A window into the liver

New approach may not just better detect liver injury, but perhaps also diagnose the cause of the injury

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Research Triangle Park, N.C.—Researchers at the Hamner Institutes for Health Sciences have found that there may be a new way to analyze blood to "peek through a window" into the health of the liver.

Utilizing rats, a team of institute researchers found that during liver injury, blood contains small particles derived from the liver that can be isolated and analyzed. According to the study, detailed in a recent issue of Hepatology, these particles contain much of the information that, until now, could only be obtained through needle biopsy of the liver, a process that is costly, inconvenient and sometimes even dangerous.

"This discovery could revolutionize the way physicians detect and even treat a wide variety of liver diseases," says Dr. Paul Watkins, professor of medicine and hepatologist at University of North Carolina-Chapel Hill, and one of the authors of the study.

Watkins notes that Pfizer scientists made the preliminary observations that indicated the potential of the technology, then collaborated with Hamner scientists throughout the running of the more extensive studies that ensued thereafter. Pfizer also licensed patent rights for the technology to the Hamner team.

The team's research could be just the tip of the iceberg, with the potential for more breakthroughs on the horizon.

"We may be on the threshold of intercepting and learning to read messages that injured liver cells are sending out to recruit aid from other sources to help overcome the injury, and perhaps move to biomarkers that really predict what will happen rather than those that just detect what has already occurred," says Dr. John R. Senior, associate director for science at Center for Drug Evaluation and Research of the U.S. Food and Drug Administration.

The researchers found that by comparing blood-borne particles obtained from rats treated with two different liver toxins, they could see large differences in the information contained in the particles.  The study suggests that it may be possible to use this approach not only to better detect liver injury, but also to diagnose the cause of the injury.

Watkins says the particles contain a diverse set of cell components—including proteins and genetic material (in particular messenger RNAs) packaged within a portion of the cell membrane.

"Both healthy and damaged cells release these particles, known as microvesicles, into the blood," he explains. "The actual protein and genetic makeup of these microvesicles is different and depends on the cell type and its status. Upon liver injury, liver cells will release more of these vesicles containing mRNAs produced only in the liver. Through the use of genomic technologies—which allow us to monitor changes in the different types of mRNAs with great sensitivity—we are able to detect this increased release through analysis of a blood sample."

Watkins says the researchers' studies demonstrated that this technique was more sensitive than the current clinical measurements used to detect liver injury.

"Further, genomic technologies allow us to monitor changes to all of the mRNAs present in these particles, allowing us to generate a genomic profile or 'fingerprint' for each sample," he says. "Such a fingerprint—once identified and characterized—would theoretically be similar in patients suffering liver injury from the same drug.  We could then compare fingerprints generated in different patients with liver injury to determine the cause of the injury."

The blood tests physicians currently use to monitor liver health are not always accurate. Even when these tests are abnormal, they often do not indicate the cause of the liver problem.

"The technology and the underlying cellular mechanisms that release these vesicles holds significant promise as a broad-based platform for biomarker development for drug-induced liver injury as well as other diseases," says Dr. Russell Thomas, senior investigator at The Hamner Institutes and the senior author of the study.

According to Watkins, drug-induced liver injury accounts for more than 50 percent of acute liver failure in the United States and is the most common cause for the withdrawal of drugs from the market.  

"At this point it is impossible to determine which patients may progress to liver failure, requiring a liver transplant to survive," he explains. "The methods currently in place to detect liver injury are not entirely specific and provide no additional information about the origin of the injury or the prognosis of the patient."

Watkins notes that his team's findings demonstrate that their technique is as sensitive if not more sensitive—and much more specific—in the detection of liver injury.

"We have also demonstrated that the genomic profiles generated are unique for each of the hepatotoxic drugs tested thus far," he says. "Further testing and generation of these profiles may provide clues into specific causes of drug-induced liver injury and factors leading to liver failure in certain patients. Consequently, this tool has the potential to not only aid researchers in selecting better, safer drugs to take to market but may also aid clinicians in determining the prognosis of patients requiring liver transplantation."

Watkins also points out that the team believes the finding of the microparticles containing liver-specific mRNAs in the healthy animal is important.  

"It may therefore be possible to monitor gene transcription in the liver through a blood test," he says. "This could be very useful in drug development to detect induction of drug metabolizing enzymes and transporters to predict drug interactions.  It may also be possible to use this technology to other liver responses to drugs, including such things as PPAR activation."

According to Watkins, the next step for this research is to translate these preclinical findings to human samples.

"Preliminary studies by our group have indeed shown that these circulating mRNAs are increased in patients suffering from drug-induced liver injury," he notes. "Collection of more patient samples and subsequent analyses are currently underway. In addition, analyses and generation of these genomic profiles following exposure to other drugs is necessary to further assess the potential of our findings."

Watkins says the team's main focus at the moment is on the collection and analysis of samples from human patients suffering from drug-induced liver injury.

"We are also perfecting methods to allow us to specifically isolate those particles in the blood that originate from the liver," he says. "This will refine our analyses significantly by excluding particles released from other tissues. In essence, we will then have a snapshot of the changes occurring specifically in the liver in these patients: a virtual liver biopsy generated through the analysis of readily available blood samples. The potential for such a tool in drug discovery-based research is enormous."

The Hamner Institutes for Health Sciences is located on a 56-acre campus in the heart of Research Triangle Park, N.C. As a cross-disciplinary nonprofit organization, The Hamner Institutes acts as a catalyst to facilitate life sciences technology development among North Carolina universities, while serving as a gateway to establish research collaborations with the bio/pharmaceutical industry and countries in Europe and Asia.

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