熊谷 秀規

BACKGROUND AND AIM: Even with increasing numbers of biologic agents available for management of ulcerative colitis (UC), infliximab (IFX) retains an important place in treatment of pediatric patients with this disease. As few reports have addressed outcomes in pediatric UC patients who had to discontinue IFX, we examined clinical course and prognosis after IFX failure in pediatric UC. METHODS: A prospective cohort study of pertinent cases enrolled in the Japanese Pediatric Inflammatory Bowel Disease Registry between 2012 and 2020 was conducted to determine outcomes for pediatric UC patients who received IFX but required its discontinuation during follow-up (IFX failure). RESULTS: Of the 301 pediatric UC patients in the registry, 75 were treated with IFX; in 36 of these, IFX was discontinued during follow-up. Severity of UC at onset and absence of concomitant immunomodulator therapy were significant risk factors for IFX failure (P = 0.005 and P = 0.02, respectively). The cumulative colectomy rate after IFX failure was 41.3% at 1 year and 47.5% at 2 years. Colectomy was significantly more frequent when IFX was discontinued before June 1, 2018, than when IFX was discontinued later (P = 0.013). This difference likely involves availability of additional biologic agents for treatment of UC beginning in mid-2018 (P = 0.005). CONCLUSION: In pediatric UC patients, approximately 50% underwent colectomy during a 2-year interval following IFX failure. Prognosis after IFX failure appeared to improve with availability of new biologic agents and small-molecule drugs in mid-2018.

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD. CASE REPORT: The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M. CONCLUSIONS: In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.

BACKGROUND: Vedolizumab (VDZ) is a humanized monoclonal antibody that binds to α4β7 integrin expressed in T-lymphocytes and is gut selective. Few studies have evaluated the safety and efficacy of VDZ in pediatric ulcerative colitis (UC) patients, especially from Asia. METHODS: A longitudinal multicenter retrospective study was conducted at 10 Japanese tertiary medical institutions. Patients aged ≤18 years old who received VDZ for UC between January 2019 and July 2021 were enrolled. Information on the clinical characteristics, prior/concomitant treatment, and safety during the observation period was collected. RESULTS: The data obtained from 48 patients (males, n = 30; females, n = 18) were analyzed. The median age at VDZ induction was 14 (range 4-18) years old. VDZ was indicated in 73% of patients as switching from previous biologics due to primary failure, loss of response, and adverse events (AEs) and was the first biologic in 27%. Remission was achieved or maintained at weeks 14, 30, and 54 in 79.2%, 75.0%, and 65.8% of patients, respectively. There were no significant differences between the number of previous biologics exposures and VDZ effectiveness. The hematocrit, serum albumin concentrations, and erythrocyte sedimentation rate (ESR) at baseline differed significantly by VDZ effectiveness. Nine AEs, including infusion reaction, were noted in seven (14.3%) patients. There were no severe AEs related to VDZ administration. CONCLUSIONS: VDZ was safe and effective in children with UC. The hematocrit, albumin, and ESR at VDZ initiation might be predictors for VDZ effectiveness. VDZ may be an important option for pediatric patients and can be used as an alternative to immunomodulators.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

BACKGROUND: As best practices for treating children with severe-onset ulcerative colitis remain controversial in the era of biologic agents, we prospectively investigated treatments and outcomes in a multicenter cohort. METHODS: Using a Web-based data registry maintained in Japan between October 2012 and March 2020, we compared management and treatment outcomes in an S1 group defined by a Pediatric Ulcerative Colitis Activity Index of 65 or more points at diagnosis with those in an S0 group defined by an index value below 65. RESULTS: Three hundred one children with ulcerative colitis treated at 21 institutions were included, with follow-up for 3.6 ± 1.9 years. Among them, 75 (25.0%) were in S1; their age at diagnosis was 12.3 ± 2.9 years, and 93% had pancolitis. Colectomy free rates in S1 were 89% after 1 year, 79% after 2, and 74% after 5, significantly lower than for S0 (P = 0.0003). Calcineurin inhibitors and biologic agents, respectively, were given to 53% and 56% of S1 patients, significantly more than for S0 patients (P < 0.0001). Among S1 patients treated with calcineurin inhibitors when steroids failed, 23% required neither biologic agents nor colectomy, similarly to the S0 group (P = 0.46). CONCLUSIONS: Children with severe ulcerative colitis are likely to require powerful agents such as calcineurin inhibitors and biologic agents; sometimes colectomy ultimately proves necessary. Need for biologic agents in steroid-resistant patients might be reduced to an extent by interposing a therapeutic trial of CI rather than turning to biologic agents or colectomy immediately.

BACKGROUND: Fermented soybean (natto)-induced hypersensitivity reactions (natto allergy) are rare and can result in late-onset anaphylaxis. The allergen in natto is considered to be poly-γ-glutamic acid (PGA), and marine sports are a risk factor for natto allergy due to epicutaneous sensitization to PGA from cnidarian stings. However, no research on natto allergy in fishery workers has yet been performed. METHODS: We conducted a chart review of inpatients diagnosed with anaphylaxis due to natto at Hokkaido Prefectural Haboro Hospital between April 1, 2009, and August 31, 2020. We also administered self-report questionnaires about food hypersensitivity reactions to Japanese fishery workers, including members of the Kitarumoi Fishery Cooperative Association and part-time workers in this area, from February 1 to May 31, 2021. RESULTS: We found six inpatients (29 inpatients with food-induced anaphylaxis among approximately 11,000 community-dwelling residents) with late-onset anaphylaxis due to natto; all were involved in scallop aquaculture. The questionnaires revealed that 27 participants had natto allergy. We divided the fishery workers into a scallop aquaculture (Scallop) group (n = 211) and other fishery group (n = 106). The Scallop group was significantly associated with natto allergy after adjustments for confounders (OR: 5.73, 95% CI: 1.46-22.56) by logistic regression analysis. In the Scallop group, older age, experience in repairing nets, and a longer length of work experience were significantly related to participants with natto allergy (n = 23), but not participants without natto allergy (n = 181). CONCLUSIONS: Our results indicated an association between scallop aquaculture and natto allergy.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the intestine. The incidence of IBD is increasing worldwide, including Japan, and in approximately 25% of all affected patients it is diagnosed before 18 years of age. For the health maintenance of such patients, planned transition to adult care systems is essential. Previous Japanese surveys have revealed gaps between adult and pediatric gastroenterologists with regard to their knowledge and perception of health-care transition for patients with childhood-onset IBD. In 2021-2022, several Web workshops to discuss issues related to the transitional care of IBD patients were held by the Ministry of Health, Labour and Welfare of Japan as part of their program for research on intractable diseases. Clinicians experienced in IBD treatment for pediatric and adult patients participated. As a result, this panel of adult and pediatric gastroenterologists developed five consensus statements on the issue of "transfer from pediatric to adult care" and nine statements on the issue of "addressing transitional care (transition program)." To address current gaps in health-care transition for childhood-onset IBD patients, a programmed approach to transition, and better partnerships between pediatric and adult gastroenterologists are indicated. It is hoped that this consensus statement will provide a basis for the development of appropriate guidelines for clinical practice.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Transition-related healthcare intervention has recently been receiving worldwide attention. Given the increasing incidence of pediatric inflammatory bowel disease (IBD) and its lifelong impact, transitional care has become an important issue. In Japan, guidelines to support the autonomy of IBD patients during transition were recently published. &lt;b&gt;&lt;i&gt;Summary:&lt;/i&gt;&lt;/b&gt; Here, we review current issues regarding care for IBD patients during transition from the pediatric to adult period in order to identify the barriers and key elements for successful transition in the context of the Japanese system. Although no single optimal model of transitional care exists, crucial elements identified so far include a joint pediatric/adult clinic or alternating visits between pediatric and adult healthcare providers, a multidisciplinary approach, and good coordination among stakeholders. Self-reliance and independence of patients with childhood-onset IBD are also considered essential for successful transition. Various tools for assessment of transition readiness have been validated and are considered useful. Better outcomes are expected for individually tailored transition, including improvements in medication adherence, perceived health status, quality of life, and self-management. The timing of transfer from a pediatric to an adult gastroenterologist should not be fixed because the issue is not chronological age but rather the degree of individual maturity. We also propose a standardized medical summary with a checklist template for official referral of patients from a pediatric to an adult gastroenterologist. &lt;b&gt;&lt;i&gt;Key Messages:&lt;/i&gt;&lt;/b&gt; Transition programs require a multidisciplinary approach with a coordinator (IBD nurse) and optimal collaboration and communication. Lack of resources and funding are also pertinent issues.

Scanning acoustic microscopy reveals information on histology and acoustic impedance through tissues. The objective of the present study was to investigate whether acoustic impedance values in the liver over time reflect the progression of steatohepatitis through different grades and stages, and whether this approach can visualize histologic features of the disease. Mice were divided into two groups: a control group and a steatohepatitis group prepared by keeping the mice on a methionine and choline-deficient diet for 56 weeks. The hepatic lobe was excised for measurement of impedance and observation of microscopic structure using a commercially available scanning acoustic microscopy system with a central frequency of 320 MHz. Scanning acoustic microscopy revealed that acoustic impedance through liver tissue with steatohepatitis temporarily decreased with the degree of fat deposition and then increased in parallel with the progression of inflammation and fibrosis. However, the acoustic images obtained did not allow discrimination of detailed microstructures from those seen using light microscopy. In conclusion, estimation of acoustic impedance appears to have potential clinical applications, such as for monitoring or follow-up studies.

腸管出血性大腸菌(enterohemorrhagic Escherichia coil:EHEC)感染症では、溶血性尿毒症症候群(hemolytic uremic syndorome;HUS)に併発する急性膵炎の報告はあるが、HUSを伴わない膵炎は非常に稀である。症例は8歳の男児。腹痛と下痢、血便が続き、感染性腸炎の診断で第4病日に入院した。入院後、志賀毒素(Shigatoxin;Stx)陽性のEHEC O26が同定された。下痢と血便は軽快傾向にあったが腹痛は持続し、第5病日に血清アミラーゼとリパーゼが上昇した。腹部造影CTで膵腫大と横行結腸間膜域の脂肪織濃度上昇があり急性膵炎と診断した。膵炎は軽症で、ウリナスタチン点滴静注で軽快し第13病日に退院した。経過中にHUSは発症しなかった。本症例では、Stxに起因する炎症性サイトカインによりVater乳頭を含む十二指腸に浮腫を来して膵液の排出が障害されたことが、膵炎発症の要因の一つと考えられた。EHEC感染症では、HUSがない場合も膵炎を併発する可能性があることを念頭に置く必要がある。(著者抄録)

OBJECTIVES: Causes of early-onset refractory diarrhea include exudative diarrhea associated with very early-onset inflammatory bowel diseases, osmotic or secretory diarrhea, and protein-losing enteropathy. Monogenic disorders are included in these diseases, yet a comprehensive genetic analysis has not been fully established. METHODS: We established targeted gene panels covering all responsible genes for early-onset diarrhea. In total, 108 patients from 15 institutions were enrolled in this study. We collected clinical data from all patients. Seventy-three patients with exudative diarrhea, 4 with osmotic or secretory diarrhea and 8 with protein-losing enteropathy were subjected to genetic analysis. RESULTS: A total of 15 out of the 108 enrolled patients (13.9%) were identified as monogenic. We identified 1 patient with RELA, 2 with TNFAIP3, 1 with CTLA4, 1 with SLCO2A1, 4 with XIAP, 3 with IL10RA, 1 with HPS1, 1 with FOXP3, and 1 with CYBB gene mutations. We also identified 1 patient with NFKB2 and 1 with TERT mutations from the gene panel for primary immunodeficiency syndromes. The patient with refractory diarrhea caused by heterozygous truncated RelA protein expression is the first case identified worldwide, and functional analysis revealed that the mutation affected nuclear factor kappa B signaling. Genotypes were significantly associated with the clinical and pathological findings in each patient. CONCLUSIONS: We identified variable monogenic diseases in the patients and found that genes responsible for primary immunodeficiency diseases were frequently involved in molecular pathogenesis. Comprehensive genetic analysis was useful for accurate molecular diagnosis, understanding of underlying pathogenesis, and selecting the optimal treatment for patients with early-onset refractory diarrhea.

小児クローン病は、診断時の病変範囲が成人より広範かつ重症で、肛門病変を合併することも少なくない。また、消化器症状にとどまらず、成長や学校生活、心理的問題を呈することもあり、小児の特性に配慮した治療指針の作成が望まれる。近年の炎症性腸疾患(IBD)診療の進歩に対応すべく、日本小児栄養消化器肝臓学会と日本小児IBD研究会により小児IBD治療指針作成委員会が立ち上げられ、2005年と2013年に報告された小児クローン病治療指針案・治療ガイドラインの改訂版を作成したので報告する。この改訂版では、成人患者に対する治療との整合性に配慮しながら、小児クローン病の治療原則、臨床的評価に基づいた治療方針、さらには、個々の治療法について、小児への適応承認の実際や小児用量も示しながら解説した。さらに、小児期特有の問題である成長障害、予防接種、心理社会的側面、成人診療科への移行期医療、超早期発症型IBDなどについても言及した。(著者抄録)

小児潰瘍性大腸炎は、一般に成人に比して短期間で全大腸炎型へ進展しやすい。重症化しやすいなどの特徴があり、また成長障害など小児期特有の問題を有することから、小児の特性に配慮した治療指針の作成が望まれる。近年の炎症性腸疾患(IBD)診療の進歩に対応すべく、日本小児栄養消化器肝臓学会と日本小児IBD研究会により小児IBD治療指針作成委員会が立ち上げられ、2004年と2008年に報告された「小児潰瘍性大腸炎治療指針案」の改訂版を作成したので報告する。この改訂版では、成人患者に対する治療との整合性に配慮しながら、小児潰瘍性大腸炎の治療原則、臨床的評価と活動性指標に基づいた治療方針、個々の治療法と小児への適用承認の実際や小児用量について解説した。さらに、小児期特有の問題である成長障害、予防接種、心理社会的側面、成人診療科への移行期医療、超早期発症型IBDなどについても言及した。(著者抄録)

小児診療科で長期管理されてきた患者は成人診療科への転科(トランスファー)が容易でないことがあり、その要因は多岐にわたる。そこで、良質な医療が継続されるよう移行(トランジション)に係る患者支援が必要である。2015年に日本小児栄養消化器肝臓学会は「移行期医療支援ワーキンググループ」を発足させた。小児の炎症性腸疾患(IBD)は患者のほとんどが成人に達するが、本疾患については成人診療科が精通していることから、小児診療科から全面的に移行し得る疾患である。しかし、これまで十分な議論がなされておらず、各施設や主治医の判断に委ねられているのが現状である。「小児慢性疾病患者の成人移行期における自立支援のための移行支援ガイドブック」(石崎優子、平成25年度厚生労働科学研究費補助金;主任研究者 水口雅)には、小児科・小児外科の各領域に共通する総論的なエッセンスが記載されている。ワーキンググループでは、その各論の一つとして小児IBDを取り上げ、成人診療科への移行支援を目的として手引書の作成に取り組んだ。その結果、目標を明確にしつつトランジションの進捗状況を確認できるツールとして以下のものを作成した:A. 移行に向けた達成状況を確認するための「自己健康管理度チェックリスト(一般)」 B. 小学校高学年を対象にした解剖と生理を記した「食べ物の消化・吸収の説明図」(自立に向けての教育用資料) C. 移行過程の目安となる「移行スケジュール」 D. 包括的な「消化器内科・外科移行チェックリスト(患者用)」 E. 「同(保護者用)」 F. 患者が自分で管理することも意識した「サマリー」 G. プロブラムに関わる多職種の専門家との連携を示す「パス」(患者、家族、小児科・小児外科医、消化器内科・外科医、看護師、薬剤師、栄養士、心理士、ソーシャルワーカー、教育機関、事務方が含まれる) これらは当学会の運営委員会で承認され、学会のホームページ(http://www.jspghan.org/)や、移行期医療支援モデル事業事務局(国立成育医療研究センター 小児慢性特定疾病情報室内)のホームページ(https://transition-support.jp/)で公開され、ダウンロードが可能である。トランジションは患者の自立へのプロセスであり、それぞれの特性に応じた説明や教育を早期から行って、本人や家族の不安を払拭していくことが重要である。本手引書のような標準的なツールを使用することにより、多職種の専門家が目標や状況を確認しやすくなることが期待できる。今後は、問題点の改善や成人診療科との共同作業を行いつつ、手引書を用いた臨床研究を計画するほか、手引書の改訂を行っていく。(著者抄録)

Hepatitis E virus subtype 3f (HEV-3f) strains are usually isolated in Europe and Thailand. Recently, HEV-3f strains were detected from six acute hepatitis E patients in Japan, none of whom had a history of travel to endemic areas. We inferred the origin and transmission route of the six HEV-3f strains. A time-scaled phylogenetic tree of the six strains with reference strains was constructed using a Bayesian statistical inference framework. The time-scaled tree indicated that the six strains independently derived from similar European strains between 2008 and 2014. The pattern suggested recent inflow of multiple HEV-3f strains from Europe to Japan. Japan imports a substantial amount of pork from European countries every year. The emergence of acute hepatitis cases caused by HEV-3f strains in Japan, in patients with no history of travel abroad, might be influenced by the increased opportunities to consume pork products imported from European countries.

Background and Aim: Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long-term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy. Methods: We retrospectively and prospectively examined children under 10 years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan. Results: Twenty-four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1 month after initiation of treatment and usually remained under 50 U/L from 1 to 8 years of treatment. Twenty four-hour urinary copper decreased significantly at 6 months and usually remained under 75 μg/day and between 1 and 3 μg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6 years old who received 50 mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1 month after initiation of treatment, as did γ-glutamyltransferase and 24-h urinary copper at 6 months. Conclusions: To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50 U/L when normalization is difficult) and 24-h urinary copper excretion between 1 and 3 μg/kg/day and under 75 μg/day is a reasonable goal. An initial dose of 50 mg/day is appropriate for patients under 6 years old.