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Digestive Disease Week 2019
This year’s Digestive Disease Week meeting took place in San Diego, California, May 18–21. We review selected sessions on the questionable benefits of fecal microbiota transplant; intrahepatic cholestasis of pregnancy and NAFLD; weight-loss drugs combined with intragastric balloon endoscopy; and beta blockers in pancreatic cancer.
Outside of C. Difficile Treatment, FMT Benefits Remain Questionable
Two studies on fecal microbiota transplant (FMT) have failed to show benefits in obese patients, but researchers favor further investigation.
In “Fecal Microbiota Transplantation for the Treatment of Obesity: A Randomized, Placebo-controlled Pilot Trial,” researchers measured glucagon-like peptide 1 (GLP-1), which affects appetite and stomach digestion, in 22 metabolically healthy, obese patients. Results indicated no increase in GLP-1 and no change in body mass index in the treatment arm or placebo arm, said Jessica Allegretti, MD, assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, at an oral presentation.
Researchers in the study “Double-Blind Randomized Placebo-Controlled Trial of Weekly Fecal Microbiota Transplantation (FMT) Capsules in Obese Adults: Evaluating Microbiota Engraftment and Improvements in Insulin Sensitivity” examined whether FMT administered by capsule could improve insulin sensitivity in 24 obese adults (72% female). More FMT-group patients experienced improvement than control-group patients, but the difference was not statistically significant (P = 0.16).
“Primary bile acid decreased in the treatment arm, which is important for lipid metabolism, so perhaps taurocholic acid is the important pathway, not the GLP-1 pathway,” said Dr. Allegretti. The next step will likely involve a more traditional dose-finding study, she added.
It is unclear what benefits, if any, might be gained by using a different dose of FMT. “The fact that a previous open label trial in 2013 showed no effect, and this study showed no effect, makes me unsure that a dose-finding study would be helpful,” said Purna Kashyap, MBBS, of the Mayo Clinic in Rochester, Minnesota.
Although the success rate of FMT was 90% in patients with refractory C. difficile infection (CDI), these patients had an acute illness as opposed to a chronic, multifactorial condition.
Fecal microbiota transplant originated as therapy for recurrent CDI. It is not FDA-approved for any indication, but research is flourishing on its potential for disorders such as inflammatory bowel disease, ulcerative colitis, liver disease, diabetes, MS, and Parkinson’s disease. Earlier studies also suggested that FMT would be useful in treating obesity and related conditions.
Previously, FMTs were performed endoscopically; administration by capsule, as in the current trials, is a relatively new method. Intestinal microorganisms play an important role in certain diseases; if a patient’s gut microorganisms can be replaced with those of a healthy person, the new microorganisms could be used therapeutically. Part of the challenge is identifying precisely which microorganisms are responsible.
“Most people would prefer not to have gastric bypass surgery, so we’d like to identify a target microorganism for microtherapy, and not have to do the whole stool transplant,” explained Dr. Allegretti.
Women with Intrahepatic Cholestasis of Pregnancy Have Increased Risk For NAFLD
Women who experience intrahepatic cholestasis of pregnancy (ICP) are six times more likely to develop non–alcoholic fatty liver disease (NAFLD) and should be referred to a liver specialist, said Dr. Tatyana Kushner, assistant professor at Icahn School of Medicine at Mount Sinai in New York City, in an oral presentation.
Pregnant women with ICP experience poor bile flow. And although severe pruritus is often the main symptom of ICP, the disease can be very dangerous for the fetus. From an obstetric perspective, said Dr. Kushner, the guidelines regarding patients with ICP are very good: if ICP develops in the later stages of pregnancy, the baby will be delivered as early as 36 weeks. Or, if bile acid levels are particularly high, delivery will be scheduled even earlier.
However, in terms of liver function, there are currently no guidelines on which patients should be followed and whether they should be followed, information that would be beneficial for physicians.
According to the authors of the study, “Intrahepatic Cholestasis of Pregnancy (ICP) is Associated With Higher Prevalence of NAFLD,” ICP has an increased prevalence among Bengali, Hispanic, and Scandinavian women. The elevated incidence is related to genetics, although researchers are not certain which mutations of bile acid transporters are involved. Women who are pregnant with multiples are also more likely to be diagnosed with ICP because estrogen is highly cholestatic. The disease is also associated with the use of oral contraceptives.
Intrahepatic cholestasis of pregnancy is one of several liver diseases that can occur during pregnancy, along with hyperemesis gravidarum and preeclampsia. Bile obstruction can cause infections, cholangitis, and extremely severe disease outcomes because it is directly hepatotoxic.
NAFLD affects 30% of the U.S. population, and a subset of patients develop inflammation, fibrosis, cirrhosis, and liver cancer. However, the association between ICP and NAFLD had not previously been evaluated.
The researchers retrospectively matched 2017 data for 149 pregnant women with ICP and 200 pregnant women with no ICP from medical records at Elmhurst Hospital in Queens, New York. The neighborhood is primarily Hispanic, and has a higher-than-usual incidence of ICP compared with the national incidence (2.53% vs. 0.32%). Hispanic women were almost twice as likely to be diagnosed with ICP as non-Hispanic women. In addition, women diagnosed with ICP had a higher prevalence of hepatitis C (OR, 1.35).
Compared with control patients, patients with ICP were more likely to have a diagnosis of NAFLD, based on the International Classification of Diseases, Tenth Edition (ICD-10) code or on evidence of steatosis on liver imaging (odds ratio [OR], 5.7).
At present, the options for managing NAFLD involve lifestyle modifications. Clinicians hope to have more therapeutic options in the near future, including combination therapy. Currently, the results from clinical trials are not encouraging: a response rate of 50% is considered good, and the placebo effect is thought to account for some of the improvement.
The researchers intend to examine ICP’s long-term consequences, and will use data from 2005 to 2014 to investigate liver morbidity and potential increases in metabolic risk factors. “Years ago, we were seeing fetal complications from ICP, so we started coding for the condition,” said Dr. Kushner. Existing data are often not well coded, making it difficult to use databases and insurance records, but there is also a substantial amount of good data from Europe.
Weight Loss Drugs Add Efficacy With Intragastric Balloon Endoscopy
Patients implanted with intragastric balloons (IGBs) lost more weight when prescribed weight-loss medication than did patients who received IGB only, according to the study “Impact of Concurrent Pharmacotherapy With Intragastric Balloons in the Treatment of Obesity.”
The relatively new IGB is a minimally invasive, endoscopic weight-loss procedure in which a balloon is implanted in the patient’s stomach and usually removed after six months. The balloons are associated with a total body weight loss (TBWL) of 10% to 15%, but recidivism often occurs when the balloon is removed, according to the study authors.
Currently, there are only five FDA-approved weight-loss medications on the U.S. market. Since fenfluramine’s removal in 1997, the FDA has employed a lengthy process for approving weight-loss drugs, said Dr. Reem Sharaiha, assistant professor of medicine at Weill–Cornell Medical Center in New York City. This has led to growth in the number of obesity specialists.
In the multicenter retrospective study, researchers examined data from 111 patients (female, > 83%; median age, 46) who received IGB at four academic hospitals between 2015 and 2018. Of those patients, 18 received IGB with concomitant pharmacotherapy and 93 received IGB only. At follow-up after one year, patients who received IGB plus medication had a 21.4% TBWL, compared with patients who received IGB alone, who had a TBWL of 13.1% (P = 0.05).
Among the IGB plus pharmacotherapy patients, the average number of medications was 1.8––most commonly metformin (16.7%), metformin with liraglutide (16.7%), and metformin with naltrexone/bupropion (11.1%). Patients could choose up to three different drugs from a total of eight weight-loss drugs.
It is not clear how metformin helps patients to lose weight, but it works well and with minimal side effects. In both arms of the trial, 20% of patients had diabetes. Up to six months, there was no difference between the IGB plus pharmacotherapy group and the IGB-only group, but at 12 months, there was a significant difference: the former had a TBWL of 12% to 13%, whereas TBWL in the latter group slowed down at 10%.
Whether the medications were responsible for all of the weight loss will have to be studied prospectively.
Beta Blockers May Have Inhibitory Effect on Pancreatic Cancer With Perineural Invasion
The use of common non-selective beta blockers such as propranolol, which is typically prescribed for hypertension, was associated with significantly increased survival in patients with pancreatic cancer, reported Dr. Alex Blair in his presentation.
The study “Non-Selective β-adrenergic Blockade Impacts Pancreatic Cancer Tumor Biology, Decreases Perineural Invasion and Improves Patient Survival” found that median survival for patients taking non-selective beta blockers was 26 months, compared to 18 months for patients who were not taking a beta blocker or taking only a beta-1 blocker.
“There’s a lot of research into re-purposing existing drugs that are safe, well-understood, and inexpensive,” said Dr. Blair, general surgery resident at Johns Hopkins Medicine in Baltimore, Maryland.
Certain beta blockers are thought to affect pancreatic cancer because they interfere with signaling between the cancer cells and nerves. Although they won’t replace chemotherapy, beta blockers may be prospectively added as adjunct therapy to improve outcomes in future research. “It could be as simple as taking a pancreatic cancer patient who is already on a beta-1 blocker, and switching them to a non-selective beta blocker,” said Dr. Blair.
A dearth of screening methods is part of the reason why pancreatic cancer has poor outcomes. It is often asymptomatic, and many people are not eligible for resection. Perineural invasion, where the cancer surrounds or tracks alongside the nerve cells, exacerbates the likelihood of a grim prognosis even further.
Previous research has indicated that beta blockers are associated with improved outcomes in breast and prostate cancer. To explore this effect in pancreatic cancer, the Johns Hopkins researchers prospectively created a database of 1,933 patients who were treated for pancreatic cancer. Of those patients, 397 were taking beta-1 blockers and 60 were taking non-selective beta blockers. Perineural invasion was found in 84.9% of patients on beta-1 blockers, and in 68.3% of patients on non-selective beta blockers (P < 0.001). The survival advantage among patients on beta-1 blockers was also statistically significant (P = 0.007).
“In the tumor micro-environment, cancer cells secrete proteins to cause nerves to grow toward them, while tumors do it to attract cancer cells,” explained Noelle Jurcak, PhD, a post-doctoral fellow at Johns Hopkins Hospital. Patients who have a higher nerve density in their pancreas also have a poorer prognosis; vascular endothelial growth factor (VEGF) is implicated in this process.
Using a single human pancreatic cancer-cell line in a complementary in vitro study, the researchers discovered that propranolol also inhibited the growth of cells that had been exposed to norepinephrine.