Tomoyuki Tsunoda

Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C

BACKGROUND AND AIMS Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment. METHODS A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis. RESULTS Propensity score-matched analysis showed no significant difference in HCC occurrence (p=0.49) and recurrence rates (p=0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment α-fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+M2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFA+M2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFA+M2BP levels was greater than that for AFP levels in ROC analysis. CONCLUSION The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFA+M2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy.

Safety and utility of capsule endoscopy for infants and young children

AIM To assess the safety and utility of capsule endoscopy (CE) for children who are unable to swallow the capsule endoscope. METHODS The medical records of all of the children who underwent CE between 2010 and 2012 were retrospectively reviewed. The patients were divided into 2 groups: group A included patients who were unable to swallow the capsule endoscope, and group B included patients who were able to swallow it. For the patients who were unable to swallow the capsule endoscope, it was placed in the duodenum endoscopically. The small bowel transit time, endoscopic diagnosis and complications of the 2 groups were compared. RESULTS During the study period, 28 CE procedures were performed in 26 patients. Group A included 11 patients with a median age of 2 years (range 10 mo-9 years), and group B included 15 patients with a median age of 12 years (range 8 years-16 years). The lightest child in the study weighed 7.9 kg. The detection rates did not differ between the 2 groups. The median small bowel transit time was 401 min (range 264-734 min) in group A and 227 min (range 56-512 min) in group B (P = 0.0078). No serious complications, including capsule retention, occurred. No significant mucosal trauma occurred in the pharynx, esophagus, stomach or duodenum when the capsule was introduced using an endoscope. CONCLUSION CE is a safe and useful procedure for infants and young children who are unable to swallow the capsule endoscope.

ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin

Sofosbuvir (SOF) and ribavirin (RBV) combination therapy produces a sustained response in many patients with genotype 2 chronic hepatitis C. However, RBV‐induced anemia is a troublesome side‐effect that may limit this treatment. Genetic variation leading to inosine triphosphatase (ITPA) deficiency is known to protect against RBV‐induced hemolytic anemia. This study aimed to evaluate the relationships between the efficacy and safety of SOF/RBV treatment and ITPA gene variants.

Characterisation of the faecal microbiota in Japanese patients with paediatric-onset primary sclerosing cholangitis.

Dear Sir, Primary sclerosing cholangitis (PSC) is a liver disease often associated with IBD.1 Dysbiosis of the gut microbiota is implicated in PSC aetiology in adults,2–4 but less is known about paediatric-onset PSC. We analysed the faecal microbiota of 27 Japanese patients with paediatric-onset PSC as well as 16 age-matched patients with UC and 23 healthy controls (HCs) (see online supplementary table S1) with pyrosequencing data of 16S rRNA gene V1-V2 region (accession #DRA004773). We assessed the influence of medications on the gut microbiota and found that salazosulfapyridine (SASP) treatment affected the microbiota structure with significant changes in the abundance of six major genera between the treated and untreated patients with PSC, perhaps due to its bactericidal property (see online supplementary figure S1). We thus report the analysis of 13 patients with PSC and 15 patients with UC and 23 HCs, all SASP untreated (see online supplementary table S2). ### Supplementary tables [gutjnl-2016-312533supp_tables.pdf] ### Supplementary figure [gutjnl-2016-312533supp_figure.pdf] Clustering analysis of the 16S reads revealed that the microbiota in the PSC and HC groups had significantly high species richness compared with the UC group, and the species richness of PSC samples was lower than that of HCs. The PSC group also exhibited an intermediate trend in the Shannons index between the UC and HC groups (figure 1A). The unweighted UniFrac metric revealed a significant difference in the overall microbiota structure among the three groups, in which the PSC samples tended to aggregate between the HC and UC samples (figure 1B, C). Collectively, the data suggested that the patients with …

Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via ABCG2

To clarify the physiological and pathophysiological roles of intestinal urate excretion via ABCG2 in humans, we genotyped ABCG2 dysfunctional common variants, Q126X (rs72552713) and Q141K (rs2231142), in end-stage renal disease (hemodialysis) and acute gastroenteritis patients, respectively. ABCG2 dysfunction markedly increased serum uric acid (SUA) levels in 106 hemodialysis patients (P = 1.1 × 10−4), which demonstrated the physiological role of ABCG2 for intestinal urate excretion because their urate excretion almost depends on intestinal excretion via ABCG2. Also, ABCG2 dysfunction significantly elevated SUA in 67 acute gastroenteritis patients (P = 6.3 × 10−3) regardless of the degree of dehydration, which demonstrated the pathophysiological role of ABCG2 in acute gastroenteritis. These findings for the first time show ABCG2-mediated intestinal urate excretion in humans, and indicates the physiological and pathophysiological importance of intestinal epithelium as an excretion pathway besides an absorption pathway. Furthermore, increased SUA could be a useful marker not only for dehydration but also epithelial impairment of intestine.

Human induced pluripotent stem cell-derived hepatic cell lines as a new model for host interaction with hepatitis B virus

Hepatitis B virus (HBV) is not eradicated by current antiviral therapies due to persistence of HBV covalently closed circular DNA (cccDNA) in host cells, and thus development of novel culture models for productive HBV infection is urgently needed, which will allow the study of HBV cccDNA eradication. To meet this need, we developed culture models of HBV infection using human induced pluripotent stem cell-derived hepatocyte lineages, including immature proliferating hepatic progenitor-like cell lines (iPS-HPCs) and differentiated hepatocyte-like cells (iPS-Heps). These cells were susceptible to HBV infection, produced HBV particles, and maintained innate immune responses. The infection efficiency of HBV in iPS-HPCs predominantly depended on the expression levels of sodium taurocholate cotransporting polypeptide (NTCP), and was low relative to iPS-Heps: however, long-term culture of iPS-Heps was difficult. To provide a model for HBV persistence, iPS-HPCs overexpressing NTCP were established. The long-term persistence of HBV cccDNA was detected in iPS-HPCs overexpressing NTCP, and depended on the inhibition of the Janus-kinase signaling pathway. In conclusion, this study provides evidence that iPS-derived hepatic cell lines can be utilized for novel HBV culture models with genetic variation to investigate the interactions between HBV and host cells and the development of anti-HBV strategies.

Association between an IL‐28B genetic polymorphism and the efficacy of the response‐guided pegylated interferon therapy in children with chronic hepatic C infection

The relation between interleukin‐28B (IL‐28B) genotypes and treatment‐induced hepatitis C virus (HCV) clearance in children is unknown. This was a retrospective study to evaluate the association between an IL‐28B genotype (rs8099917) and pegylated (PEG) interferon (IFN) response.

Efficacy of pegylated interferon-α2a monotherapy in Japanese children with chronic hepatitis C

Aim:  There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN‐α2a monotherapy for children infected by chronic hepatitis C virus (HCV).

Intestinal ascariasis at pediatric emergency room in a developed country.

Ascaris lumbricoides infection is rare among children in developed countries. Although large numbers of adult Ascaris in the small intestine can cause various abdominal symptoms, this infection remains asymptomatic until the number of worms in the intestine considerably increases in most cases. Ascaris causing bilious vomiting suggesting ileus is rare, especially in developed countries. A 6-year-old boy who lived in Japan, presented with abdominal colic, bilious vomiting at the pediatric emergency room. He appeared pale, and had no abdominal distention, tenderness, palpable abdominal mass, or findings of dehydration. He experienced bilious vomiting again during a physical examination. Laboratory tests showed mild elevation of white blood cells and C-reactive protein levels. Antigens of adenovirus, rotavirus, and norovirus were not detected from his stool, and stool culture showed normal flora. Ultrasonography showed multiple, round-shaped structures within the small intestine, and a tubular structure in a longitudinal scan of the small intestine. Capsule endoscopy showed a moving worm of Ascaris in the jejunum. Intestinal ascariasis should be considered as a cause of bilious vomiting in children, even at the emergency room in industrial countries. Ultrasound examination and capsule endoscopy are useful for diagnosis of pediatric intestinal ascariasis.

Effects of pegylated interferon‐α‐2a monotherapy on growth in Japanese children with chronic hepatitis C

The relationship between pegylated interferon (PEG IFN)‐α‐2a and growth of children with chronic hepatitis C (CHC) remains unclear. This study was to evaluate the effects of PEG IFN‐α‐2a on growth.