Fructose Malabsorption.doc

Fructose MalabsorptionA Possible Factor in Functional Bowel DisordersSheri Helms, PharmD, Fang Z. Ni, PharmD, Patricia L. Darbishire, PharmDUS PharmacistAbstract and IntroductionIntroductionFunctional bowel disorders (FBDs) are gastrointestinal (GI) disorders related to the middle or lower GI tract that lack identifiable pathoetiology.1,2FBDs include irritable bowel syndrome (IBS); recurrent abdominal pain (RAP); chronic bloating, constipation, and/or diarrhea; and other unspecified chronic bowel disorders.1Hadler et al reported FBDs in up to 40% of the community.3In 2004, it was estimated that 4 out of every 100 emergency department visits were due to FBDs, accounting for more than 11 million visits.2In a study of 3,933 subjects, 18% reported chronic diarrhea, 16% chronic constipation, 15% abdominal pain, 10% symptoms of IBS, and 2% dyspepsia. The economic burden is estimated to be as high as $1.6 billion for IBS and $621 million for chronic diarrhea.4Functional Bowel DisordersIrritable Bowel Syndrome:Despite the research dedicated to IBS, there is little known about its cause or development process. The most recent comprehensive prevalence study, conducted in 2002, found that IBS occurred in 3% to 20% of North Americans.5IBS is a similar issue globally in both developed and developing countries.6Chang et al estimated that in 1 year, IBS accounted for 500,000 inpatient hospital stays.7Women reported an incidence of 2:1 compared to men.5Triggers for IBS include stress, hormonal fluctuations, and certain foods, including chocolate, alcohol, carbonated beverages, fruits, and vegetables.5,8Diagnosis is predominantly based on symptoms, defined as abdominal pain and altered bowel activity with no organic origin.5IBS affects the large intestine, causing cramping, abdominal pain, bloating, gas, diarrhea, and constipation. It is classified into several subtypes: diarrhea (IBS-D), constipation (IBS-C), and a mixed subtype (IBS-M). Fortunately, IBS does not cause permanent damage to the colon and few people have disabling symptoms. IBS is generally managed through diet, lifestyle changes, and stress reduction techniques. When these techniques fail, symptom-based pharmacotherapy is employed. Constipation may be treated with prokinetic agents, while diarrhea may be treated with antispasmodics, opioids, 5-HT3antagonists, and/or anticholinergics.5Recurrent Abdominal PainRAP is another major form of FBD that is common in children. It is considered pain severe enough to interfere with normal functioning at least once per month for 3 consecutive months.9For decades, the pathophysiology of RAP has remained unclear. The original research and defining of RAP came from a British pediatrician, John Apley, MD. In establishing the definition of RAP, Apley and Naish surveyed 1,000 primary and secondary school children.9Approximately 11% of the children met the criteria for RAP. Another study conducted by Hyams et al evaluated 507 adolescents in an American suburban area.10Of the adolescents studied, approximately 15% experienced abdominal pain on a weekly basis. However, only half sought medical attention, implying the potential for a higher rate of occurrence than seen in clinical practice.11Many pediatricians treat RAP pre-dominantly with emotional support and reassurance for the family that no serious disease is present.12Fructose MalabsorptionOne area gaining interest with those who study FBD isfructose malabsorption, a condition characterized by gas, bloating, discomfort, nausea, disturbed bowel function, and occasionally gastroesophageal reflux ().13During fructose malabsorption, the small intestines are unable to fully absorb ingested fructose, leading to increased osmotic load and bacterial fermentation, as well as promotion of mucosal biofilm formation.14This is distinguished from fructose intolerance, a hereditary disease caused by a mutation in the aldolase B gene that renders patients unable to metabolize fructose. This metabolic disease may result in hepatic and renal injury, growth retardation, and, in severe cases, even death.1517Table 1. Common Symptoms of Fructose Malabsorption Gas Bloating Abdominal discomfort Nausea Disturbed bowel function Gastroesophageal reflux (occasionally)Source: Reference 13.Fructose, the sweetest of all naturally occurring sugars, is found in four primary forms: a naturally occurring free fructose (Figure 1), as a constituent of sucrose (Figure 2), as a polymer, and in an enzymatically produced form. Free fructose makes up as much as 35% by weight of honey and fruits such as apples, pears, and cherries (). Prior to the advent of food-processing technology in the 1960s, honey and fruits were the main dietary sources of fructose.18Since that time, technology has led to the use of alternatives, including sucrose (a disaccharide of fructose and glucose commonly known astable sugar) and highfructose corn syrup or HFCS (a monosaccharide enzymatically produced from corn). Today HFCS is commonly found in a variety of beverages and baked goods, as well as in canned and processed foods.19,20Table 2. High-Fructose Foods and AlternativesHigh-Fructose FoodsAlternativesFruits: apple, cherries, coconut milk, grapes, guava, honeydew melon, lychee, mango, pear, persimmons, pomegranate, quince, watermelonDried fruit/bars: apple, apricot, currant, date, fig, mandarin orange, raisins, pear, prune, tangeloStone fruits: apricot, nectarine, peach, plumBerries: blackberry, blueberry, boysenberry, cranberry, raspberry, strawberryCitrus fruits: grapefruit, kumquat, lemon, limeOthers: jackfruit, kiwi, passion fruit, pineapple, rhubarb, tamarilloVegetables:artichoke, asparagus, dandelion greens, endive, onion familyAny vegetable without fructans; cook with but do not consume (use whole in soups then remove)Condiments:barbecue sauce, chutney, honey, plum sauce, relish, sweet-and-sour sauce, tomato pastesGolden syrup, jam, jelly, maple syrup, marmalade, peanut butter, treacle, yeast extract spreadsWheat-based products: bread, breadcrumbs, breakfast cereals, cakes, cookies, crackers, noodles, pasta, pastriesRye, barley, and oat bread or crackers; gluten-free pasta, rice, or noodles; cereals low in dried fruit and honey; almond meal cakes and cookiesDrinks:fruit juice, chicory-based coffee, fortified wines, port, sherry, sucrose-sweetened soft drinksGlucose-sweetened sports drinks (e.g., Gatorade), unsweetened teas, coffee in moderationSweeteners: fructose sweeteners (e.g., fruit sugar or levulose), high-fructose corn syrupSucrose in moderation (e.g., table sugar, cane sugar), glucose sweeteners (e.g., dextrose or grape sugar)Source: Reference 19.Figure 1.Free FructoseFigure 2.SucroseThe availability of inexpensive, tasty, fructose-laden products makes reducing or eliminating fructose from the diet difficult. According to theU.S. Agriculture Fact Book, HFCS consumption increased from 16% to 42% of total sweetener consumption between the years 1978 and 1999.21,22In addition to its effect on the GI tract, a recent study by Stanhope et al evaluating the health consequences of excessive HFCS consumption found an increase in postprandial triglycerides, low-density lipoprotein (LDL) cholesterol, and other coronary heart disease risk factors after 2 weeks of consuming fructose- or HFCS-sweetened beverages (as 25% of their total daily energy requirement).23Furthermore, the authors discovered a decrease in postprandial glucose and insulin response following fructose consumption. These findings confirm that side effects of long-term, sugarsweetened beverage consumption can be attributed to specific properties of fructose.23,24Pathophysiology of Fructose MalabsorptionFructose empties more rapidly from the stomach in comparison to other sugars, utilizing an energy-dependent absorption process in the small intestines. GLUT5 and GLUT2 are transmembrane proteins primarily located in the lumen of the small intestines that are responsible for the transportation of fructose. GLUT5 transports fructose from the intestinal lumen into enterocytes by a facilitated energy-dependent process. Therefore, saturation of GLUT5 transporters with excessive fructose ingestion results in incomplete absorption, leading to GI symptoms ().25This transport-mediated process is limited in carrier capacity, calculated to be approximately 15 g of fructose per consumption. Fructose absorption occurs along with glucose via solvent drag and passive diffusion. Due to its osmotic effect, unabsorbed fructose combines with water and is rapidly propelled into the colonic lumen where luminal bacteria ferment fructose to carbon dioxide, hydrogen, and short-chain fatty acids. This osmotic load has a laxative effect and causes rapid gas production, leading to luminal distention, bloating, abdominal discomfort, and increased motility.19Table 1. Common Symptoms of Fructose Malabsorption Gas Bloating Abdominal discomfort Nausea Disturbed bowel function Gastroesophageal reflux (occasionally)Source: Reference 13.Assessment of Dietary Fructose IntakeThe hydrogen breath test is the foundational diagnostic assessment for identification of dietary fructose malabsorption.26One description of this test comes from a study conducted by Choi et al of 183 patients with unexplained chronic abdominal pain.27Subjects were asked to refrain from consuming foods containing high fat, lactose, or fructose for 1 day prior to testing and to fast after midnight. Subjects were asked to blow into a modified bag in order to collect a 50 mL end-expiratory breath sample. The sample was injected into a gas chromatography analyzer to measure baseline values for hydrogen and methane. The subjects were then asked to drink a 33% fructose solution. Breath samples were analyzed at 30-minute intervals for 5 hours. Based on the amount of fructose that escaped absorption in the small intestines, commensal flora in the large intestines metabolized the fructose and released hydrogen and methane consequently.28A positive breath test was inferred in subjects with a rise in breath hydrogen and/or methane of at least 3 parts per million (ppm) over three consecutive breath samples from the baseline value or from having a value 20 ppm above baseline.27The pitfall of the hydrogen breath test in diagnosis of fructose malabsorption is that 28% of the population does not expel hydrogen through the lungs and/or does not have hydrogen-producing bacteria inhabiting the GI tract.14In such patients, fructose malabsorption is often undiagnosed due to lack of an alternative diagnostic test.In the Choi et al study, fructose malabsorption was discovered in 39% of the 183 patients who had consumed 25 g of fructose and in 66% of the patients who had consumed 50 g of fructose, with 73% of total patients having a positive hydrogen breath test.27To put these quantities of fructose in perspective, depending on the type of corn syrup sweetener used, one 22-oz soft drink contains approximately 30 to 40 g of fructose.Fructose Malabsorption in IBSOne in three adults with IBS presents with the inability to absorb fructose in 25- to 50-g increments. However, fructose malabsorption is not limited to patients with IBS. Although GI symptoms associated with fructose malabsorption are generally magnified (), the perception that fructose does not play a major role in patients with IBS often leads to a lack of treatment.19Table 1. Common Symptoms of Fructose Malabsorption Gas Bloating Abdominal discomfort Nausea Disturbed bowel function Gastroesophageal reflux (occasionally)Source: Reference 13.Fructose-restricted DietInternational consensus on treatment of traditional IBS starts with increased fiber intake as first-line therapy.29However, there are no published guidelines to assist the patient with fructose malabsorption in constructing a manageable diet.11Despite the lack of specific guidelines, three separate studies demonstrated that identification and dietary monitoring of fructose consumption in patients with fructose malabsorption was clinically significant in reducing abdominal symptoms.19,30,31For instance, in the Choi et al study, 31 patients with positive hydrogen breath tests received verbal and written instructions on fructose restriction or exclusion, and then were followed up to 1 year later. Fourteen of the subjects were considered compliant patients and experienced a statistically significant reduction in abdominal pain, belching, bloating, fullness, indigestion, and diarrhea symptom scores compared to baseline 1 year prior.27In another study, Fernandez-Banares et al found that when given recommendations to eliminate all foods with free fructose, patients showed clinical symptom improvement after just 1 month of dietary adjustment. Furthermore, a group of these patients continued to have symptomatic improvement for up to 1 year later.32These two studies demonstrate positive impact on clinical symptoms with dietary intervention.27,32Lack of guidelines on fructose restriction in patients suffering from fructose malabsorption should not deter pharmacists from making such dietary recommendations.Role of the PharmacistAs a member of the health care team, pharmacists need to be aware of the common symptoms of fructose malabsorption, in addition to the foods that contain high amounts of fructose.19,33Although the normal capacity for absorption of fructose is unknown, in general, consumption of fructose in excess of 15 to 25 g in one sitting can lead to malabsorption and FBDs.12,19Recommendations to substitute foods and beverages containing high amounts of fructose for those containing lower amounts () can be helpful to patients suffering from fructose malabsorption symptoms. Pharmacists should encourage patients to focus on food alternatives.Table 3. Fructose Content of Common FoodsFoodFructose (g) per 100 g rawLow-Fructose substitutionsFructose (g) peer 100 g rawFresh FruitsGrapes8.1Apricots0.9Apples5.9Nectarines1.4Pears6.2Peaches1.5Bananas4.9Strawberries2.4Fresh VegetablesCarrots1Celery0.5Onions2Peas0.4Asparagus1Spinach0.1Sweet potatoes0.7Mushrooms0.2BeveragesBrandy16Whiskey8Cola6.1Gatorade0.2Apple juice5.7Iced teaa0Sprite5.2Coffee0Orange juice2.2Hot tea0aUnsweetened. Source: Reference 33.Realistic goals can positively impact symptoms and improve quality of life.27Patients should be encouraged to consult with a registered dietitian if they are unable to self-manage dietary needs.References1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders.Gastroenterology. 2006;130:14801491.2. Porter CK, Gormley R, Tribble DR, et al. The incidence and gastrointestinal infectious risk of functional gastrointestinal disorders in a healthy US adult population.Am J Gastroenterol.2011;106:130138.3. Hadler SL, Locke GR III, Chleck CD, et al. Natural history of functional gastrointestinal disorders: a 12-year longitudinal population-based study. Gastroenterology.2007;133:799807.4. Lembo AJ. The clinical and economic burden of irritable bowel syndrome.Pract Gastroenterol. 2007;31(suppl)39.5. Grundmann O, Yoon SL. Irritable bowel syndrome: epidemiology, diagnosis and treatment: an update for healthcare practitioners.J Gastroenterol Hepatol.2010;25:691699.6. Tally NJ. Functional gastrointestinal disorders as a public health problem.Neurogastroenterol Motil.2008;20(suppl 1): 121129.7. Chang JY, Locke GR, McNally MA, et al. Impact of functional gastrointestinal disorders on survival in the community.Am J Gastroenterol.2010;105:822832.8. Chang L. The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome.Gastroenterology.2011;140:761765.9. Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children.Arch Dis Child. 1958;33:165170.10. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents: a community-based study.J Pediatr. 1996:129:220226.11. Rao SS, Attaluri A, Anderson L, Stumbo P. The ability of the normal human small intestine to absorb fructose: evaluation of breath testing.Clin Gastroenterol Hepatol. 2007;5:959963.12. Weydert JA, Ball TM, Davis MF. Systemic review of treatments for recurrent abdominal pain.Pediatrics.2003;111:e1e11.13. Piche T, Des Varannes SB, Sacher-Huvelin S, et al. Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease.Gastroenterology.2003;124:894902.14. Gibson PR, Newnham E, Barrett JS, et al. Review article: fructose malabsorption and the bigger picture.Aliment Pharmacol Ther. 2007;25:349363.15. Wong D. Hereditary fructose intolerance.Mol Genet Metab. 2005;85:165167.16. Ali M, Rellos P, Cox TM. Hereditary fructose intolerance.J Med Genet.1998;35:353365.17. Bouteldja N, Timson DJ. The biochemical basis of hereditary fructose intolerance.J Inherit Metab Dis.2010;33:105112.18. Hanover LM, White JS. Manufacturing, composition and applications of fructose.Am J Clin Nutr.1993;58(suppl):724S732S.19. Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management.J Am Diet Assoc.2006;106:16311639.20. Skoog SM, Bharucha AE. Dietary fructose and gastrointestinal symptoms: a review.Am J Gastroenterol. 2004;99:20462050.21. Agriculture Fact Book 2000. Washington, DC: U.S. Department of Agriculture; 2000:314. /news/pubs/fbook00/factbook2000.pdf. Accessed September 9, 2011.22. Marriott BP, Cole N, Lee E. National estimates o