hepatitis C were the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver.
The mean age at initial biopsy was 41 years, almost two thirds of patients were male, and most were white. The duration of infection could be estimated in 102 subjects (83%) and averaged 14 years (range, 1-37 years). The sources of infection were transfusion of blood products and injection drug use in three fourths of the patients and occupational exposure, tattoos, and snorting of cocaine with shared straws in the remainder. Serum ALT levels were initially normal (<42 IU/L) in 16 patients (13%). Four patients had ALT levels >500 IU/L, but none had jaundice or clinical evidence of acute hepatitis. All patients were HCV RNA positive at the time of the initial liver biopsy. Genotyping was available in 89% of cases, and the distribution was typical for the United States: 70% were genotype 1, 15% genotypes 2 or 3, and 3% mixed genotypes.
Liver histology on initial biopsy
Liver tissue was available for scoring of both biopsies from all 123 subjects. The mean total inflammatory HAI score of the initial biopsy for the entire cohort was 8.7 (range, 1-17) and the fibrosis component was 2.3 (range, 0-6). Of the total, 21 patients (17%) had no fibrosis, 43 (35%) had portal fibrotic expansion (stages 1 and 2), 45 (37%) had bridging fibrosis (stages 3 and 4), and 14 (11%) had cirrhosis (stages 5 and 6).
There was a significant, direct linear association between stage of fibrosis and age (P = 0.00008) as well as age at onset of infection (P = 0.0004) but not with duration of infection. Serum bilirubin level, prothrombin time, and platelet count also correlated with stage of fibrosis. Platelet counts most clearly separated early from late stages of fibrosis, particularly bridging fibrosis and cirrhosis. Serum bilirubin level and prothrombin time were usually normal unless cirrhosis was present. There was no association of severity of fibrosis with sex, race/ethnicity, history of alcohol consumption, body weight, body mass index, or serum aminotransferase levels.
Liver histology on follow-up biopsy
The mean duration between the initial and final liver biopsies was 44 months (range, 4-211 months). At follow-up biopsy, 15 patients (12%) had no fibrosis, 50 (41%) had portal fibrotic expansion, 41 (33%) had bridging fibrosis, and 17 (14%) had cirrhosis.
Overall, the degree of fibrosis had worsened on the second liver biopsy, with the mean Ishak scores increasing from 2.3 to 2.6 (P = 0.25). In contrast, the average necroinflammatory score remained unchanged (8.7 and 8.5; P = 0.54). Among the 123 patients, 48 (39%) showed worsening of fibrosis scores, 46 (37%) showed no change, and 29 (24%) seemed to improve. Of the patients with worsening fibrosis, 36 (75%) had a 1-point increase and 12 (25%) a 2-point or greater increase in fibrosis score. Eleven patients (10% of those without cirrhosis initially) showed histologic progression to cirrhosis. All except one patient who developed cirrhosis had bridging fibrosis (stages 3 or 4) on the previous biopsy; thus, 10 of 45 patients (22%) with bridging fibrosis had cirrhosis on follow-up liver biopsy an average of 4 years later. Five patients with cirrhosis seemed to improve and had bridging fibrosis on the second liver biopsy.
The only factors that correlated with worsening on univariate analysis were serum ALT and aspartate aminotransferase values at the time of initial biopsy. Age, sex, race, estimated duration of infection, age at onset of infection, alcohol consumption, a history of alcohol abuse, MAST score, body mass index, serum bilirubin level, albumin level, and prothrombin time and initial histologic scores did not correlate significantly with progression of fibrosis. Worsening also did not correlate with the duration between liver biopsies, although the average time was relatively short (approximately 4 years) compared with the total duration of the disease (averaging 14 years in this group). patients with high aminotransferase levels and more severe necroinflammatory changes on the initial biopsy were more likely to have worsening fibrosis than patients with lower ALT levels and less hepatic inflammation and necrosis. The correlation of worsening fibrosis with low initial fibrosis stage probably reflected the fact that patients with no fibrosis initially could only stay the same or worsen, whereas patients with advanced fibrosis could only stay the same or improve...No patient admitted to heavy alcohol use between the 2 biopsies..For ALT levels, the rate of fibrosis progression was <0.05 fibrosis units per year in the groups of patients with ALT levels 5 times the upper limit of normal but was 0.96 units per year in those with ALT levels greater than that level, suggesting that progression occurred largely in patients with marked elevations in serum aminotransferase levels. Similarly, progression of fibrosis was minimal in patients with no or mild degrees of periportal inflammation and necrosis on initial liver biopsy and accelerated particularly in those with bridging necrosis (score, 5-6) and submassive necrosis (score, 10).
The 2 types of analysis also identified different predictive factors for more rapid progression of fibrosis. In longitudinal analyses, the height of elevated ALT and aspartate aminotransferase levels and presence of severe piecemeal necrosis were most predictive of subsequent progression. These factors have not been identified in most cross-sectional studies, which usually have identified patient age, age at onset of infection, male sex, and alcohol use as predictive factors. A reasonable explanation for this discrepancy is that ALT levels and piecemeal necrosis vary during the course of this disease, and the values found at the time of a single liver biopsy may not accurately reflect values that have occurred in previous years. These findings indicate that regular determination of aminotransferase values is a helpful and reliable means of monitoring disease, judging prognosis, and recommending therapy and support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment.
This study also showed that different patients progress to cirrhosis at different rates. Indeed, a sizeable proportion of patients may never progress to cirrhosis. In patients with minimal or no elevations in ALT levels and milder degrees of necroinflammation, it was difficult to show any progression during the average of 4 years of follow-up. Similar findings have recently been reported in longitudinal studies of patients with normal serum ALT levels.29 These results reinforce the recommendation that patients with mild disease activity and scant hepatic fibrosis can delay therapy for hepatitis C until therapeutics improve and regimens are available that are more effective and have fewer side effects.
In summary, in this paired biopsy study of a cohort of 123 untreated patients with hepatitis C, progression of fibrosis was found in approximately one third of cases followed up over an average of 4 years. The overall rate of fibrosis progression suggests that the average patient would require 49 years to develop cirrhosis. However, the results also suggest that progression of fibrosis is variable, correlating best with elevated serum ALT levels and degree of periportal necrosis on liver biopsy. Thus, liver biopsy and simple biochemical tests provide clinically useful information for monitoring disease progression and recommending therapy.
Gastroenterology Jan 2003. Jay Hoofnagle et al.
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