A recent study (H Gellert-Kristensen et al. Hepatology 2020; 72: 845-856. Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population) describes genetic risk score (GRS) which can stratify the risk of developing cirrhosis and hepatocellular carcinoma.

The study utilized data and plasma markers from 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. GRS scores were from 0 to 6 based on three common genetic variants: PNPLA3, TM6SF2, and HSD17B13.

Key finding:

• A GRS of 5 or 6 (compared to GRS of 0) for fatty liver disease confers up to a 12‐fold higher risk of cirrhosis and up to a 29‐fold higher risk of HCC in individuals from the general population

The editorial by RM Pfeiffer et al (Hepatology 2020; 72: 794-795. Genetic Determinants of Cirrhosis and Hepatocellular Carcinoma Due to Fatty Liver Disease: What’s the Score?) is very helpful in placing the findings in context.

• Only 0.5% of individuals had a GRS of 5 or 6. “A GRS of 4 [or more] which still conveyed large risks (cirrhosis, OR =5.2; HCC, OR =3.3) was found in approximately 5% of this population.”
• Using a GRS of 4 or more, the positive predictive value of GRS-based test in the Danish population is “0.008 for cirrhosis and 0.003 for HCC. In other words, among 1000 persons with GRS greater than or equal to 4, only 8 will develop cirrhosis and 3 will develop HCC.”

My take: This study confirms that specific genetic variants increase the risk of complications from fatty liver disease. However, poor predictive value will likely preclude routine application.