Daily Archives: July 29, 2016

IMAGING TECHNOLOGY AND MOLECULAR PROBES ADVANCE GASTROINTESTINAL THERAPY

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New developments in imaging tech­nology have enabled physicians to identify cancer in its earliest manifes­tations, which is critical for treatment. In addition, a more thorough under­standing of the numerous molecular pathways involved in tumor cell proliferation has allowed physicians to adopt a personalized approach with targeted cancer therapies.

Thomas D. Wang, MD, PhD, associate professor of internal medicine, biomedical engineering and mechanical engineering, and H. Marvin Pollard collegiate professor of endoscopy research at the University of Michigan Health System, is devel­oping very specific molecular probes to be used in conjunction with new optical imaging to identify precancerous lesions in the gastrointestinal tract.

Dr. Wang, Xiyu Duan and Gaoming Li, pictured left to right, work with a laser as part of Dr. Wang’s research.

“We are currently developing peptides that bind to molecular targets expressed in diseases of the biliary tract, colon, esophagus, and liver,” said Dr. Wang, a gastroenterologist whose research has centered on molecular imaging.

PEPTIDE-BASED PROBES

Although most existing targeted cancer thera­pies are based on monoclonal antibodies that attach to target proteins on the exterior of cancer cells, Dr. Wang is concentrating on peptide-based compounds that are considerably smaller.

“These peptide-based probes provide an attrac­tive alternative for visualizing tissue targets that would otherwise be difficult to penetrate or access,” Dr. Wang said. “This work alters current diagnostic paradigms because diagnoses can now be made based on microscopic increases in the expression of molecular targets specific to certain diseases rather than on the gross visible appear­ance of mass lesions.”

Peptides also are safe for systemic use and are less immunogenic than antibodies. Additionally, peptides can be transformed anatomically to increase stability against proteolytic degradation and can be labeled with fluorophores that will permit imaging several targets at the same time.

Dr. Wang is part of a collaboration that is respon­sible for “developing novel molecular imaging methodologies to visualize cell surface targets that are either gene amplified and/or highly overexpressed in EAC [esophageal adenocarci­noma],” as compared with Barrett’s esophagus. These cell surfaces will be seen using “highly specific peptides that are fluorescently labeled for real-time endoscopic imaging to rapidly assess esophageal mucosa” for the existence of early neoplasia.

Dr. Wang hopes that with additional research and development of peptide-based probes for molec­ular imaging, physicians will have a more precise representation of cellular and molecular activities in all areas of the GI tract.

“We have developed novel molecular probes that bind to cell surface targets that are overexpressed in a number of human diseases,” he said. “I expect to find new uses for these molecular probes to detect diseases beyond their original purpose for development.”

RESEARCH FOCUSES ON GENETIC DIAGNOSTIC AND THERAPEUTIC APPROACHES TO NAFLD

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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.

NAFLD AND OBESITY GENES DIFFER

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.”

STRATEGIES EMERGE FOR PREVENTING POST-ERCP PANCREATITIS

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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.

INDOMETHACIN AND PANCREATIC DUCT STENTS

“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.”

RESEARCH UNCOVERS CAUSES OF DRUG-INDUCED LIVER INJURY

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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.”

RARE BUT SIGNIFICANT

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.”

ALSO SUSPECT: SUPPLEMENTS

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.”

ALSO SUSPECT: SUPPLEMENTS

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.”

ERIC’S STORY

A CASE OF DRUG-INDUCED LIVER DAMAGE

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.”

NOVEL TECHNOLOGY ENABLES LESS INVASIVE DIAGNOSTIC APPROACH

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.

FibroScan®

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.