胆汁淤积性肝病“上升”病理生理学模式及用药合理性探讨

顾天翊; 陆伦根

doi:10.3969/j.issn.1001-5256.2019.02.006

胆汁淤积性肝病“上升”病理生理学模式及用药合理性探讨

DOI: 10.3969/j.issn.1001-5256.2019.02.006

上海交通大学附属第一人民医院消化科

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中图分类号: R575
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出版历程
- 出版日期: 2019-02-20

Rationality of medication based on the “ascending” pathophysiology of cholestatic liver disease

Department of Gastroenterology, The First People′s Hospital Affiliated to Shanghai Jiaotong University

摘要

摘要:
近年来,有学者提出胆汁淤积性肝病具有"上升"病理生理学模式,尤其是在原发性胆汁性胆管炎和原发性硬化性胆管炎中。该理论认为,胆汁淤积性肝病在病变过程中随时间推延,在解剖结构上呈自下而上发展。原发或早期病灶通常位于"下游"的胆管,主要病因可能为免疫介导的胆管坏死性炎症损伤;当发生胆汁淤积时,胆盐介导的毒性作用将导致"上游"的肝实质损伤,因此胆汁毒性在疾病进展期间显得更为重要。基于其"上升"病理生理学模式,可以看到不同阶段的发病部位及病因均不同,因此有必要对胆汁淤积性肝病进行分期,并根据不同疾病阶段选取不同治疗药物,以更有效的方式利用现有药物,并为新药开发指明方向。然而,目前尚缺乏胆汁淤积性肝病早期生化标志物,寻找特异性强、敏感度高的生化标志物是目前临床的主要工作。
- 肝疾病 /
- 胆汁淤积 /
- 病理学 /
- 生理学 /
- 治疗学
Abstract:
In recent years, some scholars have put forward the“ascending”pathophysiology of cholestatic liver disease, especially in primary biliary cholangitis ( PBC) and primary sclerosing cholangitis ( PSC) . According to this theory, cholestatic liver disease develops from the bottom to the top of the anatomical structure over time. Primary or early lesions are usually located in the “downstream”bile duct, with a major cause of immune-mediated biliary necrotizing inflammatory injury. When cholestasis occurs, the toxic effect mediated by bile salt will lead to the injury in the“upstream”liver parenchyma. Therefore, bile toxicity is of great importance during disease progression. According to this theory of“ascending”pathophysiology, there are different locations and causes of the disease in different disease stages, and therefore, it is necessary to establish a staging system for cholestatic liver disease and use different drugs in different stages, in order to use the existing drugs in a more effective manner and give directions for new drug development. However, there are still no early biochemical markers for cholestatic liver disease, and current clinical work should focus on the search for biomarkers with strong specificity and high sensitivity.
- liver diseases /
- cholestasis /
- pathology /
- physiology /
- therapeutics

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参考文献(25)

[1]POLLHEIMER MJ, FICKERT P, STIEGER B.Chronic cholestatic liver diseases:Clues from histopathology for pathogenesis[J].Mol Aspects Med, 2014, 37 (2) :35-56.

[2]ALVAREZ F.Is biliary atresia an immune mediated disease?[J].J Hepatol, 2013, 59 (4) :648-650.

[3]ZHAO SX, ZHANG YG, ZHOU GD, et al.Clinicopathological features of early-and late-stage primary biliary cirrhosis:Acomparative study[J].Chin J Hepatol, 2016, 24 (6) :412-416. (in Chinese) 赵素贤, 张玉果, 周光德, 等.原发性胆汁性肝硬化早晚期临床病理学对比研究[J].中华肝脏病杂志, 2016, 24 (6) :412-416.

[4]de VRIES EM, WANG J, LEEFLANG MM, et al.Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1year later:Evaluation of prognostic value[J].Liver Int, 2016, 36 (12) :1867-1875.

[5] ZWEERS SJ, SHIRYAEV A, KOMUTA M, et al.Elevated interleukin-8 in bile of patients with primary sclerosing cholangitis[J].Liver Int, 2016, 36 (9) :1370-1377.

[6]FRIEDRICH K, SMIT M, BRUNE M, et al.CD14 is associated with biliary stricture formation[J].Hepatology, 2016, 64 (3) :843-852.

[7]LI T, HUANG Y, LIU P, et al.Lower plasma levels of IL-35 in patients with primary biliary cirrhosis[J].Tohoku J Exp Med, 2018, 244 (2) :123-131.

[8]DOORENSPLEET ME, HUBERS LM, CULVER EL, et al.Immunoglobulin G4 (+) B-cell receptor clones distinguish immunoglobulin G4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies[J].Hepatology, 2016, 64 (2) :501-507.

[9]DINANI AM, FISCHER SE, MOSKO J, et al.Patients with autoimmune hepatitis who have antimitochondrial antibodies need long-term follow-up to detect late development of primary biliary cirrhosis[J].Clin Gastroenterol Hepatol, 2012, 10 (6) :682-684.

[10]VIJAYVARGIYA P, CAMILLERI M, SHIN A, et al.Methods for diagnosis of bile acid malabsorption in clinical practice[J].Clin Gastroenterol Hepatol, 2013, 11 (10) :1232-1239.

[11]CAMILLERI M, NADEAU A, TREMAINE WJ, et al.Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or7alphaC4) , a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry[J].Neurogastroenterol Motil, 2009, 21 (7) :734-e43.

[12]LIM AG, JAZRAWI RP, AHMED HA, et al.Soluble intercellular adhesion molecule-1 in primary biliary cirrhosis:Relationship with disease stage, immune activity and cholestasis[J].Hepatology, 1994, 20 (4 Pt 1) :882-888.

[13]TAKEYAMA Y, UEHARA Y, INOMATA S, et al.Alternative transporter pathways in patients with untreated early-stage and latestage primary biliary cirrhosis[J].Liver Int, 2009, 29 (3) :406-414.

[14]MASUBUCHI N, SUGIHARA M, SUGITA T, et al.Oxidative stress markers, secondary bile acids and sulfated bile acids classify the clinical liver injury type:Promising diagnostic biomarkers for cholestasis[J].Chem Biol Interact, 2016, 255:83-91.

[15]GROVER VP, SOUTHERN L, DYSON JK, et al.Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging[J].Aliment Pharmacol Ther, 2016, 44 (9) :936-945.

[16]MENDES FD, KIM WR, PEDERSEN R, et al.Mortality attributable to cholestatic liver disease in the United States[J].Hepatology, 2008, 47 (4) :1241-1247.

[17]LEE J, BELANGER A, DOUCETTE JT, et al.Transplantation trends in primary biliary cirrhosis[J].Clin Gastroenterol Hepatol, 2007, 5 (11) :1313-1315.

[18]IMAM MH, LINDOR KD.The natural history of primary biliary cirrhosis[J].Semin Liver Dis, 2014, 34 (3) :329-333.

[19]BEUERS U, TRAUNER M, JANSEN P, et al.New paradigms in the treatment of hepatic cholestasis:From UDCA to FXR, PXRand beyond[J].J Hepatol, 2015, 62 (1 Suppl) :s25-s37.

[20]LINDOR KD, KOWDLEY KV, LUKETIC VA, et al.High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis[J].Hepatology, 2009, 50 (3) :808-814.

[21]KOBAYASHI A, UTSUNOMIYA T, OHBE Y, et al.Ascending cholangitis after successful surgical repair of biliary atresia[J].Arch Dis Child, 1973, 48 (9) :697-703.

[22]DUAN WJ, ZHANG FK, OU XJ, et al.The clinical profiles of primary biliary cirrhosis with a suboptimal biochemical response to ursodeoxycholic acid[J].Chin J Hepatol, 2011, 19 (2) :118-120. (in Chinese) 段维佳, 张福奎, 欧晓娟, 等.原发性胆汁性肝硬化患者对熊去氧胆酸应答欠佳的影响因素[J].中华肝脏病杂志, 2011, 19 (2) :118-120.

[23]ZHANG LN, SHI TY, SHI XH, et al.Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis:Results of a 14-year cohort study[J].Hepatology, 2013, 58 (1) :264-272.

[24]ZHAO J, LI W, YAO DK.Role of farnesoid X receptor in treatment of primary biliary cholangitis[J].Chin J Gastroenterol, 2017, 22 (2) :109-111. (in Chinese) 赵健, 李伟, 姚定康.法尼醇X受体在原发性胆汁性胆管炎治疗中的作用[J].胃肠病学, 2017, 22 (2) :109-111.

[25]WUNSCH E, MILKIEWICZ M, WASIK U, et al.Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease[J].Sci Rep, 2015, 5:13462.

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