Hepatitis non-A, non-B: C at last

Abstract

s a 1988 editorial in GASTROENTEROLOGY (1) A was going to press, the fact emerged that, finally, the agent of non-A, non-B (NANB) hepatitis had been identified (2.3). What followed was a renaissance of interest in this important disease and a surge of new information about its virology, seroepidemiology, and clinical consequences. The paper by Bradley et al. (4) in this issue represents the first of what we anticipate will be many illuminating papers about hepatitis C to be published in GASTROENTEROLOGY. Between the years 1975, when the first definitive report on NANB hepatitis in transfusion recipients appeared, and 1988, when the discovery of the agent was announced, many important, valid observations about this virus emerged. In the 1970s. the frequency of posttransfusion NANB hepatitis measured in prospective trials ranged from approximately 7% to 12%. Typically, acute disease was mild or even asymptomatic; however, independent of the severity of acute illness, progression to chronic hepatitis occurred in approximately half of all transfusion-related cases. The rate of insidious progression over time was alarming. Among patients with chronic NANB hepatitis followed for up to 10 years-including those with chronic persistent hepatitis on initial liver biopsy and those with asymptomatic, minor elevations of alanine aminotransferase activity-cirrhosis and its complications occurred in 20%. Initial reports suggested that this high rate of progression was confined to patients with NANB hepatitis following percutaneous exposure to blood products or contaminated instruments. Subsequent observations, however, supported a similar rate of progression in sporadic cases. Indirect epidemiologic analyses suggested an asymptomatic NANB hepatitis carrier rate of 1'70-27'0 in the general population of healthy adults, and evidence supporting a link between NANB hepatitis-related cirrhosis and primary hepatocellular carcinoma began to accumulate (5). As appreciation for the clinical impact of NANB hepatitis grew so did the urgency of the search for a specific viral agent and reliable serologic tests. None of the purported serologic tests or putative virus particles described in reports published before 1988 met simple criteria for a specific association with NANB hepatitis. None of these reports could be confirmed, and tests based on these reports consistently did not distinguish under code between pedigreed infectious and pedigreed noninfectious NANB serum samples and other-disease control serum samples (6). What amounted to almost 15 years of false leads in the quest for the agent of NANB hepatitis, however, did yield several valid deductions. Chimpanzees were identified as an animal model for NANB hepatitis, and studies of this model showed that the predominant agent of transfusion-associated NANB hepatitis was chloroform-sensitive and had a virion diameter in the range of 30-60 nm, characteristics of a small lipid-coated virus (7.8). Titration studies of inocula in chimpanzees indicated that high-level viremia was rare in NANB hepatitis, a partial explanation for the difficulties encountered in visualizing virus particles. Also recognized was the fact that donor blood with elevated levels of alanine aminotransferase (ALT) or antibody to hepatitis B core antigen (anti-HBc) was more likely to transmit NANB hepatitis to recipients than blood with normal ALT levels and devoid of anti-HBc. These “surrogate” markers were introduced as donor screening tests in the late 1980s but the impact of these non-virus-specific screening tests was probably overshadowed by the beneficial effect on the blood supply of screening for antibody to human immunodeficiency virus. Such improvements in transfusion medicine in the 198Os, before the discovery of hepatitis C virus (HCV), translated into an appreciable reduction in the frequency of transfusionassociated hepatitis to a level estimated to be approximately 5%. Such was the state of affairs when, in May 1988, the