Alcohol-associated liver disease(ALD)is a rapidly increasing indication for liver transplantation(LT)globally with a significant rise in transplants for ALD with limited sobriety including patients with alcohol-associ...Alcohol-associated liver disease(ALD)is a rapidly increasing indication for liver transplantation(LT)globally with a significant rise in transplants for ALD with limited sobriety including patients with alcohol-associated hepatitis(AH).This evolution challenges the older paradigm that mandates prolonged periods of alcohol abstinence prior to LT.Due to the limited armamentarium of effective pharmacotherapy to treat severe AH,the mortality rates are significantly higher when LT is not available.In the patients who are transplanted for ALD with limited sobriety including AH,patient and graft survival are equivalent,if not better,compared to patients transplanted for other etiologies.However,due to the risk of alcohol relapse and other psychosocial factors,public opinion regarding early LT may continue to impact how the field moves forward particularly regarding organ stewardship and the need for equitable allocation of organs.Numerous tools for psychosocial evaluations have been developed to assist liver transplant teams to identify appropriate patients in a more uniform manner.In this review,we aim to assess the available evidence to support early LT for alcohol AH and propose directions for the future as the field continues to evolve.展开更多
The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis ...The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.展开更多
文摘Alcohol-associated liver disease(ALD)is a rapidly increasing indication for liver transplantation(LT)globally with a significant rise in transplants for ALD with limited sobriety including patients with alcohol-associated hepatitis(AH).This evolution challenges the older paradigm that mandates prolonged periods of alcohol abstinence prior to LT.Due to the limited armamentarium of effective pharmacotherapy to treat severe AH,the mortality rates are significantly higher when LT is not available.In the patients who are transplanted for ALD with limited sobriety including AH,patient and graft survival are equivalent,if not better,compared to patients transplanted for other etiologies.However,due to the risk of alcohol relapse and other psychosocial factors,public opinion regarding early LT may continue to impact how the field moves forward particularly regarding organ stewardship and the need for equitable allocation of organs.Numerous tools for psychosocial evaluations have been developed to assist liver transplant teams to identify appropriate patients in a more uniform manner.In this review,we aim to assess the available evidence to support early LT for alcohol AH and propose directions for the future as the field continues to evolve.
基金supported by funding from the Medical Research Council (MRC) through the WIMM Strategic Alliance (G0902418 and MC_UU_12025) and to E. Y.J. (G9900061),the Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (AOMW)the Wellcome Trust (Project Grant 093329 to AOMW and SRFT+8 种基金Investigator Award 102731 to AOMWgrant 090532/Z/09/Z supporting the Wellcome Trust Centre for Human Genetics)supported by the Crohn’s & Colitis Foundation of America (CCFA)the Leona M. and Harry B. Helmsley Charitable Trustfunded by the NIHR Oxford Biomedical Research Centresupported by the Deutsche Forschungsgemeinschaft (SCHW1730/1-1)supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn (grant number SFB841 to F.K., D.S.-A., and S.R.-J.SFB877 to S.R.-J.)the Cluster of Excellence “Inflammation at Interfaces” to S.R.-J.
文摘The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.
