Potential biomarkers help diagnose progressive stages of liver disease

Results of a national research headed by the Translational Genomics Research Institute (TGen), an affiliate of the City of Hope, pinpointed potential biomarkers that could ultimately be employed for the diagnosis of progressive stages of liver disease.

Image Credit: The Translational Genomics Research Institute

Scientists pinpointed the differences in DNA methylation (DNAm) that precisely foretells various liver fibrosis stages, scarring of the damaged liver, in around 94% of patients with non-alcoholic fatty liver disease (NAFLD). The research was published in the Clinical Epigenetics journal.

NAFLD is a prevalent chronic liver disease in Western nations. It is distinguished by the fat build-up in the liver. Methylation is a biological mechanism where methyl groups are inserted into the DNA molecule. This mechanism alters DNA activity without altering its spelling, or sequence of the billions of letters that comprise an individual’s genetic blueprint.

DNAm patterns can be used to identify distinct cell types in the liver, and changes in cell-type composition.”

Johanna DiStefano, PhD, Study Senior Author and Professor, Metabolic and Fibrotic Disease Program, The Translational Genomics Research Institute

Johanna DiStefano is also the head of TGen’s Diabetes and Fibrotic Disease Unit.

Study examined data from 325 patients

Scientists analyzed genomic data from 325 patients with NAFLD utilizing samples acquired by biopsies. They observed that 206 had no distinct liver scarring and 119 had differing levels of fibrosis, which in its highly serious form can advance to a condition known as nonalcoholic steatohepatitis (NASH), and consequently results in cirrhosis, cancer of the liver, and death.

The scientists employed DNAm to analyze the cellular composition of the samples. They identified that highly severe fibrosis levels were linked with a progressive rise in the percentage of immune cells in the liver along with a corresponding decrease in the percentage of epithelial cells—a cell kind that lines different body surfaces, including organs like the liver.

Karen Conneely, Ph.D., Associate Professor in the Department of Human Genetics at the Emory University School of Medicine and a senior author of the study, elaborated that the scientists also observed that even after considering for differences in cellular composition between individuals, DNAm levels at certain sites in the genome were reduced in patients with intense fibrosis.

The differences are remarkable that Emory’s Nicholas Johnson, Ph.D., and a lead author of the study, could create a model on the basis of DNAm at 28 genomic sites that can precisely foretell levels of fibrosis in 94% of NAFLD patients in an independent test set.

These findings are consistent with DNAm as a mechanism underpinning or marking, fibrosis-related shifts in cell composition, and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.”

Xiumei Wu, PhD, Study Author and Staff Scientist, DiStefano Lab, The Translational Genomics Research Institute

Looking ahead to future studies

The current research utilized samples directly drawn from patient livers through the comparatively invasive use of biopsies. Applying technology introduced by TGen, the researchers propose future samples may be procured from circulating blood.

According to the study, “Circulating DNAm has been suggested as a potential noninvasive biomarker of disease severity for NAFLD. These results suggest that our model could potentially predict NAFLD fibrosis in blood DNAm.”

Further investigation can be complemented by employing single-cell RNA sequencing, a more precise technique of examining genomic information, which has the capability to evaluate cell composition at a greater resolution and advancing increased understanding of the relationship between NAFLD fibrosis, cellular composition, and DNAm.

Overall, our investigation shows that DNAm provides information that is not only useful for understanding the underlying biology of NAFLD. But may also serve as a clinical tool capable of independently diagnosing fibrosis.”

Johanna DiStefano, PhD, Study Senior Author and Professor, Metabolic and Fibrotic Disease Program, The Translational Genomics Research Institute