Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project.

The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy.

PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.

Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design.

BACKGROUND: With the goal of realizing genome-based personalized healthcare, we have developed a biobank that integrates personal health, genome, and omics data along with biospecimens donated by volunteers of 150,000. Such a large-scale of data integration involves obvious risks of privacy violation. The research use of personal genome and health information is a topic of global discussion with regard to the protection of privacy while promoting scientific advancement. The present paper reports on our plans, current attempts, and accomplishments in addressing security problems involved in data sharing to ensure donor privacy while promoting scientific advancement. METHODS: Biospecimens and data have been collected in prospective cohort studies with the comprehensive agreement. The sample size of 150,000 participants was required for multiple researches including genome-wide screening of gene by environment interactions, haplotype phasing, and parametric linkage analysis. RESULTS: We established the T ohoku M edical M egabank (TMM) data sharing policy: a privacy protection rule that requires physical, personnel, and technological safeguards against privacy violation regarding the use and sharing of data. The proposed policy refers to that of NCBI and that of the Sanger Institute. The proposed policy classifies shared data according to the strength of re-identification risks. Local committees organized by TMM evaluate re-identification risk and assign a security category to a dataset. Every dataset is stored in an assigned segment of a supercomputer in accordance with its security category. A security manager should be designated to handle all security problems at individual data use locations. The proposed policy requires closed networks and IP-VPN remote connections. CONCLUSION: The mission of the biobank is to distribute biological resources most productively. This mission motivated us to collect biospecimens and health data and simultaneously analyze genome/omics data in-house. The biobank also has the mission of improving the quality and quantity of the contents of the biobank. This motivated us to request users to share the results of their research as feedback to the biobank. The TMM data sharing policy has tackled every security problem originating with the missions. We believe our current implementation to be the best way to protect privacy in data sharing.

Clinical and virological features of acute hepatitis E in Gunma prefecture, Japan between 2004 and 2015.

AIM: To evaluate the clinical and virological features of acute hepatitis E (AH-E) in Gunma prefecture and focus on the hepatitis E virus (HEV) infection in immunocompromised patients. METHODS: A total of 30 patients with AH-E diagnosed at our Gunma University Hospital, and located in 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan, and its affiliated hospitals from 2004 to 2015, were studied. We evaluated the detailed medical histories, laboratory examinations and virological features of these participants. RESULTS: Of the 30 patients, 21 patients were men, with a median age of 61 years. Three of these patients had a history of recent oversea travel. A total of 14 patients had eaten raw or undercooked meat/viscera from animals, and two patients had contracted transfusion-transmitted AH-E. Eight patients were immunocompromised, including those with hematological disease, cancer receiving systemic chemotherapy and kidney transplant or connective tissue disease undergoing immunosuppressive medications. The alanine aminotransferase and total bilirubin levels were more significantly reduced in these immunocompromised patients than in the non-immunocompromised patients. Severe thrombocytopenia, an extra-hepatic manifestation of AH-E, occurred in one case. Among the 22 HEV strains whose subgenotype was determined, two were imported strains (1a and 1f), and 11 strains formed four distinct phylogenetic clusters within subgenotype 3b. The remaining nine strains differed from each other by 9.8-22.4%, and were classified into four subgenotypes (3a, 3b, 3e and 3f). CONCLUSION: Markedly divergent HEV strains (3a, 3b, 3e and 3f) were found to circulate in Gunma. Although immunosuppression appears to play a crucial role in establishing chronic sequels, AH-E in eight immunocompromised patients, including transfusion-transmitted HEV infection in two patients, did not become chronic.

The Tohoku Medical Megabank Project: Design and Mission.

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Endoscopic treatment for esophageal varices complicated by Isaacs' syndrome involving difficulty with conventional sedation.

A 54-year-old male consulted a local doctor with a chief complaint of systemic convulsions and muscle stiffness and was diagnosed with Isaacs' syndrome based on positive findings for antibodies against voltage-gated potassium channels in 2009. He subsequently experienced repeated hematemesis in 2013, at which time he was taken to our hospital by ambulance. Emergent endoscopy revealed esophageal varices with spurting bleeding. The bleeding was stopped with urgent endoscopic variceal ligation. Three days later, the patient developed sudden dyspnea with stridor during inspiration under sedation with an intravenous injection of low-dose flunitrazepam prior to receiving additional treatment and was aroused with intravenous flumazenil, after which his dyspnea immediately improved. Dyspnea may be induced by muscle cramps associated with Isaacs' syndrome exacerbated by sedation. Endoscopic variceal ligation was performed safely using multiple ligation devices in an awake state following pre-medication with hydroxyzine, without sudden dyspnea. Endoscopists should be cautious of the use of sedatives in patients with diseases associated with muscle twitching or stiffness, as in the current case. In addition, it is necessary to administer endoscopic treatment in an awake state or under conscious sedation in patients with a high risk of dyspnea.

Prevalence of nonalcoholic steatohepatitis in Japanese patients with morbid obesity undergoing bariatric surgery.

BACKGROUND: Patients with morbid obesity selected for bariatric surgery have a high prevalence of nonalcoholic steatohepatitis (NASH); however, the incidence is varied and depends on race. The prevalence of NASH in obese Japanese patients is unknown. We evaluated the prevalence of NASH in a prospective cohort of Japanese patients with morbid obesity. METHODS: From October 2009 to July 2011, consecutive patients requiring bariatric surgery underwent a liver biopsy during the operation. The indications for bariatric surgery followed the guidelines of the Asia-Pacific Metabolic and Bariatric Surgery Society. RESULTS: One hundred two patients (55 males and 47 females, age 42.7 ± 10.7 years) were analyzed. The mean body mass index was 42.1 ± 8.2 kg/m(2). Among the 102 patients, 84 patients (82.4%) had nonalcoholic fatty liver disease and 79 patients (77.5%) had NASH. The grading and staging of NASH by Brunt's classification were as follows: grade 0 steatosis, one patient; grade 1 steatosis, 35 patients; grade 2 steatosis, 32 patients; grade 3 steatosis, 11 patients; stage 1 fibrosis, 25 patients; stage 2 fibrosis, 38 patients; stage 3 fibrosis, 16 patients, stage 4 fibrosis, no patients. The body weight, waist-hip ratio, visceral fat area, and aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, fasting plasma glucose, fasting plasma insulin, C peptide, hemoglobin A1c, and homeostasis model assessment insulin resistance levels were significantly elevated in the NASH group in comparison with the non-NASH group. The platelet count was significantly decreased in the NASH group. The waist-hip ratio and the alanine aminotransferase, fasting plasma glucose, and homeostasis model assessment insulin resistance levels were found to be independent predictors of NASH in a multivariate analysis. CONCLUSION: The prevalence of NASH was 77.5% in this prospective Japanese cohort. The prevalence of NASH in Japanese morbidly obese patients was extremely high, and early intervention should be undertaken.

A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia.

OBJECTIVES: The aim of this study was to assess the long-term prognosis, efficacy, and safety of combination therapy using ursodeoxycholic acid (UDCA) and bezafibrate (BF) for primary biliary cirrhosis (PBC) patients exhibiting dyslipidemia. METHODS: We performed a prospective, randomized, controlled, multicenter study to compare the long-term clinical results between combination therapy and UDCA monotherapy for patients refractory to UDCA monotherapy. Twenty-seven consecutive PBC patients were enrolled. RESULTS: The median treatment period in the UDCA and UDCA+BF groups was 107 and 110 months, respectively. The serum alkaline phosphatase (ALP) levels and the Mayo risk score in the combination therapy group (mean 290 IU/l and 0.91, respectively) were significantly lower than those in the UDCA monotherapy group (mean 461 IU/l and 1.42, respectively) at 8 years after the beginning of the study (P<0.05). The serum creatinine levels in the combination therapy group (mean 0.94 mg/dl) were significantly higher than those in the UDCA monotherapy group (mean 0.56 mg/dl) at 8 years after the beginning of the study (P<0.05). However, the survival rate was not significantly different between the groups. We observed dose reduction or discontinuation of the administration of BF, but not UDCA, due to renal dysfunction or muscle pain. CONCLUSIONS: Long-term combination therapy significantly improved the serum ALP levels and the Mayo risk score. However, the survival rate was not significantly different between the groups. In addition, long-term combination therapy significantly increased the serum creatinine levels. We should pay close attention to adverse events during this long-term combination therapy.

[Drug-induced liver injury caused by a dietary supplement (Kin-toki Shoga(®)) made from ginger].

A 70-year-old woman who took a dietary supplement, Kin-toki Shoga(®) made from ginger for peripheral psychroesthesia and numbness, experienced an epigastric sense of incongruity and appetite loss and passed brown urine for 2 months. Although she had stopped taking the supplement, her symptoms had not improved. She was admitted to our hospital because of jaundice and liver dysfunction. After an investigation of causes, she was diagnosed with drug-induced liver injury caused by Kin-toki Shoga(®). Liver dysfunction gradually improved with conservative treatment. She was discharged on the 25th day of illness. Liver biopsy findings were compatible with drug-induced liver injury.

MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice.

AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice. METHODS: We analyzed obese (ob/ob) 8-wk-old male mice that had been randomly divided into two groups of ob/ob mice (n = 16 each) and were treated with 1.5 or 3 mg/kg MK-0626 and two control groups of untreated ob/ob mice and lean littermates (n = 16 each). All mice were fed a normal chow diet with or without MK-0626 for either four or eight weeks. Blood samples were collected, and total hepatectomy was performed. RESULTS: The administration of dietary MK-0626 ameliorated the hepatic lipid accumulation in ob/ob mice treated with 3 mg/kg MK-0626 (3 MK), P < 0.05, vs untreated ob/ob mice (ob/ob). The MK-0626 treatment reduced the serum alanine aminotransferase levels (both treatment groups, P < 0.05 vs ob/ob) and glucoses/insulin levels/calculated HOMA scores (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) and increased the serum adiponectin levels (3 MK, P < 0.05 vs ob/ob) in a dose-dependent manner. The MK-0626 treatment increased the mRNA expression of peroxisome proliferator-activated receptor α/microsomal triglyceride transfer protein (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) but reduced the sterol regulatory element binding transcription factor-1c/fatty acid synthase/stearoyl-CoA desaturase-1 (both treatment groups, P < 0.01 vs ob/ob). The MK-0626 treatment increased the activity of AMP-activated protein kinase (AMPK) (both treatment groups, P < 0.01 vs ob/ob). CONCLUSION: MK-0626 could attenuate hepatic steatosis through enhancing AMPK activity, inhibiting hepatic lipogenic gene expression, enhancing triglyceride secretion from liver and increasing serum adiponectin levels.

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation.

Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

Extended therapy duration for therapy-refractory hepatitis C patients with genotype 2.

We devised an extended 72-wk peginterferon-α-2a/ribavirin therapy regimen for the retreatment of highly intractable cases, i.e., 48-wk peginterferon-α-2b/ribavirin therapy-intractable cases. Although 2 cases achieved a rapid virological response to 72-wk peginterferon-α-2a/ribavirin therapy, 1 case failed to achieve a sustained virological response. Although the reason for this difference in the effectiveness of 72-wk peginterferon-α-2a/ribavirin therapy between the cases was unclear, the rebound phenomenon of serum transaminase after 48-wk peginterferon-α-2b/ribavirin therapy and the resultant lower viral load compared to that before 48-wk peginterferon-α-2b/ribavirin therapy might have influenced the treatment outcome. Thus, it may be beneficial to consider the rebound phenomenon of serum transaminase and the changes in viral load resulting from previous interferon-based therapy and then cautiously determine the indication and the timing of the administration of 72-wk peginterferon-α-2a/ribavirin in highly intractable cases. Further studies should be performed to confirm this strategy.

Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation.

The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.

A prospective study of long-term outcomes in female patients with nonalcoholic steatohepatitis using age- and body mass index-matched cohorts.

In patients with nonalcoholic steatohepatitis (NASH), the prevalence of cirrhosis is higher among women than men, and hepatocellular carcinoma (HCC) develops mainly in the cirrhotic stage among women. However, the long-term outcomes in female patients with NASH have not been fully elucidated, and age, gender and BMI were not simultaneously adjusted in previous studies on the prognosis of NASH. To elucidate the outcomes in female patients with NASH, we prospectively compared NASH patients with advanced fibrosis (advanced NASH) with hepatitis C virus-related advanced fibrosis (advanced CHC) patients and NASH patients with mild fibrosis (mild NASH) using study cohorts that were adjusted for body mass index (BMI) in addition to age. The median follow-up period was 92.5 months. Liver-related complication-free survival was significantly reduced in the advanced NASH group compared to the mild NASH group. No liver-related complications developed in the mild NASH group. The overall survival, liver-related complication- and cardiovascular/cerebrovascular disease-free survival were not significantly different between the advanced NASH and CHC groups. Female patients with NASH and advanced fibrosis may have a less favorable prognosis for liver-related complications than the matched cohorts with NASH and mild fibrosis, but may have a similar prognosis to the matched cohorts with CHC.

Response-guided peginterferon-alpha-2b plus ribavirin therapy for chronic hepatitis C patients with genotype 2 and high viral loads.

AIMS: Optimization of the duration of peginterferon-α/ribavirin therapy in patients with hepatitis C virus (HCV) genotype 2 and high viral loads remains to be established. We sought to prospectively optimize the treatment duration based on their virological responses. METHODS: Serum HCV RNA levels of less than 50 IU/mL at weeks 2 and 4, and of 50 IU/mL or more at week 4, were defined as a super-rapid virological response (SRVR), rapid virological response (RVR) and late virological response (LVR), respectively. Treatment for 12, 24 or 48 weeks was assigned to the patients with an SRVR, RVR or LVR, respectively. However, patients with an LVR who expressed a desire to receive the standard therapy duration were given the 24-week therapy. RESULTS: The overall sustained virological response (SVR) rate was 78.1% (118/151). The SVR rate in the SRVR group was 93.8% (15/16), which was comparable to the 93.0% (66/71) SVR rate in the RVR group. In the LVR patients, the 48-week treatment slightly increased the SVR rate to 76.5% (13/17) compared with the 51.1% (24/47) SVR rate in LVR patients who underwent the standard 24-week treatment. The relapse rate in LVR patients was significantly decreased in patients treated for 48 weeks compared with patients treated for 24 weeks. Multivariate analysis identified the predictive factors for SVR as RVR, prior interferon therapy and total peginterferon-α-2b adherence in patients treated for 24 weeks. CONCLUSION: Response-guided therapy may be effective and useful for optimization of the treatment duration.

A case of hemorrhagic gastroduodenitis after proton beam radiation for pancreatic cancer with multiple hemorrhagic risk factors: successful treatment with argon plasma coagulation.

Radiation-induced gastroduodenitis is a well-known but rare disorder causing uncontrollable hemorrhage and has not been reported as a complication of proton beam therapy in radiation treatment. Argon plasma coagulation (APC) has been shown to be effective and safe in the management of radiation-induced hemorrhagic gastroduodenitis. We describe a case of hemorrhagic gastroduodenitis after proton beam radiation therapy for pancreatic cancer with multiple hemorrhagic risk factors, which was treated successfully with APC. A 62-year-old man was diagnosed as having early pancreatic cancer that was incidentally detected on computed tomography when screening for hepatocellular carcinoma. He opted to receive radical proton beam radiation for pancreatic cancer but not surgery because he had multiple risk factors such as liver cirrhosis due to hepatitis C virus and chronic renal failure that required hemodialysis. Three months later, however, he developed hemorrhagic gastroduodenitis induced by proton beam radiation although the cancer had been eradicated. Initially, he required frequent blood transfusions, but his disease condition improved dramatically after several endoscopic treatments using APC. The patient has been free of relapse after pancreatic cancer for >2 years.

Primary liver cancers with nonalcoholic steatohepatitis.

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.

Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis.

Adult onset type II citrullinemia (CTLN2) is an autosomal recessive disease accompanied with hyperammonemia and a sudden onset of psychiatric disorders. We demonstrated three male patients with CTLN2 having a liver histology of non-alcoholic steatohepatitis (NASH). Patients with NASH were analyzed for the causative gene of CTLN2, SLC25A13 and discussed.