Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease

Abstract

BACKGROUND A pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe. METHODS This prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives — 220 in a derivation cohort and 176 in a validation cohort — were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives. RESULTS Prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively ( P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively ( P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0–6.7), male sex (aOR: 3.79, 95% CI 1.6–9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3–9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5–57) were significant predictors of presence of advanced fibrosis (all P < 0.05). CONCLUSION First-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis. FUNDING Supported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the EFPIA.

AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

“…Targeted screening of populations at increased risk for advanced liver disease is advised to identify and manage those with clinically significant fibrosis (stage ≥ 2). [36,172,280] Screening in high-risk populations, such as those with T2DM, [112,113,116,[281][282][283][284][285] obesity with metabolic complications, [286][287][288][289][290][291][292] a family history of cirrhosis, [293,294] or significant alcohol use [211,[295][296][297] (see also separate discussion on the contributory role of alcohol), may identify those with asymptomatic but clinically significant fibrosis. Early identification of such at-risk patients allows for interventions that may prevent T A B L E 4 Screening for advanced fibrosis in high-risk populations…”

Reply to: “Screening for NAFLD and its severity in type 2 diabetic patients: Value of magnetic resonance imaging and outstanding issues”

“…whereas prior studies supporting lower cut-points were performed in heterogeneous populations and without utilization of the XL probe. We recommend clinicians incorporate both liver fat and liver stiffness into decision making and support defining advanced fibrosis based on liver stiffness irrespective of liver fat as done in the manuscript and other publications using magnetic resonance elastography [9].…”

Editorial: first‐degree relatives of Mexican Americans with HCC are at increased risk of significant fibrosis—authors' reply

“…A few recent studies have examined risk of hepatic fibrosis in first-degree relatives of patients with NAFLD. 4,5 First-degree relatives of probands with NAFLD-related cirrhosis were previously noted to have a 12-fold increase in risk of significant fibrosis, independent of clinical factors known to be associated with NAFLD progression such as T2DM. 5 More recently, it was demonstrated that the prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-related advanced fibrosis was approximately 15%, and age, male sex and T2DM were the strongest predictors of advanced fibrosis in first-degree relatives.…”

“…5 More recently, it was demonstrated that the prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-related advanced fibrosis was approximately 15%, and age, male sex and T2DM were the strongest predictors of advanced fibrosis in first-degree relatives. 4 Further studies to examine predictors of fibrosis in first-degree relatives of Mexican Americans are needed.…”

“…The majority of Mexican American probands with HCC in our cohort had T2DM, limiting subgroup analyses stratified by proband diabetes status. A few recent studies have examined risk of hepatic fibrosis in first‐degree relatives of patients with NAFLD 4,5 . First‐degree relatives of probands with NAFLD‐related cirrhosis were previously noted to have a 12‐fold increase in risk of significant fibrosis, independent of clinical factors known to be associated with NAFLD progression such as T2DM 5 .…”