Researchers have developed a new MRI contrast dye that enables more accurate and safer detection of early-stage liver disease than currently approved agents. The new compound, called ProCA32.collagen1, was developed by scientists supported by the National Institute on Alcohol Abuse and Alcoholism, part of the NIH.
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Contrast agents are the dyes used in MRI tests to enhance the visibility of internal body structures during imaging. The new contrast agent binds to liver cells in the early stage of the disease and may provide the first effective, non-invasive method for detecting the disease early.
The development represents a “revolutionary change for the field. This would help doctors monitor treatment before it is irreversible and help pharmaceutical companies to select the right patients for clinical trials or identify subjects for drug discovery."
Jenny Yang, Study Author
Early-stage liver disease is difficult to detect
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the leading causes of chronic liver disease (CLD), cirrhosis, and hepatocellular carcinoma (HCC).
In the United States, deaths from CLD among people aged 45 to 65 increased by 31% between 2010 and 2015. Causes of CLD include viral hepatitis, metabolic dysfunction, alcohol abuse and autoimmune disease. Almost all chronic liver damage leads to liver fibrosis.
Liver disease is a slowly progressing condition, but without an effective, non-invasive method that can detect disease early and prompt treatment, it can progress to more severe stages, including cirrhosis and liver cancer.
Most people do not believe they have liver fibrosis and don't want to change their lifestyle and we cannot detect it early. So, what happens is, they continue their lifestyle and at some point develop later-stage fibrosis which can become severe cirrhosis and a large portion become liver cancer."
Jenny Yang, Study Author
Biopsies are currently the gold standard for detecting and staging CLD as it relies on stage-dependent characteristic patterns of collagen expression, a biomarker of the disease. However, biopsy has many limitations, including a 33 to 50% error rate, even in the detection of late-stage diseases such as cirrhosis.
Previous research has demonstrated that imaging modalities can detect morphological characteristics of liver cirrhosis, but, in some cases, the cirrhotic liver can still look completely healthy.
Non-alcoholic steatohepatitis (NASH) and liver fibrosis are conditions that can develop with any type of CLD, including NAFLD, ALD, hepatitis and autoimmune hepatitis.
A non-invasive method for early detection is desperately needed
Many efforts have been made to develop non-invasive imaging techniques associated with fibrosis and NASH, but so far, these techniques have not provided accurate detection of early stage hepatic fibrosis and NASH.
A prerequisite for the efficient treatment of liver fibrosis and NASH is a reliable diagnostic method for early detection of the conditions.
MRI provides advantages over other techniques
Magnetic resonance imaging (MRI) provides a number of advantages over other imaging modalities including high spatial resolution and deep tissue penetration. The technique is non-invasive and suitable for detecting and monitoring the progression of NASH and fibrosis. However, it cannot reliably detect these conditions in the early stages due to major limitations, including a lack of sensitive MRI contrast agents.
Recently developed collagen-targeted contrast agents appear to image liver fibrosis with improved sensitivity and specificity, but concerns about their safety have prevented efforts to develop an MRI contrast agent capable of detecting early stage fibrosis and NASH.
The new contrast agent
Yang and colleagues from Georgia State and Emory University have developed a new contrast agent, ProCA32.collagen1, that targets the over-expression of collagen during the disease state.
As reported in the journal Nature Communications, when the researchers tested the compound in animal models, they found it could detect the early stages of both liver fibrosis and NASH.
The new compound was more accurate than conventional contrast agents, detecting tumors that were 100 times smaller than those detected by standard dyes. It also requires a significantly lower dosage than current contrast agents, meaning the risk of metal toxicity is significantly reduced.
Black and white contrast imaging with ProCA32.collagen1 can distinguish between "invisible" fibrotic regions of the liver and healthy background tissue, thereby providing an advantage over invasive biopsies that cannot cover the whole liver.
"Our contrast agent can do dual color so you have different contrast-colored features so the sensitivity shows up better and accuracy is a lot better," says Yang.
Next, Yang intends to seek FDA approval to test the new agent in clinical trials at Emory University Hospital.
Salarian, M., et al. (2019). Early detection and staging of chronic liver diseases with a protein MRI contrast agent. Nature Communications. DOI: 10.1038/s41467-019-11984-2.