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1.
Pediatr Int ; 66(1): e15786, 2024.
Article in English | MEDLINE | ID: mdl-39161233

ABSTRACT

BACKGROUND: Pediatric inflammatory bowel disease (PIBD) affects different age groups and its incidence is increasing worldwide. However, there is a lack of research focusing on age subgroups in Asian countries. In this nationwide population-based study, we investigated the epidemiology of PIBD among different age subgroups in Korea. METHODS: We analyzed Korean health administration data from 2005 to 2016. Data were divided by age at diagnosis as follows: group 1, 0-1 years; group 2, 2-5 years; group 3, 6-9 years; group 4, 10-16 years. We analyzed the overall incidence, temporal changes, and regional differences by age subgroups, using Poisson regression analysis. RESULTS: From 2005 to 2016, 2734 inflammatory bowel disease (IBD) cases were diagnosed among patients under 17 years of age. In the overall population, the incidence rate of PIBD over the entire study period was 2.248/105 person-years (PY), significantly increasing from 1.173/105 PY in 2005-2007 to 3.267/105 PY in 2014-2016. The incidence rates in groups 1 and 2 remained unchanged, whereas those of groups 3 and 4 increased significantly. The same trend was observed when analyzed separately for Crohn's disease (CD) and ulcerative colitis (UC). The incidence rates of CD in groups 3 and 4 showed differences between metropolitan and non-metropolitan areas, whereas those in groups 1 and 2, and UC of all age subgroups showed no difference. CONCLUSIONS: The temporal trend and regional differences of PIBD differed among age subgroups, suggesting that genetic and environmental factors have varying impacts on IBD development across different subgroups.


Subject(s)
Inflammatory Bowel Diseases , Humans , Republic of Korea/epidemiology , Child , Adolescent , Incidence , Male , Female , Child, Preschool , Infant , Infant, Newborn , Inflammatory Bowel Diseases/epidemiology , Age Distribution , Crohn Disease/epidemiology , Colitis, Ulcerative/epidemiology
2.
J Korean Med Sci ; 38(47): e401, 2023 Dec 04.
Article in English | MEDLINE | ID: mdl-38050913

ABSTRACT

BACKGROUND: Several cases of pediatric acute hepatitis of unknown etiology related to adenoviral infections have been reported in Europe since January 2022. The aim of this study was to compare the incidence, severity, possible etiology, and prognosis of the disease with those in the past in Korea. METHODS: The surveillance group collected data between May and November 2022 using a surveillance system. Acute hepatitis of unknown etiology was defined in patients aged < 16 years with a serum transaminase level > 500 IU/L, not due to hepatitis A-E or other underlying causes. For comparison, data from 18 university hospitals were retrospectively collected as a control group between January 2021 and April 2022. RESULTS: We enrolled 270 patients (mean age, 5 years). The most common symptom was fever. However, the incidence was similar between 2021 and 2022. Liver function test results, number of patients with acute liver failure (ALF), liver transplantation (LT), death, and adenovirus detection rates did not differ between the two groups. None of the adenovirus-positive patients in either group experienced ALF, LT, or death. In the surveillance group, adenovirus-associated virus-2 was detected in four patients, one of whom underwent LT. Patients with an unknown etiology showed significantly higher bilirubin levels, a lower platelet count, and a higher LT rate than patients with a possible etiology. CONCLUSION: The incidence of pediatric acute hepatitis of unknown etiology and adenovirus detection rate have not increased in Korea.


Subject(s)
Hepatitis , Liver Failure, Acute , Liver Transplantation , Humans , Child , Child, Preschool , Retrospective Studies , Liver Transplantation/adverse effects , Prognosis , Liver Failure, Acute/diagnosis , Liver Failure, Acute/epidemiology , Liver Failure, Acute/etiology , Acute Disease , Adenoviridae , Republic of Korea/epidemiology
3.
Liver Transpl ; 28(6): 1011-1023, 2022 06.
Article in English | MEDLINE | ID: mdl-34536963

ABSTRACT

Living donor liver transplantation (LDLT) is a significant advancement for the treatment of children with end-stage liver disease given the shortage of deceased donors. The ultimate goal of pediatric LDLT is to achieve complete donor safety and zero recipient mortality. We conducted a retrospective, single-center assessment of the outcomes as well as the clinical factors that may influence graft and patient survival after primary LDLTs performed between 1994 and 2020. A Cox proportional hazards model was used for multivariate analyses. The trends for independent prognostic factors were analyzed according to the following treatment eras: 1, 1994 to 2002; 2, 2003 to 2011; and 3, 2012 to 2020. Primary LDLTs were performed on 287 children during the study period. Biliary atresia (BA; 52%), acute liver failure (ALF; 26%), and monogenic liver disease (11%) were the leading indications. There were 45 graft losses (16%) and 27 patient deaths (7%) in this population during the study period. During era 1 (n = 81), the cumulative survival rates at 1 and 5 years after LDLT were 90.1% and 81.5% for patients and 86.4% and 77.8% for grafts, respectively. During era 2 (n = 113), the corresponding rates were 92.9% and 92% for patients and 89.4% and 86.7% for grafts, respectively. During era 3 (n = 93), the corresponding rates were 100% and 98.6% for patients and 98.9% and 95.4% for grafts, respectively. In the multivariate analyses, primary diagnosis ALF, bloodstream infection, posttransplant lymphoproliferative disease, and chronic rejection were found to be negative prognostic indicators for patient survival. Based on generalized care guidelines and center-oriented experiences, comprehensive advances in appropriate donor selection, refinement of surgical techniques, and meticulous medical management may eventually realize a zero-mortality rate in pediatric LDLT.


Subject(s)
Liver Transplantation , Living Donors , Child , Graft Survival , Humans , Liver Transplantation/methods , Prognosis , Retrospective Studies , Treatment Outcome
4.
Pediatr Transplant ; 26(3): e14207, 2022 05.
Article in English | MEDLINE | ID: mdl-34888999

ABSTRACT

BACKGROUND: Pediatric patients with biliary atresia (BA) often present liver cirrhosis-associated portal hypertension and portal vein (PV) hypoplasia. For successful liver transplantation (LT), it is essential to maintain sufficient PV inflow through stenosis-free PV reconstruction with effective ligation of collateral veins. The aim of this study was to assess the clinical usability of intraoperative cine-portogram (IOCP) in young pediatric patients who underwent LT for BA. METHODS: Medical records of pediatric patients younger than 10 years who underwent primary LT for BA from 2018 to 2020 were reviewed. RESULTS: A total of 31 patients had undergone Kasai portoenterostomy soon after birth. Their median ages at Kasai portoenterostomy and LT were 1 and 11 months, respectively. Types of LT were living-donor LT in 13, deceased-donor split LT in 15, and deceased-donor whole LT in three patients. PV interposition using an iliac vein homograft was performed in 28 patients receiving partial liver grafts. Side-to-side PV unification venoplasty was performed in three patients undergoing whole LT. All patients underwent ligation of collateral veins. IOCP was performed in 6 (19.4%) patients. Four showed no or faint residual venous collaterals. Collateral vein embolization and endovascular stenting were performed in one patient each. PV insufficiency-free survival rate was 100% at 1 year and 93.8% at 3 years. All patients are currently alive with a median follow-up period of 23 months. CONCLUSIONS: Intraoperative cine-portogram can be a useful method for identification and embolization of residual portosystemic collateral veins in young pediatric patients who undergo LT for biliary atresia.


Subject(s)
Biliary Atresia , Liver Transplantation , Biliary Atresia/complications , Biliary Atresia/surgery , Child , Constriction, Pathologic/surgery , Humans , Infant , Liver Transplantation/methods , Living Donors , Portal Vein/surgery
5.
Dig Dis Sci ; 67(11): 5079-5089, 2022 11.
Article in English | MEDLINE | ID: mdl-35094250

ABSTRACT

BACKGROUND: Research using healthcare administrative data with a validated algorithm can reveal the real-world data of rare diseases. AIMS: We investigated an accurate algorithm for detecting incident cases of inflammatory bowel disease (IBD) from healthcare data and analyzed the nationwide population-based epidemiological features in Korea. METHODS: Healthcare data from Songpa-Kangdong districts in Seoul were extracted from the National Health Insurance Service and analyzed to identify the best algorithm reflecting the cohort data. The most accurate criterion was applied to the entire database for further analysis. RESULTS: With the selected working criteria, 37,555 incident cases of IBD (Crohn's Disease [CD], 13,130; ulcerative colitis [UC], 24,425) were identified from 2005 to 2016. The male-to-female ratio was 2.5:1 for CD and 1.4:1 for UC. Over 12 years, the annual standardized incidence rate (SIR) per 100,000 people increased from 1.6 to 2.7 and 3.8 to 4.3 for CD and UC, respectively. The peak age at diagnosis of UC shifted from 55-59 years to 20-24 years, whereas that of CD shifted from 19 to 17 years. The SIR of CD was higher in metropolitan areas than in non-metropolitan areas. CONCLUSIONS: This nationwide population-based epidemiologic study of Korean IBD revealed a gradual increase in the incidence rates and a notable shift toward younger age at diagnosis. Males were predominant in both CD and UC. There was an urban-rural difference in the SIR of CD.


Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Male , Female , Humans , Middle Aged , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/epidemiology , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Crohn Disease/diagnosis , Crohn Disease/epidemiology , Republic of Korea/epidemiology , Delivery of Health Care
6.
Transfus Apher Sci ; 61(3): 103347, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35034842

ABSTRACT

Gestational alloimmune liver disease (GALD) is a materno-fetal alloimmune disorder that targets the fetal liver and often causes neonatal liver failure. GALD most commonly presents as neonatal hemochromatosis (NH), which is a severe neonatal liver injury confirmed by extra-hepatic iron accumulation at various sites. With the discovery of the alloimmune mechanism of GALD, exchange transfusion and intravenous immunoglobulin (IVIG) administration are being used as novel treatments. Here, we present a rare case of an 11-day-old female infant who presented with marked hyperbilirubinemia. Laboratory findings showed significantly elevated direct and indirect bilirubin, high ferritin and alpha fetoprotein levels, high transferrin saturation, and severe coagulopathy. Abdominal magnetic resonance imaging revealed markedly reduced T2 signal intensity in the liver and pancreas compared to the spleen, suggesting iron deposition. The infant was diagnosed with NH and successfully treated with exchange transfusion and four doses of IVIG.


Subject(s)
Fetal Diseases , Hemochromatosis , Liver Diseases , Female , Hemochromatosis/diagnosis , Hemochromatosis/drug therapy , Humans , Immunoglobulins, Intravenous/therapeutic use , Infant , Infant, Newborn , Iron/therapeutic use
7.
Biochem Biophys Res Commun ; 539: 48-55, 2021 02 05.
Article in English | MEDLINE | ID: mdl-33421768

ABSTRACT

CRISPR-Cas systems, including Cas9 and Cpf1 (Cas12a), are promising tools for generating gene knockout mouse models. Unlike Cas9, Cpf1 can generate multiple crRNAs from a single concatemeric crRNA precursor, which is favorable for multiplex gene editing. Recently, a hybrid guide RNA (hgRNA) system employing both Cas9 and Cpf1 was developed for multiplex gene editing. As the crRNA of Cpf1 was linked to the 3' end of the sgRNA for Cas9, it can be split into separate guide RNAs by Cpf1. To examine whether this Cas9-Cpf1 hybrid system is suitable for multiplex gene knockouts in the mouse embryo, we generated an hgRNA that simultaneously targets the mouse Il10ra gene by Cas9 and mouse Dr3 (or Tnfrsf25, death receptor3) gene by Cpf1. The expression of hgRNA from a single promoter induced significant indels at each gene in cultured mouse cells upon the co-expression of both Cas9 and Cpf1. Interestingly, the hgRNA exhibited comparable Cas9-mediated indel activity without Cpf1 expression. Similarly, when the hgRNA was co-microinjected with both Cas9 and Cpf1 mRNAs into mouse zygotes at the pronuclear stage, founder mice were generated harboring mutations in both the Il10ra and Dr3 genes. However, when Cas9 mRNA was used alone without Cpf1 mRNA, the mouse Il10ra gene targeting was significantly decreased. These results indicate that the hgRNA system is a possible tool for multiplex gene targeting in the mouse embryo.


Subject(s)
CRISPR-Associated Protein 9/metabolism , Embryo, Mammalian/metabolism , Endonucleases/metabolism , Gene Editing , Gene Targeting/methods , RNA, Guide, Kinetoplastida/metabolism , Animals , Cell Line , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , RNA, Guide, Kinetoplastida/genetics
8.
BMC Pediatr ; 21(1): 35, 2021 01 14.
Article in English | MEDLINE | ID: mdl-33446154

ABSTRACT

BACKGROUND: Endocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents. METHODS: This study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D3 [25(OH)D3] levels, and BMD were reviewed retrospectively. RESULTS: Short stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D3 level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below - 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased. CONCLUSIONS: Vitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health.


Subject(s)
Colitis, Ulcerative , Inflammatory Bowel Diseases , Adolescent , Bone Density , Child , Female , Humans , Inflammatory Bowel Diseases/complications , Male , Puberty , Retrospective Studies
9.
Acta Radiol ; 62(8): 1088-1096, 2021 Aug.
Article in English | MEDLINE | ID: mdl-32811156

ABSTRACT

BACKGROUND: Validated non-invasive examinations are necessary to monitor liver fibrosis in children with biliary atresia (BA) after the Kasai procedure. PURPOSE: To evaluate the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE), transient elastography (TE), and the serologic biomarkers of aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for evaluating native liver fibrosis in children with BA. MATERIAL AND METHODS: We retrospectively reviewed same-day 2D-SWE and TE liver stiffness (LS) measurements of 63 patients with BA who underwent the Kasai procedure. The APRI and FIB-4 score were computed. Hepatic fibrosis was categorized into three clinical categories based on the ultrasound (US) hepatic morphology and clinical manifestations of liver cirrhosis: I, pre-cirrhotic liver state (n = 15); II, US and/or clinical signs of liver cirrhosis with compensated liver function (n = 27); and III, liver cirrhosis with decompensated liver function (n = 21). We compared area under the receiver operating characteristic curve (AUC) data among 2D-SWE, TE, APRI, and FIB-4 score. Combined evaluation of serologic fibrosis indices and US elastography was conducted and AUCs of combinations were analyzed. RESULTS: 2D-SWE, TE, APRI, and FIB-4 score showed good to excellent diagnostic accuracy for differentiating clinical categories (AUCs 0.779-0.955). AUC values were significantly increased after adding TE to FIB-4 score for detecting liver cirrhosis (P = 0.02). CONCLUSION: 2D-SWE, TE, APRI, and FIB-4 score are accurate non-invasive markers for monitoring native liver fibrosis in patients with BA. Combined use of serologic markers and US elastography could yield more accurate diagnoses of liver fibrosis than serologic markers alone.


Subject(s)
Biliary Atresia/surgery , Elasticity Imaging Techniques/methods , Liver Cirrhosis/diagnosis , Portoenterostomy, Hepatic/adverse effects , Ultrasonography/methods , Adolescent , Aspartate Aminotransferases/blood , Biomarkers/blood , Child , Child, Preschool , Humans , Infant , Liver Cirrhosis/blood , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/etiology , Platelet Count , Portoenterostomy, Hepatic/methods , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Young Adult
10.
Pediatr Transplant ; 24(4): e13666, 2020 06.
Article in English | MEDLINE | ID: mdl-32067332

ABSTRACT

This study aimed to investigate the incidence of PTLD in pediatric liver transplant recipients and the risk factors for the development of PTLD. We also determined clinically useful quantitative EBV PCR parameters for aiding in the diagnosis of EBV-associated PTLD in the pediatric liver transplant recipients at our institute. We reviewed children < 18 years old who had undergone liver transplantations and quantitative analysis of whole blood EBV load at our institute from January 2006 to March 2015. A total of 142 liver transplant recipients were included, and their median age was 1.5 years. Clinically significant high-level EBV DNAemia ≥ 10 000 copies/mL at least twice was observed in 53.5% and PTLD occurred in 9.9%. Among PTLD group, graft failure and mortality rate were as high as 21.4% and 14.3%, respectively. Deceased donor, presence of high-level EBV DNAemia, and primary CMV infection following transplant were associated with an increased risk for PTLD in the multivariate analysis. The peak titer at 10 875 copies/mL could be used as a cutoff value with a sensitivity of 92.9% and a specificity of 37.9%; the rate of increase in EBV load suggested a sensitivity of 64.3% and a specificity of 70.9% at the cutoff value of 44 000 copies/mL/week. In conclusion, the incidence of PTLD following liver transplant in children was as high as 10%. PTLD is associated with significant morbidity and mortality. Close monitoring of EBV DNAemia is crucial for the early diagnosis and proper treatment of PTLD in pediatric liver transplant recipients.


Subject(s)
Herpesvirus 4, Human/isolation & purification , Liver Transplantation , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/epidemiology , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Viral Load , Child , Humans , Incidence , Lymphoproliferative Disorders/virology , Monitoring, Physiologic , Postoperative Complications/virology , Retrospective Studies , Risk Factors
11.
J Pediatr Gastroenterol Nutr ; 70(6): 777-782, 2020 06.
Article in English | MEDLINE | ID: mdl-32443030

ABSTRACT

OBJECTIVES: This study aims to develop a new prognostic score based on changes in serial laboratory data from patients with pediatric acute liver failure (PALF). METHODS: We retrospectively reviewed data on 146 patients with PALF at the Seoul National University Children Hospital (SNUCH) and the Asan Medical Center (AMC). Daily morning laboratory records were obtained for up to 7 days after diagnosis of PALF: total bilirubin (TB) (mg/dL), international normalized ratio for prothrombin time (INR) at enrolment; peak TB, peak INR, peak ammonia (µmol/L); the difference between the peak TB and TB at enrollment (ie, Δpeak TB), the difference between the peak INR and INR at enrollment (ie, Δpeak INR), the maximum change in serial TB (ie, Δdaily TB), the maximum change in serial INR level (ie, Δdaily INR). We assigned nontransplanted patients in SNUCH and AMC to derivation and validation cohorts, respectively. RESULTS: Δpeak TB, Δdaily TB, Δpeak INR, and Δdaily INR were significantly higher in the nonsurvival group. We developed a new score that can predict mortality in nontransplanted patients (derivation cohort n = 42, validation cohort n = 33). PALF-Delta score (PALF-Ds) = [0.232 × Δpeak TB (mg/dL)] + [2.263 × Δdaily INR] + [0.013 × peak ammonia (µmol/L)] - 4.498. The score yielded AUC 0.918 in the derivation cohort (sensitivity 81%, specificity 91%) and AUC 0.947 in the validation cohort (sensitivity 100%, specificity 89%). CONCLUSION: A prognostic scoring system using the change of TB/INR may be useful for predicting mortality in patients with PALF.


Subject(s)
Liver Failure, Acute , Bilirubin , Child , Humans , International Normalized Ratio , Liver Failure, Acute/diagnosis , Prognosis , Retrospective Studies
12.
J Ultrasound Med ; 39(11): 2231-2242, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32401363

ABSTRACT

OBJECTIVES: To investigate the diagnostic value of transient elastography (TE), 2-dimensional (2D) shear wave elastography (SWE), and the serologic fibrosis indices aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for Wilson disease (WD). METHODS: We retrospectively identified patients with a diagnosis of WD who underwent TE and 2D SWE on the same day. Their APRI and FIB-4 scores were calculated. Hepatic involvement was classified into 5 clinical categories (I-V) based on the laboratory findings, hepatic morphologic characteristics on ultrasound (US) imaging, and clinical symptoms of cirrhosis: I, normal (n = 17); II, only biochemical abnormality (n = 15); III, altered hepatic morphologic characteristics (n = 10); IV, compensated liver cirrhosis (n = 3); and V, decompensated liver cirrhosis (n = 0). We compared the area under the receiver operating characteristic curve (AUROC) data for TE, 2D SWE, the APRI, and the FIB-4 score. A combined assessment of the serologic markers and US elastography was performed, and the AUROCs of the combinations were compared. RESULTS: Forty-five patients were included in the study (median age, 16.0 years; range, 3-35 years). Transient elastography, 2D SWE, and APRI were comparable in distinguishing the clinical categories (AUROC, 0.799-0.928). The FIB-4 score showed lower diagnostic value in distinguishing clinical category I from the other categories (AUROC, 0.647). Combining the serologic markers and US elastography significantly increased the AUROC value of the FIB-4 score (with TE and 2D SWE, P = .01 and .02). CONCLUSIONS: Transient elastography and 2D SWE showed excellent diagnostic accuracy for differentiating the clinical categories of hepatic involvement. The APRI showed better diagnostic performance than the FIB-4 score. The assessment of hepatic manifestations in WD can be improved by combining US elastography with serologic indices.


Subject(s)
Elasticity Imaging Techniques , Hepatolenticular Degeneration , Adolescent , Adult , Aspartate Aminotransferases , Child , Child, Preschool , Hepatolenticular Degeneration/diagnostic imaging , Hepatolenticular Degeneration/pathology , Humans , Liver Cirrhosis , Retrospective Studies , Young Adult
13.
J Gastroenterol Hepatol ; 34(12): 2118-2125, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31039275

ABSTRACT

BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX), have been increasingly used to induce and maintain disease remission in patients with Crohn's disease (CD). Despite a considerable non-response rate, little is known about the genetic predictors of response to anti-TNF therapy in CD. Our aim in this study was to investigate the genetic factors associated with response to anti-TNF therapy in patients with CD. METHODS: We performed a two-stage genome-wide association study (GWAS) to identify loci influencing the response to IFX among Korean patients with CD, comprising 42 good responders with mucosal healing and 70 non-responders. The achievement of mucosal healing was assessed by endoscopy and imaging. The functional significance of TRAP1 (TNF receptor associated protein 1) was examined using dextran sodium sulfate-induced colitis model in TRAP1 transgenic mice. RESULTS: The GWAS identified rs2158962, an intronic single nucleotide polymorphism (SNP) of TRAP1, significantly associated with mucosal healing (odds ratio = 4.94; Pcombined  = 1.35 × 10-7 ). In the dextran sodium sulfate-induced acute colitis, TRAP1 transgenic mice showed a better response to IFX than the wild-type mice. CONCLUSIONS: The TRAP1 gene is associated with mucosal healing in CD patients following IFX therapy. Identifying the genetic predictors of mucosal healing to anti-TNF therapy can prevent patients from exposure to ineffective therapies.


Subject(s)
Crohn Disease/drug therapy , HSP90 Heat-Shock Proteins/physiology , Infliximab/therapeutic use , Intestinal Mucosa/drug effects , Wound Healing/drug effects , Adolescent , Adult , Animals , Crohn Disease/genetics , Crohn Disease/physiopathology , Female , Gastrointestinal Agents/therapeutic use , Gene Expression Regulation/physiology , Genome-Wide Association Study , Genotype , HSP90 Heat-Shock Proteins/genetics , Humans , Intestinal Mucosa/physiology , Male , Mice, Transgenic , Phenotype , Polymorphism, Single Nucleotide , RNA, Messenger/genetics , Registries , Wound Healing/genetics , Young Adult
14.
J Med Genet ; 55(9): 587-593, 2018 09.
Article in English | MEDLINE | ID: mdl-29618506

ABSTRACT

BACKGROUND: To identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup. METHODS: Detailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients) from 368 unrelated Korean families were analysed. RESULTS: Compared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings and higher serum creatinine levels, and a lower proportion with favourable outcome (62% vs 80%, P<0.016). At diagnosis, the neurological subgroup had lower serum ceruloplasmin (3.1±2.1 mg/dL vs 4.2±3.2 mg/dL, P<0.001), total copper (26.4±13.8 µg/dL vs 35.8±42.4 µg/dL, P=0.005), free copper (17.2±12.5 µg/dL vs 23.5±38.2 µg/dL, P=0.038) and urinary copper (280.9±162.9 µg/day vs 611.1±1124.2 µg/day, P<0.001) levels. Serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and total bilirubin levels, as well as prothrombin time, were also lower in the neurological subgroup. Liver cirrhosis was more common but mostly compensated in the neurological subgroup. Frameshift, nonsense or splice-site ATP7B mutations and mutations in transduction or ATP hinge domains (2.4% vs 23.1%, P=0.006) were less common in the neurological subgroup. CONCLUSION: The neurological subgroup had distinct clinical, biochemical and genetic profiles. Further studies are required to identify the factors, with or without association with copper metabolism, underlying the neurological presentation for which treatment needs to be targeted to improve the clinical outcome of this subgroup.


Subject(s)
Copper-Transporting ATPases/genetics , Copper/metabolism , Hepatolenticular Degeneration/metabolism , Mutation , Adolescent , Adult , Age of Onset , Asian People , Brain Diseases/metabolism , Ceruloplasmin/analysis , Child , Child, Preschool , Copper/blood , Copper/urine , Copper-Transporting ATPases/metabolism , Creatinine/blood , Female , Hepatolenticular Degeneration/enzymology , Hepatolenticular Degeneration/genetics , Humans , Male , Young Adult
15.
J Ultrasound Med ; 38(3): 747-759, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30117178

ABSTRACT

OBJECTIVES: To assess the diagnostic performance of ultrasound (US) elastography in evaluating portal hypertension in children and compare the liver and spleen stiffness values between the portal hypertension and control groups. METHODS: Studies in the MEDLINE and Embase databases were selected that investigated the diagnostic performance of US elastography in children with portal hypertension up to December 21, 2017. Pooled sensitivity and specificity data were assessed by hierarchical logistic regression modeling. RESULTS: Eleven studies were included in the systematic review, and a meta-analysis could be conducted in 7 of these publications to evaluate the diagnostic performance of US elastography. The summary sensitivity and specificity of this method for liver stiffness were 90% (95% confidence interval [CI], 83%-94%) and 79% (95% CI, 73%-84%), respectively, and the area under the hierarchical summary receiver operating characteristic curve was 0.92 (95% CI, 0.90-0.94). A subgroup analysis of 5 transient elastographic studies revealed similar diagnostic performance (sensitivity, 90%; specificity, 78%). In 10 of the 11 studies that investigated liver stiffness and 2 of the 3 studies that also measured spleen stiffness, patients in the portal hypertension group had a significantly higher stiffness value than the control group (P < .05). CONCLUSIONS: Ultrasound elastography shows good performance in diagnosing portal hypertension and can identify significant differences in liver and spleen stiffness in children with this condition. This method thus has considerable potential as a noninvasive tool for screening portal hypertension-related complications in children with chronic liver disease.


Subject(s)
Elasticity Imaging Techniques/methods , Hypertension, Portal/diagnostic imaging , Liver/diagnostic imaging , Liver/pathology , Spleen/diagnostic imaging , Spleen/pathology , Adolescent , Adult , Child , Child, Preschool , Databases, Factual , Humans , Hypertension, Portal/pathology , Infant , Reproducibility of Results , Sensitivity and Specificity , Young Adult
16.
J Gastroenterol Hepatol ; 33(4): 887-893, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29063720

ABSTRACT

BACKGROUND AND AIM: CDKN2A/CDKN2B locus on 9p21 is reported to be associated with various diseases, including cancer and cardiovascular and inflammatory diseases. Significant downregulation of CDKN2B-AS1 in inflamed colon tissue of inflammatory bowel disease (IBD) cases was reported in Europeans. This study aimed to confirm the suggestive association of CDKN2A/CDKN2B with IBD identified in our recent genome-wide association study (GWAS). METHODS: We examined the association of CDKN2A/CDKN2B locus with IBD in an additional sample of 574 IBD cases and 542 controls, totaling 4068 cases and 8074 controls. In silico study was performed at various levels for functional annotation of the causal variant. Co-localization of the GWAS association signals and the corresponding expression quantitative trait loci in IBD-related tissues was evaluated using eCAVIAR. RESULTS: An expanded GWAS showed genome-wide significant association of rs3731257 at 9p21 with IBD (odds ratio = 1.17, 95% confidence interval = 1.12-1.22, Pcombined  = 5.68 × 10-9 ) and Crohn's disease (odds ratio = 1.22, 95% confidence interval = 1.15-1.28, Pcombined  = 8.85 × 10-9 ) in the Korean population. Co-localization study suggested that both CDKN2B-AS1 and CDKN2A might be functionally associated with the locus in the small intestine. CONCLUSIONS: rs3731257 in CDKN2A/CDKN2B is an IBD-susceptible locus in Koreans, with a suggestive role for small intestine-specific gene regulation. Our findings suggested that alterations of the CDKN2A/CDKN2B locus could affect the pathophysiology of IBD.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p15/genetics , Cyclin-Dependent Kinase Inhibitor p18/genetics , Genome-Wide Association Study , Inflammatory Bowel Diseases/genetics , Asian People/genetics , Cyclin-Dependent Kinase Inhibitor p15/physiology , Cyclin-Dependent Kinase Inhibitor p16 , Cyclin-Dependent Kinase Inhibitor p18/physiology , Gene Expression Regulation/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Humans , Quantitative Trait Loci/genetics
17.
J Korean Med Sci ; 33(51): e324, 2018 Dec 17.
Article in English | MEDLINE | ID: mdl-30546280

ABSTRACT

Oxysterol 7α-hydroxylase deficiency is a very rare liver disease categorized as inborn errors of bile acid synthesis, caused by CYP7B1 mutations. As it may cause rapid progression to end-stage liver disease even in early infancy, a high index of suspicion is required to prevent fatal outcomes. We describe the case of a 3-month-old boy with progressive cholestatic hepatitis and severe hepatic fibrosis. After excluding other etiologies for his early liver failure, we found that he had profuse urinary excretion of 3ß-monohydroxy-Δ5-bile acid derivatives by gas chromatography/mass spectrometry analysis with dried urine spots on filter paper. He was confirmed to have a compound heterozygous mutation (p.Arg388Ter and p.Tyr469IlefsX5) of the CYP7B1 gene. After undergoing liver transplantation (LT) from his mother at 4 months of age, his deteriorated liver function completely normalized, and he had normal growth and development until the current follow-up at 33 months of age. We report the first Korean case of oxysterol 7α-hydroxylase deficiency in the youngest infant reported to undergo successful living donor LT to date.


Subject(s)
Cytochrome P450 Family 7/genetics , Liver Failure/therapy , Liver Transplantation , Steroid Hydroxylases/genetics , Bile Acids and Salts/analysis , DNA Mutational Analysis , Gas Chromatography-Mass Spectrometry , Humans , Infant , Liver Failure/diagnosis , Liver Failure/genetics , Liver Failure/pathology , Living Donors , Male , Polymorphism, Single Nucleotide , Republic of Korea , Steroid Metabolism, Inborn Errors/diagnosis , Steroid Metabolism, Inborn Errors/therapy
18.
J Hum Genet ; 62(2): 305-307, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27829683

ABSTRACT

Mutations in SLC25A13 cause citrin deficiency, which has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and adult-onset type 2 citrullinemia (CTLN2). The purpose of this study was to determine the mutation spectrum and the clinical and biochemical characteristics of citrin deficiency in Korean patients. Thirty-four patients were diagnosed with citrin deficiency based on mutations in SLC25A13, as verified by direct sequencing and long PCR screening of a large transposon insertion. A total of 66 alleles from 33 unrelated families of 34 patients with citrin deficiency (27 NICCD, 2 FTTDCD and 5 CTLN2) were retrospectively identified. The common pathogenic alleles were IVS16ins3kb (33%), c.851_854del (30%) and c.1177+1G>A (12%), and three novel variants were identified. Levels of citrulline, threonine, methionine, tyrosine and arginine and the threonine-to-serine ratio were higher in children with neonatal intrahepatic cholestasis caused by NICCD compared with that in patients with idiopathic neonatal hepatitis (INH). We concluded that Korean patients with citrin deficiency showed the highest frequency of the IVS16ins3kb mutation and that plasma amino-acid profiles can be used to differentiate between NICCD and INH.


Subject(s)
Citrullinemia/genetics , Failure to Thrive/genetics , Mitochondrial Membrane Transport Proteins/genetics , Adolescent , Adult , Alleles , Amino Acids/metabolism , Asian People/genetics , Base Sequence , Citrullinemia/metabolism , Failure to Thrive/metabolism , Female , Gene Frequency/genetics , Humans , Infant , Infant, Newborn , Male , Mitochondrial Membrane Transport Proteins/metabolism , Mutation , Polymerase Chain Reaction , Republic of Korea , Retrospective Studies , Sequence Analysis, DNA , Young Adult
19.
Endoscopy ; 49(5): 438-446, 2017 May.
Article in English | MEDLINE | ID: mdl-28399609

ABSTRACT

Background and aims: The use of endoscopic sphincterotomy (EST) in the management of pancreaticobiliary disease in children is increasing. However, studies of long-term outcomes are limited in pediatric patients. Therefore, this study evaluated the early adverse events and long-term outcomes following EST in pediatric patients. Patients and methods: We retrospectively analyzed data from 198 pediatric patients who underwent ESTs at Asan Medical Center Children's Hospital between 1994 and 2013. The median age was 8.7 years (range 18 months to17 years). We evaluated the indications, success rates, early adverse events, and long-term outcomes. Results: Long-term information was available in 198 patients with a median follow-up duration of 42 months (range, 1.8 - 232.1 months). Early adverse events (< 30 days) following 294 ESTs among 198 patients included pancreatitis in 17 (5.7 %), hemorrhages in 6 (2.0 %), sepsis in 3 (1.0 %), and perforations in 2 (0.7 %). Long-term complications ( > 30 days) developed in 12 patients (6.1 %), including cholangitis with or without bile duct stone (n = 7), and minor papilla restenosis (n = 5). The cumulative incidence rates of long-term complications were 3.1 %, 6.1 %, 9.3 %, and 9.3 %, at 1, 5, 10, and 15 years. There were no procedure-related pancreaticobiliary malignancies or deaths. All adverse events and long-term complications improved with appropriate management. Conclusions: In pediatric patients with pancreaticobiliary disease, EST has a high level of technical success. In addition, pediatric EST showed low rates of early adverse events and long-term complications, which could be managed safely. Our results suggest that EST is a safe method for treating pancreaticobiliary disease, even in the pediatric population.


Subject(s)
Biliary Tract Diseases/surgery , Gastrointestinal Hemorrhage/etiology , Pancreatic Diseases/surgery , Pancreatitis/etiology , Postoperative Complications/etiology , Sphincterotomy, Endoscopic/adverse effects , Adolescent , Child , Child, Preschool , Cholangiopancreatography, Endoscopic Retrograde , Cholangitis/etiology , Choledocholithiasis/etiology , Female , Humans , Infant , Male , Pancreatic Ducts/surgery , Recurrence , Retrospective Studies , Sepsis/etiology , Sphincter of Oddi/surgery , Treatment Outcome
20.
J Pediatr Gastroenterol Nutr ; 64(6): 892-897, 2017 06.
Article in English | MEDLINE | ID: mdl-28107286

ABSTRACT

OBJECTIVES: The aim of the study was to correlate liver stiffness (LS) and hepatic venous-pressure gradient (HVPG) and to evaluate the diagnostic performance of shear-wave elastography (SWE) for predicting clinically significant portal hypertension in children with suspected liver diseases, in consideration of the reliability criteria. METHODS: We identified 33 SWEs from 32 children who underwent HVPG measurement within 2 weeks between June 2012 and October 2015. The correlation between LS and HVPG was assessed. The diagnostic performance for predicting clinically significant portal hypertension (HVPG ≥ 10 mmHg) was assessed using the receiver-operating characteristic curve. Reliable measurement was evaluated based on the coefficient of variation (CV). RESULTS: LS was significantly correlated with HVPG (r = 0.742, P < 0.001). The area under the receiver-operating characteristic curve for predicting clinically significant portal hypertension was 0.914, and the best cutoff value of 18.4 kPa showed sensitivity of 87.5% and specificity of 84.0%. LS measurements having CV ≤ 0.2 were significantly correlated with HVPG (r = 0.774, P < .001), whereas those having CV > 0.2 did not show a significant correlation with HVPG (r = 0.598, P = 0.089). CONCLUSIONS: SWE had excellent diagnostic performance for predicting clinically significant portal hypertension in children with suspected liver diseases. LS measurements having CV ≤ 0.2 may possibly be used as a reliability criterion in SWE measurement.


Subject(s)
Elasticity Imaging Techniques/methods , Hypertension, Portal/diagnostic imaging , Liver/diagnostic imaging , Adolescent , Child , Child, Preschool , Female , Humans , Hypertension, Portal/physiopathology , Infant , Liver/physiopathology , Male , ROC Curve , Retrospective Studies , Sensitivity and Specificity
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