Acid reflux drugs may have an unintended side effect: impairment of breast cancer survivors

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Acid reflux drugs that are sometimes recommended to ease stomach problems during cancer treatment may have an unintended side effect: impairment of breast cancer survivors’ memory and concentration.

New Ohio State University research shows an association between breast cancer survivors’ use of proton pump inhibitors (PPIs) and reports of problems with concentration and memory. On average, cognitive problems reported by PPI users were between 20 and 29 percent more severe than issues reported by non-PPI users. PPIs are sold under such brand names as Nexium, Prevacid and Prilosec.

The study, the first to look at PPI use in breast cancer survivors, used data from three previous Ohio State clinical trials examining fatigue, a yoga intervention and vaccine response in breast cancer patients and survivors.

In each of those studies, participants had reported their use of prescribed and over-the-counter medications and rated any cognitive symptoms they had as part of routine data collection.

After controlling for a variety of factors that could affect cognition – such as depression or other illnesses, types of cancer treatment, age and education – the researchers found that PPI use predicted more severe concentration and memory symptoms as well as lower quality of life related to impaired cognition.

“The severity of the cognitive problems reported by PPI users in this study was comparable to what patients undergoing chemotherapy had reported in a large observational study,” said Annelise Madison, lead author of the study and a graduate student in clinical psychology at Ohio State.

“PPI non-users also reported problems, but were definitely getting better. Based on what we’re seeing, we don’t know if PPI users might not be able to fully recover cognitively after chemotherapy. It’s an area for further investigation.”

The study is published online in the Journal of Cancer Survivorship.

Madison pursued this study based on her knowledge of PPIs’ known potential to bypass the blood-brain barrier and previous research suggesting that off-label use of PPIs in cancer patients may increase tumors’ responsiveness to chemotherapy and protect the digestive system from the ravages of chemo drugs.

“I thought there could be a cognitive effect from taking PPIs, particularly in this population, because breast cancer survivors are already at risk for cognitive decline,” she said. “PPIs are over the counter and generally considered safe so there haven’t been many long-term trials, especially looking at cognitive outcomes, because nobody was really thinking that would be a downstream effect.”

As part of her graduate program, Madison works in the lab of Janice Kiecolt-Glaser, professor of psychiatry and psychology and director of the Institute for Behavioral Medicine Research at Ohio State. For this work, Madison conducted secondary analyses of three of Kiecolt-Glaser’s earlier studies examining inflammation’s connection to breast cancer treatment and survivorship.

Data from 551 women in those earlier studies, 88 of whom reported taking PPIs, were used in Madison’s analysis.

The women in the previous studies had provided self-reports of PPI use and cognitive symptoms multiple times over varied periods of time depending on the design of each study.

Women in the studies looking at fatigue in newly diagnosed patients and investigating yoga’s effect on inflammation and fatigue in survivors had completed a questionnaire rating the severity of their memory and concentration problems on a scale of 0 to 10 over the previous five days.

Madison’s analysis found that on average, PPI users’ concentration problems in the fatigue study were 20 percent more severe than those reported by non-PPI users. In the yoga study, PPI users’ concentration problems were 29 percent more severe than those reported by non-PPI users. There were no differences in reported memory problems.

In the third study, which featured data from the placebo visit of a typhoid vaccine trial, reported memory problems were 28 percent more severe in PPI users than in non-users, with no differences in reports of concentration issues.

Breast cancer survivors in this study completed an additional questionnaire measuring the functional implications of their cognitive impairment. PPI users’ scores were lower than non-users’ scores on this assessment, where PPI users reported a poorer quality of life, greater cognitive impairment and poorer cognitive abilities compared to non-users.

“The fact that this study found similar effects across three different sets of patients who are at different stages of cancer survivorship gives some weight to what we’re seeing,” said Kiecolt-Glaser, senior author of the paper and an investigator in Ohio State’s Comprehensive Cancer Center. “Had it been in only a single study, it could have been a chance effect.”

The U.S. Food and Drug Administration has approved PPIs for short-term use to treat common gastric acid conditions and longer-term use for gastric ulcers and disorders involving excessive acid secretion.

Madison noted that the off-label maintenance use of PPIs in cancer patients can last a long time: Her analysis showed that at least two-thirds of the breast cancer survivors using PPIs had taken them for between six months and two years.

Madison stressed that the study shows a correlation between PPI use and cognitive problems in breast cancer survivors, and that a clinical trial controlling PPI doses and obtaining objective cognitive data would be required to identify any causal effect.

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Gastroesophageal reflux disease (GERD) is a condition that develops when there is a retrograde flow of stomach contents causing symptoms or complications. GERD can present as Non-erosive reflux disease (NERD) when typical symptoms of GERD occur in the absence of visible mucosal injury during endoscopy, or as erosive esophagitis (EE) when patients have histopathological changes in esophageal mucosa. The latter is also called reflux esophagitis.

The typical symptom is heartburn. This most often occurs 30 min to 60 min after meals and upon reclining. Patients often report relief from antacids or baking soda. When patients present with this description of symptoms, the diagnosis can be established with a high degree of confidence.

Epidemiology

GERD is extremely common, with a prevalence of approximately 20% of adults in the western culture. Most adults with GERD have mild disease, but esophageal mucosa damage (reflux esophagitis) can develop in up to a third of the patients. Symptoms occur daily in approximately 7% of patients, weekly in 14% and monthly in 15% to 40% of all patients.

There is no significant difference in prevalence among males and females, but males seem to have a higher rate of complications. The rate of esophagitis is 2:1 and the rate of Barrett’s is 0:1 in males compared to females.

GERD incidence increases with age, particularly after age 40.

Obesity also seems to increase the risk of GERD. A meta-analysis published in the Annals of Internal Medicine in 2005 concluded that obesity was associated with a statistically significant increase in the risk of GERD symptoms, erosive esophagitis, and esophageal carcinoma. The ProGERD study published in 2005 evaluated the predictive factors for erosive reflux disease in more than six thousand patients with reflux disease. They found the odds ratio for erosive disease increased with the body mass index (BMI), with patients with a BMI greater than 30 Kg/m2 to 40 Kg/m2 having an odds ratio of 1.97 (95% confidence level 1.32 to 2.92).

Pathophysiology

There are few components of the pathophysiology of GERD.

  1. Impaired Lower Esophageal Sphincter (LES) Function: the LES functions as an anti-reflux barrier at the gastroesophageal junction, preventing acid from the stomach from entering the esophagus. In healthy individuals, a certain amount of physiologic gastroesophageal reflux occurs by means of transient relaxation of the LES, which increases after a meal to permit gas to be vented from the stomach. In patients with GERD, there may be an increased transient relaxation of the LES associated with a reduction in the pressures of the sphincter. The mechanisms of increased transient relaxation are unknown. However, there are several known risk factors for decreased LES pressures: pregnancy, diabetes, scleroderma, obesity, and medications such as calcium channel blockers, cholinergic antagonists, glucagon, nicotine from cigarette smoking and oral contraceptives.
  2. A hiatal hernia: hiatal hernias are common and usually do not cause symptoms. In patients with GERD, however, they are associated with higher amounts of acid reflux and delayed esophageal acid clearance. Large hiatal hernias seem to contribute to decreasing LES tone. Hiatal hernias are found in a fourth of patients with non-erosive GERD, in three-fourths of patients with erosive GERD, and in over 90% of patients with Barrett Disease.
  3. Irritant effects of Refluxate: the gastric acid fluid (pH less than 4) is extremely caustic. Prolonged contact of gastric contents with esophageal mucosa leads to damage (esophagitis). In some patients, reflux of bile or alkaline pancreatic secretions can also lead to damage.
  4. Abnormal esophageal clearance: the acid that reaches the esophagus is normally cleared and neutralized by esophageal peristalsis and salivary bicarbonate. During sleep, peristalsis is infrequent, prolonging acid exposure to the esophageal mucosa. Alcohol and sedatives also seem to decrease peristalsis. Researchers estimate that 50% of patients with GERD have some degree of decrease peristalsis. Also, conditions such as Sjogrën disease that affect the quality or quantity of the saliva, anticholinergic medications, and oral radiation can further worsen the natural protective mechanisms and lead to higher exposure of the esophageal mucosa to damage.

History and Physical

The typical manifestation of GERD is heartburn, regurgitation, and dysphagia. Other symptoms include a globus (lump in the throat) sensation, odynophagia, and nausea. Heartburn is defined as a retrosternal burning discomfort, located in the epigastric area that may radiate up towards and neck and typically occurs in the postprandial period. Patients often report that postural changes, such as bending forward, can worsen the symptoms. Symptoms are usually also aggravated by ingestion of certain foods or beverages such as tomato sauce, chocolate, coffee, teas, and alcohol.

Atypical presentation refers to symptoms that are extraesophageal, including pulmonary, ear, nose and throat manifestations, as well as non-cardiac chest pain.

Evaluation

Initial diagnostic tests are not warranted for patients with typical GERD symptoms. Practitioners should further investigate patients with “alarm features” such as troublesome dysphagia, odynophagia, weight loss, iron deficiency anemia, and in patients with troublesome symptoms that persist despite appropriate empiric proton pump inhibitor therapy. It must be remembered that diabetic patients may present with dyspeptic symptoms during a myocardial infarction. Thus, a high index of suspicion should be maintained in these patients in the acute setting.

Radiographic studies are of limited use in the management of GERD due to poor sensitivity in milder forms of GERD, but they can detect moderate to severe esophagitis, strictures, hiatal hernia, and tumors. The studies most commonly used are the barium swallow, which only examines the esophagus, and the upper gastrointestinal series, which examines the esophagus, stomach, and small intestines.

In addition to excluding the presence of other diseases such as tumors and peptic ulcers, an upper endoscopy can detect and grade the severity of GERD-induced esophagitis. Upper endoscopy is highly specific for GERD (90% to 95%) but has a limited sensitivity (approximately 50%). The Los Angeles (LA) Classification grades reflux esophagitis on a scale of A (one or more isolated mucosal breaks less than 5 mm that do not extend between the tops of two mucosal folds) to D (one or more mucosal breaks that involve at least 75% of the esophageal circumference).

Esophageal pH or combined esophageal impedance testing is usually unnecessary in most patients but may be indicated in patients who have atypical or extraesophageal symptoms or who are being considered for antireflux surgery. Impedance testing detects changes in the resistance of electrical current on a catheter placed within the esophagus. In addition to recording the esophageal pH, it can differentiate both antegrade and retrograde transit of liquid and gas. The test is helpful in patients who have suspected GERD but negative pH tests. Doctors only recommend this test after standard testing has failed to demonstrate significant GERD in patients with typical or atypical symptoms and patients with refractory GERD. 

Treatment / Management

The goals of treating GERD are to resolve symptoms, heal esophagitis, and prevent complications. Treatment options include lifestyle modifications, medical management with antacids and antisecretory agents, and mechanical therapies.

  • Lifestyle modifications are a cornerstone in the treatment of GERD. Medical practitioners should provide counseling about weight loss, head elevation, tobacco and alcohol cessation, avoidance of late meals, and cessation of foods that can potentially aggravate symptoms.
  • Medical treatments include antacid and antisecretory agents. Antacids are inexpensive, readily available, and effective. Histamine-2 (H2)-receptor antagonists, inhibit the secretion of gastric acid by competitively blocking the H2-receptors located in the gastric parietal cells. H2-blockers have an excellent safety profile and are available over the counter. These drugs are approximately 75% effective in patients with mild to moderate degrees of esophagitis. Proton pump inhibitors (PPIs) act by blocking the hydrogen-potassium ATPase on the apical surface of the parietal cells. PPIs are more effective than H2-blockers because they act on the common pathway of acid secretion. Practitioners use these as initial therapy in patients with moderate to severe GERD and patients with complications of GERD. These complications include bleeding and strictures. Studies comparing H2-blockers and PPIs have demonstrated that the latter has superior healing rates and decreased relapse rates.
  • Antireflux procedures include laparoscopic fundoplication and bariatric surgery in obese patients. Fundoplication offers excellent relief of symptoms and healing of esophagitis in over 85% of properly selected patients. Outcomes in patients who have extraesophageal symptoms and have had fundoplication surgery have been less encouraging.

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More information: Annelise A. Madison et al, Cognitive problems of breast cancer survivors on proton pump inhibitors, Journal of Cancer Survivorship (2020). DOI: 10.1007/s11764-019-00815-4

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