Hepatology, April 2000, p. 1014-1018, Vol. 31, No. 4 Hepatology at the Millennium

Natural History of Hepatitis C: Its Impact on Clinical Management

Adrian M. Di Bisceglie From the Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO.

Introduction

The article entitled "Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus" by Kiyosawa et al. appeared in this journal in 1990 and has been the second most highly referenced article in the area of hepatology since 1981, with more than 475 citations. It provided valuable insights into the natural history of hepatitis C virus (HCV) and the pathogenesis of hepatocellular carcinoma (HCC).1

Before the discovery of HCV, studies of post-transfusion "non-A, non-B" hepatitis permitted a keyhole view into the bigger world of chronic hepatitis not caused by any known agent. Comparison between patients with posttransfusion and sporadic non-A, non-B hepatitis showed that they had similar clinical and laboratory features. The main marker to be followed in these cases was serum transaminase. Liver biopsy studies showed that patients with non-A, non-B hepatitis (most of which turned out to be hepatitis C) had varying degrees of liver injury but that features of chronic hepatitis were common. Some patients developed cirrhosis, often within a very short time.2 We now know that HCV is distributed worldwide and accounts for a substantial proportion of chronic liver disease. In the United States, chronic hepatitis C represents a large health care burden because of the associated symptoms, extrahepatic manifestations, and the complications of cirrhosis.

HCC is the most frequent primary malignancy of the liver and a major cause of morbidity and mortality worldwide. It is interesting that the link between HCC and chronic viral hepatitis was made only in the early 1970s.
Texts published prior to this time suggested that HCC was largely caused by exposure to environmental carcinogens, based on its induction by chemicals in rodents. Initially, it was infection with the hepatitis B virus (HBV) that was linked to HCC, and investigators in sub-Saharan Africa and the Far East very clearly demonstrated a causative link between chronic HBV infection and development of HCC. However, in some parts of the world only a small proportion of patients with HCC had serological evidence of HBV infection. Individual case reports first speculated that long-standing chronic non-A, non-B hepatitis could lead to HCC. At about the same time investigators in Japan noted that the annual incidence of HCC appeared to be rising although the number of cases of HBV-related HCC was essentially unchanged.

This was the status quo until the discovery of HCV, reported in 1989, and the development of serological assays to detect antibody to HCV (anti-HCV). Two large studies, one from Italy and another from Spain, noted that the majority of patients with HCC tested positive for anti-HCV.3,4 However, these were cross-sectional surveys done in patients who already had established HCC, indicating an association but not cause and effect. It was against this background that Kiyosawa et al. Showed that a substantial proportion of Japanese patients with HBV-negative HCC tested positive for anti-HCV. Moreover, in many, a prior blood transfusion served to mark the time at which infection likely was acquired. Many of these patients had previously been identified as having chronic non-A, non-B hepatitis and had undergone liver biopsy on multiple occasions before the development of HCC.

The interval between HCV infection and subsequent development of significant liver disease is very long

Kiyosawa et al. found that the mean interval between blood transfusion (presumed source of HCV infection) and diagnosis of HCC was about 29.0 years in the 21 patients, whereas those with cirrhosis but no HCC were on average only 21.2 years and those with chronic hepatitis only 10 years from transfusion. This observation has subsequently been confirmed by several investigators in other countries. It provided one of the first real clues that the path to HCV-related HCC involved a slow, stepwise progression in liver disease. The long interval led several investigators to suggest that HCV infection does not have a significant impact on longevity, particularly for those infected via blood transfusion. Such individuals are often older and may succumb to other illnesses (perhaps those illnesses they received blood transfusions for) before hepatitis C has a chance to produce significant liver disease.

Similar observations have been made in the United States. Tong et al.5 showed that the mean interval after blood transfusion for patients with chronic HCV infection to present with mild chronic hepatitis was 13.7 years, more severe chronic hepatitis 18.4 years, cirrhosis 20.6 years, and HCC 28.3 years. The advent of anti-HCV testing showed that transfusion of blood or blood products accounted for only a relatively small proportion of cases of hepatitis C in the United States and that most cases could be linked to injection drug use. Nonetheless, the study of posttransfusion hepatitis was valuable because it provided a clear-cut time of onset of HCV infection allowing more accurate calculation of timing to various outcomes of hepatitis C, including HCC.

Progression of liver disease due to posttransfusion hepatitis C

Kiyosawa et al. were among the first to provide information related to the late effects of chronic hepatitis C. At that time several studies of the long-term natural history of posttransfusion hepatitis were underway. Because the work, for the most part, had commenced in the mid- or late 1970s, patients had been followed on average for only 10 years after transfusion. Although the development of chronic hepatitis and cirrhosis had been well documented in this interval, end-stage liver disease or HCC would not be anticipated. Furthermore, the study groups were relatively small, and comparison with control subjects was lacking.

Seeff et al. traced 568 patients who developed posttransfusion non-A, non-B hepatitis in the 1970s and found that their overall mortality after an average 18-year follow-up was 51%, not different from that in two matched control groups.6 However, liver-related mortality was greater in the non-A, non-B group although it only accounted for 3.3% of deaths after this long period. Recently, a retrospective prospective survey of women infected with HCV through contaminated lots of anti-D immune globulin usedin Ireland in 1977 and 1978 was completed. Seventeen years later, only 2% of 376 women infected in this way had cirrhosis demonstrable on liver biopsy.7 These data suggest that women who are young and otherwise healthyat the time of infection rarely develop severe liver disease from chronichepatitis C.

In contrast to these two studies showing a relatively benign outcome, Tong et al. studied 131 patients with chronic posttransfusion hepatitis C.5
They found that the majority were symptomatic with fatigue and most had hepatomegaly. Of these subjects, 50% had histological evidence of cirrhosis whereas 5% had developed HCC. Subsequent follow-up of this cohort showed that a significant proportion experienced progressive liver disease and 15% died, most related to their liver disease.

Thus, some authors emphasize the apparently low rate of clinically significant liver disease due to posttransfusion hepatitis C, whereas others focus on the alarming numbers of patients with end-stage disease presenting to liver referral centers. This apparent paradox has been only partly resolved. It is clear that the large majority of patients infected with HCV will have a good outcome. Indeed, approximately 15% seem to clear the virus soon after acute infection. Among those who go on to chronicity, most remain asymptomatic for years, even decades, in the face of persistently elevated serum transaminase levels and evolution to cirrhosis, which occurs in 20%. As many as 30% to 40% of patients with chronic HCV infection appear to have persistently normal serum transaminase levels.8 Although the natural history of this group has not been well studied, it is apparent that most of them do have histological features of chronic hepatitis, albeit much milder than that of patients with raised transaminase levels. Progression of liver disease in this group is also thought to be unusual but may occur slowly.

Many patients with histologically proven cirrhosis are asymptomatic and appear to enjoy long survival. Thus, data from a cohort of European patients with cirrhosis followed for a period of 5 years found that only 7% developed HCC and 18% hepatic decompensation.9 These investigators found that survival could be predicted from serum bilirubin, age, the presence of physical signs of liver disease, and the platelet count. The fact that cirrhosis caused by hepatitis C is now the single largest indication for liver transplantation and the most frequently encountered problem in liver clinics in this country presumably reflects the sheer number of individuals infected with HCV. Data from the N-HANES study show that 1.8% of the population are seropositive for anti-HCV and as many as 2.7 million have evidence of active HCV infection with HCV RNA in serum.8 It has been difficult to predict in advance which patients with HCV infection are likely to go on to progressive liver disease. Factors such as the severity of acute hepatitis and degree of transaminase elevations do not correlate with ultimate disease severity.

More recently, attention has focused on hepatic fibrosis as a reliable marker of disease progression. Sobesky et al.10 have suggested that the rate of progression of fibrosis in patients with chronic hepatitis C is linear and predictable. These investigators speculate that fibrosis would progress from being absent to cirrhosis over a period of as much as 40 years beginning at the age of 30. Factors that have been suggested to accelerate progression include age at infection, male gender, and excessive alcohol consumption; interferon treatment may decrease or even reverse fibrosis progression. Children acquiring HCV infection through blood transfusion appear to develop only mild liver disease compared with adults and appear more likely to clear HCV infection spontaneously over time.11 A possible role for obesity and fatty metamorphosis as a factor accelerating fibrosis has recently been suggested. Yano et al.12 found that the rate of progression to cirrhosis in chronic hepatitis C was accelerated in patients whose initial biopsies showed high grades of necroinflammatory activity and the presence of hepatic fibrosis early on. The presence of excessive iron deposits within the liver or heterogeneity for the C282Y mutation of the HFE gene have also been implicated in accelerating liver damage in hepatitis C.13 Most of these suggestions require further confirmation, but they do contribute to understanding variation in the natural history of hepatitis C.

Relationship between chronic HCV infection and HCC

The Kiyosawa article provided substantial insights into the relationship between chronic hepatitis C and HCC. Among 54 patients with HCC and non-A, non-B hepatitis in their study, 94% were seropositive for anti-HCV, and 21 (39%) gave a history of prior blood transfusion. The study included a comparison group of patients with chronic HBV infection among whom 29 had HCC. Interestingly, 10 of these (35%) had anti-HCV detectable in serum but only a small proportion had a blood transfusion. One of the key insights of these investigators was that HCV-related HCC almost always occurred in the presence of substantial liver disease, most often cirrhosis. It was noted that cirrhosis could be documented in 18 of 21 patients with posttransfusion hepatitis C and HCC. The extent of liver changes in the 3 patients who did not have cirrhosis was not described, but they presumably had fibrosis and significant architectural distortion. This point is very important because of its relevance to mechanisms of hepatocarcinogenesis. There is no conclusive evidence that HCV is directly carcinogenic.14 In contrast to HBV, it is an RNA virus whose genome does not become integrated into that of host liver cells, although it does appear that HCV core protein has some effects on cellular transformation, and transgenic mice expressing HCV core protein develop HCC. Rather, the evidence suggests that the development of HCC is closely tied to cirrhosis. HCC has long been known to be a complication of cirrhosis. Autopsy series show that as many as 10% of patients with cirrhosis have coexisting HCC. In the context of liver transplantation for cirrhosis, unsuspected HCC is present in the explant in up to 10% of cases.15

Cirrhosis is thought to give rise to dysplastic nodules, which appear to be a precursor to HCC. Dysplastic nodules are defined as nodules of hepatocytes that are atypical but not meeting criteria of malignancy.16 The atypia may be mild (low-grade dysplastic nodule) or moderate to severe (high-grade dysplastic nodule), and as the size of the lesion increases, there is a greater likelihood that high-grade or malignant lesions are present. Benign lesions are seldom greater than 2 cm in diameter. Atypia may progress to a form of "carcinoma-in-situ" and ultimately to mature HCC. Dysplastic nodules are often found incidentally by ultrasound or computed tomography examination of the liver. Longitudinal observations have documented that HCC subsequently occurs in 25% of nodules and sometimes in other areas of the liver adjacent to these nodules.17 The clonality of cirrhotic nodules is disputed.18 Using molecular techniques, some but not all investigators have found that dysplastic nodules represent a clonal expansion of transformed hepatocytes.

Regeneration of hepatocytes is probably a key factor in the development of HCC, underlying the formation of cirrhotic or dysplastic nodules. Shibata et al.19 recently described a pattern of irregular regeneration of hepatocytes occurring in patients with hepatitis and found that this correlated with subsequent development of HCC. Interestingly, irregular regeneration could be found in noncirrhotic livers, and when this was severe, HCC occurred even in the absence of cirrhosis. There appears to be synergy between HCV and HBV infection in causing HCC. Subsequent studies have confirmed that a substantial proportion of patients with HCC in some regions have both HBV and HCV infection. Other known factors that appear to speed the progression of hepatitis C to HCC include alcoholism and porphyria cutanea tarda.14

Prevention of disease progression and HCC

One consequence of establishing the link between HCV infection and development of HCC is the possibility of prevention. A safe and effective vaccine has been available for some time against HBV infection. Widespread use of this vaccine among infants has been associated with a significant decrease in the incidence of childhood HBV-related HCC in Taiwan.20 Unfortunately, similar vaccines for hepatitis C are not on the horizon, but public education appears to have substantially reduced the number of new cases of HCV infection occurring in the United States, and this could be expected to result in a decrease in cases of HCV-related HCC several decades from now.

For individuals with established chronic HCV infection and, therefore, at increased risk of HCC, some other intervention is required. The use of alfa interferon has become well established in the treatment of chronic hepatitis C and is now widely used, with the goal of achieving a sustained elimination of HCV RNA from serum. This is associated with improvement in liver injury as assessed by serum transaminase activities and liver histopathology. Long-term benefits of therapy such as a decreased risk of developing cirrhosis, progressive liver disease, or HCC have been more difficult to document. In the last few years, however, mounting evidence suggests that interferon therapy may indeed decrease the risk of HCC in patients with chronic hepatitis C. In one of the largest of these studies, Yoshida et al.21 reported on data from a large surveillance program of patients with chronic hepatitis C. They evaluated 2,890 patients with chronic hepatitis C. Of 2,400 treated with interferon, 89 (3.7%) developed HCC; of 490 untreated patients, 59 (12%) progressed to HCC. Among untreated patients, the annual risk of developing HCC increased with the degree of hepatic fibrosis from 0.5% among patients with absent or mild fibrosis to 7.9% among patients with fibrosis. In multivariate analysis interferon therapy was associated with a significantly reduced risk for HCC compared with untreated controls (adjusted risk ratio 0.516). This effect was most marked among those who experienced a sustained virological or biochemical response and only in those with advanced hepatic fibrosis or cirrhosis. Interestingly, a similar benefit of interferon could not be shown in chronic hepatitis B.22

Intriguing as these findings of a cancer-preventive effect of interferon are, the data require confirmation in a prospective study. Many additional questions remain to be answered. It is still not clear whether this beneficial effect applies only to those who experience sustained virological response or whether relapsers or nonresponders also may benefit, perhaps to a lesser extent. The recent report by Yoshida et al. suggests that patients who are treated but do not have a sustained virological response experience HCC at a rate intermediate between those with a sustained response and those who were untreated.21 Most of the studies to date have examined the effect of interferon at standard doses for 6 to 12 months.23,24 The possible effects of prolonged therapy have not been studied nor has the combination of interferon and ribavirin. A National Institutes of Health-funded study that aims to address this question has been initiated (the HALT-C trial). It is a prospective randomized, controlled trial of long-term therapy in patients with chronic hepatitis C and advanced hepatic fibrosis who have previously not responded to interferon therapy.25

Estimates of the outcome of hepatitis C infection

Based on studies conducted in the last decade since the publication by Kiyosawa et al., it has become possible to formulate an algorithm of the natural history of hepatitis C using data from a combination of prospective studies of posttransfusion and long-term follow-up of patients with established HCV infection (Fig. 1). Over a 20-year period, approximately 6% of patients can be expected to develop hepatic decompensation because of cirrhosis, 4% will develop HCC, and 3% to 4% can be expected to die or require liver transplantation.

To View Graphic:http://hepatitis-central.com/hcv/info/2000/apr/naturalhistory/impact.html

Summary and conclusions

The report by Kiyosawa et al. heralded much of what we have subsequently come to know as the natural history of HCV infection. We now understand that among those patients who develop chronic HCV infection, most can be expected to have chronic hepatitis. Progression of fibrosis appears to be slow but inexorable. In most cases, it will be too slow to have a significant impact on the life expectancy of the patient, but in a proportion of individuals, cirrhosis and its complications may develop relatively rapidly. We are now in a better position to understand the factors associated with this more rapid disease progression and to attempt to intervene, either by removing aggravating factors such as alcohol or by instituting antiviral therapy.

Abbreviations: HCV, hepatitis C virus; HCC, hepatocellular carcinoma; HBV, hepatitis B virus.

References

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25. Bonkovsky H, Di Bisceglie AM, Dienstag J, Everson G, Lindsay K, Gretch D, Hoefs J, et al. A randomized, controlled trial of long-term antiviral therapy in patients with chronic hepatitis C and advanced hepatic fibrosis who have previously not responded to interferon therapy: design of the "hepatitis antiviral long-term treatment to prevent cirrhosis (HALT-C) trial." Gastroenterology 2000 (in press) (abstract).

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