Low HDL-cholesterol levels predict hepatocellular carcinoma development in individuals with liver fibrosis

Abstract

Background & aims: Dysmetabolic conditions could drive liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), increasing susceptibility to hepatocellular carcinoma (HCC). We therefore aimed to identify novel predictive biomarkers of HCC in patients with and without liver fibrosis.

Methods: A total of 1,234 patients with putative metabolic conditions and NAFLD were consecutively assessed in our outpatient clinic. Clinical and biochemical data were recorded, and then liver ultrasonography was performed annually for 5 years to detect HCC onset. For the analysis, the population was first divided according to HCC diagnosis; then a further subdivision of those who did not develop HCC was performed based on the presence or absence of liver fibrosis at time 0.

Results: Sixteen HCC cases were recorded in 5 years. None of our patients had been diagnosed with cirrhosis before HCC was detected. Compared to patients who did not develop HCC, those who did had higher liver transaminases and fibrosis scores at time 0 (p <0.001). In addition, they presented with increased glycated haemoglobin levels and lower 25-OH vitamin D levels (p <0.05). Intriguingly, patients with higher liver fibrosis scores who subsequently developed HCC had lower HDL-cholesterol (HDL-c) levels at time 0 (p <0.001). Furthermore, in the 484 patients presenting with lower HDL-c at baseline, we found that waist circumference, and then vitamin D and glycated haemoglobin levels, were significantly different in those who developed HCC, regardless of liver fibrosis (p <0.05).

Conclusions: This study identifies HDL-c as a bona fide novel marker to predict HCC in patients with NAFLD. Increased waist circumference and deranged metabolic pathways represent additional predisposing factors among patients with low HDL-c, highlighting the importance of studying cholesterol metabolism and integrating clinical approaches with dietary regimens and a healthy lifestyle to prevent HCC.

Impact and implications: Visceral adiposity and its associated conditions, such as chronic inflammation and insulin resistance, may play a pivotal role in hepatocellular carcinoma development in patients with non-alcoholic fatty liver disease. We provide new insights on the underlying mechanisms of its pathogenesis, shedding light on the involvement of low levels of "good" HDL-cholesterol. We recommend integrating dietary regimens and advice on healthy lifestyles into the clinical management of non-alcoholic fatty liver disease, with the goal of reducing the incidence of hepatocellular carcinoma.

Keywords: ALP, alkaline phosphatase; ALT, alanine aminotransferase; APRI score; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; CVR, cardiovascular risk; FA, fatty acid; FIB-4, fibrosis-4; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; HDL-c, HDL-cholesterol; HbA1c, glycated haemoglobin; LXRs, liver X receptors; MetS, metabolic syndrome; Metabolic syndrome; NAFLD; NAFLD, non-alcoholic fatty liver disease; NASH; NASH, non-alcoholic steatohepatitis; RCT, reverse cholesterol transport; TG, triglyceride; Vitamin D; WC, waist circumference; Waist circumference.

Graphical abstract

Fig. 1

Metabolic syndrome-associated biomarkers in relation to liver fibrosis and development of HCC. Comparison of metabolic syndrome-associated biomarkers among patients without fibrosis (NO HCC-APRI <0.5) and those with liver fibrosis who will not develop HCC (NO HCC-APRI ≥0.5) or develop HCC (HCC-APRI ≥0.5). The box plots show the median (second quartile), first and third quartile, Tukey whiskers go 1.5 times the interquartile distance or to the highest or lowest point, whichever is shorter. Any data beyond these whiskers are shown as points. Comparisons were performed using one-way ANOVA test followed by Bonferroni’s post hoc test. Multiple comparison was performed by Student’s t test. Lowercase letter indicates significant difference with NO HCC-APRI <0.5 (a) and NO HCC-APRI ≥0.5 (b). APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; HbA1c, glycated haemoglobin; HCC, hepatocellular carcinoma.

Fig. 2

Transaminase levels in relation to liver fibrosis and development of HCC. Comparison of transaminase levels among patients without fibrosis (NO HCC-APRI <0.5) and those with liver fibrosis who will not develop HCC (NO HCC-APRI ≥0.5) or develop HCC (HCC-APRI ≥0.5). The box plots show the median (second quartile), first and third quartile, Tukey whiskers go 1.5 times the interquartile distance or to the highest or lowest point, whichever is shorter. Any data beyond these whiskers are shown as points. Comparisons were performed using one-way ANOVA test followed by Bonferroni’s post hoc test. Multiple comparison was performed by Student’s t test. Lowercase letter indicates significant difference with NO HCC-APRI <0.5 (a) and NO HCC-APRI ≥0.5 (b). ALT, alanine aminotransferase; ALP, alkaline phosphatase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma.

Fig. 3

Non-invasive liver fibrosis scores, insulin, and vitamin D levels in relation to liver fibrosis and development of HCC. Comparison among patients without fibrosis (NO HCC-APRI <0.5) and those with liver fibrosis who will not develop HCC (NO HCC-APRI ≥0.5) or develop HCC (HCC-APRI ≥0.5). The box plots show the median (second quartile), first and third quartile, Tukey whiskers go 1.5 times the interquartile distance or to the highest or lowest point, whichever is shorter. Any data beyond these whiskers are shown as points. Comparisons were performed using one-way ANOVA test followed by Bonferroni’s post hoc test. Multiple comparison was performed by Student’s t test. Lowercase letter indicates significant difference with NO HCC-APRI <0.5 (a) and NO HCC-APRI ≥0.5 (b). APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4; HCC, hepatocellular carcinoma.

Fig. 4

Relationships of waist circumference with metabolic biomarker and of HDL-c with vitamin D level in patients with APRI ≥0.5. Dashed line and black circles represent HCC patients, while continuous line and white circles represent NO HCC patients. r indicates Pearson’s correlation coefficient; p indicates statistical significance. APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; HDL-c, HDL-cholesterol.

Fig. 5

Comparison among patients with HDL-c ≤50 mg/dl. (A) Dot and box plots representation of HDL-c in patients without fibrosis (NO HCC-APRI <0.5) and those with liver fibrosis who will not develop HCC (NO HCC-APRI ≥0.5) or develop HCC (HCC-APRI ≥0.5). Dashed line shows the maximum HDL-c value in HCC-APRI ≥0.5 group, that is 50 mg/dl. Comparison of GGT level (B), 25-OH vitamin D (C), HbA1c (D), and WC (E) in these three groups among patients with HDL-c ≤50 mg/dl. The box plots show the median (second quartile), first and third quartile, Tukey whiskers go 1.5 times the interquartile distance or to the highest or lowest point, whichever is shorter. Any data beyond these whiskers are shown as points. Comparisons were performed using one-way ANOVA test followed by Bonferroni’s post hoc test. Multiple comparison was performed by Student’s t test. Lowercase letter indicates significant difference with NO HCC-APRI <0.5 (a) and NO HCC-APRI ≥0.5 (b). APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; HbA1c, glycated haemoglobin; HCC, hepatocellular carcinoma.