Hepatic immune regulation and sex disparities.
Journal
Nature reviews. Gastroenterology & hepatology
ISSN: 1759-5053
Titre abrégé: Nat Rev Gastroenterol Hepatol
Pays: England
ID NLM: 101500079
Informations de publication
Date de publication:
05 Sep 2024
05 Sep 2024
Historique:
accepted:
25
07
2024
medline:
6
9
2024
pubmed:
6
9
2024
entrez:
5
9
2024
Statut:
aheadofprint
Résumé
Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.
Identifiants
pubmed: 39237606
doi: 10.1038/s41575-024-00974-5
pii: 10.1038/s41575-024-00974-5
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. Springer Nature Limited.
Références
Burra, P., Zanetto, A. & Germani, G. Sex bias in clinical trials in gastroenterology and hepatology. Nat. Rev. Gastroenterol. Hepatol. 19, 413–414 (2022).
pubmed: 35610513
pmcid: 9128638
doi: 10.1038/s41575-022-00638-2
Mauvais-Jarvis, F. et al. Sex and gender: modifiers of health, disease, and medicine. Lancet 396, 565–582 (2020).
pubmed: 32828189
pmcid: 7440877
doi: 10.1016/S0140-6736(20)31561-0
Bizzaro, D. et al. Influence of sex in alcohol-related liver disease: pre-clinical and clinical settings. United Eur. Gastroenterol. J. 11, 218–227 (2023).
doi: 10.1002/ueg2.12370
Burra, P. et al. Clinical impact of sexual dimorphism in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Liver Int. 41, 1713–1733 (2021).
pubmed: 33982400
doi: 10.1111/liv.14943
Goodman, W. A., Erkkila, I. P. & Pizarro, T. T. Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 740–754 (2020).
pubmed: 32901108
pmcid: 7750031
doi: 10.1038/s41575-020-0354-0
Guarino, M. et al. Sarcopenia in chronic advanced liver diseases: a sex-oriented analysis of the literature. Dig. Liver Dis. 54, 997–1006 (2022).
pubmed: 34789397
doi: 10.1016/j.dld.2021.10.010
Toniutto, P. et al. Role of sex in liver tumor occurrence and clinical outcomes: a comprehensive review. Hepatology 79, 1141–1157 (2023).
pubmed: 37013373
doi: 10.1097/HEP.0000000000000277
Zanetto, A. et al. Vascular liver diseases: a sex-oriented analysis of the literature. Dig. Liver Dis. 55, 178–186 (2023).
pubmed: 35906168
doi: 10.1016/j.dld.2022.07.005
Lefebvre, P. & Staels, B. Hepatic sexual dimorphism – implications for non-alcoholic fatty liver disease. Nat. Rev. Endocrinol. 17, 662–670 (2021).
pubmed: 34417588
doi: 10.1038/s41574-021-00538-6
Knolle, P. A. & Thimme, R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146, 1193–1207 (2014).
pubmed: 24412289
doi: 10.1053/j.gastro.2013.12.036
Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14, 996–1006 (2013).
pubmed: 24048121
doi: 10.1038/ni.2691
Doherty, D. G. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J. Autoimmun. 66, 60–75 (2016).
pubmed: 26358406
doi: 10.1016/j.jaut.2015.08.020
Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).
pubmed: 19302037
doi: 10.1146/annurev.immunol.021908.132629
Gao, B., Jeong, W. I. & Tian, Z. Liver: an organ with predominant innate immunity. Hepatology 47, 729–736 (2008).
pubmed: 18167066
doi: 10.1002/hep.22034
Racanelli, V. & Rehermann, B. The liver as an immunological organ. Hepatology 43, S54–S62 (2006).
pubmed: 16447271
doi: 10.1002/hep.21060
Tiegs, G. & Lohse, A. W. Immune tolerance: what is unique about the liver. J. Autoimmun. 34, 1–6 (2010).
pubmed: 19717280
doi: 10.1016/j.jaut.2009.08.008
Costa, D. et al. Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality. J. Hepatol. 74, 819–828 (2021).
pubmed: 33075344
doi: 10.1016/j.jhep.2020.10.004
Liberal, R., Grant, C. R., Mieli-Vergani, G. & Vergani, D. Autoimmune hepatitis: a comprehensive review. J. Autoimmun. 41, 126–139 (2013).
pubmed: 23218932
doi: 10.1016/j.jaut.2012.11.002
Shin, E. C., Sung, P. S. & Park, S. H. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat. Rev. Immunol. 16, 509–523 (2016).
pubmed: 27374637
doi: 10.1038/nri.2016.69
Zanetto, A. et al. Severity of systemic inflammation is the main predictor of ACLF and bleeding in individuals with acutely decompensated cirrhosis. J. Hepatol. 78, 301–311 (2023).
pubmed: 36150575
doi: 10.1016/j.jhep.2022.09.005
Zanetto, A. et al. Toward a more precise prognostic stratification in acute decompensation of cirrhosis: the Padua model 2.0. United Eur. Gastroenterol. J. 11, 815–824 (2023).
doi: 10.1002/ueg2.12472
Zhang, S., Lu, S. & Li, Z. Extrahepatic factors in hepatic immune regulation. Front. Immunol. 13, 941721 (2022).
pubmed: 36052075
pmcid: 9427192
doi: 10.3389/fimmu.2022.941721
Meijnikman, A. S. et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nat. Med. 28, 2100–2106 (2022).
pubmed: 36216942
doi: 10.1038/s41591-022-02016-6
Schwabe, R. F. & Greten, T. F. Gut microbiome in HCC – mechanisms, diagnosis and therapy. J. Hepatol. 72, 230–238 (2020).
pubmed: 31954488
doi: 10.1016/j.jhep.2019.08.016
Yin, Y. et al. Gut microbiota promote liver regeneration through hepatic membrane phospholipid biosynthesis. J. Hepatol. 78, 820–835 (2023).
pubmed: 36681162
doi: 10.1016/j.jhep.2022.12.028
Karlsen, T. H. et al. The EASL-Lancet Commission on liver health in Europe: prevention, case-finding, and early diagnosis to reduce liver-related mortality. Lancet 403, 1522–1524 (2024).
pubmed: 38359860
doi: 10.1016/S0140-6736(24)00204-6
Karlsen, T. H. et al. The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality. Lancet 399, 61–116 (2022).
pubmed: 34863359
doi: 10.1016/S0140-6736(21)01701-3
Heidari, S. et al. WHO’s adoption of SAGER guidelines and GATHER: setting standards for better science with sex and gender in mind. Lancet 403, 226–228 (2024).
pubmed: 38134947
doi: 10.1016/S0140-6736(23)02807-6
Heymann, F. & Tacke, F. Immunology in the liver – from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).
pubmed: 26758786
doi: 10.1038/nrgastro.2015.200
Kasarinaite, A., Sinton, M., Saunders, P. T. K. & Hay, D. C. The influence of sex hormones in liver function and disease. Cells 12, 1604 (2023).
pubmed: 37371074
pmcid: 10296738
doi: 10.3390/cells12121604
Della Torre, S. & Maggi, A. Sex differences: a resultant of an evolutionary pressure. Cell Metab. 25, 499–505 (2017).
pubmed: 28190772
doi: 10.1016/j.cmet.2017.01.006
Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023).
pubmed: 37364790
doi: 10.1016/j.jhep.2023.06.003
Catala-Senent, J. F. et al. Hepatic steatosis and steatohepatitis: a functional meta-analysis of sex-based differences in transcriptomic studies. Biol. Sex. Differ. 12, 29 (2021).
pubmed: 33766130
pmcid: 7995602
doi: 10.1186/s13293-021-00368-1
Giles, D. A. et al. Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat. Med. 23, 829–838 (2017).
pubmed: 28604704
pmcid: 5596511
doi: 10.1038/nm.4346
Sommars, M. A. et al. Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis. Elife 8, e43922 (2019).
pubmed: 30983568
pmcid: 6464608
doi: 10.7554/eLife.43922
Nikkanen, J. et al. An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice. Science 378, 290–295 (2022).
pubmed: 36264814
pmcid: 9870047
doi: 10.1126/science.abn9886
Waxman, D. J. & Kineman, R. D. Sex matters in liver fat regulation. Science 378, 252–253 (2022).
pubmed: 36264790
doi: 10.1126/science.ade7614
Roelfsema, F. & Veldhuis, J. D. Growth hormone dynamics in healthy adults are related to age and sex and strongly dependent on body mass index. Neuroendocrinology 103, 335–344 (2016).
pubmed: 26228064
doi: 10.1159/000438904
Guillaume, M. et al. Selective liver estrogen receptor α modulation prevents steatosis, diabetes, and obesity through the anorectic growth differentiation factor 15 hepatokine in mice. Hepatol. Commun. 3, 908–924 (2019).
pubmed: 31304450
pmcid: 6601326
doi: 10.1002/hep4.1363
Oliva, M. et al. The impact of sex on gene expression across human tissues. Science 369, eaba3066 (2020).
pubmed: 32913072
pmcid: 8136152
doi: 10.1126/science.aba3066
Lin, H. Y. et al. Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology 47, 1924–1935 (2008).
pubmed: 18449947
doi: 10.1002/hep.22252
Lee, H. S. et al. The effect of testosterone replacement therapy on nonalcoholic fatty liver disease in older hypogonadal men. J. Clin. Endocrinol. Metab. 109, e757–e764 (2024).
pubmed: 37656011
doi: 10.1210/clinem/dgad511
Sarkar, M. et al. Low testosterone is associated with nonalcoholic steatohepatitis and fibrosis severity in men. Clin. Gastroenterol. Hepatol. 19, 400–402.e2 (2021).
pubmed: 31812658
doi: 10.1016/j.cgh.2019.11.053
Chen, K. W., Chen, Y. S., Chen, P. J. & Yeh, S. H. Androgen receptor functions in pericentral hepatocytes to decrease gluconeogenesis and avoid hyperglycemia and obesity in male mice. Metabolism 135, 155269 (2022).
pubmed: 35914621
doi: 10.1016/j.metabol.2022.155269
Wu, X. N. et al. Sex-determining region Y gene promotes liver fibrosis and accounts for sexual dimorphism in its pathophysiology. J. Hepatol. 80, 928–940 (2024).
pubmed: 38336346
doi: 10.1016/j.jhep.2024.01.036
Dong, J. et al. SRY is a key mediator of sexual dimorphism in hepatic ischemia/reperfusion injury. Ann. Surg. 276, 345–356 (2022).
pubmed: 33086308
doi: 10.1097/SLA.0000000000004422
Liu, C. et al. Activation of SRY accounts for male-specific hepatocarcinogenesis: implication in gender disparity of hepatocellular carcinoma. Cancer Lett. 410, 20–31 (2017).
pubmed: 28942012
doi: 10.1016/j.canlet.2017.09.013
Jaillon, S., Berthenet, K. & Garlanda, C. Sexual dimorphism in innate immunity. Clin. Rev. Allergy Immunol. 56, 308–321 (2019).
pubmed: 28963611
doi: 10.1007/s12016-017-8648-x
Shepherd, R., Cheung, A. S., Pang, K., Saffery, R. & Novakovic, B. Sexual dimorphism in innate immunity: the role of sex hormones and epigenetics. Front. Immunol. 11, 604000 (2020).
pubmed: 33584674
doi: 10.3389/fimmu.2020.604000
Gal-Oz, S. T. et al. ImmGen report: sexual dimorphism in the immune system transcriptome. Nat. Commun. 10, 4295 (2019).
pubmed: 31541153
pmcid: 6754408
doi: 10.1038/s41467-019-12348-6
Hammerich, L. & Tacke, F. Hepatic inflammatory responses in liver fibrosis. Nat. Rev. Gastroenterol. Hepatol. 20, 633–646 (2023).
pubmed: 37400694
doi: 10.1038/s41575-023-00807-x
Peiseler, M. et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits. J. Hepatol. 77, 1136–1160 (2022).
pubmed: 35750137
doi: 10.1016/j.jhep.2022.06.012
Saviano, A., Henderson, N. C. & Baumert, T. F. Single-cell genomics and spatial transcriptomics: discovery of novel cell states and cellular interactions in liver physiology and disease biology. J. Hepatol. 73, 1219–1230 (2020).
pubmed: 32534107
pmcid: 7116221
doi: 10.1016/j.jhep.2020.06.004
Ministrini, S., Montecucco, F., Sahebkar, A. & Carbone, F. Macrophages in the pathophysiology of NAFLD: the role of sex differences. Eur. J. Clin. Invest. 50, e13236 (2020).
pubmed: 32294235
doi: 10.1111/eci.13236
Han, Y. H., Choi, H., Kim, H. J. & Lee, M. O. Chemotactic cytokines secreted from Kupffer cells contribute to the sex-dependent susceptibility to non-alcoholic fatty liver diseases in mice. Life Sci. 306, 120846 (2022).
pubmed: 35914587
doi: 10.1016/j.lfs.2022.120846
Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).
pubmed: 17615358
doi: 10.1126/science.1140485
Becerra-Diaz, M., Strickland, A. B., Keselman, A. & Heller, N. M. Androgen and androgen receptor as enhancers of M2 macrophage polarization in allergic lung inflammation. J. Immunol. 201, 2923–2933 (2018).
pubmed: 30305328
doi: 10.4049/jimmunol.1800352
Bizzaro, D. et al. Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury. Clin. Sci. 132, 255–272 (2018).
doi: 10.1042/CS20171260
Chen, K. E., Lainez, N. M. & Coss, D. Sex differences in macrophage responses to obesity-mediated changes determine migratory and inflammatory traits. J. Immunol. 206, 141–153 (2021).
pubmed: 33268480
doi: 10.4049/jimmunol.2000490
Petrescu, A. D. et al. Glucocorticoids cause gender-dependent reversal of hepatic fibrosis in the MDR2-knockout mouse model. Int. J. Mol. Sci. 18, 2389 (2017).
pubmed: 29125588
pmcid: 5713358
doi: 10.3390/ijms18112389
Krishnan, A. et al. tumor necrosis factor-related apoptosis-inducing ligand receptor deficiency promotes the ductular reaction, macrophage accumulation, and hepatic fibrosis in the Abcb4
pubmed: 32240619
pmcid: 7280758
doi: 10.1016/j.ajpath.2020.02.013
Lotter, H., Jacobs, T., Gaworski, I. & Tannich, E. Sexual dimorphism in the control of amebic liver abscess in a mouse model of disease. Infect. Immun. 74, 118–124 (2006).
pubmed: 16368964
pmcid: 1346632
doi: 10.1128/IAI.74.1.118-124.2006
Lotter, H. et al. Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNγ secretion in natural killer T cells. PLoS ONE 8, e55694 (2013).
pubmed: 23424637
pmcid: 3570563
doi: 10.1371/journal.pone.0055694
Sellau, J. et al. Androgens predispose males to monocyte-mediated immunopathology by inducing the expression of leukocyte recruitment factor CXCL1. Nat. Commun. 11, 3459 (2020).
pubmed: 32651360
pmcid: 7351718
doi: 10.1038/s41467-020-17260-y
Helk, E. et al. TNFα-mediated liver destruction by Kupffer cells and Ly6Chi monocytes during Entamoeba histolytica infection. PLoS Pathog. 9, e1003096 (2013).
pubmed: 23300453
pmcid: 3536671
doi: 10.1371/journal.ppat.1003096
Er-Lukowiak, M. et al. Testosterone affects type I/type II interferon response of neutrophils during hepatic amebiasis. Front. Immunol. 14, 1279245 (2023).
pubmed: 38179044
pmcid: 10764495
doi: 10.3389/fimmu.2023.1279245
Groneberg, M. et al. HIF-1α modulates sex-specific Th17/Treg responses during hepatic amoebiasis. J. Hepatol. 76, 160–173 (2022).
pubmed: 34599999
doi: 10.1016/j.jhep.2021.09.020
Liedtke, C. et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenes. Tissue Repair. 6, 19 (2013).
doi: 10.1186/1755-1536-6-19
Gallage, S. et al. A researcher’s guide to preclinical mouse NASH models. Nat. Metab. 4, 1632–1649 (2022).
pubmed: 36539621
doi: 10.1038/s42255-022-00700-y
Cuno-Gomiz, C. et al. Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice. Biol. Sex. Differ. 14, 85 (2023).
pubmed: 37964320
pmcid: 10644614
doi: 10.1186/s13293-023-00569-w
Osonoi, S. & Takebe, T. Organoid-guided precision hepatology for metabolic liver disease. J. Hepatol. 80, 805–821 (2024).
pubmed: 38237864
doi: 10.1016/j.jhep.2024.01.002
Rezvani, M., Vallier, L. & Guillot, A. Modeling nonalcoholic fatty liver disease in the dish using human-specific platforms: strategies and limitations. Cell Mol. Gastroenterol. Hepatol. 15, 1135–1145 (2023).
pubmed: 36740045
pmcid: 10031472
doi: 10.1016/j.jcmgh.2023.01.014
Trivedi, P. J., Hirschfield, G. M., Adams, D. H. & Vierling, J. M. Immunopathogenesis of primary biliary cholangitis, primary sclerosing cholangitis and autoimmune hepatitis: themes and concepts. Gastroenterology 166, 995–1019 (2024).
pubmed: 38342195
doi: 10.1053/j.gastro.2024.01.049
Papenfuss, T. L. et al. Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J. Immunol. 186, 3346–3355 (2011).
pubmed: 21317386
doi: 10.4049/jimmunol.1001322
Seillet, C. et al. Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor α. J. Immunol. 190, 5459–5470 (2013).
pubmed: 23626011
doi: 10.4049/jimmunol.1203312
Henze, L., Schwinge, D. & Schramm, C. The effects of androgens on T cells: clues to female predominance in autoimmune liver diseases? Front. Immunol. 11, 1567 (2020).
pubmed: 32849531
pmcid: 7403493
doi: 10.3389/fimmu.2020.01567
Meester, I. et al. SeXY chromosomes and the immune system: reflections after a comparative study. Biol. Sex. Differ. 11, 3 (2020).
pubmed: 31937374
pmcid: 6958619
doi: 10.1186/s13293-019-0278-y
Zhang, X., Chen, B. D., Zhao, L. D. & Li, H. The gut microbiota: emerging evidence in autoimmune diseases. Trends Mol. Med. 26, 862–873 (2020).
pubmed: 32402849
doi: 10.1016/j.molmed.2020.04.001
Werner, M. et al. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand. J. Gastroenterol. 43, 1232–1240 (2008).
pubmed: 18609163
doi: 10.1080/00365520802130183
Gronbaek, L. et al. Incidence, prevalence and mortality of autoimmune hepatitis in England 1997-2015. A population-based cohort study. Liver Int. 40, 1634–1644 (2020).
pubmed: 32304617
doi: 10.1111/liv.14480
Webb, G. J., Ryan, R. P., Marshall, T. P. & Hirschfield, G. M. The epidemiology of UK autoimmune liver disease varies with geographic latitude. Clin. Gastroenterol. Hepatol. 19, 2587–2596 (2021).
pubmed: 33493696
pmcid: 8661127
doi: 10.1016/j.cgh.2021.01.029
Hahn, J. W. et al. Global incidence and prevalence of autoimmune hepatitis, 1970-2022: a systematic review and meta-analysis. EClinicalMedicine 65, 102280 (2023).
pubmed: 37876996
pmcid: 10590724
doi: 10.1016/j.eclinm.2023.102280
Groribæk, L., Vilstrup, H. & Jepsen, P. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J. Hepatol. 60, 612–617 (2014).
doi: 10.1016/j.jhep.2013.10.020
Al-Chalabi, T., Underhill, J. A., Portmann, B. C., McFarlane, I. G. & Heneghan, M. A. Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis. J. Hepatol. 48, 140–147 (2008).
pubmed: 18023911
doi: 10.1016/j.jhep.2007.08.013
Donaldson, P. T. et al. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 13, 701–706 (1991).
pubmed: 2010165
doi: 10.1002/hep.1840130415
Plagiannakos, C. P. et al. Treatment response and clinical event-free survival in autoimmune hepatitis: a Canadian multicentre cohort study. J. Hepatol. 81, 227–237 (2024).
pubmed: 38527524
doi: 10.1016/j.jhep.2024.03.021
Slooter, C. D. et al. Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: first report of the IAIHG retrospective registry. Hepatology 79, 538–550 (2024).
pubmed: 37676683
Montano-Loza, A. J., Carpenter, H. A. & Czaja, A. J. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am. J. Gastroenterol. 103, 1944–1951 (2008).
pubmed: 18564111
doi: 10.1111/j.1572-0241.2008.01922.x
Yan, L. J. et al. Sex and regional disparities in incidence of hepatocellular carcinoma in autoimmune hepatitis: a systematic review and meta-analysis. Hepatol. Int. 15, 1413–1420 (2021).
pubmed: 34478116
doi: 10.1007/s12072-021-10249-9
Colapietro, F. et al. Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis. J. Hepatol. 80, 53–61 (2024).
pubmed: 37802188
doi: 10.1016/j.jhep.2023.09.010
Terrabuio, D. R. B., Abrantes-Lemos, C. P., Carrilho, F. J. & Cançado, E. L. R. Follow-up of pregnant women with autoimmune hepatitis. J. Clin. Gastroenterol. 43, 350–356 (2009).
pubmed: 19077726
doi: 10.1097/MCG.0b013e318176b8c5
Trivedi, P. J. & Hirschfield, G. M. Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut 70, 1989–2003 (2021).
pubmed: 34266966
doi: 10.1136/gutjnl-2020-322362
McNally, R. J., James, P. W., Ducker, S., Norman, P. D. & James, O. F. No rise in incidence but geographical heterogeneity in the occurrence of primary biliary cirrhosis in North East England. Am. J. Epidemiol. 179, 492–498 (2014).
pubmed: 24401563
pmcid: 3908630
doi: 10.1093/aje/kwt308
Lleo, A. et al. Evolving trends in female to male incidence and male mortality of primary biliary cholangitis. Sci. Rep. 6, 25936 (2016).
doi: 10.1038/srep25906
Lv, T. et al. Regional variation and temporal trend of primary biliary cholangitis epidemiology: a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 36, 1423–1434 (2021).
pubmed: 33141955
doi: 10.1111/jgh.15329
Hirschfield, G. M. et al. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J. Hepatol. 67, 145–172 (2017).
doi: 10.1016/j.jhep.2017.03.022
Smyk, D. S. et al. Sex differences associated with primary biliary cirrhosis. Clin. Dev. Immunol. 2012, 610504 (2012).
pubmed: 22693524
pmcid: 3369468
doi: 10.1155/2012/610504
Carbone, M. et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 144, 560–569.e7 (2013).
pubmed: 23246637
doi: 10.1053/j.gastro.2012.12.005
Chen, S. et al. Prognosis of 732 ursodeoxycholic acid-treated patients with primary biliary cholangitis: a single center follow-up study from China. J. Gastroenterol. Hepatol. 34, 1236–1241 (2019).
pubmed: 30365184
doi: 10.1111/jgh.14521
Cheung, A. C. et al. Effects of age and sex of response to ursodeoxycholic acid and transplant-free survival in patients with primary biliary cholangitis. Clin. Gastroenterol. Hepatol. 17, 2076–2084.e2 (2019).
pubmed: 30616022
doi: 10.1016/j.cgh.2018.12.028
Trivedi, P. J. et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut 65, 321–329 (2016).
pubmed: 25567117
doi: 10.1136/gutjnl-2014-308351
Rong, G. H. et al. Incidence and risk factors for hepatocellular carcinoma in primary biliary cirrhosis. Clin. Rev. Allerg. Immunol. 48, 132–141 (2015).
doi: 10.1007/s12016-015-8483-x
Roberts, S. B. et al. Ethnicity, disease severity, and survival in Canadian patients with primary biliary cholangitis. Hepatology 76, 303–316 (2022).
pubmed: 35220609
doi: 10.1002/hep.32426
Boonstra, K. et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 58, 2045–2055 (2013).
pubmed: 23775876
doi: 10.1002/hep.26565
Trivedi, P. J. et al. Effects of primary sclerosing cholangitis on risks of cancer and death in people with inflammatory bowel disease, based on sex, race, and age. Gastroenterology 159, 915–928 (2020).
pubmed: 32445859
doi: 10.1053/j.gastro.2020.05.049
European Association for the Study of the Liver EASL Clinical Practice Guidelines on sclerosing cholangitis. J. Hepatol. 77, 761–806 (2022).
doi: 10.1016/j.jhep.2022.05.011
Karlsen, T. H., Folseraas, T., Thorburn, D. & Vesterhus, M. Primary sclerosing cholangitis – a comprehensive review. J. Hepatol. 67, 1298–1323 (2017).
pubmed: 28802875
doi: 10.1016/j.jhep.2017.07.022
Lunder, A. K. et al. Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease. Gastroenterology 151, 660–669.e4 (2016).
pubmed: 27342213
doi: 10.1053/j.gastro.2016.06.021
Weismuller, T. J. et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology 152, 1975–1984.e8 (2017).
pubmed: 28274849
doi: 10.1053/j.gastro.2017.02.038
Toy, E., Balasubramanian, S., Selmi, C., Li, C. S. & Bowlus, C. L. The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population. BMC Gastroenterol. 11, 83 (2011).
pubmed: 21767410
pmcid: 3160402
doi: 10.1186/1471-230X-11-83
Barberio, B. et al. Prevalence of primary sclerosing cholangitis in patients with inflammatory bowel disease: a systematic review and meta-analysis. Gastroenterology 161, 1865–1877 (2021).
pubmed: 34425093
doi: 10.1053/j.gastro.2021.08.032
Rupp, C. et al. Impact of age at diagnosis on disease progression in patients with primary sclerosing cholangitis. United Eur. Gastroenterol. J. 6, 255–262 (2018).
doi: 10.1177/2050640617717156
Sinha, T. et al. Analysis of 1135 gut metagenomes identifies sex-specific resistome profiles. Gut Microbes 10, 358–366 (2019).
pubmed: 30373468
doi: 10.1080/19490976.2018.1528822
Hsu, C. L. & Schnabl, B. The gut-liver axis and gut microbiota in health and liver disease. Nat. Rev. Microbiol. 21, 719–733 (2023).
pubmed: 37316582
doi: 10.1038/s41579-023-00904-3
Saboo, K. et al. Sex is associated with differences in gut microbial composition and function in hepatic encephalopathy. J. Hepatol. 74, 80–88 (2021).
pubmed: 32679299
doi: 10.1016/j.jhep.2020.06.046
Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).
pubmed: 23328391
doi: 10.1126/science.1233521
Collden, H. et al. The gut microbiota is a major regulator of androgen metabolism in intestinal contents. Am. J. Physiol. Endocrinol. Metab. 317, E1182–E1192 (2019).
pubmed: 31689143
pmcid: 6962501
doi: 10.1152/ajpendo.00338.2019
Cross, T. L., Kasahara, K. & Rey, F. E. Sexual dimorphism of cardiometabolic dysfunction: gut microbiome in the play? Mol. Metab. 15, 70–81 (2018).
pubmed: 29887245
pmcid: 6066746
doi: 10.1016/j.molmet.2018.05.016
Collins, S. L., Stine, J. G., Bisanz, J. E., Okafor, C. D. & Patterson, A. D. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat. Rev. Microbiol. 21, 236–247 (2023).
pubmed: 36253479
doi: 10.1038/s41579-022-00805-x
Bennion, L. J. et al. Sex differences in the size of bile acid pools. Metabolism 27, 961–969 (1978).
pubmed: 672615
doi: 10.1016/0026-0495(78)90140-3
Xie, G. et al. Profiling of serum bile acids in a healthy Chinese population using UPLC-MS/MS. J. Proteome Res. 14, 850–859 (2015).
pubmed: 25581415
doi: 10.1021/pr500920q
Baars, A. et al. Sex differences in lipid metabolism are affected by presence of the gut microbiota. Sci. Rep. 8, 13426 (2018).
pubmed: 30194317
pmcid: 6128923
doi: 10.1038/s41598-018-31695-w
Xie, G. et al. Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes. Sci. Rep. 7, 45232 (2017).
pubmed: 28345673
pmcid: 5366919
doi: 10.1038/srep45232
Wankhade, U. D. et al. Maternal high-fat diet programs offspring liver steatosis in a sexually dimorphic manner in association with changes in gut microbial ecology in mice. Sci. Rep. 8, 16502 (2018).
pubmed: 30405201
pmcid: 6220325
doi: 10.1038/s41598-018-34453-0
Paik, J. M. et al. The burden of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in every region of the world from 1990 to 2019. Hepatol. Commun. 7, e0251 (2023).
pubmed: 37782469
pmcid: 10545420
doi: 10.1097/HC9.0000000000000251
Zanetto, A. et al. New indications for liver transplantation. J. Clin. Med. 10, 3867 (2021).
pubmed: 34501314
pmcid: 8432035
doi: 10.3390/jcm10173867
Bjorkholm, B. et al. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS ONE 4, e6958 (2009).
pubmed: 19742318
pmcid: 2734986
doi: 10.1371/journal.pone.0006958
Chen, P. et al. Microbiota protects mice against acute alcohol-induced liver injury. Alcohol. Clin. Exp. Res. 39, 2313–2323 (2015).
pubmed: 26556636
pmcid: 4712135
doi: 10.1111/acer.12900
Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29, 1043–1055 (2015).
pubmed: 25466902
doi: 10.1096/fj.14-259515
Weger, B. D. et al. The mouse microbiome is required for sex-specific diurnal rhythms of gene expression and metabolism. Cell Metab. 29, 362–382.e8 (2019).
pubmed: 30344015
pmcid: 6370974
doi: 10.1016/j.cmet.2018.09.023
Jourova, L. et al. Gut microbiome alters the activity of liver cytochromes p450 in mice with sex-dependent differences. Front. Pharmacol. 11, 01303 (2020).
pubmed: 33123003
pmcid: 7566554
doi: 10.3389/fphar.2020.01303
Fu, C. et al. Sex different effect of antibiotic and probiotic treatment on intestinal microbiota composition in chemically induced liver injury rats. Genomics 115, 110647 (2023).
pubmed: 37217087
doi: 10.1016/j.ygeno.2023.110647
Cirulli, E. T. et al. A missense variant in PTPN22 is a risk factor for drug-induced liver injury. Gastroenterology 156, 1707–1716.e2 (2019).
pubmed: 30664875
doi: 10.1053/j.gastro.2019.01.034
Daly, A. K. Genetics of drug-induced liver injury: current knowledge and future prospects. Clin. Transl. Sci. 16, 37–42 (2023).
pubmed: 36194091
doi: 10.1111/cts.13424
Ellinghaus, D. How genetic risk contributes to autoimmune liver disease. Semin. Immunopathol. 44, 397–410 (2022).
pubmed: 35650446
pmcid: 9256578
doi: 10.1007/s00281-022-00950-8
Eslam, M., Valenti, L. & Romeo, S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268–279 (2018).
pubmed: 29122391
doi: 10.1016/j.jhep.2017.09.003
Karlsen, T. H., Lammert, F. & Thompson, R. J. Genetics of liver disease: from pathophysiology to clinical practice. J. Hepatol. 62, S6–S14 (2015).
pubmed: 25920091
doi: 10.1016/j.jhep.2015.02.025
Trepo, E. & Valenti, L. Update on NAFLD genetics: from new variants to the clinic. J. Hepatol. 72, 1196–1209 (2020).
pubmed: 32145256
doi: 10.1016/j.jhep.2020.02.020
Gerussi, A., Cristoferi, L., Carbone, M., Asselta, R. & Invernizzi, P. The immunobiology of female predominance in primary biliary cholangitis. J. Autoimmun. 95, 124–132 (2018).
pubmed: 30509386
doi: 10.1016/j.jaut.2018.10.015
Hirschfield, G. M., Karlsen, T. H., Lindor, K. D. & Adams, D. H. Primary sclerosing cholangitis. Lancet 382, 1587–1599 (2013).
pubmed: 23810223
doi: 10.1016/S0140-6736(13)60096-3
Cooper, K. M., Delk, M., Devuni, D. & Sarkar, M. Sex differences in chronic liver disease and benign liver lesions. JHEP Rep. 5, 100870 (2023).
pubmed: 37791378
pmcid: 10542645
doi: 10.1016/j.jhepr.2023.100870
Dixon, P. H. et al. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements. Nat. Commun. 13, 4840 (2022).
pubmed: 35977952
pmcid: 9385867
doi: 10.1038/s41467-022-29931-z
Dixon, P. H. et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am. J. Gastroenterol. 109, 76–84 (2014).
pubmed: 24366234
doi: 10.1038/ajg.2013.406
Adams, P. C., Jeffrey, G. & Ryan, J. Haemochromatosis. Lancet 401, 1811–1821 (2023).
pubmed: 37121243
doi: 10.1016/S0140-6736(23)00287-8
Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399–408 (1996).
pubmed: 8696333
doi: 10.1038/ng0896-399
Girelli, D. et al. Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene. Gastroenterology 122, 1295–1302 (2002).
pubmed: 11984516
doi: 10.1053/gast.2002.32984
Kato, J. et al. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am. J. Hum. Genet. 69, 191–197 (2001).
pubmed: 11389486
pmcid: 1226033
doi: 10.1086/321261
Montosi, G. et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108, 619–623 (2001).
pubmed: 11518736
pmcid: 209405
doi: 10.1172/JCI200113468
Njajou, O. T. et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat. Genet. 28, 213–214 (2001).
pubmed: 11431687
doi: 10.1038/90038
Papanikolaou, G. et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36, 77–82 (2004).
pubmed: 14647275
doi: 10.1038/ng1274
Roetto, A. et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat. Genet. 33, 21–22 (2003).
pubmed: 12469120
doi: 10.1038/ng1053
Risch, N. Haemochromatosis, HFE and genetic complexity. Nat. Genet. 17, 375–376 (1997).
pubmed: 9398831
doi: 10.1038/ng1297-375
Anderson, G. J. & Bardou-Jacquet, E. Revisiting hemochromatosis: genetic vs. phenotypic manifestations. Ann. Transl. Med. 9, 731 (2021).
pubmed: 33987429
pmcid: 8106074
doi: 10.21037/atm-20-5512
Bell, S. et al. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis. Commun. Biol. 4, 156 (2021).
pubmed: 33536631
pmcid: 7859200
doi: 10.1038/s42003-020-01575-z
Abdellaoui, A., Yengo, L., Verweij, K. J. H. & Visscher, P. M. 15 years of GWAS discovery: realizing the promise. Am. J. Hum. Genet. 110, 179–194 (2023).
pubmed: 36634672
pmcid: 9943775
doi: 10.1016/j.ajhg.2022.12.011
Crouch, D. J. M. & Bodmer, W. F. Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants. Proc. Natl Acad. Sci. USA 117, 18924–18933 (2020).
pubmed: 32753378
pmcid: 7431089
doi: 10.1073/pnas.2005634117
Mathieson, I. The omnigenic model and polygenic prediction of complex traits. Am. J. Hum. Genet. 108, 1558–1563 (2021).
pubmed: 34331855
pmcid: 8456163
doi: 10.1016/j.ajhg.2021.07.003
Wainschtein, P. et al. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. Nat. Genet. 54, 263–273 (2022).
pubmed: 35256806
pmcid: 9119698
doi: 10.1038/s41588-021-00997-7
Daly, A. K. et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 41, 816–819 (2009).
pubmed: 19483685
doi: 10.1038/ng.379
Lucena, M. I. et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 141, 338–347 (2011).
pubmed: 21570397
doi: 10.1053/j.gastro.2011.04.001
Nicoletti, P. et al. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology 152, 1078–1089 (2017).
pubmed: 28043905
doi: 10.1053/j.gastro.2016.12.016
Singer, J. B. et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat. Genet. 42, 711–714 (2010).
pubmed: 20639878
doi: 10.1038/ng.632
Chen, Y. et al. Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. Nat. Genet. 55, 1640–1650 (2023).
pubmed: 37709864
pmcid: 10918428
doi: 10.1038/s41588-023-01497-6
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
pubmed: 18820647
pmcid: 2597056
doi: 10.1038/ng.257
Anstee, Q. M. et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort. J. Hepatol. 73, 505–515 (2020).
pubmed: 32298765
doi: 10.1016/j.jhep.2020.04.003
Valenti, L., Dongiovanni, P., Ginanni Corradini, S., Burza, M. A. & Romeo, S. PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Dig. Liver Dis. 45, 619–624 (2013).
pubmed: 23333103
doi: 10.1016/j.dld.2012.12.006
Chung, B. K. & Karlsen, T. H. Genetic discoveries highlight environmental factors as key drivers of liver disease. Dig. Dis. 35, 323–333 (2017).
pubmed: 28468012
doi: 10.1159/000456583
Choi, S. W., Mak, T. S. & O’Reilly, P. F. Tutorial: a guide to performing polygenic risk score analyses. Nat. Protoc. 15, 2759–2772 (2020).
pubmed: 32709988
pmcid: 7612115
doi: 10.1038/s41596-020-0353-1
Ji, S. G. et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat. Genet. 49, 269–273 (2017).
pubmed: 27992413
doi: 10.1038/ng.3745
Gerussi, A. et al. Improving predictive accuracy in primary biliary cholangitis: a new genetic risk score. Liver Int. 44, 1952–1960 (2024).
pubmed: 38619000
doi: 10.1111/liv.15916
Khera, A. V. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet. 50, 1219–1224 (2018).
pubmed: 30104762
pmcid: 6128408
doi: 10.1038/s41588-018-0183-z
Invernizzi, P. et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 363, 533–535 (2004).
pubmed: 14975617
doi: 10.1016/S0140-6736(04)15541-4
Lleo, A. et al. Y chromosome loss in male patients with primary biliary cirrhosis. J. Autoimmun. 41, 87–91 (2013).
pubmed: 23375847
doi: 10.1016/j.jaut.2012.12.008
Keur, N., Ricano-Ponce, I., Kumar, V. & Matzaraki, V. A systematic review of analytical methods used in genetic association analysis of the X-chromosome. Brief. Bioinform 23, bbac287 (2022).
pubmed: 35901513
pmcid: 9764208
doi: 10.1093/bib/bbac287
Asselta, R. et al. X chromosome contribution to the genetic architecture of primary biliary cholangitis. Gastroenterology 160, 2483–2495.e26 (2021).
pubmed: 33675743
doi: 10.1053/j.gastro.2021.02.061
Sumida, T. S., Cheru, N. T. & Hafler, D. A. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nat. Rev. Immunol. 24, 503–517 (2024).
pubmed: 38374298
pmcid: 11216899
doi: 10.1038/s41577-024-00994-x
Iwakiri, Y. & Trebicka, J. Portal hypertension in cirrhosis: pathophysiological mechanisms and therapy. JHEP Rep. 3, 100316 (2021).
pubmed: 34337369
pmcid: 8318926
doi: 10.1016/j.jhepr.2021.100316
Sandahl, T. D. et al. The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis. Aliment. Pharmacol. Ther. 43, 1222–1231 (2016).
pubmed: 27061098
doi: 10.1111/apt.13618
Zhang, B., Ji, L. H., Zhang, C. G., Zhao, G. & Wu, Z. Y. Gender differences in vascular reactivity of mesenteric arterioles in portal hypertensive and non-portal hypertensive rats. World J. Gastroenterol. 25, 5953–5960 (2019).
pubmed: 31660032
pmcid: 6815798
doi: 10.3748/wjg.v25.i39.5953
Robert, R., Chagneau-Derrode, C., Carretier, M., Mauco, G. & Silvain, C. Gender differences in vascular reactivity of aortas from rats with and without portal hypertension. J. Gastroenterol. Hepatol. 20, 890–894 (2005).
pubmed: 15946136
doi: 10.1111/j.1440-1746.2005.03805.x
Wiest, R. & Groszmann, R. J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 35, 478–491 (2002).
pubmed: 11826425
doi: 10.1053/jhep.2002.31432
Kajita, M. et al. iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 300, H1021–H1031 (2011).
pubmed: 21193589
doi: 10.1152/ajpheart.00563.2009
Park, E. M. et al. Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. J. Cereb. Blood Flow. Metab. 26, 392–401 (2006).
pubmed: 16049426
doi: 10.1038/sj.jcbfm.9600194
Sacerdoti, D. et al. Arachidonic acid metabolites and endothelial dysfunction of portal hypertension. Prostaglandins Other Lipid Mediat. 120, 80–90 (2015).
pubmed: 26072731
doi: 10.1016/j.prostaglandins.2015.05.008
Graupera, M. et al. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology 37, 172–181 (2003).
pubmed: 12500202
doi: 10.1053/jhep.2003.50004
Hou, M. C. et al. Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: role in the hyperdynamic circulation. Hepatology 27, 20–27 (1998).
pubmed: 9425912
doi: 10.1002/hep.510270105
Wu, Y., Burns, R. C. & Sitzmann, J. V. Effects of nitric oxide and cyclooxygenase inhibition on splanchnic hemodynamics in portal hypertension. Hepatology 18, 1416–1421 (1993).
pubmed: 8244267
doi: 10.1002/hep.1840180621
Reiberger, T. et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 62, 1634–1641 (2013).
pubmed: 23250049
doi: 10.1136/gutjnl-2012-304038
Jachs, M. et al. Carvedilol achieves higher hemodynamic response and lower rebleeding rates than propranolol in secondary prophylaxis. Clin. Gastroenterol. Hepatol. 21, 2318–2326.e7 (2023).
pubmed: 35842118
doi: 10.1016/j.cgh.2022.06.007
Villanueva, C. et al. β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 393, 1597–1608 (2019).
pubmed: 30910320
doi: 10.1016/S0140-6736(18)31875-0
Villanueva, C. et al. Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. J. Hepatol. 77, 1014–1025 (2022).
pubmed: 35661713
doi: 10.1016/j.jhep.2022.05.021
Thalheimer, U., Bosch, J. & Burroughs, A. K. How to prevent varices from bleeding: shades of grey – the case for nonselective β blockers. Gastroenterology 133, 2029–2036 (2007).
pubmed: 18054573
doi: 10.1053/j.gastro.2007.10.028
Reiberger, T. et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J. Hepatol. 58, 911–921 (2013).
pubmed: 23262249
doi: 10.1016/j.jhep.2012.12.011
Jachs, M. et al. Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut 70, 1758–1767 (2021).
pubmed: 33199442
doi: 10.1136/gutjnl-2020-322712
Walle, T., Walle, U. K., Cowart, T. D. & Conradi, E. C. Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects. Clin. Pharmacol. Ther. 46, 257–263 (1989).
pubmed: 2776391
doi: 10.1038/clpt.1989.136
Burza, M. A., Marschall, H. U., Napoleone, L. & Molinaro, A. The 35-year odyssey of beta blockers in cirrhosis: any gender difference in sight? Pharmacol. Res. 119, 20–26 (2017).
pubmed: 28099882
doi: 10.1016/j.phrs.2017.01.015
Mortensen, C., Andersen, O., Krag, A., Bendtsen, F. & Moller, S. High-sensitivity C-reactive protein levels predict survival and are related to haemodynamics in alcoholic cirrhosis. Eur. J. Gastroenterol. Hepatol. 24, 619–626 (2012).
pubmed: 22441510
doi: 10.1097/MEG.0b013e328351db6e
Bernardi, M., Moreau, R., Angeli, P., Schnabl, B. & Arroyo, V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J. Hepatol. 63, 1272–1284 (2015).
pubmed: 26192220
doi: 10.1016/j.jhep.2015.07.004
Zanetto, A. et al. Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death. J. Hepatol. 77, 660–669 (2022).
pubmed: 35364225
doi: 10.1016/j.jhep.2022.03.009
D’Amico, G. et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment. Pharmacol. Ther. 39, 1180–1193 (2014).
pubmed: 24654740
doi: 10.1111/apt.12721
Deltenre, P., Zanetto, A., Saltini, D., Moreno, C. & Schepis, F. The role of transjugular intrahepatic portosystemic shunt in patients with cirrhosis and ascites: recent evolution and open questions. Hepatology 77, 640–658 (2023).
pubmed: 35665949
Ripoll, C. et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133, 481–488 (2007).
pubmed: 17681169
doi: 10.1053/j.gastro.2007.05.024
Simbrunner, B. et al. Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response. Hepatol. Int. 17, 1045–1056 (2023).
pubmed: 36881247
doi: 10.1007/s12072-023-10496-y
Austin, A. S., Mahida, Y. R., Clarke, D., Ryder, S. D. & Freeman, J. G. A pilot study to investigate the use of oxpentifylline (pentoxifylline) and thalidomide in portal hypertension secondary to alcoholic cirrhosis. Aliment. Pharmacol. Ther. 19, 79–88 (2004).
pubmed: 14687169
doi: 10.1046/j.1365-2036.2003.01809.x
Caraceni, P., Abraldes, J. G., Gines, P., Newsome, P. N. & Sarin, S. K. The search for disease-modifying agents in decompensated cirrhosis: from drug repurposing to drug discovery. J. Hepatol. 75, S118–S134 (2021).
pubmed: 34039483
doi: 10.1016/j.jhep.2021.01.024
Jepsen, P. & Younossi, Z. M. The global burden of cirrhosis: a review of disability-adjusted life-years lost and unmet needs. J. Hepatol. 75, S3–S13 (2021).
pubmed: 34039490
doi: 10.1016/j.jhep.2020.11.042
Cherubini, A., Della Torre, S., Pelusi, S. & Valenti, L. Sexual dimorphism of metabolic dysfunction-associated steatotic liver disease. Trends Mol. Med., https://doi.org/10.1016/j.molmed.2024.05.013 (2024).
doi: 10.1016/j.molmed.2024.05.013
pubmed: 38890029
Hofer, B. S. et al. Acute hemodynamic response to propranolol predicts bleeding and nonbleeding decompensation in patients with cirrhosis. Hepatol. Commun. 6, 2569–2580 (2022).
pubmed: 35808889
pmcid: 9426394
doi: 10.1002/hep4.2021
Sanyal, A. J. et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology 70, 1913–1927 (2019).
pubmed: 30993748
doi: 10.1002/hep.30664
Garcia-Tsao, G. et al. Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J. Hepatol. 72, 885–895 (2020).
pubmed: 31870950
doi: 10.1016/j.jhep.2019.12.010
Reiberger, T. et al. The rationale and study design of two phase II trials examining the effects of BI 685,509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis. Trials 24, 293 (2023).
pubmed: 37095557
pmcid: 10123479
doi: 10.1186/s13063-023-07291-3
Harrison, S. A. et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N. Engl. J. Med. 390, 497–509 (2024).
pubmed: 38324483
doi: 10.1056/NEJMoa2309000
Burghart, L. et al. Distinct prognostic value of different portal hypertension-associated features in patients with primary biliary cholangitis. J. Gastroenterol. 57, 99–110 (2022).
pubmed: 34893924
doi: 10.1007/s00535-021-01839-3
Geer, E. B. & Shen, W. Gender differences in insulin resistance, body composition, and energy balance. Gend. Med. 6, 60–75 (2009).
pubmed: 19318219
pmcid: 2908522
doi: 10.1016/j.genm.2009.02.002
Bredella, M. A. Sex differences in body composition. Adv. Exp. Med. Biol. 1043, 9–27 (2017).
pubmed: 29224088
doi: 10.1007/978-3-319-70178-3_2
Fain, J. N., Madan, A. K., Hiler, M. L., Cheema, P. & Bahouth, S. W. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145, 2273–2282 (2004).
pubmed: 14726444
doi: 10.1210/en.2003-1336
Heymsfield, S. B. & Wadden, T. A. Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med. 376, 254–266 (2017).
pubmed: 28099824
doi: 10.1056/NEJMra1514009
Ebadi, M. et al. Review article: prognostic significance of body composition abnormalities in patients with cirrhosis. Aliment. Pharmacol. Ther. 52, 600–618 (2020).
pubmed: 32621329
doi: 10.1111/apt.15927
Mitsiopoulos, N. et al. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J. Appl. Physiol. 85, 115–122 (1998).
pubmed: 9655763
doi: 10.1152/jappl.1998.85.1.115
Kim, G., Kang, S. H., Kim, M. Y. & Baik, S. K. Prognostic value of sarcopenia in patients with liver cirrhosis: a systematic review and meta-analysis. PLoS ONE 12, e0186990 (2017).
pubmed: 29065187
pmcid: 5655454
doi: 10.1371/journal.pone.0186990
van Vugt, J. L. et al. Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation. Am. J. Transpl. 16, 2277–2292 (2016).
doi: 10.1111/ajt.13732
Carey, E. J. et al. A multicenter study to define sarcopenia in patients with end-stage liver disease. Liver Transpl. 23, 625–633 (2017).
pubmed: 28240805
pmcid: 5762612
doi: 10.1002/lt.24750
Carey, E. J. et al. A North American expert opinion statement on sarcopenia in liver transplantation. Hepatology 70, 1816–1829 (2019).
pubmed: 31220351
doi: 10.1002/hep.30828
Nishikawa, H. et al. Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): recommendation from the working group for creation of sarcopenia assessment criteria. Hepatol. Res. 46, 951–963 (2016).
pubmed: 27481650
doi: 10.1111/hepr.12774
van Vugt, J. L. A. et al. Low skeletal muscle mass is associated with increased hospital costs in patients with cirrhosis listed for liver transplantation – a retrospective study. Transpl. Int. 31, 165–174 (2018).
pubmed: 28871624
doi: 10.1111/tri.13048
Montano-Loza, A. J. et al. Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation. Liver Transpl. 20, 640–648 (2014).
pubmed: 24678005
doi: 10.1002/lt.23863
Ando, Y. et al. Sarcopenia impairs health-related quality of life in cirrhotic patients. Eur. J. Gastroenterol. Hepatol. 31, 1550–1556 (2019).
pubmed: 31206408
doi: 10.1097/MEG.0000000000001472
Kaido, T. et al. Impact of sarcopenia on survival in patients undergoing living donor liver transplantation. Am. J. Transpl. 13, 1549–1556 (2013).
doi: 10.1111/ajt.12221
Montano-Loza, A. J. et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 10, 166–173.e1 (2012).
pubmed: 21893129
doi: 10.1016/j.cgh.2011.08.028
Montano-Loza, A. J. et al. Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis. J. Cachexia, Sarcopenia Muscle 7, 126–135 (2016).
pubmed: 27493866
doi: 10.1002/jcsm.12039
Baracos, V. E. & Arribas, L. Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann. Oncol. 29, ii1–ii9 (2018).
pubmed: 29506228
doi: 10.1093/annonc/mdx810
Eslamparast, T., Montano-Loza, A. J., Raman, M. & Tandon, P. Sarcopenic obesity in cirrhosis – the confluence of 2 prognostic titans. Liver Int. 38, 1706–1717 (2018).
pubmed: 29738109
doi: 10.1111/liv.13876
Pou, K. M. et al. Patterns of abdominal fat distribution: the Framingham Heart Study. Diabetes Care 32, 481–485 (2009).
pubmed: 19074995
pmcid: 2646033
doi: 10.2337/dc08-1359
Kim, D. et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 14, 132–138.e134 (2016).
pubmed: 26226099
doi: 10.1016/j.cgh.2015.07.024
Koo, B. K. et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J. Hepatol. 66, 123–131 (2017).
pubmed: 27599824
doi: 10.1016/j.jhep.2016.08.019
Pan, X. Y. et al. Low skeletal muscle mass is associated with more severe histological features of non-alcoholic fatty liver disease in male. Hepatol. Int. 16, 1085–1093 (2022).
pubmed: 35829867
doi: 10.1007/s12072-022-10384-x
Cao, Y. T. et al. Sex- and reproductive status-specific relationships between body composition and non-alcoholic fatty liver disease. BMC Gastroenterol. 23, 364 (2023).
pubmed: 37875811
pmcid: 10598923
doi: 10.1186/s12876-023-02997-9
Montano-Loza, A. J. et al. Visceral adiposity increases risk for hepatocellular carcinoma in male patients with cirrhosis and recurrence after liver transplant. Hepatology 67, 914–923 (2018).
pubmed: 29023899
doi: 10.1002/hep.29578
Terjimanian, M. N. et al. Abdominal adiposity, body composition and survival after liver transplantation. Clin. Transplant. 30, 289–294 (2016).
pubmed: 26717257
pmcid: 4777665
doi: 10.1111/ctr.12688
Ha, N. B. et al. Sarcopenic visceral obesity is associated with increased post-liver transplant mortality in acutely ill patients with cirrhosis. Am. J. Transpl. 22, 2195–2202 (2022).
doi: 10.1111/ajt.17079
Saponaro, C., Gaggini, M., Carli, F. & Gastaldelli, A. The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients 7, 9453–9474 (2015).
pubmed: 26580649
pmcid: 4663603
doi: 10.3390/nu7115475
Johannsen, D. L. et al. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the “adipose tissue expandability” hypothesis. Diabetes Care 37, 2789–2797 (2014).
pubmed: 25011943
pmcid: 4170127
doi: 10.2337/dc14-0761
Ebadi, M. et al. Low subcutaneous adiposity associates with higher mortality in female patients with cirrhosis. J. Hepatol. 69, 608–616 (2018).
pubmed: 29709682
doi: 10.1016/j.jhep.2018.04.015
Rodrigues, S. G., Brabandt, B., Stirnimann, G., Maurer, M. H. & Berzigotti, A. Adipopenia correlates with higher portal pressure in patients with cirrhosis. Liver Int. 39, 1672–1681 (2019).
pubmed: 31207018
doi: 10.1111/liv.14175
Labeur, T. A. et al. Body composition is an independent predictor of outcome in patients with hepatocellular carcinoma treated with sorafenib. Liver Cancer 8, 255–270 (2018).
pubmed: 31602369
pmcid: 6738194
doi: 10.1159/000493586
Alberino, F. et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 17, 445–450 (2001).
pubmed: 11399401
doi: 10.1016/S0899-9007(01)00521-4
Quiroz-Aldave, J. E. et al. From liver to hormones: the endocrine consequences of cirrhosis. World J. Gastroenterol. 30, 1073–1095 (2024).
pubmed: 38577191
pmcid: 10989500
doi: 10.3748/wjg.v30.i9.1073
Foresta, C., Schipilliti, M., Ciarleglio, F. A., Lenzi, A. & D’Amico, D. Male hypogonadism in cirrhosis and after liver transplantation. J. Endocrinol. Invest. 31, 470–478 (2008).
pubmed: 18560267
doi: 10.1007/BF03346393
Lundsgaard, A. M. & Kiens, B. Gender differences in skeletal muscle substrate metabolism – molecular mechanisms and insulin sensitivity. Front. Endocrinol. 5, 195 (2014).
doi: 10.3389/fendo.2014.00195
Harimoto, N. et al. Sarcopenia is a poor prognostic factor following hepatic resection in patients aged 70 years and older with hepatocellular carcinoma. Hepatol. Res. 46, 1247–1255 (2016).
pubmed: 26880049
doi: 10.1111/hepr.12674