Use of PNPLA3, TM6SF2, and HSD17B13 for detection of fibrosis in MASLD in the general population

• Published in: Clinics and research in hepatology and gastroenterology 2024-08, Vol.48 (7), p.102389, Article 102389
• Main Authors: Rashu, Elias Badal, Werge, Mikkel Parsberg, Hetland, Liv Eline, Thing, Mira, Nabilou, Puria, Kimer, Nina, Junker, Anders Ellekaer, Jensen, Anne-Sofie Houlberg, Nordestgaard, Børge Grønne, Stender, Stefan, Gluud, Lise Lotte
• Format: Article
• Language: English
• Subjects: 17-Hydroxysteroid Dehydrogenases - genetics; Acyltransferases; Adult; Aged; Cirrhosis; Fatty Liver - diagnosis; Fatty Liver - genetics; Female; Fibrosis; Humans; Lipase - genetics; Liver Cirrhosis - genetics; Male; Masld; Membrane Proteins - genetics; Metabolic dysfunction-associated liver disease; Middle Aged; Non-alcoholic fatty liver disease; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Phospholipases A2, Calcium-Independent; PNPLA3; Polymorphism, Single Nucleotide; Steatohepatitis
• ISSN: 2210-7401; 2210-741X; 2210-741X
• DOI: 10.1016/j.clinre.2024.102389

•414 individuals at risk of MASLD from the Danish general population agreed to participate to a hepatological assessment at Gastro Unit, Hvidovre Hospital, Copenhagen Denmark.•Four patients screened turned out to have malignant diseases or autoimmune liver diseases.•27 participants underwent a liver biopsy due to risk of significant liver fibrosis.•The combination of Fib-4 and PNPLA3 (CC/CG) increased diagnostic accuracy and had excellent sensitivity.•The study found no evidence to support the use of a 3-SNP genetic risk score. Genetic testing can be used to evaluate disease risk. We evaluated if the use of three Single Nucleotide Polymorphisms (SNPs), alone or combined into a genetic risk score (GRS), can aid identify significant fibrosis in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed three known risk variants: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567. The study included 414 adult individuals invited from the Danish population, who were defined as at-risk of MASLD due to elevated ALT and body mass index (BMI) >25 kg/m2. Participants were assessed clinically and by the Fibrosis-4 (FIB-4) index and Fibroscan. In total, 17 participants (4.1 %) had alcohol-related liver disease, 79 (19.1 %) had no evidence of liver disease, and four (1.0 %) were diagnosed with other liver diseases, including malignant disease. The remaining 314 participants (75.8 %) were diagnosed with MASLD. Of the 27 who underwent a liver biopsy for suspected fibrosis, 15 had significant fibrosis (≥F2) and 12 had no/mild fibrosis (F0/F1). The GRS was not associated with significant fibrosis (p = 0.09) but PNPLA3 was with an odds ratio of 6.75 (95 % CI 1.29 – 50.7; p = 0.039) risk allele CG/GG versus CC. The diagnostic accuracy of PNPLA3 combined with an increased Fib-4 (>1.3) was excellent for detecting significant fibrosis with a sensitivity of 1.00 (95 % CI 0.72–1.00), but the specificity was no better than for FIB-4 alone. This study found no evidence to support the use of GRS for diagnosing significant fibrosis in MASLD. However, the combination of PNPLA3 and Fib-4 increased sensitivity considerably. In addition, ALT remains a useful tool for screening diagnosing other liver diseases than MASLD. [Display omitted]