Interferon and cyclosporin A in the treatment of fulminant viral hepatitis

The prognosis of fulminant hepatitis due to non-A, non-B virus infection and acute reactivation of hepatitis B virus in HB carriers is generally poor, and the treatment of choice in Western countries is recognized as liver transplantation. In countries such as Japan where liver transplantation is not readily available, however, these intractable types of fulminant hepatitis have to be treated medically. Based on the assumption that persistent replication of causal viruses and enhanced host immune responses, especially cellular immunity, to eradicate the viruses are the key mechanism in progressive liver cell destruction and the poor prognosis, we attempted a combination treatment with interferon and cyclosporin A for these types of fulminant viral hepatitis. Subjects in the present study consisted of 1 patient with acute severe hepatitis without coma and 13 patients with coma (13 with fulminant hepatic failure) due to non-A, non-B virus and acute reactivation of hepatitis B virus. The patients were given interferon-beta, 300 × 10⁴U daily, and cyclosporin A, at an initial dose of 3 mg/kg, with tapering. Fourteen patients with coma received artificial liver support that we devised. The patient with acute severe hepatitis survived, showing histologically remarkable liver regeneration. Eight of the 14 patients with hepatic coma, all of whom were indications for liver transplantation according to the criteria of the King's College group, survived. Decreased transaminase level, increased liver volume, and histological liver regeneration were observed in all the survivors. The combination of interferon and cyclosporin A is worth attempting in fulminant hepatitis caused by non-A, non-B virus and acute reactivation of hepatitis B virus in HB carriers.     

Reactivation of hepatitis viruses following immunomodulating systemic chemotherapy

Reactivation of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection following anticancer chemotherapy and immunosuppressive therapy is a well‐known complication. HBV reactivation has been reported to be associated with anti‐CD20 monoclonal antibody rituximab‐containing chemotherapy and tumor necrosis factor‐α inhibitor‐containing immunosuppressive therapy in HBV resolved patients (hepatitis B surface antigen negative and antibodies against hepatitis B core antigen positive and/or antibodies against surface antigen positive). On the other hand, HCV reactivation has been reported to be associated with liver damage or hepatic dysfunction, but fulminant hepatitis due to HCV reactivation is a rare complication. In this review, we describe the pathophysiology of the reactivation of HBV and HCV infection, as well as the clinical evidence and management of HCV reactivation.     

Combined glucocorticoid and antiviral therapy of hepatitis B virus-related liver failure

Acute hepatic failure due to hepatitis B virus(HBV)can occur both during primary infection as well as after reactivation of chronic infection.Guidelines recommend considering antiviral therapy in both situations,although evidence supporting this recommendation is weak.Since HBV is not directly cytopathic,the mechanism leading to fulminant hepatitis B is thought to be primarily immunemediated.Therefore,immunosuppression combined with antiviral therapy might be a preferred therapeutic intervention in acute liver failure in hepatitis B.Here wereport our favourable experience in three hepatitis B patients with fulminant hepatic failure who were treated by combining high-dose steroid therapy with standard antiviral treatment,which resulted in a rapid improvement of clinical and liver parameters.     

Chronic HBV with pregnancy: reactivation flare causing fulminant hepatic failure

Chronic HBV infection is a dynamic state of interaction between HBV, hepatocytes, and the immune system of the host. A series of reactivation flares and remissions may occur due to multiple causes. Among them, spontaneous reactivation and immunosuppressive drugs including steroids or cancer chemotherapy are well known. This is due to immune-mediated destruction of HBV-expressing cells following withdrawal of immunosuppressive effect. Few cases have been reported in females during postpartum period. We report a case of fulminant hepatic failure during pregnancy in a previously unrecognized hepatitis B positive female requiring emergent liver transplantation.     

Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation

Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.     

Systemic inflammatory response syndrome strongly affects the prognosis of patients with fulminant hepatitis B

Background Hepatitis B virus infection is the most frequent cause of fulminant hepatic failure. Recently, systemic inflammatory response syndrome has been reported to be important in patients with fulminant hepatic failure. However, prognostic factors for fulminant hepatitis B have not been fully examined. In this study, we analyzed prognostic factors for fulminant hepatitis B in order to accurately identify patients with fatal outcomes. Methods Of 110 consecutive patients with fulminant hepatic failure, 36 (33%) were diagnosed with fulminant hepatitis B. Five of the 36 patients received liver transplants, and we analyzed prognostic factors associated with fatal outcomes in the other 31 patients, who consisted of 15 men and 16 women with a median age of 45 (range, 20–74) years. Results Eleven patients (35%) survived without liver transplantation, and the remaining 20 (65%) died. Nonsurvivors were older and had a higher prevalence ratio of systemic inflammatory response syndrome than survivors. Treatments were similar between survivors and nonsurvivors. Using a multivariate Cox proportional hazard model, age (>45 years), systemic inflammatory response syndrome, and ratio of total to direct bilirubin (>2.0) were associated with fatal outcomes. In particular, 1-week and overall survival rates of patients with systemic inflammatory response syndrome at the time of diagnosis were 39% and 8%, respectively, while those of patients without systemic inflammatory response syndrome were 94% and 56%, respectively. Conclusions Systemic inflammatory response syndrome strongly affects the short-term prognosis of patients with fulminant hepatitis B, and patients with systemic inflammatory response syndrome might need urgent liver transplantation.     

Liver Transplantation for Viral Hepatitis: Current Status

Liver transplantation is now considered definitive therapy for end-stage liver disease and has been playing an increasingly important role in the management of fulminant hepatic failure. With the advent of effective immunosuppression and improved surgical techniques, high survival rates can be expected for most transplanted patients. It has become apparent, however, that transplantation for patients with viral hepatitis is associated with some unique problems because of the propensity for viral reinfection of the grafted liver. Patients with actively replicating hepatitis B viral infection pretransplantation appear to be most likely to experience clinically significant recurrent hepatitis. Recurrent hepatitis D (delta) and hepatitis C appear to be relatively less serious in the transplanted liver. Interventions to prevent or treat graft reinfection have thus far met with limited success. Further studies are needed to define more precisely which patients with viral hepatitis are likely to do poorly after liver transplantation, and to develop strategies for treating recurrent hepatitis in transplant recipients.     

Complete recovery from fulminant hepatic failure with severe coma by living donor liver transplantation

In Japan, living donor liver transplantation has been established as a therapeutic strategy for the rescue of terminal liver disease, including fulminant hepatic failure that shows no signs of recovery. We performed living donor liver transplantation for a subacute type fulminant hepatic failure patient, who had developed a hepatic coma of grade V (no right reflex, no response to pain stimuli). The electroencephalogram indicated almost flat waves. However, cranial computed tomography revealed that brain edema was not severe in this case. The recipient did not have hepatitis virus and had not taken medication that had been determined to cause hepatitis. The recipient was a 12-year-old boy, 165.5 cm in height and 45.5 kg in weight. The donor was his mother, who was 42 years old; her blood type, type B, was identical to that of the boy. The mother's right hepatic lobe was transplanted to her son (the recipient). The post-transplantation condition of recipient was quite excellent. He recovered consciousness 3 days after liver transplantation, and rapidly attained normal hepatic function. The donor was discharged on the 20th postoperative day without any problems. The recipient was discharged on the 79th postoperative day without any neurological deficits. This case suggests that deep coma without electroencephalogram waves may not be a contraindication for living donor liver transplantation in fulminant hepatic failure patients, if the brain edema is not severe.     

CASE REPORT: Fibrosing cholestatic hepatitis after living related-donor renal transplantation

A 43-year-old man underwent living related-donor renal transplantation because of chronic renal failure in 1991. During the transplant period, both donor and recipient were seronegative for hepatitis B surface antigen (HBsAg). The donor was seropositive for antibody to hepatitis B surface antigen (anti-HBs) due to hepatitis B virus (HBV) vaccination. After transplantation, FK506 and methylprednisolone had been administered to the patient as immunosuppressants. In 1993, HBsAg appeared in his serum. His alanine aminotransferase level elevated gradually during 1995 and then in 1996, general fatigue, ascites and jaundice developed. At this time his serum was positive for hepatitis B e antibody, contained more than 100000 Meq/mL HBV-DNA and 100% precore mutant. Despite subsequent intensive therapy, liver dysfunction progressed and this patient died of hepatic failure 2 months following admission. At autopsy, the liver exhibited cholestasis, fibrosis extending from the portal tracts, mild inflammation and hepatocytes with a ground-glass appearance. In addition, HBsAg and hepatitis B core antigens had accumulated in the hepatocytes. Consequently, the final diagnosis was fibrosing cholestatic hepatitis (FCH) due to precore mutant HBV infection contracted after renal transplantation. It is unclear when and where the recipient liver became HBV infected. Nevertheless, after renal transplantation, while receiving immunosuppressive drugs, HBV appeared to have the potential to cause hepatic failure and FCH may have been a fatal complication for the recipient.     

HEPATITIS-ASSOCIATED APLASTIC ANEMIA AND ACUTE PARVOVIRUS B19 INFECTION: A REPORT OF TWO CASES AND A REVIEW OF THE LITERATURE

Hepatitis-associated aplastic anemia is rare in general, but occurs in up to 28% of patients receiving liver transplantation for fulminant non-A, non-B hepatitis. Cases are commonly young men with mild hepatitis but severe aplastic anemia. Although cases have been reported in association with hepatitis A, B, and C, most appear to be due to a non-A-B-C virus. We report two cases of acute hepatitis subsequently complicated by marrow hypoplasia in patients with acute parvovirus B19 infection. Hepatic manifestations of parvovirus B19 infection range from liver chemistry abnormalities to fulminant hepatic failure and aplastic anemia. Our cases demonstrate a less severe form of hepatitis-associated aplastic anemia, and together with other data, suggest that parvovirus B19 is at least one cause of hepatitis-associated aplastic anemia, and may be a heretofore underrecognized hepatotrophic virus.     

Lamivudine treatment failure in preventing fatal outcome of de novo severe acute hepatitis B in patients with haematological diseases

BACKGROUND: Patients with malignant haematological diseases administered or no longer receiving immunosuppressive therapy are at high risk of reactivation or de novo hepatitis B infection and fulminant hepatitis. Despite promising results in the treatment of chronic hepatitis and its use in selected patients with acute hepatitis B, there is no consensus on lamivudine treatment in severe acute hepatitis portending a fatal clinical outcome. CASE REPORTS: Of the ten patients with malignant haematological disorders who became infected with the same strain of hepatitis B virus during hospitalisation in a haematology ward, five received lamivudine (and in some cases, ganciclovir and famciclovir). The other patients received only supportive therapy, since deteriorating clinical conditions hampered specific treatment efforts. Eight patients died from acute liver failure and one from a fatal course of the haematological disease; one had a favourable outcome from the therapy. There was no significant difference in terms of survival between the treated and untreated patients. CONCLUSIONS: Although lamivudine has proved promising in the therapy of chronic hepatitis B and of recurrent hepatitis after liver transplantation, its use in de novo severe acute hepatitis should be investigated further, particularly in immunocompromised patients.     

Fulminant hepatic failure: to transplant or not to transplant

Despite progress in intensive care regimens and the introduction of various hepatic support procedures, the survival rate for fulminant hepatic failure remained around 20%. In the past few years, orthotopic liver transplantation has increased the survival rate to more than 50% and thus is generally considered the treatment of choice. However, since about 20% of the patients on standard therapy recover spontaneously, not all patients presenting with fulminant hepatic failure should undergo transplantation immediately. Therefore attempts should be made to identify the patients with "potentially reversible" liver disease in an early phase. In this article strategies for deciding which therapy fits the individual patient are proposed. The decision "to transplant or not to transplant" should be based on residual functioning liver-cell mass (e.g. factor V is less or greater than 15%), the presence or absence of systemic complications such as lactic acidosis and renal failure and the aetiology of the liver disease (e.g. reversible causes such as viral hepatitis B and irreversible causes such as Wilson's disease). A flow diagram has been constructed.     

A case of fulminant liver failure associated with hepatitis C virus

Fulminant hepatitis due to acute hepatitis C virus (HCV) infection is rarely observed. We present a case study of a 21-year-old male patient who developed HCV-associated fulminant hepatitis after receiving steroid pulse therapy for optic neuritis. Despite daily plasmapheresis, the disease progressed to irreversible liver failure with grade 3 hepatic encephalopathy by the 6th day after symptom onset. The patient received a liver transplant on the 8th day. Serum anti-HCV antibody was negative at that time, but became positive on the 12th day. Positive HCV RNA in the serum at admission was reported after transplantation. Positive changes in anti-HCV antibodies and acute hepatitis with massive necrosis in the histology of the explanted liver indicated fulminant hepatitis due to acute HCV infection. Because of severe hepatitis recurrence, he started 12 months of interferon therapy on the 48th day, and obtained sustained virological response. His anti-HCV antibodies became negative again by 1.5 years after cessation of therapy. HCV genomes recovered from the patient’s serum on the 7th and 48th days revealed 2 different clones out of 20 clones with 30 % amino acid difference in hypervariable region 1 of HCV second envelope glycoprotein. One of the 2 clones expanded further after liver transplantation. We conclude that early diagnosis of HCV-associated fulminant hepatitis requires the detection of HCV RNA in the serum. Severe hepatitis recurrence after liver transplantation might occur in patients with fulminant hepatitis due to HCV because of its monoclonal expansion.     

Acute viral hepatitis

Opinion statement The mainstay of treatment for acute viral hepatitis is supportive care, as most cases are self-limited. General measures in all types of acute viral hepatitis include bedrest if the patient is very symptomatic, a high-calorie diet, avoidance of hepatotoxic medications, and abstinence from alcohol with the anticipation that most patients will recover uneventfully. In severe cases, hospitalization may be necessary for intravenous rehydration if the patient is unable to maintain adequate oral intake due to nausea and vomiting or if there is any alteration of mental status to suggest evolving fulminant hepatic failure. Acute hepatitis A is a self-limited disease, but can be fulminant. Lamivudine at a dosage of 100 mg/d orally may be beneficial in acute hepatitis B. Interferon-alpha therapy in acute hepatitis C may decrease the risk of developing chronic hepatitis C. Fulminant liver failure due to acute viral hepatitis is uncommon, but orthotopic liver transplantation occasionally may be life saving.     

Hemophagocytic syndrome occurring in an adult liver transplant recipient having Still's disease

Hemophagocytic syndrome is a potentially fatal complication that rarely occurs after liver transplantation. We present a 25-year-old man with a history of Still's disease who presented with fever, arthralgia, and elevated serum ferritin levels 6?months after undergoing liver transplantation for fulminant hepatic failure due to autoimmune hepatitis potentially triggered by infliximab therapy. Liver biopsy demonstrated features consistent with hemophagocytic syndrome. The patient was successfully treated with a course of high dose steroids and had complete resolution of his symptoms and normalization of liver chemistry test abnormalities. Patients with Still's disease may rarely complicate with fulminant hepatic failure with infliximab therapy. Hemophagocytic syndrome a rare potentially life threatening condition may occur in such patients following liver transplantation.     

Fulminant hepatitis after allogenic bone marrow transplantation caused by reactivation of hepatitis B virus with gene mutations in the core promotor region

Under immunosuppressive conditions after hematopoietic stem cell transplantation (HSCT), even if hepatitis B virus (HBV) antigen is negative but hepatitis B surface antibody (HBsAb) or hepatitis B core antibody (HBcAb) is presented, HBV reactivates and sometimes causes fulminant hepatitis. However, it remains unclear which patients will develop fulminant hepatitis, or whether fulminant hepatitis is caused by host-related factors or by virus-related factors. A 30-yr-old man with a history of aplastic anemia since 3 yr of age underwent allogenic BMT, when HBsAb and HBcAb were positive but HBs antigen (HBsAg) was negative. The donor was negative for HBsAg, HBsAb and HBcAb. After transplantation, the patient was complicated by acute graft-vs.-host disease (GVHD), cytomegalovirus infection, intestinal thrombotic microangiopathy and aspergillus colitis. Chronic GVHD was well controlled by FK506 and prednisolone. Twenty months after transplantation, the patient was admitted with general fatigue and liver dysfunction and was found to be positive for HBsAg and HBeAg. His serum HBV-DNA level was >8.8 log of the genome equivalent (LGE)/mL. Therefore, he was diagnosed as having hepatitis B caused by HBV reactivation and 100 mg/d lamivudine treatment was started. However, jaundice and hepatic failure deteriorated and became fatal. On analysis of the HBV-DNA, two adjacent gene mutations in the core promoter region (T1762/A1764) were detected. Increased replication of the mutated HBV might have caused HBV reactivation which progressed to fulminant hepatitis.     

Hepatitis B vaccination in liver transplant candidates

Liver transplantation has become the treatment of choice for patients with end-stage liver disease. De novo hepatitis B infection after liver transplantation is a rare event and usually runs a mild clinical and histological course. Despite the favourable outcome, a wide spectrum of hepatitis B virus (HBV)-associated liver disease may develop, ranging from asymptomatic carriage to severe chronic active hepatitis or cirrhosis and even fulminant hepatic failure. The achievement of protective titres of anti-HBs through vaccination has been suggested to be protective against the development of de novo HBV infection. The results of vaccination in cirrhotic patients awaiting for liver transplant have been very disappointing. High-dose/short-term schedules have been tried in transplant candidates in order to increase the response rate. New and more immunogenic formulations (containing new adjuvants or additional pre-S1/pre-S2 recombinant antigens), and, more importantly, early vaccination of potential transplant candidates at earlier stages of their liver disease should further prevent de novo hepatitis B in transplant recipients.     

Fulminant hepatic failure

Opinion statement The rare but potentially devastating clinical syndrome of fulminant hepatic failure has as its components severe encephalopathy and finally cerebral edema, hemodynamic instability, renal failure, coagulopathy, profound metabolic disturbances and a particular susceptibility to bacterial and fungal infection. Despite advances in medical management, fulminant hepatic failure in its most severe form carries a high mortality rate unless urgent orthotopic liver transplantation is carried out. However, availability of cadaveric donor organs is limited and, due to the rapidly progressive clinical course in many cases, a substantial proportion of patients will die or develop contraindications to transplantation before the procedure can be performed. Consequently, recent interest has centred on living donor transplantation and the possibility of providing temporary liver support, either through auxiliary partial organ transplantation, extracorporeal perfusion or transplantation of hepatocytes, to allow time for either a liver graft to become available or native liver regeneration, on which spontaneous survival ultimately depends, to occur.     

History and prevention of de novo hepatitis B virus-related hepatitis in Japan and the world

Hepatitis B virus (HBV) replication has been shown to persist at low levels in the liver for decades, even in patients with resolved HBV infection. In these cases, reactivation of HBV and ensuing hepatitis during or after cytotoxic or immunosuppressive therapy is now recognized as de novo HBV-related hepatitis. The occurrence of de novo HBV-related hepatitis has become more frequent after the introduction of rituximab for the treatment of hematological disorders, such as malignant lymphomas. More alarmingly, reactivation can lead to fatal fulminant hepatic failure, indicating a need to establish guidelines to prevent the occurrence of de novo HBV-related hepatitis. It is possible that lamivudine prophylaxis and close surveillance of serum HBV DNA are effective in this regard. However, such measures are currently not available to hepatitis B surface antigen (HBsAg)-negative patients in Japan. A preliminary guideline for preventing HBV reactivation during and after cytotoxic or immunosuppressive therapies was made in 2008 by two collaborative study groups from the Japanese Ministry of Health, Labour, and Welfare, including measures not only for HBV carriers, but also for patients with resolved HBV infection. Since this recommendation is a tentative one, further testing and improvements are being planned.     

Acute fulminant hepatitis B in a patient with diabetic nephropathy treated successfully with concomitant lamivudine and molecular adsorbents recirculating system

A 36-year-old man with type 2 diabetes and diabetic nephropathy treated with hemodialysis developed hepatitis B virus (HBV)-induced acute fulminant hepatic failure (FHF). Despite supportive treatment, the condition rapidly progressed as manifested by severe jaundice, coagulopathy and hepatic coma. He was placed on the waiting list for liver transplantation and was treated with lamivudine and extracoporeal liver support with the molecular adsorbent recirculating system (MARS). After three 8-h sessions of MARS treatment in 1 week, he had remarkable improvement in clinical symptoms and serum biochemistry. On the 14th hospital day, surface antigen seroconversion was noted with undetectable hepatitis B virus surface antigen (HBs Ag) and low titre of anti-HBs antibody, indicating a complete recovery from acute fulminant hepatitis B. MARS treatment has been reported to benefit patients with liver failure from different causes including acute exacerbation of chronic hepatitis B, poisoning, post transplantation and Wilson's disease. The present case suggests its potential benefit when combined with lamivudine in treating uremic patients with acute fulminant hepatitis B.