EPIDEMIOLOGICAL STUDIES

Gallbladder Disease in Pima Indians

In a study of an American Indian tribe the prevalence of diagnosed gallbladder disease was found to be six times higher than that in a similar study done among Caucasians in Framingham, Massachusetts. The Pima Indians of the Gila River Reservation were examined by Institute scientists at the Clinical Field Studies Unit in Phoenix, Arizona, and were compared with the Framingham population.

Epidemiological studies, which evaluate relationships of various factors (such as age, sex, environment) and determine frequencies and distributions of disease states in specific human communities, are necessary to clarify the determinants of gallstone formation.

In both sexes, significantly more gallbladder disease was found in the Pimas than in the people of Framingham; for example, 5.9 percent of Framing females aged 30-62 had "definite" gallbladder disease, as compared with 36.0 percent among Pima females of the same ages. The study also showed the relationship of the disease to age in each sex. Pima males had little gallbladder disease prior to the age of 55, while Pima females showed a high prevalence of the disease in all decades after the second.

Having documented a high prevalence of gallbladder disease in these Indians, the scientists tried to associate this with possible predisposing conditions. None of the following factors increased numbers of pregnancies. diabetes, body weight, serum cholesterol, or diet appeared to be responsible for the excess gallbladder disease in the Pimas.

Further biochemical and physiologic studies to supplement the current epidemiologic investigations are continuing in an effort to find out whether genetic or environmental factors play the stronger role in determining the difference in the frequency of gallbladder disease between these American Indians and Caucasians.

Red-Cell Defect and Chronic Bowel Disease

A simultaneous occurrence of two uncommon diseases in several families originating from a relatively circumscribed geographical region has been the subject of epidemiological investigation for Institute-supported scientists at Boston Floating Hospital of the New England Medical Center Hospitals and at Tufts University School of Medicine, also in Boston.

Erythrocyte glucose-6-phosphate dehydrogenase deficiency (G6PD) and chronic granulomatous bowel disease were the two unusual diseases observed. The G6PD disorder, a red blood cell metabolic defect due to mutations of

enzyme structures, is inherited as a sex-linked characteristic. It is found largely among persons with a Mediterranean or African ancestry and the administration of a number of common drugs (such as the sulfonamides) may lead to hemolysis (destruction of red blood cells) in patients with G6PD deficiency.

Closely related forms of chronic granulomatous bowel disease of unknown origin are regional enteritis and granulomatous colitis (small and/or large bowel inflammation and granulomatous scarring). Previous studies have shown that 10 percent of those affected with regional enteritis have close relatives also afflicted with granulomatous diseases of the bowel, suggesting a genetic link.

In the Boston study, the G6PD deficiency was found in association with either regional enteritis or granulomatous colitis in five unrelated persons of Ashkenazic Jewish origin. In two of these five, four further family members were found to have both diseases. A survey of 53 patients with regional enteritis and granulomatous colitis revealed G6PD disease in 9.6 percent, whereas none of 50 patients with ulcerative colitis, another colon disorder, had a similar red-cell defect.

Several of the agents commonly recommended for treatment of regional enteritis may lead to marked hemolysis in patients with a severe form of red-cell G6PD deficiency. Therefore, all patients with chronic granulomatous diseases of the bowel, especially those with the familial form, should be tested for the red-cell defect before drug therapy is initiated. Antacids and Gastric Hypersecretion

Rebound gastric hypersecretion induced by some antacids has long been suspected, and recently, investigators at the University of Texas Southwestern Medical School in Dallas reported that a commonly used antacid, calcium carbonate, induces rebound gastric hypersecretion in duodenal ulcer patients in contrast to aluminum-magnesium hydroxide and sodium bicarbonate, two other commonly used antacids.

Extensive investigations in a patient sensitive to calcium carbonate were made to discover the mechanism by which this antacid induces hypersecretion. Apparently, calcium salts provoke gastric hypersecretion through the action of calcium ion within the gastrointestinal tract, an action potentiated by ingestion of food. Although calcium carbonate therapy, in addition to neutralizing gastric acid, also increases serum calcium concentration, the data obtained suggested that hypercalcemia is not the mechanism by which this antacid stimulates gastric secretion. The clinical significance of this finding is clear because calcium carbonate is extensively used in treatment of peptic ulcer, but whether this has a deleterious effect on the long-term course of peptic ulcer is not yet known.

OUTLOOK

The wide-ranging and significant accomplishments of the past year in the treatment or prevention of malabsorptive disorders, regional enteritis, and fatty livers precursor of cirrhosis of the liver- give renewed hope for improved diagnostic, therapeutic, and surgical techniques.

While some of these advances have found immediate application at the bedside, others, of a more basic nature, are contributing to the broader base of research knowledge from which comes future progress in these disorders. These and other research findings are systematically uncovering promising scientific approaches in the search for improved treatment for the millions of individuals disabled by gastrointestinal diseases.

SPECIAL REPORT:

GASTROENTEROLOGY

Encompassing all the diseases of the digestive tract, which may range from peptic ulcer and ileitis to ulcerative colitis, gastroenterology is an area of medicine perhaps second only to heart disease in the frequency of physician house calls and office visits required. There are numerous diseases of the gastrointestinal tract and its associated organs about which much remains to be learned, such as diseases of the liver, gallbladder and pancreas. The diversity and magnitude of these disorders combine to place these diseases in a high position among the chronic afflictions affecting man.

The National Institute of Arthritis and Metabolic Diseases (NIAMD) bears the responsibility for the Government's program of research in gastroenterology. The increasing research interest in gastrointestinal disorders had led to the establishment during this reporting year of a Digestive and Hereditary Diseases Branch within the Institute. Enhancing the research interest of the former Gastroenterology Section, which it supersedes, the Branch is conducting clinical and laboratory investigations to determine abnormalities in structure and function of the esophagus, stomach, small and large intestines, pancreas and liver, and research on certain hereditary metabolic diseases. Other investigations are seeking to clarify enzyme and metabolic pathways within the tissues of the gastrointestinal tract. Branch scientists are also examining the pathogenesis of digestive diseases and studying improved treatment methods.

Through grants to scientists at research centers across the country, a broad array of ailments of the digestive tract is also undergoing investigation. Research progress has been achieved only through the most intensive and comprehensive laboratory experiments and clinical trials. The past year

has seen the development of numerous important research findings, several of far-reaching importance.

Research Developments

Prevention of Gastrointestinal Bleeding

It is well known that large doses of aspirin in tablet form may cause a significant degree of gastrointestinal bleeding in many patients. This is of special interest in the management of patients with rheumatoid arthritis where aspirin, in high doses, is the initial drug of choice because of its antiinflammatory and analgesic action.

Institute grant-supported scientists at Case Western Reserve University and the State University of New York have shown that aspirin-induced gastrointestinal bleeding may be reduced or prevented by administering the drug in a soluble form in a buffered effervescent solution. The data suggest that the gastrointestinal blood loss associated with administration of aspirin in tablet (solid) form, especially when given in large doses, is a local rather than systemically mediated phenomenon, and that the bleeding potential of available aspirin preparations can be reduced or even eliminated by appropriate pharmaceutical formulation.

Prepared January 1970 as background information for the Director, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, U. S. Department of Health, Education, and Welfare, in connection with the fiscal year 1971 appropriation hearings.

The aspirin solutions were also more rapidly absorbed and, thus, caused higher plasma salicylate concentrations than did the aspirin tablets, lending support to the theory that aspirin-induced gastrointestinal blood loss is a local rather than a systemic effect. Further development may provide a sodium-free agent with just sufficient buffering capacity to prevent such bleeding and to permit side effect-free long-term administration of aspirin in high doses. The possible use of sodium-free buffering agents may further enhance the suitability of such solutions for the longterm administration of aspirin in high doses.

Chest Pain of Unexplained Origin

A definitive etiological diagnosis is often difficult to establish in patients with symptoms of substernal pain, difficulty in swallowing, or both, and such unexplained chest pain may be misinterpreted as being of cardiac origin. A study by Institute-supported scientists at the University of Alabama Medical Center has shown that excessive stomach muscle contractions should be considered as the source of difficulty in such patients, inasmuch as such a diagnosis can easily be established and appropriate and effective treatment is available.

During a two year period, eleven of 381 patients referred for diagnostic testing of the esophagus were found to have excessive contractions at the gastroesophageal junction. The principal characteristic of these patients was the prolonged duration of contraction. Symptomatically, chest pain and difficulty in swallowing were prominent complaints.

The condition of the symptomatic patients usually improved with reassurance, symptomatic treatment, and medical management of hiatal hernia which co-existed. Surgery provided excellent relief of symptoms in two of the latter patients.

New Approaches to Peptic Ulcer Treatment

Several years ago NIAMD-supported investigators at Washington University, St. Louis, successfully produced antibodies in rabbits that were directed against the functional portion of the gastrin molecule. Subsequently, they showed in animal studies that these antibodies inhibit the ability of exogenous gastrin to stimulate the secretion of gastric acid in the stomach.

The same team of scientists, during the past year, has shown in animal studies that the same antibody preparation also inhibits the potent gastric acid stimulatory action of endogenous by-produced gastrin. The degree of antibody inhibition of gastric acid secretion in experimental rats averaged 73 percent.

Inhibition of excessive gastrin-mediated acid secretion might have important clinical application. It is possible that acid secretion rates and, thereby, disease processes associated with excessive secretion of gastric acid, such as peptic ulcer, may be modified by antibody binding of endogenous gastrin molecules.

Unrestricted Diet in Ulcer Treatment

In another important finding, Institute-supported researchers at the Veterans Administration Hospital and the University of Iowa College of Medicine, have found that the traditional ulcer diet ("bland diet") does not affect the outcome in the treatment of patients with duodenal ulcers.