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Nonalcoholic fatty liver disease (NAFLD), now esti­mated to be the most common form of liver disease in the United States and worldwide, is expected to be the primary cause for liver transplantation by the end of the decade.

Dr. Speliotes examines human liver cell lines through a microscopy.

However, regardless of its pervasiveness, there are many unknowns surrounding the disease. Elevations in liver enzymes may indicate NAFLD; however, the accuracy of such tests is poor, and the standard procedure for diagnosis, liver biopsy, is aggressive. Further, the condi­tion can manifest from a plethora of factors, and initial symptoms, including abdominal pain and fatigue, are indis­tinct, if expressed at all.

As a result, many individuals with NAFLD are initially oblivious to even having it, until it advances to something much more serious, such as cirrhosis or liver failure. Additionally, there are inadequate treatments for the disease, so patients are frequently left without viable options, even if diagnosed early and accurately.

Because of these difficulties, Elizabeth K. Speliotes, MD, PhD, MPH, assistant professor of internal medicine, compu­tational medicine and bioinformatics at the University of Michigan Health System, hopes to uncover the disease’s actual pervasiveness and risk, in addi­tion to identifying effective treatments through genetic research.


In working with the Genetics of Obesity- Related Liver Disease Consortium, Dr. Speliotes’ team has identified five genetic loci associated with NAFLD. Using a group of approximately 7,000 people, the investigators calculated liver fat based on CT scans and carried out related genome-wide associa­tion analyses to recognize genetic patterns related to fatty liver. They then performed genetic analyses of people with NAFLD.

One noteworthy finding was that genes related to NAFLD are different from those associated with obesity.

Dr. Speliotes and Alissa Wall, medical student, open a liquid nitrogen tank containing human liver cell lines, which are used to model human disease.

“Obesity was one of my first interests and, in part, what drove me to study fatty liver disease,” Dr. Speliotes said. “Ultimately, I do think they are linked. But in terms of genetics, it looks like the main drivers of obesity are more neurologically based, whereas the drivers that seem to be causing fatty liver disease are more lipid-and glucose-based. That changes how we think about these diseases.”

Dr. Speliotes’ team also is exploring the relationship between NAFLD-related genes and environmental factors.

“Our studies suggest that approximately 25 to 30 percent of how much fat is in your liver is due to genetics, and the rest is probably environmental,” Dr. Speliotes said. “Some of my patients are the epitome of health. They tell me they work out every day. But it doesn’t matter. They still have a lot of fat in their liver.

“We’ve identified genetic variants that put some individuals at much higher risk for developing fat in the liver, even without being overweight. For example, we’ve identified one variant that confers a sixfold higher risk for developing scar­ring and cirrhosis, and another variant that is associated with a twelvefold higher risk for developing liver cancer.”

Future studies will be designed to identify new genes related to NAFLD in order to better inform people who are at risk for the disease and to develop more effective treatments.

“Currently, we can make specific recom­mendations for people who are at risk for developing some types of cancer, for example,” Dr. Speliotes said. “But it’s only through this kind of research that we’re going to be able to make similar recommendations for people with meta­bolic diseases.”


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University of Michigan Health System (U-M) researchers guided by James M. Scheiman, MD, professor of internal medicine and GI lead in the hospi­tal’s Multidisciplinary Pancreatic Cancer Destination Program, have been actively engaged in studies designed to identify ways to improve the standard of care in patients undergoing endoscopic retrograde cholan­giopancreatography (ERCP).

In 2012, the team published the results of a groundbreaking study in The New England Journal of Medicine (2012;366:1414-1422) that found indo­methacin administered rectally was a highly effective approach to prevent post-ERCP pancreatitis (PEP).

An analysis of that trial further suggested that indomethacin was more effective and more cost-effective for preventing PEP than pancreatic duct stents or a combination of the two (The American Journal of Gastroenterology 2013;108:410-415). This has led to an increased use of the drug—a less-inva­sive approach—at U-M and elsewhere. Dr. Scheiman noted the insertion of prophylactic pancreatic duct stents, an approach used in patients considered to be at high risk for complications after ERCP, can be difficult, and injury to the pancreatic orifice is a possibility.


“ERCP is the most dangerous procedure we do as gastroenterologists.” -James M. Scheiman, MD

Dr. Scheiman and his team are seeking to build on these findings with new research into whether the use of stents further reduces the risk for PEP in ERCP patients who also are receiving indomethacin prophylaxis, and to explore why there is significant interin­dividual variability in patient response to ERCP. Ultimately, the primary goal is to develop a method for identifying and pretreating patients at increased risk for postprocedural complications.

“ERCP is the most dangerous proce­dure we do as gastroenterologists,” Dr. Scheiman explained. “Our initial research led to more widespread use of indomethacin in our institution and nationally, and has helped patients tremendously. Now, we are trying to understand why patients get pancre­atitis following ERCP and how to best reduce this risk. Our group is committed to groundbreaking research in this area, and to training gastroenterologists at an extraordinarily high skill level to practice state-of-the-art ERCP.”

Pursuant to this goal, Dr. Scheiman served as one of the co-authors of a paper published in the American Journal of Gastroenterology (2015;110:48-59) that proposed metrics for assessing quality and efficiency in training programs for endoscopic procedures such as ERCP and endoscopic ultrasound (EUS). In addition, Dr. Scheiman’s team is collaborating with U-M biomedical engi­neering faculty in National Institutes of Health–funded research on the potential for characterization of pancreatic tissue using optical spectroscopy. They hope the technology will assist in the “differ­entiation of various pancreatic diseases,” Dr. Scheiman explained, and in better patient selection for procedures such as ERCP and EUS, ultimately making these procedures safer.

“We have been involved in studying the process by which we learn these various endoscopic procedures and are involved in an ongoing study that assesses training programs nationally,” Dr. Scheiman said.

“Our in-depth understanding of the risks and benefits of invasive procedures involving the pancreas has really helped us target the safest and most-effective approach to diagnosing patients with pancreatic disease. Because we have high-quality, less-risky alternatives such as EUS, we’ve been able to use these approaches to make sure ERCP is the right procedure to do and, if it is, we’ve pioneered approaches to make that procedure safer.”


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Significant adverse events that pose risks to patients treated with specific drugs are usually identified in preap­proval clinical trials, but relatively rare complications can go undetected.

“We’re trying to figure out why selected patients who take a drug that is considered safe and medically helpful in the majority of people will get drug-induced liver injury.” -Robert J. Fontana, MD

One such rare complication is drug-in­duced liver injury (DILI), and physicians at the University of Michigan are at the forefront of ongoing research designed to identify drugs that carry this risk, as well as genetic or other factors that may predispose patients to this complication.

“Unfortunately, there is often a big disconnect between the results of preclinical and clinical trials and what happens in patients who use these drugs in clinical practice,” said Robert J. Fontana, MD, medical director of liver transplantation at the University of Michigan Health System. Dr. Fontana has been leading research in DILI at the University of Michigan for more than 15 years.

When you have clinical trials of 1,000 to 2,000 patients, you may not see an adverse event that occurs in only 1 of 10,000 or 1 of 100,000 treated patients,” he said. “So we’re trying to figure out why selected patients who take a drug that is considered safe and medically helpful in the majority of people will get DILI.”


Research conducted by Dr. Fontana’s team suggests the incidence of DILI is approximately 15 events per 100,000 in the general population. Although rare, these events are hardly insignificant. Indeed, they can result in significant morbidity and mortality, particularly as one of the leading causes of acute liver failure in the United States, and have proven to be “important barriers to new drug development and marketing.”

This is why the research initiative called the Drug-Induced Liver Injury Network (DILIN), an ongoing multicenter trial funded by the National Institutes of Health, has generated great interest in the health care community. Patients experiencing DILI may suffer from chronic liver disease and may ulti­mately require a liver transplant. Based on the team’s research, DILI seems to indiscriminately affect children and adults of various demographic groups equally.

According to Dr. Fontana, the DILIN registry already includes more than 1,600 patients (300 of whom are from the University of Michigan system). Using this registry, the team has identified trends in DILI in the United States over a 10-year period. In a paper published in Gastroenterology (2015;148:1340-1352.e7), they found dozens of drugs associated with a fairly high incidence of DILI, and drugs in the antimicrobial class, particularly amoxicillin-clavulanate (Augmentin, Beecham Pharmaceuticals) and isoni­azid, were among the leaders.

“Amoxicillin-clavulanate is prescribed to millions of patients each year,” Dr. Fontana said. “It is a very commonly used antibiotic, with a good spectrum of activity that is very efficacious. Unfortunately, it is also the number one cause of DILI, although most patients recover. Isoniazid, of course, is less commonly used, but it is prescribed frequently to health care workers who may have been exposed to tuberculosis, and right now there is no alternative choice.”


The use of dietary and herbal supple­ments has also been associated with a relatively high incidence of DILI. These supplements are not subject to FDA testing requirements and are often used without the super­vision and direction of health care professionals.

Dr. Fontana and Dr. Brian Nedeau, an internal medicine resident, examine a patient for physical signs of chronic liver disease.

“We’re not suggesting that people stop using these drugs or supplements,” he said. “We merely want physicians to include the potential for DILI in their risk–benefit analysis. Now, when doctors see patients with unexplained liver injury, we want them to ask what medications or supplements the patients are taking as part of their evaluation.”

According to Dr. Fontana, the ulti­mate goal of DILIN is to identify genetic polymorphisms that may put certain patients at increased risk for DILI. He and his team have been collecting DNA and other biological samples from patients in the DILIN registry, hoping to find differences between people developing DILI and the general population. Although they have yet to identify common risk factors among DILI patients—such as age, gender, and race—the team has begun to identify some genetic risk factors that are drug-specific, and hopes to present its findings in the near future.

“We really see this as a vital part of the precision medicine movement,” Dr. Fontana said. “Most precision medi­cine has been geared toward efficacy, but we’re looking at it from a ‘do no harm’ or safety perspective. If we can identify a genetic risk factor for DILI and confirm it through a blood test, we can ultimately determine if one drug is a better option for one patient than another. We can use the latest molecular techniques to develop blood tests to improve the overall safety of the practice of medicine.”


The use of dietary and herbal supple­ments has also been associated with a relatively high incidence of DILI. These supplements are not subject to FDA testing requirements and are often used without the super­vision and direction of health care professionals.

“We’re not suggesting that people stop using these drugs or supplements,” he said. “We merely want physicians to include the potential for DILI in their risk–benefit analysis. Now, when doctors see patients with unexplained liver injury, we want them to ask what medications or supplements the patients are taking as part of their evaluation.”

According to Dr. Fontana, the ulti­mate goal of DILIN is to identify genetic polymorphisms that may put certain patients at increased risk for DILI. He and his team have been collecting DNA and other biological samples from patients in the DILIN registry, hoping to find differences between people developing DILI and the general population. Although they have yet to identify common risk factors among DILI patients—such as age, gender, and race—the team has begun to identify some genetic risk factors that are drug-specific, and hopes to present its findings in the near future.

“We really see this as a vital part of the precision medicine movement,” Dr. Fontana said. “Most precision medi­cine has been geared toward efficacy, but we’re looking at it from a ‘do no harm’ or safety perspective. If we can identify a genetic risk factor for DILI and confirm it through a blood test, we can ultimately determine if one drug is a better option for one patient than another. We can use the latest molecular techniques to develop blood tests to improve the overall safety of the practice of medicine.”



In 2009, a 45-year-old otherwise healthy male patient presented to an emergency department in Kalamazoo with the typical symptoms of pneumonia. The emergency department physi­cians prescribed high-dose azithromycin (Zithromax, Pfizer), known colloquially as a “Z-Pak,” which the patient took for the prescribed five-day treatment period.

Azithromycin has proved effective for the treatment of bacterial infections, and unsurprisingly, the patient’s pneumonia improved over the course of therapy. However, unfortunately, the patient began to experience other troubling symptoms, including upper abdominal pain, nausea, and dark-colored urine.

“I started feeling better right away with my pneumonia, but within about two weeks I started feeling more ill every day,” recalled Eric Barth. “It’s like what the fast-talking voice-over says in the commercials, ‘Be careful for a yellowing of the skin and eyes, as this can be the signs of a serious infection.’ It turns out, in my case, that’s what it was.”

Barth visited his primary care physician, and blood tests revealed that his liver values were high. According to Dr. Fontana, Barth was experiencing the hallmark symptoms of drug-induced liver injury (DILI). Research performed in Dr. Fontana’s clinic has revealed that azithromycin use, in a relatively small subset of patients, can lead to DILI. Indeed, it is one of a long list of drugs in the antimicrobial class associated with liver-related adverse events.

Barth was referred to Dr. Fontana and ultimately diagnosed with cholestatic hepatitis. He has been receiving treatment for the condi­tion, which is chronic, with an immunosuppressant for the past six years now, and his condition is in remission, Dr. Fontana said.

“It was clear Dr. Fontana had so much experience with my condi­tion, through his research and the liver injury network,” Barth said. “There was always a real sense of reassurance from him that I would get better. And that was a huge help in my recovery. It’s kind of cool to know, too, that my experience is informing the ongoing research.”

“The message here isn’t that people who need antibiotics like azithromycin shouldn’t take them because of the risks,” Dr. Fontana added. “These drugs have been proven safe and effective for the majority of patients. However, as physicians we should consider the possibility of liver damage in some patients and warn all patients of these risks. We should advise them of how to recognize the symptoms and what to do if they experience them.”


Long-needle biopsy has long been used for the diagnosis of cirrhosis and other liver diseases, although it is not without complications. This is an invasive procedure and takes several hours to perform. Patients can also experience pain and, in rare instances, bleeding following the procedure, the latter of which may require admission to the hospital for overnight observation.


Now, a new technology has the potential to make diagnosis of cirrhosis, chronic hepatitis C, and perhaps fatty liver disease easier for physicians and patients alike. The device is called FibroScan (Echosens), and the University of Michigan Health System is one of the few centers in the state to offer it.

“This is a simple, noninvasive procedure that enables us to assess the amount of scar tissue in the liver in a matter of minutes,” explained Dr. Fontana “It’s really a nice point-of-care test that allows us to get the information right there in the exam room.”

The FDA approved FibroScan for use in diagnostics in 2014. According to Dr. Fontana, the device is similar to an ultrasound system in that it uses radio frequency waves to capture a visual image of the surface of the liver. During assessment, which takes approximately five minutes, an ultrasound probe is positioned just beneath a patient’s right rib cage for approximately “10 gentle touches,” Dr. Fontana said.

“The liver is close to the surface of the skin, so effectively this device takes advantage of that,” said Dr. Fontana. “We can use it to get an accurate picture of the amount of scar tissue in the liver, or the stiff­ness of the liver.”

Dr. Fontana and his team are currently using FibroScan for the prelim­inary diagnosis of liver disease, and as a result are now performing biopsies on fewer patients, usually only to confirm a diagnosis. Physicians who suspect their patients may have liver disease can refer them directly to Dr. Fontana’s clinic for the test only—without them needing to be evaluated by clinic physicians beforehand.


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“Don’t forget about the possibility of a colorectal cancer diagnosis in young patients.” Elena Stoffel, MD

Clinicians should consider colorectal cancer as a possible diagnosis when a younger patient presents with symptoms of intestinal bleeding, anemia, or a change in bowel habits.

Research spearheaded at the University of Michigan Comprehensive Cancer Center (UMCCC) found that 10 percent of patients with colorectal cancer were under age 50, and young individuals were more likely to be diagnosed at advanced stages compared with older patients. The results that Samantha Hendren, MD, associate professor of surgery at the University of Michigan Medical School, and her team culled from the Surveillance, Epidemiology, and End Results (SEER) database and published in the journal Cancer (2016;122:929-934) suggest clinicians should consider colon cancer as a possible diagnosis when a patient presents with symptoms of intestinal bleeding, anemia, or a change in bowel habits.

“While colorectal cancer incidence is decreasing overall, thanks to routine screening in individuals age 50 and older, it’s on the rise in younger patients,” said Elena Stoffel, MD, assistant professor of internal medicine and a gastroenterologist at the UMCCC, who was not involved in the Cancer paper.

The SEER findings are important for gastroenterolo­gists and other clinicians to remember: “Don’t forget about the possibility of a colorectal cancer diagnosis in young patients,” she added. “It’s important to keep colon cancer on the radar rather than dismissing bleeding or other symptoms as hemorrhoids.”


Samantha Hendren, MD

The reasons for the increase in colorectal cancer cases among young people are unknown. Incidence is highest among blacks who develop tumors at younger ages, when compared with non-Hispanic whites. In a paper under review, Dr. Stoffel and her colleagues examined the SEER data on outcomes for colorectal cancer patients under 50, and found the survival rate for blacks was lower at every stage of the disease and partic­ularly striking among individuals with stage II cancers.

“While differences in treatment may play a role in racial disparities of outcomes, we have to consider there may be genetic factors that influence cancer risk and outcomes that haven’t been accounted for,” said Dr. Stoffel, who also runs the University of Michigan’s Cancer Genetics Clinic. “The current algorithms used for colorectal cancer risk assess­ment don’t account for race. So, we’re working to find a better way to assess people’s cancer risk.

“There’s also an observable trend that the rise in colon cancer in young people has tracked alongside the rise in obesity, but we haven’t identified specific mechanisms to explain how obesity might increase risk for polyps or colon cancer,” said Dr. Stoffel.

“There are a number of genetic conditions associated with inherited predisposition to colon cancer, including familial adenomatous polyposis, MYH-associated polyp­osis, and Lynch syndrome,” Dr. Stoffel said. “Individuals who carry germline mutations associated with hereditary cancer syndromes tend to develop colorectal polyps at young ages, so they should be screened early.”

It is important to remember that 70 percent of colorectal cancers occur in people with no known predisposition or obvious risk factors. Thus, there may be genetic and environmental components to colorectal cancer risk that researchers have yet to identify.

Lowering the recommended age for colorectal cancer screening for everyone is not the answer; however, University of Michigan researchers continue to research ways of identifying patients at higher risk who would benefit from early screening.


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“ I think most physicians right now are trying to manage diet by giving patients a sheet of paper with a list of foods to eliminate, and that’s simply inadequate.” —WILLIAM D. CHEY, MD

Successful management of irritable bowel syndrome (IBS) requires a comprehensive approach to care that combines the expertise of multiple health care professionals who specialize in dietary and behavioral counseling, in addition to medical treatments and pharmaceutical therapies.

“Over the last five years, we have identified and assembled the puzzle pieces that allow us to offer a more holistic approach to patients with IBS,” said William D. Chey, MD, who is a widely known expert on IBS.

That means thinking critically about how diet, lifestyle, and behavior might interact to bring about the symptoms of IBS. “We consider how we might offer interventions for each of those components of care to really maximize the benefit of medical treatments for patients with IBS,” he said.

“If you asked any of the gastroenterologists at the University of Michigan five years ago, diet and behavior would have been very low on their list of priorities,” Dr. Chey said. “Now, our gastroenterologists say they can’t imagine how we did it before we had these assets in place. It has really been a transformation in care over the past five years, and we’re extremely proud of that.”

Successful long-term management of IBS, it turns out, is a multidisciplinary affair.


For many patients, symptoms of IBS are triggered by what they eat, and increasingly, physicians are recognizing the critical role of diet in managing the symptoms of IBS. Unfortunately, few physicians are trained to provide nutri­tional counseling.

“The reality is most gastroenterologists receive little to no training in nutrition or the practical elements of adminis­tering diet therapies for patients with IBS,” Dr. Chey said.

Emerging evidence suggests diets free of gluten and diets low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols—commonly known as the low-FODMAP diet—can be beneficial for patients with IBS. The low-FODMAP diet, in particular, is a fairly complicated diet, Dr. Chey noted. Patients following this diet require the assistance of professional nutrition specialists.

“I think most physicians right now are trying to manage diet by giving patients a sheet of paper with a list of foods to eliminate, and that’s simply inadequate,” he said. “Diets are definitely more comprehensive and complicated than can be conveyed with a sheet of paper—even potentially dangerous if not administered in a medically responsible way.”

As a result, many diets do not work as well in clinical practice as evidence from clinical trials might suggest, he noted. In order to achieve similar results, diets need to be administered by experts who understand gastrointestinal (GI) nutrition and know how to help patients incorporate dietary changes into their daily routines, he said.

“One of the problems right now is there aren’t that many trained GI dietitians around. There are dietitians, but they’re not specially trained in gastroenterology,” Dr. Chey said.

“One of the things that needs to happen on a national level to improve the quality of care for patients with IBS is to train a population of dietitians that have expertise in GI disorders, and to have them work closely with gastroenterologists to administer dietary interventions in a medically responsible way,” he added.

This is just one of the many areas where the University of Michigan sets itself apart: the Division of Gastroenterology has the equivalent of four GI dietitians—two full-time GI dieti­tians at University Hospital and others who assist in caring for patients at offsite facilities that are part of the University of Michigan Health System.


Just as diet has come into focus as an essential aspect of treatment for IBS, so have behavior and lifestyle. The way in which an individual responds to stress can greatly affect symptoms of IBS.

“There are certainly some things that gastroenterologists can recom­mend to try to facilitate changes in lifestyle or behavior,” Dr. Chey said. For example, yoga or a regular exercise plan can be very helpful in managing stressors that can lead to the symptoms of IBS, he noted.

But as in the case of diet, many gastroenterologists are not trained to provide more advanced behavioral counseling to patients with IBS. For example, cognitive-behavioral therapy, hypnosis and interper­sonal psychotherapy can be very beneficial for patients with IBS. But these therapies require specialized training—even more specialized than many clinical psychologists are equipped to offer.


“Medications still play the really important role,” Dr. Chey noted.

Therapy for IBS is symptom-driven, depending on a patient’s needs. “For patients with mild or moderate IBS symptoms, sometimes all they need is a little bit of medication, such as an over-the-counter antidiarrheal or antispasmodic on an as-needed basis, and they’ll do just fine. Patients with more severe IBS symptoms will almost always need one or more medications,” Dr. Chey said.

Notably, Dr. Chey’s group has been involved in some capacity in the research that led to the FDA approval of all five prescription drugs indicated for the treatment of IBS in the United States.

Because of its dedication to research, patients at the University of Michigan have the opportunity to participate in ongoing IBS clin­ical trials, such as those involving the low-FODMAP diet and an upcoming trial of prebiotics in patients with IBS.

Building on this foundation in GI nutrition and behavioral therapy, a new effort—the Digestive Disorders Nutrition and Lifestyle Program—will bring together the diverse elements necessary to provide support in nutrition and behavior, as well as “vertically inte­grate research from the bench to the bedside,” Dr. Chey said. “So we’re not only providing excellent quality of care for patients, we’re also striving to make discoveries that will transform the role of diet and behavior and how they interact with medications to maximize benefit for patients with IBS and other functional disorders.”


The University of Michigan offers patients with GI disorders an opportunity to address symp­toms with a specially trained GI psychologist.

Megan Riehl, PsyD, is a clin­ical health psychologist at the University of Michigan, and the state’s only psychologist with a specific focus on GI disorders. IBS is the most common GI illness that brings patients to her clinic. “About 65 percent of patients present with IBS or a functional bowel disorder,” she said.

Megan Riehl, PsyD

Typically, patients are referred to Dr. Riehl by a gastro­enterologist who may have exhausted medical treatment options and/or believes a patient would benefit from stress and anxiety management techniques. Increasingly, behavioral therapy is becoming routine in the treatment of patients with IBS. “As more patients become aware of the GI behavioral health service, more of them are asking their gastroenterologists for a referral to the program,” Dr. Riehl said.

Behavioral therapy is personalized for each patient, but in general, therapy is designed to help patients deal with the “uncontrollable” and “unpredict­able” aspects of IBS. Patients learn relaxation and stress management techniques they can apply to everyday life stressors.

“My goal is to help patients learn to cope effec­tively and efficiently with worries that can interfere with social, occupational, and family life,” Dr. Riehl said.


Most often, behavioral therapy for patients with IBS involves interventions based on cognitive-behavioral therapy (CBT), a short-term, collaborative treatment that is focused on a patient’s current problems.

“CBT involves helping patients find new ways of thinking and behaving to help in managing stressful situations,” Dr. Riehl explained. For example, patients with IBS may experience anxiety-provoking thoughts such as, “Where will a bathroom be if I need it?”, “What if I’m having symptoms before a big exam or presentation?”, or “How will I ever be intimate with a partner?” CBT teaches patients how to manage emotional responses to these potentially stress-inducing situations.

“My goal is to aid patients in self-management strategies that benefit GI health, emotional well-being, and overall quality of life,” Dr. Riehl said. “People learn tools to create long-term change, without remaining in treat­ment for long periods of time. It’s very rewarding.”


The Division of Gastroenterology at the University of Michigan emphasizes a holistic approach to IBS treatment that incorporates modifications in diet, behavior, and lifestyle in the management of symptoms of IBS.

When a diagnosis of IBS has been confirmed, consider the following approaches to treatment:

  • Are symptoms triggered or exacerbated by diet? Consider a referral to a dietitian with specialized training in the treatment of GI disorders.
  • Are symptoms triggered or exacerbated by stress or a mood disorder? Consider a referral to a behavioral therapist with specialized training in the treatment of GI disorders.
  • How frequent and severe are symptoms? Are symptoms comprised mainly of diarrhea, constipation, or both? Consider using medi­cations that target the relevant symptoms in combination with strategies that address diet, lifestyle, and behavior.
  • Are symptoms severe and/or medically refrac­tory? Consider a referral to a tertiary referral center.


Morgan Blenkhorn missed high school several times because of symptoms that doctors said were related to irritable bowel syndrome (IBS).

“Anything I would eat, I would get sick,” she said. “I was nauseous; I would have headaches, stomachaches; I had diarrhea and I was just ill all day, every day.”

Morgan’s symptoms started a few months after a severe food poisoning incident in 2010 during her junior year of high school. She endured pain, particularly while dancing and playing soccer. She eventually turned to apples and honey for relief, but they only made her symptoms worse.

“It was really hard having to come home from school being sick all the time, waking up sick, and trying to go to school and act like everything was fine,” she said.


Over the next three years, several doctors told her she was exhibiting IBS symptoms and gave her probiotics for treat­ment. But a chance meeting on an airplane between her father and gastroenterologist William Chey, MD, would lead to a series of interviews, tests, and a final diagnosis from the University of Michigan’s gastroenterology and dietitian team.

Her first visit to the University of Michigan was in 2013, during the fall of her sophomore year of college. She had several blood tests done before meeting with Dr. Chey. Upon her first appointment with him, she was promptly told what to expect: a fructose test, a lactose test, more blood tests, and an endoscopy.

According to Morgan, Dr. Chey went above and beyond preliminary tests to find the root of the problem. The test that changed it all, she said, was the fructose test, which consisted of a fructose mixture, water, and a breath test. A few weeks after her appointment, Dr. Chey spoke with Morgan and her family and told them the diagnosis: fructose intolerance.

“We all cried,” Morgan said.


This experience was unlike any other for Morgan. The team’s gastroenterologists were briefed on her case and knew exactly how to address her issues. The dietitian they referred her to mapped out a zero-fructose eating plan that catered to her vegetarian diet and her love for veggies, pasta, and curry.

“They listened to my specific wants, not just me as a patient but me as Morgan,” she said.

After being diagnosed with fructose intolerance, Morgan now plans out her own meals and has full control of her symptoms. She continues to dance and play sports. Last summer, she was even able to study abroad in the Netherlands.

“It was beautiful, life-changing, something I didn’t think I’d ever be able to do before because I couldn’t sit in a car for two hours without having to pull over,” she said. “Biking 10 miles to work and backpacking alone through Germany was something I thought I’d never be able to do because I was so sick.”

Morgan is finishing up her fourth year at Grand Valley State University in Allendale, Mich., with another year left to complete her special education degree. She still checks in with Dr. Chey every once in a while. For now, she hopes to be accepted into Grand Valley’s Consortium for Overseas Student Teaching program in Ireland this summer.


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Patients with severe defecation disorders or pelvic floor dysfunctions require care spanning multiple medical specialties, which is why the Michigan Bowel Control Program (MBCP) exists.

Dee Fenner, MD

“There are very few programs nationally that allow patients to get a comprehensive and integrated care plan from people who—we like to believe—are national experts in the care of patients with severe constipation and fecal incontinence,” said William D. Chey, MD, Director of Medical Services at MBCP and Timothy T. Nostrant professor of gastroenterology and the University of Michigan.

“In 2005, when we started this program, gastroenterologists, urogynecologists, and colorectal surgeons were all completely siloed,” Dr. Chey explained.

Over a decade ago, Dr. Chey, Dr. Fenner, and Emina Huang, MD, then a colorectal surgeon at the University of Michigan, established MBCP, with the vision of providing truly multidisciplinary patient care. “We thought we could do things a whole lot better if we saw patients together and developed integrated care plans.” Dr. Chey said.

Chronic Conditions Require Dedicated Follow-Up

If the success of their original idea can be measured by the growth of the program, then consider the team members visionaries.

Using a model of the pelvis, Dr. Fenner, with Anne Mcleod, helps a patient understand the relationship between constipation and pelvic organ prolapse.

“The first year we saw about 50 new patient referrals, and they were almost all from within the university,” Dr. Chey recalled. “Last year we saw over 500 new patient referrals, and we continue to grow on an annual basis.” The word is definitely out about the excellence of the program with some patients traveling thousands of miles to be treated at MBCP.

“A key message we stress to patients is that these are chronic conditions” Dr. Fenner noted. “Patients need to think about them as they would other chronic conditions, such as diabetes. The key is that we maintain contact; we don’t just send the patient out and then have them come back 3 months later,” Dr. Fenner said. Key to the program’s success is its careful attention to follow-up care. MBCP has a dedicated nurse concierge team that assists in the implementation of care plans, shepherds patients through their journey at MBCP, and provides follow-up care that is essential to positive patient outcomes.

Continuing Research

Dr. Chey cited innovative research as another feature that sets MBCP apart from other programs. For example, Dr. Fenner played an integral role in clinical trials of the novel TOPAS (Astora Women’s Health) minimally invasive surgical procedure that is under evaluation for fecal incon­tinence in women. Additionally, her team has just begun using an FDA-approved modification of the Eclipse System (Pelvalon).

Dr. Chey, along with University of Michigan gastroenterologist Stacy Menees, MD, is currently leading a randomized controlled trial comparing dietary fiber supplemen­tation with a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for the treatment of fecal incontinence. He also has designed a glove-based manometry system, for which he holds a patent, that is being tested in clinical trials as a low-cost alternative to anorectal manometry for the evaluation of anal sphincter function. “At MBCP, we’re trying to grow beyond providing excellent care,” Dr. Chey said. “We’re trying to learn from the care we deliver, to create novel ways of understanding why patients suffer from the symptoms that they do, and to improve upon the excellent care we are currently able to deliver.


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Clinicians at the University of Michigan Frankel Cardiovascular Center say their refined processes have optimized aortic stenosis treatment, shortened the time between referral and surgery, and led to excellent outcomes.

According to G. Michael Deeb, MD, who is Herbert Sloan Collegiate Professor of Cardiac Surgery and Director of the Multidisciplinary Aortic Clinic at the Frankel Cardiovascular Center, aortic stenosis patients are treated by a team of cardiovascular surgeons, cardiologists and a host of other subspecialists who collaboratively choose the most appropriate treatment, whether it be open surgery or transcatheter aortic valve replacement (TAVR).

“The Centers for Medicare & Medicaid Services have guidelines that specify these surgeries should be joint efforts by interventional cardiologists and cardiac surgeons, but we’ve taken that model several steps further,” said Dr. Deeb.

A Team Approach

Above: Stanley Chetcuti, MD; Himanshu Patel, MD; P. Michael Grossman, MD; G. Michael Deeb, MD; Matthew Romano, MD; and Daniel Stephen Menees, MD

Each Tuesday, subspecialists at the Frankel Cardiovascular Center meet and review upcoming valve replacement patients. They discuss topics ranging from the physiology of aortic stenosis to the ethics of performing a particular procedure in a patient, and then determine the most suitable treatment for a given patient.

“The team includes three interventional cardiologists; four cardiac surgeons; imaging physicians who help us decide which size valve to use and where to position it; and research coordinators,” Dr. Deeb explained. “We decide whether patients qualify for TAVR, open surgery, if they are a good fit for one of our clinical trials or if they are too sick to undergo a procedure at all.”

According to Stanley J. Chetcuti, MD, who is Eric J. Topol Collegiate Professor of Cardiovascular Medicine and Associate Professor of Internal Medicine at the university, the devices used for TAVR are “constantly evolving, and we have access to the most sophisticated and effective valves.”

The two most frequently used commercial valves at the University of Michigan are Medtronic’s Evolut R and Edwards Lifesciences’ SAPIEN 3, both of which reduce the risk for valvular leakage, Dr. Chetcuti said. The Evolut R is repositionable, allowing clinicians to place the valve, release it up to 90%, determine if there is a leak and then either fully release the valve or reposition it in another location if necessary.

“If we need to, we repeat this process until we find a good position,” said Dr. Chetcuti.

The SAPIEN 3, on the other hand, reduces the risk for leakage by placing a skirt around the valve to tightly seal the edges, Dr. Chetcuti explained.

Ongoing Clinical Trials

Dr. Chetcuti added that the team is also participating in several studies, most of which involve randomization of patients to open surgery or a TAVR device.

CIC_Feb_deeb3“Right now, we’re completing two trials for patients at moderate risk of mortality with surgery,” said Dr. Chetcuti. “We’re also excited to be studying Boston Scientific’s Lotus Valve, which is a self-adjusting, repositionable and retrievable valve. Further, we anticipate an upcoming study with a larger-diameter version of the Evolut R, which would allow us to treat an additional 10% of patients with aortic stenosis who would otherwise have anatomy too large to qualify for TAVR.”

The university closely tracks patient outcomes, logging clinical, demographic, procedural and follow-up information from each procedure into separate national and state registries.

“Our outcomes from 2014 were very encouraging,” noted Dr. Chetcuti, who anticipated the team will have conducted more than 600 TAVR procedures by the end of 2015. “In fact, our outcomes with the Medtronic CoreValve and the Edwards SAPIEN 3 were better than the data from other pivotal studies. Our model is clearly working in our patients’ favor.”


Recently, an important option for heart valve implantation has been approved, and is already available at the University of Michigan (U-M) Frankel Cardiovascular Center.

The SAPIEN XT (Edwards Lifesciences) transcatheter heart valve allows for minimally invasive aortic valve-in-valve procedures, which offers an important option for the patient whose previously implanted but compromised prosthetic valve needs to be replaced, but who wishes to avoid open surgery.

There is a large population of patients whose prosthetic valves await replacement. Many patients with congenital heart diseases whose bicuspid valves were replaced with prosthetic valves will require numerous procedures through the years as their implanted valves become compromised. These repeated cardiac surgeries are associated with significant morbidity and mortality.

In the valve-in-valve procedure, the new valve is tightly placed within the failing bioprosthetic valve. Although the procedure has been approved, it had been performed selectively at U-M several times; thus, expertise in this complex approach is already available.

The PARTNER II (Placement of AoRTic TraNscathetER Valves) trial found an overall one-year survival rate of 86.6% and a stroke rate of 3.7% in a 197-patient, multicenter study of this high-risk population. Survival at 30 days was 100%.

Sapien 3

High-risk and inoperable patients underwent TAVR and received the Edwards Sapien 3 aortic valve. Most patients were more than 80 years old and underwent transfemoral TAVR.

One-year survival rate: 85.6%
Disabling stroke rate after one year: 2.4%*
Patients with severe paravalvular leak: 0
* Although 2.7% had moderate paravalvular leak, this type of leak was not associated with increased risks for death, clinical valve thrombosis or structural valve deterioration.

Evolut R

Another study of 60 patients who underwent TAVR and received the Evolut R valve showed similar survival rates at one year. Patients in this multicenter international study were considered to be at high or extreme risk for mortality with surgery.

6-month survival rate: 95%
One-year survival rate: 93.3%
One-year stroke rate: 3.4%


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Left to right: Keith Aaronson, MD, Todd Koelling, MD, Francis Pagani, MD, PhD

In recent years, the University of Michigan Frankel Cardiovascular Center has played a key role in a flurry of research in how to conquer heart failure. A number of ongoing studies at the university hope to add to available treatment options.

“The EXPAND trial is probably the most important trial we have ongoing now. It might transform the way we do heart transplantation in this country,” said Francis Pagani, MD, PhD, a cardiac surgeon at the Frankel Cardiovascular Center.

“We are one of 12 centers participating in EXPAND,” he said. The trial is evaluating a new portable organ care system that perfuses the heart with oxygen and nutrients and keeps a donor heart functioning at normal body temperature while it is transported to a recipient. The trial is testing whether this method of maintaining the donor organ is superior to the current method of storing the heart on ice.


The MOMENTUM III trial, ongoing at 60 centers in the United States, is evaluating a new left ventricular  assist device (LVAD) called HeartMate 3 (Thoratec). This implantable device circulates blood throughout the body when the heart is too weak to pump blood adequately on its own. Patients must have advanced heart failure that is refractory to current treatment to be eligible for the study. So far, 200 patients have been enrolled in the trial at the Frankel Cardiovascular Center.

The SynCardia Total Artificial Heart 50-cc trial is testing a smaller total artificial heart for use in women and smaller men. “One of the limitations with artificial heart technology is that it is so large it only fits in large-bodied people,” said Dr. Pagani, speaking about the 70-cc total artificial heart. “The 50-cc size of this model makes it more suitable for smaller-bodied individuals.”

The Cardiothoracic Surgical Trials Network Cell Therapy LVAD Trial II is examining whether injecting allogeneic stem cells into the heart during implantation of an LVAD can improve long-term myocardial function. “This is a significant trial that could give us important insights into the potential for stem cells to improve heart function in patients with advanced heart failure,” said Dr. Pagani.

Heart Failure Studies and Support

Scott Hummel, MD, MS

Scott Hummel, MD, MS, a cardiologist at the Frankel Cardiovascular Center, said his main area of interest is “diastolic” or “preserved ejection fraction” heart failure (HFpEF). “There are no broad evidence-based therapies for HFpEF yet, but we use exercise testing, imaging and sometimes catheterization to phenotype patients and direct treatment to the underlying mechanisms,” said Dr. Hummel. “We also lead several clinical studies that are looking at the importance of dietary modifications.”

For example, the DASH-DHF 2 (Dietary Approaches to Stop Hypertension in ‘Diastolic’ Heart Failure 2) study is investigating how recommended dietary changes affect heart and blood vessel function in patients with hypertensive HFpEF.


Patient Management and Referral

In addition to the expertise of heart failure specialist physicians, nurse practitioners and physician assistants, patients benefit from a team of nurse case managers whose sole responsibility is to manage patients with heart failure. “We are studying the best methods for CIC_Feb-photo2patient telemonitoring across the spectrum of heart failure, including patients with LVADs,” said Dr. Hummel.

Dr. Hummel said the Frankel Cardiovascular Center welcomes referrals from and collaboration with other practices. Referring physicians should consult the suggested guidelines for referral of advanced heart failure patients. See table.

“One of the biggest challenges that can happen is when someone is referred too late, when other organs in the body are failing besides the heart,” said Dr. Hummel. “Getting involved in a patient’s care when he or she is not yet critically ill is the best time to have conversations about what treatments are available.”

New Drugs Offer New Options

In the past year, two new drugs have been approved for heart failure. Ivabradine (Corlanor, Amgen) was approved for patients:

  • who have stable, symptomatic chronic heart failure with a left ventricular ejection fraction of 35% or less;
  • who are also in sinus rhythm with a resting heart rate of at least 70 beats per minute; and
  • who either are on maximally tolerated doses of β-blockers or have a contraindication to β blocker use.

Sacubitril-valsartan (Entresto, Novartis) was approved for the treatment of chronic heart failure with reduced ejection fraction. The drug is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker already used to treat heart failure.

“In a large clinical trial, Entresto was compared to an angiotensin-converting enzyme inhibitor and found to reduce cardiovascular death and heart failure hospitalization by 20%. The results are undeniably impressive, and the drug may have a big impact on our patients,” said Scott Hummel, MD, MS. He said one challenge for clinicians is determining whether to use sacubitril-valsartan in patients who don’t meet the enrollment criteria that were used in the clinical trial, for example, those with low blood pressure or more than moderate chronic kidney disease.




“I have a good life right now, and the LVAD keeps me there – it keeps me happy.”

After a heart attack at 41 years of age and an eventual diagnosis of heart failure, David Pierce underwent implantation in 2004 of a left ventricular assist device (LVAD),  at the age of 52.  Today, he is the long living recipient of a HeartMate II LVAD in the entire United States.

Before receiving an LVAD, David had difficulty negotiating stairs, and a favored pastime, dancing with his wife, was becoming a thing of the past “I couldn’t walk more than 15 feet without stopping,” he said. “I had zero stamina—none whatsoever.”

He was very concerned about what doctors could do for him as his disease progressed, and was worried about what would happen to his wife and whether he would be able to watch his grandkids grow up. At first, upon hearing about the option of LVAD implantation, Mr. Pierce was not enthusiastic, struggling with the notion of having the medical device implanted in him. But as he discussed it with his doctors he gradually realized that this was his one option, the only way he could stay alive.

As Mr. Pierce’s condition inexorably worsened, he was referred for implantation to Francis D. Pagani, MD, PhD, the director of U-M’s Center for Circulatory Support.

Patients approved for LVAD  implantation suffer not only from a steadily deteriorating disease state but also a greatly reduced quality of life. LVAD implantation is a game changer for many of these patients, as it can suddenly improve a patient’s quality of life and immediately heighten his or her chances for survival.

The U-M Frankel Cardiovascular Center’s LVAD program has successfully implanted about 600 of these devices, amassing extensive, vital experience in the procedure.

Mr. Pierce’s health sharply improved after implantation of the LVAD device.  His wife noted that, on the morning of surgery, “David went in with cold feet and came out with warm feet, and a new outlook on life. He was so nice and warm, which he hadn’t been in a long time.”

He spent a week or two in the ICU, and with multiple lines hooked up to him he thought the experience was difficult at the time. He now looks back on those days as not being as onerous as he imagined, and realizes that the operation he had back then has set up years of enjoying a life that had been slipping away from him.

Commonly among heart patients, Mr. Pierce suffered from some depression around this time, but worked with a psychologist to regain perspective, a process he recommends for others. “It’s helped me immensely.”

He is still waiting for a heart, but he can accept living the rest of his life with the LVAD if necessary since he is satisfied with its performance and is used to it. “I have a good life right now, and [the LVAD] keeps me there … it keeps me happy.”

The U-M’s LVAD team can be reached at 800-962-3555.




Electrophysiology Treatment for Arrhythmia

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There is a bidirectional relationship between research and clinical care. Research at the highest level helps improve outcomes, while challenges faced in clinical care raise the next questions that will advance treatment options.CIC_Feb_AF2

The electrophysiology (EP) lab at the University of Michigan Frankel Cardiovascular Center is one of the preeminent facilities for EP in the United States. “

We have been a pioneer and leader for many of the techniques that have improved outcomes in patients with complex and difficult-to-treat arrhythmias, with a comprehensive focus on the patient, and we have had excellent outcomes,” said Hakan Oral, MD, director of Cardiac Electrophysiology.


Whether patients are referred for atrial fibrillation (AF), paroxysmal supraventricular tachycardia, Wolff-Parkinson-White (WPW) syndrome, life-threatening ventricular arrhythmias or for cardiac implantable devices such as ICDs, pacemakers, cardiac resynchronization therapy or other devices for prevention of stroke in patients with AF, the Cardiac Arrhythmia Service at the Frankel Cardiovascular Center is well prepared to offer optimal therapeutic options.

For AF, the Cardiac Arrhythmia Service has been one of the pioneers and a leader in ablation of AF and other arrhythmias—specifically ventricular arrhythmias—and has helped to move the field forward. “AF, and ventricular arrhythmias in general, has been a rapidly expanding field, and it is important for the clinicians who first see these patients to understand there are advanced treatment options,” said Dr. Oral. “There are many opportunities to help these patients.”


The Cardiac Arrhythmia Service has nine faculty clinical cardiac electrophysiologists with substantial expertise and experience in their CIC_Feb_teamfields, both in clinical care and research. Drs. Fred Morady, Frank Bogun, Aman Chugh, Frank Pelosi, Thomas Crawford, Rakesh Latchamsetty, Hamid Ghanbari, Ryan Cunnane and Oral have collectively contributed more than 500 peer-reviewed studies in advancing the field of electrophysiology over the last decades.

In addition to its faculty, a major strength of the Cardiac Arrhythmia Service is the dedicated team of nurse practitioners, physician assistants, nurses, technologists and staff who help to deliver ideal patient experiences and play a critical role in this clinical mission.


AF is the most common sustained arrhythmia, with surging incidence and prevalence rates over the past two decades. This increase has been particularly steep in the United States, which has one of the highest incidence rates on a per-capita basis in the world. AF places patients at increased risk for thromboembolic events, stroke, heart failure and death.


Hakan Oral, MD

“ It is important for the clinicians who first see these patients to understand that there are advanced treatment options. The most important is proper and timely identification of the patients who may benefit from more advanced specialized diagnostic and treatment options.”

—Hakan Oral, MD



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The correlation between volume of mitral valve repairs performed each year and the success rate of those repairs has been demonstrated repeatedly in published studies. That’s important since very few centers in the United States come anywhere near the CIC_Feb_Mvalvevolume of mitral valve repairs performed by cardiac surgeons at the University of Michigan Frankel Cardiovascular Center.

“Mitral valve regurgitation is a disease you can often cure. If a repair can be performed, the life expectancy of the patient can be restored to what it would have been in the absence of regurgitation,” explained Steven F. Bolling, MD, professor of cardiac surgery and director of the Multidisciplinary Mitral Valve Clinic at the Frankel Cardiovascular Center.

In hospitals that are not equipped to offer repair, the default treatment is often a prosthetic valve, whether mechanical or created from animal tissue. For patients who otherwise have an extended expected survival, the data are clear.


“Bioprosthetic valves fail over time. In eight to 10 years, the patient will need a replacement, which introduces additional costs as well as risks. In good candidates, repair will eliminate mitral valve regurgitation as a cause of cardiovascular dysfunction,” said Dr. Bolling, who is one of the preeminent experts in this field. Indeed, Dr. Bolling is one of only three cardiac surgeons in the United States who perform more than 100 cases of mitral valve repair annually.

It has been estimated that 175 mitral valve repairs are required before cardiac surgeons achieve an optimal level of skill, yet few cardiac surgeons perform this many cases in their lifetime. Indeed, most do only a few cases per year. At the Frankel Cardiovascular Center, where Dr. Bolling is one of several cardiac surgeons performing a high volume of mitral valve repairs, the success rate now exceeds 99%. By contrast, surveys show that surgeons who do not do a high rate of these procedures have lower success rates (Ann Thorac Surg 2010;90[6]:1904-1911).


While early referral is key for best outcomes, not every patient with mitral valve regurgitation is a candidate for repair. In some, a prosthesis may be the best option, particularly for those with a limited life span who have significant deterioration of the mitral valve, rheumatic disease or possibly some ischemic-related causes of mitral valve regurgitation. In others, newer options can be considered. Many of these innovations are being developed or tested at the Frankel Cardiovascular Center through clinical trials.

“We are not just specialists in repair. Our strength is that we are skilled with the full spectrum of options so we can individualize therapy,” Dr. Bolling said.


Steven F. Bolling, MD

“ The data suggest that volume is perhaps the single most important factor for determining success, and we manage thousands of patients with mitral valve disease.”
—Steven F. Bolling, MD

“ Physicians who detect or suspect mitral valve regurgitation should send their patients for evaluation before there is significant deterioration. In addition, repairs will improve quality of life in a symptomatic patient, so there is no value in waiting.”
—Steven F. Bolling, MD