A case of giant cell hepatitis recurring after liver transplantation and treated with ribavirin

Giant cell hepatitis (GCH) is a relatively common pathological finding in neonates and infants, and is associated with a variety of conditions, such as intraand extrahepatic biliary atresia, infectious or metabolic diseases, and the so-called neonatal hepatitis (1). It has occasionally been described in adults, with features suggesting a viral origin and a rapidly progressive course (2). Its recurrence after liver transplantation has been reported (3), as has its treatment with ribavirin after orthotopic liver transplantation (OLT) in one patient (4). We report a patient in whom GCH recurred twice after OLT and was treated with ribavirin. CASE PRESENTATION A 42-year-old patient underwent OLT in June 1990 for GCH with cirrhosis. Before liver transplantation, he tested negative for hepatitis B surface antigen (HBsAg), hepatitis B surface antibodies, hepatitis B core antibodies, hepatitis C virus antibodies, Epstein Barr virus (EBV) (viral capsid antigen and EBV-determined nuclear antigen) antibodies, antihuman immunodeficiency virus antibodies, antimitochondrial antibodies, antinuclear antibodies and smooth muscle antibodies. He proved later to be hepatitis C virus RNAnegative as well. He was immune to cytomegalovirus. GCH


Récurrence d'une hépatite à cellules géantes traitée à la ribavirine après une greffe du foie
RÉSUMÉ : On présente ici le cas d'un patient qui a subi une greffe du foie orthotopique pour une hépatite à cellules géantes avec cirrhose et chez qui l'hépatite à cellules géantes est réapparue deux fois après la greffe.Le patient a été traité à la ribavirine avec un excellent résultat.La littérature sur ce sujet est passée en revue.Ce rapport de cas confirme clairement l'efficacité de la ribavirine pour le traitement de l'hépatite à cellules géantes confirmant de ce fait son origine virale.recurred after OLT, and he acquired hepatitis B virus (HBV) at the time of transplantation.In the years that followed, he remained HB s Ag-positive, hepatitis e antigen-positive and HBV DNA-positive.Serum transaminase levels were persistently abnormal (around 100 U/L).His disease progressed to cirrhosis, with serial liver biopsy specimens showing mixed features of syncytial GCH and chronic hepatitis B with HB s Ag and hepatitis B core antigen (HB c Ag) positivity.He was started on lamivudine 100 mg daily in March 1996.Eight weeks later, his serum was negative for HBV DNA when tested with the Digene (USA), Abbott (USA) and Chiron (USA) assays, but serum transaminase concentrations remained persistently abnormal, and two liver biopsies performed six and 12 months after starting lamivudine showed no change in the inflammatory activity in the liver nor in the intensity of Hb c Ag staining.His serum was HBV DNA-positive when measured by polymerase chain reaction (National Genetics Institute, USA) in May 1997.The HBV genome was sequenced, and a YMDD mutation was demonstrated.Famciclovir 500 mg tid was added in August 1997.Liver function continued to deteriorate, and the patient received a second liver transplant in May 1998.He initially received hepatitis B immune globulin, famciclovir and lamivudine prophylaxis; famciclovir was subsequently withdrawn.Liver function test (LFT) results remained abnormal, while HB s Ag and HBV DNA test results were negative.A liver biopsy performed in July 1998 showed portal and periportal infiltration, with mononuclear elements, bridging necrosis, mild intralobular degeneration and focal necrosis.Within the lobule, numerous multinucleated hepatocytes were noted; there was moderate fibrosis.The patient was negative for HB s Ag and HB c Ag on immunohistochemistry, and for cytomegalovirus, EBV and herpes simplex virus.Lamivudine and hepatitis B immune globulin were continued, and ribavirin (400 mg bid) was added in August 1998.LFT results improved gradually and normalized completely in February 1999; ribavirin was then stopped.In April 1999, LFT results deteriorated, with an increase in serum bilirubin up to 400 µmol/L.A liver biopsy showed recurrence of severe GCH (Figure 1), and ribavirin was reintroduced with a drastic improvement in LFT results, which normalized completely in August 1999 and have remained normal with continued ribavirin treatment (Figure 2).A control liver biopsy performed in May 1999 demonstrated a marked decrease in portal and lobular inflammation, and in the number of giant cells.

DISCUSSION
GCH is characterized by the presence throughout the liver of numerous enlarged multinucleated hepatocytes with abundant cytoplasm (1).It is a nonspecific reaction in neonates and infants with various liver diseases.The term 'postinfantile GCH' was coined by Thaler (5) to describe this histological finding in the older patient.In 1991, Phillips et al (2) described 10 patients who had syncytial GCH, with a severe course and a poor outcome.Structures resembling the nucleocapsids of paramyxoviruses were seen on electron microscopy, but the putative virus could not be identified.In 1993, Roberts et al (6) reported an infant with severe neonatal GCH who was treated effectively with a 10-day course of intravenous ribavirin.In 1994, Pappo et al (3) described five patients who had GCH that recurred after liver transplantation.In 1997, Durand et al ( 4) reported an adult patient with subfulminant GCH leading to OLT and recurring in the transplanted liver.This patient was treated with two 21-day courses of intravenous ribavirin; LFT results and liver histology normalized.In 1998, Fimmel et al (7) performed elaborate molecular biology manipulations on the liver tissue of a patient affected by GCH and obtained a positive signal on in situ hybridization studies with a probe directed against the measles fusion protein.Taken together, these observations suggest that a yet unidentified virus, related to Paramyxoviridae, may play a role in the pathogenesis of GCH.Some authors have suggested, however, that other etiological factors may be implicated in GCH, based on retrospective case reviews and case reports (8)(9)(10)(11)(12)(13)(14).The patients described had a variety of associated conditions, including autoimmune features, with or without overt autoimmune  disease, and hypereosinophilia.In some patients, there was an identifiable cause of liver disease -autoimmune hepatitis, acute hepatitis A or B, chronic hepatitis C or drug exposure.
In others, the etiological work-up remained negative.Patients with or without autoimmune features have been treated with immunosuppressive therapy (8,(10)(11)(12)14), with favourable results in most cases.Even in untreated patients, the outcome appeared to be much less ominous than that described by Phillips et al (2).
Our patient had the typical histopathological features of GCH, and no cause was found before the first transplantation and after the second one.GCH recurred on the two transplanted livers despite immunosuppression with a tripledrug regimen (prednisone, azathioprine and cyclosporine) and was effectively treated with oral ribavirin.On withdrawal of this antiviral drug, severe recurrence of GCH that responded to the reinitiation of therapy was documented.It might be implied from this observation that GCH was, in this case, related to a transmissible factor that responded to ribavirin and was thus likely to be viral.It is noteworthy that continuous treatment seemed necessary, while short courses of intravenous ribavirin appeared to be sufficient in the two previously published cases (4,6).

CONCLUSIONS
GCH seems to encompass a wide spectrum of liver diseases in adults, as it does in children.A cause may be evident in some cases and absent in others.Autoimmunity and infection with an as yet unidentified virus have been implicated most frequently.Clinical courses are highly variable.In some cases, GCH seems to respond to immunosuppressive therapy and in others to antiviral therapy; sometimes it responds to none of these therapies (15).We present a case that demonstrates clearly the efficacy of ribavirin treatment for GCH and thus adds evidence for its viral origin in some cases.

Figure 1 )
Figure 1) Biopsy specimen showing recurrence of giant cell hepatitis on the second transplanted liver after the withdrawal of ribavirin.Numerous multinucleated giant cells (arrowheads) are visible on this photomicrograph, as are multiple areas of lobular inflammation.

Figure 2 )
Figure 2) Biochemical profile of the patient after the second liver transplantation, showing the evolution of serum alanine aminotransferase (ALT) and bilirubin with respect to ribavirin treatment.Time 0 is the time of the second orthotopic liver transplantation (OLT)