Birrer Dominique L, Linecker Michael, López-López Víctor, Brusadin Roberto, Navarro-Barrios Álvaro, Reese Tim, Arbabzadah Sahar, Balci Deniz, Malago Massimo, Machado Marcel A, Ardiles Victoria, Soubrane Olivier, Hernandez-Alejandro Roberto, de Santibañes Eduardo, Oldhafer Karl J, Popescu Irinel, Humar Bostjan, Clavien Pierre-Alain, Robles-Campos Ricardo
Department of Surgery and Transplantation, University Hospital of Zurich, Zurich, Switzerland.
Department of Surgery & Transplantation, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Ann Surg. 2022 Nov 1;276(5):875-881. doi: 10.1097/SLA.0000000000005635. Epub 2022 Jul 27.
To explore potential sex differences in outcomes and regenerative parameters post major hepatectomies.
Although controversial, sex differences in liver regeneration have been reported for animals. Whether sex disparity exists in human liver regeneration is unknown.
Data from consecutive hepatectomy patients (55 females, 67 males) and from the international ALPPS (Associating-Liver-Partition-and-Portal-vein-ligation-for-Staged-hepatectomy, a two stage hepatectomy) registry (449 females, 729 males) were analyzed. Endpoints were severe morbidity (≥3b Clavien-Dindo grades), Model for End-stage Liver Disease (MELD) scores, and ALPPS interstage intervals. For validation and mechanistic insight, female-male ALPSS mouse models were established. t , χ 2 , or Mann-Whitney tests were used for comparisons. Univariate/multivariate analyses were performed with sensitivity inclusion.
Following major hepatectomy (Hx), males had more severe complications ( P =0.03) and higher liver dysfunction (MELD) P =0.0001) than females. Multivariate analysis established male sex as a predictor of complications after ALPPS stage 1 (odds ratio=1.78; 95% confidence interval: 1.126-2.89; P =0.01), and of enhanced liver dysfunction after stage 2 (odds ratio=1.93; 95% confidence interval: 1.01-3.69; P =0.045). Female patients displayed shorter interstage intervals (<2 weeks, 64% females versus 56% males, P =0.01), however, not in postmenopausal subgroups. In mice, females regenerated faster than males after ALPPS stage 1, an effect that was lost upon estrogen antagonism.
Poorer outcomes after major surgery in males and shorter ALPPS interstage intervals in females not necessarily suggest a superior regenerative capacity of female liver. The loss of interstage advantages in postmenopausal women and the mouse experiments point to estrogen as the driver behind these sex disparities. Estrogen's benefits call for an assessment in postmenopausal women, and perhaps men, undergoing major liver surgery.
探讨大肝切除术后结局和再生参数方面潜在的性别差异。
尽管存在争议，但已有报道称动物肝脏再生存在性别差异。人类肝脏再生中是否存在性别差异尚不清楚。
分析连续肝切除患者（55名女性，67名男性）以及国际ALPPS（联合肝脏分隔和门静脉结扎分期肝切除术，一种两阶段肝切除术）登记处（449名女性，729名男性）的数据。终点指标为严重并发症（≥3b级Clavien-Dindo分级）、终末期肝病模型（MELD）评分以及ALPPS分期间隔。为进行验证和深入了解机制，建立了雌性-雄性ALPSS小鼠模型。采用t检验、χ²检验或Mann-Whitney检验进行比较。进行单因素/多因素分析时纳入敏感性因素。
大肝切除术后，男性比女性有更严重的并发症（P = 0.03）和更高的肝功能障碍（MELD，P = 0.0001）。多因素分析确定男性性别是ALPPS第一阶段后并发症的预测因素（比值比 = 1.78；95%置信区间：1.126 - 2.89；P = 0.01），以及第二阶段后肝功能障碍加重的预测因素（比值比 = 1.93；95%置信区间：1.01 - 3.69；P = 0.045）。女性患者的分期间隔较短（<2周，女性为64%，男性为56%，P = 0.01），然而，绝经后亚组并非如此。在小鼠中，ALPPS第一阶段后雌性比雄性再生更快，雌激素拮抗后这种效应消失。
男性大手术后结局较差以及女性ALPPS分期间隔较短，不一定表明女性肝脏具有更强的再生能力。绝经后女性分期优势的丧失以及小鼠实验表明雌激素是这些性别差异背后的驱动因素。雌激素的益处需要在接受大肝脏手术的绝经后女性甚至男性中进行评估。
