Introduction

The rationale for establishing the natural history of any disease is to inform both the patient and physician of future expectations and to assess the need for treatment. Unfortunately, the characteristics of hepatitis C—its silent onset, evolution to a generally asymptomatic and greatly prolonged chronic phase, its co-mingling with other morbid conditions, and the fact that treatment that alters the course is now almost routine—have limited the ability to accurately define its natural history. Several strategies have been used for this purpose, all of which have their drawbacks but still have provided useful information. Because of the many inherent difficulties, there is much controversy regarding the natural history of hepatitis C. The outcome of concern is increasing fibrosis progression, culminating in cirrhosis and, occasionally, advancement to hepatocellular carcinoma (HCC). Some believe this sequence to be common; others believe that serious progression is relatively limited. Both of these views may be valid, both identifying a frequency of progression that is modified by differing demographic characteristics of the population studied and by varying intrinsic and extrinsic factors. In essence, the controversy derives from the uncertainty of whether or not fibrosis progression is linear.

Advancement from Acute to Chronic Hepatitis

The natural history is a product of the outcome of the acute infection as well as the outcome of the subsequent chronic hepatitis. A problematic issue is the actual timing of evolution to chronic hepatitis. Traditionally, this has been based on persistence of virus for at least 6 months. However, viremia may persist beyond this time, although it is believed that loss of virus after one year is exceptional. Prospective study has indicated that chronic hepatitis evolves in about 85 percent of acutely infected persons. On the other hand, cross-sectional studies of large, untreated anti-HCV positive cohorts, consisting mainly of young persons, many of them female, have reported absent virus in as many as 45–50 percent of instances, implying a higher rate of spontaneous recovery in some groups. Thus, spontaneous recovery from acute hepatitis C occurs in 15–45 percent of instances.

Progression to Cirrhosis

Once chronic hepatitis has developed, the question then is: What are the long-term sequelae? Numerous efforts have been made to define the frequency and rate of progression to cirrhosis and HCC. Evident in all these studies is that clinically overt liver disease is generally not seen in the first two decades following the acute infection. This does not imply that cirrhosis does not evolve during this period, but the actual timing of its onset cannot be determined without performing serial liver biopsies. Early reports, based largely on retrospective studies, indicated that, at the end of two decades of infection, about 20 percent had developed cirrhosis,  although some of the studies have reported rates of almost 50 percent. The drawbacks of retrospective studies are that evaluation is limited to those who have achieved an end point and that tracing to disease onset is hindered by the paucity of symptoms at onset. Thus, ascertainment bias may exist using this approach. Later prospective studies, mainly of HCV-infected transfusion recipients, reported a lower rate of development of cirrhosis (7–16 percent), but most of these studies were too short in duration to provide an accurate assessment of the ultimate outcome. Even lower rates of cirrhosis have been reported among several groups in whom it was possible to trace back far in the past to the time of onset or near onset. Thus, among children infected through transfusion in the first years of life and traced 20 years later, and among young women infected through receipt of HCV-contaminated Rh immunoglobulin and traced over approximately the same time period, cirrhosis was noted to have occurred in about 2 percent. A similar rate was noted in a 45-year followup of young HCV-positive military recruits who had been bled at the time of serving on a military base, the samples having been retained in a repository. The common theme of this lower rate of cirrhosis is that it was noted among persons infected at a young age.

Taking the numerous variety of studies into account, a group of Australian investigators who reviewed the world’s literature for the rate of cirrhosis development at 20 years concluded that the studies could be divided into 4 broad categories: those performed in liver clinics, the mean cirrhosis rate being 22 percent (95 percent CI, 18–26 percent); post-transfusion hepatitis studies, with a mean of 24 percent (11–37 percent); studies of blood donors, with a mean of 4 percent (1–7 percent); and studies of community-based cohorts, with a mean of 7 percent (4–10 percent). They concluded that selection bias accounted for the two higher rates, and that the community-based cohort studies appeared more representative in estimating disease progression at a population level. These data provide useful figures for the frequency of progression to cirrhosis two decades after acute infection that appears to range between about 2–4 percent to 20–25 percent, depending on several factors, to be described below. However, many of those infected are young and are destined to live for several more decades. Therefore the question that must be posed is: What happens after the first two decades with regard to liver disease progression? Does fibrosis progression continue to increase at a linear rate? Does the rate level off and remain the same throughout life? Does fibrosis progression increase as age advances? Certainly, many chronically infected persons are known to live for a lifetime without succumbing to liver disease, whereas others are known to develop end-stage liver disease 30 to 60 years after acute infection. Thus, these questions can only be answered by conducting markedly extended studies, few of which have been accomplished for obvious reasons. Other approaches have been to model the expected outcome based on preconceived notions, models that may or may not turn out to be valid. Most important, is it possible to predict in the individual HCV-infected person what the outcome is likely to be? The answer is a qualified maybe, taking into account the many factors that might enhance progression.

Factors That May Determine Progression

The differing outcomes suggest that there are variables that may contribute to the rate of liver disease progression. These can be considered as being viral-related, host-related, or a consequence of external factors.

Viral-Related

Factors that might contribute include viral load, viral genotype, and quasispecies diversity. There is little evidence to indicate that viral load plays a role in disease progression; there are suggestions that progression is more likely following infection with genotypes 1a and 1b than genotype 2, although this has been disputed, most studies now reporting that there is no effect of genotype characteristics on disease outcome. While the degree of quasispecies diversity appears to play a role in evolution from acute to chronic hepatitis, there is no evidence that it enhances progression of already established chronic hepatitis.

Host-Related

One of the most important determinants is age at the time of infection, the relationship being an inverse one. What is not yet established is whether the relatively mild disease seen two decades after infection of young people will begin to accelerate with increasing age. This brings into account the fact of duration of infection, since it is rare although not unheard of, to identify  end-stage liver disease in under one-and-a-half to two decades. Perhaps the flourishing of liver disease with time may be a consequence in part of age-related immune depression. Certainly, an immune suppressed state vigorously enhances disease progression as is noted among infected persons with hypogammaglobulinemia and, especially, HIV co-infection. Hepatitis B and schistosomal co-infection also increase disease progression perhaps through induced immune dysfunction as well as through direct cytotoxicity. Genetic background also may be of importance. Genes of the major histocompatability complex appear also to play a role, not so much in fibrogenesis, but in clearance of the virus. HLA class I antigens seem to be associated with viral persistence whereas class II antigens (DRB1 alleles) are identified more frequently in those who clear virus and therefore have milder disease. Inheritance of high TGF-â 1 and angiotensinogen-producing genotypes has been linked to fibrosis progression. Co-morbid conditions such as hemochromatosis and non-alcoholic steatohepatitis are also associated with advancing chronic liver disease. In addition, outcome may be influenced by gender and race.

Females are reported to have a slower rate of progression, a finding that seems to be emerging also among African-Americans. Finally, the expression of the disease plays a role in outcome. HCV-infected persons with raised aminotransferase levels are far more likely to develop progressive liver disease than are those with normal serum enzymes.

External Factors

Clearly, associated chronic alcoholism is a powerful co-factor in liver disease progression. Yet to be determined is what is the least amount of alcohol and the type of drinking pattern that plays a role in advancing chronic hepatitis C. Also of note are the data suggesting that smoking may increase disease progression. Exposure to toxic products, either in the form of administered drugs that may be hepatotoxic or as environmental contaminants, may have important effects. It is noteworthy that death associated with chronic hepatitis C in the United States is more likely to be a result of end-stage liver disease rather than HCC, whereas in Japan, virtually all deaths are attributed to HCC. It has been suggested that the difference is a consequence of a longer duration of HCV infection in Japan than in the United States, a view that may or may not be valid. Another possible explanation is that toxic environmental contaminants may play a contributory role in Japan.

Progression From Cirrhosis to HCC

HCC rarely (if ever) develops in persons with chronic hepatitis C without preceding cirrhosis or significant fibrosis. The strongest evidence for a relationship between HCV infection and HCC comes from Japan, but supporting evidence comes from many other countries including the United States, Italy, Spain, Egypt, France, and elsewhere. Recent evidence indicates that the incidence of HCC increasing in the United States is presumed to be a consequence of the mushrooming of hepatitis C infection in the 1960s and 1970s. The data in the United States indicate that once cirrhosis has developed, HCC evolves at the rate of 1–4 percent per year. The figure in Japan is even higher.

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