A better blood test for liver damage

As the body’s chemical clearinghouse, the liver is prone to drug-induced injury. Detecting liver damage, though, is complicated because the standard protein biomarkers of liver damage are expressed throughout the body; they don’t necessarily reflect what’s going on in that organ. Now, by focusing on only those proteins expressed at high levels in the liver, researchers have identified a panel of blood biomarkers that detect acetaminophen-induced liver injury better than the standard medical test (J. Proteome Res. 2016, DOI:10.1021/acs.jproteome.6b00547). The approach could be applied to the development of diagnostic tests for a host of organ-specific conditions.

For many years, clinicians have relied on assays for two enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), to detect liver injury. These biomarkers have limitations, says Leroy Hood of the Institute for Systems Biology, such as a short half-life and a tendency to underreport damage in certain individuals. Hood has been thinking about how to find better disease biomarkers for many years. “I had this idea that if we could identify organ-enriched proteins that actually appear in the blood, they would be fantastic biomarkers of disease in an organ.”

To identify liver-enriched proteins, Hood’s team first scoured databases cataloging human gene expression in many different organs in order to find RNA transcripts that are more abundant in the liver than in the rest of the body. But just because the proteins are abundant in the liver doesn’t mean they’ll show up in blood. So the researchers used mass spectrometry to analyze human blood samples for the proteins identified in the transcript search. With this method, they successfully detected 66 liver-enriched proteins in blood.

The next step was to figure out if any of those proteins could be useful markers of drug-induced liver injury. Again using mass spectrometry, the researchers tested blood samples from 14 acetaminophen-overdose patients and 12 healthy controls. Of the 66 liver-enriched proteins, 23 were at least three times as concentrated in overdose patients as in healthy controls. A subset of five proteins provided the best discrimination between acetaminophen-overdose patients and healthy controls, correctly identifying 12 out of the 14 sick patients, whereas ALT and AST detected only three. The researchers suspect the poor diagnostic performance of ALT and AST is due to differences in dosages of the drug, the length of time since the patients had taken the drug, and patients’ underlying health.

B. Alex Merrick of the National Institute of Environmental Health Sciences applauds the researchers’ systematic approach. “Rather than hang your hat on any one or two biomarkers, there is strength in using a panel,” he says. “The next step is to expand this study to larger patient populations to be able to test out the robustness of the panel.”