Detection of bacterial DNA by in situ hybridization in patients with decompensated liver cirrhosis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is often difficult to diagnose because bacteria in ascites cannot be detected accurately by conventional culture. In situ hybridization (ISH) was previously developed for rapid detection of genes from bacteria phagocytized by neutrophils. SBP may develop after bacteria enter into the systemic circulation following bacterial translocation. Therefore, we performed ISH to identify bacteria in blood samples collected from patients with decompensated liver cirrhosis (LC). METHODS: In this retrospective study, peripheral blood samples were collected from 60 patients with decompensated LC, and bacteria were detected by both blood culture and ISH. Moreover, 35 patients underwent paracentesis for diagnosis of SBP. RESULTS: Eight of 35 patients were diagnosed with SBP by polymorphonuclear neutrophil counts, and one patient was diagnosed with bacterascites. Seven of the nine patients showed positive results for ISH, whereas bacteria were detected in only two cases by blood culture. Thirty-seven of 60 cases (62%) showed positive results for ISH, whereas only six samples (10%) were positive by blood culture analysis. Compared with the 23 cases of negative ISH, the 37 cases of positive ISH showed a higher frequency of fever, higher Child-Pugh scores, and lower albumin levels. CONCLUSIONS: Detection of bacteria by ISH suggested that bacterial translocation, which cannot be proven by conventional culture, occurred in these patients, and that ISH could be helpful for the early diagnosis of some types of infection and prevention of SBP in these patients.

Continuous Regional Arterial Infusion of Protease Inhibitors Has No Efficacy in the Treatment of Severe Acute Pancreatitis: A Retrospective Multicenter Cohort Study.

OBJECTIVE: The aim of this study is to assess the effectiveness of continuous regional arterial infusion (CRAI) of protease inhibitors in patients with severe acute pancreatitis (SAP) including acute necrotizing pancreatitis. METHODS: This retrospective study was conducted among 44 institutions in Japan from 2009 to 2013. Patients 18 years or older diagnosed with SAP according to the criteria of the Japanese Ministry of Health, Labour and Welfare study group (2008) were consecutively enrolled. We evaluated the association between CRAI of protease inhibitors and mortality, incidence of infection, and the need for surgical intervention using multivariable logistic regression analysis. RESULTS: Of 1159 patients admitted, 1097 patients with all required data were included for analysis. Three hundred and seventy-four (34.1%) patients underwent CRAI of protease inhibitors and 723 (65.9%) did not. In multivariable analysis, CRAI of protease inhibitors was not associated with a reduction in mortality, infection rate, or need for surgical intervention (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.47-1.32, P = 0.36; OR 0.97, 95% CI 0.61-1.54, P = 0.89; OR 0.76, 95% CI 0.50-1.15, P = 0.19; respectively). CONCLUSIONS: Continuous regional arterial infusion of protease inhibitors was not efficacious in the treatment of patients with SAP.

Simeprevir/pegylated interferon/ribavirin triple therapy for recurrent hepatitis C after living donor liver transplantation.

AIM: Simeprevir (SMV) is a protease inhibitor which demonstrates good tolerability and high antiviral response in patients with hepatitis C. The clinical outcomes of triple therapy using simeprevir, pegylated interferon and ribavirin (SMV/PEG IFN/RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT) have not been well reported. In this study, we assessed the outcomes of patients with recurrent hepatitis C (genotype 1) after LDLT who received triple therapy at our hospital. METHODS: SMV/PEG IFN/RBV was administrated for 12 weeks (triple therapy), followed by another 12 weeks or extended period of PEG IFN/RBV (dual therapy). Virological response, interaction with calcineurin inhibitors and adverse events were retrospectively analyzed. RESULTS: Ten patients with recurrent hepatitis C after LDLT completed 12 weeks of triple therapy. Nine patients achieved rapid or early virological response, and one patient was a non-responder. The nine responders received subsequent dual therapy, and the duration of dual therapy was extended (24 to 36 weeks) in five cases. Although one patient was in relapse 8 weeks after completing the standard duration (12 weeks) of dual therapy, eight patients achieved sustained virological response for 12 weeks (SVR12). The SVR12 rate was 80%. Trough levels of calcineurin inhibitor did not show marked changes after introduction of SMV in all cases. There were no major adverse events associated with SMV. CONCLUSION: SMV treatment may be a safe and effective option for recurrent hepatitis C after LDLT.

Ampullary Adenoma Treated by Endoscopic Double-Snare Retracting Papillectomy.

We report herein improved methods for the safe and successful completion of endoscopic papillectomy (EP). Between January 2008 and November 2011, 12 patients underwent double-snare retracting papillectomy for the treatment of lesions of the major duodenal papilla. The main outcomes were en bloc resection rates, pathological findings, and adverse events. All of the patients (mean age, 60.1 years; range, 38 to 80 years) were diagnosed with ampullary adenoma by endoscopic forceps biopsies prior to endoscopic snare papillectomy. En bloc resection by double-snare retracting papillectomy was successfully performed for all lesions (median size, 12.3 mm), comprising six tubular adenomas, one tubulovillous adenoma, three cases of epithelial atypia, one hamartomatous polyp, and one case of duodenitis with regenerative change. Significant hemorrhage and pancreatitis were observed in one case after EP. Adenoma recurrence occurred in three patients during follow-up (median, 28.5 months) at a mean interval of 2 months postoperatively (range, 1 to 3 months). No serious adverse events were observed. Double-snare retracting papillectomy is effective and feasible for treating lesions of the major duodenal papilla. Further treatment experience, including a single-arm phase II study, needs to be accumulated before conducting a randomized controlled study.

Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C.

Hepatitis C virus (HCV) genotype 1 infections are significantly more difficult to eradicate with PEG-IFN/ribavirin therapy, compared to HCV genotype 2. The aim of this work is to investigate the difference of immunological impairments underlying this phenomenon. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes and CD56+CD3- NK cells from cases of chronic hepatitis C were analyzed and assessed by treatment effect. Two strains of HCV were used to co-incubate with immune cells in vitro. NKG2D expression on peripheral CD56+CD3+ lymphocytes, but not NK cells, was significantly impaired in genotype 1 infection, compared to genotype 2. When peripheral blood mononuclear cells from healthy donors were co-incubated with TNS2J1, a genotype 1b/2a chimera strain, or with JFH1, a genotype 2a strain, genotype-specific decrease of NKG2D on CD56+CD3+ lymphocytes, but not NK cells, was observed.　Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes significantly correlated with reduction in serum HCV RNA levels from week 0 to week 4, and predicted treatment response. Ex vivo stimulation of peripheral CD56+CD3+ lymphocytes showed NKG2D expression-correlated IFN-γ production. In conclusion, Decreased NKG2D expression on CD56+CD3+ lymphocytes in chronic HCV genotype 1 infection predicts inferior treatment response to PEG-IFN/ribavirin therapy compared to genotype 2.

[Diagnostic accuracy for alcoholic liver disease with controlled Attenuation Parameter (CAP) measured by transient elastography for the non-invasive assessment of liver steatosis].

Along with the development of interferon and therapeutic medication, the incidence of viral hepatitis constituting the largest part of liver disease decreased, and the main target in the field of liver disease is now shifting from viral hepatitis to alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) as metabolic liver disease. Although these diseases tend.to. be gathered as non-viral liver disease because the similar specific liver tissue, the natural history and etiology are considerably different between them. We need to distinguish both of them to do appropriate treatment intervention. Questioning of amount of drinking is needed, but we experience some difficult cases to understand drinking history because of a too little declaration of amount of drinking. A new ultrasonic image analyses using propagation speed in the organization of the pulse vibration wave was developed as Fibroscan by Echosens company in recent years. Fibroscan is a non-invasive test to quantify liver fibrosis as Liver Stiffness Measurement (LSM). It also detects and quantifies steatosis simultaneously using the Controlled Attenuation Parameter (CAP). CAP is a measurement of the ultrasound attenuation. We measured liver steatosis of patients using Fibroscan, and other blood tests. 63 cases of ALD, 177 cases of NAFLD, 57 cases of Virus and 271 cases of Normal were enrolled. CAP value were significantly lower in the ALD group compared with NAFLD group. (P < 0.0053, ALD 268 dB/m : NAFLD 290 dB/m) We elucidate the diagnostic accuracy of CAP using Fibroscan for ALD patients, comparing the results of them to those of virus patients and NAFLD patients.

Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus.

Most of experiments for HCV infection have been done using lytic infection systems, in which HCV-infected cells inevitably die. Here, to elucidate metabolic alteration in HCV-infected cells in a more stable condition, we established an HCV-persistently-infected cell line, designated as HPI cells. This cell line has displayed prominent steatosis and supported HCV infection for more than 2 years, which is the longest ever reported. It enabled us to analyze metabolism in the HCV-infected cells integrally combining metabolomics and expression arrays. It revealed that rate-limiting enzymes for biosynthesis of cholesterol and fatty acids were up-regulated with actual increase in cholesterol, desmosterol (cholesterol precursor) and pool of fatty acids. Notably, the pentose phosphate pathway was facilitated with marked up-regulation of glucose-6-phosphate dehydrogenase, a rete-limiting enzyme, with actual increase in NADPH. In its downstream, enzymes for purine synthesis were also up-regulated resulting in increase of purine. Contrary to common cancers, the TCA cycle was preferentially facilitated comparing to glycolysis pathway with a marked increase of most of amino acids. Interestingly, some genes controlled by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master regulator of antioxidation and metabolism, were constitutively up-regulated in HPI cells. Knockdown of Nrf2 markedly reduced steatosis and HCV infection, indicating that Nrf2 and its target genes play important roles in metabolic alteration and HCV infection. In conclusion, HPI cell is a bona fide HCV-persistently-infected cell line supporting HCV infection for years. This cell line sustained prominent steatosis in a hypermetabolic status producing various metabolites. Therefore, HPI cell is a potent research tool not only for persistent HCV infection but also for liver metabolism, overcoming drawbacks of the lytic infection systems.

Classification of the etiologies of acute liver failure in Japan: A report by the Intractable Hepato-Biliary Diseases Study Group of Japan.

The Intractable Liver Diseases Study Group of Japan, supported by the Ministry of Health, Labor and Welfare, established novel diagnostic criteria for "acute liver failure" in 2011. In these criteria, patients without histological findings of hepatitis are included in the disease entity of "acute liver failure", as in Europe and the USA. In this report, classification criteria for the etiologies of "acute liver failure" in Japan are proposed.

Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier.

A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30 years ago. He was diagnosed with renal cell carcinoma when he was 57 years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers.

CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion.

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: Summary of the annual nationwide survey between 2004 and 2009.

AIM: To summarize the annual nationwide survey on fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) between 2004 and 2009 in Japan. METHODS: The annual survey was performed in a two-step questionnaire process to detail the clinical profile and prognosis of patients in special hospitals. RESULTS: Four hundred and sixty (n = 227 acute type; n = 233 subacute type) patients had FH and 28 patients had LOHF. The mean age of patients with FH and LOHF were 51.1 ± 17.0 and 58.0 ± 14.4 years, respectively. The causes of FH were hepatitis A virus in 3.0%, hepatitis B virus (HBV) in 40.2%, other viruses in 2.0%, autoimmune hepatitis in 8.3%, drug allergy-induced in 14.6% and indeterminate etiology in 29.6% of patients. HBV reactivation due to immunosuppressive therapy was observed in 6.8% of FH patients. The short-term survival rates of patients without liver transplantation (LT) were 48.7% and 24.2% for the acute and subacute type, respectively, and 13.0% for LOHF. The prognosis was poor in patients with HBV reactivation. The implementation rate for LT in FH patients was equivalent to that in the previous survey. The short-term survival rates of total patients, including LT patients, were 54.2% and 40.8% for the acute and subacute type, respectively, and 28.6% for LOHF. CONCLUSION: The demographic features and etiology of FH patients has gradually changed. HBV reactivation due to immunosuppressive therapy is problematic. Despite advances in therapeutic approaches, the prognosis of patients without LT has not improved.

Obesity, type 2 diabetes, age, and female gender: significant risk factors in the development of alcoholic liver cirrhosis.

BACKGROUND: Recent epidemiological studies show that alcoholic liver cirrhosis (ALC) continues to increase in spite of a gradual decrease in the alcohol intake beyond 1999, indicating that there are other risk factors for the development of ALC. METHODS: A nationwide survey of liver cirrhosis (LC) was undertaken by asking major hospital institutions to provide the number of patients with LC admitted between 2007 and 2008 together with their etiologic findings including the daily intake of alcohol, period of drinking, and other relevant demographic measurements. RESULTS: The intake of alcohol in female ALC patients was lower together with a shorter drinking period versus male patients. The prevalence of diabetes mellitus (DM) in ALC patients was higher in habitual drinkers (<110 g/day) than in heavy drinkers (≥110 g/day), 49.5 versus 20.3%, respectively (P < 0.001). In male ALC patients, the prevalence of DM was higher in habitual drinkers, 55.2 versus 20.6% for the female gender (P < 0.001). The same tendency was seen in patients with a body mass index ≥25. The prevalence of obesity was higher in habitual drinkers than in heavy drinkers, 49.7 versus 31.1%, respectively. More than 90% of the male habitual drinkers either had DM or were obese, whereas less than half of the female habitual drinkers had a concomitant complication. More than 70% of the male ALC patients were over 60 years. CONCLUSION: Obesity, DM, age, and female gender appear to be additional significant risk factors for ALC. Our impression is that these additional risk factors might help to identify alcoholic patients who may progress to ALC even without excessive alcohol intake.

MyD88-dependent interleukin-10 production from regulatory CD11b⁺Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice.

We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88⁻/⁻ mice administered cerulein developed severe pancreatitis as compared with MyD88⁺/⁺ WT mice. The number of IL-10-expressing CD11b⁺Gr-1(high) cells in cerulein-administered MyD88⁻/⁻ mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4⁺ T cells as compared with that in control MyD88⁺/⁺ mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis.

CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice.

BACKGROUND & AIMS: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein- and L-arginine-induced acute pancreatitis in mice. METHODS: Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages. RESULTS: Almost all types of immune cells, except for CD11b(high)CD11c(-) cells, were detected in the pancreas of healthy mice. However, activated CD11b(high)CD11c(-) cells, including Gr-1(low) macrophages and Gr-1(high) cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2(-/-) mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b(high)CD11c(-)Gr-1(low) macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b(high)CD11c(-)Gr-1(low) macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1(low) macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b(high)CD11c(-)Gr-1(low) macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2. CONCLUSIONS: Cerulein induction of pancreatitis in mice involves migration of CD11b(high)CD11c(-)Gr-1(low) macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3-dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.

Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis.

Mesenteric venous thrombosis is an insidious disease, with a high mortality rate typically attributed to the long delay in diagnosis. Rapid diagnosis and treatment are important. Here, we present a patient with idiopathic inferior mesenteric venous (IMV) thrombosis. A 65-year-old man presented with constant abdominal pain associated with fever and bloody diarrhea. He was diagnosed with severe ulcerative colitis and was treated with mesalazine and prednisolone. The prednisolone was tapered because of liver dysfunction, and he received total parenteral nutrition for a month. His abdominal pain and bloody diarrhea worsened, and he lost 5 kg of weight. He was then transferred to our institute. Computed tomography showed thickening of the left colon. Colonoscopy showed diffuse colitis with multiple ulcers, large edematous folds, congested mucosa, and stenosis of the sigmoid colon, with sparing of the rectum, raising the possibility of IMV thrombosis. Angiography confirmed IMV thrombosis. Anticoagulation therapy was initiated with intravenous heparin followed by oral warfarin. His abdominal pain and diarrhea resolved, and he was discharged from hospital. Six months later, he remained asymptomatic with normal colonoscopic findings.

Hemobilia due to biliary intraepithelial neoplasia associated with Zollinger-Ellison syndrome.

A 58-year-old man was transferred to us from his local hospital because of failure to control his gastrointestinal bleeding by endoscopic hemostasis. Abdominal imaging suggested a hypervascular tumor of the pancreatic head (36 mm diameter), and laboratory testing showed an elevated serum gastrin level (17,800 pg/mL). Gastroduodenal endoscopy revealed multiple duodenal ulcers and active bleeding from the ampulla of Vater. The selective arterial secretagogue injection test suggested a gastrinoma in the pancreatic head, but no gastrinoma in the pancreatic tail. The patient was diagnosed with solitary pancreatic head gastrinoma complicated by hemosuccus pancreaticus, and pancreaticoduodenectomy was performed. Intraoperatively, the diagnosis was changed to primary peripancreatic lymph node gastrinoma without pancreatic involvement. The gastrointestinal bleeding stopped postoperatively and serum gastrin levels returned to normal. Histological examination of the surgical specimens revealed a small submucosal gastrinoma in the duodenum (7 mm diameter). The final diagnosis was microgastrinoma of the duodenum with peripancreatic lymph node metastasis. The cause of bleeding from the ampulla of Vater was initially obscure, but eventually a hemorrhagic erosion with moderate atypia was found in the common bile duct, indicating biliary intraepithelial neoplasia (BilIN). This is the first report of hemobilia due to BilIN with gastrinoma.

Prediction of effect of pegylated interferon alpha-2b plus ribavirin combination therapy in patients with chronic hepatitis C infection.

Treatment with pegylated interferon alpha-2b (PEGIFN) plus ribavirin (RBV) is standard therapy for patients with chronic hepatitis C. Although the effectiveness, patients with high titres of group Ib hepatitis C virus (HCV) respond poorly compared to other genotypes. At present, we cannot predict the effect in an individual. Previous studies have used traditional statistical analysis by assuming a linear relationship between clinical features, but most phenomena in the clinical situation are not linearly related. The aim of this study is to predict the effect of PEG IFN plus RBV therapy on an individual patient level using an artificial neural network system (ANN). 156 patients with HCV group 1b from multiple centres were treated with PEGIFN (1.5 µg/kg) plus RBV (400-1000 mg) for 48 weeks. Data on the patients' demographics, laboratory tests, PEGIFN, and RBV doses, early viral responses (EVR), and sustained viral responses were collected. Clinical data were randomly divided into training data set and validation data set and analyzed using multiple logistic regression analysis (MLRs) and ANN to predict individual outcomes. The sensitivities of predictive expression were 0.45 for the MLRs models and 0.82 for the ANNs and specificities were 0.55 for the MLR and 0.88 for the ANN. Non-linear relation analysis showed that EVR, serum creatinine, initial dose of Ribavirin, gender and age were important predictive factors, suggesting non-linearly related to outcome. In conclusion, ANN was more accurate than MLRs in predicting the outcome of PEGIFN plus RBV therapy in patients with group 1b HCV.

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.