Kosuke Ushijima

Neonatal Dubin‐Johnson Syndrome with Severe Cholestasis: Effective Phenobarbital Therapy

ABSTRACT. We described Dubin‐Johnson syndrome (DJS) with severe cholestasis in a 20‐day‐old Japanese boy. Although neonatal DJS has been sporadically reported, DJS with severe cholestasis has not to our knowledge been described in the English literature. The ratio of urinary coproporphyrin isomer I to urinary total coproporphyrin in our patient was high (93%). Liver histology showed cytoplasmic pigment granules in the liver cells. Administration of phenobarbital (PB) significantly decreased the levels of bilirubin and bile acids in the serum. There was a significant elevation of 1β‐hydroxylated bile acids in the urine. It is predicted that severe cholestasis in neonatal DJS may cause metabolic abnormalities in both bilirubin and bile acids transport.

Serum cystatin-C values in children by age and their fluctuation during dehydration

Background : Serum creatinine level (Cr) is extensively used as an index of glomerular filtration rate (GFR) with bedside patients. As serum Cr level differ by the muscle volume, the use of serum Cr as an index of GFR has long been considered problematic in children.

Pediatric chronic intestinal pseudo-obstruction is a rare, serious, and intractable disease: A report of a nationwide survey in Japan☆

BACKGROUND/PURPOSE A nationwide survey was conducted to identify the clinical presentation of pediatric chronic intestinal pseudo-obstruction (CIPO) in Japan. METHODS Data were collected via a questionnaire, ensuring patient anonymity, from facilities that treat pediatric gastrointestinal diseases in Japan. RESULTS Ninety-two responses were collected from forty-seven facilities. Sixty-two patients (28 males, 34 females) met formal diagnostic criteria for CIPO. The estimated pediatric prevalence was 3.7 in 1 million individuals. More than half the children (56.5%) developed CIPO in the neonatal period. Full-thickness intestinal specimens were available for histopathology assessment in forty-five patients (72.6%). Forty-one (91.1%) had no pathological abnormalities and were considered to be idiopathic. Patients were treated according to the local protocol of each facility. Forty-one patients (66.1%) had restricted oral intake of ordinary diets, and twenty-nine (46.8%) depended on parenteral nutrition. No therapeutic intervention, including medication and surgery, successfully improved oral food intake or obstructive symptoms. Only three patients (4.8%) died from enteritis or sepsis. CONCLUSIONS In Japan, pediatric CIPO is a rare, serious, and intractable disease. The prognosis with respect to survival is good, but unsatisfactory because of the need for prolonged parenteral nutrition and associated potential for restricted quality of life.

Efficacy and Safety of Azathioprine and 6-Mercaptopurine in Japanese Pediatric Patients with Ulcerative Colitis: A Survey of the Japanese Society for Pediatric Inflammatory Bowel Disease

Background and Aims: Azathioprine (AZA) and 6-mercaptopurine (6-MP) have recently been used in Japanese pediatric patients with ulcerative colitis. The aims of this study were to evaluate both the therapeutic efficacy and safety of AZA/6-MP in this group of patients. Methods: Fourteen members of the Japanese Society for Pediatric Inflammatory Bowel Disease reported 35 retrospective cases that received AZA/6-MP and were evaluated for adverse drug effects. In those who tolerated AZA/6-MP, disease activity and corticosteroid doses before and during the first 6 months of therapy were assessed. Results: AZA or 6-MP was safely used in 21 of 35 patients (60%) without adverse drug effects. The disease activity began to decrease from the first month of therapy and the maximum effect was achieved after 3 months. The mean daily prednisolone dose was decreased from 26.9 to 11.6 mg and dose reduction was achieved in 58% of patients after 6 months of therapy. Fourteen of the 35 patients (40%) experienced adverse drug effects, including leukopenia (n = 11), aplastic anemia (n = 1), pancreatitis (n = 1) and liver dysfunction (n = 1). Conclusions: The majority of Japanese children with ulcerative colitis tolerated AZA/6-MP and experienced favorable effects. However, 40% experienced adverse drug effects, mainly myelosuppression.

Intestinal Absorption of Ursodeoxycholic Acid in Children and Adolescents with Inflammatory Bowel Disease

BACKGROUND Ursodeoxycholic acid absorption in the proximal intestine may be impaired in patients with inflammatory bowel disease. METHODS We examined the intestinal absorption of ursodeoxycholic acid by the oral ursodeoxycholic acid tolerance test in 19 children and adolescents with inflammatory bowel disease at various stages, including 8 patients with unoperated Crohns disease, 3 patients with ileal-resected Crohns disease, 8 with ulcerative colitis, and 8 healthy control subjects. RESULTS Ursodeoxycholic acid malabsorption was present in all patients with unoperated Crohns disease in the first diagnosed active stage, in 3 of 5 patients in a relapsing active stage, and in 2 of 8 patients in remission. Ursodeoxycholic acid absorption was significantly lower in patients in the first diagnosed active stage than in the healthy controls (p < 0.01) or in patients in remission (p < 0.01). There was no significant difference between healthy controls and the patients in a relapsing active stage or in remission. Ursodeoxycholic acid absorption was abnormal during the first postoperative month in patients with ileal-resected Crohns disease, but normalized over time. Malabsorption of ursodeoxycholic acid was not observed in any patients with ulcerative colitis. CONCLUSIONS These findings suggest that absorption of ursodeoxycholic acid in the proximal intestine is impaired in patients with Crohns disease and that the oral ursodeoxycholic acid tolerance test is a convenient and useful means of evaluating the absorption of bile acid in the proximal intestine in pediatric patients with ileal or ileocolic Crohns disease.

The burden of rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis among children aged less than 6 years in Japan: a retrospective, multicenter epidemiological survey

BackgroundRotavirus is a leading worldwide cause of acute gastroenteritis in young children. This retrospective hospital-based study assessed the burden of rotavirus gastroenteritis in children younger than 6 years in Japan.MethodsChildren admitted to eight hospitals for acute gastroenteritis between 2008 and 2009 were identified from hospital admission databases. Diagnosis of acute gastroenteritis/rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis was confirmed based on either the International Classification of Diseases and Related Health Problems 10th revision (ICD10) codes (intestinal infectious diseases [AA00-AA09] and rotavirus gastroenteritis [A08.0]) or from rapid rotavirus diagnostic test results.ResultsOf 13,767 hospitalized children, 11.9% (1,644), 4.8% (665) and 0.6% (81) were diagnosed with acute gastroenteritis, rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis, respectively. Among acute gastroenteritis hospitalizations, 40.5% (665/1,644; ICD10 and rapid test) and 57.7% (645/1,118; rapid test only) were confirmed as rotavirus positive. Of 1,563 children with community-acquired acute gastroenteritis, 584 (37.4%) cases were confirmed as rotavirus positive. The median durations of hospitalization for all and community-acquired rotavirus gastroenteritis were 5.0 days (range: 2.0−133.0 days) and 5.0 days (range: 2.0-34.0 days), respectively. Among rotavirus gastroenteritis hospitalizations, 12.2% (81/665) of cases were hospital-acquired and the median duration of hospitalization was 10.0 days (range: 2.0-133.0 days). The median duration of additional hospitalization due to hospital-acquired rotavirus gastroenteritis was 3.0 days (range: 0–14 days). The overall incidence rate of hospital-acquired rotavirus gastroenteritis was 1.0 per 1,000 children hospital-days. The number of rotavirus gastroenteritis cases peaked between February and May in both 2008 and 2009, and the highest number of cases was reported in March 2008 (21.8%; 145/665). The highest number of rotavirus gastroenteritis hospitalizations (24.1%; 160/665) was observed in children aged 12–18 months. The proportion of hospital-acquired rotavirus gastroenteritis was higher in children aged below 18 months as compared to children at least 18 months of age (0.94 [95% CI: 0.71-1.21] vs. 0.39 [95% CI: 0.25-0.58]) and for children hospitalized for at least 5 days compared to those hospitalized for less than 5 days (0.91 [95% CI: 0.72-1.14] vs. 0.15 [95% CI: 0.05-0.32]).ConclusionsBoth community- and hospital-acquired rotavirus gastroenteritis are significant public health problems in Japan. Data from this study justify the need for the introduction and implementation of rotavirus vaccination in the Japanese national immunization program.Trial registrationClinicalTrials.gov, NCT01202201

Leukocytapheresis in Pediatric Patients With Ulcerative Colitis

Objective: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. Patients and Methods: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. Results: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. Conclusions: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

Efficacy of interferon-α treatment in Japanese children with chronic hepatitis C

Background: We investigated the efficacy of natural interferon (IFN)‐α treatment in 34 Japanese children with chronic hepatitis C.

A role for fosfomycin treatment in children for prevention of haemolytic–uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection

The role of antimicrobial therapy for Shiga toxin-producing Escherichia coli (STEC) infection has not been clearly defined. A prospective study identified antibiotic use as a significant risk factor for subsequent development of haemolytic-uraemic syndrome (HUS). However, early treatment with fosfomycin, a bacteriostatic antibiotic, resulted in a significantly decreased risk of HUS. The aim of this study was to evaluate a role of fosfomycin therapy in the development of HUS in children who contracted STEC infection. The study included 118 children who contracted a STEC infection between 1997 and 2013. A pre-defined questionnaire was utilised to collect patient information regarding age, sex, presenting symptoms (fever, abdominal pain, diarrhoea and bloody stool), results of stool culture examination, initial results of white blood cell counts and C-reactive protein (CRP), use of antibiotics, the timing of introduction of antibiotics, and complications including HUS. Of the 118 patients, 64 were diagnosed with HUS and the remaining 54 did not develop HUS. Multivariate analysis showed that three independent factors (age, initial values of CRP and use of fosfomycin) were significantly associated with the occurrence of HUS; of particular note, the adjusted odds ratio for use of fosfomycin was 0.15 (95% confidence interval 0.05-0.45). Use of fosfomycin within the first 5 days of illness may decrease the development of STEC-related HUS in children.

Profile of urinary bile acids in familial intrahepatic cholestasis with Coombs’negative haemolytic anaemia

We present two male siblings with intrahepatic cholestasis and prolonged indirect hyperbilirubinaemia. Their familial intrahepatic cholestasis syndrome was characterized by Coombs’negative haemolytic anaemia, without giant cell transformation of hepatocytes and high concentrations of serum γ‐glutamyl transpeptidase and cholesterol. By gas chromatography‐mass spectrometry, we detected large amounts of 1β‐hydroxylated bile acids, especially lβ,3α,7α,12α‐tetrahydroxy‐5β‐cholan‐24‐oic acid (25.5‐67.9% of total urine bile acids) in the urine during phenobarbital therapy. However, the amount of urinary 1β‐hydroxylated bile acids gradually decreased as the disease progressed. At the end‐stage, we detected large amounts of 7α,12α‐dihydroxy‐3‐oxochol‐4‐en‐24‐oic acid (19.6% of total urine bile acids). The ratio of 7α,12α‐dihydroxy‐3‐oxochol‐4‐en‐24‐oic acid to cholic acid in the urine was 0.8. We conclude that in infants with end‐stage liver failure, the microsomal hydroxylation of bile acids is impaired and the excretion of Δ4‐3‐oxo bile acids is increased.Familial intrahepatic cholestasis, Coombs’negative haemolytic anaemia, 1β‐hydroxylated bile acids, unsaturated ketonic bile acids