신생아에서 폐혈증 연관성 담즙정체증의 임상 양상

윤수정,김천수,이상락 대한소아과학회 2004 小兒科 Vol.47 No.4

Cholestasis beyond the Neonatal and Infancy Periods

Racha Khalaf,Claudia Phen,Sara Karjoo,Michael Wilsey 대한소아소화기영양학회 2016 Pediatric gastroenterology, hepatology & nutrition Vol.19 No.1

Cholestasis results from impairment in the excretion of bile, which may be due to mechanical obstruction of bile flow or impairment of excretion of bile components into the bile canaliculus. When present, cholestasis warrants prompt diagnosis and treatment. The differential diagnosis of cholestasis beyond the neonatal period is broad and includes congenital and acquired etiologies. It is imperative that the clinician differentiates between intrahepatic and extra-hepatic origin of cholestasis. Treatment may be supportive or curative and depends on the etiology. Recent literature shows that optimal nutritional and medical support also plays an integral role in the management of pediatric patients with chronic cholestasis. This review will provide a broad overview of the pathophysiology, diagnostic approach, and management of cholestasis beyond the neonatal and infancy periods.

Cholestasis beyond the Neonatal and Infancy Periods

Khalaf, Racha,Phen, Claudia,Karjoo, Sara,Wilsey, Michael The Korean Society of Pediatric Gastroenterology 2016 Pediatric gastroenterology, hepatology & nutrition Vol.19 No.1

Cholestasis results from impairment in the excretion of bile, which may be due to mechanical obstruction of bile flow or impairment of excretion of bile components into the bile canaliculus. When present, cholestasis warrants prompt diagnosis and treatment. The differential diagnosis of cholestasis beyond the neonatal period is broad and includes congenital and acquired etiologies. It is imperative that the clinician differentiates between intrahepatic and extrahepatic origin of cholestasis. Treatment may be supportive or curative and depends on the etiology. Recent literature shows that optimal nutritional and medical support also plays an integral role in the management of pediatric patients with chronic cholestasis. This review will provide a broad overview of the pathophysiology, diagnostic approach, and management of cholestasis beyond the neonatal and infancy periods.

Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing

Lee, Su Jeong,Kim, Jung Eun,Choe, Byung-Ho,Seo, An Na,Bae, Han-Ik,Hwang, Su-Kyeong The Korean Society of Pediatric Gastroenterology 2017 Pediatric gastroenterology, hepatology & nutrition Vol.20 No.2

Purpose: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. Methods: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. Results: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. Conclusion: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.

Toxicoproteomic analysis of phalloidin-induced cholestasis in mouse liver

Heo, Sun-Hee,Oh, Jung-Hwa,Park, Han-Jin,Kwon, Myung-Sang,Rana, Suresh V.S,Yoon, Seok-Joo The Korean Society of Toxicogenomics and Toxicopro 2010 Molecular & cellular toxicology Vol.6 No.1

Phalloidin induces cholestasis by preventing microfilament depolymerization. Phalloidin has been widely used as an agent to induce intrahepatic cholestasis in experimental animals. The objective of this study was to examine the effects of phalloidin on protein expression profiles in mouse liver, so as to identify potential biomarkers of intrahepatic cholestasis. Phalloidin was administered to BALB/c mice at a predetermined dose of 1 mg/kg for 7 days, and phalloidin-induced cholestasis was observed. Hepatic protein expression was investigated via two-dimensional (2D) electrophoresis, and 21 protein spots showing significantly different expression between the treated and control groups were excised from the gels and identified by MALDI-TOF/TOP. The identified proteins were involved in cytoskeletal changes, lipid metabolism, gluconeogenesis, detoxification, and transport mechanisms. Among these proteins, the up-regulation of HSP90-$\beta$ in phalloidin-treated mice was confirmed by Western blot analysis and then by RT-PCR, indicating that it may serve as a useful biomarker of cholestasis. In summary, these results provide insight into the mechanism involved in phalloidin-induced cytoskeletal change and cholestasis.

주정중독 흰쥐에서 총담관결찰이 혈청 및 간의 Alkaline Phosphatase활성에 미치는 영향

김여희,곽춘식,이숙형,문교철 啓明大學校 醫科大學 1991 계명의대학술지 Vol.10 No.1

The activities of the serum and hepatic alkaline phosphatase(ALP) were studied for acute ethanol intoxication after cholestasis, or cholestasis after chronic ethanol intoxication in order to manifest to the biochemical background of alcohol intoxication in hepatobiliary disease. The group that received common bile duct(CBD) ligation after intoxicating chronically with ethanol showed remarkable increase in the liver cytosolic and micrisimal ALP activities. However, the activity showed a less degree than the activity of the CBD ligation group. The liver mitochondrial ALP activity of the CBD ligation after chronic ethanol intoxication group showed considerable increase after the 7th and 14th day of the ligation. But the activity showed a less degree on the same term than group of CBD ligation. At the 24th hour following the acute ethanol intoxication which was done on the 14th day after the CBD ligation, the rats showed more significant increase in the liver cytosolic and microsomal ALP activities than the rats with only the CBD ligation foor 14 days. Both the CBD ligation group and the group that received the same ligation after intoxicating chronically with ethanol showed remarkable increase in the serum ALP activity. But the serum ALP activity fo the group that received the CBD lightion after chronic ethanol intoxication showed far more significant increase than the group with only the CBD ligation, and also considerable increase in the serum ALP activity was shown when the group was acutely intoxicated with ethanol after the ligation. In brief, cytosolic and microsomal ALP in the liver is the enzyme whose activity is decreased in chronic ethanol intoxication with cholestasis more than in cholestasis. On the other hand cytosolic and microsomal ALP in the liver are the enzymes with increased activity in acute ethanol intoxication with cholestasis more than in cholestasis. Especially, when the cholestasis with acute and chronic ethanol intoxication occurred, the activity of serum ALP is higher than that of the cholestasis because of increased permeability secondary to liver cell membrane damage, which causes the enzyme to leak into the blood in great quantity. Accordingly, these resuls will be the data supporting that alcoholic dring is enzymologically harmful in hepatobiliary disease.

Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing

이수정,김정은,최병호,서안나,배한익,황수경 대한소아소화기영양학회 2017 Pediatric gastroenterology, hepatology & nutrition Vol.20 No.2

Purpose: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. Methods: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. Results: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. Conclusion: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.

The Clinicopathological Parameters for Making the Differential Diagnosis of Neonatal Cholestasis

이희진,강준규,김경모,장주영,장세진,유은실 대한병리학회 2009 Journal of Pathology and Translational Medicine Vol.43 No.1

Background : The diseases that cause neonatal cholestasis display several overlapping clinical feature. Making the differential diagnosis using liver biopsy specimens from infants with neonatal cholestasis is important for delivering the proper treatment. Methods : We assessed the clinical manifestations, laboratory data, and histopathologic features of the pretreatment liver biopsy specimens from patients suffering with biliary atresia (n=66), intrahepatic bile duct paucity (n=15), and neonatal hepatitis (n=21). Results : The gender distribution was nearly equal for the patients with biliary atresia and intrahepatic bile duct paucity, whereas males predominated for the cases of neonatal hepatitis. Only the gamma-glutamyl transferase level differed significantly amongst the groups. The diagnostic features for making the differential diagnosis of bile duct lesions included marked bile ductular proliferation, severe fibrosis, and bile duct loss. The difference of the average percentage of portal tracts with bile duct loss was statistically significant between the patients with intrahepatic bile duct paucity (73.9%) and those patients with neonatal hepatitis (39.1%) (p<0.001). Conclusions : Bile ductular proliferation, bile duct loss, and advanced fibrosis are useful for the differential diagnosis of neonatal cholestasis. Moreover, stricter diagnostic criteria for bile duct loss (more than 2/3 of bile ducts) should be applied for the definitive diagnosis of intrahepatic bile duct paucity, because bile duct loss also frequently occurs in infants suffering with neonatal hepatitis. Background : The diseases that cause neonatal cholestasis display several overlapping clinical feature. Making the differential diagnosis using liver biopsy specimens from infants with neonatal cholestasis is important for delivering the proper treatment. Methods : We assessed the clinical manifestations, laboratory data, and histopathologic features of the pretreatment liver biopsy specimens from patients suffering with biliary atresia (n=66), intrahepatic bile duct paucity (n=15), and neonatal hepatitis (n=21). Results : The gender distribution was nearly equal for the patients with biliary atresia and intrahepatic bile duct paucity, whereas males predominated for the cases of neonatal hepatitis. Only the gamma-glutamyl transferase level differed significantly amongst the groups. The diagnostic features for making the differential diagnosis of bile duct lesions included marked bile ductular proliferation, severe fibrosis, and bile duct loss. The difference of the average percentage of portal tracts with bile duct loss was statistically significant between the patients with intrahepatic bile duct paucity (73.9%) and those patients with neonatal hepatitis (39.1%) (p<0.001). Conclusions : Bile ductular proliferation, bile duct loss, and advanced fibrosis are useful for the differential diagnosis of neonatal cholestasis. Moreover, stricter diagnostic criteria for bile duct loss (more than 2/3 of bile ducts) should be applied for the definitive diagnosis of intrahepatic bile duct paucity, because bile duct loss also frequently occurs in infants suffering with neonatal hepatitis.

신생아 담즙정체증의 원인질환 및 장기추적 예후인자에 관한 고찰

김경모,서정기,Kim, Kyung-Mo,Seo, Jeong-Kee 대한소아소화기영양학회 1999 Pediatric gastroenterology, hepatology & nutrition Vol.2 No.1

목 적: 신생아 담즙정체증은 소아과 소화기 영역에서 중요한 질환의 하나임에도 불구하고 원인 질환 및 장기추적 고찰에 대한 국내의 보고가 드문 실정이다. 따라서 저자들은 신생아 담즙정체증의 원인 및 추적조사시의 합병증 등의 임상적 고찰과 함께 예후인자를 분석하여 신생아 담즙정체증 환아의 진료에 도움을 주고자 본 연구를 시행하였다. 방 법: 1981년부터 1992년까지 12년간 신생아 혹은 초기 영아기에 발생한 담즙정체증으로 서울대학교 어린이병원 소아과에 입원하였던 190명을 대상으로 하였다. 담즙정체증의 원인질환, 추적조사시에 관찰된 합병증 및 사인, 특발성신생아간염과 담도폐쇄증의 초기의 임상적 차이점, 예후 및 예후 인자를 분석하였다. 결 과: 1) 담즙정체증의 원인질환은 190명에서 신생아 간염이 101례(53%), 간외담도계 질환이 84례(44%), 간내담도형성부전증이 5례(3%)이었다. 신생아간염은 특발성신생아간염이 77례(41%), 감염성 신생아 간염이 24례(12%)이었고, 간외담도질환은 담도폐쇄증이 79례(41%), 총수담관낭이 5례(3%)이었다. 2) 추적조사시에 관찰된 주요한 임상적 문제점은 지속적인 고열, 위장관출혈, 간성혼수, 복수 등이었다. 3) 담도폐쇄증 환아에서 지속적인 고열의 원인은 상행성담관염, 혹은 line-related sepsis가 58%이었고, 폐렴이 15%, 요로감염이 8%, 상기도 감염이 7%이었다. 4) 상행성담관염 혹은 line related sepsis의 원인균은 Escherichia coli가 28%로 가장 빈도가 많았고, Coagulase negative staphylococcus가 14%, Streptococcus pneumoniae, Klebsiela pneumoniae가 각각 10%, Enterococcus가 6%, Candida albicans가 4%이었다. 5) 주요한 사인은 간성혼수와 위장관출혈이었다. 6) 특발성신생아간염은 71%, 감염성 신생아간염은 75%의 환아에서 회복되었으며, 대부분 생후 12개월 이내, 주로 6개월 이내에 회복되었다. 미숙아, 초기의 간종대가 작은 경우, 초기 알부민치 높은 경우, 콜레스테롤치, ${\gamma}$-GT치, 빌리루빈치 및 AST치가 낮은 경우에서 예후가 양호하였다. 7) 담도폐쇄증 환아의 Kasai수술후의 5년 생존율은 40%이었고 사망의 대부분은 12개월 이내에 관찰되었다. 가장 중요한 예후인자는 수술시기이었고 수술시기가 12주 이전인 49%가 양호한 예후를 보인 반면에, 12주 이후인 경우는 12%이었다. 8) 담즙정체증의 초기 임상소견중 가장 중요한 예후인자는 원인질환이었다. 9) 특발성신생아간염과 담도폐쇄증 사이에서 차이를 보인 임상소견은 성별, 제태연령, 콜레스테롤 치 및 ${\gamma}$-GT치 이었다. 특발성신생아간염은 남아, 미숙아에서 호발하였고, 낮은 콜레스테롤치 및 ${\gamma}$-GT치를 보였다. 결 론: 우리나라에서 신생아 담즙정체증의 흔한 원인으로는 담도폐쇄증과 특발성신생아간염의 빈도가 가장 높았고, 이외에 감염성 신생아 간염, 총수담관낭, Alagille 증후군 등이었으며, 유전성, 대사성질환은 관찰되지 않았다. 신생아 담즙정체증에서 원인질환은 예후를 결정하는 가장 중요한 요인으로 원인질환에 대한 적절한 진단이 요구되며, 또한 상행성 담관염, 폐렴, 패혈증 등의 감염문제, 간성혼수, 위장관 출혈 등은 장기 추적시의 자주 발생하는 심각한 임상적 문제점으로서 이에 대한 적절한 치료대책이 요구된다고 하겠다. Purpose: The aim of the present study was to evaluate the long-term clinical profile including the underlying etioligy and the prognostic factors of the neonatal cholestasis. Method: We studied the 190 infants presented with neonatal cholestasis for the last 12 years (from 1981 to 1992). The underlying causes, clinical findings and long-term outcomes were evaluated. And the prognostic factors were also analyzed. Result: Underlying disease were neonatal hepatitis in 101 (idiopathic in 77 and infectious in 24), intrahepatic bile duct paucity in 5, biliary atresia in 79, choledochal cyst in 5. Metabolic disease was not observed in this study. The important clinical problems during follow-up were persistent high fever, gastrointestinal bleeding, hepatic encephalopathy and ascites. The main causes of the death were hepatic encephalopathy and gastrointestinal bleeding. While three fourth of infants with idiopathic and infectious neonatal hepatitis recovered usually within a year, five-year survival rate for biliary atresia was just 40%, the mortality observed usually within the first year after Kasai operation and prognostic factor was the time of operation. Underlying disease was the most important prognostic factor of neonatal cholestasis. Conclusion: This study showed that most common causes of neonatal cholestasis were biliary atresia and idiopathic neonatal hepatitis, infectious neonatal hepatitis, choledochal cyst and Alagille syndrome, but few neonatal cholestasis of genetic or metabolic liver disease was observed. The most important long-term prognostic factor of neonatal cholestasis was the underlying disease.

신생아 간내 담즙 정체증의 예후 인자: 비가족성, 비대사성, 비증후성 담즙 정체증

김형석,이창훈,김인주,박재홍,Kim, Hyung Suck,Lee, Chang Hoon,Kim, In Ju,Park, Jae Hong 대한소아소화기영양학회 2004 Pediatric gastroenterology, hepatology & nutrition Vol.7 No.2

목적: 신생아 간내 담즙 정체증을 일으키는 질환들은 임상적으로 감별이 용이하지 않으며, 예후와 관련된 인자들에 대한 연구가 부족한 실정이다. 병리 조직 검사, 혈청 생화학 검사, DISIDA 신티그래피 소견들과 예후와의 관련성에 대하여 알아보고자 본 연구를 시행하였다. 방법: 1995년 7월부터 2002년 7월까지의 기간 중 부산대학병원 소아과에 신생아 담즙 정체증으로 내원한 생후 3개월 이내 신생아 및 영아 중 간내 담즙 정체증으로 진단된 32명을 대상으로, 진단 후 6개월 이전에 혈청 ALT치가 정상화 된 환아들을 A군으로, 진단 후 6개월 이상 지속적으로 혈청 ALT치가 증가된 환아들을 B군으로 구분하고, 의무기록을 바탕으로 한 후향적 분석을 하였다. 생화학 검사로는 혈청 ALT치, 총 빌리루빈, 직접형 빌리루빈, alkaline phosphatase의 최고치 등을 비교하였으며, 간 생검에 대한 분석은 담즙관의 증식, 문맥간 가교형성, 다핵 간세포, 간세포 부종, 담세관 마개 5가지 항목에 대한 조직 소견을 정도에 따라 임의로 1점부터 3점까지 점수화하여 조사하였고, DISIDA 신티그래피에서 담낭과 소장이 보인 시간을 두 군에 대하여 비교하였다. 결과: 신생아 간염이 29명, 신생아 간염과 간내 담도 부족증을 동반한 환아가 3명이였다. 간 생검 검사상 예후가 좋지 않은 군에서 담즙관 증식, 문맥간 가교 형성이 심하였으며, 다핵 간세포, 간세포 부종, 담세관 마개의 정도는 예후와 관련성이 없었다. 생화학 검사상 ALT의 최고치가 높은 군에서 예후가 좋지 못하였으며, DISIDA 신티그래피의 담낭과 소장이 보인 시간, 총 빌리루빈, 직접형 빌리루빈, alkaline phosphatase의 최고치는 예후와 관련성이 없었다. 결론: 신생아 간내 담즙 정체증이 있는 환자에서 간 조직 검사상 담즙관 증식과 문맥간 가교 형성이 심하거나 혈청 ALT의 최고치가 높을수록 예후가 나쁘므로 이들에 대한 주의 깊은 관찰 및 검사가 필요할 것으로 생각한다. Purpose: The prognosis of neonates with cholestasis is not clear. Some factors, such as high peak bilirubin levels and liver histologic findings have been claimed to affect the prognosis adversely. Our study aims to define which factors influence the prognosis of neonatal intrahepatic cholestasis. Methods: Retrospective reviews of the medical records were performed in 32 cases with neonatal intrahepatic cholestasis, who were admitted to Department of Pediatrics, Pusan National University Hospital from July 1995 to July 2002. Neonates were classified into 2 groups according to the duration of elevated serum alanine aminotransferase (ALT) levels more or less than 6 months. The data, such as biochemical, histopathologic and radiologic findings, were compared in both groups. Biochemical data included mean peak level of serum ALT, total bilirubin, direct bilirubin, and alkaline phosphatase. Histologic parameters related to lobular architecture, fibrosis, inflammatory infiltration and degenerative features of hepatocytes were arbitrary estimated on a scale of 1 to 3. Results: There were 19 males and 13 females, whose mean age was 48 days (14~77 days). The peak serum ALT levels were higher in the poor outcome group. Ductular proliferation and portoportal bridging were more severe in the poor outcome group. But the degree of multinucleated hepatocytes, hepatocellular swelling and canalicular plug did not appear to be significantly related to the long-term outcome. The DISIDA scintigraphy by visualization time of gall bladder and intestine was not useful in predicting outcome of neonatal intrahepatic cholestasis. Conclusion: Neonates who have intrahepatic cholestasis with high serum ALT levels, severe ductular proliferation and portoportal bridging in the liver biopsy specimen should be carefully followed up because they may have a poor prognosis.