• 제목/요약/키워드: Cholestasis

검색결과 134건 처리시간 0.026초

Analysis of Gene Expression in 4,4'-Methylenedianiline-induced Acute Hepatotoxicity

  • Oh, Jung-Hwa;Yoon, Hea-Jin;Lim, Jung-Sun;Park, Han-Jin;Cho, Jae-Woo;Kwon, Myung-Sang;Yoon, Seok-Joo
    • Toxicological Research
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    • 제25권2호
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    • pp.85-92
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    • 2009
  • 4,4'-Methylenedianiline (MDA) is an aromatic amine that is widely used in the industrial synthetic process. Genotoxic MDA forms DNA adducts in the liver and is known to induce liver damage in human and rats. To elucidate the molecular mechanisms associated with MDA-induced hepatotoxicity, we have identified genes differentially expressed by microarray approach. BALB/c male mice were treated once daily with MDA (20 mg/kg) up to 7 days via intraperitoneal injection (i.p.) and hepatic damages were revealed by histopathological observation and elevation of serum marker enzymes such as AST, ALT, ALP, cholesterol, DBIL, and TBIL. Microarray analysis showed that 952 genes were differentially expressed in the liver of MDA-treated mice and their biological functions and canonical pathways were further analyzed using Ingenuity Pathways Analysis (IPA). Toxicological functional analysis showed that genes related to hepatotoxicity such hyperplasia/hyperproliferation (Timp1), necrosis/cell death (Cd14, Mt1f, Timp1, and Pmaip1), hemorrhaging (Mt1f), cholestasis (Akr1c3, Hpx, and Slc10a2), and inflammation (Cd14 and Hpx) were differentially expressed in MDA-treated group. This gene expression profiling should be useful for elucidating the genetic events associated with aromatic amine-induced hepatotoxicity and for discovering the potential biomarkers for hepatotoxicity.

Glycochenodeoxycholic Acid Induces Cell Death in Primary Cultured Rat Hepatocyte: Apoptosis and Necrosis

  • Chu, Sang-Hui;Park, Wol-Mi;Lee, Kyung-Eun;Pae, Young-Sook
    • The Korean Journal of Physiology and Pharmacology
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    • 제3권6호
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    • pp.565-570
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    • 1999
  • Intracellular accumulation of bile acids in the hepatocytes during cholestasis is thought to be pathogenic in cholestatic liver injury. Due to the detergent-like effect of the hydrophobic bile acids, hepatocellular injury has been attributed to direct membrane damage. However histological findings of cholestatic liver diseases suggest apoptosis can be a mechanism of cell death during cholestatic liver diseases instead of necrosis. To determine the pattern of hepatocellular toxicity induced by bile acid, we incubated primary cultured rat hepatocytes with a hydrophobic bile acid, Glycochenodeoxycholate (GCDC), up to 5 hours. After 5 hours incubation with $400\;{\mu}M$ GCDC, lactate dehydrogenase released significantly. Cell viability, quantitated in propidium iodide stained cells concomitant with fluoresceindiacetate was decreased time- and dose-dependently. Most nuclei with condensed chromatin and shrunk cytoplasm were heavily labelled time- and dose-dependently by a positive TUNEL reaction. These findings suggest that both apoptosis and necrosis are involved in hepatocytes injury caused by GCDC.

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Toxic Bile Salts-Induced Apoptosis of Hepatocytes in Biliary Obstruction Involves Fas-independent Pathway

  • Oh, Seon-Hee;Lee, Byung-Hoon
    • Toxicological Research
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    • 제19권1호
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    • pp.67-72
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    • 2003
  • Cholestatic liver injury results from the accumulation of toxic bile salts within the liver. The aim of the present study is to elucidate the changes in expression and cellular localization of apoptosis related proteins in the liver of bile duct-ligated (BDL) rat. Extrahepatic cholestasis was induced by double ligation of the common bile duct and cut between the ligatures. Animals were sacrificed at day 3 and at week 1, 2, 4, 6, and 8 after BDL. The number of TUNEL positive cells was increased significantly after 3 days of BDL, decreased over 2 weeks and remained constant thereafter. Fas expression was not changed and activation of caspase 8 did not occur. Fas immunoreactivity was exclusively observed in the cytoplasm of hepatocytes, indicating that Fas expressed in rat hepatocytes is a soluble form. Hepatocyte apoptosis was associated with Bax expression, which showed a peak at day 3 and decreased over time gradually. Immnunostaining of Bax was observed in hepatocytes and bile duct epithelial cells (BEC) of control and BDL rats. Bcl-2 was increased over time in BDL rats. These results suggest that apoptosis of hepatocytes in BDL rats is independent of Fas and controlled by Bax expression.

단백질메칠화 반응과 간독성간의 상관관계 (Correlation between Protein Methylation and Hepatotoxicity)

  • 김재현;박창원;이주한;백윤기;문화회;홍성렬;이향우
    • Biomolecules & Therapeutics
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    • 제2권1호
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    • pp.47-53
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    • 1994
  • The methylation response as well as the level of methyl donor substance, 5-adenosyl-L-methionine (SAM) has been suggested to be related to hepatotoxicity including hepatocarcinogenesis. But direct correlation between protein methylation and hepatotoxicity has not been established to the present. To observe relationship between protein methylation and short-term hepatotoxicity induced by chemical substances, the activities of protein methylase I and II (PM I, PM II) were examined in cytosolic fraction of SD rat treated orally with acetaminophen(AA), $\alpha$-naphtyl-isothiocyanate (ANIT) and tetracycline (TC) that was known to produce necrosis, cholestasis and steatosis respectively. To evaluate the degree of hepatotoxicity induced by each chemicals, we observed the serum levels of indicative parameters and histopathological alteration. In AA treated group, the activities of PM I were increased at 6, 12 hours after administration, prior to the appearance of the hepatotoxicity by clinical parameters. It was suggested that the levels of PM I were related with the initial stage of hepatotoxic mechanism induced by AA. In ANIT treated group, though most of clinical parameters were significantly increased at 24, 48 hours after administration, the activity of PM I was not changed, indicating that ANIT induced hepatotoxicity was not coupled to protein methylation.

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Intestinal Hypoganglionosis Leading to Intestinal Failure and the Compassionate Use of OmegavenTM

  • Khalaf, Racha;Karjoo, Sara;Danielson, Paul;Wilsey, Michael;Shakeel, Fauzia
    • Pediatric Gastroenterology, Hepatology & Nutrition
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    • 제20권1호
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    • pp.55-60
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    • 2017
  • Intestinal hypoganglionosis is a rare innervation disorder that provides numerous nutritional, medical and surgical challenges. In this case report, we present a case of a newborn with intestinal hypoganglionosis leading to intestinal failure and intestinal failure-associated liver disease who responded to $Omegaven^{TM}$, a fat emulsion comprised of omega-3 fatty acids. $Omegaven^{TM}$ has been shown to be beneficial in the management of cholestatic liver injury. Clinical success with $Omegaven^{TM}$ was seen in this patient with a clear decrease in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and complete resolution of cholestasis with a direct bilirubin of zero within two weeks of initiation of $Omegaven^{TM}$. No current guidelines for the diagnosis and management of hypoganglionosis are available. We recommend a multidisciplinary approach and the use of novel therapies such as fat emulsions composed of omega-3 fatty acids for improved patient outcomes. Appropriate compassionate use protocols should be obtained from the Food and Drug Administration prior to initiation of $Omegaven^{TM}$.

Toxicogenomics Study on ${\alpha}-Naphthylisothiocyanate\;(ANIT)$ Induced Hepatotoxictiy in Mice

  • Hwang, Ji-Yoon;Lim, Jung-Sun;Jeong, Sun-Young;Park, Han-Jin;Cho, Jae-Woo;Yoon, Seok-Joo
    • Molecular & Cellular Toxicology
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    • 제2권1호
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    • pp.48-53
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    • 2006
  • [ ${\alpha}-Naphthylisothiocyanate$ ] (ANIT) induces intrahepatic cholestasis, involving damage to biliary epitheial cells. This study investigates hepatic gene expression and histopathological alterations in response to ANIT treatment in order to elucidate early time response of ANIT-induced hepatotoxicity. ANIT was treated with single dose (3, 6, and 60 mg/kg) in corn oil by oral gavage. Serum biochemical and histopathological observation were performed for evaluation of hepatotoxicity level. Affymetrix oligo DNA chips were used for gene expression profile by ANIT-induced hetpatoxicity. Hepatic enzyme levels (ALT, AST, and ALP) were increased in 24 hr high dose group. In microscopic observations, moderate hepatocellular necrosis, were confirmed 24 hr high dose groups. We found that gene expression patterns were dependent on time and dose. Our selected genes were related inflammation and immunomodulation. In this study, ANIT-induced hepatotoxicity was involved in acute phase responses and provides evidence for role of neutrophil could be mechanism associated with ANIT-mediated hepatotoxicity.

Primary hepatic sarcoidosis presenting with cholestatic liver disease and mimicking primary biliary cholangitis: a case report

  • Park, Young Joo;Woo, Hyun Young;Kim, Moon Bum;Ahn, Jihyun;Heo, Jeong
    • Journal of Yeungnam Medical Science
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    • 제39권3호
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    • pp.256-261
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    • 2022
  • Sarcoidosis often involves the liver. However, primary hepatic sarcoidosis confined to the liver without evidence of systemic involvement is rare. We report the case of a 37-year-old man with hepatic sarcoidosis who initially presented with elevated liver enzymes and suspicious cirrhotic nodules on computed tomography. The patient had cirrhosis but did not have portal hypertension. Based on the initial histopathologic finding of chronic granulomatous inflammation and the common clinical characteristics of sarcoidosis, he was initially diagnosed with primary biliary cholangitis, and his daily dosage of ursodeoxycholic acid was increased to 900 mg. After 14 months of treatment, his total serum bilirubin concentration was 10.9 mg/dL (upper normal limit, 1.2 mg/dL). Additionally, a transjugular liver biopsy revealed multiple noncaseating granulomas. He was diagnosed with primary hepatic sarcoidosis involving the lungs, heart, spleen, kidneys, and skin. Treatment with methylprednisolone was initiated. Two weeks later, he was started on azathioprine, and the dose of steroid was simultaneously reduced. These findings indicate the importance of including hepatic sarcoidosis as a possible diagnosis in patients with elevated liver enzymes or cryptogenic cirrhosis.

신생아 담즙 정체증에서 무담즙변의 유무와 $Tc^{99m}$ DISIDA 간담도 주사 결과간의 상관성과 생화학적 검사의 차이에 관한 연구 (The Correlation between Acholic Stool and the Result of $Tc^{99m}$ DISIDA Hepatobiliary Scintigraphy and Biochemical Test in Neonatal Cholestasis)

  • 주은영;안연모;김용주;문수지;최윤영
    • Pediatric Gastroenterology, Hepatology & Nutrition
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    • 제5권1호
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    • pp.51-61
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    • 2002
  • 목적: 신생아 담즙 정체증 환아의 감별을 위해 $Tc^{99m}$ DISIDA 간담도 주사 검사 상 신생아 간염과 간외 담도 폐쇄증 의증의 임상증상, 이학소견, 생화학 검사 등을 비교하고, 무담즙변과 $Tc^{99m}$ DISIDA 간담도 주사 검사의 관련성을 비교함으로서 진단에 도움을 얻고자 하였다. 방법: 1993년 6월부터 2001년 1월까지 한양대학병원 소아과 및 소아외과에 직접반응형 고빌리루 빈혈증을 주소로 입원했던 4개월 미만의 환아 중 $Tc^{99m}$ DISIDA 간담도 주사를 시행한 29명의 환아들을 대상으로 하였다. 이 중 간외 담도 폐쇄증 의증은 9명이고 신생아 간염은 20명으로 임상증상 및 이학적 소견, 생화학적 검사, $Tc^{99m}$ DISIDA 간담도 주사 결과를 조사하였다. 결과: 1) 간외 담도 폐쇄증 의증 환아가 신생아 간염보다 더 빨리 진단되고, 두 집단 모두 정상체중, 만삭아가 대부분이고, 남아에서 호발했다. 황달은 두집단 모두에게, 무담즙변은 간외 담도 폐쇄증 의증환아 모두에게 나타났으며 신생아 간염은 무담즙 변이 10%에서만 나타났다. 2) 내원 당시 검사상 direct bilirubin이 간외 담도 폐쇄증 의증일 때는 $6{\pm}2.6$ mg/dL, 신생아 간염은 $4.0{\pm}2.5$ mg/dL로 간외 담도 폐쇄증 의증에서 유의하게 증가되었고, 간외 담도 폐쇄증 의증은 소변 bilirubin이 더 많이 나타났다. 3) 간외 담도 폐쇄증 의증에서 direct bilirubin, total bilirubin, ALT, AST, ALP의 정상화되는 기간이 좀 더 오래 걸렸다. bilirubin 수치의 호전을 보이는 비율은 비슷했고 간외 담도 폐쇄증 의증이 심화되는 경우가 22.2%로 더 많았고 주로 수술 후 부작용에 의한 것이었다. 4) 무담즙변 환아 중에 $Tc^{99m}$ DISIDA 간담도 주사 상 소장 내 방사활성이 있는 환아가 18.2%였고, 방사활성이 없는 환아가 81.8%로 나타났고, 간외 담도 폐쇄증 의증으로 판단되어 수술한 환아가 63.6%로 나타났다. 5) 무담즙변 여부와 $Tc^{99m}$ DISIDA 간담도 주사 결과간의 상관계수에서 r 값은 -0.858로서 절대값이 1에 가깝고 음수로 이는 역상관 관계가 높아 무담즙변 환아와 방사활성이 없을 경우, 담즙변 환아와 방사활성이 있는 경우간 상관관계가 높게 나타났다. 6) 무담즙변 환아 중$Tc^{99m}$ DISIDA 간담도 주사 검사 상 소장 내 방사활성이 없는 환아에서 total bilirubin이 유의하게 증가되어 있고, direct bilirubin, total bilirubin, ALT, AST도 증가되어 있었으나 유의하지는 않았다. 7) $Tc^{99m}$ DISIDA 간담도 주사 검사 상 소장 내 방사활성이 있는 환아 중 무담즙변이 없는 경우에 ALT가 유의하게 높았고, direct bilirubin, total bilirubin, AST는 유의하지 않게 높았으며 무담즙변일 경우에는 ALP, 소변 bilirubin 양성률이 더 높았지만 유의하지는 않았다. 그러나 이에 대해서는 더 많은 환자에 대한 검사가 필요하리라 생각된다. 결론: 간외 담도 폐쇄증 의증 환아는 무담즙변, direct bilirubin 4 mg/dL 이상, 소변 bilirubin 양성, $Tc^{99m}$ DISIDA 간담도 주사 검사 상 방사활성이 없을 때 가능성이 높다. 간외 담도 폐쇄증 의증에서 수술 후 검사결과의 정상화되는 기간이 좀 더 오래 걸리고, 호전되는 경우는 간외 담도 폐쇄증 의증, 신생아 간염이 각각 66.7%, 70%로 두 군이 비슷했다. 심화되는 경우는 간외 담도 폐쇄증 의증에서 더 많았고 주로 수술 후 부작용에 의한 것으로 생각되며 오히려 수술하지 않은 2명에서 특별한치료 없이 호전 양상을 보이기도 했다. 무담즙변 환아 중 방사활성이 없는 환아에서 total bilirubin이 유의하게 증가되었고, 방사활성이 있는 환아 중 무 담즙변이 없는 경우에 ALT가 오히려 유의하게 증가되었으나 더 많은 환자군에 대한 연구가 필요하리라 본다. 무담즙변과 소장 내 방사활성이 없는 경우간에는 유의한 상관관계가 있지만 무담즙변 11명 중 2명(18.2%)에서 소장 내 방사활성이 관찰되었다는 점, 소장 내 방사활성이 없는 환아 9명중 수술 없이도 호전된 환아가 2명(22.2%)으로 관찰되었다는 점등은 무담즙변이 있다는 것과 소장 내 방사활성이 없다는 것만으로 간외 담도 폐쇄증으로 판단될 수 없으며 경피 간침 생검이나 시험 개복술로 확진하여야 한다는 것을 말해 준다.

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저담의 효능에 관한 문헌연구 (Literature Study on the Efficacy of Fel Sus Scrofa)

  • 이병국;김명동
    • 동의생리병리학회지
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    • 제23권1호
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    • pp.7-14
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    • 2009
  • Bile juice prevents deposition of cholesterol in the blood vessel, digests fat, and absorbs fatty acid and vitamins, and it plays a great role on metabolism. Recently, emotional stimulus and mentally over-depression cause a person to come to illness, and westernization of way of life makes more patients with cholelithiasis, resulting into without bile secretion after cholelithotomy. Ageing, and gastrectomy and kidney transplantation are also the causes of more cholelithiasis occurrences. To solve these medical problems, we studied how Fel Sus Scrofa, which is not different from human bile juice, was used in the traditional Korean medicine. We I researched flavor, property, efficacy of Fel Sus Scrofa and how it was used by folk medicine, and we studied the usage examples of Fel Sus Scrofa in Sanghanlon and Dongeuibogam. The property of Sus Scrofa is bitter and cold. Its efficacy is to deposit glycogen. So it is known that it has been widely used, with many edible forms, without any humoral loss, for the inflammatory disease from various fever, problems of urine and feces, cutaneous disease, pulmonary disease, opthalmopathy, fever, thirst from diabetes, hepatocystic duct disorder. Fel Sus Scrofa can be used internally and externally to prevent humoral loss, and to control cutaneous disease among various pediatric disorder full of fever. And as we have in mind that it also can be used to treat patients with cholestasis after cholecystectomy, it is expected that post study of it must be done.

Interleukin-2 Inhibits Secretin-Induced Bile Secretion in Cholangiocytes

  • Ko, Yoo-Seung;Hwang, Seock-Yeon;Park, Jae-Seung
    • 대한의생명과학회지
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    • 제19권2호
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    • pp.158-163
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    • 2013
  • Cholestatic liver is associated with hepatic inflammation and elevated proinflammatory cytokines. Recent studies indicate that certain cytokines can modulate bile secretion. In the present study, we have examined the role of interleukin (IL-2) on the bile secretion by a combination of study models. To examine the relevance of IL-2 on bile secretion, the expression of IL-2 and IL-2 receptor (IL-2R) of isolated normal and bile duct ligated (BDL) rats cholangiocytes was first measured by RT-PCR. In BDL rats, the expression of IL-2 and IL-2R was significantly increased compared with normal rats. To study the effect of IL-2 on bile secretion, bile flow was measured in normal and BDL rats. At the level of cholangiocytes, secretory responses of isolated bile duct unit (IBDU)s were quantified by videomicroscopy. The administrations of IL-2 had no significant effect on basal bile secretion in normal and BDL rats. There was no significant effect of IL-2 on basal bile ductular secretion as evidenced by no significant difference in luminal area of the IBDUs perfusedwith 100 pM of IL-2 from those of albumin carrier control. However, the secretin-stimulated bile ductular secretion was significantly (P < 0.01) inhibited by $34{\pm}4%$ (normal, n = 12), $21{\pm}5.3%$ (BDL 2 wk, n = 12) and $15{\pm}5.2%$ (BDL 4 wk, n = 12) with the co-administration of IL-2. As with other cytokines, physiologically relevant concentration of IL-2 can significantly inhibit secretin-stimulated bile ductular secretion. These findings support the important roles of cytokines in modulating bile secretion and may contribute to the cholestasis seen in cholestatic liver diseases.