Progressive reduction of blood lysosomal acid lipase activity according to stage of adult chronic liver disease and altered enzymatic cellular distribution in cirrhosis

Lysosomal acid lipase (LAL), a key enzyme in lipid metabolism, is reduced in NAFLD compared to healthy controls (HC) and in cryptogenic cirrhosis compared to cirrhosis of other etiologies. We aimed to: compare whole blood LAL activity (WB-LAL) according to different stages and etiologies of chronic liver disease (CLD) and assess whether cirrhotics have a deficit of LAL in white blood cells (WBCs) and platelets (PLTs). WB-LAL was measured by a fluorimetric method in: NASH/cryptogenic cirrhosis (NASH-C; n=53); HCV/alcoholic cirrhosis (HCV/A-C; n=76); histological NAFLD without cirrhosis (NAFLD; n=47); HCV/alcoholic chronic hepatitis (HCV/A-CH; n=50); HC (n=37). In 9 NASH-C, 7 HCV/A-C and 22 HC, LAL was also measured in isolated PLTs and WBCs. Medians and interquartile ranges of WB-LAL were 0.54 [0.42-0.73], 0.65 [0.51-0.93], 0.77 [0.61-1.06], 0.97 [0.79-1.38] and 1.05 [0.85-1.42] nanomoles/spot/hour in the NASH-C, HCV/A-C, NAFLD, HCV/A-CH, and HC group, respectively. At logistic regression, independently from age, gender and BMI, low WB-LAL was associated with: a)NASH-C compared to NAFLD (OR 0.063; CI95% 0.009-0.420; P=0.004) and b)NAFLD compared to HCV/A-CH (OR 0.077; CI95% 0.013-0.450; P=0.004). Low WB-LAL was associated with HCV/A-C compared to HCV/A-CH (OR 0.107; CI95% 0.025-0.457; P=0.003), independently from age, gender, BMI, amount and years of daily alcohol consumption at risk for cirrhosis development and years since HCV-infection. WB-LAL did not differ between HCV/A-CH and HC. Intracellular PLT’s LAL was significantly (P<0.001) reduced in cirrhotics compared to HC (11.75[3.23-42.55] vs 65.90[44.43-91.85] nanomoles/mg protein/hour), while no intergroup difference was found in WBCs activity. In fatty liver disease, as disease worsens, WB-LAL is progressively reduced at all stages. In HCV and alcoholic CLD, low WB-LAL is associated only with the cirrhotic stage. Cirrhotics have reduced intracellular LAL in PLTs. We hypothesize that reduced LAL in PLTs may play a role in CLD pathophysiology, and especially in fatty liver disease