Non-A, non-B hepatitis: evolving epidemiologic and clinical perspective

Evidence for the existence of human hepatitis agents besides HAV and HBV is compelling. Transmitted predominantly by transfusion and percutaneous inoculation, the type of NANB hepatitis encountered most frequently is epidemiologically similar to type B hepatitis. NANB hepatitis accounts for more than 90% of TAH, but can be transmitted by nonpercutaneous routes as well. Approximately 15 to 30% of sporadic hepatitis cases are attributable by serologic exclusion to NANB hepatitis agents, and, in addition, there is an epidemic form of NANB hepatitis that resembles hepatitis A epidemiologically in its transmission by the enteric route. Clinical features of the predominantly percutaneously transmitted forms of NANB hepatitis are similar to those of hepatitis B, but tend to be less severe during acute illness, on the one hand, but to lead more frequently to chronic hepatitis, on the other; 40 to 60% of patients with TAH have chronic elevations of aminotransferase activity, often in an episodic, fluctuating pattern. CAH can be identified histologically in a majority of patients with chronic NANB TAH. Despite a relatively quiescent course, progression of such chronic cases may be quite insidious; cirrhosis occurs in 10 to 20% of patients with chronic hepatitis after acute TAH. The frequency of chronic liver disease after nonpercutaneously acquired sporadic NANB hepatitis tends to be lower, on the order of 10% or less, and chronic hepatitis has not been recorded after the epidemic type of NANB hepatitis. Evidence supports the existence of an asymptomatic chronic NANB hepatitis carrier state that is several-fold more frequent than the chronic HBV carrier state. Neither viruses nor virus markers have been described that fulfill accepted criteria reproducibly for a specific causal association with NANB hepatitis; on the other hand, evidence suggests (but does not prove) the existence of two different blood-borne NANB hepatitis agents and, in addition, an enterically transmitted NANB hepatitis agent. Effective therapy for and immunoprophylaxis against NANB hepatitis are lacking. Until specific screening tests are developed, interim screening based on indirect, nonvirus-specific tests may be the only practical approach to minimizing the frequency of NANB hepatitis after transfusion. Identification of virus-specific serologic markers remains a high priority.     

Non-A, non-B hepatitis after open-heart surgery in Sweden

In recent years evidence has emerged that most post-transfusion hepatitis is caused by one or more previously unknown agents named non-A, non-B. A prospective investigation was made of 74 patients who underwent open-heart surgery. Only volunteer blood was used for transfusions. Transfusion-associated hepatitis appeared in 15 (20%) of the patients 4-12 weeks after the operation. In no case was the hepatitis found to be caused by hepatitis B, A or Epstein-Barr virus. One patient had a cytomegalovirus infection; the other 14 cases (19%) were classified by definition as non-A, non-B hepatitis. Although most of the patients were asymptomatic and all were anicteric, the course of the hepatitis was protracted in many cases. Thus, 6/12 observed patients still had pathologic transferase values more than a year after the onset of hepatitis. Liver biopsy was performed in 3 cases and showed histologic signs of chronic active hepatitis in all of them.     

Non-A, non-B hepatitis among participants in a plasmapheresis stimulation program.

Non-A, non-B hepatitis was transmitted to seven of nine participants in a red blood cell-stimulation program following transfusion of blood from one asymptomatic donor. Five of the seven patients had clinical as well as biochemical evidence of infection, and three of these five were icteric. Incubation periods for the clinical cases ranged from 28 to 50 days, and duration of illness was from two to eight weeks. None of the seven patients showed serologic evidence of acute infection or reinfection with hepatitis A virus, hepatitis B virus, cytomegalovirus, or Epstein-Barr virus. Viremia persisted in the donor for at least 34 days, since non-A, non-B hepatitis was transmitted to program participants during that period.     

Non-A, non-B chronic hepatitis is chronic hepatitis C: a sensitive assay for detection of hepatitis C virus RNA in the liver.

To study the role of hepatitis C virus in non-A, non-B chronic hepatitis, 49 liver biopsy samples from 40 patients with non-A, non-B chronic hepatitis and 9 control patients were analyzed by complementary DNA/polymerase chain reaction. Two segments of the HCV genome, one in the nonstructural region and the other in the noncoding region, were amplified by two sets of primer pairs. With use of the nonstructural region primers, hepatitis C virus RNA was detected in 24 (60%) of 40 patients with non-A, non-B chronic hepatitis. Of these 40 patients, RNA was detected in 19 (70%) of 27 patients positive for antibody to hepatitis C virus and in 5 (38%) of 13 patients negative for antibody to hepatitis C virus. However, with the noncoding region primers, hepatitis C virus RNA was detected in 38 (95%) of 40 patients with non-A, non-B chronic hepatitis. Of these patients, the RNA was detected in 26 (96%) of 27 patients positive for antibody to hepatitis C virus and also in 12 (92%) of 13 patients positive for antibody to hepatitis C virus. Hepatitis C virus RNA was not detected in any of the control patients. Sequence analysis showed homology between our samples and the prototype to be only 66% to 77% in the nonstructural region but 99% to 100% in the noncoding region. We conclude that almost all patients with non-A, non-B chronic hepatitis in Japan are currently infected with hepatitis C virus, regardless of the presence or absence of antibody to hepatitis C virus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Non-A, non-B hepatitis: is there more than a single blood-borne strain?

Fourteen chimpanzees were challenged with the Hutchinson strain inoculum that has been shown by many workers to produce non-A, non-B (NANB) hepatitis associated with characteristic cytoplasmic ultrastructural changes observable by electron microscopy. Nine of these animals had a history of definite NANB hepatitis induced by seven different human viral isolates; all of these animals resisted rechallenge. The five animals without a history of NANB hepatitis all developed definite histological changes associated with NANB hepatitis after challenge. Homologous rechallenge with a 100-fold higher infectivity titer was carried out in five of the nine chimpanzees. Cytoplasmic ultrastructural changes developed after challenge in two of these animals; the remaining three had evidence of possible mild reinfection on the basis of liver histopathology or mild elevations of transaminase or both. We conclude that most, if not all, blood-borne NANB isolates belong to a single class of agents and that this virus produces immunity to rechallenge, but this immunity may be overwhelmed by high-dose inocula.     

Non-A, non-B hepatitis-like nuclear particles in nonparenchymal cells of the liver

Nuclear particles, morphologically similar to those seen in hepatocytes during non-A, non-B (NANB) hepatitis, were detected in several types of nonparenchymal cells in 10 human liver-biopsy specimens, including cases of hepatitis A and B and nonviral hepatic disease. They were also found in nonparenchymal cells of the liver in two of four normal chimpanzees and in two of four chimpanzees during experimental NANB viral hepatitis. In nonparenchymal cells the particles formed loose-to-intermediate aggregates, similar to those first described in hepatocytes during NANB hepatitis. Tightly packed aggregates, the predominant pattern in hepatocytes, were generally missing. The high prevalence of morphologically identical particles in various liver diseases and their presence in healthy livers, both in hepatocytes and in nonparenchymal cells not presumed to support the growth of hepatitis viruses, speak against their specificity for NANB hepatitis viruses. It is proposed that the particles represent a newly recognized and widespread cellular feature, of as yet unknown function.     

Non-A,non-B fulminant viral hepatitis in France in returnees from Asia and Africa

Among 61 patients admitted for non-A, non-B fulminant viral hepatitis to Hôpital Beaujon, 10 had returned from Asia or Africa, and 51 had not been outside France, within the month preceding jaundice. This suggests that hepatitis might have been contracted in Asia or Africa in the former, and in France in the latter. The interval between the onset of jaundice and the onset of hepatic encephalopathy was 10 days in the former and 26 days in the latter (P<0.03). The serum of the patient returning from Asia contained, and the sera of the nine patients returning from Africa did not contain, antibodies to a virus isolated from the stools of patients suffering from an epidemic fecal-oral non-A, non-B viral hepatitis in Central Asia. It is concluded that infection with Asian-African non-A, non-B viruses can be the cause of fulminant hepatitis in persons returning from these countries, that the course of this type of non-A, non-B fulminant viral hepatitis is shorter than that of non-A, non-B fulminant hepatitis contracted in France, and that different viruses might be responsible for non-A, non-B hepatitis in Asia and Africa.     

Detection of hepatitis C viral RNA sequences in fresh and paraffin-embedded liver biopsy specimens of non-A, non-B hepatitis patients.

In this study methods of HCV-RNA detection in fresh frozen and formalin-fixed, paraffin-embedded liver biopsies are described. Of 22 untreated chronic non-A, non-B hepatitis patients and 6 control patients, a plasma sample and part of a liver biopsy were freshly frozen for hepatitis C virus (HCV) cDNA-PCR. From 16 of the same non-A, non-B hepatitis patients and from 5 of the same control patients formalin-fixed, paraffin-embedded liver tissue from the same biopsy was available also for HCV cDNA-PCR. In 13 of 22 non-A, non-B hepatitis patients HCV-RNA could be detected in plasma as well as in liver tissue. In the other 9 non-A, non-B hepatitis patients and in 6 control patients, no HCV-RNA was detectable in either plasma or liver tissue. The comparison between HCV cDNA-PCR results in fresh frozen versus formalin-fixed, paraffin-embedded liver biopsies showed that although detection of HCV-RNA in both correlated 100% the quantity of HCV-RNA was lower in the formalin-fixed, paraffin-embedded liver biopsies of 5 of 8 patients for whom end-point dilution titration of liver RNA was performed. We conclude that using the procedures described HCV-RNA can be reliably detected in both fresh-frozen and formalin-fixed, paraffin-embedded liver biopsies and that HCV cDNA-PCR in liver tissue may become an important assay, especially for monitoring anti-viral therapy.