Lab Tests and procedures
H2 Blockers and Continued Reflux
Proton Pump Inhibitors and Adenocarcinoma Risk
Nutrient and Supplemental Therapy
FUNCTIONAL AND PRACTICAL MEDICINE
GERD and Esophageal Cancer
Cooperative Nutrient Interactions
Life Style Changes
LIFE EXTENSION’S INTEGRATED PROTOCOL
OVERVIEW OF GASTROESOPHAGEAL REFLUX DISEASE
Acid reflux or heartburn is a very common condition; 14% of Americans experience daily symptoms, while weekly symptoms are experienced by 20%. (Locke GR, III, Talley NJ et al. 1997;Nandurkar S, Talley NJ 2000)Known medically as gastroesophageal reflux disease, or GERD, it is caused by backflow of stomach contents into the esophagus.
Heartburn occurs after eating and can last from a few minutes to a few hours. It is a burning sensation that can begin in the pit of the stomach or lower breastbone region. The sensation can then move upward into the chest and throat, causing a bitter acid taste. Heartburn is called acid regurgitation, acid indigestion, or sour belching. Heartburn occurs from bending over or lying down. When esophageal inflammation occurs, symptoms manifest as a sharp, stabbing pain in the center of the chest. Symptoms can take a week to subside, even after initiation of acid-suppressing therapy. (Goyal RK 2001)
Malfunctioning of the lower esophageal sphincter, which allows gastric contents to reflux back into the esophagus, causes GERD. The lower esophageal sphincter is a circular band of muscle found at the junction of the esophagus and stomach. The sphincter is normally closed due to contraction of the sphincter muscles, but it opens briefly during swallowing in response to a stimulus from the vagus nerve. It also opens to permit belching and vomiting. When the sphincter is closed, pressure at the sphincter is greater than in the stomach, thereby blocking reflux. Reflux occurs when normal muscle tone of the lower esophageal sphincter is relaxed. Increased pressure on the stomach walls, either from consumption of large meals or from obesity, can cause sphincter relaxation. Pregnancy causes an increased incidence of reflux due to the relaxing effect of the hormone progesterone on the sphincter. Drugs can lead to sphincter relaxation.
The components of reflux can come from the stomach or duodenum (the first part of the small intestine). When food enters the stomach, bulk of the food and certain substances in the food stimulate secretion of the hormone gastrin. Gastrin stimulates secretion of hydrochloric acid, which activates the enzyme pepsin. When acid levels are normal, a feedback mechanism shuts down gastrin secretion. When partially digested food (chyme) enters the duodenum, bile and other digestive enzymes are secreted. These duodenal contents can reenter the stomach under some circumstances.
Risk factors associated with GERD are BMI (body mass index), sex, and estrogen replacement therapy. (Nilsson M, Johnsen R et al. 2003)BMI, the most widely used method to express obesity, is directly associated with reflux symptoms in males and females. The association is strong in females, particularly postmenopausal women receiving estrogen-only hormone therapy. (Nilsson M, Johnsen R et al. 2003) Genetic predisposition may be a risk factor particularly in families with multiple affected members. (Hu FZ, Preston RA et al. 2000;Trudgill N 2002;Trudgill NJ, Kapur KC et al. 1999)
The highly acid conditions in the stomach are necessary to begin the digestion of proteins. The stomach protects itself by the secretion of thick mucus that coats the stomach lining. A majority of patients exhibiting symptoms of heartburn have non-erosive reflux disease with normal-appearing esophageal mucosa (inner lining). (Bateman DN, Colin-Jones D et al. 2003) However, injury can occur to the esophageal mucosa because it lacks a serosal coat lining similar to the stomach that could provide protection against acid reflux. Injury causes an immune response characterized by inflammation. GERD can progress to the erosive phase, which is characterized by mucosal damage, redness, friability, bleeding, ulcers, and exudates. Untreated GERD can result in excessive growth of fibrous connective tissue with narrowing of the esophageal passageway. This condition causes constriction of the esophageal opening, making swallowing difficult.
Severe reflux esophagitis may cause a change in epithelial cell structure from the normal squamous form to the columnar form. Although the columnar form is abnormal for the esophagus, it is actually a protective response from the body: the columnar form is more resistant to acid and pepsin damage. Barrett’s esophagus can be partially reversed, but not totally cured. Barrett’s esophagus is particularly important due to the risk of progression to esophageal cancer.
There are two types of esophageal cancer: squamous cell and adenocarcinoma.
Squamous cell esophageal cancer has been largely attributed to causes not related to GERD (e.g., smoking and alcohol consumption). (Mayer R 2001)
Adenocarcinoma arises within the columnar epithelium that is characteristic of Barrett’s esophagus. It typically occurs in the lower third of the esophagus, the region with greatest exposure to reflux. A possible association exists between GERD symptoms and esophageal adenocarcinoma. The more frequent, more severe, and more long-lasting the symptoms of reflux are, the greater is the risk of adenocarcinoma. (Lagergren J, Bergstrom R et al. 1999)Over the past 25 years, incidence of adenocarcinoma has increased 350% faster than any other malignancy in the western world. (Glenn TF 2001)
A history detailing a patient’s symptoms is sufficient to diagnose GERD. If GERD is more complex, more diagnostic tests may be used. (Goyal RK 2001;Rodrigues SL 2003;Topazian M 2005)
Lab Tests and Procedures
Barium swallow is a radiological test used if symptoms include dysphasia (difficulty in swallowing). The patient drinks a barium solution. Barium coats the esophagus, so an X-ray outlines the esophageal lining. Barium reveals esophageal ulcers or a narrowed esophagus.
Endoscopy (esophagoscopy) identifies lesions not identified by barium. A physician examines the esophagus through a flexible viewing tube. Biopsies are taken during the procedure if there is suspicion that GERD has progressed to cancer.
Esophageal manometry determines proper functioning of the esophagus and lower esophageal sphincter. A physician passes a catheter through the nose and esophagus into the stomach. The patient drinks a small quantity of water. The catheter is slowly withdrawn while measurements are made of the peristaltic activity of the esophagus and the pressure of the lower esophageal sphincter.
pH monitoring is a procedure that correlates symptoms with presence of acid is in the esophagus.
Mechanisms of Action
Pharmacology refers to the mechanisms by which drugs exert their effects on the body. A broad range of drug treatments is available for GERD that has benefits and potentially harmful effects. (Horwitz BJ, Fisher RS 1995)
Antacids are the first medications commonly used in GERD. Antacids function to neutralize stomach acidity, which can irritate the esophageal lining during reflux. Typically, antacids used are aluminum or magnesium hydroxides or sodium bicarbonate. These antacids allow sustained neutralizing action, but do not accumulate to corrosive levels. Examples of antacids are Maalox®, Gelusil®, Mylanta®, Rioplan®, Tums®, Maalox®, and Milk of Magnesia®.
H2 blockers prevent secretion of acid by inhibiting the action of histamine. Examples of H2 blockers are Tagamet®, Zantac®, Axid®, and Pepsid®. (Hoogerwerf W, Pasricha P 2001)
Proton Pump Inhibitors
Proton pump inhibitors inhibit secretion of acid by preventing the secretion of protons from inside the parietal cells of the stomach to the stomach cavity. Proton pump inhibitors have been found especially useful when GERD is not well controlled by H2 blockers. (Vanderhoff BT, Tahboub RM 2002)Examples of proton pump inhibitors are Nexium®, Prilosec®, and Prevacid®.
Baclofen is a unique drug that acts to overcome the basic problem in GERD. Baclofen directly inhibits lower esophageal sphincter relaxations thereby preventing reflux.
Baclofen significantly reduced the number of reflux episodes, including reductions in frequency and intensity of symptoms, including pain, regurgitation, and bitter taste. The percentage of time that the esophagus was exposed to acid conditions was also significantly lower. (Ciccaglione AF, Marzio L 2003;Zhang Q, Lehmann A et al. 2002)
H2 Blockers and Continued Reflux
Long-term use of H2 blockers could be dangerous for individuals who have GERD. Although these agents help suppress the symptoms of heartburn pain, reflux can still occur which causes continuing damage to the esophagus. Continuing reflux consists of pepsin, as well as duodenal components such as bile and trypsin. Some physicians are concerned that suppressing heartburn pain with H2 receptor antagonist drugs might result in patients not making the lifestyle changes needed to control chronic esophageal reflux. Failure to adequately control GERD can result in esophagitis and esophageal cancer. (Farrow DC, Vaughan TL et al. 2000;Suleiman UL, Harrison M et al. 2000)
Proton-Pump Inhibitors and Adenocarcinoma Risk
Short-term use of proton-pump inhibitors cures 90% of esophagitis cases. Increasingly, physicians prescribe these drugs for long-term use to prevent heartburn and to keep esophagitis from returning. However, other components of reflux, including conjugated and unconjugated bile acids, pancreatic trypsin, and gastrin can irritate the esophageal lining. (Shepherd NA 2000)The use of proton-pump inhibitors results in low stomach acid levels. This situation results in a more continuous secretion of gastrin because the feedback inhibition of normal acid levels is not active. Excess levels of gastrin are associated with cell growth in Barrett’s esophagus. (Haigh CR, Attwood SE et al. 2003)Adenocarcinoma cells of the esophagus have a large number of gastrin receptor sites. (Moore TC, Jepeal LI et al. 2004)Binding of gastrin to these receptor sites stimulates proliferation of esophageal adenocarcinoma cells.
Several research groups investigated the role of continued reflux of bile on progression of Barrett’s esophagus and concluded that bile plays a significant role in esophageal disease, in synergism with other constituents of reflux, and may contribute to complications of Barrett’s esophagus. (Marshall RE, Anggiansah A et al. 1997;Nehra D, Howell P et al. 1998;Vaezi MF, Richter JE 1997;Vaezi MF, Singh S et al. 1995)
Nutrient and Supplemental Therapy
Food Groups: Relationship to Esophageal Cancer
A relationship of dietary components to incidence of GERD and esophageal cancer is well established. At least 26 studies confirmed a beneficial effect of fruits and vegetables in prevention of esophageal squamous cell cancer. (Block G, Patterson B et al. 1992;Cheng KK, Day NE 1996;Tzonou A, Lipworth L et al. 1996)Fruits, vegetables, and fiber also have protective effects against adenocarcinoma. (Chen H, Ward MH et al. 2002;Dworak O, Kuspert G 1995;Wolfgarten E, Rosendahl U et al. 2001)
Vegetables and fruits can protect against cancer due to their content of phytochemicals (plant chemicals). (Steinmetz KA, Potter JD 1991) Among the thousands of phytochemicals identified, three are particularly promising. Indole-3-carbinol and sulforaphane in the form of glucosinolates are found in cruciferous vegetables, such as cabbage, broccoli and Brussels sprouts. Resveratrol is found in grapes and other fruits.
Common vitamin supplements lower esophageal cancer risk. Many studies have shown that vitamins C, E, and beta-carotene significantly reduced the risk of adenocarcinoma and squamous cell cancer. (Blot WJ, Li JY et al. 1993a;Bollschweiler E, Wolfgarten E et al. 2002;Taylor PR, Li B et al. 1994;Terry P, Lagergren J et al. 2000;Zheng W, Sellers TA et al. 1995)Other studies have shown that folic acid, niacin, and riboflavin may have a protective effect when part of supplement packages. (Chen H, Tucker KL et al. 2002;Franceschi S, Bidoli E et al. 2000;Siassi F, Pouransari Z et al. 2000)
Selenium is an essential trace element with a protective effect against many cancers. Adequacy of selenium in humans, as measured by serum selenium levels, appears to be related to susceptibility to esophageal cancer. (Mark SD, Qiao YL et al. 2000;Rudolph RE, Vaughan TL et al. 2003)
Digest RC, a natural herbal supplement, has been introduced in the United States after being used very successfully in Europe. Digest RC enhances peristaltic movement and facilitates digestion of fats and proteins by promoting release of bile. When Digest RC facilitates digestion, food moves out of the stomach faster. Improved digestion reduces pressure on the lower esophageal sphincter associated with a risk of relaxation and subsequent opening of the sphincter.
Individuals with certain diseases, as well as the elderly, may lack sufficient digestive enzymes to adequately digest food. (Watson WC 2005)These individuals may benefit from taking supplemental enzyme products that contain protease, amylase, and lipase. These enzymes should be protected from acid breakdown in the stomach, so they can exert their effects in the small intestine.
Particularly in Asia, a direct relationship exists between green tea consumption and protection against esophageal cancer, an effect apparently due to polyphenols, a natural antioxidant compound found in tea plants. Green tea consumption had a significant protective effect to prevent esophageal cancer in women; the effect was non-significant for men. If subjects did not smoke or drink alcohol, the protective effect benefited both sexes. (Gao YT, McLaughlin JK et al. 1994)Other studies described beneficial effects of green tea consumption against risk of esophageal cancer. (Bushman JL 1998;Cheng KK, Day NE 1996)
DGL (a product known as deglycyrrhyzinated licorice) protects the digestive tract from stomach acids by increasing the number of mucus-secreting cells from glands in the upper portion of the stomach (the fundus). Mucus coats and protects the lining of the stomach and esophagus. (van MJ, Aarsen PN et al. 1981)Studies have shown that DGL significantly promotes healing of aphthous ulcers (canker sores). (Das SK, Das V et al. 1989;Turpie AG, Runcie J et al. 1969)
Alginic acid-based products (Gastrocote®, Gaviscon®) diminish GERD with foaming, floating, viscous properties, (Malmud LS, Charkes ND et al. 1979) and alleviate symptoms. (Eriksen CA, Cheadle WG et al. 1988)
FUNCTIONAL AND PRACTICAL MEDICINE
GERD and Esophageal Cancer
Untreated GERD can result in erosive esophagitis. Long-term complications can result in Barrett’s esophagus, precancerous changes which can eventually lead to esophageal adenocarcinoma. Pharmacological treatment reduces acid content in the stomach with antacids, H2 receptor antagonists, and proton pump inhibitors. These drugs effectively relieve heartburn symptoms, but reflux and other stomach components can continue to damage the esophagus. (Shepherd NA 2000)
(The Risk Factors section describes the disease progression complications of GERD, and the Pharmacotherapeutics section describes the risks associated with the use of H2 blockers and proton pump inhibitors on disease progression).
Cooperative Nutrient Interactions
The antioxidant nutrients vitamin A, beta-carotene, vitamins C and E, and selenium were most often associated with lower incidence of adenocarcinoma. (Blot WJ, Li JY et al. 1993b;Bollschweiler E, Wolfgarten E et al. 2002;Taylor PR, Li B et al. 1994;Zheng W, Sellers TA et al. 1995) Antioxidant nutrients protect against cancer by neutralizing free radicals before they can harm tissue, the first step in development of cancer. (Oh TY, Lee JS et al. 2001) Antioxidants can stimulate cancer suppressor genes and inhibit blood vessel formation in tumors (angiogenesis). (Shklar G 1998)
Vitamin A helps maintain mucus membranes in the esophagus and stimulate cell differentiation. Cancer cells are noted for lack of differentiation. Adequate vitamin A can promote cancer cell death by apoptosis. Vitamin C stimulates the immune system and protects white blood cells. Vitamin E appears to protect cell membranes from oxidation. Selenium in cell cytoplasm destroys free radicals before they damage cell membranes. Selenium and vitamin E acts in concert to protect cell membranes. (Scott ML 1986)
Vitamin B12 (cobalamin) is intimately associated with folic acid metabolism. Without cobalamin, folic acid cannot perform its role in nucleic acid synthesis and red blood cell formation. H2 blockers and proton pump inhibitor drugs can interfere with the utilization of cobalamin. To be utilized, cobalamin must be released from native proteins in foods by the action of hydrochloric acid and pepsin. Additionally, intrinsic factor must be secreted from parietal cells of the stomach along with hydrochloric acid. Studies have shown that H2 receptor drugs suppress gastric acid and intrinsic factor secretion, resulting in cobalamin malabsorption. (Binder HJ, Donaldson RM, Jr. 1978)Studies have shown that the proton pump inhibitor drug omeprazole causes malabsorption of cobalamin from protein bound cyanocobalamin, but not from the purified vitamin.
Use of drugs that reduce stomach acidity is associated with a weak acid environment in the stomach. Yet, the stomach is not intended to have a weak acid environment. An important function of hydrochloric acid in the stomach is to begin protein breakdown. Digestion of proteins is completed in the small intestine, with absorption of individual amino acids into the blood stream. If the initial acid breakdown of proteins is compromised, there is risk that protein fragments may stimulate an allergic reaction. Food allergies are an immune response involving T-cells or B-cells. Although many factors are involved, incomplete digestion may cause an allergic reaction to some food proteins that normally would not cause allergies. (Bannon GA 2004;Kimber I, Dearman RJ 2002;Untersmayr E, Scholl I et al. 2003)
Life Style Changes
GERD symptoms can be alleviated without drugs. Lifestyle changes can control GERD in as many as 20% of patients. (DeVault KR 1996)
- Weight reduction. Obesity increases pressure on the abdomen and stomach which can increase pressure on the lower esophageal sphincter and cause reflux. If weight is above guidelines for your height and sex, undertake a weight reduction program. (Nilsson M, Johnsen R et al. 2003;Nilsson M, Lagergren J 2004)
- Smoking. Smoking increases GERD symptoms. It decreases lower esophageal sphincter pressure and reduces salivary secretion. (Pandolfino JE, Kahrilas PJ 2000;Smit CF, Copper MP et al. 2001;Trudgill NJ, Smith LF et al. 1998)
- Fatty foods. The relationship of dietary fat with GERD is unclear. Dietary fat is thought to delay emptying of stomach. Reducing dietary fat is important for overall health and part of an overall strategy to reduce GERD symptoms. (Colombo P, Mangano M et al. 2002;Pkehl C, Waizenhoefer A et al. 1999;Penagini R, Mangano M et al. 1998;Ruhl CE, Everhart JE 1999)
- Irritating foods and beverages. Avoid tomatoes, garlic, onions, chocolate, peppermint, coffee, and citrus fruits that can irritate the digestive tract. Reactions vary considerably. Monitor reactions to specific foods.
- Meal size and frequency. Avoid eating large meals that can stimulate sensors that affect lower esophageal sphincter relaxation. Eat smaller meals more frequently, perhaps four or five times daily. Do not eat for at least 2 or 3 hours before bedtime.
- Elevate the head. Use gravity to help keep stomach contents out of the esophagus. Elevate the head at least 6 inches (e.g., with telephone books, foam, or wood blocks; pillows are less effective). Lie on the right side to exert less pressure on the esophageal sphincter (the esophagus is on the left side as it enters the stomach). (Gray H 1995)
- Limit aspirin, ibuprofen, and other NSAIDs. NSAIDs (nonsteroidal anti-inflammatory drugs) inhibit formation of prostaglandins, thus promoting reflux. Prostaglandins inhibit gastric acid secretion and stimulate secretion of mucus and bicarbonate to minimize the effects of acid reflux.
LIFE EXTENSION’S INTEGRATED PROTOCOL
- Vitamin A: 5000 IU (part in the form of beta carotene)
- Vitamin C: 150–500 mg
- Vitamin E: 30–200 IU
- Folic Acid: 800 mcg
- Vitamin B12: 300 mcg (amount this high needed only with long-term acid-reduction therapy)
- Selenium: 100 mcg
- Zinc: 30 mg
- Indole-3-carbinol/resveratrol: 200 mg indole-3-carbinol and 7 mg resveratrol to reduce cancer risk
- Phytofood: 1 tablespoon daily provides 9 mg sulforaphane to reduce cancer risk
- Super green tea extract: 1 capsule daily provides 122.5 mg epigallocatechin gallate to reduce cancer risk (or several cups of green tea can be brewed as a beverage daily)
- Digest RC: 1-2 capsules daily with meals to alleviate GERD symptoms
- Super Digestive Enzymes: 2 capsules at the beginning of each meal to alleviate GERD symptoms (if there is reason to believe that secretion of digestive enzymes is reduced)
About the Author
David Olle holds a M.S. in Biochemistry and Certificates in Medical Writing. He is a freelance writer, and specializes in gastrointestinal diseases and cancer. He has broad experience in animal nutrition and veterinary drug development. David has coordinated clinical trials and prepared documents for FDA submissions.
Bannon GA. What makes a food protein an allergen? Curr Allergy Asthma Rep. 2004 Jan;4(1):43-6.
Bateman DN, Colin-Jones D. et al. Mortality study of 18 000 patients treated with omeprazole. Gut. 2003 Jul;52(7):942-6.
Binder HJ, Donaldson RM, Jr. Effect of cimetidine on intrinsic factor and pepsin secretion in man. Gastroenterology. 1978 Feb;74(2 Pt 2):371-5.
Block G, Patterson B. et al. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18(1):1-29.
Blot WJ, Li JY. et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993 Sept 15a;85(18):1483-92.
Blot WJ, Li JY. et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993 Sept 15b;85(18):1483-92.
Bollschweiler E, Wolfgarten E. et al. Vitamin intake and risk of subtypes of esophageal cancer in Germany. J Cancer Res Clin Oncol. 2002 Oct;128(10):575-80.
Bushman JL. Green tea and cancer in humans: a review of the literature. Nutr Cancer. 1998;31(3):151-9.
Chen H, Tucker KL. et al. Nutrient intakes and adenocarcinoma of the esophagus and distal stomach. Nutr Cancer. 2002;42(1):33-40.
Chen H, Ward MH. et al. Dietary patterns and adenocarcinoma of the esophagus and distal stomach. Am J Clin Nutr. 2002 Jan;75(1):137-44.
Cheng KK, Day NE. Nutrition and esophageal cancer. Cancer Causes Control. 1996 Jan;7(1):33-40.
Ciccaglione AF, Marzio L. Effect of acute and chronic administration of the GABA B agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease. Gut. 2003 Apr;52(4):464-70.
Colombo P, Mangano M. et al. Effect of calories and fat on postprandial gastro-oesophageal reflux. Scand J Gastroenterol. 2002 Jan;37(1):3-5.
Das SK, Das V. et al. Deglycyrrhizinated liquorice in aphthous ulcers. J Assoc Physicians India. 1989 Oct;37(10):647.
DeVault KR. Current management of gastroesophageal reflux disease. Gastroenterologist. 1996 Mar;4(1):24-32.
Dworak O, Kuspert G. Re: Adenocarcinoma of the esophagus: role of obesity and diet. J Natl Cancer Inst. 1995 Jun 7;87(11):847-8.
Eriksen CA, Cheadle WG. et al. Combined cimetidine-alginate antacid therapy versus single agent treatment for reflux oesophagitis: results of prospective double-blind randomized clinical trial. Ann Chir Gynaecol. 1988;77(4):133-7.
Farrow DC, Vaughan TL. et al. Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer. Cancer Causes Control. 2000 Mar;11(3):231-8.
Franceschi S, Bidoli E. et al. Role of macronutrients, vitamins and minerals in the aetiology of squamous-cell carcinoma of the oesophagus. Int J Cancer. 2000 Jun 1;86(5):626-31.
Gao YT, McLaughlin JK. et al. Reduced risk of esophageal cancer associated with green tea consumption. J Natl Cancer Inst. 1994 Jun 1;86(11):855-8.
Glenn TF. Esophageal cancer. Facts, figures, and screening. Gastroenterol Nurs. 2001 Nov;24(6):271-3.
Goyal RK. Diseases of the Esophagus In: Braunwald E, Fauci AS, Kasper DL et al., Eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2001: 15(284):1642-7.
Gray H. The Stomach In: Pick TP, Howden R, Eds. Gray’s Anatomy. New York: Barnes & Noble; 1995: 15:887-94.
Haigh CR, Attwood SE. et al. Gastrin induces proliferation in Barrett’s metaplasia through activation of the CCK2 receptor. Gastroenterology. 2003 Mar;124(3):615-25.
Hoogerwerf W, Pasricha P. Agents used for control of gastric acidity and treatment of peptic ulcers and gastroesophageal reflux disease. In: Hardman JG, Limbird LL, Eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2001: 10.
Horwitz BJ, Fisher RS. Intervening in GERD: the phases of management. Hosp Pract (Off Ed). 1995 Sep 15;30(9):43-50.
Hu FZ, Preston RA. et al. Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14. JAMA. 2000 Jul;%19;284(3):325-34.
Kimber I, Dearman RJ. Factors affecting the development of food allergy. Proc Nutr Soc. 2002 Nov;61(4):435-9.
Lagergren J, Bergstrom R. et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999 Mar 18;340(11):825-31.
Laifer S. Modern Science Confirms the Myriad Disease-Preventive Effects of this Ancient Drink. Life Extension. 2005 (Jan 2005):38-44.
Locke GR, III, Talley NJ. et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology. 1997 May;112(5):1448-56.
Malmud LS, Charkes ND. et al. The mode of action alginic acid compound in the reduction of gastroesophageal reflux. J Nucl Med. 1979 Oct;20(10):1023-8.
Mark SD, Qiao YL. et al. Prospective study of serum selenium levels and incident esophageal and gastric cancers. J Natl Cancer Inst. 2000 Nov 1;92(21):1753-63.
Marshall RE, Anggiansah A. et al. Bile in the oesophagus: clinical relevance and ambulatory detection. Br J Surg. 1997 Jan;84(1):21-8.
Mayer R. Gastrointestinal Tract
Cancer In: Braunwald E, Fauci AS, Kasper DL et al., Eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2001: 15(90):578-9.
Moore TC, Jepeal LI. et al. Gastrin stimulates receptor-mediated proliferation of human esophageal adenocarcinoma cells. Regul Pept. 2004 Aug 15;120(1-3):195-203.
Nandurkar S, Talley NJ. Epidemiology and natural history of reflux disease. Baillieres Best Pract Res Clin Gastroenterol. 2000 Oct;14(5):743-57.
Nehra D, Howell P. et al. Assessment of combined bile acid and pH profiles using an automated sampling device in gastro-oesophageal reflux disease. Br J Surg. 1998 Jan;85(1):134-7.
Nilsson M, Johnsen R. et al. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. JAMA. 2003 Jul 2;290(1):66-72.
Nilsson M, Lagergren J. The relation between body mass and gastro-oesophageal reflux. Best Pract Res Clin Gastroenterol. 2004 Dec;18(6):1117-23.
Oh TY, Lee JS. et al. Oxidative stress is more important than acid in the pathogenesis of reflux oesophagitis in rats. Gut. 2001 Sep;49(3):364-71.
Pandolfino JE, Kahrilas PJ. Smoking and gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol. 2000 Aug;12(8):837-42.
Paterson WG, Mayrand S. The Esophagus. Internet.2004 First Principles of Gastroenterology:The Basis of Disease and an Approach to Management.(3).
Pehl C, Waizenhoefer A. et al. Effect of low and high fat meals on lower esophageal sphincter motility and gastroesophageal reflux in healthy subjects. Am J Gastroenterol. 1999 May;94(5):1192-6.
Penagini R, Mangano M. et al. Effect of increasing the fat content but not the energy load of a meal on gastro-oesophageal reflux and lower oesophageal sphincter motor function. Gut. 1998 Mar;42(3):330-3.
Rodrigues SL. Diagnostic Testing for GERD. ContinuingEducation Com.2003.Mar.14
Rudolph RE, Vaughan TL. et al. Serum selenium levels in relation to markers of neoplastic progression among persons with Barrett’s esophagus. J Natl Cancer Inst. 2003 May 21;95(10):750-7.
Ruhl CE, Everhart JE. Overweight, but not high dietary fat intake, increases risk of gastroesophageal reflux disease hospitalization: the NHANES I Epidemiologic Followup Study. First National Health and Nutrition Examination Survey. Ann Epidemiol. 1999 Oct;9(7):424-35.
Scott ML. The Vitamins In: Anonymous Nutrition of Humans & Selected Animal Species. New York: John Wiley & Sons; 1986(4):265-71.
Shepherd NA. Barrett’s oesophagus and proton pump inhibitors: a pathological perspective. Gut. 2000 Feb;46(2):147-9.
Shklar G. Mechanisms of cancer inhibition by anti-oxidant nutrients. Oral Oncol. 1998 Jan;34(1):24-9.
Siassi F, Pouransari Z. et al. Nutrient intake and esophageal cancer in the Caspian littoral of Iran: a case-control study. Cancer Detect Prev. 2000;24(3):295-303.
Smit CF, Copper MP. et al. Effect of cigarette smoking on gastropharyngeal and gastroesophageal reflux. Ann Otol Rhinol Laryngol. 2001 Feb;110(2):190-3.
Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control. 1991 Nov;2(6):427-42.
Suleiman UL, Harrison M. et al. H2-receptor antagonists may increase the risk of cardio-oesophageal adenocarcinoma: a case-control study. Eur J Cancer Prev. 2000 Jun;9(3):185-91.
Taylor PR, Li B. et al. Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. Cancer Res. 1994 Apr 1;54(7 Suppl):2029s-31s.
Terry P, Lagergren J. et al. Antioxidants and cancers of the esophagus and gastric cardia. Int J Cancer. 2000 Sep 1;87(5):750-4.
Topazian M. Gastrointestinal Endoscopy In: Braunwald E, Fauci AS, Kasper DL et al., Eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2005: 15(283):1635-42.
Trudgill N. Familial factors in the etiology of gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma. Chest Surg Clin N Am. 2002 Feb;12(1):15-24.
Trudgill NJ, Kapur KC. et al. Familial clustering of reflux symptoms. Am J Gastroenterol. 1999 May;94(5):1172-8.
Trudgill NJ, Smith LF. et al. Impact of smoking cessation on salivary function in healthy volunteers. Scand J Gastroenterol. 1998 Jun;33(6):568-71.
Turpie AG, Runcie J. et al. Clinical trial of deglydyrrhizinized liquorice in gastric ulcer. Gut. 1969 Apr;10(4):299-302.
Tzonou A, Lipworth L. et al. Diet and risk of esophageal cancer by histologic type in a low-risk population. Int J Cancer. 1996 Nov 4;68(3):300-4.
Untersmayr E, Scholl I. et al. Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in BALB/c mice. J Allergy Clin Immunol. 2003 Sep;112(3):616-23.
Vaezi MF, Richter JE. Contribution of acid and duodenogastro-oesophageal reflux to oesophageal mucosal injury and symptoms in partial gastrectomy patients [see comment]. Gut. 1997 Sep;41(3):297-302.
Vaezi MF, Singh S. et al. Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies. Gastroenterology. 1995 Jun;108(6):1897-907.
van MJ, Aarsen PN. et al. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol. 1981 Jun;%19;72(2-3):219-25.
Vanderhoff BT, Tahboub RM. Proton Pump Inhibitors: An Update. Am Fam Physician. 2002 Jul 15;66(2):273-80.
Watson WC. Malabsorption Syndromes In: Beers MH, Berkow R, Eds. The Merck Manual. Rahway, NJ: Merck & Co., Inc.; 2005(30).
Wolfgarten E, Rosendahl U. et al. Coincidence of nutritional habits and esophageal cancer in Germany. Onkologie. 2001 Dec;24(6):546-51.
Zhang Q, Lehmann A. et al. Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease. Gut. 2002 Jan;50(1):19-24.
Zheng W, Sellers TA. et al. Retinol, antioxidant vitamins, and cancers of the upper digestive tract in a prospective cohort study of postmenopausal women. Am J Epidemiol. 1995 Nov 1;142(9):955-60.