Chronic liver disease is a growing health concern in the U.S. and around the world, with links to alcoholism, diabetes and even obesity. One of the early manifestations of the disease is fibrosis, an excessive buildup of scar tissue that results from repeated injury to the liver. While its effects can be halted or even reversed if caught early enough, fibrosis can also cause considerable damage, with sometimes devastating outcomes. Untreated, liver fibrosis can progress to cirrhosis, the twelfth leading cause of death in the U.S.; to primary liver cancer; or to liver organ failure.
Now, a team of investigators in the MGH Martinos Center for Biomedical Imaging has reported a novel means of detecting and staging liver fibrosis that could yield important advances in how we manage chronic liver disease. They describe this new imaging approach in a paper in the journal Hepatology.
“We combined two imaging techniques that measure different biophysical properties of liver fibrosis—tissue stiffness and collagen content—to stage the severity of fibrotic progression,” said Bo Zhu, first author of the Hepatology paper. “This allows us to take advantage of the strengths of both while also overcoming their respective limitations. The robustness of the combined approach can prove especially important in the clinic, where we rarely know non-invasively the extent to which the disease has progressed, or even regressed in the case of anti-fibrotic treatment.”
At the time of the study, Zhu was a student working in the Caravan Lab in the Martinos Center. He is now a postdoctoral fellow in Matthew Rosen’s Low-field Imaging Lab, also in the Center, developing neural network-based image reconstruction techniques.
Currently, biopsy is the gold standard in detecting and staging fibrosis. But this solution is in many ways limited. It suffers sampling error, since it only measures 1/50,000th of the entire liver, which is not necessarily representative of the rest of the organ. And because it is an invasive procedure there is always a risk of complications. Indeed, as many as five percent of biopsy cases result in hospitalization. For these reasons, noninvasive methods that can image the entire liver, repeatedly with little or no chance of complications, would be of tremendous value in the clinic.
Zhu and colleagues looked at two such methods. First was magnetic resonance elastography (MRE). Over the past decade researchers have focused increasing attention on this technique because of its ability to assess liver fibrosis by imaging the stiffness of the tissue. MRE can reliably stage advanced fibrosis as this is when the tissue stiffens the most. But it is less effective at detection and staging of early fibrosis when interventions could still stem or even reverse the progression of fibrosis.
This is where the second approach comes in. In more recent years, Peter Caravan’s group in the Center has developed a gadolinium-based MR contrast agent, EP-3533, that can target Type I collagen fibers. Caravan is an associate professor of radiology at Harvard Medical School, a senior faculty member in the Center and senior author of the Hepatology paper. How can this help in imaging liver fibrosis? Collagen fibers make up much of the excess connective tissue deposited by fibrosis, so imaging the collagen itself means researchers and clinicians can more directly probe the molecular mechanisms of fibrosis. This in turns allows them to detect fibrosis in its earlier stages.
The researchers initially set out to simply compare and contrast the effectiveness of the two methods but soon realized they could take advantage of their complementary capabilities—collagen imaging was most useful in distinguishing early fibrosis; MRE, in distinguishing advanced fibrosis—to come up with a better means of staging liver disease. “Our findings allowed us to develop a composite fibrosis staging metric, utilizing data from both techniques, obtained in a single imaging exam, which demonstrated superior discrimination across all stages of fibrosis progression,” Zhu said.
Because of its potential for advancing the detection and staging of liver fibrosis—an important clinical need—the researchers are exploring the possibility of developing the combined approach for use in clinical settings. MRE has already received FDA approval so the primary hurdle to be overcome is approval of the gadolinium-based agent. A company, Collagen Medical, is now pursuing this commercially.
At the same time, the Martinos team is planning further studies with the approach, exploring the ways it can help in other models of liver disease.
“We are now looking in a model of non-alcoholic steatohepatitis, or NASH, which is a associated with the epidemics in obesity and diabetes,” Caravan said. “NASH is a cause for great concern these days because it can lead to liver failure, cirrhosis and primary cancer of the liver.”
The authors of the Hepatology paper also include Nicholas Rotile, Helen Day, Tyson Rietz, Christian Farrar, Bruce Rosen and Peter Caravan of the MGH Martinos Center; Lan Wei, Kenneth Tanabe and Bryan Fuchs of the Massachusetts General Hospital Cancer Center; and Gregory Lauwers of the Massachusetts General Hospital Department of Pathology.