Richard Ehman, M.D.

Physicians Can't Touch the Tissue, But Now They Can "Feel" it by Imaging

For centuries physicians have used a traditional physical examination technique called "palpation" to detect some diseases by touch. Many cancers of the breast, thyroid, and prostate are first detected by this simple but powerful technique. Unfortunately, many parts of the body are not accessible for palpation, and it is a subjective technique that may not reveal the presence of a disease until it is fairly advanced.

"Feeling" for Fibrosis: the Liver as Model

Your liver responds to many diseases that damage its cells by developing scar tissue or fibrosis. If poked, a healthy liver is very soft. A liver that has developed fibrosis is firmer, and if the condition progresses to cirrhosis, the liver can almost rock-hard. The critical point: if detected early, fibrosis of the liver can in many cases be treated. Once the disease progresses to cirrhosis, the condition is irreversible. About half of all patients diagnosed with cirrhosis will die within five years unless they receive a liver transplant.

Meng Yin

Imaging researchers at Mayo Clinic have developed a new technology that shows great promise for evaluating patients at risk for developing fibrosis. Conventional imaging techniques are not effective in these cases. The traditional diagnostic "gold standard" is to obtain an actual specimen of liver tissue through a needle biopsy.

"In a needle biopsy we obtain a tiny specimen of liver tissue and we then need to assume that it reflects the condition of the entire organ," says Richard Ehman, M.D., lead researcher on the MRE project. "The procedure is invasive and not without potential complications such as bleeding and infection - and the accuracy of liver biopsy is affected by the sampling issue."

What MRE Feels Like: A Patient Experience

Mayo Clinic patient Kathy Anderson describes herself as "a 43 year old fairly healthy mother of two teenage boys." She recently volunteered to undergo an MRE. "Part of me just wanted to know how exactly someone could vibrate my liver ...the other part of me wanted to know why my liver enzymes are always a little high, something my family physician assures me is nothing to be concerned about."

"On my day off, I went to the lab to experience MRE. It is an experience like no other, and I do mean that in a good way. No needles, no poking and prodding, just as small circular device (much like the surface of a drum) that was strapped around my abdomen before I was moved into the MRI machine. Once in the machine, I was asked to inhale, exhale and then hold my breath. The "drum" literally vibrated in different drum beats which then helped the physician see a better scan of my liver. It was pretty amazing. MRE and what it does, makes me think of a marshmallow. Just like a marshmallow fresh out of the bag, a soft liver is good. As a marshmallow gets stale, the surface hardens. I was happy to learn that my liver is soft and healthy -- and to find that out without experiencing any pain."

Some patients don't have a sufficiently high probability of liver disease to warrant an invasive biopsy. This could include the tens of millions of people in the world who have hepatitis C, since a small but significant fraction of these individuals will develop progressive liver fibrosis. Many could be candidates for an MRE screening test.

Good Vibrations & Algorithms

The MRE technology developed by Dr. Ehman and colleagues uses a special kind of mechanical energy called "shear waves" to probe the mechanical properties of tissue. Meng Yin, a student in the Mayo Graduate School , worked to overcome a key challenge associated with this project, under the mentorship of Dr. Ehman. She devised a way to reliably generate shear waves in the liver. In her initial experiments, she found that she could deliver these waves to liver using a drum-like device, powered by remotely-located audio speaker operating at very low, almost inaudible frequencies. Unfortunately, in the early tests, the audio speaker was quickly destroyed by the high power levels that were required. That's when engineer Phil Rossman stepped in. He worked with Meng Yin to solve the problem using some unexpected resources. Dr. Ehman's teenage son, Eric, heard about the need and "donated" his high-powered subwoofer speaker to the research team. Based on this idea, the group went on to develop a specially-designed acoustic driver system for MRE that still uses a major component from the audio industry.

Elastograms of a normal liver (top) and a fibrotic liver, validated by biopsy.

The propagating waves are imaged in the liver using a Mayo-invented MRI technique that is so sensitive that it can reveal cyclic motions that are less than the wavelength of light in size. The special MRI scanning technique, perfected by programmer Roger Grimm, allows these images to be acquired in a time of less than a minute.

So now that they could create the waves, and see and record them, how could they make sense of them? This problem was solved by Armando Manduca, Ph.D., a Mayo mathematician, who developed an "algorithm" or method to process the wave images in order calculate the stiffness of the tissue.

"The mathematics to do this did not exist prior to this work," says Dr. Ehman. "Dr. Manduca created a whole new field of inversion techniques. It represents a decade of work on his part. As a result we were able to generate information that is unique in medical imaging."

By using Dr. Manduca's algorithm to process the wave images, researchers developed "elastograms" -- color images that quantitatively show tissue stiffness. By analyzing elastograms from healthy participants, researchers were able to form measurable standards for comparison.

"One of the most exciting aspects of this work is that we now have a new way to image the body. It reminds me of the early days of MRI," says Dr. Ehman. "In those days, those of us who were lucky to be involved in the early exploration of MRI were energized by the fact that everything we were seeing was new. Each observation was new scientific knowledge." "With MRE, we're experiencing that again."

The device worked fine in the laboratory, but would it work reliably in patients? And would it be accurate enough to allow for dependable diagnosis?

Animation of sheer waves in liver during MRE

Working with clinicians like Jay Talwalkar, M.D. and others, Dr. Ehman and his group have been pursuing the answers to these questions. In a recent series of 77 examinations, the group found that all patients with liver fibrosis had stiffness values higher than those of normal volunteers. The results predict that MRE will have a sensitivity for diagnosing liver fibrosis of 98 percent and a specificity level (absence of false positives) of 99 percent. These results are extremely promising.

Broad Applications

Many diseases cause the mechanical properties of tissue to change and would be likely candidates for diagnosis using MRE in the future. Breast cancer is one example, says Dr. Ehman. His group is also exploring the potential of MRE to detect the amyloid plaque deposition in brain tissue that causes Alzheimer's disease. In other applications, MRE is being used to study muscle physiology by Kai-Nan An, Ph.D. and colleagues in Biomechanics research. It seems safe to guess that the prospects for MRE are just beginning to unfold.