Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature.

Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.

Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis.

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.

Natural history and clinical features of hepatitis C virus infection during childhood: A nationwide, observational survey in Japan.

AIM: Few data on spontaneous clearance rates of cases of mother-to-child transmission of hepatitis C viral (HCV) infection are available in Japan. Furthermore, the treatment courses of interferon-based and direct-acting antiviral agent (DAA) therapies for children are also unclear. Our aim was thus to clarify the long-term natural progression of HCV infection and the treatment outcomes of children in Japan. METHODS: We conducted a combined multicenter, observational survey involving 65 pediatric institutions in Japan. Pediatric HCV infection cases with patients born between 1973 and 2021 were collected over the 11-year period from 2012 to 2022. A total of 563 patients were enrolled, with 190 excluded for having insufficient laboratory data or treatment information, resulting in 373 eligible cases. RESULTS: Of 328 cases of mother-to-child infection, 34 (10.4%) had spontaneous clearance, with a median time to spontaneous clearance of 3.1 years (range 0.9-7.2 years). Of the total 373 eligible cases, 190 received antiviral therapy (interferon-based therapy, 158; DAA therapy, 32). Sustained virologic response rates after first-line treatment were 75.3% (119/158) and 100% (32/32) for interferon-based therapy and DAA therapy, respectively, with the DAA group showing a shorter time from therapy initiation to viral negativity (2.7 vs. 1.0 months; p = 0.0031). CONCLUSIONS: Approximately 10% of Japanese children infected by mother-to-child transmission achieve spontaneous resolution of HCV infection. Our findings indicate that DAA therapy is safe and highly effective in Japanese children, achieving higher sustained virologic response rates and shorter time to clearance of the virus compared with interferon-based therapy.

Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2.

BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS: From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS: Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS: Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.

Bile acid profiles in adult patients with biliary atresia who achieve native liver survival after portoenterostomy.

Bile acids have received increasing attention as a marker of the long-term prognosis and a potential therapeutic target in patients with biliary atresia, which is a progressive disease of the hepatobiliary system. A detailed analysis of serum and urinary bile acid compositions was conducted to assess the characteristics of bile acid profiles and the correlation between bile acid profiles and liver fibrosis markers in adult patients with biliary atresia who achieved bilirubin normalization. Serum total bile acids and glucuronide-conjugated (glyco- and tauro-) cholic acids (GCA and TCA) and chenodeoxycholic acids (GCDCA and TCDCA) were significantly higher in patients with biliary atresia than in healthy controls, whereas unconjugated CA and CDCA showed no significant difference. There were no significant differences in CA to CDCA ratios and glycine-to-taurine-conjugated ratios. Urinary glycocholic acid 3-sulfate (GCA-3S) was significantly higher in patients with biliary atresia. Serum GCDCA showed a strong positive correlation with Mac-2 binding protein glycosylation isomer (M2BPGi). These results demonstrate that bile acid congestion persists into adulthood in patients with biliary atresia, even after cholestasis has completely improved after Kasai portoenterostomy. These fundamental data on bile acid profiles also suggest the potential value of investigating bile acid profiles in patients with biliary atresia.

Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.

Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites.

OBJECTIVE: To examine whether it is possible to screen for bile acid synthesis disorders (BASDs) including peroxisome biogenesis disorder 1a (PBD1A) and Niemann-Pick type C1 (NPC1) at the time of newborn mass screening by measuring the intermediary metabolites of bile acid (BA) synthesis. METHODS: Patients with 3ß-hydroxy-ΔSuchy et al. (2021)5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency (n = 2), 3-oxo-ΔPandak and Kakiyama (n.d.)4-steroid 5ß-reductase (SRD5B1) deficiency (n = 1), oxysterol 7α-hydroxylase (CYP7B1) deficiency (n = 1), PBD1A (n = 1), and NPC1 (n = 2) with available dried blood spot (DBS) samples collected in the neonatal period were included. DBSs from healthy neonates at 4 days of age (n = 1055) were also collected for the control. Disease specific BAs were measured by newly optimized liquid chromatography-tandem mass spectrometry with short run cycle (5-min/run). The results were validated by comparing with those obtained by the conventional condition with longer run cycle (76-min/run). RESULTS: In healthy specimens, taurocholic acid and cholic acid were the two major BAs which constituted approximately 80% in the measured BAs. The disease marker BAs presented <10%. In BASDs, the following BAs were determined for the disease specific markers: Glyco/tauro 3ß,7α,12α-trihydroxy-5-cholenoic acid 3-sulfate for HSD3B7 deficiency (>70%); glyco/tauro 7α,12α-dihydroxy-3-oxo-4-cholenoic acid for SRD5B1 deficiency (54%); tauro 3ß-hydroxy-5-cholenoic acid 3-sulfate for CYP7B1 deficiency (94%); 3α,7α,12α-trihydroxy-5ß-cholestanoic acid for PBD1A (78%); and tauro 3ß,7ß-dihydroxy-5-cholenoic acid 3-sulfate for NPC1 (26%). *The % in the parenthesis indicates the portion found in the patient's specimen. CONCLUSIONS: Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs. The present method is a quick and affordable test for screening for these inherited diseases.

Differentiation of Active Ulcerative Colitis vs Noninflammatory Bowel Disease Proctitis by Transperineal Superb Microvascular Imaging.

BACKGROUND: Transabdominal ultrasonography and transperineal ultrasonography (TPUS) appear correspond to colonoscopy (CS) for evaluating ulcerative colitis (UC) activity, but their utility in UC diagnosis remains unclear. This research compared the accuracy of TPUS and CS for assessing rectal activity and differentiating noninflammatory bowel disease proctitis from UC in pediatric cases. METHODS: The study is a blinded, prospective, and controlled trial. Prospectively, values of fecal calprotectin (FCP) and findings of the TPUS and CS were compared between child cases of UC and non-IBD proctitis. Findings of rectal wall thickening (RWT), rectal wall flow (RWF) on power Doppler, and microvascular signal at wall circumference (MSWC) on monochrome superb microvascular imaging assessed using TPUS were compared with the CS. RESULTS: Thirty patients with Mayo endoscopic subscore (MES) 0 to 1 UC, 57 with MES 2 to 3 UC, and 44 with proctitis were registered. Fecal calprotectin, RWF, and MSWC indicated significant differences among the groups (P < .05). Rectal wall thickening showed no significant difference between MES 0-1 and proctitis (P = .76). Rectal wall thickening and MSWC were independent predictors of endoscopic activity of UC, resulting in a sensitivity and specificity of 100% for RWT ≥4.5 mm and positive MSWC. Fecal calprotectin and RWF were independent predictors for differentiating MES 0 to 1 and proctitis, and FCP and RWT were independent predictors for differentiating MES 2 to 3 and proctitis. Sensitivity and specificity were 77.2% and 80.9%, respectively, for FCP >242.5 µg/g and RWF negative; and they were both 100% for RWT >4.1 mm and MSWC positive. CONCLUSIONS: Transperineal ultrasonography with mSMI may enable the evaluation of rectal activity and differentiation of UC from non-IBD proctitis with accuracy comparable to endoscopy.

Transperineal ultrasonography with superb microvascular imaging can differentiate ulcerative colitis from noninflammatory bowel disease proctitis and is therefore useful in distinguishing whether diarrhea and bloody stool during the treatments of ulcerative colitis are due to recurrence or infection.

Pediatric Pancreatic Endocrine Tumor Presenting as Acute Pancreatitis: A Case Report.

Pancreatic neuroendocrine tumors (PNETs) are relatively rare, especially in the pediatric age group. This report describes a pediatric case of acute pancreatitis secondary to stenosis of the main pancreatic duct due to a PNET. The patient was a boy, thirteen and a half years old, who presented with persistent low-grade fever, nausea, and abdominal pain. He was diagnosed with acute pancreatitis based on the elevation of serum pancreatic enzyme levels and abdominal ultrasonography findings of enlargement of the pancreas and dilatation of the main pancreatic duct. Abdominal contrast-enhanced computed tomography (CT) showed a 5.5 mm, contrast-enhanced mass in the head of the pancreas. His symptoms resolved with conservative treatment, although the pancreatic tumor grew slowly. At fifteen years and four months, since the tumor had enlarged to 8.0 mm, the patient underwent pancreaticoduodenectomy for therapeutic and diagnostic purposes. Based on the pathological evaluation, he was diagnosed with PNET (grade: G1). The patient has been free of tumor recurrence for 10 years and requires no additional therapy. In this report, the clinical characteristics of PNETs are also discussed, comparing the clinical features of adult-onset and pediatric-onset cases that initially present as acute pancreatitis.

Eosinophilic enteritis requiring differentiation from chronic enteropathy associated with SLCO2A1 gene: A case report.

BACKGROUND: Eosinophilic gastrointestinal disease (EGID) is a disorder characterized by infiltration of eosinophils causing mucosal damage and dysfunction of the gastrointestinal tract. The endoscopic findings of eosinophilic enteritis (EoN), an EGID variant, are nonspecific and occasionally difficult to diagnose. In contrast, chronic enteropathy associated with SLCO2A1 (CEAS) is a chronic persistent small intestinal disorder characterized by endoscopic findings such as multiple oblique and circular ulcers. CASE SUMMARY: We report the case of a 10-year-old boy who had suffered abdominal pain and fatigue for the preceding 6 mo. He was referred to our institute for investigation of suspected gastrointestinal bleeding because of severe anemia with hypoproteinemia and positive fecal human hemoglobin. The upper and lower gastrointestinal endoscopic findings were normal; however, double-balloon small bowel endoscopy showed multiple oblique and circular ulcers with discrete margins and mild constriction of the intestinal lumen in the ileum. The findings were highly consistent with CEAS, but urine prostaglandin metabolites were within normal limits, and no previously reported mutations in the SLCO2A1 gene were identified. Histological evaluation demonstrated moderate to severe eosinophilic infiltration localized to the small intestine suggesting a diagnosis of EoN. Clinical remission was maintained with montelukast and a partial elemental diet, but emergent surgery for bowel obstruction due to small intestinal stenosis was performed two years after the initial treatment. CONCLUSION: EoN should be considered in the differential diagnosis of CEAS-like small intestinal ulcerative lesions and normal urinary prostaglandin metabolite levels.

Age at surgery and native liver survival in biliary atresia: a systematic review and meta-analysis.

Biliary atresia (BA) is a childhood rare disease of the liver and bile ducts that requires prompt surgical intervention. Age at surgery is an important prognostic factor; however, controversy exists with regard to the benefit of early Kasai procedure (KP). We aimed to conduct a systematic review and meta-analysis to examine the relationship between the age at KP and native liver survival (NLS) of BA patients. We performed the electronic database search using Pubmed, EMBASE, Cochrane, and Ichushi Web and included all relevant studies published from 1968 up to May 3, 2022. Studies that examined the timing of KP at ages 30, 45, 60, 75, 90, 120, and/or 150 days were included. The outcome measures of interest were NLS rates at 5, 10, 15, 20, and 30 years post-KP and the hazard ratio or risk ratio for NLS. The quality assessment was used using the ROBINS-I tool. Among 1653 potentially eligible studies, nine articles met the inclusion criteria for the meta-analysis. Meta-analysis for hazard ratios revealed that there was a significantly faster time to liver transplantation in the group of patients who had KP at later timing as compared with earlier KP (HR = 2.12, 95% CI 1.51-2.97). The risk ratio comparing KP ≤ 30 days and KP ≥ 31 days on native liver survival was 1.22 (95% CI 1.13-1.31). The sensitivity analysis showed that comparing KP ≤ 30 days and KP 31-60 days, the risk ratio was 1.13, 95% CI 1.04-1.22.  Conclusion: Our meta-analysis showed the importance of early diagnosis and surgical interventions ideally before 30 days of life in infants with BA on native liver survival on 5, 10, and 20 years. Therefore, effective newborn screening of BA targeting KP ≤ 30 days is needed to ensure prompt diagnosis of affected infants. What is Known: • Age at surgery is an important prognostic factor. What is New: • Our study performed an updated systematic review and meta-analysis to examine the relationship between age at Kasai procedure and native liver survival in patients with BA.

Accuracy of Transperineal Ultrasonography for Assessing Rectal Lesions in Paediatric Ulcerative Colitis: A Prospective Study.

BACKGROUND AND AIMS: Transabdominal ultrasonography [TAUS] appears comparable to colonoscopy for evaluating ulcerative colitis [UC] activity, but it has low accuracy in rectal evaluation. In this study, the accuracy of transperineal ultrasonography [TPUS] for evaluating rectal activity was compared to that of colonoscopy in paediatric UC cases. METHODS: Faecal calprotectin [FCP] values and TPUS and colonoscopic findings were compared prospectively in paediatric UC cases. Rectal wall thickening [RWT] and rectal wall flow [RWF] on power Doppler evaluated by TPUS were compared with the colonoscopy findings and were also measured on TAUS and assessed for the concordance rate of each finding. RESULTS: Thirty Mayo endoscopic sub-score [MES] 0-1 UC cases and 57 MES 2-3 UC cases were enrolled. FCP, RWT and RWF showed significant differences between the two groups [p < 0.05]. RWT and RWF were independent predictors of UC endoscopic activity, showing sensitivity of 95.8% and specificity of 100% with RWT ≥ 4.5 mm and positive RWF. The concordance rates between TPUS and TAUS findings in MES 2-3 were moderate to fair, whereas those in MES 0-1 were fair to poor. The concordance rates between ultrasonic examiners were good for both TAUS and TPUS. CONCLUSIONS: TPUS may evaluate rectal activity of UC with accuracy comparable to endoscopy. If accurate ultrasonic screening for the total colon can be performed by TPUS and TAUS, repeated evaluation of short-term treatment response may be possible.

Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease.

CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3ß-hydroxy-5-cholesten-(25R)26-oic acid (3ßHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3ßHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3ßHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1-/- mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3ßHCA levels were maintained at basal levels in ND-fed Cyp7b1-/- mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1-/- mice developed insulin resistance (IR) with subsequent 26HC/3ßHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1-/- mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3ßHCA accumulation. The results suggest 26HC/3ßHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3ßHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.

An Isolated Intestinal Juvenile Polyp Diagnosed by Abdominal Ultrasonography and Resected by Double-Balloon Endoscopy: A Case Report and Literature Review.

Juvenile polyps, typically localized in the rectum and sigmoid colon, are a common cause of pediatric bloody stool. An isolated small intestinal juvenile polyp is uncommon and generally difficult to diagnose. The first case of an isolated juvenile polyp diagnosed by abdominal ultrasonography before acute abdomen had developed and resected by double-balloon endoscopy is presented along with a review of previous reports including this case. A two-year-old Japanese boy was referred to our institute for further evaluation of anemia persisting from one year of age. Laboratory findings showed mild iron deficiency anemia and elevated fecal human hemoglobin (Hb) and fecal calprotectin values. Upper and lower endoscopic findings showed no abnormalities. Because the abdominal ultrasonography performed one year later demonstrated a 15 mm jejunal polyp, combined with a similar finding on small intestinal capsule endoscopy, this was diagnosed as an isolated lesion. The lesion was resected by cautery with double-balloon endoscopy and diagnosed as a juvenile polyp pathologically. All clinical symptoms disappeared, and all laboratory data improved after treatment, without recurrence for more than one year after the procedure. Abdominal ultrasonographic screening and the fecal calprotectin value led to the diagnosis and non-surgical invasive treatment of an isolated small intestinal juvenile polyp.

The Coexistence of TRPV6 Variants With Other Pancreatitis-Associated Genes Affects Pediatric-Onset Pancreatitis.

OBJECTIVES: Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 ( TRPV6 ). Interestingly, 20%-57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen, serine protease inhibitor Kazal type 1, chymotrypsin C, cystic fibrosis transmembrane conductance regulator, and carboxypeptidase A1. In this study, we focused on pediatric patients with acute recurrent pancreatitis or CP with at least 1 variant in these 5 genes and investigated the presence of coexisting TRPV6 mutations. METHODS: Ninety Japanese pediatric patients (median age at first onset, 8.0 years) who had at least 1 variant of these 5 genes were enrolled in this study. DNA samples were extracted for analysis from peripheral blood leukocytes. Coding regions of TRPV6 were screened by Sanger sequencing. RESULTS: Regardless of functional defects or non-defects in TRPV6 variants, 14 of the 90 patients (15.6%) were trans-heterozygous for TRPV6 variants [p.A18S (n = 3), p.C197R (n = 3), p.I223T (n = 3), p.D324N (n = 4), p.M418V (n = 3), p.V540F (n = 1), p.A606T (n = 1), and p.M721T (n = 3)] and the 5 susceptibility genes noted above. Of these variants, p.D324N, p.V540F, and p.A606T are associated with pancreatitis. Three patients had the ancestral haplotype [p.C197R + p.M418V + p.M721T]. CONCLUSIONS: Overall, 4 of 90 patients (4.4%) had the coexistence of clearly pathogenic TRPV6 variants with pancreatitis-associated variants. The cumulative accumulation of these genetic factors may contribute to the development of pancreatitis at a young age.

Cost-Effectiveness Analysis of Universal Screening for Biliary Atresia in Japan.

OBJECTIVE: To evaluate the cost-effectiveness of universal newborn screening using stool color card or direct bilirubin (DB) testing when comparing with no screening for biliary atresia in Japanese setting. STUDY DESIGN: A decision analytic Markov microsimulation model was developed to evaluate the universal screening for biliary atresia. Our screening strategies included stool color card, DB, or no screening. The outcomes of all newborns undergoing 3 strategies were simulated to analyze event-free life-years defined as liver transplant-free survival, costs, and incremental cost-effectiveness ratio (ICER) over a 25-year period with an annual discount rate of 2% applied for both costs and outcomes. A 1-way sensitivity analysis was performed to assess the uncertainty. RESULTS: There were 941 000 newborn infants in our cohort and 114 cases of biliary atresia. The base case analysis showed that the stool color card strategy was $14 927 337 higher than no screening with an increase in 44 more event-free life-years gained, resulting in an ICER of $339 258 per event-free life-year gained. The DB screening strategy compared with stool color card was $138 994 060 higher with an increase in 271 more event-free life-years gained and an ICER of $512 893 per event-free life-year gained. The DB screening strategy compared with no screening resulted in an ICER of $488 639 per event-free life-year gained. The DB screening resulted in 16 fewer liver transplants than stool color card and stool color card had 2 fewer liver transplants than no screening. CONCLUSIONS: Universal screening for biliary atresia could be cost-effective depending on the willingness to pay thresholds for health benefits.

Profiling of Urinary Glucuronidated Bile Acids across Age Groups.

We investigated the age-dependent changes in urinary excretion of glucuronidated bile acids at the C-3 position. Bile acid 3-glucuronides accounted for 0.5% of urinary bile acids in neonates, and the proportion of bile acid 3-glucuronides plateaued at 1-3 years of age. The 3-glucuronides of secondary bile acids were first secreted at 3 months of age, the same time as the establishment of the gut bacterial flora in infants. A considerable portion of bile acid 3-glucuronides were present as non-amidated forms. Our results indicate dynamic hepatic enzyme activity in which the levels of uridine 5'-diphospho-glucuronosyltransferases (UGTs) differ by age group, with higher glucuronidation activity of UGTs towards nonamidated bile acids than amidated bile acids.