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Progression of fibrosis in chronic hepatitis C
GASTROENTEROLOGY 2003;124:97–104
Progression of Fibrosis in Chronic Hepatitis C MARC G. GHANY,* DAVID E. KLEINER,‡ HARVEY ALTER,§ EDWARD DOO,* FAROOQ KHOKAR,* KITTICHAI PROMRAT,* DAVID HERION,* YOON PARK,* T. JAKE LIANG,* and JAY H. HOOFNAGLE* *Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; ‡Laboratory of Pathology, National Cancer Institute; and §Department of Transfusion Medicine, the Warren E. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland
Background & Aims: Fibrosis is the hallmark of hepatic cirrhosis, worsening of which is probably the best surrogate marker for progression of chronic liver disease. We evaluated a large cohort of patients with chronic hepatitis C (CHC) using liver histology to assess the rate and predictors of progression of fibrosis. Methods: The cohort consisted of 123 patients with CHC who underwent 2 liver biopsies 4 –212 months (mean, 44 months) apart without intervening treatment. Liver histology was graded using the histology activity index (score, 0 –18) and fibrosis staged using a scoring system of 0 (no fibrosis) to 6 (cirrhosis). Results: Among 123 patients, 48 (39%) showed progression in fibrosis scores, 46 (37%) showed no change, and 29 (24%) showed improvement. Of those with worsening fibrosis, 75% had a 1-point increase and 25% a 2-point or greater increase in scores, and 9% showed progression to cirrhosis. The overall rate of progression was 0.12 fibrosis units per year, a rate that predicts progression to cirrhosis in 50 years if progression was linear. The rate of fibrosis progression was variable, and it was higher among older patients, those with higher serum alanine and aspartate aminotransferase levels, and those with the most extensive periportal necrosis on initial liver biopsy. Conclusions: The best predictors of fibrosis progression in CHC are the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy. These findings support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment.
hronic hepatitis C is estimated to affect 170 million persons worldwide and at least 2.7 million in the United States.1 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.2 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 de-
C
velop 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.3–11 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.1,12–17 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.
Materials and Methods Patients A database of all patients who were antibody to HCV positive and had undergone 2 or more liver biopsies at the Clinical Center of the National Institutes of Health between 1980 and 2000 was obtained, and clinic charts of patients were reviewed. This process identified 241 patients, of whom 115 were excluded because they had received antiviral treatment between the 2 biopsies and 3 because of incomplete clinical information. The study cohort thus consisted of 123 untreated patients, of whom 46 were blood donors enrolled in a natural history study of chronic hepatitis C,18 52 were untreated control patients who were participating in randomized trials evaluating interferon alfa19 or ribavirin,20 and 25 were patients referred for evaluation and possible therapy who elected not to undergo treatment. All patients were enrolled in clinical research protocols that had been approved by the National Institute of Diabetes and Digestive and Kidney Diseases InAbbreviations used in this paper: HAI, histology activity index. This is a US government work. There are no restrictions on its use. 0016-5085/03/$0.00 doi:10.1053/gast.2003.50018
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stitutional Review Board, and patients gave written informed consent for participation and liver biopsy.
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.22 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⫹, ⱕ25%; 2⫹, 26%–50%; 3⫹, 51%–75%; 4⫹, ⱖ76%). 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.10 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
Statistical Analysis The host and viral factors that were assessed for association with progression in fibrosis were sex, race or ethnicity, age, age at infection, estimated duration of infection, weight, body mass index, number of alcoholic drinks per week, history of alcohol abuse, MAST score, serum alanine aminotransferase (ALT) level, aspartate aminotransferase level, albumin level, bilirubin level, platelet count, prothrombin time, HCV genotype, the individual components and total HAI score, and the Ishak score. Associations were first examined by univariate analysis using Student t test, and then independent predictors of fibrosis progression were assessed using linear and stepwise
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Table 1. Demographic and Clinical Characteristics of Study Cohort Characteristic Mean age (yr) at first biopsy (range) No. of men (%) No. (%) of Whites Blacks Asian Americans Mean duration (yr) of infection (range) Median Source of infection (no. [%]) Transfusion Injection drug use Nasal cocaine use Occupational Tattoo Unknown Genotype (no. [%]) 1 2 3 4 Mixed Unknown Mean values (range) ALT (IU/L) AST (IU/L) Total bilirubin (mg/dL) Albumin (g/dL) Platelet count (mm3) Prothrombin time (s) Duration between liver biopsies (mo) HAI inflammatory score Ishak fibrosis score
n 41 (18–70) 77 (63) 102 (83) 18 (15) 3 (2) 14 (1–37) 14 42 (34) 50 (41) 4 (3) 4 (3) 2 (2) 21 (17) 86 (70) 16 (13) 3 (2) 1 (1) 4 (3) 13 (11) 150 (11–1038) 95 (15–929) 0.74 (0.1–2) 4.2 (2.6–4.9) 224 (64–411) 11.8 (10.2–14.7) 44 (4–211) 8.7 (1–17) 2.3 (0–6)
NOTE. n ⫽ 123. AST, aspartate aminotransferase.
logistic regression; Spearman’s test was used to determine the correlation between the 2 methods used to assess rate of fibrosis progression (Statview version 5.0.1; SAS Institute Inc., Cary, NC).
Results Patient Characteristics The clinical characteristics and patient demographics of the 123 patients at the time of the initial liver biopsy are shown in Table 1. 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
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Table 2. Comparison of Clinical Characteristics With Stage of Fibrosis at Initial Biopsy Stage Characteristic
0 (n ⫽ 21)
1 (n ⫽ 24)
2 (n ⫽ 19)
3 (n ⫽ 28)
4 (n ⫽ 17)
5 (n ⫽ 10)
6 (n ⫽ 4)
P
Mean age at initial biopsy (yr) Mean age at infection (yr) Mean duration of infection (yr) Male sex Race White Black Asian American Mean weight (kg) Mean body mass index (kg/m2) Alcohol use (drinks/wk) No. with a history of alcohol abuse MAST score (0–15) Mean values ALT (IU/L) AST (IU/L) Total bilirubin (mg/dL) Albumin (g/dL) Platelet count (mm3) Prothrombin time (s)
36 19 17 52%
34 23 12 50%
40 26 14 63%
42 30 11 68%
45 29 15 70%
48 31 15 70%
54 53 6 75%
0.00008 0.0004 0.2 0.7
81% 14% 5% 76 26 3.3 8 1.8
79% 21% 0% 80 26 4 7 2
84% 16% 0 78 27 1.3 7 2.5
82% 14% 4% 90 29 2.8 11 2.8
94% 6% 0 78 26 1.6 3 1.3
80% 10% 10% 85 29 .2 3 1.4
75% 25% 0 78 27 .5 0 0
0.12 0.24 0.5 0.6 0.7
124 64 .60 4.2 249 11.5
96 50 .67 4.2 244 11.4
132 98 .74 4.2 227 11.6
175 108 .78 4.2 224 12.0
217 134 .76 4.3 205 12.2
161 131 .96 4.2 169 12.4
215 153 1.1 3.8 161 13.9
0.3 0.23 0.04 0.51 0.004 ⬍0.0001
0.88
AST, aspartate aminotransferase.
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). A comparison of patients with different stages of fibrosis is shown in Table 2. 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 (Table 3). 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
Table 3. Comparison of Intial and Final Stages of Fibrosis Final stage
Initial stage 0 1 2 3 4 5 6 Total
0
1
2
3
4
5
6
Total
9 6 0 0 0 0 0 15
8 11 6 2 1 0 0 28
2 5 6 5 4 0 0 22
1 1 4 7 7 1 0 21
1 1 2 12 0 3 1 20
0 0 0 2 4 3 0 9
0 0 1 0 1 3 3 8
21 24 19 28 17 10 4 123
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Table 4. Clinical and Histologic Characteristics of Individuals Who Showed No Progression and Those Who Showed Progression in Hepatic Fibrosis Characteristic
No progression (n ⫽ 75)
Progression (n ⫽ 48)
P
43 27 65%
46 27 56%
0.07 0.80 0.32
64 10 1 81 27 18 2.7 23 2.3
38 8 2 81 28 17 2.0 16 1.5
0.32
84% 10% 4% 1%
79% 21% 0% 0%
118 72 0.75 4.2 224 11.7 8.60 2.59
204 133 0.73 4.1 223 12.0 8.90 2.75
0.02 0.03 0.77 0.17 0.88 0.23 0.70 0.40
3.52 1.96 2.53 0.54
3.48 2.19 2.04 0.75
0.77 0.28 0.10 0.14
Mean age at follow-up biopsy (yr) Mean age at infection (yr) Male sex Race/ethnicity White Black Asian American Mean weight (kg) Mean body mass index (kg/m2) Mean estimated duration of infection (yr) Alcohol use (no. of drinks/wk) No. with a history of alcohol abuse MAST score (0–15) Genotype 1 2 3 4 Mean values ALT (IU/L) AST (IU/L) Total bilirubin (mg/dL) Albumin (g/dL) Platelet count (mm3) Prothrombin time (s) Necroinflammatory HAI score (0–18) Piecemeal necrosis score (0–10) Lobular inflammation and necrosis score (0–4) Portal inflammation score (0–4) Fibrosis score (0–6) Steatosis score (0–4)
0.89 0.37 0.84 0.5 0.8 0.2
0.83
AST, aspartate aminotransferase.
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. Table 4 compares patients who had worsening of liver fibrosis on the second liver biopsy with those whose histology did not change or seemed to improve. 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 fibro-
sis. 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). Stepwise linear regression analysis was performed to assess factors independently associated with rate of change in fibrosis score over time and to develop a model to predict progression. The factors listed in Table 4 were analyzed in a stepwise linear regression model. The optimal model comprised 3 factors from the time of the initial biopsy: low initial fibrosis score (P ⬍ 0.0001), piecemeal necrosis (P ⬍ 0.01), and serum ALT levels (P ⬍ 0.0001). Age at initial biopsy, age at onset, duration of infection, HCV genotype, serum bilirubin level, albumin level, and platelet count did not improve the model, although age at initial biopsy just missed the discriminating cutoff for inclusion into the model. Thus, patients with high aminotransferase levels and more severe necroinflammatory changes on the initial biopsy were more
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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. Rate of Progression of Fibrosis The rate of progression of fibrosis was estimated by 2 methods. Dividing the average change in fibrosis score by the average duration between liver biopsies yielded an estimated rate of progression of 0.12 fibrosis units per year. In contrast, dividing the initial fibrosis score by the estimated total duration of infection (in 102 patients with this estimate) yielded an estimated rate of progression of 0.44 fibrosis units per year. The 3.5-fold difference in estimated rates of progression would change the averaged predicted time from no fibrosis to cirrhosis from 49 to 14 years. The correlation coefficient between the 2 methods used to assess progression in liver fibrosis was 0.35. No patient admitted to heavy alcohol use between the 2 biopsies. We assessed the role of alcohol in progression of liver fibrosis using several indicators of alcohol use: number of alcoholic drinks per week, history of alcohol abuse, and MAST score, which is also a reliable indicator of alcohol abuse. Using these 3 parameters, we found no association between alcohol consumption and progression of liver fibrosis. This lack of association was confirmed by detailed lifetime estimation of alcohol intake in a subset of 36 patients (29%). In this subset, patients whose fibrosis worsened consumed lesser amounts of alcohol on average (120 kg/lifetime) compared with those whose fibrosis did not worsen (159 kg/lifetime); this difference was not significant. Serum Aminotransferase Levels and Progression of Fibrosis The role of elevated ALT levels and extent of periportal necroinflammation, identified as factors in predicting progression of fibrosis, were further analyzed in a post-hoc manner. We also analyzed age, which has been shown in other studies and in our cross-sectional analysis to be a factor in progression of fibrosis. The effect of age on progression of fibrosis was direct and linear, increasing with each 15-year period (Figure 1A). For ALT levels, the rate of fibrosis progression was ⬍0.05 fibrosis units per year in the groups of patients with ALT levels ⱕ5 times the upper limit of normal but was 0.96 units per year in those with ALT levels greater than that level (Figure 1B), suggesting that progression
Figure 1. Mean rate of worsening scores for fibrosis per year between 2 liver biopsies according to (A) patient age at initial liver biopsy (by every 15 years), (B) initial ALT level (n ⫽ 118; by fold elevation above the upper limit of normal), and (C) initial reading for periportal necrosis and inflammation (0 –1, no or mild piecemeal necrosis; 3– 4, moderate or marked piecemeal necrosis; 5– 6, moderate or marked piecemeal necrosis plus bridging necrosis; 10, multilobular necrosis). The Knodell scores for lobular and portal inflammation are not included in this figure; hence, the maximal score is 10 and not 18.
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 bridg-
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ing necrosis (score, 5– 6) and submassive necrosis (score, 10) (Figure 1C).
Discussion The natural history of chronic hepatitis C remains poorly defined, in large part because of the difficulties in studying an infection that is often asymptomatic throughout its course until the development of irreversible cirrhosis and end-stage liver disease.3 Hepatitis C typically has a subclinical onset and a slow rate of progression, with cirrhosis developing only after 10 –50 years of infection. For these reasons, studies of the natural history of hepatitis C focus either on patients during the early years of infection3–5 or separately on patients who have already developed advanced disease.6 –11 Similarly, studies of therapy for hepatitis C must rely on surrogate markers that are expected to ultimately correlate with long-term outcome. Because the major long-term complication of chronic hepatitis C is the development of cirrhosis and end-stage liver disease, the degree of fibrosis on liver biopsy would seem to be an appropriate surrogate marker. Using degree of fibrosis and estimated duration of infection as markers, investigators have predicted the rate of progression of disease from onset to be 10 to more than 50 years, depending on cofactors that correlated with disease progression such as age, sex, and alcohol use.3–5,10 In this retrospective-prospective study of 123 untreated patients with chronic hepatitis C, the rate of progression of fibrosis was estimated based on fibrosis scores of 2 liver biopsies performed an average of 44 months apart. This study also used a more discriminating system for scoring fibrosis that allows for a broader spread of results (7 points: 0 – 6) compared with previous studies that have used the conventional HAI fibrosis score (4 points: 0, 1, 3, and 4)12–17 or the METAVIR score (5 points: 0 – 4).10,11 Using this system, the rate of fibrosis progression was 0.12 fibrosis units per year, at which rate cirrhosis would require an average of 49 years to develop. This estimate is not too different from estimates from Europe and Japan predicting that cirrhosis might take 30 –50 years to develop in the nonalcoholic population.4,5,10,11 Poynard et al. reported on rates of fibrosis progression using 2 cohorts followed up longitudinally without treatment: a group of 70 patients with 170 liver biopsies and a group of 58 control patients used in randomized trials with 116 biopsies.10 Duration between liver biopsies is not provided in the study by Poynard et al., but mean rates of fibrosis progression in the 2 groups were 0.297 and 0.231 fibrosis units per year, respectively.
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These rates would predict a faster progression to cirrhosis than found in our cohort (0.12 fibrosis units per year). Because clinical data were not provided in the report by Poynard et al., we can only speculate that the difference may be due to the fact that our patients were younger, had less advanced fibrosis on initial liver biopsy, and consumed lesser quantities of alcohol. In the cross-sectional analysis by Poynard et al., age at infection, estimated duration of infection, male sex, and alcohol consumption were found to be associated with progression of fibrosis. In contrast, we found no association between alcohol consumption and progression of fibrosis. The most likely explanation for this is that most of our study population did not consume alcoholic beverages between liver biopsies; therefore, they may not be representative of other populations with chronic hepatitis C. A striking finding in this study was the lack of correlation between results of cross-sectional and longitudinal analyses. Cross-sectional analysis based on the initial liver biopsy and historical estimates of disease duration yielded a 4-fold higher rate of fibrosis progression than did longitudinal data based on changes between biopsies. This discrepancy was probably due to the inaccuracy in determining the time of onset of infection, which is needed to calculate rate of progression and, perhaps more importantly, the lack of linearity in fibrosis progression. Thus, fibrosis may progress nonlinearly in fits and starts, progressing more rapidly at specific times, perhaps during flares of disease. In addition, progression of fibrosis may not be linear in the same manner as the scoring system, in that progression from stage 0 to 1 may take longer than from stage 3 or 4 or vice versa. Finally, the discrepancy may have been exacerbated by problems in sampling error of staging fibrosis (suggested by the finding of improvement in hepatic fibrosis in a proportion of patients)25–27 and characteristics of this tertiary referral patient population, which consisted of volunteer blood donors enrolled in a natural history study as well as patients referred for possible antiviral therapy.18 –20 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.10,11,18 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
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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.28 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.
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Yurdaydin C, Swain M, Kleiner DE, Mahaney K, Hoofnagle JH. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: 897– 893. Desmet V, Gerber M, Hoofnagle JH, Manns M, Scheuer P. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520. Ishak KG, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RNM, Phillips MJ, Portmann BG, Poulsen H, Scheuer PJ, Schmid M, Thaler H. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22: 696 – 699. Damen M, Cuypers HT, Zaaijer HL, Reesink HW, Schaasberg WP, Gerlich WH, Niesters HG, Lelie PN. International collaborative study on the second EUROHEP HCV-RNA reference panel. J Virol Methods 1996;58:175–185. Mahaney K, Tadeschi V, Maertens G, Di Bisceglie AM, Vergalla J, Hoofnagle JH, Sallie R. Genotypic analysis of hepatitis C virus in American patients. Hepatology 1994;20:1405–1411. Baunsgaard P, Snachez GC, Lundborg CJ. The variation of pathological changes in the liver evaluated by double biopsies. Acta Pathol Microbiol Scand [A] 1979;87:51–57.
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26. Braunstein H. Needle biopsy of the liver in cirrhosis. Arch Pathol 1956;62:87–95. 27. Waldstein SS, Szanto PB. Accuracy of sampling by needle biopsy in diffuse liver disease. Arch Pathol 1950;50:326 –328. 28. National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology 1997;26(suppl 1):2S–10S. 29. Martinot-Peignoux M, Boyer N, Cazals-Hatem D, Pham B-N, Gervais A, Le Breton V, Levy S, Degott C, Valla D-C, Marcellin P. Prospective study on anti-hepatitis C virus-positive patients with persistently normal serum alanine transaminase with or without detectable serum hepatitis C virus RNA. Hepatology 2001;34: 1000 –1005.
Received December 20, 2001. Accepted October 9, 2002. Address requests for reprints to: Marc G. Ghany, M.D., Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9B-06, 10 Center Drive, MSC 1800, Bethesda, Maryland 20892-1800. e-mail: [email protected]; fax: (301) 402-0491. M.G.G. and D.E.K. contributed equally to this study.
Progression of Fibrosis in Chronic Hepatitis C MARC G. GHANY,* DAVID E. KLEINER,‡ HARVEY ALTER,§ EDWARD DOO,* FAROOQ KHOKAR,* KITTICHAI PROMRAT,* DAVID HERION,* YOON PARK,* T. JAKE LIANG,* and JAY H. HOOFNAGLE* *Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; ‡Laboratory of Pathology, National Cancer Institute; and §Department of Transfusion Medicine, the Warren E. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland
Background & Aims: Fibrosis is the hallmark of hepatic cirrhosis, worsening of which is probably the best surrogate marker for progression of chronic liver disease. We evaluated a large cohort of patients with chronic hepatitis C (CHC) using liver histology to assess the rate and predictors of progression of fibrosis. Methods: The cohort consisted of 123 patients with CHC who underwent 2 liver biopsies 4 –212 months (mean, 44 months) apart without intervening treatment. Liver histology was graded using the histology activity index (score, 0 –18) and fibrosis staged using a scoring system of 0 (no fibrosis) to 6 (cirrhosis). Results: Among 123 patients, 48 (39%) showed progression in fibrosis scores, 46 (37%) showed no change, and 29 (24%) showed improvement. Of those with worsening fibrosis, 75% had a 1-point increase and 25% a 2-point or greater increase in scores, and 9% showed progression to cirrhosis. The overall rate of progression was 0.12 fibrosis units per year, a rate that predicts progression to cirrhosis in 50 years if progression was linear. The rate of fibrosis progression was variable, and it was higher among older patients, those with higher serum alanine and aspartate aminotransferase levels, and those with the most extensive periportal necrosis on initial liver biopsy. Conclusions: The best predictors of fibrosis progression in CHC are the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy. These findings support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment.
hronic hepatitis C is estimated to affect 170 million persons worldwide and at least 2.7 million in the United States.1 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.2 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 de-
C
velop 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.3–11 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.1,12–17 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.
Materials and Methods Patients A database of all patients who were antibody to HCV positive and had undergone 2 or more liver biopsies at the Clinical Center of the National Institutes of Health between 1980 and 2000 was obtained, and clinic charts of patients were reviewed. This process identified 241 patients, of whom 115 were excluded because they had received antiviral treatment between the 2 biopsies and 3 because of incomplete clinical information. The study cohort thus consisted of 123 untreated patients, of whom 46 were blood donors enrolled in a natural history study of chronic hepatitis C,18 52 were untreated control patients who were participating in randomized trials evaluating interferon alfa19 or ribavirin,20 and 25 were patients referred for evaluation and possible therapy who elected not to undergo treatment. All patients were enrolled in clinical research protocols that had been approved by the National Institute of Diabetes and Digestive and Kidney Diseases InAbbreviations used in this paper: HAI, histology activity index. This is a US government work. There are no restrictions on its use. 0016-5085/03/$0.00 doi:10.1053/gast.2003.50018
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stitutional Review Board, and patients gave written informed consent for participation and liver biopsy.
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.22 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⫹, ⱕ25%; 2⫹, 26%–50%; 3⫹, 51%–75%; 4⫹, ⱖ76%). 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.10 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
Statistical Analysis The host and viral factors that were assessed for association with progression in fibrosis were sex, race or ethnicity, age, age at infection, estimated duration of infection, weight, body mass index, number of alcoholic drinks per week, history of alcohol abuse, MAST score, serum alanine aminotransferase (ALT) level, aspartate aminotransferase level, albumin level, bilirubin level, platelet count, prothrombin time, HCV genotype, the individual components and total HAI score, and the Ishak score. Associations were first examined by univariate analysis using Student t test, and then independent predictors of fibrosis progression were assessed using linear and stepwise
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Table 1. Demographic and Clinical Characteristics of Study Cohort Characteristic Mean age (yr) at first biopsy (range) No. of men (%) No. (%) of Whites Blacks Asian Americans Mean duration (yr) of infection (range) Median Source of infection (no. [%]) Transfusion Injection drug use Nasal cocaine use Occupational Tattoo Unknown Genotype (no. [%]) 1 2 3 4 Mixed Unknown Mean values (range) ALT (IU/L) AST (IU/L) Total bilirubin (mg/dL) Albumin (g/dL) Platelet count (mm3) Prothrombin time (s) Duration between liver biopsies (mo) HAI inflammatory score Ishak fibrosis score
n 41 (18–70) 77 (63) 102 (83) 18 (15) 3 (2) 14 (1–37) 14 42 (34) 50 (41) 4 (3) 4 (3) 2 (2) 21 (17) 86 (70) 16 (13) 3 (2) 1 (1) 4 (3) 13 (11) 150 (11–1038) 95 (15–929) 0.74 (0.1–2) 4.2 (2.6–4.9) 224 (64–411) 11.8 (10.2–14.7) 44 (4–211) 8.7 (1–17) 2.3 (0–6)
NOTE. n ⫽ 123. AST, aspartate aminotransferase.
logistic regression; Spearman’s test was used to determine the correlation between the 2 methods used to assess rate of fibrosis progression (Statview version 5.0.1; SAS Institute Inc., Cary, NC).
Results Patient Characteristics The clinical characteristics and patient demographics of the 123 patients at the time of the initial liver biopsy are shown in Table 1. 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
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Table 2. Comparison of Clinical Characteristics With Stage of Fibrosis at Initial Biopsy Stage Characteristic
0 (n ⫽ 21)
1 (n ⫽ 24)
2 (n ⫽ 19)
3 (n ⫽ 28)
4 (n ⫽ 17)
5 (n ⫽ 10)
6 (n ⫽ 4)
P
Mean age at initial biopsy (yr) Mean age at infection (yr) Mean duration of infection (yr) Male sex Race White Black Asian American Mean weight (kg) Mean body mass index (kg/m2) Alcohol use (drinks/wk) No. with a history of alcohol abuse MAST score (0–15) Mean values ALT (IU/L) AST (IU/L) Total bilirubin (mg/dL) Albumin (g/dL) Platelet count (mm3) Prothrombin time (s)
36 19 17 52%
34 23 12 50%
40 26 14 63%
42 30 11 68%
45 29 15 70%
48 31 15 70%
54 53 6 75%
0.00008 0.0004 0.2 0.7
81% 14% 5% 76 26 3.3 8 1.8
79% 21% 0% 80 26 4 7 2
84% 16% 0 78 27 1.3 7 2.5
82% 14% 4% 90 29 2.8 11 2.8
94% 6% 0 78 26 1.6 3 1.3
80% 10% 10% 85 29 .2 3 1.4
75% 25% 0 78 27 .5 0 0
0.12 0.24 0.5 0.6 0.7
124 64 .60 4.2 249 11.5
96 50 .67 4.2 244 11.4
132 98 .74 4.2 227 11.6
175 108 .78 4.2 224 12.0
217 134 .76 4.3 205 12.2
161 131 .96 4.2 169 12.4
215 153 1.1 3.8 161 13.9
0.3 0.23 0.04 0.51 0.004 ⬍0.0001
0.88
AST, aspartate aminotransferase.
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). A comparison of patients with different stages of fibrosis is shown in Table 2. 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 (Table 3). 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
Table 3. Comparison of Intial and Final Stages of Fibrosis Final stage
Initial stage 0 1 2 3 4 5 6 Total
0
1
2
3
4
5
6
Total
9 6 0 0 0 0 0 15
8 11 6 2 1 0 0 28
2 5 6 5 4 0 0 22
1 1 4 7 7 1 0 21
1 1 2 12 0 3 1 20
0 0 0 2 4 3 0 9
0 0 1 0 1 3 3 8
21 24 19 28 17 10 4 123
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Table 4. Clinical and Histologic Characteristics of Individuals Who Showed No Progression and Those Who Showed Progression in Hepatic Fibrosis Characteristic
No progression (n ⫽ 75)
Progression (n ⫽ 48)
P
43 27 65%
46 27 56%
0.07 0.80 0.32
64 10 1 81 27 18 2.7 23 2.3
38 8 2 81 28 17 2.0 16 1.5
0.32
84% 10% 4% 1%
79% 21% 0% 0%
118 72 0.75 4.2 224 11.7 8.60 2.59
204 133 0.73 4.1 223 12.0 8.90 2.75
0.02 0.03 0.77 0.17 0.88 0.23 0.70 0.40
3.52 1.96 2.53 0.54
3.48 2.19 2.04 0.75
0.77 0.28 0.10 0.14
Mean age at follow-up biopsy (yr) Mean age at infection (yr) Male sex Race/ethnicity White Black Asian American Mean weight (kg) Mean body mass index (kg/m2) Mean estimated duration of infection (yr) Alcohol use (no. of drinks/wk) No. with a history of alcohol abuse MAST score (0–15) Genotype 1 2 3 4 Mean values ALT (IU/L) AST (IU/L) Total bilirubin (mg/dL) Albumin (g/dL) Platelet count (mm3) Prothrombin time (s) Necroinflammatory HAI score (0–18) Piecemeal necrosis score (0–10) Lobular inflammation and necrosis score (0–4) Portal inflammation score (0–4) Fibrosis score (0–6) Steatosis score (0–4)
0.89 0.37 0.84 0.5 0.8 0.2
0.83
AST, aspartate aminotransferase.
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. Table 4 compares patients who had worsening of liver fibrosis on the second liver biopsy with those whose histology did not change or seemed to improve. 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 fibro-
sis. 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). Stepwise linear regression analysis was performed to assess factors independently associated with rate of change in fibrosis score over time and to develop a model to predict progression. The factors listed in Table 4 were analyzed in a stepwise linear regression model. The optimal model comprised 3 factors from the time of the initial biopsy: low initial fibrosis score (P ⬍ 0.0001), piecemeal necrosis (P ⬍ 0.01), and serum ALT levels (P ⬍ 0.0001). Age at initial biopsy, age at onset, duration of infection, HCV genotype, serum bilirubin level, albumin level, and platelet count did not improve the model, although age at initial biopsy just missed the discriminating cutoff for inclusion into the model. Thus, patients with high aminotransferase levels and more severe necroinflammatory changes on the initial biopsy were more
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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. Rate of Progression of Fibrosis The rate of progression of fibrosis was estimated by 2 methods. Dividing the average change in fibrosis score by the average duration between liver biopsies yielded an estimated rate of progression of 0.12 fibrosis units per year. In contrast, dividing the initial fibrosis score by the estimated total duration of infection (in 102 patients with this estimate) yielded an estimated rate of progression of 0.44 fibrosis units per year. The 3.5-fold difference in estimated rates of progression would change the averaged predicted time from no fibrosis to cirrhosis from 49 to 14 years. The correlation coefficient between the 2 methods used to assess progression in liver fibrosis was 0.35. No patient admitted to heavy alcohol use between the 2 biopsies. We assessed the role of alcohol in progression of liver fibrosis using several indicators of alcohol use: number of alcoholic drinks per week, history of alcohol abuse, and MAST score, which is also a reliable indicator of alcohol abuse. Using these 3 parameters, we found no association between alcohol consumption and progression of liver fibrosis. This lack of association was confirmed by detailed lifetime estimation of alcohol intake in a subset of 36 patients (29%). In this subset, patients whose fibrosis worsened consumed lesser amounts of alcohol on average (120 kg/lifetime) compared with those whose fibrosis did not worsen (159 kg/lifetime); this difference was not significant. Serum Aminotransferase Levels and Progression of Fibrosis The role of elevated ALT levels and extent of periportal necroinflammation, identified as factors in predicting progression of fibrosis, were further analyzed in a post-hoc manner. We also analyzed age, which has been shown in other studies and in our cross-sectional analysis to be a factor in progression of fibrosis. The effect of age on progression of fibrosis was direct and linear, increasing with each 15-year period (Figure 1A). For ALT levels, the rate of fibrosis progression was ⬍0.05 fibrosis units per year in the groups of patients with ALT levels ⱕ5 times the upper limit of normal but was 0.96 units per year in those with ALT levels greater than that level (Figure 1B), suggesting that progression
Figure 1. Mean rate of worsening scores for fibrosis per year between 2 liver biopsies according to (A) patient age at initial liver biopsy (by every 15 years), (B) initial ALT level (n ⫽ 118; by fold elevation above the upper limit of normal), and (C) initial reading for periportal necrosis and inflammation (0 –1, no or mild piecemeal necrosis; 3– 4, moderate or marked piecemeal necrosis; 5– 6, moderate or marked piecemeal necrosis plus bridging necrosis; 10, multilobular necrosis). The Knodell scores for lobular and portal inflammation are not included in this figure; hence, the maximal score is 10 and not 18.
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 bridg-
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ing necrosis (score, 5– 6) and submassive necrosis (score, 10) (Figure 1C).
Discussion The natural history of chronic hepatitis C remains poorly defined, in large part because of the difficulties in studying an infection that is often asymptomatic throughout its course until the development of irreversible cirrhosis and end-stage liver disease.3 Hepatitis C typically has a subclinical onset and a slow rate of progression, with cirrhosis developing only after 10 –50 years of infection. For these reasons, studies of the natural history of hepatitis C focus either on patients during the early years of infection3–5 or separately on patients who have already developed advanced disease.6 –11 Similarly, studies of therapy for hepatitis C must rely on surrogate markers that are expected to ultimately correlate with long-term outcome. Because the major long-term complication of chronic hepatitis C is the development of cirrhosis and end-stage liver disease, the degree of fibrosis on liver biopsy would seem to be an appropriate surrogate marker. Using degree of fibrosis and estimated duration of infection as markers, investigators have predicted the rate of progression of disease from onset to be 10 to more than 50 years, depending on cofactors that correlated with disease progression such as age, sex, and alcohol use.3–5,10 In this retrospective-prospective study of 123 untreated patients with chronic hepatitis C, the rate of progression of fibrosis was estimated based on fibrosis scores of 2 liver biopsies performed an average of 44 months apart. This study also used a more discriminating system for scoring fibrosis that allows for a broader spread of results (7 points: 0 – 6) compared with previous studies that have used the conventional HAI fibrosis score (4 points: 0, 1, 3, and 4)12–17 or the METAVIR score (5 points: 0 – 4).10,11 Using this system, the rate of fibrosis progression was 0.12 fibrosis units per year, at which rate cirrhosis would require an average of 49 years to develop. This estimate is not too different from estimates from Europe and Japan predicting that cirrhosis might take 30 –50 years to develop in the nonalcoholic population.4,5,10,11 Poynard et al. reported on rates of fibrosis progression using 2 cohorts followed up longitudinally without treatment: a group of 70 patients with 170 liver biopsies and a group of 58 control patients used in randomized trials with 116 biopsies.10 Duration between liver biopsies is not provided in the study by Poynard et al., but mean rates of fibrosis progression in the 2 groups were 0.297 and 0.231 fibrosis units per year, respectively.
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These rates would predict a faster progression to cirrhosis than found in our cohort (0.12 fibrosis units per year). Because clinical data were not provided in the report by Poynard et al., we can only speculate that the difference may be due to the fact that our patients were younger, had less advanced fibrosis on initial liver biopsy, and consumed lesser quantities of alcohol. In the cross-sectional analysis by Poynard et al., age at infection, estimated duration of infection, male sex, and alcohol consumption were found to be associated with progression of fibrosis. In contrast, we found no association between alcohol consumption and progression of fibrosis. The most likely explanation for this is that most of our study population did not consume alcoholic beverages between liver biopsies; therefore, they may not be representative of other populations with chronic hepatitis C. A striking finding in this study was the lack of correlation between results of cross-sectional and longitudinal analyses. Cross-sectional analysis based on the initial liver biopsy and historical estimates of disease duration yielded a 4-fold higher rate of fibrosis progression than did longitudinal data based on changes between biopsies. This discrepancy was probably due to the inaccuracy in determining the time of onset of infection, which is needed to calculate rate of progression and, perhaps more importantly, the lack of linearity in fibrosis progression. Thus, fibrosis may progress nonlinearly in fits and starts, progressing more rapidly at specific times, perhaps during flares of disease. In addition, progression of fibrosis may not be linear in the same manner as the scoring system, in that progression from stage 0 to 1 may take longer than from stage 3 or 4 or vice versa. Finally, the discrepancy may have been exacerbated by problems in sampling error of staging fibrosis (suggested by the finding of improvement in hepatic fibrosis in a proportion of patients)25–27 and characteristics of this tertiary referral patient population, which consisted of volunteer blood donors enrolled in a natural history study as well as patients referred for possible antiviral therapy.18 –20 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.10,11,18 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
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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.28 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.
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6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
References 1. Liang TJ, Reherman B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med 2000;132:296 –305. 2. Seaberg EC, Belle SH, Beringer KC, Schivins JL, Detre K. Liver transplantation in the United States from 1987-1998: updated results from the Pitt-UNOS Liver Transplant Registry. In: Cecka M, Terasaki PI, eds. Clinical transplants 1998. Los Angeles, CA: UCLA Tissue Typing Laboratory, 1998:17–37. 3. Seeff LB, Hollinger FB, Alter HJ, Wright EC, Cain CMB, Buskell ZJ, Ishak KG, Iber FL, Toro D, Samanta A, Koretz R, Perrillo RP, Goodman ZD, Knodell RG, Gitnick G, Morgan TR, Schiff ER, Lasky S, Stevens C, Vlahcevic RZ, Weinshel E, Tanwandee T, Lin HJ, Barbosa L. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001; 33:455– 463. 4. Kenny-Walsh E for the Irish Hepatology Research Group. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 1999;340:1228 –1233. 5. Vogt M, Lang T, Frosner G, Klinger C, Sendl AF, Zeller A, Wiebecke B, Langer B, Meisner H, Hess J. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery
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Received December 20, 2001. Accepted October 9, 2002. Address requests for reprints to: Marc G. Ghany, M.D., Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9B-06, 10 Center Drive, MSC 1800, Bethesda, Maryland 20892-1800. e-mail: [email protected]; fax: (301) 402-0491. M.G.G. and D.E.K. contributed equally to this study.