The dramatically falling cost of genetic sequencing is among the factors helping to make the promise of personalized medicine a reality in hepatology, said Scott L. Friedman, MD, at the American Association for the Study of Liver Diseases (AASLD) Meeting and Postgraduate Course.

Dr Friedman is the Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai.

He described personalized or precision medicine as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person,” or, he said, “Put simply, the right treatment for the right patient and the right time.”

Personalized medicine allows for clinicians to “establish a cause or predict risk of illness and design a personalized plan to prevent or detect diseases early,” Dr Friedman explained. “It allows for the use of medications and other treatments based on what would work best for each individual and also avoid adverse effects.”

It can now be expanded, he said, into the recognition that health information is as critical in healthy individuals as well as those with illness, and that we can use devices and technology to collect information, establish personal baselines and follow deviations from those baselines. “Health maintenance is part of personalized medicine, as well,” he said.

Dr Friedman noted that the cost of genome sequencing “has gone down far more than predicted,” allowing for gathering “different depths of information” from genetic panels for some cancers at prices of $1000 to $5000 to whole exome sequencing of protein-coding regions for as little as $300 to $500.

One example of the value of whole exome sequencing is illustrated by a project at Yale University in which this testing was used in 19 adults with idiopathic liver disease, he explained. “They did deep phenotyping and whole-exome sequencing” and found that 5 out of the 19 participants (26.3%) had identifiable monogenic disorders affecting 5 genes. The presenting features were typically lean nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis.

One of the patients was that of a woman aged 34 years with normal body mass index (BMI), severe hypertriglyceridemia, steatosis, and fibrosis, elevated alanine transaminase (ALT) and aspartate aminotransferase (AST), who had undergone pancreatectomy and splenectomy due to recurrent pancreatitis. After whole-exome sequencing the investigators found “a missense mutation in the peroxisome proliferator-activated receptor gamma (PPAR-γ) gene which is predicted to disrupt DNA binding and thus completely eliminate the normal function of the PPAR-γ gene, which is a critical gene for the differentiation of adiopocytes.” The patient’s very low serum leptin supported this conclusion. The patient was diagnosed with familial partial lipodystrophy, type 3 due to PPAR-γ inactivating mutation.

“This is an example of how genetic sequencing can translate into actionable information that results in personalized medicine ,” Dr Friedman said. It can help to identify populations that may have different responses to drugs and be used to screen patients to avoid using a drug to which they may genetically predisposed to be resistant, he explained.

For example, Dr Friedman detailed, “a landmark paper” by Ge et al, published in Nature in 2009, explained why patients of certain ethnicities were less responsive to therapy with α-interferon for hepatitis C virus. The researchers found that a IL-28B TT genotype made certain patients—particularly African-Americans—resistant to the drug, causing much lower rates of response and viral clearance in these patients. “This underscores the value of genotyping in helping us determine which drug is the right drug for a patient, and can also be used to predict drug toxicities in some isolated cases.”

Genetic variants do not necessarily cause disease but can contribute to disease phenotypes. “This is nowhere better exemplified than in the case of nonalcoholic fatty liver disease or NAFLD,” Dr Friedman said. Different genetic variants can cause fibrogenesis; some influence glucose metabolism and insulin resistance, others affect oxidative stress response, and more.

These genotypes do not operate in isolation, however, he explained; they operate in conjunction with clinical features of NAFLD. In one study, researchers discovered the synergy between high BMI and the risk allele PNPLA3, which results in high hepatic triglycerides and increases the risks of elevated ALT and cirrhosis. “We now see the integration of genetic and clinical factors that influence the expression of disease.”

Dr Friedman added, “Let’s not forget about the microbiome. A microbiome signature can distinguish between healthy liver, fibrosis and cirrhosis via stool analysis and machine learning technology. These signatures may have embedded within them clues and critical information that can tell us how different bacteria can influence liver cell function.”

He also discussed how the analysis of liquid components—a “liquid biopsy”— could obviate need to obtain direct liver tissue for the presence of liver cancer by revealing circulating tumor cells, exosomes, or cell-free DNA. Such studies could allow for mutation profiling of cell-free DNA that may predict response to different therapies and thus influence the choice of therapy.”

Building on success stories in discovering genetic markers that can predict risk of disease and responses to therapy, these technologies can also be used to classify disease and disease drivers, discover new biomarkers, and predict the risk of complications, Dr Friedman said.

“The integration of ‘omics’ data with clinical information is steadily entering clinical practice and is already useful in many diseases,” he said. “Personalized medicine will slowly but surely integrate into clinical hepatology, but this will be evolutionary, not revolutionary.  Barriers to implementation will wane as we develop better systems to integrate this information into the medical record, so doctors don’t have to become geneticists.”

The cost of sequencing is dropping, he noted, making reimbursement increasingly likely,“if we can prove that this actually improves health and reduces health care costs.”

“Hepatologists will learn the language of personalized medicine and seek opportunities to implement this in clinical practice,” he added. “We will only appreciate the impact of this evolution in retrospect, over the coming years.”

—Rebecca Mashaw

Reference:

Friedman SL. The evolution of personalized medicine in hepatology practice. Talk presented at: American Association for the Study of Liver Diseases annual meeting. November 14, 2020. Virtual.