Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response

Abstract

Background & Aims Curing hepatitis C virus (HCV) infection reduces the risk of hepatocellular carcinoma (HCC) development, yet HCC occurs despite sustained virologic response (SVR) in 2%‐8% of cirrhotic patients. Sphingolipids (SLs) have been identified as new biomarkers of chronic liver disease and HCC. The aim of this study was to evaluate serum SLs as diagnostic HCC biomarkers in patients with HCV‐associated cirrhosis at SVR12. Methods From 2014 to 2016, 166 patients with HCV‐cirrhosis and SVR were recruited and SL profiles were measured at baseline and 12 weeks after completion of direct‐acting antiviral (DAA) therapy. All patients received HCC surveillance in line with current guideline recommendations. Minimum follow‐up period comprised 6 months. Results Our study included 130 (78%) patients without history of HCC, 25 (15%) with history of HCC prior DAA therapy and 11 (7%) patients with de novo HCC after FU12. In those with upcoming de novo HCC serum C24DHC (P = 0.006), C24:1DHC (P = 0.048) and C16Cer (P = 0.011) were significantly upregulated at FU12, but not AFP (P = 0.138). Contemporaneous ultrasound did not visualize HCC, at this time. C16Cer stayed sole independent predictor with high diagnostic accuracy of AFP‐positive (AUC = 0.741) and ‐negative (AUC = 0.766) HCC development. Serum SL parameters decreased from baseline to SVR12. Conclusions C24DHC, C24:1DHC and especially C16Cer were superior to AFP in early detection of AFP‐positive and ‐negative de novo HCC development. We observed significant SL profile changes upon SVR. SLs may play a role in non‐invasive HCC surveillance and hepatocarcinogenesis.

Residual risk of liver disease after hepatitis C virus eradication

“…HCC risk was associated with increased expression of SPHK1, a lipid kinase that phosphorylates sphingosine leading to the formation of sphingosine-1-phosphate, an important regulator of cell proliferation and apoptosis which is increased in patients with HCC. 86 The latter finding remains to be confirmed, because in an extensive analysis of sphingolipid changes before and after successful DAA-based therapy in 166 patients with HCV-related cirrhosis, 87 de novo HCC development was only associated with increases in serum C24 dihydroceramide, C24:1 dihydroceramide and C16 ceramide levels, while sphingosine-1-phosphate levels were significantly reduced following viral clearance.…”

Functions of Sphingolipids in Pathogenesis During Host–Pathogen Interactions

“…HCV infectivity is positively correlated with plasma sphingolipid levels, and plasma GSL levels are correlated with viral load in genotype 2 HCV patients ( Zhang et al, 2016 ). Serum sphingolipids have recently garnered more attention because they are currently used as a novel biomarker for hepatic diseases in clinical diagnosis and decision-making ( Grammatikos et al, 2016 ; Muecke et al, 2019 ). By regulating lipid peroxidation, SphK2 restricts the replication of HCV in Huh-7 human liver cells and primary human hepatoblasts.…”

Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover

“…Chang and collaborators have also identified key metabolic changes in a fibrosis rat model, where lactosylceramide levels are increased along the progression of the disease [109]. Such alterations in sphingolipid profile also allow for classification of cirrhosis patients into compensated and non-compensated, relating it with their survival rate [6,110] or associating with another serum marker such as low-density lipoprotein (LDL) levels [111]. Ceramide levels have also been characterized to be altered during necroinflammation in patients with normal alanine aminotransferase (ALT) levels [112], the routine diagnose method in monitoring liver health.…”