Aplastic anaemia complicating hepatitis is a rare but well-documented phenomenon; however in many patients the cause remains unknown. We present a 24-year-old man with a well-defined community-acquired hepatitis, probably due to hepatitis G virus (HGV), who developed severe aplastic anaemia. In this case, the absence of other agents likely to cause the clinical manifestations, and the detection of HGV RNA at the time of illness, clearly point to this agent as being responsible for both the hepatitis and the aplastic anaemia. Further studies in serial serum samples and meticulous evaluation of the disorders associated with the infection will be needed to prove or dispute a causal association of HGV and aplastic anaemia.
- hepatitis G virus
- aplastic anaemia
Statistics from Altmetric.com
Aplastic anaemia complicating hepatitis is a rare but well-documented phenomenon. The mechanisms leading to marrow failure remain unclear.1 2 The recent identification of the hepatitis G virus (HGV) has opened the field to the study of disease association with these new agents.3 4 HGV-RNA has been reported in sera from patients with acute, chronic, and fulminant hepatitis who lacked evidence of infection with known hepatitis viruses.3 4 Of interest is an apparent link between HGV infection and cases of aplastic anaemia.5 6
On 10 July 1992, a previously healthy white 24-year-old heterosexual man presented with 5 weeks of malaise and 3 weeks of jaundice. The patient had had no exposure to industrial chemicals or to any proprietary or non-proprietary drugs. He denied use of any medications, intravenous drug abuse, blood transfusion, or alcohol ingestion. On examination, the patient was alert with minimal scleral icterus and without stigmata of chronic liver disease. Serologic markers for HAV, HBV, HCV, HEV, and HIV were repeatedly negative. HBV and HCV testing by polymerase chain reaction (PCR) did not detect HBV-DNA or HCV-RNA. Virological and microbiological tests, including cytomegalovirus, Parbovirus B-19 (IgG and IgM), toxoplasma, Epstein-Barr virus, herpes simplex virus, coxiella, and leptospira, were all negative. Antinuclear antibodies, anti-smooth muscle antibody, antimitochondrial antibody, and screen for Wilson′s disease and haemochromatosis were also negative. Chest X-ray and ultrasound examination of the abdomen were normal. His clinical state improved over the next 10 weeks; liver function tests returned to normal levels by week 12. On 5 August 1993 he was admitted to our hospital for evaluation of nose and gum bleeding and multiple haematomata. Examination revealed purpura of his oral mucosa and multiple petechiae. Virological and microbiological tests were again negative. Bone marrow biopsy showed a severely hypoplastic marrow and this, together with his low platelet and white cell counts, satisfied the criteria for severe aplastic anaemia. Over the following 2 weeks, he became progressively more pancytopenic and his aspartate transaminase and alanine transaminase returned to near normal ranges. On 25 August 1993 he received an allogenic bone marrow transplant. He has remained well for more than 2 years after transplantation. The laboratory results are summarised in table 1.
HCV-RNA was investigated by PCR amplification of the 5′ NCR as described previously.7 No cross-reactivity with HGV-RNA was found. HGV-RNA was investigated by PCR amplification of the 5′ NCR as described previously.8 Briefly, nucleic acids were extracted from 100 μl of serum using extraction columns (Quiagen, Hilden, Germany). RNA was transcribed into cDNA with M-MLV retrotranscriptase. The primers were NCR1: 5′-CGGCCAAAAGGTGGTGGATG-3′ and NCR2: 5′-CGACGAGCCTGACGTC GGG-3′. Amplified cDNA sequences were detected by agarose gel electrophoresis with ethidium bromide staining. The specificity of the amplified bands was confirmed by an electro-immunoassay procedure (PCR ELISA (Dig detection, Boehringer Mannheim, Germany). Sera obtained before any blood products were given and throughout the clinical course, were positive for HGV. Similarly, serum obtained on presentation with aplastic anaemia was positive for HGV. Unfortunately, fresh bone marrow aspirates were not available to show whether HGV RNA was present in bone marrow. Sera obtained in July and December 1994, were negative for HGV.
Hepatitis-associated aplastic anaemia (HAAA) is a severe disorder with a high mortality; the responsible agent for most cases of HAAA has not been identified, although it is presumed to be viral. HGV has been postulated as the aetiologic agent of acute hepatitis, chronic liver disease of unknown aetiology, fulminant hepatitis, and HAAA.3 4 In our patient, we were able to detect HGV-RNA in the serum repeatedly before any blood transfusion. In this case, the HGV infection was demonstrated coincident with the two flares of hepatic necrosis, and for this reason a causative association can be inferred. The role of HGV in non-A–E community-acquired hepatitis is under investigation.9-11 Published case series have claimed an association between HGV and acute liver diseases, but case-control studies are required to confirm whether or not HGV is an aetiologic agent of viral hepatitis.9 The negative HGV RNA by PCR in the post-bone marrow transplant serum suggests HGV clearance in this patient. Few reports have analysed the role of HGV in the development of HAAA (table 2); however, the high prevalence of HGV in these cases may arise from disease treatment rather than from HGV being a causative agent of aplastic anaemia.
The patient with HGV hepatitis we report here followed a pattern noted to be typical of HAAA. Moreover, after the bone marrow transplant, there was no further evidence of chronic hepatitis or HGV infection. Although the detection of HGV RNA at the time of illness, in the absence of other agents likely to cause the clinical manifestations, clearly points to this agent as being responsible for both the hepatitis and the aplastic anaemia, controversial issues should be addressed. First, the clinical significance of HGV remains uncertain.8-10 Second, neither a specific location nor replication in the liver has yet been verified and HGV RNA has not been documented in fresh marrow aspirates. Third, we cannot exclude that our patient with HGV infection may have simultaneously acquired another unidentified agent(s) which might have caused the rise in liver enzymes and/or the aplastic anaemia. Fourth, several features of the HAAA suggest that it is mediated by immunopathologic mechanisms; for this reason, the causative agent of this syndrome may not be an infectious agent.1-2
In summary, in this case the absence of other agents likely to cause the clinical manifestations, and the detection of HGV RNA at the time of illness, clearly point to this agent as being responsible for both the hepatitis and the aplastic anaemia.
This work was supported by a grant from the Fondo de Investigaciones Sanitarias de las Seguridad Social, Spain (FISSss 94/1411) and by a grant from the Fundación Marqués de Valdecilla, Santander, Spain
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.