肝硬化合并糖尿病患者血糖管理专家共识

doi:10.3969/j.issn.1672-5069.2022.05.039

摘要/Abstract

摘要： 针对肝硬化患者糖尿病高流行率和非酒精性脂肪性肝病相关肝硬化日益增多的趋势，肝硬化合并糖尿病人群面临的诊断和治疗问题越来越突出。基于此，中国医药生物技术协会慢病管理分会组织消化病学、传染病学、内分泌学等领域专家，聚焦肝硬化患者糖尿病的分型和血糖管理，最终形成《肝硬化合并糖尿病患者血糖管理专家共识》。本共识总结了肝硬化合并糖尿病的患病率、发病机制、临床特征和转归，将肝硬化合并糖尿病分为4种类型，明确提出了肝源性糖尿病这一亚型，推荐了在肝硬化患者中进行糖尿病诊断、监测和根据肝功能选择降糖药物的基本原则。

关键词: 肝硬化, 糖尿病, 诊断, 治疗, 共识

Abstract: In view of the high prevalence of diabetes mellitus in patients with liver cirrhosis and the increasing trend of non?alcoholic fatty liver disease?associated cirrhosis, the diagnosis and treatment of diabetes mellitus in patients with liver cirrhosis are becoming widespread concerns. Therefore, the Chronic Disease Management Branch, China Pharmaceutical Biotechnology Association, organized multidisciplinary experts from gastroenterology, infective disease, endocrinology, etc, to draw up expert consensus on the management of diabetes mellitus in patients with liver cirrhosis, with focusing on the classification and management of hyperglycemia in cirrhotic patients. The consensus summarizes the prevalence, pathogenesis, clinical setting and prognosis of the concomitant diabetes mellitus in patients with liver cirrhosis, and definitely puts forward a proposal regarding "hepatogenous diabetes" as one of the four subtypes of diabetes mellitus in cirrhotic patients, and further recommends the basic principles for diagnosing and monitoring diabetes mellitus and the selection of antidiabetic drugs based on liver functions in patients with liver cirrhosis.

Key words: Liver cirrhosis, Diabetes mellitus, Diagnosis, Treatment, Consensus

中国医药生物技术协会慢病管理分会. 肝硬化合并糖尿病患者血糖管理专家共识[J]. 实用肝脏病杂志, 2022, 25(5): 0-S1.

Chronic Disease Management Branch, China Pharmaceutical Biotechnology Association. Expert consensus on the management of diabetes mellitus in patients with liver cirrhosis[J]. Journal of Practical Hepatology, 2022, 25(5): 0-S1.

参考文献

[1] Asrani SK, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world[J]. J Hepatol, 2019, 70(1):151-171. DOI: 10.1016/j.jhep.2018.09.014.
[2] Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J]. Nat Rev Endocrinol, 2018, 14(2):88-98. DOI: 10.1038/nrendo.2017.151.
[3] Lee WG, Wells CI, McCall JL, et al. Prevalence of diabetes in liver cirrhosis: a systematic review and meta-analysis [J]. Diabetes Metab Res Rev, 2019, 35(6): e3157. DOI: 10.1002/dmrr.3157.
[4] Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis[J]. J Hepatol, 2019, 71(4): 793-801. DOI: 10.1016/j.jhep.2019.06.021.
[5] Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008[J]. Clin Gastroenterol Hepatol, 2011, 9(6): 524-530. e1; quiz e60. DOI: 10.1016/j.cgh.2011.03.020.
[6] Chen GY, Cao HX, Li F, et al. New risk-scoring system including non-alcoholic fatty liver disease for predicting incident type 2 diabetes in East China: Shanghai Baosteel Cohort[J]. J Diabetes Investig, 2016, 7(2): 206-211. DOI: 10.1111/jdi.12395.
[7] Paik JM, Golabi P, Younossi Y, et al. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD[J]. Hepatology, 2020, 72(5): 1605-1616. DOI: 10.1002/hep.31173.
[8] European Association for the Study of the Liver. EASL Clinical Practice Guidelines on nutrition in chronic liver disease[J]. J Hepatol, 2019, 70(1):172-193. DOI: 10.1016/j.jhep.2018.06.024.
[9] Elkrief L, Rautou PE, Sarin S, et al. Diabetes mellitus in patients with cirrhosis: clinical implications and management[J]. Liver Int, 2016, 36(7): 936-948. DOI: 10.1111/liv.13115.
[10] Addepally NS, George N, Martinez-Macias R, et al. Hemoglobin A1c has suboptimal performance to diagnose and monitor diabetes mellitus in patients with cirrhosis [J]. Dig Dis Sci, 2018, 63(12): 3498-3508. DOI: 10.1007/s10620-018-5265-3.
[11] Boursier J, Anty R, Carette C, et al. Management of diabetes mellitus in patients with cirrhosis: an overview and joint statement[J]. Diabetes Metab, 2021, 47(5): 101272. DOI: 10.1016/j.diabet.2021.101272.
[12] Xu C, Chen J, Zhang PA. Relationship between diabetes mellitus and cirrhosis risk in chronic hepatitis B patients in Wuhan, China[J]. Med Sci Monit, 2019, 25:8112-8119. DOI: 10.12659/MSM.917000.
[13] Petit JM, Hamza S, Rollot F, et al. Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis[J]. Acta Diabetol, 2014, 51(3):455-460. DOI: 10.1007/s00592-013-0538-y.
[14] American Diabetes Association Protessinal Practice Committee. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022[J]. Diabetes Care, 2022, 45 Suppl 1:S17-S38. DOI: 10.2337/dc22-S002.
[15] El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence[J]. Clin Gastroenterol Hepatol, 2006, 4(3): 369-380. DOI: 10.1016/j.cgh.2005.12.007.
[16] Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, et al. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management[J]. World J Gastroenterol, 2009, 15(3): 280-288. DOI: 10.3748/wjg.15.280.
[17] Perseghin G, Mazzaferro V, Sereni LP, et al. Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation[J]. Hepatology, 2000, 31(3):694-703. DOI: 10.1002/hep.510310320.
[18] García-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ, et al. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study[J]. Ann Hepatol, 2012, 11(2):240-248.
[19] 王雪涛. 乙肝肝硬化合并肝源性糖尿病患者与2 型糖尿病患者临床特征比较[D]. 长春: 吉林大学, 2021.
[20] 陈光榆, 范建高. 糖尿病合并肝病的机制及其处理对策[J]. 中华肝脏病杂志, 2014, 22(3): 171-173. DOI: 10.3760/cma.j.issn.1007-3418.2014.03.004.
[21] Holstein A, Hinze S, Thiessen E, et al. Clinical implications of hepatogenous diabetes in liver cirrhosis[J]. J Gastroenterol Hepatol, 2002, 17(6): 677-681. DOI: 10.1046/j.1440-1746.2002.02755.x.
[22] Carnovale C, Pozzi M, Dassano A, et al. The impact of a successful treatment of hepatitis C virus on glyco-metabolic control in diabetic patients: a systematic review and meta-analysis[J]. Acta Diabetol, 2019, 56(3): 341-354. DOI: 10.1007/s00592-018-1257-1.
[23] García-Compeán D, Orsi E, Kumar R, et al. Clinical implications of diabetes in chronic liver disease: diagnosis, outcomes and management, current and future perspectives[J]. World J Gastroenterol, 2022, 28(8): 775-793. DOI: 10.3748/wjg.v28.i8.775.
[24] Aparisi L, Sabater L, Del-Olmo J, et al. Does an association exist between chronic pancreatitis and liver cirrhosis in alcoholic subjects? [J]. World J Gastroenterol, 2008, 14(40):6171-6179. DOI: 10.3748/wjg.14.6171.
[25] Calzadilla-Bertot L, Vilar-Gomez E, Torres-Gonzalez A, et al. Impaired glucose metabolism increases risk of hepatic decompensation and death in patients with compensated hepatitis C virus-related cirrhosis[J]. Dig Liver Dis, 2016, 48(3): 283-290. DOI: 10.1016/j.dld.2015.12.002.
[26] Goh GB, Pan A, Chow WC, et al. Association between diabetes mellitus and cirrhosis mortality: the Singapore Chinese Health Study[J]. Liver Int, 2017, 37(2): 251-258. DOI: 10.1111/liv.13241.
[27] Vilar-Gomez E, Calzadilla-Bertot L, Wong VW, et al. Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, Child-Pugh A cirrhosis[J]. Clin Gastroenterol Hepatol, 2021, 19(1):136-145.e6. DOI: 10.1016/j.cgh.2020.04.083.
[28] Huang YW, Yang SS, Fu SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study[J]. Hepatology, 2014, 60(3): 807-814. DOI: 10.1002/hep.27212.
[29] Huang YW, Wang TC, Lin SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study[J]. Clin Infect Dis, 2013, 57(12):1695-1702. DOI: 10.1093/cid/cit603.
[30] Li X, Gao Y, Xu H, et al. Diabetes mellitus is a significant risk factor for the development of liver cirrhosis in chronic hepatitis C patients[J]. Sci Rep, 2017, 7(1):9087. DOI: 10.1038/s41598-017-09825-7.
[31] Wang Y, Wang B, Yan S, et al. Type 2 diabetes and gender differences in liver cancer by considering different confounding factors: a meta-analysis of cohort studies[J]. Ann Epidemiol, 2016, 26(11): 764-772. DOI: 10.1016/j.annepidem.2016.09.006.
[32] 唐淬蓉, 胡承光, 周宇辰, 等. 乙型肝炎肝硬化合并糖尿病时发生肝细胞癌的风险:一项随访5 年的前瞻性队列研究 [J]. 南方医科大学学报, 2021, 41(3): 313-318. DOI: 10.12122/j.issn.1673-4254.2021.03.01.
[33] 杨玲玲, 何金秋, 张雪珍. 乙型肝炎肝硬化合并2 型糖尿病预后分析[J]. 中华传染病杂志, 2016, 34(1):10-14. DOI: 10.3760/cma.j.issn.1000-6680.2016.01.003.
[34] 张利利, 李玉芳, 张驰, 等. 乙型肝炎肝硬化合并2型糖尿病发生原发性肝癌的风险研究[J]. 中华肝脏病杂志, 2019, 27(10): 788-792.DOI: 10.3760/cma.j.issn.1007-3418.2019.10.010.
[35] 岑光力, 岑柏春. 糖脂代谢异常对肝硬化患者疾病进展的影响[J]. 中华实验和临床病毒学杂志, 2015, 29(2):142-144. DOI: 10.3760/cma.j.issn.1003-9279.2015.02.016.
[36] 赵世姝. 肝硬化合并糖尿病临床、预后和糖代谢指标的观察研究[J/CD]. 临床医药文献电子杂志, 2015 (20): 4134-4135.
[37] Imano E, Nishida T, Shibata M, et al. Significance of oral glucose tolerance test for the diagnosis of diabetes mellitus in patients with liver cirrhosis[J]. Intern Med, 1999, 38(11):918. DOI: 10.2169/internalmedicine.38.918.
[38] Nishida T. Diagnosis and clinical implications of diabetes in liver cirrhosis: a focus on the oral glucose tolerance test [J]. J Endocr Soc, 2017, 1(7): 886-896. DOI: 10.1210/js.2017-00183.
[39] Lahousen T, Hegenbarth K, Ille R, et al. Determination of glycated hemoglobin in patients with advanced liver disease[J]. World J Gastroenterol, 2004, 10(15): 2284-2286. DOI: 10.3748/wjg.v10.i15.2284.
[40] Trenti T, Cristani A, Cioni G, et al. Fructosamine and glycated hemoglobin as indices of glycemic control in patients with liver cirrhosis[J]. Ric Clin Lab, 1990, 20(4): 261-267. DOI: 10.1007/BF02900711.
[41] Inada S, Koga M. Alcohol consumption reduces HbA1c and glycated albumin concentrations but not 1, 5-anhydroglucitol[J]. Ann Clin Biochem, 2017, 54(6): 631-635. DOI: 10.1177/0004563216675646.
[42] 张婷婷. 肝硬化患者口服葡萄糖耐量试验临床意义及研究进展[J]. 实用肝脏病杂志, 2019, 22(3): 449-452. DOI: 10.3969/j.issn.1672-5069.2019.03.035.
[43] Honda F, Hiramatsu A, Hyogo H, et al. Evaluation of glycemic variability in chronic liver disease patients with type 2 diabetes mellitus using continuous glucose monitoring[J]. PLoS One, 2018, 13(4): e0195028. DOI: 10.1371/journal.pone.0195028.
[44] Nadelson J, Satapathy SK, Nair S. Glycated hemoglobin levels in patients with decompensated cirrhosis[J]. Int J Endocrinol, 2016, 2016: 8390210. DOI: 10.1155/2016/8390210.
[45] 赵娟, 惠威, 窦爱华, 等. 肝硬化合并糖尿病患者发生低血糖症的临床分析[J]. 临床肝胆病杂志, 2020, 36(2): 329-332. DOI: 10.3969/j.issn.1001-5256.2020.02.019.
[46] Sonoda N, Morimoto A, Ugi S, et al. Predictors for mild and severe hypoglycemia in insulin-treated japanese diabetic patients[J]. PLoS One, 2015, 10(6): e0130584. DOI: 10.1371/journal.pone.0130584.
[47] Pietraszek A, Gregersen S, Hermansen K. Alcohol and type 2 diabetes. A review[J]. Nutr Metab Cardiovasc Dis, 2010, 20(5):366-375. DOI: 10.1016/j.numecd.2010.05.001.
[48] Costa D, Louren?o J, Monteiro AM, et al. Clinical performance of flash glucose monitoring system in patients with liver cirrhosis and diabetes mellitus[J]. Sci Rep, 2020, 10(1): 7460. DOI: 10.1038/s41598-020-64141-x.
[49] American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2021[J]. Diabetes Care, 2021, 44 Suppl 1:S73-S84. DOI: 10.2337/dc21-S006.
[50] American Diabetes Association. 12. Older adults: standards of medical care in diabetes-2021[J]. Diabetes Care, 2021, 44 Suppl 1: S168-S179. DOI: 10.2337/dc21-S012.
[51] Kumar R. Hepatogenous diabetes: an underestimated problem of liver cirrhosis[J]. Indian J Endocrinol Metab, 2018, 22(4):552-559. DOI: 10.4103/ijem.IJEM_79_18.
[52] Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention[J]. Drug Saf, 2010, 33(9): 727-740. DOI: 10.2165/11536790-000000000-00000.
[53] Gangopadhyay KK, Singh P. Consensus statement on dose modifications of antidiabetic agents in patients with hepatic impairment[J]. Indian J Endocrinol Metab, 2017, 21(2):341-354. DOI: 10.4103/ijem.IJEM_512_16.
[54] Vilar-Gomez E, Vuppalanchi R, Desai AP, et al. Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis[J]. Aliment Pharmacol Ther, 2019, 50(3):317-328. DOI: 10.1111/apt.15331.
[55] Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes[J]. Hepatology, 2014, 60(6): 2008-2016. DOI: 10.1002/hep.27199.
[56] Singh S, Singh PP, Singh AG, et al. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis[J]. Am J Gastroenterol, 2013, 108(6): 881-891, quiz 892. DOI: 10.1038/ajg.2013.5.
[57] Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies[J]. Gut, 2013, 62(4):606-615. DOI: 10.1136/gutjnl-2011-301708.
[58] Yen FS, Huang YH, Hou MC, et al. Metformin use and cirrhotic decompensation in patients with type 2 diabetes and liver cirrhosis[J]. Br J Clin Pharmacol, 2022, 88(1): 311-322. DOI: 10.1111/bcp.14970.
[59] Musso G, Cassader M, Paschetta E, et al. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a Meta-analysis[J]. JAMA Intern Med, 2017, 177(5): 633-640. DOI: 10.1001/jamainternmed.2016.9607.
[60] Kawamori R, Kadowaki T, Onji M, et al. Hepatic safety profile and glycemic control of pioglitazone in more than 20, 000 patients with type 2 diabetes mellitus: postmarketing surveillance study in Japan[J]. Diabetes Res Clin Pract, 2007, 76(2): 229-235. DOI: 10.1016/j.diabres.2006.08.017.
[61] Yen FS, Wei JC, Chiu LT, et al. Thiazolidinediones were associated with higher risk of cardiovascular events in patients with type 2 diabetes and cirrhosis[J]. Liver Int, 2021, 41(1):110-122. DOI: 10.1111/liv.14714.
[62] Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [J]. Diabetes Care, 2020, 43(2):487-493. DOI: 10.2337/dci19-0066.
[63] Yen FS,Wei JC, Yip HT, et al. Dipeptidyl peptidase-4 inhibitors may accelerate cirrhosis decompensation in patients with diabetes and liver cirrhosis: a nationwide population-based cohort study in Taiwan[J]. Hepatol Int, 2021, 15(1):179-190. DOI: 10.1007/s12072-020-10122-1.
[64] Scheen Aj.Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: a common comorbidity associated with severe complications[J]. Diabetes Metab, 2019, 45(3):213-223. DOI: 10.1016/j.diabet.2019.01.008.
[65] Saffo S, Taddei T. SGLT2 inhibitors and cirrhosis: a unique perspective on the comanagement of diabetes mellitus and ascites[J]. Clin Liver Dis (Hoboken), 2018, 11(6): 141-144. DOI: 10.1002/cld.714.
[66] Gentile S, Guarino G, Romano M, et al. A randomized controlled trial of acarbose in hepatic encephalopathy[J]. Clin Gastroenterol Hepatol, 2005, 3(2): 184-191. DOI: 10.1016/s1542-3565(04)00667-6.
[67] Singh AK, Singh R. Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs[J]. Expert Rev Clin Pharmacol, 2020, 13(1): 53-64. DOI: 10.1080/17512433.2020.1698291.
[68] 《2 型糖尿病短期胰岛素强化治疗专家共识》编写委员会. 2 型糖尿病短期胰岛素强化治疗专家共识(2021 年版)[J]. 中华糖尿病杂志, 2022, 14(1):21-31. DOI: 10.3760/cma.j.cn115791-20211109-00611.
[69] Wada K, Wada Y, Tsuruoka S.
[Effects of long-acting insulin degludec on type 2 diabetic hemodialysis patients with poor glycemic control] [J]. Nihon Jinzo Gakkai Shi, 2015, 57(5):872-877.