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BACKGROUND & AIMS: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. METHODS: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. RESULTS: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). CONCLUSIONS: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. IMPACT AND IMPLICATIONS: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.
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