If you’ve ever had a liver function test as part of an annual physical, you may know that the exam screens for certain biomarkers, like liver enzymes in the blood. If these substances are found to be elevated, it may mean that you have a liver disease or have been exposed to some medications or environmental toxins.
Liver biomarkers are also important tools in the drug development process. Before a drug can be tested in humans, it must be studied for potential safety risks, including the liver where adverse effects often arise. If a medicine is toxic to the liver, damaged liver cells will release certain enzymes and molecules into the blood, which are measured as biomarkers.
In recent years, however, scientists have found that the liver biomarkers most commonly considered the gold standard in medicine, such as ALT (alanine aminotransferase) and bilirubin, aren’t the best tools for studying some patient populations. Doctors and researchers typically focus on about 20 blood proteins, but there are thousands more circulating in our blood that have yet to be explored.
“Many biomarkers that are routinely measured have been used for decades and the more we learn about them the more we’re finding there are gaps with these type of markers,” says Shashi Ramaiah, Executive Director, Global Head of Biomarkers within the Drug Safety R&D organization at Pfizer. “Our main purpose is to help understand and mitigate any safety issues in clinical trials. Identifying new biomarkers and repurposing existing biomarkers can help inform specific organ toxicity before it is tested in humans,” he adds.
Sorting out mixed signals
In a recent clinical trial for a new therapy for Duchenne muscular dystrophy (DMD), a genetic muscle wasting disease seen primarily in boys, scientists were challenged to identify a biomarker specific to the liver to be used in the trial. The current standard, ALT, is elevated in patients with both muscle and liver injuries. “For boys in this trial who have muscle degeneration from their disease, ALT is increased due to muscle injury so you can’t tell if they have ongoing liver injury,” says Shelli Schomaker, a principal scientist who is a part of Ramaiah’s team in Groton. “We needed a new marker so we could better monitor for liver injury in these kids in the clinic.”
The more we learn about [commonly used] biomarkers, the more we’re finding there are gaps with them.
The team proposed a new biomarker, glutamate dehydrogenase (GLDH), a mitochondrial enzyme commonly found in the liver that increases due to liver damage but not muscle injury — making it a more precise test for liver safety. “When you have injury to the liver cells, the membranes in cells become damaged — they become leaky — and you get an increase in blood GLDH over what you’d see in a healthy individual,” says Schomaker. “GLDH has been in the literature for a long time but no one had done the work to prove that it’s a better biomarker than ALT in specific populations,” she adds.
After years of study, Schomaker and her team have prepared a case for GLDH to be used not only in this current trial, but to be used across other trials with similar liver safety issues as an “exploratory marker.” They are also working to develop the GLDH test as a diagnostic for clinical use so that it may some day be a biomarker measured in hospital settings and improve the standard of care for patients living with muscle disease.
“This new biomarker allows us to do clinical trials with confidence as it provides a way to monitor for potential liver issues reliably in the clinic. It’s all about patient safety,” says Schomaker.