Liver‐related and extrahepatic events in patients with non‐alcoholic fatty liver disease: a retrospective competing risks analysis

Abstract

Summary Background & Aim Non‐alcoholic fatty liver disease (NAFLD), and especially fibrotic non‐alcoholic steatohepatitis, is associated with high risks of liver‐related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy‐proven NAFLD stratified according to baseline severity of fibrosis. Methods Two thousand one hundred thirty‐five patients with biopsy‐proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause‐specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with liver fibrosis severity estimated by liver stiffness measurement by transient elastography was also enrolled. Results Observed CIFs indicated that the 60‐month probabilities of LRE and EHE were 0.2% and 3% in F0‐F1, 2% and 3.8% in F2 and 9.7% and 6.4% in F3‐F4 patients, respectively. The cause‐specific Cox model indicated that in F0‐F1 and F2 patients, age > 50 years (HR 2.7) was the only predictor of LRE, while age > 50 years (HR 2.96), previous cardiovascular events (CVE, HR 2.07), and previous extra‐hepatic cancer (HR 2.36) were independent risk factors for EHE. In F3‐F4 patients, age > 55 years (HR 1.73), obesity (HR 1.52), PLT < 150 000/mmc (HR 3.66) and log(GGT) (HR 1.77) were associated with LRE, while age > 55 years (HR 1.74) and previous CVE (HR 2.51) were independent predictors of EHE. Predicted CIFs for HE and EHE in F0‐F1, F2 and F3‐F4 patients stratified the risk of events. The results were externally replicated. Conclusion The likelihood of EHE in NAFLD patients is relevant and increases according to the severity of liver fibrosis, while the risk of LRE is negligible in F0‐F1, low but clinically relevant in F2 and high in F3‐F4 patients.

Liver Stiffness Is Associated with the Burden of Carotid and Systemic Atherosclerosis in an Unorganized Cohort of Patients 40–64 Years Old

“…In a meta-analysis of 36 prospective studies, which included more than 5.8 million participants, the risk of fatal or nonfatal cardiovascular events significantly increased in accordance with the increasing severity of fibrosis [ 15 ]. A series of more recent studies have also confirmed the dose-dependent effects of liver fibrosis on the development of cardiovascular and other extrahepatic adverse events [ 16 , 17 ]. Thus, it is perhaps the assessment of liver fibrosis that may make it the most important tool in the assessment of cardiovascular risks in patients with NAFLD and other categories of patients.…”

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

“…[OSAS] and chronic obstructive pulmonary disease diabetes [COPD]), osteoporosis, osteopenia and sarcopenia, obesity, and extrahepatic cancers. [20][21][22] This NAFLD heterogeneity has led to the increasing acceptance that NAFLD patients need a more personalized approach probably by the use of molecular tools (-omics approaches, genetic testing), liver fibrosis biomarkers, advanced imaging techniques, and detailed evaluation of each patient's clinical features. 23 NAFLD has been proven a sexual dimorphic disease, with women having a lower risk of developing NAFLD than men and fertile age of women being associated with more severe hepatocyte injury and inflammation but with a lower risk of liver fibrosis than men.…”

“…Indeed, the heterogeneous spectrum of NAFLD manifestations, spanning from hepatic to extra‐hepatic has been increasingly emerging in recent years. While the most frequent hepatic complications are well characterized, 20,21 the extra‐hepatic complications list is expanding continuously, including cardiovascular events, endocrine disorders, respiratory disorders (obstructive sleep apnea syndrome [OSAS] and chronic obstructive pulmonary disease diabetes [COPD]), osteoporosis, osteopenia and sarcopenia, obesity, and extrahepatic cancers 20–22 23 .…”

Concise review: gamma-glutamyl transferase - evolution from an indiscriminate liver test to a biomarker of cardiometabolic risk

“…Of note, the study supports the notion that raised GGT values may be a marker of sedentary behavior. Therefore, the recent attempts to introduce GGT as a parameter for stratifying dysmetabolic patients may improve our personalized medicine approach to metabolic disorders and NAFLD [51][52][53] .…”