Makiko Taniai

Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

We describe six patients with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). From 1990 to 2001, we treated 82 patients with NASH and observed six patients (three men and three women, aged 56-72 years) in this group who were referred with HCC or developed the complication during follow-up. In five of these six patients, NASH was associated with obesity (cases 3, 4 and 5), hyperlipidemia (case 5), or diabetes mellitus (cases 1, 3 and 6). We confirmed the presence of HCC by ultrasonography-guided tumor biopsy or surgery except in case 3 where we diagnosed the tumor by ultrasonography, computed tomography and selective hepatic arteriography. The carcinomas measured 1.5-6.0 cm in diameter and three were well differentiated. When HCC was diagnosed, cirrhosis was present in all instances. Four of the six tumor patients also had esophageal varices but only one patient had a history of variceal bleeding and ascites. Treatment of HCC consisted of surgery (cases 1 and 5), transcatheter arterial embolization or infusion and/or percutaneous ethanol injection (cases 2, 3, 4, and 6). In patients with NASH cirrhosis, the development of treatable HCC is sufficiently common to warrant regular screening for this grave complication.

Genome-wide Association Study Identifies TNFSF15 and POU2AF1 as Susceptibility Loci for Primary Biliary Cirrhosis in the Japanese Population

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84xa0× 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38xa0× 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined pxa0= 3.66xa0× 10(-8), 3.66xa0× 10(-9), and 3.04xa0× 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11xa0× 10(-6) and 1.42xa0× 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Hepatitis C virus antibody in patients with primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma) in Japan

Background. In hepatocellular carcinoma (HCC), a high prevalence of hepatitis C virus antibody (anti‐HCV) has been reported, indicating that it may be an important etiologic factor in the pathogenesis of HCC. In this study, the authors investigated the prevalence of anti‐HCV in HCC patients, as well as the same prevalence in patients with cholangiocarcinoma (CC) and combined hepatocellular–cholangiocarcinoma (combined HCC‐CC), to study the clinicopathologic features of anti‐HCV–positive cases.

Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by the histological features of steatohepatitis in the absence of significant alcohol consumption. The natural history of NASH is poorly defined. Here we report our experience with a patient to illustrate the clinical course of cirrhotic NASH. A 67-year-old woman was admitted with hematemesis due to the rupture of esophageal varices. Her varices were treated by endoscopic ligation and endoscopic sclerotherapy. Her medical history was unremarkable. Both the patient and her family members were asked about alcohol intake several times during her illness, but all of them denied a history of alcohol intake. She had insulin resistance, as determined by homeostasis model assessment. Serological tests for viral hepatitis were all negative. Viral hepatitis, autoimmune liver disease, iron overload, and metabolic liver disorders were all excluded. Imaging tests failed to reveal any steatosis, because of the presence of severe fibrosis. Liver biopsy showed moderate steatosis, moderate inflammation, ballooning degeneration, and Mallory bodies. We diagnosed NASH associated with cirrhosis based on the clinicopathological features. Almost 2 years later, she developed hepatocellular carcinoma (HCC) and she died of multiple HCCs. At autopsy, tumor invasion was seen throughout liver segment 8. The noncancerous liver showed burnt-out NASH; the steatosis, necroinflammation, ballooning degeneration, and Mallory bodies had all disappeared. In Japan, the prevalence of nonalcoholic fatty liver disease will increase as obesity has been increasing, so it is important to understand how to diagnose NASH. When a patient has NASH, careful follow-up should be performed.

Diagnosing autoimmune hepatitis in nonalcoholic fatty liver disease: is the International Autoimmune Hepatitis Group scoring system useful?

BackgroundThere are no surrogate serum markers for autoimmune hepatitis (AIH) and nonalcoholic fatty liver disease (NAFLD). An AIH scoring system was reported by the International Autoimmune Hepatitis Group; however, the criteria did not focus on making the distinction between AIH and NAFLD. We examined the effectiveness of using the AIH score for diagnosing AIH in NAFLD patients. We also identified the prevalence of autoimmune phenomena, in terms of various auto-antibodies, including antinuclear antibodies (ANA), to determine whether these markers had any clinicopathological significance, and whether they were related to the patients clinical courses.MethodsWe studied 212 patients (103 males and 109 females) with biopsy-proven NAFLD. The AIH score of each patient was calculated without including the liver biopsy results. The patients were divided into three groups based on their clinicopathological features: the overlap group (those with clinical and histological features of both NAFLD and AIH), the systemic group (those with systemic antoimmune disease other than AIH), and the “other” group (patients with no antoimmune disease). To evaluate the clinicopathological significance of ANA in NAFLD patients, those without autoimmune diseases (the “others” group) were classified according to their ANA positivity and ANA titer.ResultsSeventy patients (33.0%) were positive for ANA. Among the female patients, 106 patients (97.2%) had an AIH score of 10 or more. Of the 103 male patients, 21 (20.4%) had an AIH score of 10 or more. However, after liver biopsy, only 1 patient (0.5%) could be classified as “definite AIH.” In the NAFLD patients without autoimmune diseases (“other” group), multivariate logistic regression analysis found that female sex was an independent predictor of the presence of ANA (P = 0.029). In contrast, multivariate logistic regression analysis found that severe obesity (body mass index [BMI], ≥30u2009kg/m2) was the only independent predictor of the presence of an ANA titer of 1u2009:u200980 or more (P = 0.026).ConclusionsThe AIH score without liver biopsy findings was not useful for diagnosing AIH in NAFLD patients. In patients with elevated ANA titers and risk factors for NAFLD, it is very important to perform a liver biopsy to make a definitive diagnosis before treatment.

Autoantibody status and histological variables influence biochemical response to treatment and long‐term outcomes in Japanese patients with primary biliary cirrhosis

The aim of the present study is to evaluate the factors influencing biochemical response to treatment and the value of biochemical response for predicting long‐term outcomes in Japanese patients with primary biliary cirrhosis (PBC).

Long-term clinical outcome of living-donor liver transplantation for primary biliary cirrhosis.

Aim:u2002 We described the recurrence of primary biliary cirrhosis (PBC) after living donor liver transplantation (LDLT) (Liver Transplantation, 7, 2001: 588). However, since the follow‐up period in that study was insufficiently long (median 35.5 months), we performed a long‐term study to further characterize recurrence of PBC after LDLT.

Combined pantethine and probucol therapy for Japanese patients with non-alcoholic steatohepatitis

Aims:u2002 To evaluate the efficacy and mechanism of combined pantethine and probucol therapy in Japanese patients with non‐alcoholic steatohepatitis (NASH), liver function, serum cytokines, serum adiponectin and liver biopsy findings were investigated.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

&NA; A previous genome‐wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10‐9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Immunohistochemical characterization of hepatic lymphocytes in acute hepatitis, A, B, and C

The distinctive histologic findings in acute hepatitis A, B, and C suggest that different immunological mechanisms are involved in the pathogenesis of these diseases. This study was undertaken to define the immune response in each type of acute hepatitis by identification of the intrahepatic lymphocyte subsets. Thirty paraffin-embedded liver biopsy specimens from 10 patients with acute hepatitis A, 10 patients with acute hepatitis B, and 10 patients with acute hepatitis C were evaluated. Immunohistochemical staining was performed by the indirect immunoperoxidase technique using the following monoclonal or polyclonal antibodies: CD45RO, CD20-cy, CD57, and Mac387. Inflammatory infiltrates varied from specimen to specimen. However, CD45RO+ memory T cells were the predominant infiltrating mononuclear cells in all specimens. In the portal areas, CD45RO+ memory T cells were the most prominent in AHC, followed by AHA and AHB, and the difference between AHC and AHB was statistically significant. CD20-cy+ B cells were seen mainly in the portal areas, and were significantly less common in AHB than in AHA and AHC. In addition, the ratio of CD20-cy+ B cells to CD45RO+ memory was significantly lower in AHB than in the other types of acute hepatitis. The necrotic areas in all specimens contained mainly CD45RO+ memory cells in association with a few CD57+ NK and T cells or CD20-cy+ B cells. Our study revealed differences of the intrahepatic lymphocyte subsets among the various types of acute hepatitis, but the meaning of these differences is presently unknown. Therefore, further studies are required to fully elucidate the mechanism of the immune response in acute hepatitis.