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Noninvasive tests (NITs) including platelets (PLTs) have been proposed to replace hepatic biopsy for the diagnosis of nonalcoholic fatty liver disease (NAFLD), or as more recently redefined, metabolic dysfunction-associated steatotic liver disease (MASLD). There has been reported an inverse correlation between PLTs and progressive MASLD, which is also affected by the patatin-like phospholipase domain-containing protein 3 (<i>PNPLA3)</i> rs738409 C>G mutation. However, the correlation between low PLTs and <i>PNPLA3</i> genotype has been poorly investigated. We stratified 1155 biopsy-proven MASLD patients according to <i>PNPLA3</i> genotype. The hepatic expression of genes involved in megakaryopoiesis was investigated in <i>n</i> = 167 bariatric patients by RNAseq. PLT count progressively decreased according to the number of <i>PNPLA3</i> at-risk alleles, irrespective of the presence of advanced fibrosis. The hepatic expression of genes involved in PLT biogenesis was associated with the <i>PNPLA3</i> GG genotype. Finally, the presence of the <i>PNPLA3</i> homozygosity flattened the accuracy of fibrosis-4 (FIB-4) in discriminating histological fibrosis stages. The <i>PNPLA3</i> GG genotype may underpower the accuracy of NITs which include PLT count in identifying those patients with potentially reversible stages of fibrosis.