Cover Story
Gut Response
Gastroenterologists are treating more and more patients with obesity-related illnesses.
By Howard Bell
When Sarah Jane Schwarzenberg was a pediatric resident in the early 1980s, she rarely saw an obese child. “They stood out,” says the pediatric gastroenterologist at the University of Minnesota. “They were a point of discussion.” Today, obese children make up a large part of her practice. “Many of them are incurring tremendous health problems,” says Schwarzenberg, who directs the university’s Pediatric Weight Management Clinic, which opened in 2003. “If you’d told me 25 years ago that I—a gastroenterologist—would one day run a clinic for overweight children, emphatically, I wouldn’t have believed it.”
It’s old news that Americans have a weight problem. And our well-known excess fat raises our risk for diabetes, hypertension, and heart disease. Now a growing body of research shows excess fat also wreaks havoc on the gut. Obesity is a risk factor for a number of benign and malignant gastrointestinal conditions, including gastroesophageal reflux disease (GERD), precancerous Barrett’s esophagus, esophageal cancer, fatty liver disease, gallstones, pancreatitis, colon cancer, chronic abdominal discomfort, diarrhea, and constipation.
At Minnesota Gastroenterology in Minneapolis, John Allen, M.D., is seeing far more obese patients than he did when he started practicing 25 years ago. “No question about it,” he says. “The number has grown tremendously. And we’ve seen a marked increase in liver, esophageal, and gallbladder disease.” The demand for procedural work in GI has increased “massively,” according to Allen, in part because of obesity’s effects.
Supersize Me
Those effects were vividly shown in the documentary Supersize Me, as the film’s producer ate nothing but fast food for 30 days. Every measure of his mental and physical health deteriorated. But what most alarmed his internist was the damage to his liver, which became so engorged with fat, his doctor told him it looked like pate.
The film raised public awareness of nonalcoholic fatty liver disease (NAFLD), which can progress to cirrhosis. “Ten to 15 years ago, there was almost no awareness that obesity could cause fatty liver and cirrhosis,” says Charles Billington, M.D., an endocrinologist at the University of Minnesota and Minneapolis Veterans Affairs Medical Center who studies the physiology of appetite and weight gain.
A direct and natural result of obesity, NAFLD is becoming increasingly common. Thirty percent of the U.S. population is estimated to have the condition. Most people with NAFLD do not develop complications. “Usually, the liver peacefully co-exists with the fat,” says Keith Lindor, M.D., a Mayo Clinic gastroenterologist and liver specialist who studies the condition. But he explains that 20 percent of people with NAFLD develop inflammation, which can lead to a more serious condition, nonalcoholic steatohepatitis (NASH). A fourth of those with NASH develop liver scarring that can progress to cirrhosis.
Thus far, fewer than 10 percent of patients with NASH reach the point of needing a transplant. But Schwarzenberg is worried that with obesity starting earlier in life, this could change in years to come. About 25 percent of the overweight children she sees in the Pediatric Weight Management Clinic have elevated liver enzymes—likely caused by fatty liver disease. According to a study of children using liver biopsies, 8 percent of children with fatty liver disease already have advanced scarring. “Scarring at such a young age suggests that these children may be at increased risk of developing cirrhosis in early adulthood,” she says. “We may have a generation of kids who will require more frequent and earlier liver transplantation.”
There’s no way to treat fatty liver disease other than with weight loss, either surgical or dietary. “Simply losing 10 to 15 pounds can reduce liver test abnormalities, if not return them to normal,” Lindor says. Lindor has conducted several clinical trials on a variety of pharmaceutical interventions. None proved effective enough to merit further study. All that can be done now is to identify as early as possible those with NASH. Which is why Allen, Schwarzenberg, and every other gastroenterologist—and many primary care physicians for that matter—are doing more liver evaluations. But liver function tests don’t distinguish between NAFLD and NASH. The challenge, says Lindor, is to come up with a way to noninvasively identify those with the inflammatory version of the condition in order to try to prevent it from progressing. Biopsies are the gold standard, but besides being invasive, they’re reliable only 75 percent of the time, Lindor notes.
Obesity and the Esophagus
Rates of GERD, precancerous Barrett’s esophagus, and esophageal cancer appear to parallel rising rates of obesity, according to Allen. Esophageal disorders in general doubled between 1998 and 2005, according to the U.S. Agency for Health Care Research and Quality. Esophageal cancer rates have risen six-fold in the past 20 years, and most of these cancers are associated with GERD, Allen says. Fewer than one in five people diagnosed with esophageal cancer survives longer than five years.
Gastroesophageal reflux disease is also “a significant issue” among obese children, according to Schwarzenberg. “Usually, if a child presents with symptoms of GERD,” she says, “we institute treatment and perform endoscopy only if they don’t respond to medication.” Esophageal cancer is rare in children, as is Barrett’s esophagus.
Gastroenterologists say they are endoscopically screening more adults for Barrett’s than they used to. Some studies show screening is effective for finding dysplasia and early cancer, according to Robert Ganz, M.D., a colleague of Allen’s at Minnesota Gastroenterology. But screening’s effectiveness is debated within the profession. “For many years,” Allen says, “the American College of Gastroenterology (ACG) recommended screening symptomatic adults for Barrett’s, but there was no scientific evidence this had any effect on esophageal cancer mortality.” So now the ACG only recommends screening for Caucasian males age 50 or older with longstanding heartburn—the group at highest risk.
Why obesity raises the risk for esophageal disease is not entirely understood. It’s widely believed the daily acid bath of reflux injures tissues and triggers cellular changes that lead to cancer. As for why GERD is on the rise in the obese, many believe that excess visceral fat increases abdominal pressure, which forces gastric acids into the esophagus. “What’s striking about these patients is the tense adiposity you can feel in their peritoneal sac,” Billington says. “That tension exerts upward pressure against food and acids.” And Ganz points out that excess fat increases the gradient from the stomach to the esophagus, making it more likely to reflux.
A high-fat diet was once thought to raise the risk for GERD because dietary fat can delay gastric emptying and reduce esophageal sphincter pressure. Studies show diet is not a factor, according to Richard Locke, M.D., a gastroenterologist at Mayo Clinic who heads their esophageal group. But sleep apnea, which is common among the obese, compounds the problem, he says. “[People with sleep apnea] must generate higher negative pressures in order to breathe,” he says. “This pressure can pull acids up into the esophagus.” Locke adds that fat cells themselves may also alter metabolism, secreting substances that may decrease muscle tone in the gastroesophageal sphincter.
Even though GERD rates are rising, Allen says he and his colleagues are referring far fewer patients for fundiplication surgery, in which the sphincter is tightened by wrapping part of the stomach around the lower esophagus. “That’s because drug therapies for GERD are so effective,” he says.
Surgically removing the esophagus has long been the standard treatment to stop high-grade dysplasia in Barrett’s from turning into cancer. But new guidelines encourage first slicing off the precancerous layer endoscopically and at the same time checking to see that the dysplasia hasn’t already turned malignant. Any remaining Barrett’s tissue is then burned away with electrocautery or laser light. Another approach called phototherapy injects Barrett’s cells with a chemical that makes them light sensitive. Laser light aimed at the precancerous cells destroys them.
Ganz and others now prefer removing Barrett’s tissue using “balloon-based radiofrequency ablation,” otherwise known as Barrx. They nestle a balloon directly on the esophagus, through which they beam radio-frequency energy, which destroys precancerous cells. The hope is that healthy tissue will grow back in its place. Small studies show Barrx can successfully treat precancerous spots in about 90 percent of patients, with no regrowth in two years. “Barrx is safer and more effective than phototherapy, laser, or electrocautery,” Ganz says. As of now, this therapy is only available in select centers.
Metabolic Mischief-Maker
Nobody knows exactly why excess fat increases risk for so many GI conditions. Insulin resistance, and the metabolic changes associated with it, often gets blamed. But new studies show that fat itself, especially visceral fat that surrounds vital organs, may be a metabolic mischief-maker. Yet it’s not clear why visceral fat would be more harmful than subcutaneous fat.
Far from being inert repositories, all fat cells, especially visceral fat cells, are immunologically active. They may directly and actively increase risk by overproducing inflammatory cytokines, including tumor necrosis factor and interleukin-6 (IL-6), which can cause insulin resistance. Inflammatory cytokines cause tissue inflammation throughout the gut. The more fat cells, the more inflammatory cytokines, the more tissue inflammation. Chronic inflammation, Billington explains, is thought to trigger a biochemical chain reaction that causes cells to slip out of their normal growth controls, leading to colon and esophageal cancer and perhaps liver fibrosis.
Ironically, insulin resistance actually has anti-inflammatory effects, which led authors of a recent literature review in Alimentary Pharmacology and Therapeutics to conclude: “Whatever the mechanism behind the link between obesity and GI diseases, insulin resistance is unlikely to play a role. The higher incidence of certain GI cancers in the obese traditionally attributed to insulin resistance may not be so. Instead, inflammation at the tissue level may be the primary mechanism.”
Insulin resistance may, in fact, be a byproduct of cytokine-induced inflammation produced by excess fat cells, according to Billington. “The evidence linking the two is not totally solid,” he says, “but there is strong evidence that cytokines cause insulin resistance and create mischief throughout the body, including the GI system.”
Several studies suggest that NSAIDS may protect against colon and esophageal cancer, which supports the notion that inflammation contributes to development of these cancers. Bariatric surgery reduces the production of inflammatory cytokines by decreasing the number of fat cells in the body. The inflammation theory also may help explain why bariatric surgery reduces insulin resistance.
Obesity is also associated with elevated levels of asymptomatic bowel inflammation. The question remains: Does such inflammation set the stage in some people for colon cancer? “We’re still at a stage of rampant speculation about what causes colon cancer,” Billington says. “That speculation is probably going to take us into the role of cytokines.”
Another theory for why the obese have more GI problems centers on bacteria in the gut. “Overweight people have a different population ratio of intestinal bacteria and yeast compared to lean people,” says Locke. Something about that gut flora might set up a biochemical chain of events that increases risk. At this point, it’s just a theory, and it’s not even known which parts of the GI system might be affected. It could play a role in irritable bowel syndrome, according to Lindor, who says this theory may also help explain why only some people with fatty liver go on to develop fibrosis.
Managing Bariatric Patients
One way to reduce overproduction of inflammatory cytokines is by reducing the volume of fat cells with bariatric surgery. Gastroenterologists are being called on more often than before to manage bariatric patients, usually after surgery. Seven to 10 percent of bariatric patients have significant postsurgical complications that must be located and managed endoscopically, according to Allen. “Sometimes the opening into the intestine ulcerates or strictures,” he says. Most gastroenterologists were not trained in bariatric management. As chair of the American Gastroenterology Association’s Clinical Practice and Quality Committee, Allen is overseeing development of curriculum and guidelines to help gastroenterologists manage bariatric patients.
Even without complications, bariatric surgery is not a one-procedure-and-you’re-fixed deal, according to Schwarzenberg, who works with surgeons at the University of Minnesota to co-manage adolescent bariatric patients. “Postoperatively, adolescents must change their diet and begin to exercise or they will gain back weight,” she says. “The bariatric surgery procedure is part of lifelong management of obesity.”
Drugs and Devices
Researchers have been looking for drugs that can help bariatric patients and others do just that. Although physicians are seeing some success with orlistat, which blocks absorption of about one-third of dietary fat eaten and can produce 7 percent more weight loss than lifestyle changes alone, or sibutramine, which suppresses appetite, we are, according to Billington, at least 10 years away from a “fat pill,” some type of appetite blocker that short-circuits appetite-stimulating signals transmitted between the gut and hypothalamus, which regulates appetite and eating behavior. “The gut-brain interface might be where the action is,” he says.
Specifically, Billington believes that the key to such a pill lies with metabolic hormones secreted by the stomach and duodenum that travel through the bloodstream to the hypothalamus and signal hunger and satiety. “These hormones help explain why gastric bypass works better than gastric banding,” he says. “Bypass changes the secretion of these hormones and reduces appetite, but banding doesn’t.”
The most promising agent thus far is a ghrelin blocker. The so-called hunger hormone, ghrelin, is produced in the fundus of the stomach. It’s present in higher amounts when the stomach is empty, sending appetite-stimulating signals to the hypothalamus. “A ghrelin blocker would reduce appetite,” Billington says. One antidote to ghrelin might be another hormone called PYY-336, which triggers a feeling of fullness, so drug researchers are working that angle, too.
Vagus nerve stimulators offer another approach to appetite suppression being used experimentally in humans. The vagus nerve travels between the gut and the brain, transmitting signals of hunger and satiety. An electrode implant stimulates the nerve in a way that slows emptying and gut function, thereby reducing appetite. “Results are encouraging,” says Billington, who’s working on the device with others. “But we’re in the early stages.”
Cytokine blockers theoretically could reduce the chronic tissue inflammation caused by obesity that’s believed to be the source of some GI problems. “There is strong evidence that fat cells overproduce tumor necrosis factor and IL-6,” Billington says. “These also do good things, so the idea is to somehow block only some of their effects.”
The idea of treating obesity like an illness, with medication, is catching on as scientists learn that genes largely establish a person’s weight range. For instance, researchers have found that some people naturally produce more appetite-stimulating ghrelin than others. Persons with the rare genetic disorder Prader-Willi Syndrome produce so much ghrelin that they can literally eat themselves to death without intervention.
Although diet, exercise, and medication can lower weight long-term by only about 5 percent to 10 percent in most cases, genes and GI hormones like ghrelin help explain why most dieters gain back most of what they lose. Whatever the drug companies come up with, the pace of research must quicken, Schwarzenberg says, “if we’re going to keep obesity from creating long-term health problems for today’s youth.”
For now, physicians from all specialties will continue to see more obese patients. Schwarzenberg says those who see children will see far more obesity-related conditions traditionally considered adult diseases—hypertension, diabetes, fatty liver disease, and reflux. “All of us in pediatrics, family practice, and gastroenterology need to review how to diagnose and manage conditions we used to consider adult diseases,” she says. “When most gastroenterologists were in training, we weren’t taught how to manage obesity. Now pediatricians from many subspecialties, including gastroenterology, are specializing in it.” MM
Howard Bell is a medical writer in Onalaska, Wisconsin.