From the AGA Journals

PNPLA3 genotype predicts cirrhosis in NAFLD

Publish date: April 3, 2023
By
Will Pass
MDedge News

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Study will help establish referral pathways for high-risk liver disease

Nonalcoholic fatty liver disease (NAFLD) is becoming globally a leading cause of cirrhosis and related complications, namely decompensation and hepatocellular carcinoma. Since NAFLD affects a large fraction of the population, and especially people with obesity, type 2 diabetes and metabolic comorbidities, it is difficult to identify those at risk of cirrhosis and liver-related versus more frequent cardiometabolic events. The first step in risk stratification is based on the calculation of simple liver fibrosis scores, such as the FIB4, but this too often leads to indeterminate results requiring additional testing.

Luca Valenti, MD, is an associate professor of internal medicine in pathophysiology and transplantation at the Università degli Studi di Milano, Italy.

Dr. Luca Valenti

This study by Chen and colleagues confirmed that inherited factors play a major role in NAFLD progression to cirrhosis, with an impact comparable with the main clinical determinants. Importantly, they identified the presence of diabetes and carriage of two copies of the PNPLA3 rs738409 variant (p.I148M), the main genetic determinant of NAFLD, as a combination that can effectively reclassify individuals with an indeterminate FIB4 test to be at high risk of cirrhosis.

These results will contribute to establish referral pathways to identify persons at high risk of liver disease, even at a young age. This may enable preventive programs based on intensified lifestyle and diabetes management, specific treatments for fibrotic NAFLD once these become available, and close surveillance for complications. What’s more, therapeutic approaches directly targeting liver PNPLA3 p.I148M are already under clinical evaluation to prevent disease progression specifically in this high-risk group.

Luca Valenti, MD, is an associate professor of internal medicine in pathophysiology and transplantation at the Università degli Studi di Milano. He is head of the Precision Lab and Biological Resource Center Unit. Dr. Valenti has no relevant disclosures.


 

FROM GASTROENTEROLOGY

Patients with nonalcoholic fatty liver disease (NAFLD) who carry two copies of the PNPLA3 p.I148M variant, may exhibit faster progression to cirrhosis, while those with this genotype who also have diabetes and indeterminate Fibrosis-4 (FIB4) scores may have the same risk of cirrhosis as patients with a high FIB4, according to investigators.

These findings suggest that NAFLD patients with indeterminate FIB4 and metabolic risk factors should routinely undergo PNPLA3 genotyping, lead author Vincent L. Chen, MD, of the University of Michigan, Ann Arbor, and colleagues reported.

Dr. Vincent L. Chen incent L. Chen, MD, of the University of Michigan, Ann Arbor Michigan Medicine

Dr. Vincent L. Chen

“Whether incorporating genetics into risk stratification results in meaningful improvement over clinical predictors, such as FIB4, diabetes, and obesity status, is unknown,” the investigators wrote in Gastroenterology. “Improved understanding of how genetics influences the rate of disease progression and how it interacts with established risk factors for advanced liver disease is crucial for genetic testing to be applicable in clinical practice.”

To evaluate the risk presented by the PNPLA3 p.I148M variant, Dr. Chen and colleagues analyzed data from two independent cohorts with 7,893 patients and 46,880 patients each.

They first characterized the relationship between PNPLA3 genotype and cirrhosis via univariable and multivariable analyses. These efforts revealed that the genotype predicted cirrhosis in both cohorts, with associations also detected for well-documented clinical risk factors, including diabetes, obesity, and high ALT. Of note, PNPLA3 genotype demonstrated an additive effect for cirrhosis when detected in conjunction with these risks.

Further analysis revealed that homozygous carriers of PNPLA3 p.I148M with indeterminate FIB4 scores (1.3-2.67) and diabetes had an incidence rate of cirrhosis on par with patients who had high-risk FIB4 (greater than 2.67).

The effects of the risk allele were also made evident by comparing patients with diabetes and indeterminate FIB4 based on presence or absence of the marker – those testing positive for h PNPLA3 p.I148M had 2.9-4.8 times greater risk of cirrhosis. Conversely, patients with FIB4 scores less than 1.3, regardless of other risk factors, had little change in cirrhosis rate regardless of PNPLA3 status.

“We found that PNPLA3 genotyping in conjunction with clinical risk factors may improve risk stratification in patients with NAFLD,” the investigators concluded. “Although it may be possible to develop more complex polygenic risk scores for cirrhosis, these findings suggest that genotyping of PNPLA3 alone, which is less expensive than genomewide genotyping and easier to understand, may have similar clinical applicability for NAFLD.”

Dr. Chen and colleagues therefore recommended that NAFLD patients with metabolic risk factors (particularly diabetes) and indeterminate FIB4 routinely undergo PNPLA3 genotyping, with referral to hepatology if positive for two risk alleles.

The study was supported by the American Association for the Study of Liver Diseases, National Institutes of Health, and the University of Michigan department of internal medicine. The investigators disclosed no conflicts of interest.

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