代谢功能障碍相关的脂肪肝疾病（MASLD; 以前被称为NAFLD）是全球肝细胞癌（HCC）最快增长的原因。然而，MASLD患者的家庭成员是否也有较高发展肝细胞癌的风险尚不清楚。本研究涉及所有瑞典成人中经活检证实的MASLD（1969-2017）的直系亲属和匹配的一般人口对照群体，利用瑞典多代人登记表，我们确定了38,018例MASLD一级亲属（父母、兄弟姐妹、子女）和9,381例MASLD配偶，以及197,303例对照群体一级亲属和47,572例对照群体配偶。我们使用Cox比例风险模型计算了HCC、肝硬化、脱水性肝病或肝移植、肝相关死亡、非肝癌性死亡的调整风险比（aHR）。在中位随访时间17.6年内，MASLD一级亲属的主要结果HCC的发病率高于对照一级亲属（13 vs. 8/100,000PY; aHR=1.80, 95%CI=1.36-2.37）。与MASLD患者肝纤维化/肝硬化的亲属的HCC风险进一步增加（aHR=2.14, 95%CI=1.07-4.27; PHeterogeneity=0.03）。MASLD一级亲属的重大不良肝脏结果（73 vs. 51/100,000PY; aHR=1.52, 95%CI=1.36-1.69）和肝相关死亡率（20 vs. 11/100,000PY; aHR=2.14, 95%CI=1.67-2.74）也较高。当成为MASLD患者的一级亲属时，任何伴有慢性肝病的个体都会加速肝病的进展（aHR=1.47, 95%CI=1.29-1.67）。MASLD配偶在重大不良肝脏结果（86 vs. 74/100,000PY; aHR=1.23, 95%CI=1.01-1.51）和肝相关死亡（25 vs. 19/100,000PY; aHR=1.93, 95%CI=1.15-3.23）方面的风险更高，但HCC风险不高（aHR=1.43, 95%CI=0.87-2.35）。在经活检证实的MASLD患者家庭中存在明显的不良肝脏相关结果群集，以及HCC、进行性肝病和肝相关死亡的相对风险升高，但绝对风险较低。代谢功能障碍相关的脂肪肝疾病（MASLD; 据称非酒精性脂肪性肝炎; NAFLD）在有高遗传易感性和共享环境危险因素的家族中聚集，但MASLD患者的家庭成员发展肝细胞癌（HCC）和其他重大肝脏相关结果的风险在很大程度上是未知的。本研究涉及与活检证实的MASLD个体的家庭成员（直系亲属和配偶）以及配对的一般人口对照者，发现了一级亲属中微增的HCC风险，并对所有活检证实的MASLD个体的家庭成员发展肝硬化和肝相关死亡的风险也稍微增加。本研究结果提供了大规模的证据，可用于制定临床实践指南，以对高风险肝脏疾病和死亡的个体进行早期识别的建议。版权所有© 2023 作者。由Elsevier B.V.出版。保留所有权利。

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) is the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. However, whether family members of individuals with MASLD also share an increased risk of developing HCC is unknown.This nationwide multigeneration cohort-study involved family members of all Swedish adults diagnosed with biopsy-proven MASLD (1969-2017), and matched general population comparators. Using the Swedish Multigeneration Register, we identified 38,018 MASLD first-degree relatives (FDRs: parents, siblings, offspring) and 9,381 MASLD spouses as well as 197,303 comparator FDRs and 47,572 comparator spouses. We used Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for HCC, major adverse liver outcomes (cirrhosis, decompensated liver disease or liver transplantation), liver-related mortality, extrahepatic cancer, and non-liver-related mortality.Over a median of 17.6 years, the rate of the primary outcome, HCC was higher in MASLD FDRs vs. comparator FDRs (13 vs. 8/100,000PY; aHR=1.80, 95%CI=1.36-2.37). The HCC risk was further increased in FDRs to individuals with liver fibrosis/cirrhosis (aHR=2.14, 95%CI=1.07-4.27; PHeterogeneity=0.03). MASLD FDRs also had higher rates of major adverse liver outcomes (73 vs. 51/100,000PY; aHR=1.52, 95%CI=1.36-1.69) and liver-related mortality (20 vs. 11/100,000PY; aHR=2.14, 95%CI=1.67-2.74). Individuals with any concomitant chronic liver condition experienced accelerated progression of liver disease when being FDR to an individual with MASLD (aHR=1.47, 95%CI=1.29-1.67). MASLD spouses were at higher risks of major adverse liver outcomes (86 vs. 74/100,000PY; aHR=1.23, 95%CI=1.01-1.51) and liver-related mortality (25 vs. 19/100,000PY; aHR=1.93, 95%CI=1.15-3.23), but not of HCC (aHR=1.43, 95%CI=0.87-2.35).There is distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD with higher relative risks of HCC, progressive liver disease, and liver-related mortality, but absolute risks are low.Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly termed Nonalcoholic fatty liver disease; NAFLD) clusters in families with high genetic susceptibility and shared environmental risk factors, but the risks of developing hepatocellular carcinoma (HCC) and other major liver-related outcomes in family members of individuals with MASLD are largely unknown. This large nationwide multigeneration cohort study involving family members (first-degree relatives and spouses) of individuals with biopsy-proven MASLD and of matched general population comparators found slightly increased risks of HCC in first-degree relatives, and of developing cirrhosis and liver-related mortality in all family members of individuals with biopsy-proven MASLD. The findings of this study provide large-scale evidence to inform clinical practice guidelines for recommendations on the early identification of individuals at higher risk of liver-related morbidity and mortality.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.