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Reflux may be inherited AGH study sees genetic link in children with the ailment Wednesday, July 19, 2000 By Byron Spice, Science Editor, Post-Gazette
Gastroesophageal reflux is as natural as a burp and as common as heartburn. But for millions of Americans, it is so frequent and severe that it is nothing less than a disease. And doctors admit they are stumped about what causes it.
Researchers at Allegheny General Hospital may have found one missing piece of the puzzle. They have evidence that a gene may be a culprit, at least in children who have severe gastroesophageal reflux disease, or GERD.
The researchers have yet to identify the specific gene, but based on a study of five families with a history of severe pediatric GERD, they have narrowed the search to a portion of chromosome 13. Their findings are reported in today's Journal of the American Medical Association.
Whether this study provides clues that will lead to effective treatment of a disease that afflicts millions of American children and at least 40 million adults or applies only to a small subgroup of patients is unclear.
Caroline McGraw of Escondido, Calif., co-director of a family support group called Pediatric/Adolescent Gastroesophageal Reflux Association, or PAGER, said many families in her organization have multiple children with GERD, as well as parents and grandparents. The possibility that pediatric GERD had a genetic cause or component seemed obvious, said McGraw, the mother of four children with the disease.
Gastroesophageal reflux is the backflow of stomach contents into the esophagus. Without reflux, people couldn't burp or vomit. Normally, reflux is limited by a sphincter at the base of the esophagus. But in some people, reflux is so frequent that the stomach acids damage the esophageal lining. GERD is more than just heartburn -- it can cause hoarseness and esophageal ulcers and increase the likelihood of esophageal cancer.
In children, GERD can cause colic, vomiting several times a day, food avoidance, failure to thrive, hoarseness, irritability, asthma, recurrent ear infections and sudden infant death syndrome. Most children outgrow this problem by the time they are 18 months old, but children with severe disease may suffer with symptoms through adolescence.
Yet some leading pediatricians and gastroenterologists were skeptical when PAGER asked them to do genetic studies. "They laughed at us," McGraw said. How could something so common, they wondered, have a genetic cause?
Dr. Christopher Post, a pediatric ear, nose and throat specialist, had the same suspicions as the PAGER parents. He noticed that many of the GERD patients he treated for recurrent ear infections had siblings with the same problem.
When Post and microbiologist Garth Ehrlich jumped from Children's Hospital of Pittsburgh to Allegheny General in 1997, they took plans for the GERD study with them.
Ehrlich, director of the Center for Genomic Sciences, said he and Post identified five PAGER families -- three related by marriage -- with a multigenerational history of the disease. In 1998, they took blood samples of family volunteers and began analyzing them with genetic markers to see if they could find patterns that differed between family members with GERD and those unaffected.
The laboratory analysis, spearheaded by Fen Ze Hu, went rapidly, but the $1.5 billion bankruptcy that summer of the hospital's parent organization, the Allegheny Health, Education and Research Foundation, brought the research to a halt.
"Literally, for a while, we were funding the research off our credit cards," Post said.
He and Ehrlich finished the study in spring 1999 and submitted their findings to the Journal of the AMA that May.
"It took 13 months to get our paper accepted," Post said. That's an unusually long wait, even for a major medical journal. "Initially, the reviewers wouldn't believe it."
One problem is that GERD is a poorly understood disease and a poorly defined term. Some doctors, such as Dr. Judith Sondheimer, chief of pediatric gastroenterology at the University of Colorado Health Sciences Center in Denver, hesitate to use GERD to describe the problem in children under 18 months. About four of every 10 children under that age have reflux symptoms, she explained, and most outgrow them.
But the condition causes great anxiety for parents. Doctors are frustrated, too, because they can't explain why reflux is occurring, she said. It's also difficult to treat; none of the medicines available for adults has been proven safe in children.
For instance, a study at Children's Hospital examining the safety of the drug Propulsid was cut short this spring, after the drug's manufacturer announced it was withdrawing Propulsid from the market. A 9-month-old Munhall baby enrolled in the study died last November; Allegheny County Coroner Dr. Cyril Wecht ruled that the baby died of cardiac arrhythmia, a known Propulsid side effect.
Post said he suspects pediatric GERD is underdiagnosed because many pediatricians are reluctant to diagnose a disease that they can't effectively treat.
Many of these cases of GERD have simply been dismissed as colicky babies, said Dr. Thomas Self, a pediatric gastroenterologist at the University of California, San Diego, and a collaborator on the Allegheny General study. "I used to tell my medical students that colic is a five-letter word for 'We don't know,' " he added.
Ehrlich is now trying to find the specific gene implicated in the disease. That would allow doctors to test for the gene, a potential aid to diagnosis. It is probably not the only gene involved in the disease, he cautioned.
Colorado's Sondheimer isn't sure a gene test will be of much help. But she said finding the gene and determining its function may finally give researchers a clue about what causes pediatric GERD, and maybe even what causes GERD in adults. That might finally lead to effective treatments that address the cause of the disease, rather than just the symptoms.
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