Drug-related IBD, hepatotoxicity at DDW

Drugs, supplements linked with GI disorders

Focus on GI disorders

In late May, nearly 16,000 clinicians, researchers, and physicians learned about the latest advances in gastroenterology at (DDW). The annual meeting is cosponsored by four organizations: the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract. Key highlights from the meeting that focus on research related to pharmaceuticals and gastrointestinal (GI) disorders are presented in this article.

IBD: Drug-related?

Hamed Khalili, MD, gastroenterology fellow at Massachusetts General Hospital, conducted two studies that assessed the association between use of hormone replacement therapy or oral contraceptives and the development of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn disease. In the first study, Khalili and colleagues analyzed data collected from the Nurses’ Health Study I, which included questionnaire information from more than 100,000 nurses spanning 17 years. The investigators focused their analysis on older postmenopausal women who used hormone replacement therapy. They noted that hormone replacement therapy was associated with a 70% increase in the risk of ulcerative colitis, but no association was found between this type of therapy and Crohn disease. In addition, the risk of ulcerative colitis was noted to increase as the duration of therapy increased.

“The major implication of our study is we now know that estrogen-related pathways play a role in the development of ulcerative colitis, which may have significant consequences for treatment,” said Khalili in a DDW news release. He noted that estrogen receptors are found in the colon and the use of oral estrogen therapy has been associated with alterations in colonic permeability, a process that may be involved in the pathology of ulcerative colitis. He cautioned against concluding that women should not use hormone replacement therapy because of this finding, adding that “while the risk is real, the impact on one’s absolute risk of developing ulcerative colitis is small.”

In the second study, Khalili and colleagues assessed the association between reproductive factors such as use of oral contraceptives, pregnancy, age at first child, total number of ovulatory years, and age at menarche and the risk of ulcerative colitis and Crohn disease. The investigators used data from two large prospective cohorts, the Nurses’ Health Study I and II, which included data from more than 230,000 nurses who were followed for more than 30 years.

The analysis revealed that the use of oral contraceptives was associated with a nearly threefold increased risk in the development of Crohn disease, but no association was noted for ulcerative colitis. In addition, no other reproductive factors were associated with the development of either condition.

Commenting on the implications of these findings, Khalili noted that prescribers may consider providing alternative forms of contraception to patients who have a strong family history of Crohn disease, as this may decrease their likelihood of developing the disease in the future.

IBD drug exposure and pregnancy outcomes

Results from a prospective study assessing the safety of medications used in the management of IBD in pregnant women were presented by Uma Mahadevan, MD, Associate Professor of Medicine and Co-Medical Director at the University of California, San Francisco, Center for Colitis and Crohn’s Disease. A total of 1,100 pregnant women were enrolled from 30 IBD centers around the United States and followed throughout their pregnancy and for 12 months postpartum to determine whether fetal complication rates were higher among women exposed to various IBD medications compared with those who were not exposed.

The patients were divided into four groups: those unexposed, those exposed to azathioprine or 6-mercaptopurine (i.e., thiopurines), those exposed to anti–tumor necrosis factor (TNF) agents, and those exposed to both thiopurines and anti-TNF agents. Fetal complications including spontaneous abortions, congenital abnormalities, preterm birth, intrauterine growth retardation, cesarean section, and neonatal intensive care unit stays were assessed.

The investigators identified 33 spontaneous abortions and 37 infants who were born with congenital anomalies; however, no association was found between the use of thiopurines or anti-TNF agents and any fetal complications. The investigators noted that 72% of newborns were breastfed and that breastfeeding was not associated within an increase in the risk of infections in the newborn. At 12 months of age, however, infants exposed to combination therapy had a significantly greater number of infections compared with the unexposed group (relative risk 1.50 [95% CI 1.08–2.09]).

“We can continue biologic medications in pregnant women, thereby keeping them in remission, which not only reduces complications from disease activity, but also allows them to take better care of their newborn,” said Mahadevan in a written statement. She also noted that biologics are used to treat a variety of other conditions in women of childbearing age, such as rheumatoid arthritis and dermatologic conditions, and many patients need to continue these therapies during pregnancy to maintain their quality of life. Mahadevan plans to follow the infants for an additional 3 years to assess further effects on developmental milestones.

Golimumab for ulcerative colitis

The efficacy and safety of subcutaneously administered golimumab (Simponi—Janssen) for the management of ulcerative colitis were evaluated by William J. Sandborn, MD, Professor of Clinical Medicine at the University of California, San Diego, and colleagues. The investigators conducted a Phase II/III randomized, placebo-controlled, double-blind study of approximately 1,000 adult patients with moderate to severe ulcerative colitis. Patients eligible for the trial included those who had an inadequate response to conventional ulcerative colitis therapies and were not exposed to any anti-TNF therapies in the past. Patients were randomized to one of three treatment groups for 6 weeks: golimumab 50–100 mg, golimumab 100–200 mg, or placebo.

At week 6, patients given golimumab had a significantly better response than the placebo group in terms of clinical response, clinical remission, mucosal healing, and improved quality of life. Sandborn commented that these findings were noteworthy because there are minimal treatment options for the management of moderate to severe ulcerative colitis in patients who have an inadequate response to conventional ulcerative colitis therapies. In addition, he noted that only one biologic, infliximab (Remicade—Janssen), is currently approved for ulcerative colitis in the United States.

“These findings … demonstrate the usefulness of golimumab to rapidly control symptoms and induce significant and meaningful clinical benefit,” Sandborn explained in a statement. Golimumab is currently approved by FDA for the management of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Inappropriate acetaminophen use still real concern

New research from Jesse Civan, MD, a gastrointestinal fellow with the Division of Gastroenterology at the Thomas Jefferson University Hospital, shows that acetaminophen administered in doses exceeding 4 g/d is still common in hospitalized patients. Civan and colleagues reviewed hospital admission data for more than 46,000 patients over a 2-year period and identified records for about 1,100 patients who received more than 4 g of acetaminophen in a 24-hour period.

The investigators also assessed whether patients had any signs of a liver injury or reduction in liver function by reviewing alanine aminotransferase levels when available. Only a small number of patients had this test performed, however, so no formal analysis could be conducted.

The research showed that more patient education is needed regarding the safe daily dosage of acetaminophen since many patients will continue medications administered in the hospital once at home, noted Civan. In addition, patients receiving acetaminophen-containing products need to be monitored closely to ensure that every dose is accounted for and that they do not exceed recommended maximum daily limits.

Hepatotoxicity and dietary supplements

New research from the U.S. Drug-Induced Liver Injury Network (DILIN) found that dietary supplements used for body building and weight loss were most commonly associated with hepatotoxicity. DILIN researchers analyzed about 100 cases of liver damage suspected to be caused by dietary supplements. Most cases were in white, overweight males who were using various products for body building or weight loss.

“There is so little regulation of the many products on the market; we couldn’t possibly begin to figure out which products to target without doing this research,” said Victor J. Navarro, MD, an investigator participating in the DILIN study, in a statement from DDW. Now that a subset of products has been identified, he noted, future research will be targeted to determine which components of these products are potentially hepatotoxic.

For example, green tea extract has been identified as hepatotoxic if given in high doses. The problem, Navarro pointed out, is that up to 40% of products may contain green tea extract without the ingredient being listed on the label. This makes it more difficult to determine an association between ingredients of green tea and liver toxicity unless a careful analysis of each individual product is performed.

For now, DILIN is working with FDA to pinpoint various contaminants in dietary supplements and identify those currently on the market that are most harmful. Patients should be reminded that dietary supplements are not regulated and that some may be dangerous, resulting in serious adverse events such as liver toxicity.


The 2012 DDW meeting was packed with data on the latest advances in GI research. Only a fraction of studies relevant to pharmacists were presented in this overview. Other data of interest included the use of statins to decrease the risk of hepatic decompensation in patients with cirrhosis, health-related outcomes in patients receiving the new oral agents for the management of hepatitis C, and the use of a novel oral formulation of methylnaltrexone (Relistor—Salix) to relive opioid-induced constipation. Additional information from the 2012 DDW meeting can be accessed .