When former NFL linebacker Matt Millen went to his doctor, complaining of shortness of breath, he was told he had the heart of a 22-year-old.
“They did a bunch of tests on me and they said, ‘There's nothing wrong with you’,” recounts Millen, 62, who played on four Super Bowl-winning teams, including the Oakland Raiders and San Francisco 49ers. Since retiring, he’s been a football commentator for ESPN, NFL on Fox, and NFL Network’s “Thursday Night Football,” among others.
Millen thought he was in the clear. So he went back to business as usual, which included cutting five acres of grass on his hilly farmland in Pennsylvania. But, one day, after mowing to the top of one particularly long hill, he could hardly breath. “My heart was pounding out of my chest,” says Millen. “So I went back to my doctor, and this time they did a heart biopsy and they said, ‘Nothing's wrong, your heart's in great shape. And I said, ‘Well, something's wrong. I'm telling you something's wrong. I know my body’.”
A long journey to a correct diagnosis
Thus began a nearly six-year medical journey in which Millen sought answers. He went to hospitals in Philadelphia, Chicago, Los Angeles, and several institutions in New York, and had all sorts of tests done—including a bone marrow biopsy and a belly fat test. Still, no one could tell him what was wrong.
Finally, through a recommendation from a physician friend of his, Millen travelled to Mayo’s Jacksonville campus, where he met with internist Gary Lee, M.D.
“He’s another Philly guy, like myself, so we spoke the same language,” says Millen. “And he said, ‘I know what you’ve got and you're not going like it.’ So I said, ‘Wait, I've been to doctors all over the country, they all came up with nothing, and you're going to sit there and tell me, within 10 minutes, without doing any tests, you know what I’ve got?’ And he said, ‘Yeah, you have amyloidosis’.”
Amyloidosis occurs when an abnormal protein called “amyloid” builds up in the body. Amyloid is produced in the bone marrow and can be deposited in tissue and organs. The disease affects different organs in different people, most frequently the heart, kidneys, liver, spleen, nervous system, and digestive tract. Severe amyloidosis can eventually destroy an organ. Currently, there is no cure for this rare disease, which affects about 10 people per one million.
“There are over thirty different types of proteins that can cause amyloid deposits, so the diagnosis is critical because the treatment is highly dependent on which type of protein is depositing in the body,” says David Murray, M.D., Ph.D., pathologist in Mayo’s Division of Laboratory Medicine & Pathology in Rochester, MN, who oversees Millen’s case along with Dr. Lee.
Millen typifies the long journey it takes for many patients to be diagnosed with amyloidosis, because the disease mimics other conditions. “Patients may end up with several different diagnosis, even something like fibromyalgia,” says Dr. Murray. “And a lot of times they get sort of pushed aside in the healthcare field and they end up waiting a long time—five years is what studies have shown it takes from when one symptom started until the diagnosis of amyloidosis has been made.”
Typing the disease with new methodology
Before moving forward with any treatment protocol, Dr. Lee’s diagnosis of amyloidosis had to be confirmed, and typed, with further testing in Rochester.
“In order to get a good diagnosis for amyloidosis, you need to actually detect the protein that's precipitating in the organ itself,” says Dr. Murray. “And so it really requires a biopsy.
At Mayo, we have a very unique method for diagnosing amyloidosis in the tissue. We use mass spectrometry in order to characterize and make sure we identify the right protein. We’ve also extended our capabilities to use mass spectrometry to detect the immunoglobulin light chains in serum, which allows us to track the progression of the disease over time.
“Matt had a biopsy done while having surgery at another institution and we were able to get that biopsy, and we could actually see the amyloid in that tissue. Unfortunately, there was not enough to adequately type it. So we did a second biopsy at Mayo to get enough tissue to type the amyloid.”
In Millen’s case, the composition of the deposits was determined to come from a portion of an immunoglobulin. Immunoglobulins (aka antibodies) are proteins that are synthesized in the body by plasma cells. They are the third most abundant protein in human serum. In fact, there are 100,000 slightly different immunoglobulins in every person, which serve to protect us from recurrent infections. Every time we get sick, our body produces new immunoglobulins. Hence, when a person gets a flu shot, their body makes new immunoglobulins.
“Unfortunately, some plasma cells become dysregulated and overproduce their immunoglobulin,” says Dr. Murray. “Detection of this overexpressed immunoglobulin is a key step to raise suspicion for amyloidosis, and in Matt’s case the overproduced immunoglobulin’s light chain started to misfold and deposit in his heart. This in turn makes the heart stiff like an old garden hose and the heart loses its pumping ability.”
Using a new and novel serum based assay that can identify patients with a higher risk for AL amyloidosis and leveraging Mayo Clinic's expertise using mass spectrometry in amyloidosis protein typing, Millen’s amyloidosis was typed as “immunoglobulin light chain amyloidosis” (AL amyloidosis). Now, a treatment protocol could begin, and none too soon.
“Typing the disease is a big deal because some proteins that cause amyloid come from the liver, and some come from the bone marrow,” says Dr. Murray. “If the protein is coming from the liver, then the patient could need a liver transplant. If the protein is coming from the bone marrow, then the patient needs a bone marrow transplant. You really don’t want to get this wrong for obvious reasons.”
The long road to healing
With his heart nearly destroyed, Millen was put on a waiting list for a heart transplant. Next, he received 10 months of chemotherapy to stop the plasma cells from making the protein that was depositing in the heart.
“You wouldn’t want to give someone a new heart if the abnormal immunoglobulin protein was still around,” says Dr. Murray. “This is why we also do a stem cell bone transplant, because the plasma cells are part of the bone marrow. We find this treatment to be the best way to give long-term benefit.”
After spending 100 days in the hospital, Millen received his new heart on Christmas Eve of 2018. The new heart, combined with the chemotherapy and stem cell bone transplant brought him onto remission from the disease.
“The doctors are optimistic about my outcome, and there are new medicines that have come on that weren't available to me even a year ago,” says Millen. “So whatever I have to do next, I’ll do it.”
Arresting disease progression and mitigating damage
Previous to Mayo’s mass spectrometry method, the disease that causes immunoglobulin light chain (as in Millen’s case) was usually detected using “gel electrophoresis,” a technology that separates proteins based on their size and charge. Electrophoresis involves running a current through a gel containing the molecules of interest.
“Honestly, this method of gel electrophoresis hasn't changed since 1965 at Mayo Clinic,” says Dr. Murray. “This new immunoglobulin detection test came about because we were looking for a way to modernize the method and to speed it up in the lab, and to really just make a better assay for our patients. We were not expecting to detect a new risk marker for AL amyloidosis, but because we are such a high volume lab, the marker popped out from the testing results.”
Mayo’s newly launched method for detecting overexpressed immunoglobulins is not only more specific, it will also allow pathologists to identify patients at risk for developing amyloidosis. For example, while amyloidosis is rare, the overproduction of an immunoglobulin is quite common in the over-50 population; in fact, 3- to 5-percent of people in this group will have overproduced immunoglobulin.
“Our new mass spec test can help stratify this large population so we can more closely follow patients at risk for amyloidosis,” says Dr. Murray. “Very few of these patients will get amyloidosis, but if they have symptoms consistent with this rare disease, we can do things like biopsy and hopefully intervene earlier than the typical five years. If Matt would have been diagnosed earlier, we may have been able to arrest the disease and avoid the heart transplant.”
New heart, new hope
So, how does the Super Bowl veteran feel today?
“I feel great . . . I've got my strength back,” Millen says. “I've got some endurance back. I'm walking that hill again. That doesn't bother me. I'm in the shop every day. But there are times when you just don't have the same energy that you did. I'm trying to train this new heart and get it to a level that's where I want it to be.”
Moving forward, Millen will be closely followed for possible transplant rejection, and periodically tested for markers indicating the return of the disease. “If the disease were to return, he would most likely get more chemo,” says Dr. Murray.
Along with his dear wife and children, Millen credits his training as a pro athlete for helping him endure all he went through from his disease. As far as what lies ahead, he’s taking each new day much like he approached game day in the NFL.
“Game day is when you want all the waters flowing into one stream ,” he says. “You’ve got to be on top of your mental game, your physical game, you’ve got to be on top of the emotional game. Everything's got to come together. And sometimes, sometimes they line up and you play the game of your life. Sometimes they don't, and you have to fight through it. The key is for you to play your best game on that day.”