甲状腺功能异常与胆汁酸代谢关系的研究进展

摘要

甲状腺疾病是常见内分泌代谢病,常伴肝功能与血糖代谢异常,其发病与甲状腺激素和胆汁酸的双向调控紧密相关。甲状腺激素可直接激活胆汁酸合成关键限速酶胆固醇7α-羟化酶(CYP7A1),或通过调节胆固醇代谢、肠道菌群间接影响胆汁酸合成,还能抑制胆固醇12α-羟化酶改变胆汁酸组成;促甲状腺激素则通过上调3-羟基-3-甲基戊二酸单酰辅酶A还原酶、激活相关信号通路降低CYP7A1水平。胆汁酸可反向激活G蛋白偶联受体5,促进甲状腺素向更具活性的三碘甲状腺原氨酸转化。甲状腺功能异常者常伴胆汁酸水平异常,肝脏疾病也伴随着甲状腺激素的变化。因此,本文就甲状腺功能异常与胆汁酸代谢关系进行探讨,旨在为临床治疗提供新视角。

关键词

甲状腺功能 / 胆汁酸代谢 / 法尼醇X受体 / G蛋白偶联受体5 / 胆固醇7α-羟化酶 / 胆固醇12α-羟化酶

参考文献

[1] Yan Y, Niu Z, Sun C, et al. Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism[J]. Nat Commun, 2022, 13(1): 6408.

[2] Chiang JYL, Ferrell JM . Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis[J]. Liver Res, 2020, 4(2): 47-63.

[3] 汪晓露, 赵勇, 谢敏, 等 . 自身免疫性甲状腺疾病的代谢组学研究进展[J]. 中西医结合研究, 2021, 13(2): 122-125.

[4] 杨艳艳, 李治锋, 王静 . 甲状腺功能亢进症初诊患者的肝功能检验项目评价[J]. 国际检验医学杂志, 2016, 37(19): 2779-2781.

[5] 顾雷君, 黄满仙, 姜雯, 等 . 血清胆汁酸谱检测在妊娠合并亚临床甲状腺功能减退症诊治中的应用[J]. 中国妇幼保健, 2022, 37(7): 1184-1188.

[6] 金素丽, 赵景, 张杰, 等 . 毒性弥漫性甲状腺肿患者甲状腺激素与胆汁酸亚组分、血脂的关系[J]. 检验医学, 2023, 38(6): 563-568.

[7] Laukkarinen J, Sand J, Autio V, et al. Bile duct stone procedures are more frequent in patients with hypothyroidism. A large, registry-based, cohort study in Finland[J]. Scand J Gastroenterol, 2010, 45(1): 70-74.

[8] Liu J, Fu J, Jia Y, et al. Serum metabolomic patterns in patients with autoimmune thyroid disease[J]. Endocr Pract, 2020, 26(1): 82-96.

[9] 朱旭东 . 血清促甲状腺激素、胆汁酸表达水平在妊娠期肝内胆汁淤积症患者的表达及联合检测意义[J]. 肝脏, 2018, 23(6): 519-521.

[10] 陈学权, 陆仲昌, 柏圣还 . 肝硬化患者血清甲状腺激素与胆汁酸水平相关性探讨[J]. 江苏医药, 2002(6): 450-451.

[11] 肖建国, 刘娓玉, 施文杰 . 肝硬化患者检测甲状腺激素及总胆汁酸的临床价值[J]. 河北医药, 2012, 34(6): 868-869.

[12] Skonieczna-Zydecka K, Jakubczyk K, Maciejewska-Markiewicz D, et al. Gut biofactory-neurocompetent metabolites within the gastrointestinal tract. a scoping review[J]. Nutrients, 2020, 12(11): 3369.

[13] Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation[J]. Nature, 2006, 439(7075): 484-489.

[14] Chiang JYL . New drug therapies for metabolic dysfunction-associated steatohepatitis[J]. Liver Res, 2025, 9(2): 94-103.

[15] 丁祥梅, 彭辉勇, 柳迎昭 . 微小RNA在自身免疫性甲状腺疾病中的研究进展[J]. 江苏大学学报(医学版), 2020, 30(1): 80-85.

[16] 刘琳琳, 金墨竹, 窦德强 . 基于UPLC-QqQ-MS/MS探究人参属中药对甲亢大鼠胆汁酸成分代谢影响[J]. 质谱学报, 2023, 44(4): 567-575.

[17] Feng Q, Xia W, Dai G, et al. The aging features of thyrotoxicosis mice: malnutrition, immunosenescence and lipotoxicity[J]. Front Immunol, 2022, 13: 864929.

[18] Bonde Y, Breuer O, Lütjohann D, et al. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans[J]. J Lipid Res, 2014, 55(11): 2408-2415.

[19] 符静, 刘佳, 王广 . 胆汁酸代谢产物与Graves病患者甲状腺功能的相关性探讨[J]. 解放军医学院学报, 2021, 42(8): 802-807.

[20] Li L, Liu S, Yu J . Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?[J]. Therapeutic Advances Endocrinology, 2020, 11: 2042018820958329.

[21] Yang X, Zhang C, Williamson C, et al. Association of maternal thyroid function with gestational hypercholanemia[J]. Thyroid, 2022, 32(1): 97-104.

[22] Wafa B, Faten H, Mouna E, et al. Hyperthyroidism and hepatic dysfunction: report of 17 cases[J]. JGH Open, 2020, 4(5): 876-879.

[23] Nicolaou M, Toumba M . Lipid profile pitfalls in subclinical hypothyroidism pathophysiology and treatment[J]. Lipidology, 2024, 1(2): 105-116.

[24] Yang F, Xu W, Wu L, et al. NTCP deficiency affects the levels of circulating bile acids and induces osteoporosis[J]. Front Endocrinol, 2022, 13: 898750.

[25] Ellis EC . Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes[J]. World J Gastroenterol, 2006, 12(29): 4640-4645.

[26] Yorke E. Hyperthyroidism and liver dysfunction: a review of a common comorbidity[J]. Clin Med Insights Endocrinol Diabetes, 2022, 15: 11795514221074672.

[27] Creo AL, Cannon BC, Pittock ST . Thyroid storm after choking[J]. J Pediatr Endocrinol Metab, 2018, 31(8): 933-936.

[28] Legakis I, Chrousos GP, Chatzipanagiotou S . Thyroid diseases and intestinal microbiome[J]. Horm Metab Res, 2023, 55(12): 813-818.

[29] Tiburcio ÁZ, RUIZ HB, LóPEZ SA, et al. Hypothyroidism and hyperthyroidism: are they related to the gut microbiome and its metabolites?[J]. EC Microbiology, 2025, 21: 1-8.

[30] Fang L, Ning J . Recent advances in gut microbiota and thyroid disease: pathogenesis and therapeutics in autoimmune, neoplastic, and nodular conditions[J]. Front Cell Infect Microbiol, 2024, 14: 1465928.

[31] Funabashi M, Grove TL, Wang M, et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome[J]. Nature, 2020, 582(7813): 566-570.

[32] Song Y, Zhao M, Zhang H, et al. Thyroid-stimulating hormone levels are inversely associated with serum total bile acid levels: a cross-sectional study[J]. Endocr Pract, 2016, 22(4): 420-426.

[33] Song Y, Xu C, Shao S, et al. Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis[J]. J Hepatol, 2015, 62(5): 1171-1179.

[34] Kube I, Tardio LB, Hofmann U, et al. Hypothyroidism increases cholesterol gallstone prevalence in mice by elevated hydrophobicity of primary bile acids[J]. Thyroid, 2021, 31(6): 973-984.

[35] Scappaticcio L, Longo M, Maiorino MI, et al. Abnormal liver blood tests in patients with hyperthyroidism: systematic review and meta-analysis[J]. Thyroid, 2021, 31(6): 884-894.

[36] Farrell J, Khokhar I, Altomare J . S5544 autoimmune collision: severe liver injury in thyroid storm with overlapping Grave′s disease and autoimmune hepatitis[J]. Am J Gastroenterol, 2025, 120(10S2): S1182-S1183.

[37] Vargas-Beltran AM, Armendariz-Pineda SM, Martínez-Sánchez FD, et al. Interplay between endocrine disorders and liver dysfunction: mechanisms of damage and therapeutic approaches[J]. World J Gastroenterol, 2025, 31(32): 108827.

[38] Liu X, Xu B, Zeng Y, et al. Case report: severe cholestatic jaundice associated with hyperthyroidism treated with methimazole[J]. Medicine, 2023, 102(45): e35972.

[39] Ezhilarasan D. Thyromimetics and MASLD: unveiling the novel molecules beyond resmetirom[J]. J Gastroenterol Hepatol, 2025, 40(2): 367-378.

[40] Hatziagelaki E, Paschou SA, Schön M, et al. NAFLD and thyroid function: pathophysiological and therapeutic considerations[J]. Trends Endocrinol Metab, 2022, 33(11): 755-768.

[41] Lee J, Kwak J, Kim MH, et al. Association between metabolic dysfunction-associated steatotic liver disease and the risk of thyroid cancer: a nationwide cohort study[J]. Korean J Intern Med, 2025, 40(5): 813-822.

[42] Dobre MZ, Virgolici B, Cioarcă-Nedelcu R . Lipid hormones at the intersection of metabolic imbalances and endocrine disorders[J]. Curr Issues Mol Biol, 2025, 47(7): 565.

[43] Ayesh H, Beran A, Suhail S, et al. Efficacy and safety of resmetirom in MASLD and MASH: network meta-analysis of randomized clinical trials[J]. J Basic Clin Physiol Pharmacol, 2025, 36(1): 3-11.

[44] Ratziu V, Scanlan TS, Bruinstroop E . Thyroid hormone receptor-β analogues for the treatment of metabolic dysfunction-associated steatohepatitis (MASH)[J]. J Hepatol, 2025, 82(2): 375-387.

[45] Chng CL, Goh GBB, Yen PM . Metabolic and functional cross talk between the thyroid and liver[J]. Thyroid, 2025, 35(6): 607-623.

[46] 崔德慧, 张丽明 . TSH、FT4、IL-12及sICAM-1在妊娠期肝内胆汁淤积症患者血清中表达水平及意义[J]. 解放军预防医学杂志, 2018, 36(6): 762-764.

基金资助

山西省科技厅国际合作项目(202204041101008)