Nobuaki Nakayama

Fulminant hepatitis and late onset hepatic failure in Japan

Aim:  A nationwide survey was performed to clarify the present state of fulminant hepatitis and late onset hepatic failure (LOHF) between 1998 and 2003 in Japan.

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

To summarize the annual nationwide survey on fulminant hepatitis (FH) and late‐onset hepatic failure (LOHF) between 2004 and 2009 in Japan.

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.

Outcomes After Living Donor Liver Transplantation for Acute Liver Failure in Japan: Results of a Nationwide Survey

Nationwide surveys of acute liver failure (ALF) are conducted annually in Japan, and 20% of patients with ALF undergo liver transplantation (LT). We extracted data for 212 patients who underwent LT for ALF from the nationwide survey database of the Intractable Liver Diseases Study Group of Japan. After the exclusion of 3 patients who underwent deceased donor LT, 209 recipients of living donor liver transplantation (LDLT) were analyzed. ALF patients were placed into 3 subgroups according to the time from the onset of the disease to the occurrence of encephalopathy: patients who presented with encephalopathy within 10 days of the diseases onset were classified as having acute ALF, patients who presented within 11 to 56 days were classified as having subacute ALF, and patients who presented within 9 to 24 weeks were classified as having late‐onset hepatic failure (LOHF). Long‐term follow‐up data were obtained from the registry of the Japanese Liver Transplantation Society. The 2 data sets were merged, and descriptive and survival data were analyzed. A Cox regression analysis was performed to define factors predicting overall mortality, short‐term mortality (≤90 days after LT), and long‐term mortality (>90 days after LT). One hundred ninety of the analyzed patients (91%) were adults (age ≥ 18 years); 70 patients (34%) were diagnosed with acute ALF, 124 (59%) were diagnosed with subacute ALF, and 15 (7%) were diagnosed with LOHF. Hepatitis B virus was the most common cause of acute ALF (61%), whereas autoimmune hepatitis (14%) and drug allergy–induced hepatitis (14%) were more frequent in patients with subacute ALF or LOHF. The cumulative patient survival rates 1, 5, and 10 years after LT were 79%, 74%, and 73%, respectively. Patient age was associated with short‐ and long‐term mortality after LT, whereas ABO incompatibility affected short‐term mortality, and donor age affected long‐term mortality. In conclusion, the long‐term outcomes of LDLT for ALF in this study were excellent, regardless of the etiology or classification. The majority of the donors were living donors. Increasing the deceased donor pool might be an urgent necessity. Liver Transpl, 2012.

Case–control study for the identification of virological factors associated with fulminant hepatitis B

Background:  Host and viral factors can promote the development of fulminant hepatitis B (FHB), but there have been no case–control studies for figuring out virological parameters that can distinguish FHB.

Re-evaluation of the Guideline published by the Acute Liver Failure Study Group of Japan in 1996 to determine the indications of liver transplantation in patients with fulminant hepatitis

Aim:  The indications for liver transplantation in cases of fulminant hepatitis are currently determined according to the Guideline of the Acute Liver Failure Study Group of Japan in 1996, which is based on assessment of the prognosis of the patients at the onset of hepatic encephalopathy and reassessed 5 days later. This Guideline was prepared based on the clinical findings in patients seen between 1988 and 1992, and showed a predictive accuracy of 82% in the patients seen between 1993 and 1995. In this study, the usefulness of the Guideline was re‐evaluated, since the therapeutic strategies for fulminant hepatitis have advanced remarkably over the last 10 years.

Novel scoring system as a useful model to predict the outcome of patients with acute liver failure: Application to indication criteria for liver transplantation.

Aim:  In Japan, the indication for liver transplantation in patients with acute liver failure (ALF) is currently determined according to the guideline published in 1996. However, its predictive accuracy has fallen in recent patients. Thus, we attempted to establish a new guideline.

Development of rare resistance-associated variants that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy by a two-hit mechanism

The virologic characteristics of resistance‐associated variants (RAVs) developing in patients receiving dual oral therapy with daclatasvir/asunaprevir, including those with previous triple therapy with simeprevir, were evaluated.

Development of rare RAVs that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy Via a Two-Hit mechanism.

The virologic characteristics of resistance‐associated variants (RAVs) developing in patients receiving dual oral therapy with daclatasvir/asunaprevir, including those with previous triple therapy with simeprevir, were evaluated.