지속성 고빌리루빈혈증과 연관된 모유 황달에서UGT1A1(Gly71Arg, TATA box) 다형성에 대한 연구

이재명,한영지,김지숙,김은령 대한소아청소년과학회 2008 Clinical and Experimental Pediatrics (CEP) Vol.51 No.2

Purpose:It has been known that breast milk cause prolonged unconjugated hyperbilirubinemia. UGT1A1 is a important gene of uridine diphosphate glucuronosyltransferase (UGT) which has a major role of bilirubin metabolism. These findings suggest that there is a relationship between UGT1A1 gene mutation and prolonged jaundice of breast feeding infant. The aim of study was to investigate whether a polymorphism of the UGT1A1 gene exist in prolonged hyperbilirubinemia of breast milk feeding Korean infant. Methods:The genomic DNA was isolated from 50 full term Korean neonates, who had greater than a 10 mg/dL of serem bilirubin after 2 weeks of birth with no significant cause, and the other genomic DNA was isolated from 162 full term Korean neonates of the control population. Both group fed breast milk. We performed direct sequencing of TATA box and Gly71Arg polymorphism of the UGT1A1 gene. Results:Two of the 50 neonates with hyperbilirubinemia had AA polymorphism, and 40 had GA polymorphism. Five of the 129 neonates of the control group had AA polymorphism, and 4 had GA polymorphism. The allele frequency of G>A polymorphism in the hyperbilirubinemia group was 44.0%; it was significantly higher than 5.4% of the control group. TATA box polymorpism was not different both group significantly. Conclusion:Our result indicated that Gly71Arg polymorphism is associated with the prolonged hyperbilirubinemia of breast milk-feeding infant in Korean, while TATA box polymorphism is not associated with the prolonged hyperbilirubinemia of breast milk-feeding infant in Korean. (Korean J Pediatr 2008;51:150-155) Purpose:It has been known that breast milk cause prolonged unconjugated hyperbilirubinemia. UGT1A1 is a important gene of uridine diphosphate glucuronosyltransferase (UGT) which has a major role of bilirubin metabolism. These findings suggest that there is a relationship between UGT1A1 gene mutation and prolonged jaundice of breast feeding infant. The aim of study was to investigate whether a polymorphism of the UGT1A1 gene exist in prolonged hyperbilirubinemia of breast milk feeding Korean infant. Methods:The genomic DNA was isolated from 50 full term Korean neonates, who had greater than a 10 mg/dL of serem bilirubin after 2 weeks of birth with no significant cause, and the other genomic DNA was isolated from 162 full term Korean neonates of the control population. Both group fed breast milk. We performed direct sequencing of TATA box and Gly71Arg polymorphism of the UGT1A1 gene. Results:Two of the 50 neonates with hyperbilirubinemia had AA polymorphism, and 40 had GA polymorphism. Five of the 129 neonates of the control group had AA polymorphism, and 4 had GA polymorphism. The allele frequency of G>A polymorphism in the hyperbilirubinemia group was 44.0%; it was significantly higher than 5.4% of the control group. TATA box polymorpism was not different both group significantly. Conclusion:Our result indicated that Gly71Arg polymorphism is associated with the prolonged hyperbilirubinemia of breast milk-feeding infant in Korean, while TATA box polymorphism is not associated with the prolonged hyperbilirubinemia of breast milk-feeding infant in Korean. (Korean J Pediatr 2008;51:150-155)

Epidemiology of Hyperbilirubinemia in a Quaternary Pediatric Emergency Department over a Three-Year Period

Timmons, Zebulon,Timmons, Jaci,Conrad, Christina,Miloh, Tamir The Korean Society of Pediatric Gastroenterology 2018 Pediatric gastroenterology, hepatology & nutrition Vol.21 No.4

Purpose: There is a lack of scholarly reports on pediatric emergency department (PED) exposure to hyperbilirubinemia. We aimed to describe the epidemiology of hyperbilirubinemia in patients presenting to a PED over a three-year period. Methods: This was a retrospective cohort study, completed at an urban quaternary academic PED. Patients were included if they presented to the PED from 2010 to 2012, were 0 to 18 years in age, and had an elevated serum bilirubin for age. A chart review was completed to determine the incidence of hyperbilirubinemia, etiology, diagnostic work up and prognosis. The data set was stratified into four age ranges. Results: We identified 1,534 visits where a patient was found to have hyperbilirubinemia (0.8% of all visits). In 47.7% of patients hyperbilirubinemia was determined to have arisen from an identifiable pathologic etiology (0.38% of all visits). First-time diagnosis of pathologic hyperbilirubinemia occurred in 14% of hyperbilirubinemia visits (0.11% of all visits). There were varying etiologies of hyperbilirubinemia across age groups but a male predominance in all (55.0%). 15 patients went on to have a liver transplant and 20 patients died. First-time pathologic hyperbilirubinemia patients had a mortality rate of 0.95% for their initial hospitalization. Conclusion: Hyperbilirubinemia was not a common presentation to the PED and a minority of cases were pathologic in etiology. The etiologies of hyperbilirubinemia varied across each of our study age groups. A new discovery of pathologic hyperbilirubinemia and progression to liver transplant or death during the initial presentation was extremely rare.

Epidemiology of Hyperbilirubinemia in a Quaternary Pediatric Emergency Department over a Three-Year Period

Zebulon Timmons,Jaci Timmons,Christina Conrad,Tamir Miloh 대한소아소화기영양학회 2018 Pediatric gastroenterology, hepatology & nutrition Vol.21 No.4

Purpose: There is a lack of scholarly reports on pediatric emergency department (PED) exposure to hyperbilirubinemia. We aimed to describe the epidemiology of hyperbilirubinemia in patients presenting to a PED over a three-year period. Methods: This was a retrospective cohort study, completed at an urban quaternary academic PED. Patients were included if they presented to the PED from 2010 to 2012, were 0 to 18 years in age, and had an elevated serum bilirubin for age. A chart review was completed to determine the incidence of hyperbilirubinemia, etiology, diagnostic work up and prognosis. The data set was stratified into four age ranges.Results: We identified 1,534 visits where a patient was found to have hyperbilirubinemia (0.8% of all visits). In 47.7% of patients hyperbilirubinemia was determined to have arisen from an identifiable pathologic etiology (0.38% of all visits). First-time diagnosis of pathologic hyperbilirubinemia occurred in 14% of hyperbilirubinemia visits (0.11% of all visits). There were varying etiologies of hyperbilirubinemia across age groups but a male predominance in all (55.0%). 15 patients went on to have a liver transplant and 20 patients died. First-time pathologic hyperbilirubinemia patients had a mortality rate of 0.95% for their initial hospitalization.Conclusion: Hyperbilirubinemia was not a common presentation to the PED and a minority of cases were pathologic in etiology. The etiologies of hyperbilirubinemia varied across each of our study age groups. A new discovery of pathologic hyperbilirubinemia and progression to liver transplant or death during the initial presentation was extremely rare.

Transarterial Chemolipiodolization for Hepatocellular Carcinoma with Central Bile Duct Invasion Causing Conjugated Hyperbilirubinemia: Safety and Prognostic Factors for Survival

( Pil Soo Sung ),( Jung Suk Oh ),( Ho Jong Chun ),( Jeong Won Jang ),( Si Hyun Bae ),( Jong Young Choi ),( Seung Kew Yoon ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Bile duct invasion of hepatocellular carcinoma (HCC) is relatively uncommon. For patients with conjugated hyperbilirubinemia caused by HCC with bile duct invasion, it has been reported that effective biliary drainage followed by transarterial chemolipiodolization (TACL) may prolong survival. However, there are few reports comparing the clinical outcomes between tumors with central bile duct invasion causing conjugated hyperbilirubinemia and tumors with central bile duct invasion without hyperbilirubinemia, after TACL. Methods: Between January 2005 and December 2017, a total of 50 patients with HCC invading central bile duct (right or left hepatic duct, common hepatic or bile duct) and treated with TACL were enrolled. Patients were divided into three groups: hyperbilirubinemia (total bilirubin ≥ 2.5mg/dL) with pre-TACL biliary drainage group (n=12), hyperbilirubinemia without biliary drainage group (n=12), and without hyperbilirubinemia group (n=26). Tumor response to TACL, survival outcomes, length of hospitalization, adverse events recorded using Common Terminology Criteria for Adverse Events (CTCAE), and factors affecting overall survival were compared among three groups. Results: The mean length of hospitalization was shorter in patients without hyperbilirubinemia compared to hyperbilirubinemia (10.2 vs 14.5 days, P=0.017), although mean CTCAE grade for laboratory parameters were not significantly increased after TACL among three groups. Significant decrease in serum bilirubin level was observed among patients who underwent pre-TACL biliary drainage (mean of differences: 5.860, P=0.002). However, there were no significant differences in serum bilirubin level between that of the TACL day and highest level within one month after TACL, in all three groups. The tumor response was also not significantly different between patients with hyperbilirubinemia and without hyperbilirubinemia (P=0.573). Survival between patients with hyperbilirubinemia and without hyperbilirubinemia was not significantly different (P=0.097). In multivariate analysis, α-fetoprotein less than 400 ng/dL (HR = 0.477, P=0.048), and highest total bilirubin < 2.5 mg/dL within one month after TACL (HR = 0.335, P=0.004) were significantly associated with longer survival. Conclusions: TACL can be a safe and effective treatment for patients who have HCCs with central bile duct invasion, irrespective of the presence of conjugated hyperbilirubinemia.

Comparison of Bilirubin Levels in Neonates with Hyperbilirubinemia according to Delivery Methods

( Gwang Yeon Lee ),( Jong Woon Choi ) 대한주산의학회 2019 大韓周産醫學會雜誌 Vol.30 No.3

Objective: This study aimed to find out the correlation between bilirubin levels and delivery methods in term babies with neonatal hyperbilirubinemia. Methods: This retrospective study was performed in a single center. The subjects were full-term neonates (37-41 weeks of gestational age) with a chief complaint of hyperbilirubinemia (serum total bilirubin ≥12 mg/dL) admitted to the Bundang Jesaeng General Hospital from May 2015 to July 2018. The subjects were divided into two groups according to delivery methods (vaginal delivery [VD] and cesarean section [CS]). Total bilirubin levels were compared between the two groups, and the correlation between severe hyperbilirubinemia (serum total bilirubin ≥25 mg/dL) and delivery methods was analyzed. Results: A total of 87 neonates were enrolled. Of 87 neonates, 59 (67.8%) were born by VD and 28 (32.2%) by CS. The mean serum total bilirubin level of the VD group was significantly higher than that of the CS group (21.5±4.0 mg/dL and 17.5±3.4 mg/dL, respectively; P<0.001). There were also significant differences in bilirubin levels according to delivery methods in subgroups based on demographic characteristics, except in cases when the age of neonates exceeded 7 days on admission and in breast-feeding neonates. In addition, VD was significantly correlated with an increased risk of severe hyperbilirubinemia (relative risk 1.5; 95% confidence interval 1.2-1.9; P=0.031). Conclusion: This study showed that term neonates with hyperbilirubinemia born by VD had significantly higher bilirubin levels than those born by CS, and were also significantly correlated with severe hyperbilirubinemia.

한국 신생아 황달에서 UDP-Glucuronosyltransferase 유전자(UGT1A1)의 다형성에 관한 연구

홍기웅,강훈,김일수,김지숙,김은령,이희제,김성우,정주호 대한소아과학회 2004 小兒科 Vol.47 No.1

한국인 신생아 황달과 UGT1A1 유전자의 2056G>C 단일염기다형성에 관한 연구

하상균 외 중앙대학교 의과대학 의학연구소 2006 中央醫大誌 Vol.31 No.1·2·3

The incidence of neonatal hyperbilirubinemia is twice as high in East Asians as in Caucasians. Although it has not been clearly defined, the UDP-glucuronosyltransferase gene (UGT1A1) mutation was found to be a risk factor of neonatal hyperbilirubinemia. We studied whether neonatal hyperbilirubinemia is associated with the 2056G>C (rs8330) polymorphism of the UGT1A1 gene. The genomic DNA was isolated from 80 Korean full term neonates who had greater than a 12 mg/dl level of serum bilirubin with no obvious cause, and also isolated from 164 Korean neonates of the control population. We studied a single nucleotide polymorphism (SNP) of 2056G>C in the untranslated region of the UGT1A1 gene by direct sequencing. Three of the 80 neonates with a serum bilirubin level above 12 mg/dl had homozygous mutations and 10 of the 80 neonates had heterozygous mutation. Thirteen of the 164 neonates of the control group had homozygous mutation and 16 neonates of the control group had heterozygous mutation. The allele frequency of 2056G>C polymorphism of UGT1A1 in the hyperbilirubinemia group was 0.1, which was not significantly different from 0.128 in the control group. In this study, our results indicated that this SNP is not associated to the hyperbilirubinemia in Korean neonates.

한국인 신생아 황달과 Glutathione S-transferase 다형성에 관한 연구

강창석,홍승수,김지숙,김은령 대한소아청소년과학회 2008 Clinical and Experimental Pediatrics (CEP) Vol.51 No.3

Purpose:Glutathione S-transferase (GST) is a polymorphic supergene family of detoxification enzymes that are involved in the metabolism of numerous diseases. Several allelic variants of GSTs show impaired enzyme activity and are suspected to increase the susceptibility to diseases. Bilirubin is bound efficiently by GST members. The most commonly expressed gene in the liver is GSTM1, and GSTT1 is expressed predominantly in the liver and kidneys. To ascertain the relationship between GST and neonatal hyperbilirubinemia, the distribution of the polymorphisms of GSTT1 and GSTM1 were investigated in this study. Methods:Genomic DNA was isolated from 88 patients and 186 healthy controls. The genotypes were analyzed by polymerase chain reaction (PCR). Results: The overall frequency of the GSTM1 null was lower in patients compared to controls (P=0.0187, Odds ratio (OR) =0.52, 95% confidence interval (CI), 0.31-0.88). Also, the GSTT1 null was lower in patients compared to controls (P=0.0014, OR=0.41, 95% CI=0.24-0.70). Moreover, the frequency of the null type of both, in the combination of GSTM1 and GSTT1, was significantly reduced in jaundiced patients (P=0.0008, OR=0.31, 95% CI=0.17-0.61). Conclusion:We hypothesized that GSTM1 and GSTT1 might be associated with neonatal hyperbilirubinemia. However, the GSTT1 and GSTM1 null type was reduced in patients. Therefore the null GSTT1, null GSTM1, and null type of both in the combination of GSTM1 and GSTT1 may be not a risk factor of neonatal jaundice. (Korean J Pediatr 2008;51:262-266) Purpose:Glutathione S-transferase (GST) is a polymorphic supergene family of detoxification enzymes that are involved in the metabolism of numerous diseases. Several allelic variants of GSTs show impaired enzyme activity and are suspected to increase the susceptibility to diseases. Bilirubin is bound efficiently by GST members. The most commonly expressed gene in the liver is GSTM1, and GSTT1 is expressed predominantly in the liver and kidneys. To ascertain the relationship between GST and neonatal hyperbilirubinemia, the distribution of the polymorphisms of GSTT1 and GSTM1 were investigated in this study. Methods:Genomic DNA was isolated from 88 patients and 186 healthy controls. The genotypes were analyzed by polymerase chain reaction (PCR). Results: The overall frequency of the GSTM1 null was lower in patients compared to controls (P=0.0187, Odds ratio (OR) =0.52, 95% confidence interval (CI), 0.31-0.88). Also, the GSTT1 null was lower in patients compared to controls (P=0.0014, OR=0.41, 95% CI=0.24-0.70). Moreover, the frequency of the null type of both, in the combination of GSTM1 and GSTT1, was significantly reduced in jaundiced patients (P=0.0008, OR=0.31, 95% CI=0.17-0.61). Conclusion:We hypothesized that GSTM1 and GSTT1 might be associated with neonatal hyperbilirubinemia. However, the GSTT1 and GSTM1 null type was reduced in patients. Therefore the null GSTT1, null GSTM1, and null type of both in the combination of GSTM1 and GSTT1 may be not a risk factor of neonatal jaundice. (Korean J Pediatr 2008;51:262-266)

고빌리루빈혈증과 담도 침범을 동반한 간세포암에 대한 경동맥화학 리피오돌색전술의 안전성과 예후 인자

양경모 ( Keungmo Yang ),성필수 ( Pil Soo Sung ),오정석 ( Jung Suk Oh ),천호종 ( Ho Jong Chun ),장정원 ( Jeong Won Jang ),배시현 ( Si Hyun Bae ),최종영 ( Jong Young Choi ),윤승규 ( Seung Kew Yoon ) 대한간암학회 2018 대한간암학회지 Vol.18 No.2

Background/Aims: The treatments and outcomes of hepatocellular carcinoma (HCC) with bile duct invasion are not well known. We aimed to confirm the safety of transarterial chemolipiodolization (TACL) and identify prognostic factors for patients with bile duct invasion treated with TACL. Methods: Fifty patients with central bile duct invasion treated with TACL between 2005 and 2017 were enrolled. Patients were divided into three groups: hyperbilirubinemia (total bilirubin ≥2.5 mg/dL) with pre-TACL biliary drainage, hyperbilirubinemia without biliary drainage, and without hyperbilirubinemia. Tumor response to TACL, survival outcomes, length of hospitalization, adverse events using Common Terminology Criteria for Adverse Events (CTCAE), and factors affecting overall survival were compared. Results: TACL-induced changes of mean CTCAE grades for albumin, alanine aminotransferase, creatinine, prothrombin time, and platelet were not significantly different among patients with or without initial hyperbilirubinemia. Serum bilirubin level was not significantly changed after TACL in all the three groups. Overall survival was not significantly different among the three groups (P=0.097). On multivariate analysis, alpha-fetoprotein <400 ng/dL (hazard ratio [HR]=0.477, P=0.048) and highest total bilirubin level of <2.5 mg/dL within one month after TACL (HR=0.335, P=0.004) were significantly associated with longer survival. Conclusions: TACL was a safe treatment for HCC patients with central bile duct invasion, irrespective of the presence of initial hyperbilirubinemia. (J Liver Cancer 2018;18:121-129)

신생아 특발성 비용혈성 고빌리루빈혈증의 위험 요인에 따른 임상 양상

박숙현,강지현,권순학,김용선,김행미 대한신생아학회 2010 Neonatal medicine Vol.17 No.2

목적: 최근 출생 후 조기 퇴원과 모유수유 증가로 인해 신생아고빌리루빈혈증에 의한 재입원 비율이 증가하고 있다. 신생아 고빌리루빈혈증은 적절한 시기에 치료하지 않으면 빌리루빈 뇌증을 유발하여 치명적인 신경학적 후유증을 남길 수 있어 적절한치료와 함께 조기 예방의 중요성이 부각되고 있다. 이에 저자는우리나라 신생아의 특발성 비용혈성 고빌리루빈혈증의 임상 경과와 위험 인자, 뇌 MRI 결과를 조사함으로써 황달의 역학 조사와 치료 방침 설정의 기초 자료를 얻고자 본 연구를 시행하였다. 방법: 2006년 1월부터 2009년 9월까지 고빌리루빈혈증으로진단받고 경북대학교병원 신생아 집중치료실에 입원한 환아 중재태연령이 35주 이상, 총혈청 빌리루빈이 20 mg/dL 이상이면서 용혈성 질환이 없으면서 감염, 대사 질환등 황달의 원인이 없는 79명의 환아를 대상으로 의무 기록을 후향적으로 조사하였다. 결과: 평균 재태주령은 38+3±1+4주였고 내원 당시 나이는 8.8±4.0일이었다. 내원 당시 체중은 3,105±479 g으로 출생 체중3,174±406 g과 비교하여 평균 2.8±6.4% 감소하였다. 모유수유, 두혈종, 경막하출혈 및 ABO 부적합증과 같은 위험인자가 있는 환아와 위험인자가 없는 환아를 비교하였으며 최고 총혈청빌리루빈, 광선요법의 시행 기간 및 반응 정도에서 유의한 차이를 보이지 않았다. 출생 체중과 입원 당시 체중을 비교하여 체중이 증가한 군과 감소한 군의 비교에서는 재태주령, 내원 당시 연령과 최고 혈청 빌리루빈치가 유의한 차이를 보였다. 뇌 MRI를시행한 39명의 환아 중 21명은 T1 강조 영상에서 창백핵의 음영이 피각 및 인접한 피질척수로의 음영과 비교하여 증가된 소견을 보였다. 43명의 환아가 ABR을 시행하였는데 5명의 환아에서이상 소견이 보였다. J Korean Soc Neonatol 2010;17:223-31 • doi: 10.5385/jksn.2010.17.2.224 231결론: 우리나라에서 발생하는 특발성 비용혈성 고빌리루빈혈증은 수유량 부족이 원인이 될 수 있으므로 수유방법에 대한 충분한 교육과 퇴원 후 정기적인 추적 관찰이 필요하다. 본 연구는많은 대상군을 포함하지 않아 더 많은 대상군과 대조군의 비교분석이 필요하고 향후 장기적인 추적 관찰을 통해서 만성 빌리루빈 뇌증에 대한 연구도 필요할 것으로 생각된다. Purpose: Hospital readmissions have recently increased due to early hospital discharge and increased trends in breast-feeding. Neonatal hyperbilirubinemia can lead to fatal permanent neurological sequelae without appropriate management. Early detection and intervention are critical. We evaluated the clinical features, risk factors, and brain MRI findings of Korean newborns with idiopathic nonhemolytic hyperbilirubinemia to determine the optimal management policy. Methods: A retrospective review of the medical records of 79 newborns with idiopathic nonhemolytic hyperbilirubinemia was performed at the NICU of the Kyungpook National University Hospital from January 2006 to September 2009. All patients were 35 or more weeks of gestation, and their peak level of serum total bilirubin was more than 20 mg/dL. Results: The mean gestational age was 38+3±1+4 weeks, and the mean age on admission was 8.8±4.0 days. The mean body weight (3,105±479 g) was decreased by 2.8±6.4 percent compared to the mean birth weight (3,174±406 g). There were no statistically significant differences for the peak serum bilirubin level or the duration and effects of phototherapy between the patients with and without risk factors, which included: breastfeeding, cephalohematoma, subdural hemorrhage, and/or ABO incompatibility. Patients were grouped according to change of body weight. Group I consisted of patients that gained weight compared to birth weight, and group II of patients that lost weight compared to birth weight. There were significant differences in the peak serum total bilirubin level between the two groups. Thirty nine patients had brain MRI evaluation; 21 patients had bilateral symmetric signal intensity increases in the globus pallidus compared to adjacent corticospinal tract and putamen on T1-weighted images. Conclusion: Bilirubin encephalopathy is preventable with early screening and proper management. Parents require instruction on feeding practices and follow-up to prevent complications from idiopathic nonhemolytic hyperbilirubinemia.