A better blood test for liver damage | Chemical & Engineering News
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Web Date: October 25, 2016

A better blood test for liver damage

A set of five proteins in patient blood samples can diagnose acetaminophen-induced liver injury
Department: Science & Technology
News Channels: Analytical SCENE, Biological SCENE
Keywords: diagnostics, liver damage, acetaminophen, biomarkers, proteomics, genomics, organ-enriched protein, toxicology
Too-high doses of acetaminophen can damage the liver. A panel of newly identified biomarkers could diagnose damage more accurately than existing blood tests.
Credit: Linda Wang/C&EN
Photo of Tylenol bottle and pills.
Too-high doses of acetaminophen can damage the liver. A panel of newly identified biomarkers could diagnose damage more accurately than existing blood tests.
Credit: Linda Wang/C&EN

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.”

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K Combrink (October 26, 2016 2:00 PM)
Could this technique be used to detect cirrhosis? A painful and risky liver biopsy is the normal method for assessing liver damage for liver diseases like Hepatitis C. Could this protein profiling identify fibrosis, the stage of fibrosis or the cause of the liver damage?
Shizhen Qin (October 29, 2016 8:22 PM)
This is a very good question. Actually, we have published a paper 4 years ago (Qin et al., Proteomics 2012, 12, 1244–1252). With a similar strategy, we quantified 38 liver-specific proteins and found 5 proteins that are promising as candidate biomarkers to distinguish patients at different stages of hepatic fibrosis due to chronic infection with hepatitis C virus or distinguishing liver fibrosis patients from healthy controls. The results were later confirmed by an independent study sowing all five proteins were detected with significant differential abundance with the same expression trends in liver fibrosis patients (Baker et al., Mol Cell Proteomics. 2014, 13, 1119–1127). Recently we have generated a more comprehensive organ-enriched protein list including over a hundred highly liver-enriched proteins and believe that, by testing more patient samples, there is a much better chance to discover more specific markers to identify fibrosis at different stages.
Thyagaraju Kedam (October 27, 2016 2:31 AM)
We worked on expression of aminotransferases under the influence of acetaminophen in mice liver and found their expression due to over dose and some more may be involved. This study may advise some thing new.
Lee (October 27, 2016 4:56 AM)
Will be interesting to see if this opens the doors to better detection of NASH (Nonalcoholic steatohepatitis)

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