Since the development of the sensitive serological tests for the diagnosis of hepatitis C infection, many reports have been published about the prevalence, epidemiology and clinical characteristics of acute and chronic hepatitis C^1–3). Before the development of this sensitive method detecting hepatitis C viral infection, non-A, non-B hepatitis could be diagnosed by careful history and checking the surrogate hepatitis viral markers⁴⁾. Although it has been suggested that the most consistent histological features of non-A, non-B hepatitis are the formation of lymphoid follicles with germinal centers in the portal tracts and steatosis in the liver parenchyma, until now only a few reports on the histologic findings of chronic hepatitis C were published and characteristic histologic findings of chronic hepatitis C have been not yet determined^5–6).

The aims of this study are to analyze retrospectively the histologic findings of the chronic active hepatitis C diagnosed serologically and to determine the presence of the characteristic differential points between chronic active hepatitis C and chronic active hepatitis B.

The subject population consisted of nineteen patients with chronic active hepatitis C (CAH-C) and nineteen patients with chronic active hepatitis B (CAH-B). The clinical characteristics of the subjects were summarized in Table 1. Diagnosis of chronic active hepatitis was made by peritoneoscopic liver biopsy with the compatible clinical and laboratory findings. Of those patients who had a peritoneoscopic liver biopsy between January 1989 and August 1990 in the Yonsei University College of Medicine, we selected the patients whose blood samplings were cryo-preserved and feasible for hepatitis viral markers study. The subjects were divided into two groups according to the results of the hepatitis viral markers. One group (CAH-C) was the 19 patients who had positive tests for Anti-HCV (EIA, Chiron Co., USA) and negative tests for HBsAg (RIA, Abbott Co., USA). The other group (CAH-B) was the 19 patients who had negative tests for Anti-HCV and positive tests for HBsAg. There were no differences in age, sex, and liver function tests between these two groups, but past medical history such as transfusion and acupuncture was found more frequently in CAH-C group (13 of 19 cases) than in CAH-B group (2 of 19 cases).

Three pathologists and two physicians reviewed the pathologic slides individually, without previous informations on the patients, and made scores according to the histologic activity index (HAI), modified from Knodell’s proposal⁷⁾. Histological features were analyzed between the CAH-C and CAH-B groups in terms of portal inflammation (1. scattered, 2. diffuse, 3. follicular), periportal necroinflammation (1. expansile, 2. stellate, 3. bridging, 4. precirrhotic), focal necrosis or acidophilic body (1. 1/100×, 2. 2–3/100×, 3. 3/100×, 4. confluent), sinusoidal lymphocytic reaction (0. absent, 1. mild to moderate, 2. severe), regeneration (1. scattered, 2. diffuse cobble, 3. follicular), polyploid nuclear change (0. absent, 1. present), terminal hepatic vein fibrosis (0. absent, 1. perivenular or perihepatocellular), fatty change (0. absent, 1. mild, 2. moderate, 3. severe) (Table 2).

We used the Odds ratio and p value to compare the HAI between the CAH-C and CAH-B groups. Statistical significance was determined when the p value was below 0.05. Odds ratio, which is a classical index used to measure the association and strength of association between the disease and expression, was used to clarify arithmatically the association between the HAI and type of viral hepatitis.

Although clinical and experimental evidence suggesting that etiologic agents of hepatitis C are virus-like in nature have accumulated in the last decade, and there have been intensive efforts in many laboratories throughout the world in the past few years to identify and characterize the agents responsible for this infection, no hepatitis C agents have been identifed as an antigenic, ultrastructural or molecular entity⁸⁾. An almost 15-year quest to identify an agent of non-A, non-B (NANB) viral hepatitis ended in 1988 with the identification of a RNA virus with an immunologic specificity for transfusion associated NANB hepatitis with the molecular biological advances^9–10). Eighty percent of patients with transfusion-associated NANB hepatitis and sixty percent with sporadic form, formerly presumptively suggested by checking surrogate hepatitis viral markers, have detectable anti-HCV antibody¹¹⁾. Thereafter, it has been determined that hepatitis C accounts for a substantial proportion of acute, chronic liver diseases, and hepatocellular carcinoma¹²⁾. Further studies to detemine the roles of infections with hepatitis C virus to this leading cause of liver diseases are now underway worldwide^13,14).

Although several histological patterns have been described in patients with acute and chronic NANB virus infection, none of them facilitates a definite histological diagnosis, and the criteria to be described must be regarded as suggestive rather than diagnostic¹⁵⁾. Until now, the most consistent feature of NANB hepatitis has been the formation of lymphoid follicles with germinal centers in portal tracts, but these have also been found in some patients with chronic HBV infections¹⁶⁾. Some characteristics such as steatosis in the parenchyma, giant cells, diffuse sinusoidal cells infiltrates and bile duct lesions have been emphasized as more or less indicative of NANB etiology of viral hepatitis¹⁷⁾. The histological features of patients with sporadic NANB hepatitis were described by Bamber et al.¹⁸⁾ Histologic findings in liver biopsy covered the whole spectrum of acute and chronic hepatitis. The notable features in these biopsies were the presence of fatty changes and excessive cellularity of sinusoids in relation to the degree of hepatic necrosis. The presence of considerable fatty change, particularly in the early weeks of acute hepatitis, was noteworthy because it has been regarded as unusual in other types of acute viral hepatitis. Dienes et al.¹⁹⁾ studied the specimens from 57 patients with acute or chronic hepatitis NANB and found the two types of pathologic features. One was an eosinophilic alternation of the hepatocyte cytoplasm associated with many eosinophilic bodies. The second feature consisted of sinucoidal lymphocytic infiltrations. Both features were associated with portal and mild periportal inflammation unrelated to the degree of parenchymal reaction. Similar findings were also noted in our studies such as dense, compact portal lymphocytes infiltrations with expansions of portal tract and severe sinusoidal lymphocytic reactions.

The report about the histopatholgic comparison between 86 cases of hepatitis A and 76 cases of NANB hepatitis published by Krager and Christoffersen²⁰⁾ revealed that hepatitis A was charcterized by more pronounced portal inflammations than hepatitis NANB, but less conspicuous parenchymal changes such as focal nerosis, Kupffer cell proliferations, acidophilic bodies and ballooning change of hepatocytes. Steatosis occurred in 10% of hepatitis A compared with 26% in hepatitis NANB. Jove et al.²¹⁾ analyzed retrospectively the clinical, morphological and evolutive features of 60 patients with chronic hepatitis NANB and found that there were some differences in morphological categories between sporadic and transfusion related cases. Takada et al.²²⁾ reported that there are at least two or more types of acute NANB hepatitis. In one type hepatocyte necrosis was prominent in the periportal area (portal type), and in the other there was no such characteristic distribution of hepatocyte necrosis (non-portal or diffuse type). Takase et al.²²⁾ also stressed that a histological analysis of the liver is important in order to distingish between the types of acute NANB hepatitis.

Recently, Patel et al.²⁴⁾ reviewed histological features in 24 cases of HCV antibody positive post-transfusion hepatitis and found that the majority of these biopsies showed portal, periportal and lobular inflammation with lymphoid follicles, considered to be characteristic of HCV liver disease. Govindarajan et al.²⁵⁾ also retrospectively analyzed pathologic features of 11 liver biopsies of chronic HCV infection. They concluded that serologically documented chronic HCV infection frequently exhibited morphologic features such as fat, sinusoidal collagen, glycogen in nuclei and atypical ducts, which are unsual for the other type of chronic viral hepatitis.

Beside the microscopic features described above, the ultrastructural findings in NANB were reported by many authors^26–28). In NANB hepatitis, the liver ceil nuclei are characterized by irregular outlines, increased lobulization, thickening of the nuclear membrane, condensation and margination of the chromatin and intranuclear cytoplasmic inclusions. The most consistently reported finding is the presence of intranuclear aggregates. An overview of the various ultrastructural alternations reported in NANB hepatitis leads to the conclusion that the search for the morphologic components of this viral agent has not yet been completed.

Although there were no characteristic histologic features peculiar to chronic hepatitis C, dense, follicular portal lymphocytic inflammations and expansion with sinusoidal lymphocytic reactions seem to be more or less prominent histologic findings in diagnosing hepatitis C. However, further studies on the identification of hepatitis C virus and its characteristic histologic features will be continued.