Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia.

BACKGROUND AND AIM: Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. METHODS: From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. RESULTS: Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. CONCLUSIONS: Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

PARVB and HSD17B13 variants are associated with nonalcoholic fatty liver disease in children.

BACKGROUND AND AIM: The aim of this study was to investigate the comprehensive genetic effects of exploratory variants of LYPLAL1, GCKR, HSD17B13, TRIB1, APOC3, MBOAT7, and PARVB on pediatric nonalcoholic fatty liver disease in addition to the previously reported variants of TM6SF2, PNPLA3, and SAMM50 in Korean children. METHODS: A prospective case-control study was conducted involving 309 patients diagnosed using ultrasound and 339 controls. Anthropometric measurements, liver function tests, and metabolic marker analysis were conducted, and fibrosis scores were calculated. Transient elastography was performed in 69 some patients with nonalcoholic fatty liver disease. TaqMan allelic discrimination assays were used for genotyping. The genetic risk scores were calculated using significant variants, namely, HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2, to evaluate the additive effect. RESULTS: Risk allele carriers of the PARVB variant showed significantly higher levels of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, pediatric nonalcoholic fatty liver disease fibrosis score, and aspartate aminotransferase/platelet ratio index. Individuals with a homozygous variant of HSD17B13 showed significantly lower levels of aminotransferase, gamma-glutamyl transferase, liver stiffness measurement, and aspartate aminotransferase/platelet ratio index than those with other genotypes. These parameters did not significantly differ among other variants of LYPLAL1, GCKR, TRIB1, APOC3, and MBOAT7. The genetic risk scores was identified as an independent risk factor for nonalcoholic fatty liver disease and had a positive association with severity. CONCLUSION: HSD17B13 has protective effects on the severity of pediatric nonalcoholic fatty liver disease. Variants of HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2 had an additive effect on nonalcoholic fatty liver disease.

Characteristics of chronic enteropathy associated with SLCO2A1 gene (CEAS) in children, a unique type of monogenic very early-onset inflammatory bowel disease.

BACKGROUND:  Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a unique type of inflammatory bowel disease. CEAS is monogenic disease and is thought to develop from childhood, but studies on pediatric CEAS are scarce. We analyzed characteristics of pediatric CEAS. METHODS: Eleven patients diagnosed with CEAS at Seoul National University Children's Hospital were identified and analyzed. Clinical data of patients were collected. Sanger sequencing of SLCO2A1 was performed on all patients. RESULTS: Patients were diagnosed at a median age of 16.0 years (IQR 11.0 ~ 20.0), and the median age at symptoms onset was only 4.0 years (IQR 2.5 ~ 6.0). Growth delay was observed at the time of diagnosis. Patients showed multiple ulcers or strictures in the small intestine, while the esophagus and colon were unaffected in any patients. Almost half of the patients underwent small intestine resection. The major laboratory features of pediatric CEAS include iron deficiency anemia (IDA), hypoalbuminemia, and near-normal levels of C-reactive protein (CRP). Two novel mutations of SLCO2A1 were identified. The most prevalent symptoms were abdominal pain and pale face. None of the immunomodulatory drugs showed a significant effect on CEAS. CONCLUSIONS: Pediatric CEAS typically develop from very young age, suggesting it as one type of monogenic very early onset inflammatory bowel disease. CEAS can cause growth delay in children but there is no effective treatment currently. We recommend screening for SLCO2A1 mutations to pediatric patients with chronic IDA from a young age and small intestine ulcers without elevation of CRP levels.

Ssu72 phosphatase directly binds to ZAP-70, thereby providing fine-tuning of TCR signaling and preventing spontaneous inflammation.

ZAP-70 is required for the initiation of T cell receptor (TCR) signaling, and Ssu72 is a phosphatase that regulates RNA polymerase II activity in the nucleus. However, the mechanism by which ZAP-70 regulates the fine-tuning of TCR signaling remains elusive. Here, we found that Ssu72 contributed to the fine-tuning of TCR signaling by acting as tyrosine phosphatase for ZAP-70. Affinity purification-mass spectrometry and an in vitro assay demonstrated specific interaction between Ssu72 and ZAP-70 in T cells. Upon TCR stimulation, Ssu72-deficient T cells increased the phosphorylation of ZAP-70 and downstream molecules and exhibited hyperresponsiveness, which was restored by reducing ZAP-70 phosphorylation. In vitro assay demonstrated that recombinant Ssu72 reduced tyrosine phosphorylation of ZAP-70 via phosphatase activity. Cd4-CreSsu72fl/fl mice showed a defect in the thymic development of invariant natural killer T cells and reductions in CD4+ and CD8+ T cell numbers in the periphery but more CD44hiCD62Llo memory T cells and fewer CD44loCD62Lhi naïve T cells, compared with wild-type mice. Furthermore, Cd4-CreSsu72fl/fl mice developed spontaneous inflammation at 6 mo. In conclusion, Ssu72 phosphatase regulates the fine-tuning of TCR signaling by binding to ZAP-70 and regulating its tyrosine phosphorylation, thereby preventing spontaneous inflammation.

Global Incidence and Prevalence of Eosinophilic Esophagitis, 1976-2022: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Owing to 2018 expanded diagnostic criteria for eosinophilic esophagitis (EoE) and thus a possible increase in diagnosis, previous studies on the global incidence and prevalence of EoE may need to be updated. We aimed to describe global, regional, and national trends in the incidence and prevalence of EoE from 1976 to 2022 and analyze their associations with geographic, demographic, and social factors through a systematic review. METHODS: We searched the PubMed/MEDLINE, Embase, CINAHL, Google Scholar, and Cochrane databases from their inception dates to December 20, 2022, for studies that reported the incidence or prevalence of EoE in the general population. We calculated the global incidence and prevalence of EoE using pooled estimates with 95% confidence intervals (CIs) and performed subgroup analysis based on age, sex, race, geographical area, World Bank income group, and diagnostic criteria of EoE. RESULTS: Forty studies met the eligibility criteria, including over 288 million participants and 147,668 patients with EoE from 15 countries across the five continents. The global pooled incidence and prevalence of EoE were 5.31 cases per 100,000 inhabitant-years (95% CI, 3.98-6.63; number of studies, 27; sample population, 42,191,506) and 40.04 cases per 100,000 inhabitant-years (95% CI, 31.10-48.98; number of studies, 20; sample population, 30,467,177), respectively. The pooled incidence of EoE was higher in high-income countries (vs low- or middle-income countries), males, and North America (vs Europe and Asia). The global prevalence of EoE followed a similar pattern. The pooled prevalence of EoE gradually increased from 1976 to 2022 (1976-2001; 8.18; 95% CI, 3.67-12.69 vs 2017-2022; 74.42; 95% CI, 39.66-109.19 cases per 100,000 inhabitant-years). CONCLUSIONS: The incidence and prevalence of EoE have increased substantially and vary widely across the world. Further research is needed to evaluate the incidence and prevalence of EoE in Asia, South America, and Africa.

Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS; OMIM #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present 3 unrelated Korean SDS patients who carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiologic consequences. However, the milder EFL1 variant was still solely able to impair 80S ribosome assembly and induce SDS features in cell line and animal models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligopyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.

The Effectiveness and Safety of Methotrexate as the First-Line Immunomodulator of Maintenance Therapy in Pediatric Crohn Disease.

OBJECTIVES: Methotrexate (MTX) has been used as maintenance therapy for Crohn disease (CD) in adults and children. However, there are only a few studies on the MTX's effectiveness in thiopurine-naïve CD adult patients and children. This study aimed to evaluate the MTX's effectiveness and safety as first immunomodulator for maintenance therapy in pediatric CD. METHODS: This retrospective cohort study recruited 64 pediatric CD patients treated with MTX as a first-line immunomodulator. Clinical remission (CR) was assessed at weeks 14, 26, and 52. Mucosal healing (MH) was assessed at weeks 26 and 52. RESULTS: Of 64 patients who received MTX, CR was noted in 60.9% at week 14, 29.7% with MH in 68.0% at week 26, and 27.8% with MH in 81.8% at week 52. When comparing age subtypes according to the Paris classification, the CR rate was higher in A1a than in the other subtypes at week 26 (60.0% in A1a, 26.5% in A1b, 0% in A2; P = 0.038). There were no differences in disease location, behavior, or perianal involvement. Adverse effects were noted in 30 of 64 (46.9%) patients, including 1 patient who stopped MTX before 26 weeks owing to side effects; increased liver enzymes in 25 (39.0%) patients, leukopenia in 5 (7.8%), nausea in 5 (7.8%), skin erosion in 1 (1.6%), and headache in 1 (1.6%). CONCLUSION: MTX as a first-line immunomodulator may be an effective and safe maintenance therapy for pediatric CD patients.

A Report on a Nationwide Surveillance System for Pediatric Acute Hepatitis of Unknown Etiology in Korea.

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.

Ssu72 regulates alveolar macrophage development and allergic airway inflammation by fine-tuning of GM-CSF receptor signaling.

BACKGROUND: Fine-tuning of immune receptor signaling is critical for the development and functioning of immune cells. Moreover, GM-CSF receptor (GM-CSFR) signaling plays an essential role in the development of certain myeloid lineage cells, including alveolar macrophages (AMs). However, the significance of fine-tuning of GM-CSFR signaling in AMs and its relevance in allergic inflammation have not been reported. OBJECTIVE: Our aim was to explore whether phosphatase Ssu72, originally identified as a regulator of RNA polymerase II activity, regulates AM development and allergic airway inflammation by regulating GM-CSF signaling. METHODS: To address these issues, we generated LysM-CreSsu72fl/fl and Cd11c-CreSsu72fl/fl mice and used ovalbumin- or house dust mite-induced allergic asthma models. RESULTS: Following GM-CSF stimulation, Ssu72 directly bound to the GM-CSFR ß-chain in AMs, preventing phosphorylation. Consistently, mature Ssu72-deficient AMs showed higher phosphorylation of the GM-CSFR ß-chain and downstream molecules, which resulted in greater dysregulation of cell cycle, cell death, cell turnover, mitochondria-related metabolism, and LPS responsiveness in AMs than in mature wild-type AMs. The dysregulation was restored by using a Janus kinase 2 inhibitor, which reduced GM-CSFR ß-chain phosphorylation. LysM-CreSsu72fl/fl mice exhibited deficits in development and maturation of AMs, which were also seen postnatally in Cd11c-CreSsu72fl/fl mice. Furthermore, LysM-CreSsu72fl/fl mice were less responsive to ovalbumin- or house dust mite-induced allergic asthma models than the control mice were; however, their responsiveness was restored by adoptive transfer of JAK2 inhibitor-pretreated mature Ssu72-deficient AMs. CONCLUSION: Our results demonstrate that Ssu72 fine-tunes GM-CSFR signaling by both binding to and reducing phosphorylation of GM-CSFR ß-chain, thereby regulating the development, maturation, and mitochondrial functions of AMs and allergic airway inflammation.

Dextroplantation of Left Liver Graft in Infants.

The position of the left side liver graft is important, and it could lead to complications of the hepatic vein (HV) and portal vein (PV), especially in a small child using a variant left lateral section (vLLS) graft. The purpose of this study was to evaluate the outcome of a novel technique for the implantation of a vLLS graft to the right side (dextroplantation) in infants. For 3 years, 10 consecutive infants underwent dextroplantation using a vLLS graft (group D). The graft was implanted to the right side of the recipient after 90° counterclockwise rotation; the left HV graft was anastomosed to inferior vena cava using the extended right and middle HV stump, and PV was reconstructed using oblique anastomosis without angulation. Surgical outcomes were compared with the historical control group (n = 17, group C) who underwent conventional liver transplantation using a vLLS during infancy. Group D recipients were smaller than group C (body weight <6 kg: 50.0% versus 11.8%; P = 0.03). The rate of graft-to-recipient weight ratio >4% was higher in group D (60.0%) than C (11.8%; P = 0.01). Surgical drains were removed earlier in group D than in group C (15 versus 18 postoperative days [PODs]; P = 0.048). Each group had 1 PV complication (10.0% versus 5.9%); no HV complication occurred in group D, but 3 HV complications (17.6%) occurred in group C (P > 0.05). Hospital stay was shorter in group D than in group C (20 versus 31 PODs; P = 0.02). Dextroplantation of a vLLS graft, even a large-for-size one, was successful in small infants without compromising venous outcomes, compared with conventional vLLS transplantation. We could remove the surgical drains earlier and reduce hospital stays in cases of dextroplantation.

Stage IV Classical Hodgkin Lymphoma-type Posttransplant Lymphoproliferative Disorder in a Pediatric Liver Transplant Patient: A Case Report and Review of the Literature.

Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases with abnormal proliferation of lymphoid tissue and classical Hodgkin lymphoma (CHL) type PTLD is a very rare subtype. We describe a successfully diagnosed and treated CHL-PTLD stage IV pediatric patient, 8 years after liver transplantation. The patient was treated with standard CHL (Children's Cancer Group 5942 group 3) chemotherapy, rituximab and reduction of immunosuppressant. The patient remains in complete remission after 3 years with stable graft function. To our best knowledge, this is the first pediatric case report of a successfully treated stage IV CHL-PTLD after a liver transplant.

The usefulness of noninvasive liver stiffness assessment using shear-wave elastography for predicting liver fibrosis in children.

BACKGROUND: Pediatric patients with liver disease require noninvasive monitoring to evaluate the risk of fibrosis progression. This study aimed to identify the significant factors affecting liver stiffness values using two-dimensional shear-wave elastography (2D-SWE), and determine whether liver stiffness can predict the fibrosis stage of various childhood liver diseases. METHODS: This study included 30 children (22 boys and 8 girls; mean age, 5.1 ± 6.1 years; range, 7 days-17.9 years) who had undergone biochemical evaluation, 2D-SWE examination, histopathologic analysis of fibrosis grade (F0 to F3), assessment of necroinflammatory activity, and steatosis grading between August 2016 and March 2020. The liver stiffness from 2D-SWE was compared between fibrosis stages using Kruskal-Wallis analysis. Factors that significantly affected liver stiffness were evaluated using univariate and multivariate linear regression analyses. The diagnostic performance was determined from the area under the receiver operating curve (AUC) values of 2D-SWE liver stiffness. RESULTS: Liver stiffness at the F0-1, F2, and F3 stages were 7.9, 13.2, and 21.7 kPa, respectively (P < 0.001). Both fibrosis stage and necroinflammatory grade were significantly associated with liver stiffness (P < 0.001 and P = 0.021, respectively). However, in patients with alanine aminotransferase (ALT) levels below 200 IU/L, the only factor affecting liver stiffness was fibrosis stage (P = 0.030). The liver stiffness value could distinguish significant fibrosis (≥ F2) with an AUC of 0.950 (cutoff value, 11.3 kPa) and severe fibrosis (F3 stage) with an AUC of 0.924 (cutoff value, 18.1 kPa). The 2D-SWE values for differentiating significant fibrosis were 10.5 kPa (≥ F2) and 18.1 kPa (F3) in patients with ALT levels below 200 IU/L. CONCLUSION: The liver stiffness values on 2D-SWE can be affected by both fibrosis and necroinflammatory grade and can provide excellent diagnostic performance in evaluating the fibrosis stage in various pediatric liver diseases. However, clinicians should be mindful of potential confounders, such as necroinflammatory activity or transaminase level, when performing 2D-SWE measurements for liver fibrosis staging.

Colorectal Cancer associated with pediatric inflammatory bowel disease: a case series.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of Colorectal cancer (CRC), and its most important risk factors are the duration and extent of the disease. Pediatric-onset inflammatory bowel disease has a tendency for a more extensive, more severe, and longer predicted disease duration than adult-onset inflammatory bowel disease. This study aimed to identify the clinical characteristics of patients with CRC related to pediatric-onset IBD and consider the appropriateness of current surveillance endoscopy recommendations for the detection of premalignant lesions and early-stage CRC. METHODS: We searched a research platform based on the SUPREME electronic medical record data-mining system to identify cases of colorectal malignancy in patients with pediatric IBD that presented between 2000 and 2020. RESULTS: During the follow-up, 4 (1.29 per 1000 person years) out of 443 patients with PIBD was diagnosed with CRC. The median age at diagnosis of CRC was 18.5 (range: 15-24) years, and the median period from diagnosis of IBD to CRC was 9.42 (range: 0.44-11.96) years. The sigmoid colon was the most frequent location of CRC (in 3 of the 4 cases). Adenocarcinoma was the most common histological type (in 2 of the 4 cases). CONCLUSIONS: Patients with pediatric-onset IBD exhibited a much shorter disease duration than that of adult-onset IBD at the time of diagnosis of CRC, suggesting that surveillance endoscopy for the detection of precancerous lesions and early-stage cancer should be initiated earlier in pediatric patients than in adult patients.

Development of a Prognostic Score to Predict Mortality in Patients With Pediatric Acute Liver Failure.

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.

Mutation spectrum and biochemical features in infants with neonatal Dubin-Johnson syndrome.

BACKGROUND: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder presenting as isolated direct hyperbilirubinemia.DJS is rarely diagnosed in the neonatal period. The purpose of this study was to clarify the clinical features of neonatal DJS and to analyze the genetic mutation of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2). METHODS: From 2013 to 2018, 135 infants with neonatal cholestasis at Seoul National University Hospital were enrolled. Genetic analysis was performed by neonatal cholestasis gene panel. To clarify the characteristics of neonatal DJS, the clinical and laboratory results of 6 DJS infants and 129 infants with neonatal cholestasis from other causes were compared. RESULTS: A total of 8 different ABCC2 variants were identified among the 12 alleles of DJS. The most common variant was p.Arg768Trp (33.4%), followed by p.Arg100Ter (16.8%). Three novel variants were identified (p.Gly693Glu, p.Thr394Arg, and p.Asn718Ser). Aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in infants with DJS than in infants with neonatal cholestasis from other causes. Direct bilirubin and total bilirubin were significantly higher in the infants with DJS. CONCLUSIONS: We found three novel variants in 6 Korean infants with DJS. When AST and ALT levels are normal in infants with neonatal cholestasis, genetic analysis of ABCC2 permits an accurate diagnosis.

Development of Hepatocellular Carcinoma in Patients with Glycogen Storage Disease: a Single Center Retrospective Study.

BACKGROUND: Glycogen storage disease (GSD) is an inherited disorder leading to abnormal glucose metabolism and glycogen accumulation, and is associated with various complications including hepatic adenoma and hepatocellular carcinoma. The aim of this study was to analyze the risk factors for hepatic adenoma and its malignant change, and the hepatocellular carcinoma-free survival rate in patients with GSD who developed adenoma. METHODS: A total of 72 patients with GSD who were enrolled from March 1982 to September 2013 at Seoul National University Children's Hospital were retrospectively analyzed, and the median follow-up period was 19.2 years. RESULTS: Thirty-two patients (44.4%) developed hepatic adenoma at an age range of 7.9-26.3 years (median, 14.3 years). Among the 32 patients with hepatic adenoma, 4 patients (12.5%) developed hepatocellular carcinoma on an average interval of 6.7 years between the diagnosis of adenoma and the development of hepatocellular carcinoma. GSD type I and portacaval shunt operation were found to be the risk factors for hepatic adenoma development. The hepatocellular carcinoma-free survival rate at 10 years from adenoma development was 82%. CONCLUSION: The present study found that portacaval shunt operation increases the risk of development of hepatic adenoma in GSD patients, especially in GSD type I. The hepatic adenoma in GSD patients has a potential of malignant transformation, which should be keep in mind in follow-up process of the disease.

A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas.

Consumptive hypothyroidism is a rare paraneoplastic syndrome characterized by excessive inactivation of the thyroid hormones due to increased type 3 iodothyronine deiodinase activity of tumors. We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis. Diffuse infiltration of hepatic hemangiomas was detected on abdominal imaging studies, and thyroid function screening test revealed severe hypothyroidism, which necessitated the administration of higher-than-usual doses of levothyroxine for the normalization of thyroid function. The patient was successfully treated with propranolol, prednisolone, and levothyroxine, and he showed normal thyroid function at 3 months of age and normal neurodevelopment at 9 months of age. This case highlights the importance of early recognition and prompt management of consumptive hypothyroidism in patients with infantile hepatic hemangiomas.

A Pediatric Case of a D-Penicillamine Induced ANCA-associated Vasculitis Manifesting a Pulmonary-Renal Syndrome.

D-penicillamine has been reported to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis presenting as rapidly progressive glomerulonephritis or pulmonary-renal syndrome mostly in adults. We report a pediatric case of D-penicillamine induced ANCA-associated vasculitis that manifests as a pulmonary-renal syndrome with a mild renal manifestation. A 13-year-old girl who has been taking D-penicillamine for five years under the diagnosis of Wilson disease visited the emergency room because of hemoptysis and dyspnea. She had diffuse pulmonary hemorrhage, microscopic hematuria, and proteinuria. Myeloperoxidase ANCA was positive, and a renal biopsy revealed pauci-immune crescentic glomerulonephritis. Under the diagnosis of D-penicillamine-induced ANCA-associated vasculitis, D-penicillamine was switched to trientine, and the patient was treated with plasmapheresis, glucocorticoid, cyclophosphamide, and mycophenolate mofetil. Pulmonary hemorrhage improved rapidly followed by the disappearance of the hematuria and proteinuria five months later.

Prevalence and risk factors of elevated alanine aminotransferase among Korean adolescents: 2001-2014.

BACKGROUND: An elevated alanine aminotransferase (ALT) level is a surrogate marker of non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in adolescents. The majority of previous NAFLD studies in adolescents were performed in selected obese populations or had a cross-sectional design without a time-trend analysis. The purpose of this study was to estimate the prevalence and time trends of elevated ALT levels in a general adolescent population and to identify factors associated with ALT elevation. METHODS: We analysed data of adolescent participants (aged 10-18 years) from the Korean National Health and Nutrition Examination Survey 2001-2014, a representative sample of the general population in South Korea. Suspected NAFLD was defined as ALT elevation (> 30 U/L) without hepatitis B surface antigen. In all statistical analyses, sampling weight- and design-based data were used. RESULTS: ALT was elevated in 5.3% (standard error: 0.3%) of the study population of adolescent participants (N = 8455). No significant trends were found from 2001 to 2014 in the prevalence of elevated ALT among male and female adolescents. In multiple logistic regression analysis, elevated ALT was independently associated with sex (odds ratio [OR] male versus female 4.5; 95% CI, 3.3-6.2), obesity (OR 7.6; 95% CI, 5.3-11.0), and truncal obesity (OR 2.5; 95% CI, 1.8-3.5). Furthermore, male sex, obesity, truncal obesity and high household income level were associated with log-transformed ALT levels in multiple regression analysis. CONCLUSIONS: In Korean adolescents of both genders, the prevalence of elevated ALT levels was stable from 2001 to 2014. This study has revealed that sex, obesity, truncal obesity and household income level are associated with ALT elevation in adolescents.