Dyslipidemia and cardiovascular complications are comorbidities of
nonalcoholic fatty liver disease (
NAFLD), which ranges from simple steatosis to
nonalcoholic steatohepatitis,
fibrosis, and
cirrhosis up to
hepatocellular carcinoma.
Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with
NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy-proven
NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic
fibrosis prediction. Hepatic expression of
lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by
RNA sequencing in a subset of patients with
NAFLD for whom Lp(a) dosage was available (n = 183). In patients with
NAFLD, elevated Lp(a) levels were modestly associated with circulating
lipids, carotid plaques, and
hypertension (P < 0.05). Conversely, patients with low serum Lp(a) displayed
insulin resistance (P < 0.05),
transaminase elevation (P < 0.05), and increased risk of developing severe
fibrosis (P = 0.007) and
cirrhosis (P = 0.002). In addition, the diagnostic accuracy of Lp(a) in predicting
fibrosis increased by combining it with
transaminases (area under the curve
fibrosis stage 4, 0.87; P < 0.0001). Hepatic LPA expression reflected serum Lp(a) levels (P = 0.018), and both were reduced with the progression of
NAFLD (P < 0.05). Hepatic LPA
messenger RNA levels correlated with those of genes involved in
lipoprotein release,
lipid synthesis, and fibrogenesis (P < 0.05). Finally, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926,
apolipoprotein E (
ApoE) rs445925, and
proprotein convertase subtilisin/kexin type 9 (PCSK9) rs7552841, known variants that modulate circulating
lipids, may influence serum Lp(a) levels (P < 0.05). Conclusion: Circulating Lp(a) combined with
transaminases may represent a novel noninvasive
biomarker to predict advanced
fibrosis in patients with
NAFLD.