RESEARCH UNCOVERS CAUSES OF DRUG-INDUCED LIVER INJURY

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.

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