The history of the “natural history” of hepatitis C(1968–2009)

Acute transfusion-associated hepatitis

The acute hepatitis cases identified in the transfusion studies were mostly unaccompanied by symptoms and were characterized by mild to moderately raised serum enzymes and generally normal serum bilirubin levels. Accordingly, the condition was initially regarded as a relatively inconsequential problem. However, continued serum enzyme monitoring revealed that, in approximately 50% of them, elevated serum enzyme values persisted beyond 6 months, fulfilling the definition of chronic hepatitis (3, 4). Nevertheless, concern remained somewhat muted because early biopsies revealed only mild chronic hepatitis. However, when repeat liver biopsies showed the presence in some instances of increasing necroinflammation, accompanied by advancing fibrosis and even cirrhosis, apprehension about the disease increased. Also of concern at that time were the occasional reports of hepatocellular carcinoma (HCC) identified in persons whose only history was an earlier bout of apparent transfusion-associated NANB hepatitis (14, 15). Thus, even before the recognition of HCV, treatment trials with interferons were initiated (16).

The discovery of HCV and the resultant serological and virological assays yielded additional information that intensified the concerns. While acute hepatitis was believed to advance to chronic hepatitis based on continuing enzyme elevations in about 50% of those with NANB hepatitis, HCV RNA was found to persist beyond 6 months in a far greater proportion, i.e. 75–85% of cases. Furthermore, reports of the detection of HCV in individuals with so-called cryptogenic cirrhosis and with HCC were emerging (17).

Other investigations were simultaneously discovering that NANB/C hepatitis was not confined to the transfusion setting. At first referred to as sporadic or community-acquired hepatitis C (18), the virus was identified under other circumstances of percutaneous exposure, such as among illicit drug users, healthcare workers exposed through a needlestick, recipients of such biologicals as clotting factor concentrates and later Rh immunoglobulin, newborns of infected mothers, and possibly through sexual contact (18–20). Like transfusion-associated hepatitis C, persons infected under these circumstances developed few or no symptoms, and yet many also advanced to chronic hepatitis C, albeit at differing rates (19–22).

Collectively, these data indicated that more information was needed about the long-term sequelae of chronic hepatitis C. But how was this to be accomplished when onset of the acute illness was mostly unrecognized because of the absence or paucity of clinical symptoms; available data indicated that progression from acute to chronic hepatic C occurred unobtrusively, and the rate of evolution was determined to be exceedingly slow, occurring over periods of two to four decades. Moreover, because antiviral therapy was being increasingly utilized, would it be possible to conduct a true ‘natural history’ study?

Items requiring consideration for evaluating the natural history

As knowledge of hepatitis C began to grow, it became clear that in order to better understand the process of evolution of hepatitis C, consideration must be directed at the very least towards the following four questions:

1. What is the rate of spontaneous resolution of acute hepatitis C that brings the disease to an end, thus confining progression only to those in whom the virus persists?

2. Among those who do not spontaneously recover, what outcomes can be anticipated, with what frequency and over what duration of time?

3. What are the variables and risk factors that help predict that progression of chronic hepatitis is likely to occur?

4. What is the pathogenesis of disease persistence and progression?

Frequency of spontaneous virological resolution

Early studies found that spontaneous virological resolution occurred in about 15–25% of persons who developed transfusion-associated acute hepatitis C, and, conversely, that HCV infection persisted in 75–85% of infected persons (23, 24). Similar results were reported in later studies of diverse populations (HCV-infected blood donors, persons with ‘community-acquired’ infection, IV drug abusers and children with leukaemia), spontaneous resolution occurring in 14–29% of these cohorts (25–28). Later, a far higher rate of spontaneous resolution was noted among infected children (21, 29), young women (20, 22) and even some persons with community-acquired hepatitis C (30), the figures ranging between 42 and 45%. These data suggested that young age at the time of infection is an important determinant of the likelihood of spontaneous recovery.

Frequency and rates of serious outcomes

Infected persons whose acute HCV infection does not resolve are at risk for progressive liver disease, characterized by continuing hepatocellular inflammation and an increase in fibrosis from mild to advanced (bridging), followed by cirrhosis, first compensated then decompensated, and, finally, HCC. These developments occur over periods of two to four decades, however, so that investigators have used differing strategies to evaluate the frequency and rate of progression of the chronic liver disease (31) (Fig. 1).

One strategy is to perform a prospective study beginning with persons who develop acute hepatitis C under observation. The advantages of this approach are that disease onset is precisely established (normal baseline serum enzymes and negative HCV RNA at transfusion, followed by appearance of HCV RNA and enzyme increases weeks to months later), and that all persons infected, whether or not they have symptoms, can be identified. This approach also permits recognition of spontaneous resolution. Furthermore, matched uninfected transfusion recipients can be selected as controls for a paired follow-up. The disadvantages are that the onset of acute hepatitis C is usually silent and therefore difficult to identify unless there is a recognized point-source outbreak, and that liver disease progression is exceedingly slow, so that decades of follow-up are required to establish a full outcome; moreover, antiviral treatment is likely to be instituted in the interim that will preclude a true ‘natural’ history study.

Another strategy is a retrospective study of a large cohort of persons with established chronic hepatitis C, tracing them back to their original exposure, presumed to be a first receipt of a transfusion, a needle-stick exposure or the first percutaneous use of illicit drugs. While offering the advantage of shortening the time needed in the study to determine the interval between ‘exposure’ and the current chronic hepatitis status, this approach suffers from the bias of focusing on living persons with HCV-related chronic liver disease without the ability to identify those who had spontaneously recovered, were too mild and asymptomatic to be recognized or conversely had already died from chronic liver disease. Moreover, the precise timing of disease onset cannot be accurately established. Retrospective studies thus tend to emphasize the more serious outcomes while de-emphasizing chronically infected individuals without overt liver disease progression, a so-called ascertainment bias.

The third strategy is the retrospective-prospective (non-concurrent prospective) study. This requires the serendipitous discovery of a distant well-characterized point-source outbreak of hepatitis C where data from all infected persons are recoverable, the ability to recall them to determine their current status and then to follow them prospectively. Provided data on all originally infected persons can be resurrected and the full cohort recalled, this strategy has the advantage of reducing the time needed to determine the outcome.

A review of many, although by no means all, studies that used these differing strategies follows:

Risk factors for disease progression

Factors that could conceivably play a role in progression of chronic hepatitis C include features of the virus, the host or items of environmental or extraneous origin (70–72).

Regarding the virus, attention has been focused on viral concentration and viral genotype, but there is little definitive evidence that these factors affect liver disease progression.

In contrast, there are numerous host factors that appear to influence fibrosis progression that include the demographical features of age, gender and race. As already noted, infection at a young age is associated with a slow rate of progression (21, 29), confirming other published data (73–75). Men with chronic HCV infection are more likely to progress to cirrhosis than are women as is evident from the data of the Irish and German women infected by the contaminated Rh immunoglobulin (20, 22), and as has been demonstrated in other reports (73, 75, 76). Paradoxically, given their high rate of evolution to HCC and their lower rate of response to treatment, African Americans appear to have a slow rate of progression to cirrhosis (77, 78). Genetic polymorphisms have been evaluated for their influence on disease progression, with a focus on major histocompatibilty class I and II alleles (79, 80) as well as on profibrogenic cytokines (81, 82). Metabolic factors with inter-relationships among steatosis (83, 84), diabetes (85, 86) and obesity (87, 88) have all been reported as affecting disease progression. As noted earlier, normal values of alanine aminotransferase and its associated lesser degree of histological inflammation appear to predict a lower level and rate of fibrosis progression (61, 69). Finally, the rate of progression is increased in the face of co-infection with HIV (53–57), hepatitis B (89, 90) and schistosomiasis (91, 92), as well as with the comorbidity of haemochromatosis (93).

Regarding extraneous issues, by far the most significant impact on disease progression is the cofactor of associated alcoholism (94–96), although the exact extent of alcohol intake likely to add to the injury is uncertain (97). Similarly, smoking has been reported to be associated with increased fibrosis progression to both cirrhosis and HCC (98, 99).

Pathogenesis of chronic hepatitis C

An extensive discussion of the mechanisms responsible for recovery from HCV infection is beyond the scope of this article. Control of HCV infection is clearly immunologically mediated as is evident by the appearance of virus-specific T cells with the occurrence of clinically apparent hepatitis C (100). Persistence of HCV infection results when innate responses are blunted, thus diminishing the direct antiviral effects and dampening the priming of adaptive responses (101). T-cell induction of interferon (IFN)-γ clears HCV infection, while a poor response to IFN-γ permits continued viral replication with its effects on cytokine release.

Conclusion

It is evident that hepatitis C is a progressive disease, and that a variable proportion of chronically infected persons will advance to end-stage liver disease, namely hepatocellular failure and/or HCC. Such persons are highly likely to die as a consequence of the liver disease unless they undergo liver transplantation. A presumably larger group of chronically infected individuals, primarily those who do not develop cirrhosis, are likely to die from other non-liver-related illnesses or traumatic events that represent the more common causes of death. Some will even progress through life without ever knowing that they are HCV infected, while others may suffer from varying degrees of fatigue and a decreased quality of life. In order to accurately establish the frequency of these variable outcomes, it would be necessary to mount a life-long study of a large cohort from the time of the initial infection and follow them until their demise, but for this to be a true natural history study, infected persons would have to forego treatment of the infection, clearly not an acceptable option. Moreover, it would be almost impossible to pursue a study of this duration, both for the infected cohort and for the investigator. The natural history has particular relevance for those infected at birth or in early childhood. Even though evolution to cirrhosis in the first two to three decades after infection among these individuals is relatively infrequent, it is unclear whether disease progression will begin to increase as this population ages. There is increasing evidence that disease progression does not follow a linear path and that it is likely to increase as the infected person ages (73, 105). Suffice it to say, because of the advent of effective treatment, the era of natural history studies of chronic hepatitis C has passed, except perhaps under rare circumstances. As treatment improves, the illness will come to be viewed as an infectious disease requiring treatment for all, with less concern about the long-term sequelae.