Fulminant Hepatitis In Japan Research Articles

Acute liver failure in Japan: definition, classification, and prediction of the outcome.

Acute liver failure is a clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to severe impairment of liver function caused by massive or submassive liver necrosis. Viral hepatitis is the most important and frequent cause of acute liver failure in Japan. The diagnostic criteria for fulminant hepatitis, including that caused by viral infections, autoimmune hepatitis, and drug allergy induced-liver damage, were first established in 1981. Considering the discrepancies between the definition of fulminant hepatitis in Japan and the definitions of acute liver failure in the United States and Europe, the Intractable Hepato-Biliary Disease Study Group established the diagnostic criteria for “acute liver failure” for Japan in 2011, and performed a nationwide survey of patients seen in 2010 to clarify the demographic and clinical features and outcomes of these patients. According to the survey, the survival rates of patients receiving medical treatment alone were low, especially in those with hepatic encephalopathy, despite artificial liver support, consisting of plasma exchange and hemodiafiltration, being provided to almost all patients in Japan. Thus, liver transplantation is inevitable to rescue most patients with hepatic encephalopathy. The indications for liver transplantation had, until recently, been determined according to the guideline published by the Acute Liver Failure Study Group in 1996. Recently, however, the Intractable Hepato-Biliary Disease Study Group established a scoring system to predict the outcomes of acute liver failure patients. Algorithms for outcome prediction have also been developed based on data-mining analyses. These novel guidelines need further evaluation to determine their usefulness.

Diagnostic criteria of acute liver failure: A report by the Intractable Hepato‐Biliary Diseases Study Group of Japan

The diagnostic criteria of fulminant hepatitis in Japan are different from those of acute liver failure in Europe and the United States, both in regard to the histological features in the liver and the cutoff values of the prothrombin time. Thus, the Intractable Hepato-Biliary Disease Study Group established novel diagnostic criteria for "acute liver failure" in Japan based on the demographic and clinical features of the patients. Patients showing prothrombin time values of 40% or less of the standardized values or international normalized ratios of 1.5 or more caused by severe liver damage within 8 weeks of onset of the symptoms are diagnosed as having "acute liver failure", where the liver function prior to the current onset of liver damage is estimated to be normal. Acute liver failure is classified into "acute liver failure without hepatic coma" and "acute liver failure with hepatic coma," depending on the severity of the hepatic encephalopathy; the latter is further classified into two types, the "acute type" and the "subacute type", in which grade II or more severe hepatic coma develops within 10 days and between 11 and 56 days, respectively, after the onset of disease symptoms. Patients without histological findings of hepatitis, such as those with liver damage caused by drug toxicity, circulatory disturbance or metabolic disease, are also included in the disease entity of "acute liver failure", while acute-on-chronic liver injuries, such as liver injury caused by alcohol, are excluded. A nationwide survey of "acute liver failure" in Japan based on the novel criteria is proposed.

Changing etiologies and outcomes of acute liver failure: A perspective from Japan

Acute liver failure in Japan usually consists of fulminant hepatitis (FH) due to viral infection, autoimmune hepatitis and drug-allergy-induced liver injury. The annual incidence of FH was estimated at 429 cases in 2004. FH is classified into acute or subacute type, and the prognosis of the latter is poor. Hepatitis B virus (HBV) is the most frequently identifiable agent that causes FH in Japan. Transient HBV infection is more prevalent in the acute than subacute type, whereas the frequency of HBV carriers is greater in the subacute type. FH due to HBV reactivation from resolved hepatitis B has been increasingly observed in patients with malignant lymphoma treated with rituximab and corticosteroid combination therapy. The prognosis is poor in HBV carriers with acute exacerbation, especially in patients with HBV reactivation from resolved hepatitis B. Despite careful investigation, the etiology is still unknown in 16% and 39% of the acute and subacute type of FH, respectively. Autoimmune hepatitis and drug-allergy-induced liver injury are found in 7% and 10%, respectively, and are more frequently observed in the subacute type of FH. Living donor liver transplantation is now the standard care for individuals with poor prognosis. Artificial liver support with plasmapheresis and hemodiafiltration plays a central role while waiting for a donor liver or for the native liver to regenerate. Further research is necessary to identify the causes of unknown origin. In addition, to improve the prognosis of FH, it is necessary to establish treatment modalities that are effective for liver regeneration.

Clinical epidemiology of fulminant hepatitis in Japan

The annual incidence of fulminant hepatitis (FH) in Japan has decreased from 3700 patients in 1972 to 1000 patients in 1989, 1050 patients in 1995 and 426 in 2004. The most frequent cause of FH in Japan is hepatitis B virus (HBV)-related hepatitis, which accounts for around 40%, with hepatitis A accounting for around 10%; drug reaction accounts for around 10%; other hepatitis, including an unknown cause, accounts for around 40%. The acute type FH, which has a disease duration as 10 days or shorter before the development of encephalopathy (onset-coma days [OCD]), mainly consists of hepatitis A and B and has relatively better prognosis, with an approximately 40% survival rate without transplantation. The subacute type FH, which has 11 to 56 days OCD, mainly consists of unknown hepatitis including acute-onset autoimmune hepatitis and has poorer prognosis of about 20% survival. Approximately 25% of FH patients underwent liver transplantation and about 80% of them survived. High volume plasma exchange (PE) and hemodialysis filtration (HDF) have been the most common and principal therapies and they are administered to about 90% and 70% of patients, respectively. The progress of artificial liver support such as combination treatment of PE with HDF is considered to play a role in the slight improvement of the survival proportion of patients with acute type FH in recent years.

Severe Alcoholic Hepatitis in Japan: Prognosis and Therapy

Recently, the incidence of alcoholic liver disease (ALD) has been increasing in Japan; this associated with an increase in alcoholic beverage consumption. Multiple organ failures are frequently observed in patients with severe alcoholic hepatitis (AH), most of whom have a poor prognosis similar to fulminant hepatitis; as well numbers of severe AH patients appear to be increasing. Although prognosis of fulminant hepatitis in Japan has been recently improved by intensive treatments such as plasma exchange (PE) that of severe AH has not changed. The objective of this study was to determine whether there was any factor that could determine the prognosis of severe AH. We carried out nation-wide survey by asking hospitals certified by the Japanese Society of Gastroenterology and hospitals related to ours hospital for the current status of patients seen with severe alcoholic hepatitis since 1998. We investigated correlations between various factors including blood laboratory data, presence of other organ failure, and prognosis. Mortality of patients with severe AH was high (66.4%). The ratio of female patients with severe AH (26%) was higher than that for other ALD (approximately 10%). Mean age was older (Alive: 44 +/- 11; Dead: 50 +/- 11 years old), white blood cell (WBC) counts were higher (11600 +/- 5200; 21800 +/- 13400/microl), red blood cell counts were lower (320 +/- 95; 265 +/- 72 x 10/microl) and prothrombin time (PT) was prolonged (36.2 +/- 10.4; 29.1 +/- 9.4%, respectively) in patients who had died than in patients who had survived. However, as all differences diminished after carrying out PE, we analyzed data in patients without PE. The results were similar to those in all patients. Prevalence of infection, gastrointestinal (GI) bleeding and disseminated intravascular coagulation (DIC) was higher in patients who had died. Although intensive treatments such as PE, hemodialysis, and anticoagulation therapy did not change the prognosis of severe AH, PE improved the prognosis of patients without either GI bleeding or DIC. WBC counts were also slightly higher in patients who had died after carrying out PE. Two cases had been cured by granulocytapheresis (GCAP) CONCLUSIONS: PE can compensate for and reduce the risk due to prolonged PT in patients with severe AH. These results suggest that the patients with markedly elevated WBC counts, prolonged PT, or anemia should, if possible, be treated at an earlier stage with an intensive treatment such as PE, hemodialysis, or anticoagulation therapy before infection, GI bleeding or DIC occurs. Further, GCAP might be useful for severe AH patients with higher WBC counts.

Clinical epidemiology of fulminant hepatitis in Japan before the substantial introduction of liver transplantation: an analysis of 1309 cases in a 15-year national survey

BACKGROUND:: The low incidence of fulminant hepatitis (FH) makes it difficult to accurately assess its viral etiology and clinical characteristics. Additionally, the therapeutic options for FH have markedly changed over the years because of the substantial introduction of living-donor liver transplantation. AIM:: To analyze and summarize a large-scale national survey on FH in the pretransplantation era in Japan. METHOD:: An analysis of answers to an annual questionnaire sent to 313 centers for liver diseases in Japan between 1983 and 1997. RESULTS:: During the study period, 1309 patients were registered as having fulminant hepatitis. The causes of FH were: hepatitis A virus (HAV) in 7.8%, hepatitis B virus (HBV) in 23.8%, probable HBV (positive for serum HBs antigen or HBV DNA and negative for the IgM anti-hepatitis B core antibody) in 13.8%, non-A, non-B hepatitis in 29.3%, drug-induced in 9.3, and unknown in 16.0% of these patients. The incidence of HBV-related cases did not decrease during the study period. The acute type had a significantly better prognosis than the subacute type (survival rate, 36.2% versus 15.3%, P < 0.001). The survival rate tended to improve in the third 5-year period for the acute type (28.6% [1983-1987] versus 43.3% [1994-1997]), but not for the subacute type (15.4% versus 12.3%). CONCLUSIONS:: HBV remains a major cause of fulminant hepatitis in Japan. New therapeutic modalities, including liver transplantation, are required for improving the prognosis, in particular, for the subacute type of fulminant hepatitis.

Full-Length Sequences of Six Hepatitis E Virus Isolates of Genotypes III and IV from Patients with Sporadic Acute or Fulminant Hepatitis in Japan

Objective: Ranges of variation and conservation in sequence need to be defined for detecting and genotyping hepatitis E virus (HEV). Methods: Six HEV isolates from Japanese patients were sequenced over the entire genome and compared phylogenetically along with 16 reported HEV isolates, including two from pigs. Results: Three of the six HEV isolates were of genotype III, and the remaining three were of genotype IV. Local clusterings of Japanese HEV isolates were observed in the phylogenetic analyses, including a swine HEV isolate reported previously (swJ570). All six HEV isolates possessed three open reading frames (ORFs). The ORF3 in the three isolates of genotype III were in a different reading frame, while that in the three isolates of genotype IV were in the same reading frame as ORF1. A stretch of 46–96 nucleotides was identified, point mutations and deletions in which were specific for the four genotypes (I–IV). A polymerase chain reaction method was developed with 9 nested universal primers, deduced from conserved regions in the 5′-terminal sequences of the 22 HEV genomes. Conclusions: Conserved and genotype-specific variation in HEV sequences, identified in the comparison of 22 full-length genomes, would be useful in designing primers for sensitive detection and specific genotyping of HEV RNA.

Human herpesvirus 6 from patients with NANBNC fulminant hepatitis in Japan

Human herpesvirus 6 from patients with NANBNC fulminant hepatitis in Japan

我が国における劇症肝炎の治療の現況と将来

我が国における劇症肝炎の治療の現況と将来

Detection of GBV-C RNA in patients with non-A-E fulminant hepatitis by reverse-transcription polymerase chain reaction.

GBV-C might be a causative agent of fulminant hepatitis of unknown etiology. Fulminant hepatitis is an indication for liver transplantation. However, in Japan, because of the legal difficulties associated with cadaveric donation, patients with fulminant hepatitis are still treated by plasmapheresis and multiple transfusions of fresh frozen plasma. So, the possibility that GBV-C might be transmitted by transfusions after the onset of fulminant hepatitis is real. Therefore, we have examined the possible role of GBV-C in non-A-E fulminant hepatitis. Nine patients with non-A-E fulminant hepatitis and one with non-A-E late onset hepatic failure were examined. Sera were obtained from the patients at admission before any blood or blood products were given, and again after transfusions. GBV-C RNA was detected by nested reverse transcription polymerase chain reaction with primers based on the reported sequence. GBV-C RNA was negative in all 10 pretransfusion patients with non-A-E fulminant hepatitis or late onset hepatic failure. Then, fresh frozen plasma was transfused to these patients, and four of them became seropositive. GBV-C is unlikely to be a major etiologic agent for non-A-E fulminant hepatitis in Japan.

Hepatitis C virus infection involved in fulminant hepatitis in Japan

Serum samples obtained from 32 patients with fulminant hepatitis (FH) of varying etiology were tested for anti-hepatitis C virus antibody (anti-HCV) and HCV RNA. Both anti-HCV and HCV RNA were detected in one of eight patients (13%) with FH due to hepatitis A virus (HAV) and three of nine hepatitis B virus (HBV)-induced FH patients (33%) in serum samples obtained prior to plasma exchange therapy and blood transfusion. Of the four patients positive for anti-HCV, three had an anti-HCV exceeding the cut-off index of 5.00. On the other hand, all 15 patients with non-A, non-B FH were negative for anti-HCV in the initial samples. However, HCV RNA was detected in four of the 15 patients (27%) negative for anti-HCV. These results strongly suggest that acute HCV infection may exist in some patients with non-A, non-B FH. Moreover, it is suggested that superinfection of HAV or HBV to HCV carrier may enhance the risk of FH in some patients.

Contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan

To assess the contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan, we compared 10 major clinical features among 7 patients with type B fulminant hepatitis (type B group), 13 patients with non-A, non-B fulminant hepatitis with evidence of hepatitis C virus infection (type C group) and 10 patients without evidence of hepatitis C virus infection (NANB group). Duration from first symptom to coma and that from onset of jaundice to coma was significantly longer in the type C group (median = 39 and 25 days, respectively) and in the non-A, non-B group (median = 29 and 12 days, respectively) than in the type B group (median = 9 and 2 days, respectively) (p < 0.01). The maximum median AST level was significantly lower in the type C (1,689 U/L) and non-A, non-B groups (1,353 U/L) than in the type B group (5,780 U/L) (p < 0.05). Serum transaminase levels showed a single peak in six of seven of the type B patients, whereas they formed two or more peaks in all of the type C patients and in most of the non-A, non-B group (p < 0.05). Six of seven in the type B group, 6 of 13 in the type C group and 4 of 10 in the non-A, non-B group survived (p < 0.05). We found no significant difference in any of the 10 clinical features between the type C and non-A, non-B groups. Compared with type B fulminant hepatitis, type C and most cases of non-A, non-B fulminant hepatitis in Japan are, thus, characterized by slower and less severe but more persistent hepatocyte destruction. (HEPATOLOGY 1994;19:829–835.)

Contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan

To assess the contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan, we compared 10 major clinical features among 7 patients with type B fulminant hepatitis (type B group), 13 patients with non-A, non-B fulminant hepatitis with evidence of hepatitis C virus infection (type C group) and 10 patients without evidence of hepatitis C virus infection (NANB group). Duration from first symptom to coma and that from onset of jaundice to coma was significantly longer in the type C group (median = 39 and 25 days, respectively) and in the non-A, non-B group (median = 29 and 12 days, respectively) than in the type B group (median = 9 and 2 days, respectively) (p < 0.01). The maximum median AST level was significantly lower in the type C (1,689 U/L) and non-A, non-B groups (1,353 U/L) than in the type B group (5,780 U/L) (p < 0.05). Serum transaminase levels showed a single peak in six of seven of the type B patients, whereas they formed two or more peaks in all of the type C patients and in most of the non-A, non-B group (p < 0.05). Six of seven in the type B group, 6 of 13 in the type C group and 4 of 10 in the non-A, non-B group survived (p < 0.05). We found no significant difference in any of the 10 clinical features between the type C and non-A, non-B groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation.

Hepatitis B virus (HBV) variants with precore mutation(s) resulting in the absence of HBeAg production have been associated with the occurrence of fulminant hepatitis in Japan, Israel, and southern Europe, where the prevalence of this HBV strain appears common. In areas such as United States, where HBV infection is not endemic, the role of this mutant virus in fulminant hepatitis is unknown. We developed an amplification refractory mutation detection system to detect specifically the presence of the G to A mutation at nucleotide position 1898, which is the most frequently observed mutation resulting in a precore stop codon. In addition, this method provided a quantitative measurement of the relative ratio of one strain to the other. Using this system, we tested HBV strains for the presence of the stop codon mutation in sera from 40 cases of fulminant hepatitis B occurring in the United States. Serum HBV DNAs from 28 patients were analyzed successfully. A mixture of wild-type and mutant strains in various ratios were observed in 15 patients, wild type exclusively in 11, and mutant exclusively in 2. Four of these patients had undergone liver transplantation for HBV-associated cirrhosis and developed fulminant HBV-associated hepatitis after transplantation. Pre- and posttransplant serum samples from one patient were analyzed: a mixture of wild-type and mutant HBV strains was detected in both samples. Our study demonstrated that both wild-type and mutant HBV strains are associated with fulminant hepatitis, and that in some patients in the United States, factors other than precore mutations contribute to the development of fulminant hepatitis.

The present-day status of exchange blood transfusion and ACTH &amp; corticosteroid therapy on fulminant hepatitis in Japan

The present-day status of exchange blood transfusion and ACTH &amp; corticosteroid therapy on fulminant hepatitis in Japan