STRESS AND THE GUT: MIND OVER MATTER? (Part 1)
(PART 1 OF 2)

The ability of emotional stress to cause various physical symptoms and disorders has been widely recognized since antiquity. This phenomenon is particularly prevalent in primitive peoples, and as Walter Cannon illustrated in ''Voodoo'' Death, could prove lethal if a taboo was violated, even if this was done unknowingly and only recognized at a much later date. A few centuries ago, disease was frequently viewed as a similar punishment from a divine being for some transgression and there was a firm belief that imagination could also cause disease. Imagination then referred to how the mind might induce various physical or mental disorders rather than our current concepts of creativity, artistic talent or flights of fancy. Certain individuals seem to be more susceptible to stress or to overreact to routine challenges. Others, obsessed with fears of having a serious illness, tend to interpret minor signs and symptoms as being due to a dangerous disease, or become preoccupied with imaginary complaints. Hypochondria is hardly a modern malady. The word comes from hypoch?ndrios, Greek for ''beneath the breast bone cartilage'', which is where the heart is located. But this region also includes the upper abdomen, which was believed to be the seat of melancholy due to an excess of black bile (Gr. melās, black + cholē, bile). Galen and other ancient physicians noted that patients with chronic complaints in this area often had no physical illness and tended to be melancholy or depressed.

The ranks of these ''worried well'' have swelled over the past two decades after direct to consumer drug advertising was allowed. It's difficult to watch TV today without being bombarded by commercials to ''Ask your doctor'' if some medication ''is right for you.'' As emphasized in a prior Newsletter, this is usually preceded by a list of symptoms that are commonly experienced by many people and do not necessarily mean that they have a disease or require the drug that is being promoted. Some conditions, such as erectile dysfunction, are not diseases, but normal consequences of aging. Many other ads, like those for Irritable Bowel and Restless Leg Syndromes, exaggerate the magnitude and hype the seriousness of relatively minor conditions. Nevertheless, they are extremely successful in selling drugs whose efficacy is not only dubious, but are sometimes later banned because of serious side effects. To avoid any stigma and to facilitate pushing a product, some disorders are frequently referred to by catchy acronyms like ED, RLS and IBS.

Thus, it would appear that we now also have an epidemic of GERD (Gastroesophageal Reflux Disease). Sales have soared for a class of drugs known as proton pump inhibitors that raked in over $13 billion in 2005 due to aggressive advertising. Almost anyone who watches TV has heard about Nexium, ''the healing purple pill''. Nexium ($4.4 billion) and Prevacid ($3.8 billion) were the third and fourth best sellers after Lipitor and Zocor for lowering cholesterol. Nexium moved up to second place in 2006 when it raked in more than $5 billion and over the counter sales of Prilosec, the original ''purple pill'' Nexium replaced, also skyrocketed. The fact is that almost everyone has occasional distress due to acid reflux from the stomach that backs up into the esophagus and most patients get relief from simple antacids or nonprescription drugs like Zantac. If significant heartburn occurs two or more days a week for at least three months, you may have GERD, but most people taking these powerful proton pump inhibitors do not have this degree of frequency or severity of symptoms. Many have no complaints but are arbitrarily started on these drugs for a year to prevent problems because of esophageal inflammation discovered on endoscopy. They are also widely prescribed to prevent ulcerations in arthritis and other patients who take NSAIDs (nonsteroidal anti-inflammatory drugs). However, interactions can occur with common medications like digoxin, coumadin, Valium or iron and there are a variety of adverse allergic reactions and gastrointestinal side effects. Proton pump inhibitors also interfere with calcium absorption and in one recent study, patients over 50 who had taken them for at least a year suffered 44 percent more hip fractures. Risk of hip fracture due to osteoporosis is much greater in senior citizens or people who take higher doses for longer periods.

Prilosec, AstraZeneca's original ''little purple pill'', was the number one selling prescription drug in 2001, when its patent expired. As noted, it was immediately replaced by Nexium, which is almost identical, although a massive advertising blitz touted its superiority and most doctors automatically switched their prescriptions over to this. The AFL-CIO and seniors groups in California filed a false advertising lawsuit against AstraZeneca alleging that it sought to preserve market share and profits as the Prilosec patent expired by scheming to convince consumers and doctors that studies showed that Nexium was significantly better. Massachusetts consumers also filed a suit claiming that these studies had compared 20 mg. of Prilosec with 40 mg. of Nexium and the company refused to release ''detailed descriptions of two studies that showed even the higher dose of Nexium to be no more effective than Prilosec.'' Prilosec is now marketed by Procter & Gamble over the counter and several companies also make generic versions.

There are additional concerns about the recent surge in prescribing these drugs. A study released a few weeks ago found that over the past four years, ''The number of young children on prescription drugs for heartburn and other digestive problems jumped about 56 percent''. Researchers found that ''557,259 infants and children up to age 4, or about 3 percent of youngsters in that age range, were taking these drugs last year.'' According to another news report, ''the use of proton pump inhibitors has become so prevalent, that in 2006, they were prescribed for ''an estimated 2 million children in the United States.'' In commenting on this, a pediatric gastroenterologist at the Hospital for Sick Children in Toronto explained, ''Increased use of the treatments could stem from higher rates of obesity and stress, conditions linked with the disorder in adults. It may also mean that children with occasional symptoms are treated as if they have the full-blown disease. The question is whether people are prescribing more medications because they're treating symptoms or whether they're actually treating the disease. . . . Furthermore, children with occasional reflux should not be given drugs because gastroesophageal reflux disease doesn't interfere with their growth, it doesn't cause them pain or irritability.'' The chief medical officer of the company that conducted the study also warned, ''While there are babies that require drug treatments for extreme cases of GERD and other gastrointestinal problems, in some cases, parents and physicians may be looking to medications when non-drug treatments might be adequate.''

Reflux symptoms may be due to a hiatus hernia and are apt to be precipitated by lying down or going to bed shortly after eating, particularly in obese people. Spicy or greasy foods, onions, chocolate and peppermint can cause heartburn by stimulating certain gastric hormones that cause the sphincter muscle between the esophagus and stomach to relax. Large meals also cause the muscle to relax by distending the stomach. Alcohol, acidic foods like coffee, orange juice and tomato products can aggravate symptoms by directly irritating the esophagus. Avoiding these problems can often prevent or reduce complaints as can shedding extra pounds if you are significantly overweight. Obesity is a well established risk factor for GERD, particularly in females. This may be due to estrogen, since in one study of obese women, postmenopausal females were much less likely to have reflux symptoms than premenopausal controls with similar weights. In addition, postmenopausal subjects on estrogen replacement therapy also had more symptoms. One explanation for this is that estrogen increases the synthesis of nitric oxide, a chemical that relaxes the lower esophageal sphincter. Support for this comes from a study of over 350 subjects with moderate or severe symptoms of heartburn due to regurgitation. Half were given a cocktail containing melatonin, a readily available sleep aid supplement that inhibits the production of both nitric oxide and stomach acid. The other half received a similar cocktail that replaced the melatonin with Prilosec, a nonprescription proton pump inhibitor. After seven days, 100 percent of those in the melatonin group reported marked improvement, compared with only 66 percent after nine days on Prilosec.

Stress, Heartburn, Dyspepsia, Pyrosis And ''Agita''

The first scientific report on physiologic responses to stress was actually Walter Cannon's study of the effects of stress on the esophagus. In 1896, during his first year as a Harvard medical student, he had been assigned to investigate the mechanisms of swallowing by taking advantage of the newly discovered Roentgen rays. These x-rays, as they were later called, could display a faint image of internal body structures using a fluoroscope but it was necessary to sit in a very dark room or wear red goggles to get the best results. Cannon included bismuth in foods since it was opaque and blocked x-rays, which markedly improved his ability to distinguish the peristaltic motion of waves that progressively propelled the contents of the gut forward. Bismuth was subsequently replaced by barium sulfate, which was less toxic, and is still used in GI series, barium enemas and other x-ray imaging procedures. As an aside, medications containing bismuth, like Pepto Bismol, also show up on x-rays and should be avoided for two or three days before any such diagnostic procedures.

Cannon demonstrated the movement of a pellet through the gullet of a goose using his new technique at a meeting of the American Physiological Society. The results of this and other studies showing the effects of stress on the esophagus and stomach were published in 1898 in the inaugural issue of The American Journal of Physiology in a paper entitled ''The movements of the stomach studied by means of roentgen rays'' He continued his research after graduating in 1900, and in 1906, was appointed Professor and Chairman of the Department of Physiology at Harvard and served in this position for 36 years. In a 1911 publication, ''Conditions affecting the activities of the cardia'', he explained how acid reflux occurred as a normal phenomenon. The ''cardiac sphincter'' (now called the lower esophageal sphincter) located at the junction between the esophagus and stomach was a thickened band of circular smooth muscle. When stimulated to contract, it prevented the backup of gastric contents into the esophagus, and provided ''pleasant security'' from its ''nauseating odors and highly disagreeable taste.'' However, everyone normally experiences some degree of reflux that usually causes no symptoms or damage, and this is particularly common in infants. Cannon described in detail this spontaneous and periodic occurrence of normal reflux as follows, ''I noted repeated regurgitation from the stomach into the esophagus…. The animal lay comfortably on a holder, unanesthetized, and was examined by means of the X rays. Each regurgitation was followed at once by a peristaltic wave which pushed the escaped material back again into the stomach. Soon after it was thus restored, the cardia again relaxed and it again rushed out.'' He reasoned that the ability to temporarily deactivate the cardiac sphincter was particularly important in cattle, sheep and goats that chew a cud consisting of regurgitated, partially digested food. These and other ruminant animals with compartmentalized stomachs need to be able to vent the large volumes of gas that are generated to maintain proper gut function. Reflux and vomiting are also valuable protective mechanisms when toxins are ingested that require a coordinated deactivation of sphincter activity. In 1912 he demonstrated that hunger pangs were due to cramp-like contractions of the stomach.

Cannon had observed early on that peristaltic waves ceased whenever his experimental animals were under stress or excited, which aroused his interest in the autonomic nervous system. Starting in 1911, he and many of his students published numerous papers over the following two decades, showing how stress stimulated the sympathetic system and the adrenal medulla to produce visceral and other changes in body function that could facilitate life saving ''fight or flight.'' As he wrote in his 1945 autobiography, The Way of an Investigator. A Scientist's Experiences in Medical Research: ''The whole purpose of my effort was to see the peristaltic waves and to learn their effects. Only after some time did I note that the absence of activity was accompanied by signs of perturbation, and when serenity was restored the waves promptly reappeared. This observation, a gift for my troubles, led to a long series of studies on the effects of strong emotions on the body. The idea flashed through my mind that [these changes] could be nicely integrated if conceived of as bodily preparations for supreme effort in flight or in fighting. The inhibition of digestive activity by emotional excitement was an interruption of a process which is not essential in a life-or-death emergency and which uses a supply of blood urgently needed elsewhere.''

The earliest recorded use of the term ''heartburn''' was in the 18th century, to describe a sharp, gnawing or burning pain under the lower sternum that could radiate upwards to the neck. Pain was often worsened by bending or lying down and was usually located in the epigastric region where the esophagus joins the stomach. As noted above, this area had previously been named the cardia, since it was originally believed that such symptoms emanated from the heart. Cardiospasm is still used to refer to a spasm of the lower esophageal sphincter that causes chest pain, regurgitation of food and inability or difficulty in swallowing. It has largely been replaced by achalasia, (from the Greek a, no or without and khalasis, relaxation, which comes from khalān, to loosen). Although there may be a physical basis, there is little doubt that this condition can be caused or aggravated by stress. In one study of 25 male and female patients with cardiospasm, all but one stated that the attack had been precipitated by severe emotional stress and that they had previously not been able to ''ventilate'' their problems. It was not until 1934 that complaints of heartburn were correlated with reflux-induced esophageal inflammation because patients described lower substernal pain that was accompanied by ''sour'' regurgitation and ''belching''. Although reflux-induced chest pain is not indicative of heart disease, some overlap still occurs, since indigestion or ''dyspepsia'', terms that refer to epigastric distress, are complaints that are not uncommon in patients with coronary disease, especially those with impending infarcts.

The medical term for heartburn is pyrosis, from pyrōsis, the Greek word for burning. This can be severe at times, since gastric acid can be stronger than the acid in car batteries. In French, heartburn is br?lure ?pigastrique (burning or searing sensation in the upper abdomen), in Spanish and Italian, arder de est?mago and bruciore di stomaco (burning in the stomach) and in Yiddish, it is harz-brenenisch, (heart burning), which reflects its American roots. In that regard, there is also ''agita'', an Italian-American slang word of uncertain origin. Some linguists believe this comes from agitare, Italian for ''to agitate' or ''to trouble'', which is derived from the Latin agitare, meaning ''to stir up.'' To be ''agitato'' is to be very excited and a musical score marked ''agitato'' is intended to be played at a frenzied pace. Others suggest that the source is ''acido'' (pronounced Ah-chee-do), Italian for ''stomach acid,'' which later became ''agita'' (Ah-jih-ta). In either case ''agita'' seems to have arrived in New York with Italian immigrants around the turn of the last century. It has been in constant use since then, especially in New York City and other metropolitan areas, where it is often more synonymous with stress than heartburn. Comedian Jackie Mason explained ''agita'' as ''when you have been aggravated to the point where it feels like you have a serious migraine headache throughout your whole body.'' Woody Allen, nominated for an Academy Award for his 1984 film, Broadway Danny Rose, made the song ''Agita'' it's centerpiece. The setting was the Carnegie Delicatessen, a famous Jewish eatery and gathering place in Manhattan. Although the song dealt with indigestion, its thrust was that ''agita'' is the Italian-American equivalent of ''tsuris'', which is Yiddish for ''misery''.

Stress, GERD, Gastritis, Stomach And Duodenal Ulcers

It is estimated that more than 40 percent of U.S. adults have heartburn at least once a month and that 7 percent experience it daily. How many actually suffer from GERD is more difficult to determine since these terms are frequently used as synonyms, especially in TV ads for drugs. Patients are also confused and are likely to refer to their complaints as GERD, since this may have more of the connotation of a disease over which they have little control. Having heartburn is less socially acceptable because it can result from overindulgence, eating the wrong foods and other faulty and preventable habits that imply some defect in character such as lack of will power. As noted previously, an association between heartburn and stress has long been recognized. A recent Gallup poll found that 64 percent of respondents with heartburn reported that stress increased their symptoms. To verify this, researchers studied sixty subjects with current heartburn symptoms and rated the frequency and severity of stressful life change events that had been experienced over the preceding 6 months. They were then followed for 4 months, during which symptom severity and quality of life were recorded in a daily diary and levels of anxiety and depression were measured. The results confirmed that severe and/or sustained stress during the previous 6 months significantly predicted an increase in heartburn symptoms during the 4 month follow-up period. Heartburn severity correlated best with major life stress events rather than an accumulation of minor stresses or change in mood, although chronically depressed patients reported taking more heartburn medications.

It was initially assumed that stress induced heartburn resulted from an increase in the frequency and or duration of acid reflux events. However, one study found that when heartburn patients were subjected to acute stress in a laboratory setting, there was no evidence of increased acid measured by a probe placed at the end of the esophagus. Moreover, acid concentrations were similar when those patients who reported increased symptoms during stress were compared to others who had no change in complaints. Other attempts to demonstrate increased acid in the esophagus during stress have also yielded negative results, despite higher concentrations of acid in the stomach.

(To be continued next week…)

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Be sure and read Part 2 of this article in next week's
Youthful Aging Health Newsletter by guest author:
Paul Rosch, M.D. , American Institute of Stress.