Phenotypic characteristics of pediatric inflammatory bowel disease in Japan: results from a multicenter registry.

BACKGROUND/AIMS: There are few published registry studies from Asia on pediatric inflammatory bowel disease (IBD). Registry network data enable comparisons among ethnic groups. This study examined the characteristics of IBD in Japanese children and compared them with those in European children. METHODS: This was a cross-sectional multicenter registry study of newly diagnosed Japanese pediatric IBD patients. The Paris classification was used to categorize IBD features, and results were compared with published EUROKIDS data. RESULTS: A total of 265 pediatric IBD patients were initially registered, with 22 later excluded for having incomplete demographic data. For the analysis, 91 Crohn's disease (CD), 146 ulcerative colitis (UC), and 6 IBD-unclassified cases were eligible. For age at diagnosis, 20.9% of CD, 21.9% of UC, and 83.3% of IBD-unclassified cases were diagnosed before age 10 years. For CD location, 18.7%, 13.2%, 64.8%, 47.3%, and 20.9% were classified as involving L1 (ileocecum), L2 (colon), L3 (ileocolon), L4a (esophagus/stomach/duodenum), and L4b (jejunum/proximal ileum), respectively. For UC extent, 76% were classified as E4 (pancolitis). For CD behavior, B1 (non-stricturing/non-penetrating), B2 (stricturing), B3 (penetrating), and B2B3 were seen in 83.5%, 11.0%, 3.3%, and 2.2%, respectively. A comparison between Japanese and European children showed less L2 involvement (13.2% vs. 27.3%, P< 0.01) but more L4a (47.3% vs. 29.6%, P< 0.01) and L3 (64.8% vs. 52.7%, P< 0.05) involvement in Japanese CD children. Pediatric perianal CD was more prevalent in Japanese children (34.1% vs. 9.7%, P< 0.01). CONCLUSIONS: Upper gastrointestinal and perianal CD lesions are more common in Japanese children than in European children.

Clinical Features, Molecular Genetics, and Long-Term Outcome in Congenital Chloride Diarrhea: A Nationwide Study in Japan.

OBJECTIVE: To clarify clinical and genetic features of Japanese children with congenital chloride diarrhea (CCD). STUDY DESIGN: This was a multi-institutional, retrospective survey of 616 pediatric centers in Japan with identified patients with CCD between 2014 and 2018. Mutations involving SLC26A3 were detected by Sanger sequencing. RESULTS: Thirteen patients met all entry criteria including mutations in SLC26A3, and 14 patients satisfied clinical diagnostic criteria. Homozygous or compound heterozygous mutations in SLC26A3, including 6 novel mutations, were identified in 13 of these 14 patients (93%). The most common (detected in 7 of 13) was c.2063-1g>t. Median age at diagnosis was 1 day. Nine of the patients meeting all criteria were diagnosed as neonates (69%). Median follow-up duration was 10 years. When studied, 8 patients had <5 stools daily (62%), and all had fewer than in infancy. Only 1 patient had nephrocalcinosis, and 3 (23%) had mild chronic kidney disease. Neurodevelopment was generally good; only 1 patient required special education. Five patients (38%) received long-term sodium, potassium, and chloride supplementation. CONCLUSIONS: Early fetal ultrasound diagnosis and prompt long-term sodium, potassium, and chloride supplementation were common management features. Genetic analysis of SLC26A3 provided definitive diagnosis of CCD. In contrast with previously reported localities, c.2063-1g>t might be a founder mutation in East Asia.

Tacrolimus for ulcerative colitis in children: a multicenter survey in Japan.

BACKGROUND/AIMS: Tacrolimus is effective for refractory ulcerative colitis in adults, while data for children is sparse. We aimed to evaluate the effectiveness and safety of tacrolimus for induction and maintenance therapy in Japanese children with ulcerative colitis. METHODS: We retrospectively reviewed the multicenter survey data of 67 patients with ulcerative colitis aged < 17 years treated with tacrolimus between 2000 and 2012. Patients' characteristics, disease activity, Pediatric Ulcerative Colitis Activity Index (PUCAI) score, initial oral tacrolimus dose, short-term (2-week) and long-term (1-year) outcomes, steroid-sparing effects, and adverse events were evaluated. Clinical remission was defined as a PUCAI score < 10; treatment response was defined as a PUCAI score reduction of ≥ 20 points compared with baseline. RESULTS: Patients included 35 boys and 32 girls (median [interquartile range] at admission: 13 [11-15] years). Thirty-nine patients were steroid-dependent and 26 were steroidrefractory; 20 had severe colitis and 43 had moderate colitis. The initial tacrolimus dose was 0.09 mg/kg/day (range, 0.05-0.12 mg/kg/day). The short-term clinical remission rate was 47.8%, and the clinical response rate was 37.3%. The mean prednisolone dose was reduced from 19.2 mg/day at tacrolimus initiation to 5.7 mg/day at week 8 (P< 0.001). The adverse event rate was 53.7%; 6 patients required discontinuation of tacrolimus therapy. CONCLUSIONS: Tacrolimus was a safe and effective second-line induction therapy for steroid-dependent and steroid-refractory ulcerative colitis in Japanese children.

Shwachman-Diamond syndrome: Nationwide survey and systematic review in Japan.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder associated with exocrine pancreatic insufficiency. The present study reports the results of a nationwide survey and a systematic review on SDS to develop consensus guidelines for intractable diarrhea including SDS. METHODS: Questionnaires were sent to 616 departments of pediatrics or of pediatric surgery in Japan in a nationwide survey. A second questionnaire was sent to doctors who had treated SDS patients and included questions on clinical information. Additionally, a systematic review was performed using digital literature databases to assess the influence of medical (i.e. non-surgical) treatment on SDS prognosis. RESULTS: Answers were received from 529 institutions (85.9%), which included information on 24 patients with SDS (median age, 10.4 years; male, n = 15) treated from January 2005 to December 2014. Although 75% of patients received pancreatic enzyme replacement therapy, there was no significant association between treatment and prognosis. Systematic review identified one clinical practice guideline, two case series, eight case reports and 26 reviews. Patient information from those studies was insufficient for meta-analysis. CONCLUSIONS: The rarity of SDS makes it difficult to establish evidence-based treatment for SDS. According to the limited information from patients and published reports, medical treatment for malabsorption due to SDS should be performed to improve fat absorption and stool condition, but it is not clear whether this treatment improves the prognosis of malabsorption.

Epidemiologic features of 348 children with hepatitis C virus infection over a 30-year period: a nationwide survey in Japan.

BACKGROUND: Although the epidemiology of hepatitis C virus (HCV) infection among children may be rapidly changing, few reports have characterized large nationwide cohorts of children with HCV infection. We, therefore, sought to clarify the epidemiology and natural history of HCV infection in Japanese children born over the last three decades. METHODS: Sixty-five pediatric centers retrospectively and prospectively recruited consecutive, otherwise-healthy HCV-infected children born during 1986 to 2015. RESULTS: Entry criteria were met by 348 children. Age at initial diagnosis of infection has decreased significantly in recent years. Cirrhosis and hepatocellular carcinoma were not identified. Prevalence of spontaneous clearance and of interferon treatment with/without ribavirin were 9 and 54%, respectively. Maternal transmission has increased significantly, representing over 99% of cases in the last decade. No transfusion-related cases have been seen after 1994. HCV genotype 2 has increased to become the most prevalent in Japanese children. Histopathology examination of liver specimens showed no or mild fibrosis in most children with chronic hepatitis C; none showed cirrhosis. CONCLUSIONS: This largest nationwide cohort study of Asian children with HCV infection spanned the last three decades. None of these Japanese children developed cirrhosis or hepatocellular carcinoma. Maternal transmission increased to account for 99% of cases during the last decade. Genotype 2 now is most prevalent in these children. Histopathologically, most children with chronic hepatitis C showed mild fibrosis or none.

Enhanced TH17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD.

BACKGROUND: IL10 receptor (IL10R) deficiency causes severe infantile-onset inflammatory bowel disease. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell functions in mice. We have previously reported a key role of IL10 in the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4 T-cell function. METHODS: Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4 T-cell subsets, naive T-cell proliferation, regulatory T cell (Treg)-mediated suppression, and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time polymerase chain reaction. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa. RESULTS: Analysis of 16 IL10- and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared with control subjects. In addition, in vitro Treg suppression of CD4 T-cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naive cells exhibited higher proliferative capacity, a strong TH17 signature, and an increase in polarization toward TH17 cells, compared with controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1ß leads to enhanced production of IL17A. CONCLUSIONS: IL10R signaling regulates TH17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.

Study to determine guidelines for pediatric colonoscopy.

AIM: To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. METHODS: The present study evaluated consecutive patients aged ≤ 15 years who had undergone their first colonoscopy in Kurume University between January 2007 and February 2015. Data were retrospectively analyzed. We identified 110 pediatric patients who had undergone colonoscopy that had reached the cecum, allowing the observation of the total colon. RESULTS: Hematochezia, abdominal pain, and diarrhea were the most common symptoms. For bowel-cleansing preparation, pediatric patients aged ≤ 12 years were treated with magnesium citrate, and patients aged 13-15 years were treated with polyethylene glycol 4000. For sedation, thiamylal with pentazocine, which has an analgesic effect, was used in patients aged ≤ 6 years, and midazolam with pentazocine was used in patients aged ≥ 7 years. Regarding the choice of endoscope, short and thin endoscopes were selected for younger patients, particularly patients aged ≤ 3 years. Positive diagnoses were made in 78 patients (70.9%). Inflammatory bowel disease (n = 49, 44.5%), including ulcerative colitis (n = 37, 33.6%) and Crohn's disease (n = 12, 10.9%), was the most common diagnosis. CONCLUSION: Colonoscopy offers a high diagnostic capability for pediatric patients with gastrointestinal symptoms. The selection of appropriate management the performance of colonoscopy is important in pediatric patients.

Interleukin 1ß Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency.

Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1ß. We demonstrated that innate immune production of IL1ß mediates colitis in IL10R-deficient mice. Transfer of Il1r1-/- CD4+ T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4+ T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-α, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1ß through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb-/- mice or IL10R-deficient patients resulted in increased production of IL1ß. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1ß secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4+ T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency.

Novel exonic mutation inducing aberrant splicing in the IL10RA gene and resulting in infantile-onset inflammatory bowel disease: a case report.

BACKGROUND: Although deleterious mutations in interleukin-10 and its receptor molecules cause severe infantile-onset inflammatory bowel disease, there are no reports of mutations affecting this signaling pathway in Japanese patients. Here we report a novel exonic mutation in the IL10RA gene that caused unique splicing aberrations in a Japanese patient with infantile-onset of inflammatory bowel disease in association with immune thrombocytopenic purpura and a transient clinical syndrome mimicking juvenile myelomonocytic leukemia. CASE PRESENTATION: A Japanese boy, who was the first child of non-consanguineous healthy parents, developed bloody diarrhea, perianal fistula, and folliculitis in early infancy and was diagnosed with inflammatory bowel disease. He also developed immune thrombocytopenic purpura and transient features mimicking juvenile myelomonocytic leukemia. The patient failed to respond to various treatments, including elemental diet, salazosulfapyridine, metronidazole, corticosteroid, infliximab, and adalimumab. We identified a novel mutation (c.537G > A, p.T179T) in exon 4 of the IL10RA gene causing unique splicing aberrations and resulting in lack of signaling through the interleukin-10 receptor. At 21 months of age, the patient underwent allogeneic hematopoietic stem cell transplantation and achieved clinical remission. CONCLUSIONS: We describe a novel exonic mutation in the IL10RA gene resulting in infantile-onset inflammatory bowel disease. This mutation might also be involved in his early-onset hematologic disorders. Physicians should be familiar with the clinical phenotype of IL-10 signaling defects in order to enable prompt diagnosis at an early age and referral for allogeneic hematopoietic stem cell transplantation.

Successful diuretics treatment of protein-losing enteropathy in Noonan syndrome.

There are few reports on successful high-dose spironolactone treatment of refractory protein-losing enteropathy (PLE) caused by Fontan procedure. We report successful diuretics treatment with spironolactone and furosemide at standard dose, of refractory PLE in a patient with Noonan syndrome and repaired congenital heart disease. This is the first successful application of diuretics treatment in a patient with refractory PLE without Fontan procedure. This case illustrates that diuretics treatment can be the first-line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome.

Distinguishing primary from secondary Δ(4) -3-oxosteroid 5ß-reductase (SRD5B1, AKR1D1) deficiency by urinary steroid analysis.

OBJECTIVE: Deficiency of Δ(4) -3-oxosteroid 5ß-reductase (5ß-reductase), a bile acid synthesis disorder, presents findings of neonatal cholestasis and hyper-3-oxo-Δ(4) bile aciduria. The 5ß-reductase enzyme participates in not only bile acid synthesis but also hepatic steroid metabolism. Deficiency of 5ß-reductase includes 2 types: primary deficiency, with an SRD5B1 gene mutation; and secondary deficiency, lacking a mutation. Secondary deficiency is caused by fulminant liver failure from various aetiologies including neonatal hemochromatosis (NH). Distinguishing primary from secondary deficiency based on γ-glutamyltransferase (GGT), serum total bile acids (TBA), and urinary bile acid analysis using gas chromatography-mass spectroscopy (GC-MS) is very difficult. SRD5B1 gene analysis is the only reliable method. We examined urinary steroid analysis as a way to distinguish primary from secondary 5ß-reductase deficiency. DESIGN, PATIENTS AND MEASUREMENTS: We examined 12 patients with cholestatic jaundice, normal or slightly elevated GGT, and hyper-3-oxo-Δ(4) bile aciduria using urinary steroid analysis by GC-MS of both cortisol and cortisone compounds, such as 5ß-tetrahydrocortisol (5ß-THF) and 5ß-tetrahydrocortisone (5ß-THE). Patients previously were diagnosed with primary 5ß-reductase deficiency (n = 3), deficiency secondary to NH (n = 3) and deficiency secondary to other liver disorders (n = 6). RESULTS: Urinary steroid analysis in 3 primary deficiency and 3 NH patients showed low 5ß-THE and elevated 5α/5ß-THE ratios, making distinction difficult without also considering the clinical course and abdominal magnetic resonance imaging (MRI) findings, such as a very low signal intensity in liver and/or pancreas, especially in T2 -weighted images. In the six patients with other secondary deficiencies, urinary 5ß-THF and 5α/5ß-THF differed from those in primary deficiency (P < 0·05). CONCLUSIONS: Urinary steroid analysis can distinguish primary and NH-related deficiencies from other secondary deficiencies.