• BMB Reports
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• 제32권4호
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• pp.331-338
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• 1999

Ethanol catabolism is thought to produce metabolic disorders resulting in alcoholic liver disease. To investigate the mutual effects of ethanol catabolism and cholestasis induced by common bile duct ligation on the activities of carboxylesterase, we have determined the enzyme activities in rat hepatic (cytosolic, mitochondrial, and microsomal) preparations as well as in rat serum using ten animal models: normal rats (group 1), sham-operated rats (group 2), common bile duct-ligated rats (group 3), ethanol-intoxicated rats (group 4), sham-operation plus chronic ethanol-intoxicated rats (group 5), common bile duct-ligated plus chronic ethanol-intoxicated rats at 1.5h and 24h (groups 7A and 7B), and duct-ligated and acute ethanol intoxicated rats at 1.5 h and 24 h (groups 8A and 8B). The $K_m$ and $V_{max}$ values of carboxylesterase from these hepatic preparations of cholestatic rat liver combined with chronic ethanol intoxication were also measured by using ethyl valerate as the substrate from the 14th day post-ligation. Carboxylesterase activities of all hepatic preparations and rat serum (group 3) showed significant decreases compared to the activities from the sham-operated control (group 2). Enzyme kinetic parameters indicated that $V_{max}$ of carboxylesterase from all the hepatic preparations in cholestatic rats (group 3) decreased significantly, although the $K_m$ values were about the same as in the sham-operated control (group 2). When cholestasis was combined with chronic ethanol intoxication (group 6), carboxylesterase activities showed further decrease in all the hepatic preparations and serum compared to the control activity (group 5). The $V_{max}$ also decreased significantly, although $K_m$ values did not change. When common bile duct ligation was combined with acute ethanol intoxication (group 8), the enzyme activities in the rat liver and serum showed significant decrease compared to the activity from acute ethanol-intoxicated rats (group 7). However, quite contrary to this, the activities of serum from acute ethanol intoxication 1.5 h (group 7A) increased significantly compared to the activities in the normal control (group 1). These results, therefore, suggest that the biosynthesis of hepatic carboxyl-esterase seems to decrease when cholestasis is combined with chronic and acute ethanol intoxication, and the decrease in activity is more significant than from cholestasis alone.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제3권1호
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• pp.63-67
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• 2000

목 적: 신생아 담즙정체증의 흔한 원인중 하나인 담도폐쇄증의 진단에 많이 이용되고 있는 Tc-99m DISIDA간담도 주사의 진단적 의의에 대하여 알아보고자 하였다. 방 법: 1995년 1월부터 1999년 8월까지 4년 8개월 동안 서울 중앙병원 소아과와 소아외과에서 신생아담즙정체증으로 Tc-99m DISIDA간담도 주사를 시행한 60명의 환자를 대상으로 그 결과를 분석하였다. 결 과: 전체 60명의 환자 중에서 담도폐쇄증으로 14례(23%), 신생아 간염으로 33례(55%), 간내 담도형성부전증으로 9례(15%), 경정맥 고영양법으로 인한 황달로 4례(7%)가 진단되었다. Tc-99m DISIDA 간담도주사의 민감도는 100%를 보였고 특이도는 80%였다. 결 론: Tc-99m DISIDA 간담도주사에서 장관내 방사능이 관찰되면 담도폐쇄증을 진단에서 제외할 수 있지만 관찰되지 않을 경우에는 경피간침생검이나 시험적 개복술 등의 적극적인 진단방법을 고려해야 할 것으로 생각된다.

• 대한유전성대사질환학회지
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• 제14권2호
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• pp.186-190
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• 2014

시트룰린혈증 2형은 SLC25A13 유전자 결함으로 인한 시트린 결핍에 의한 상염색체 열성 유전질환이다. 시트룰린혈증 2형은 임상적으로 '시트린 결핍증에 의한 신생아 간내 담즙정체(NICCD)'와 '성인기 발병형 시트룰린혈증 2형'의 두 가지 형태로 나타난다. NICCD는 영아기 간내 담즙정체, 지방간, 간기능 장애, 저단백혈증과, 혈액 응고장애, 저혈당증, 성장부진 등의 증상이 나타나며 임상증상과 생화학적 검사 결과를 바탕으로 질환을 의심하에 SLC25A13 유전자 검사를 통해 확진할 수 있다. 또한 최근에는 무증상 상태에서 신생아 대사이상 선별검사를 통해 진단되기도 한다. 저자들은 신생아 대사이상 선별검사는 정상이었으나 지속되는 황달로 입원한 3개월 남아에서 SLC25A13 유전자 검사로 확진된 NICCD 1례를 경험하였기에 문헌 고찰과 함께 보고하는 바이다. 환아는 지속적 황달과 경도의 고암모니아 혈증과 간효소 수치의 상승, 직접 빌리루빈의 상승을 보이고, 혈장 아미노산 분석 결과 시트룰린과 메티오닌, 트레오닌 상승을 보였다. 시트룰린 혈증 2형 의심 하에 시행한 SLC25A13 유전자 염기서열 분석 결과, c.[852_855delTATG](p.Met285Profs*2)과 c. [1180+1G>A] 이형접합 변이가 발견되었다. 신생아 대사이상 선별검사 결과가 정상이었다고 하더라고 간내 담즙정체가 있는 영아는 NICCD를 감별진단 중 하나로 고려하여 암모니아 및 혈장 아미노산 분석을 포함하여 검사를 시행하는 것이 감별진단에 도움이 될 것으로 사료된다.

• 대한의생명과학회지
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• 제10권2호
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• pp.93-98
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• 2004

The effects of intravenously administered of high concentration of taurocholic acid (TCA) on $\alpha$-D- and $\beta$-D-mannosidase activities in rat liver lysosomes were studied. These liver lysosomal enzymes, and serum lysosomal $\alpha$-D- and $\beta$-D-mannosidase isozymes activities were determined in experimental rats with common bile duct ligation (CBDL). The liver lysosomal $\beta$-D-mannosidase activity as well as the serum lysosomal $\alpha$-D- and $\beta$-D-mannosidase isozymes activities were found to be significantly increased in the CBDL plus TCA injected group than in the control group such as CBDL alone group. However, the liver lysosomal $\alpha$-D-mannosidase activity was found to be significantly decreased in the CBDL plus TCA injected group. The above results suggest that TCA repress the biosynthesis of the lysosomal $\alpha$-D-mannosidase and induce the biosynthesis of the lysosomal $\beta$-D-mannosidase in the liver. And that the elevated serum lysosomal $\alpha$-D- and $\beta$-D-mannosidase isozymes activities are most likely due to increased hepatocyte membrane permeability caused by TCA mediated liver cell necrosis.

• 대한핵의학회지
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• 제22권2호
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• pp.181-185
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• 1988

Since hepatocyte clearance, leading edge parencymal transit time and biliary excretion can be evaluated separately with hepatobiliary scan using $^{99m}Tc-DISIDA$, hepatobiliary scan may be useful in differentiating intrahepatic cholestasis from extrahepatic cholestasis. Excretory liver function was analysed in 13 healthy subjects and 11 patients with clinically suspected hepatocellular disease and 9 patients with extrahepatic biliary obstruction confirmed by surgery, radiological and clinical evidence. Indices of total liver activity (% TLA), liver parechymal uptake (% LPU), heart pool clearance (% HPC) and liver-heart rate (% LHR) were calculated from time activity curve over heart and liver. Compared with healthy subjects, significant reduction (p<0.05) in total liver activity (% TLA) and liver-heart rate (% LHR) was observed in all patients group. But no useful indices was demonstrated in differentiating hepatocellular disease from extrahepatic biliary obstruction.

• BMB Reports
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• 제32권1호
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• pp.67-71
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• 1999

We have investigated the effect of cholestasis on the closely related acyl-CoA:amino acid N-acyltransferase, benzoyltransferase, and phenylacetyltransferase activities in rat liver. Benzoyltransferase and phenylacetyltransferase activities in the liver cytosol, mitochondria, and microsome were investigated for a period of 42 d after common bile duct ligation. Both the mitochondrial and microsomal benzoyltransferases showed significant increase in their activities between the 1st and 7th day after common bile duct ligation, although the cytosolic benzoyltransferase activity did not show a significant change compared to the activities from the sham-operated control. The cytosolic phenylacetyltransferase activity showed a significant increase between the 1st and 2nd day, the mitochondrial activity showed a significant increase between the 2nd and 7th day, and microsomal activity showed a significant increase between the 1st and 7th day, respectively. Enzyme kinetic parameters of hepatic benzoyltransferase were analyzed using benzoyl coenzyme A as a substrate with the preparations from the 1st day post-ligation. Enzyme parameters of hepatic phenylacetyltransferase were also analyzed using phenylacetyl coenzyme A as a substrate with the preparations from the 2nd day post-ligation. The results indicated that although the $K_m$ values of these enzymes were about the same as the sham-operated control, the $V_{max}$ values of both enzymes increased significantly. These results, therefore, suggest that the biosynthesis of benzoyltransferase and phenylacetyltransferase has been induced in response to cholestasis.

• 생약학회지
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• 제30권1호
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• pp.12-17
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• 1999

The youngkaechulgamtang (Y) composed of four herb drugs, including Hoelen (H). Cinnamomi Ramulus (C). Atractylodis Rhizoma Alba (A) and Glycyrrhizae Radix (G). In oriental medicine literatures, Youngkaechulgamtang is described to be effective in headache, inflammation, uremia, gastritis, diarrhea and hypertension. To estimate the clinical effectiveness of Youngkaechulgamtang, several pharmacological experiments were carried out. The results are summerized as follows; On acetaminophen-induced hepatotoxicity, C+A, Y-G, Y-H, MIX and Y showed the significant elevation of glutathione-S-transferase. But, C+A, Y-G, Y-H, MIX and Y showed the significant suppression of serum aminotransferases. On ANIT-induced cholestasis, U (Ursodesoxycholic acid 50 mg/kg)+$Y_l$ (760 mg/kg) showed the significant increase of bile juice volume. $Y_l,\;Y_2$ (1520 mg/kg), U, $U+Y_l$ showed the remarkable increase of cholic acid. U and $U+Y_l$ showed the significant decrease of total bilirubin. From these results, it is suggest that Y shows liver protective effect against various hepatic injury. Especially, Youngkaechulgamtang was more effective than mixture of 4 ingredients in the elevation of glutathione-S-transferase in acetaminophen-induced hepatotoxicity.

• Clinical and Experimental Pediatrics
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• 제49권7호
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• pp.737-744
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• 2006

목 적 : 담도 폐쇄증의 생존율을 높이기 위해서는 조기 진단 및 치료가 필수적이다. 빠른 감별 진단이 중요함에도 불구하고 DISIDA 스캔은 담도 폐쇄증을 진단하는데 있어 민감도(100%)는 높으나 특이도가 낮아 진단 가치가 낮다. 그러나 감별 진단을 할 시간이 비교적 충분한 경우에는 시도할 수 있는 검사이므로 DISIDA 스캔의 시행 가치가 있는 임상적 기준을 찾아보고자 한다. 방 법 : 1996년 4월부터 2005년 12월까지 경북대학교병원 소아과에 신생아 또는 영아기 담즙정체증으로 내원한 환자 중 담도 폐쇄증과 감별이 필요하였던 총 87명의 영아(남아 58명, 여아 29명)를 대상으로 DISIDA 스캔을 시행하였다. 대상 환아의 나이는 평균 59.1일(생후 18-139일)이었다. 환아들을 후향적으로 담도 폐쇄증 환아 군, 비담도 폐쇄증군(신생아 간염 증후군, 총 정맥영양 관련 담즙정체증 포함)으로 분류하였다. 비담도 폐쇄증군은 DISIDA 스캔에서 소장 내 방사능이 보이는 군과 보이지 않은 군으로 나누었다. 환아의 최종 진단과 DISIDA 스캔 결과에 따라 5개 군으로 분류한 다음 각 환자의 나이, 직접 빌리루빈, AST, ALT, ALP, GGT 간의 상관 관계를 산점도를 통해 비교 분석하였다. 분석한 그림을 바탕으로 환자를 직접 빌리루빈이 5 mg/dL 이상인 군과 5 mg/dL 미만인 군으로 나누어 담도 폐쇄증에 대한 DISIDA 스캔의 진단적 민감도, 특이도, 정확도를 비교 분석하였다. 결 과 : DISIDA 스캔을 시행한 87명 중 담도 폐쇄증 환아는 16명 모두에서 소장 내 방사능이 나타나지 않았다. 담도 폐쇄증이 아니었던 71명 중에서는 25명(35%)에서 소장 내 방사능이 보이지 않아 높은 위양성 결과를 보였다. 담도 폐쇄증에 대한 DISIDA 스캔의 진단 민감도와 특이도는 각각 100%(16/16)와 70.4%(50/71)였으며 정확도는 75.9%(66/87)였다. 총 87명의 환아들을 5개 군으로 분류한 후 산점도를 통해 비교 분석한 결과 나이, AST, ALT, ALP, GGT 등은 최종 진단을 예측하는데 도움을 주지 못하였으며 DISIDA 스캔의 진단율에도 영향을 주지 않았다. 직접 빌리루빈 수치 5 mg/dL 미만인 경우 위양성률은 9.7%(5/31)였으나 5 mg/dL 이상인 경우의 위양성률은 42.5%(17/40)에 달하였다. 결 론 : 신생아 담즙정체성 간질환에서 담도 폐쇄증 감별을 위한 DISIDA 스캔은 직접 빌리루빈이 5 mg/dL 이상일 경우 진단적으로 유용하지 않으므로 가능한 다른 진단법을 신속히 시행하여 담도 폐쇄증을 진단하는 것이 바람직할 것으로 생각한다.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제23권6호
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• pp.558-566
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• 2020

Purpose: Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic autosomal recessive disease caused by mutations in ATP8B1, ABCB11 or ABCB4. Mutational analysis of these genes is a reliable approach to identify the disorder. Methods: We collected and analyzed relevant data related to clinical diagnosis, biological investigation, and molecular determination in nine children carrying these gene mutations, who were from unrelated families in South China. Results: Of the nine patients (five males, four females) with PFIC, one case of PFIC1, four cases of PFIC2, and four cases of PFIC3 were diagnosed. Except in patient no. 8, jaundice and severe pruritus were the major clinical signs in all forms. γ-glutamyl transpeptidase was low in patients with PFIC1/PFIC2, and remained mildly elevated in patients with PFIC3. We identified 15 different mutations, including nine novel mutations (p.R470HfsX8, p.Q794X and p.I1170T of ABCB11 gene mutations, p.G319R, p.A1047P, p.G1074R, p.T830NfsX11, p.A1047PfsX8 and p.N1048TfsX of ABCB4 gene mutations) and six known mutations (p.G446R and p.F529del of ATP8B1 gene mutations, p.A588V, p.G1004D and p.R1057X of ABCB11 gene mutations, p.P479L of ABCB4 gene mutations). The results showed that compared with other regions, these three types of PFIC genes had different mutational spectrum in China. Conclusion: The study expands the genotypic spectrum of PFIC. We identified nine novel mutations of PFIC and our findings could help in the diagnosis and treatment of this disease.

• Toxicological Research
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• 제17권3호
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• pp.187-194
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• 2001

The oxidative stress causes the cell damage and death and thereby, stimulates membrane lipid peroxidation. In this study, the correlation between the lipid peroxidation product and the parameter of liver fibrosis (cirrhosis) was investigated in cholestasis induced rats. The Sprague-Dawley rats were divided into 3 groups (sham: sham operation, BDL/S-I and BDL/S-II : bile duct ligation/scission) and were observed for 2 or 4 weeks. After observation period, the organs were weighed and the ratio of organ weight/body weight was calculated. Sera and liver tissue were used for the measurement of malondealdehyde (MDA), parameter of clinical biochemistry, total collagen content and the staining. The ratio of organ weight/body weight in BDL/S-I and BDL/S-II was significantly increased compared to sham operated group. Serological parameters (Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and Total bilirubin) in BDL/S-I and BDL/S-II group were significantly higher than those in sham operated group. Concentration of MDA in BDL/S-I (261%) and BDL/S-II(790%) was significantly increased compared to MDA in sham operated group. And the content of hydroxyproline (hyp) in BDL/S-I and BDL/S-II group was significantly increased 2~4 times than in sham operated group. The good correlations between hyp in liver tissue and MDA in sera of sham operated group and all operated group were found (r=0.825). The significantly higher value of MDA, hyp and serological parameters in BDL/S-I and BDL/S-II group suggests the stimulation of lipid peroxidation and chronic liver damage. Especially the activation of lipid peroxidation and the stimulation of liver fibrosis was stronger in BDL/S-II group than in BDL/S-I group. The stronger fibrosis, portal-portal septum formation, the more massive bile duct proliferation in portal triads and stroma, and hepatocytes swelling were observed in liver tissue of and BDL/S-II group compared to BDL/S-I group. Conclusively, a good correlation between MDA as a lipid peroxidation marker and hyp as a liver fibrotic parameter could be connected with the process of liver fibrosis. Moreover, cholestasis condition may cause jaundice, activation of lipid peroxidation, and collagen accumulation in liver. Additionally, optimal observation period of bile duct obstruction for the screening of antioxidant and antifibrotic effect in rats would be four weeks.