Gut 2004;53:451–455. doi: 10.1136/gut.2003.021691

Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data

Patients: We studied 214 HCV infected patients (126 male; median age 36 years (range 5–8)) with

Results: Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23

Conclusions: One third of patients with predominantly mild hepatitis C showed significant fibrosis

What is the Natural History of Hepatitis C?  

The Virus

HCV is an RNA virus of the Flaviviridae family. There are 6 HCV genotypes and more than 50 subtypes. These genotypes differ by as much as 30 to 50 percent in their nucleotide sequences. The virus also has a high propensity to mutate. The lack of a vigorous T-lymphocyte response appears to promote a high rate of chronic infection.

The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. Genotype 1 accounts for 70 to 75 percent of all HCV infections in the United States and is associated with a poorer response to treatment.

HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. During acute infection, the level of viral genomes/mL of plasma or serum has been reported to range from 105 to 107. Chronic HCV RNA levels are quite variable from person to person and generally range from 50,000 to 5 million. However, within the same individual, RNA levels are relatively stable.  

Epidemiology

According to the National Health and Nutrition Examination Survey (NHANES) of 1988 - 1994, 3.9 million Americans were infected with hepatitis C, and of this group, 2.7 million are estimated to have chronic infection. However, NHANES is a population-based household survey that largely excludes groups with a substantially increased prevalence of infection, such as persons who are incarcerated, homeless, or institutionalized due to mental illness.

Although difficult to assess accurately, the incidence of HCV infection declined sharply in the late 1980s. Transmission from blood products was virtually eliminated by the introduction of a more sensitive test for anti-HCV antibodies in mid-1992. Currently, approximately 35,000 acute HCV infections are estimated to occur each year. Because of the high rate of persistent infection, a fourfold increase in the number of persons with chronic HCV infection is projected to occur from 1990 to 2015. The prevalence of HCV is presently believed to be at least 1.8 percent, making HCV the most common blood-borne infection in the United States. Persons aged 40 to 59 years have the highest prevalence of HCV infection, and in this age group, the prevalence is highest in African-Americans (6.1 percent).

HCV transmission occurs primarily through exposure to infected blood. This exposure exists in the context of injection drug use (IDU), blood transfusion, solid organ transplantation from infected donors, unsafe medical practices, occupational exposure to infected blood, birth to an infected mother, multiple heterosexual partners, and high-risk sexual practices. High HCV seroprevalence rates (from 15 to 50 percent) have been observed in specific subpopulations, such as the homeless, incarcerated persons, and hemophiliacs, with the highest rates (70 percent to more than 90 percent) reported in IDUs.

Acute Infection

After initial exposure, HCV RNA can be detected in blood in 1 to 3 weeks and is present at the onset of symptoms. Antibodies to HCV are detected by enzyme immunoassay (EIA) in only 50 to 70 percent of patients at the onset of symptoms, increasing to approximately 90 percent of these patients after 3 months. Within an average of 2 to 8 weeks, liver cell injury is manifested by elevation of serum alanine aminotransferase (ALT). Acute infection can be severe but is rarely fulminant. Symptoms are uncommon but can include malaise, weakness, anorexia, and jaundice. Symptoms usually subside after several weeks as ALT levels decline.

Chronic Infection

Chronic HCV infection is diagnosed by the detection of HCV RNA at least intermittently in the blood by either qualitative or quantitative tests for a period of at least 6 months. In general, prospective studies have shown that the majority of HCV-infected persons develop chronic infection. Factors associated with spontaneous clearance of HCV infection appear to include younger age, female gender, and certain major histocompatability complex genes. African-American men appear to be least likely to spontaneously clear the virus.

The most important sequelae of chronic HCV infection are progressive liver fibrosis leading to cirrhosis, end stage liver disease (ESLD), and HCC. Estimates of the proportion of chronically infected persons who develop cirrhosis 20 years after initial infection have been substantially higher from retrospective studies (17 to 55 percent) than from prospective studies (7 -16 percent). The actual risk of progressive disease at 20 years is now considered to be closer to the estimates from prospective studies. There is little evidence that the risk of progression of liver disease is affected significantly by virologic factors, including viral load, viral genotype, and quasispecies diversity. However, many host factors are observed to increase this risk, including older age at time of infection; male gender; and an immunosuppressed state, such as HIV infection. Hepatitis B appears to increase the risk of progressive liver disease.

Alcohol use plays an important role in increasing the risk of progressive liver disease, with strong evidence for the detrimental effects of 60 g/day in men (equivalent to six beers, four glasses of wine, or three mixed drinks) and 40 g/day in women, but there is suggestive evidence that lower amounts can also increase the risk of liver damage associated with HCV. Other factors, including iron overload, nonalcoholic fatty liver disease, schistosomal coinfection, potentially hepatotoxic medications, and environmental contaminants, may also have important effects.

In the United States, deaths associated with chronic HCV are currently more likely to be due to ESLD than to HCC. Data from death certificates in 1999 found that approximately 4,000 deaths were attributed to HCV infection, but this is likely to be an underestimate. The only treatment option for persons who have developed ESLD (decompensated cirrhosis) is transplantation.

Currently, HCV is the primary reason for liver transplantation in the United States. Little is known about the clinical course and risks of HCV-related complications in persons who have been infected longer than two decades. HCV accounts for an estimated one-third of HCC cases in the United States. HCC rarely occurs in the absence of cirrhosis or advanced fibrosis. The incidence of HCV-related HCC is continuing to rise in United States and worldwide, in part because of the increasing numbers of persons who have been chronically infected for decades, the presence of comorbid factors, and the longer survival of persons with advanced liver disease due to improved management of complications. Risk factors for HCC in persons with chronic HCV infection are largely the same as those for the development of ESLD.

Extrahepatic Manifestations of HCV

Patients with chronic HCV can present with extrahepatic manifestations or syndromes considered to be of immunologic origin, such as rheumatoid symptoms, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, and essential mixed cryoglobulinemia. Cryoglobulins have been detected in the serum of up to one-half of patients with chronic HCV, but the clinical features of essential mixed cryoglobulinemia are less frequent. Chronic hepatitis C is also related to porphyria cutanea tarda.

06/17/02

Introduction:
There are many uncertain issues regarding hepatitis C virus (HCV) infection, chief among which is the question of its natural history. Outcome data are needed for two obvious reasons:(1) the need to inform hepatitis C virus (HCV) carriers of what to anticipate in their future and, if possible, to reassure them about potential sequelae, and (2) the need to make rational decisions regarding treatment with drugs that currently are of only limited therapeutic value. The problem is compounded by the conflicting views held with respect to the natural history, some regarding chronic HCV infection as a universally progressive disease that will inevitably be responsible for serious chronic liver disease or liver disease-related demise provided other disease entities do not intervene first, while others regard it as a progressive disease limited to a minority of infected individuals, its course dictated by as yet not fully defined factors that might promote liver disease progression.

What is recognized is that persons who develop acute HCV infection rarely recover completely, more than 80% of them remaining HCV-infected. The result is progression to chronic hepatitis, generally defined by persistence of serum enzyme abnormalities for at least six months, advancement in a proportion of instances to cirrhosis, and culmination among a few in the development of hepatocellular carcinoma (HCC). What is not well established is the frequency of these changes, the tempo of advancement, and whether or not there are existing factors that curb or promote disease progression.

Basis for Uncertainty Regarding Natural History: The difficulties inherent in attempting to define the natural history of HCV infection are numerous. First, a natural history study requires knowledge of onset of acute disease in order to establish frequency and rate of progression. Unfortunately, onset of acute HCV infection is rarely recognized; in 80% or more of instances, persons with chronic HCV infection do not recall ever having had an illness resembling acute hepatitis. Second, full knowledge of natural history must include long-term evaluation of the entire spectrum of the acute disease, ranging from the mildest to the most severe forms. Because of the paucity of symptoms in most persons infected with HCV, those with the milder disease are generally overlooked, thus biasing outcome data in the favor of those with the more severe illness. Third, a valid study requires equally intense evaluation of a non-infected control group. Again, the lack of symptoms inhibits selection of such a group thus foiling conduct of a case-control study. Fourth, the extraordinarily indolent nature of the disease process in chronic hepatitis C coupled with its highly extended course before sequelae are recognized makes study of the natural history a daunting task, difficult to accomplish. Indeed, the natural history of the disease is generally more extended than the natural history of the clinical investigator. Finally, the disease course is obviously altered if treatment is instituted. Currently, it is almost routine to attempt treatment of most persons with compensated chronic HCV infection. It is these items that have made study of the natural history of hepatitis C so difficult.

Available data therefore have derived either from relatively short term prospective studies beginning from onset of acute disease, mostly transfusion-related, or from study of persons with already established chronic liver disease.

Follow-Up Studies Beginning with Acute Hepatitis: Most such studies have not exceeded 10 to 15 years in duration (with the exception of one which is a 17-year follow-up of an outbreak of HCV infection induced by contaminated immunoglobulin). This time period is obviously insufficient since in two retrospective/prospective studies, one from Japan and one from the U.S.A., progression from apparent acute to chronic hepatitis was estimated to average 10 years, to cirrhosis, 20 years, and to HCC, 30 years, some developing HCC 40 to 50 years after the presumed acute infection. Nevertheless, these studies have yielded useful and important information. In five prospective studies, clinical symptoms have been noted in about 10% of cases, histologic cirrhosis in 15% to 20%, and HCC identified in 0.7% to 1.3%. Mortality ranged from 1.6% to 6.0%. In the 17-year follow-up study of imunoglobulin recipients, outcome was reported to be benign in the majority of instances; 60% did have moderate enzyme abnormalities, but only 1.8% had histologic evidence of severe fibrosis (cirrhosis). These prospective studies thus revealed that during the first two decades following acute infection, liver-related morbidity and death is modest in frequency.

Follow-Up Studies Beginning with Already Established Chronic Liver Disease:
Not surprisingly, in four such studies, two from Japan , one from the U.S., and one from Australia, far more serious sequelae were noted. In the two studies from Japan, cirrhosis developed in 30% and 42% respectively, and HCC in 15% and 19%. In the U.S. study, similar devastating outcomes were identified. Thus, in studies beginning with already identifiable chronic liver disease, serious sequelae are common. The problem with such studies is that they are "biased" in the direction of severe forms of the disease; persons infected with HCV who have no symptoms - perhaps the bulk of cases - do not come to the attention of investigators in tertiary care or liver transplantation centers.

More complete information on natural history, therefore, requires a long-term, prospective study that starts at the time of acute infection. Such a study has been progress in the U.S. for the past 8 years, sponsored by the National Institutes of Health (National Heart, Lung and Blood Institute [NHLBI]).

NHLBI Long-Term Follow-Up Study of Transfusion-Associated Non-A, Non-B (NANB) Hepatitis:
This study aims to determine both mortality and morbidity among infected transfusion recipients. The study has incorporated all persons who developed hepatitis, identified by serial serum enzyme monitoring, in five transfusion studies that had been performed between 1968 and 1980, as well as a matched control group consisting of approximately twice the number of subjects who were transfused but did not develop hepatitis. The two groups consisted of 568 cases and 984 controls. Among the cases with an original diagnosis of NANB hepatitis, 71% were later identified to be anti-HCV reactive by the 2nd generation ELISA.

Mortality was examined after an average of 18 to 20 elapsed years since transfusion. All-cause mortality was found to be almost identical between the cases and controls (both+50%) regardless of whether the cohorts consisted of the entire group of NANB hepatitis cases or of the hepatitis C cases. Liver-related mortality, derived from examination of death certificates, was significantly higher among the cases than the controls (3.2% vs 1.5%).

Morbidity has been determined by recalling all living subjects (cases and controls) for historical interview, physical examination, and phlebotomy for biochemical, serologic and molecular biologic evaluation. Liver biopsy was performed, whenever possible, among those with biochemically-defined chronic hepatitis. 205 cases and 335 controls were available for analysis, a subgroup of 146 cases having all original (repository) and follow-up sera available, permitting paired analysis of the HCV data. Among the main group, 31% of the cases and 4% of the controls in followup had biochemical evidence of chronic hepatitis while anti-HCV and HCV RNA was found in 53% of the cases and 6% of the controls. Evaluation of the 146 cases with original and follow-up sera revealed that 104 (71%) were originally anti-HCV positive and 42, anti-HCV-negative. Followup of the anti-HCV positive cases showed that one-half remained viremic and had chronic hepatitis, one-fifth remained viremic without biochemical evidence of chronic hepatitis, 15% continued to be anti-HCV positive but negative for HCV RNA and without evidence of chronic hepatitis, and 10% appeared to have recovered completely showing no evidence of chronic hepatitis nor of any serologic marker of the original HCV infection. Among the 42 cases that were originally anti-HCV negative (as well as negative for all other viral hepatitis markers), almost all remained HCV-negative in followup, although 19% had chronic hepatitis as defined by persisting ALT abnormalities.

Liver biopsies among those with chronic hepatitis revealed the presence of chronic hepatitis without cirrhosis in 58% of them, and the presence of cirrhosis in 28%. Correlating the histologic findings with overt clinical evidence of chronic liver disease (splenomegaly, thrombocytopenia, prolonged prothrombin time, ascites, varices), only 5% of those with histologically defined chronic hepatitis alone had observable clinical findings of chronic liver disease, none manifesting advanced chronic liver disease, whereas among those with histologically-established cirrhosis, 70% had clinical findings, 40% of this group having features of advanced chronic liver disease. Thus, advanced liver disease could be found in about 5% of the entire 205 cases in followup, or in 13% of those with biochemical dysfunction of chronic hepatitis.

These data suggest that during the first two decades after initial HCV infection, an indolent disease ensues that is associated with relatively low mortality and relatively low overt clinical morbidity. However, since those with histologic cirrhosis - representing nearly a third of those biopsied or about 10% of the entire case cohort in followup - show features of overt chronic liver disease of mild to moderate severity, this group seems poised for progressive worsening as followup extends into the third and fourth decades after initial infection. Whether those with histologically-defined chronic hepatitis alone will progress to cirrhosis with the passage of time remains to be seen.

Further long-term followup of the above groups is required and, indeed, is in process. In this regard, another study is being conducted to determine mortality and morbidity among young persons who were phlebotomized almost 50 years ago and whose resultant blood samples had been stored in deep freeze over this period of time. Serologic screening of almost 10,000 stored blood samples has revealed the presence of HCV seropositivity in some, and they and a large matched control group are presently being scrutinized for sequelae.

Predictive Factors for Outcome of Chronic HCV Infection:
Since it seems likely that only a limited proportion of HCV-infected individuals manifest progressive disease, there is speculation that there may be definable factors that might be predictive of progressive disease. Viral-related factors that have been examined include viral dose, viral genotype, and the presence of quasispecies. Host factors scrutinized have included the age at the time of infection, race, gender, and geographic location. Extraneous influences sought have included co-infection with other viruses, exposure to viral contaminants, smoking, and concomitant chronic alcoholism. Of these, the latter has proven to play the most obviously important role, but further studies are warranted.

References:
1. Alter MJ. Epidemiology of hepatitis C in the West. Sem Liver Dis 1995;15:5-14.

2. Mansell CJ, Locarnini SA. Epidemiology of hepatitis C in the East. Sem Liver Dis 1995;15:3:15-32.

3. Seeff LB; Natural history of viral hepatitis, type C. Sem Gastrointestinal Dis 1995;6:20-7.

4. Crowe J, Doyle C, Fielding JF, et al: Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation (abstr). Gastroenterology 1995;108:A1054.

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Introduction

Of the many perplexing issues regarding viral hepatitis, type C, none is more uncertain and, indeed, more controversial than the matter of its natural history. Knowledge of outcome of the disease is critical in order to provide meaningful information to persons who are chronically infected and in order to make judicious and prudent decisions regarding treatment.

In the course of the last decade of study of what was initially referred to as non-A, non-B (NANB) hepatitis, and then more recently, hepatitis C, it had become clear that the vast majority of persons who develop acute hepatitis C-perhaps over 80 percent-remain infected. The consequence of this is progression in many such individuals from acute to chronic hepatitis, advancement in a proportion of instances to cirrhosis, ending in the development by some of hepatocellular carcinoma (HCC). This sequence has been particularly well-recognized among infected persons in Japan,(1,2) Italy,(3) and Spain. (4) While similar outcomes have been observed among persons infected in the United States, the frequency of termination in end-stage liver disease and particularly HCC has seemed to be less frequent. This has led to two contradictory viewpoints, the first being that all or most chronically infected persons will advance to serious or terminal liver disease if they do not succumb first to another lethal illness, the second holding the position that only a limited proportion of infected persons develop progressive disease, the challenge being to determine which persons will follow this path and the reason or reasons why. Only by conducting appropriate long-term natural history studies is it possible to resolve the conflict.

Such studies have been difficult to perform for the following reasons: (l) most persons who develop acute hepatitis C do so in the complete absence of symptoms, thus frustrating the ability to accurately determine onset and hence duration of disease; (2) the total lack or paucity of symptoms at onset of the illness hinders the ability to recognize the full disease spectrum, the focus then being on those with the more severe forms of the illness; (3) the lack of symptoms associated with the acute illness precludes the opportunity to select a noninfected control group to perform appropriate casecontrol followup studies; (4) treatment is now commonplace which has the clear potential of altering the natural history of the disease; and (5) the extremely slow rate of progression of the disease, ranging from 2 to 4 decades, makes it a daunting task for any investigator to embark on the necessary long-term studies. Consequently, most data on natural history have come from relatively short-term followup studies starting with disease onset, from studies that begin with already established chronic liver disease, or from retrospective studies. These approaches tend to focus attention on the more severe form of the dlsease while neglecting the milder cases that may not come to attention, thus creating potential outcome bias.

Prospective Studies Beginning from Disease Onset

Five prospective studies have been reported from the United States and Europe involving persons with transfusion-associated NANB hepatitis, predominantly but not exclusively due to hepatitis C virus (HCV) infection. (5-9) The mean duration of followup was 8-15 years. About 10 percent of study subjects were reported in followup to have clinical symptoms, histologic cirrhosis was noted in 15-20 percent, and HCC was identified in two of the studies (0.7 percent and 1.3 percent, respectively). Mortality ranged from 1.6-6.0 percent. These studies, with somewhat small numbers and relatively short durations of followup, demonstrated an unequivocal but modest frequency of mortality and morbidity over their limited time courses.

More benign data come from a study reported from Ireland of HCV-infection following receipt of HCV-contaminated immunoglobulin products. (10,11) A followup of 232 infected persons over a 1 7-year period showed that about one-quarter had mild fatigue, none were jaundiced or had hepatosplenomegaly, and about 60 percent had modest enzyme abnormalities. Liver biopsies revealed the presence of chronic hepatitis, mostly mild, in the majority of instances, only 2.4 percent of them showing early cirrhosis and 1.8 percent showing severe fibrosis. The authors concluded from these data that there was minimal evidence of progressive disease.

Followup Studies Beginning with Already Established Chronic Liver Disease

Among three such studies with mean followup periods of 9-15 years, cirrhosis was reported to develop in 8 percent, 30 percent, and 42 percent, and HCC in 15 percent and 19 percent. (12-14) The high frequency of cirrhosis and HCC was noted in the two studies from Japan. (12,13) It is of more than passing interest that this strikingly high frequency of HCC among persons infected in Japan may not be replicated once they move to other countries. In a recent examination of records in Hawaii over a 25-year period seeking information on HCC among descendants of Japanese immigrants, 28 HCC cases were identified, 24 of which had sera available for serologic evaluation. (15) Fifteen of the 24 had hepatitis B virus markers, while none had HCV markers. This implies that there is either an extremely low prevalence of HCV in Hawaii, or that another factor-cultural, nutritional, environmental-exists in Japan that helps promote carcinogenesis among HCV carriers residing in that country.

Two other important studies must be considered in the context of evaluating the natural history of those with already existing chronic hepatitis C. In one from Japan, involving a followup of transfusionassociated chronic NANB/C hepatitis cases, HCC development was found to be common. (16) Attempting to establish the rate of progression by extending information back to the time of initial infection based on transfusion histories, the investigators estimated that chronic hepatitis emerges after 10 years, cirrhosis after 21.2 years, and HCC after 29 years. In three cases, the interval even exceeded 50 years. In a similar study from the United States, involving an initial and followup evaluation of 131 transfusionassociated cases of chronic hepatitis C, initial evaluation revealed fatigue among 67.2 percent, hepatomegaly among 67.9 percent, histologically-defined "chronic active hepatitis" in 22.9 percent, and HCC in 5.3 percent. (17) During the followup period of 3.9 years, an additional 5.3 percent developed HCC, and 15.3 percent died. Emulating the Japanese study, the investigators estimated that, following acute infection, chronic hepatitis could be identified 13.7+10.9 years later, chronic active hepatitis 18.4+11.2 years later, cirrhosis 20.6+10.1 years later, and HCC, 28.3+11.5 years later. These studies demonstrated two important points: (l) serious outcomes are common in studies that begin with already established endstage or near-endstage chronic liver disease; and (2) the rate of progression is exceptionally slow, serious sequelae generally beginning to emerge only in the third or later decades after initial infection. Therefore, satisfactory information regarding the natural history of chronic hepatitis C can come only from longer-term prospective studies.

The National Heart, Lung, and Blood Institute (NHLBI) Long-Term Followup Study of Transfusion-Associated NANB Hepatitis

A long-term followup study has been in progress during the past 8 years directed at evaluating the sequelae of acute NANB hepatitis that had developed among persons participating in five separate transfusion studies conducted in the United States between 1968 and 1980. (18) In all five studies, hepatitis had been sought by prospective, repetitive serum enzyme monitoring of blood recipients, thus identifying even the entirely subclinical cases. Over 90 percent of these cases were defined as NANB hepatitis, 71 percent of whom were established to be HCV in origin. A total of 568 hepatitis cases were identified and matched with a transfused, non-hepatitis control group (984 subjects) from the same studies, both cohorts then being subjected to long-term followup evaluation.

All-cause mortality after an average of 18 years of followup was approximately 50 percent in both the cases and the controls, indicating no difference between cases and controls. Liver-related mortality, based on death certificate analysis, was 3.2 percent for the cases and 1.5 percent for the controls, a difference that was significant even though the frequency was quite low. Of note is that 71 percent of the study subjects who had died as a consequence of liver disease were found after enrollment to be heavy drinkers, some with hospitalizations for this problem. Evaluation of mortality by life-table analysis at the end of 20 years continued to demonstrate no difference on mortality between cases and controls. Furthermore, no difference in mortality could be found when the analysis was restricted to the HCVpositive cases and their controls.

Morbidity is also being assessed by recalling all living patients to determine their current status clinically, biochemically, serologically, and histologically. Two hundred and five cases and 335 controls were available for analysis, with a subgroup of 146 cases among whom all original (repository) and followup sera were available, permitting paired comparisons. Among the main group, certain marked differences were found between cases and controls. This included the frequency of fatigue and hepatomegaly, both found to be present slightly more commonly among cases than controls, the presence of raised serum enzymes (noted in one-third of cases and 4 percent of controls), and the presence of HCV-related hepatitis serology (anti-HCV and HCV RNA in 53 percent of cases and 6 percent of controls). Focusing on the 146 with available original and followup sera, 104 (71 percent) of them could be shown to have originally developed acute HCV-related transfusion-associated hepatitis. In followup of these individuals, one-half remained HCV RNA-positive in association with biochemical evidence of chronic hepatitis; one-fifth remained HCV RNA-positive but without biochemically defined chronic hepatitis; 15 percent showed anti-HCV alone, and 10 percent appeared to have recovered completely, both biochemically and seologically. Followup of the originally HCV-negative cases revealed that 93 percent remained negative, but 19 percent showed chronic hepatitis of undefined etiology.

Liver biopsies revealed the histology of chronic hepatitis alone in 58 percent and of cirrhosis in 28 percent. Correlating the histologic findings with overt clinical evidence of chronic hepatitis, clinical disease could be identified in 5 percent of those with chronic hepatitis alone, but in 70 percent of those with cirrhosis. However, among the latter, only about one-third of those with evident chronic liver disease had clearly advanced or moderately advanced chronic liver disease. Thus, 15-18 years after the initial infection, advanced liver disease could be demonstrated in 5-8 percent of the entire living cohort of NANB hepatitis cases among whom followup could be accomplished, or in 13 percent of those who had been defined biochemically to have chronic hepatitis. These data suggest that, at this juncture in the followup of the transfusion-associated NANB/C hepatitis cases, both mortality and severe morbidity are present, but in relatively low frequency. Moreover, overt morbidity appears confined largely to those with histologically identified cirrhosis. Whether persons with histologically detected chronic hepatitis alone will ultimately advance to cirrhosis and then assume the risks of the cirrhotic group remains to be determined through continued followup.

Another long-term followup study is also in progress that involves approximately 10,000 young Air Force recruits who were phlebotomized between 1948 and 1954 in the course of the evaluation, at that time, of an outbreak of streptococcal infection. The samples had been stored in deep freeze for the past 40-45 years. With their rediscovery, the entire group was tested for the presence of HCV markers. A number of positive samples having been identified, a mortality and morbidity study is now in progress, comparing outcome among those who are positive with those selected as negative controls. This represents a unique opportunity to determine outcome among young persons found to be HCV-positive almost 50 years ago. Data will be presented.

Predictive Factors for Outcome of Chronic HCV Infection

If progression of chronic HCV infection is not inevitable, is it possible to identify factors that might help in predicting outcome? Viral factors that have been examined include viral dose, genotype, and the presence of quasispecies, each of which have been identified as having predictive value, although available data are conflicting. (19-24) Host-related factors include age, race, gender, and geographic location. Age may play an important role, the rate of progression appearing to be more rapid as the age at the time of infection rises. Geographic location also may be of importance, perhaps related to cultural or environmental differences. Extraneous influences may consist of co-infection with other viruses, exposure to environmental contaminants, smoking, or concomitant chronic alcoholism. Co-infection with hepatitis B has been reported to increase the severity of chronic hepatitis C and the likelihood of development of HCC. (25) Co-infection with HIV has been shown in hemophiliacs to increase HCV RNA levels(26) and to worsen the course of the disease. (27) Co-infection with hepatitis G was earlier considered likely to play a promoting role in disease progression, but careful studies have recently disproved these views. (28,29) Chronic alcoholism quite clearly enhances disease progression, either because it promotes increased viral replication or because it is an additive liver-damaging factor. (30,31) The use of alcohol should be strongly condemned in persons who have chronic HCV infection.

Summary

It is quite clear that a proportion of persons with chronic HCV infection will advance in time to cirrhosis and progress eventually to terminal chronic liver disease, in some instances after developing HCC. These are the seriously ill patients seen in tertiary care and liver transplant centers. The perception of the frequency of these adverse events depends, in part, on the stage of the disease at the time that follow-up studies are initiated. If they begin when chronic liver disease has already evolved, the frequency and tempo of progression is found to be high, particularly in some geographic areas such as Japan and Italy. If, however, studies begin with disease onset, serious sequelae seem to be defined less frequently. Current data suggest that during the first two decades after infection, with occasional exceptions, the disease runs an indolent course with relatively low frequencies of mortality and overt morbidity. If cirrhosis has developed during this period, symptomatic disease is more common than is noted when the histology demonstrates chronic hepatitis without cirrhosis. It can be anticipated that future morbidity and liver-related mortality is likely to emerge predominantly from the group that has developed cirrhosis, and this will become apparent as the disease process moves into its third or later decades. Whether progression is enhanced by definable factors is not yet fully established, but it does appear that late age of infection, genotype characteristics, and concomitant alcoholism may play promoting roles. Other promoting factors must continue to be sought. Whether persons with histologic evidence of chronic hepatitis alone at the end of the second decade will ultimately advance to cirrhosis and then assume the increased risks that accompany that lesion needs further evaluation through additional long-term studies. The proportion of cases whose disease remains completely stable is not yet known but might well represent the bulk of cases. The problem at present is that while helpful aggregate data are beginning to emerge, prediction of outcome for the individual case remains difficult to define. Indeed, the need for this information would be reduced if available treatment were more effective, less uncomfortable, and less costly. Continued long-ter n studies both of natural history and treatment strategies are, therefore, sorely needed. Finally, there is critical need for natural history and treatrnent studies involving children and adolescents with chronic HCV infection because of the extended life that awaits them.

References

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2. Tanaka K, Hirohata T, Koga S, et al. Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 1991;51:2842-7.
3. Colombo M, Choo QL, Del Ninno E, et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989;2:100~8.
4. Bruix J, Calvet X, Costa J, et al. Prevalence of antibody to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004-6.
5. Hopf U, Moller B, Kuther D, et al. Long-term followup of posttransfusion and sporadic chronic hepatitis nonA, non-B and frequency of circulating antibodies to hepatitis C virus. J Hepatol 1990;10:69-76.
6. Di Bisceglie AM, Goodman ZD, Ishak, KG, et al. Long-term clinical and histopathological followup of chronic post-transfusion hepatitis. Hepatology 1991;14:969-74.
7. Tremolada F, Casarin C, Alberti A, et al. Long-term followup of non-A, non-B (type C) post-transfusion hepatitis. J Hepatol 1992; 16:273-81.
8. Koretz RL, Abbey H, Coleman E, Gitnick G. Non-A, non-B post-transfusion hepatitis: looking back in the second decade. Ann Intern Med 1993; 119:110-15 .
9. Mattson L, Sonnerborg A, Weiland 0. Outcome of acute symptomatiG non-A, non-B hepatitis: a 13-year followup study of hepatitis C virus markers. Liver 1993; 13 :274-8.
10. Crowe J, Doyle C, Fielding JF, et al. Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation (Abstract). Gastroenterology 1995;108:AI 054.
11. Power JP, Lawlor E, Davidson F, et al. Hepatitis C viremia in recipients of Irish intravenous anti-D immunoglobulin. Lancet 1994;344:1166-7.
12. Takahashi M, Yamada G, Miyamoto R, et al. Natural course of chronic hepatitis C. Am J Gastroenterol 1993;88:240-3.
13. Yano M, Yatsuhasi H, Inoue 0, et al. Epidemiology and long-term prognosis of hepatitis C virus infection in Japan. Gut 1993;34(Suppl):S13-S16.
14. Roberts JM, Searle JW, Cooksley WGE: Histological patterns of prolonged hepatitis C virus infection. Gastroenterol Jpn 1993;28:901-5.
15. Nomura A, Stemmermann GN, Chyou P-H, Tabor E: Hepatitis B and C serologies among Japanese Americans with hepatocellular carcinoma. J Infect Dis 1996;173:1474 6.
16. Kiyosawa K, Sodeyama T, Tanaka E, et al. Interrelationship of blood transfusion non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibidy to hepatitis C virus. Hepatology 1990;12:671-5.
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