Before the late 1930s, pathologic examination of the liver required either an open-liver biopsy at the time of surgery or death of the patient and an autopsy. Consequently, little information was available regarding the pathologic changes in uncomplicated infectious hepatitis. The findings in acute yellow atrophy were well documented 166, and the relationship between acute yellow atrophy and nonfatal hepatitis was increasingly recognized 46, 80, 88, although the heterogeneity of etiologic factors contributing to cases of acute yellow atrophy was probably underappreciated.
Percutaneous Liver Biopsy
Iversen and Roholm revolutionized liver biopsies by developing a percutaneous technique that is remarkably similar to that in use todaya transthoracic approach with a suction needle 128. In their paper describing the histopathology of acute hepatitis, "sporadic acute benign jaundice of the catarrhal type," they reported on the findings in 38 aspiration biopsy specimens 128. Their descriptions are as apt today as they were 60 years ago. They observed hepatocellular necrosis with ballooning and eosinophilic degeneration, an inflammatory infiltrate of mostly mononuclear cells, and a variable amount of collagen. In follow-up biopsies on 12 patients 25 to 35 days later, there was less inflammation and the connective tissue was unchanged. One patient was biopsied 16 h before succumbing to fulminant hepatitis. The biopsy showed findings similar to those following a benign course but of greater severity, with destruction of the parenchyma and an inflammatory infiltrate.
The technique of percutaneous liver biopsy was rapidly adopted by others. A British study from 1943 reported findings in 14 patients with epidemic hepatitis (mostly HAV), 7 with serum jaundice (HBV), and 35 with jaundice in relation to arsenotherapy (mostly HBV) 66. No histopathological differences were perceived between the various supposed etiologies. The researchers observed necrosis that was most marked pericentrally and inflammation that was maximal in the portal areas. The extent of involvement was increased with more severe disease. Similar findings were observed in large series reported over the ensuing 30 years 127, 158, 195, 225. All agreed that the cardinal features of acute hepatitis were the presence of hepatocellular degeneration, characterized as either ballooning or acidophilic (apoptotic) change, together with various degrees of portal and lobular inflammation and hepatocyte regeneration.
Modern-Era Liver Biopsy
Although the number of biopsy samples examined was extensive, the older studies of the pathology of acute hepatitis lacked the ability to compare hepatitis A with hepatitis B and hepatitis C in well-documented serologically defined cases. This distinction is of only modest importance since the overwhelming bulk of the findings, like the clinical manifestations, are qualitatively identical 141, 184, 242. As part of the Copenhagen Hepatitis Acuta Programme that monitored over 100,000 patients, liver biopsies were performed routinely until 1980. With the advent of serodiagnosis for acute hepatitis A as a research tool in the late 1970s, a comparison study was undertaken 141. The parenchymal changes (focal necrosis, ballooning, and acidophilic degeneration) were less marked in the biopsy specimens from 86 patients with hepatitis A than in specimens from 78 patients with hepatitis B, whereas the degree of portal inflammation was similar. Follow-up liver biopsy samples (two to four per patient) were obtained for 36 patients at intervals of 1 to 24 months after the acute illness. The biopsy samples were classified as normal (17 of 54 biopsies) and nonspecific reactive changes (24 of 54); continuing acute hepatitis was observed for 1 to 5 months after initial presentation for 13 141. Fibrin ring granulomas, more often associated with diseases such as Q fever, were described in acute hepatitis A biopsy samples by some investigators 197, 268.
The technique of in situ hybridization was recently used to localize HAV sequences in human liver biopsies 241. Viral RNA was detected in hepatocytes, sinusoidal cells, and inflammatory cells. Replicative intermediates were not detected. Using a macrophage-specific marker, the investigators confirmed the presence of viral nucleic acids in the cytoplasm of phagocytic cells. Clearance of virus by uptake of antigen-antibody complexes between virions and anti-HAV into these cells seems a plausible explanation for this observation, rather than phagocytosis of virus directly.