Fructose Malabsorption ...... 3 Introduction ...... 3 Metabolism ...... 4 Fructose Malabsorption ...... 5 Diagnosis ...... 6 Diet ...... 7 Fructose Malabsorption: A Possible Factor in Functional Bowel Disorders ...... 7 Functional Bowel Disorders ...... 8 Fructose Malabsorption ...... 8 ...... 10 Pathophysiology of Fructose Malabsorption ...... 10 Assessment of Dietary Fructose Intake ...... 10 Fructose Malabsorption in IBS ...... 11 Fructose-Restricted Diet ...... 11 Role of the Pharmacist ...... 11 REFERENCES ...... 12 Fructose malabsorption ...... 14 Pathophysiology ...... 14 Symptoms ...... 15 Diagnosis ...... 15 Treatment ...... 15 Xylose isomerase ...... 15 Diet ...... 15 Dietary guidelines for the management of fructose malabsorption[edit]...... 17 Food-labeling ...... 17 New research ...... 18 See also ...... 18 References ...... 18 Use and abuse of hydrogen breath tests ...... 19 Abstract ...... 19 Hydrogen breath tests ...... 20 Carbohydrate malabsorption ...... 21 Carbohydrate digestion and absorption ...... 21 Lactose malabsorption ...... 21 Fructose malabsorption ...... 23 Small intestinal bacterial overgrowth ...... 24 Normal bowel flora ...... 25 Definition of SIBO ...... 25 Tests for SIBO ...... 26 Is there a link between SIBO and IBS? ...... 28 Conclusion ...... 29 Abbreviations ...... 29 Footnotes ...... 29 References ...... 29 FOFMAPs to the rescue…………………..38

Fructose Malabsorption Fructose malabsorption is a digestive disorder in which the absorption capacity of the sugar fructose in the small intestine is reduced. This leads to an increase of fructose in the large intestine where the sugar is degraded by intestinal bacteria to several chemical compounds which will then cause symptoms like bloating, wind, abdominal pain, diarrhea and/or constipation.

Introduction

The natural occurrence of fructose as a monosaccharide (molecular fructose) is mainly in fruits and vegetables. It is also a component of the disaccharide sucrose, the table sugar, which is composed of one molecule glucose and one molecule fructose. Molecular fructose is sweeter than glucose and is therefore often used as sweetener in pastries, sweets and sodas. The average daily intake of fructose has increased dramatically over the last 40 years mainly due to the increased usage of this High Fructose Corn Syrup (HFCS) as a sweetener.

Fig. 1:Sucrose (Disaccharid)

Fig. 2:Molecular Fructose (Monosaccharid)

Fructose is absorbed in the small intestine via the GLUT-5 transporter. This transport from the intestinal lumen into the enterocytes, the intestinal absorptive cells, is passive and driven by the concentration difference of fructose between the intestinal lumen and the plasma of the cells. The capacity of this transport system is limited and varies greatly between individuals. About 40% of the population show signs of malabsorption after a single dose of 25g of fructose, a dosis far below the average daily intake which is estimated to be around 70g per day. Sorbitol, a sugar alcohol which is widely used as sugar substitute in industrial foods, further reduces the fructose absorption capacity by binding to the GLUT-5 transporter. Concomitant consumption of glucose with a fructose-rich meal can increase the absorption capacity of fructose which is why most of patients suffering from fructose malabsorption tolerate table sugar quite well. It is believed that this effect may be due to an increased integration of the GLUT-2 transporter into the membrane of the enterocytes. GLUT-2 acts as a passive transporter for glucose, galactose and fructose with low affinity (that means it only transports these sugars if their concentration is high). This transporter is only integrated into the membrane after a meal when the sugar concentration in the intestine is high. This detection of sugar in the intestinal lumen only works with glucose and therefore a fructose-rich meal will not trigger this integration of GLUT-2.

Metabolism

Unlike glucose fructose can only be utilized by a few cells of the body directly. Most of the absorbed fructose is transported to the liver where it is phosphorylated and converted into fat, glucose or energy (figure 3). Currently there is an ongoing discussion whether fructose may induce obesity and non-alcoholic fatty liver disease. Until now there is no hard evidence to support this thesis as most studies investigating this effect yielded conflicting results. But considering the differences between fructose and glucose metabolism it is a reasonable conclusion:

 Fructose has no effect on insulin secretion which in turn may reduce the satiation experienced after a meal.

 Fructose is metabolized primarily in the liver putting more strain on the liver cells. Furthermore the energy available in the liver cells is increased which can affect the synthesis of fat (excess energy is stored as body fat).

There is little difference between the free fructose of high fructose corn syrup and the bound fructose in table sugar. Both have very similar effects on the body. This does not mean that the fructose from fruits is also detrimental. In the western civilizations only a small portion of the average daily intake of fructose comes from natural sources and this comparatively low amount of fructose has no detrimental effect on health.

Fig. 3: Metabolismus of Fruktose in the liver

Since fructose has no effect on insulin levels it was widely used in foods for diabetics. But with the rising concern on the health effects of excessive fructose uptake the usage of fructose has reduced.

Fructose Malabsorption

Fig. 4: Effect of Fructose Malabsorption

Although up to 50% of the population are not able to absorb a single dose of 25g of fructose which is the cutoff dose for malabsorption determination only approximately 5 to 7% of the population suffer from symptomatic fructose malabsorption. Only these 5 to 7% will develop symptoms after a fructose-rich meal. The malabsorption alone cannot be seen as a disorder but occurs throughout the population. The symptoms are triggered by the degradation products that arise from the decomposition of the fructose in the large intestine by the intestinal bacteria. Mainly Hydrogen (H2), Methane (CH4), Carbon Dioxide (CO2) and short chain fatty acids (SCFAs) are generated. These compounds can cause the typical symptoms like bloating, wind, abdominal pain, diarrhea and/or constipation. Since the composition of the intestinal bacterial population varies between humans also the amount and composition of the generated degradation products varies. Furthermore the tolerance of the intestine to negative influences is affected by several parameters like stress, inflammation and others. Both these factors influence the severity of the symptoms the patient with fructose malabsorption will experience after a fructose rich meal.

There is also no guideline that can tell which amount of fructose is needed to invoke symptoms. The absorption capacity of patients suffering from fructose malabsorption is reduced but still significant. If the ingested amount of fructose is below this absorption capacity no symptoms should be generated. The factors influencing this absorption capacity are not well understood. For example inflammation of the small intestine will decrease the amount of absorbed fructose. But until now no reason for the innate difference of the absorption capacity for fructose between the individuals could be found. Additionally it is of great importance how the fructose is ingested. Free fructose is taken up differently than sucrose. Fructose malabsorption must not be confused with the hereditary fructose intolerance, a disease caused by a rare genetic defect of the liver enzyme Aldolase B. In this disease the body can no longer process dietary fructose which causes symptoms like hypoglycemia and vomiting after a fructose containing meal. Repeated exposure to fructose will lead to hepatomegalia and liver failure. The prevalence of this potentially fatal disease is approximately 1 in 25000 in Western Europe.

Diagnosis

Medical tests require a hydrogen breath test with fructose. During this test the patient is administered a single dose of 25g of fructose in 100ml water on an empty stomach. Then over the course of 3 hours the amount of hydrogen in the exhaled air is measured. If the fructose is not absorbed completely it will be degraded by the bacteria in the large intestine into hydrogen which travels through the blood stream to the lungs where it is exhaled. The test is considered positive if the concentration of hydrogen in the exhaled breath rises to 20ppm.

About 10% of the population have no hydrogen producing bacteria in their intestine. For these patients the test can be done by measuring the methane in the exhaled air.

The best indication for a symptomatic fructose malabsorption is the disappearance of digestional problems during an exclusion diet. A fructose malabsorption can be assumed if after 4 weeks without dietary fructose the symptoms have disappeared.

Diet

The first step is a 4 week long strictly fructose-free diet. This should help to bring the digestion system into balance again. After this period increasing amounts of fructose can be introduced into the diet. Every patient should test how much fructose he/she can tolerate without suffering from symptoms. It is recommendable to eat as much fructose as tolerated if the source is natural because the absorption capacity for fructose can decline if the GLUT-5 transporter is not used (no fructose is ingested).

Generally foods with high fructose corn syrup (HFCS) or table sugar should be avoided when dealing with fructose malabsorption. [Link]Here[/Link] is a list of foods and their fructose, glucose, sucrose and sorbitol contents. As a rule of thumb foods with a balanced amount of fructose and glucose are generally well tolerated. This may not be true for all patients suffering from fructose malabsorption because some even develop symptoms from small amounts of table sugar which is chemically an equimolar mixture of glucose and fructose. Sorbitol should be avoided as it temporarily reduces the absorption capacity of fructose.

For the composition of a detailed diet sheet a nutritionist should be consulted. Very often dietary supplements are needed to ensure an optimal supply of the patient with vitamins and trace elements.

Fructose Malabsorption: A Possible Factor in Functional Bowel Disorders

Sheri Helms, PharmD Director of Professional Program Laboratories Purdue University College of Pharmacy West Lafayette, Indiana

Fang Z. Ni, PharmD Rutgers Pharmaceutical Industry Fellow Rutgers University New Brunswick, New Jersey

Patricia L. Darbishire, PharmD Clinical Associate Professor of Pharmacy Practice Director of Introductory Pharmacy Practice Experience Purdue University College of Pharmacy West Lafayette, Indiana

12/20/2011

US Pharm. 2011;36(12):41-44.

Functional bowel disorders (FBDs) are gastrointestinal (GI) disorders related to the middle or lower GI tract that lack identifiable pathoetiology.1,2 FBDs include irritable bowel syndrome (IBS); recurrent abdominal pain (RAP); chronic bloating, constipation, and/or diarrhea; and other unspecified chronic bowel disorders.1 Hadler et al reported FBDs in up to 40% of the community.3 In 2004, it was estimated that 4 out of every 100 emergency department visits were due to FBDs, accounting for more than 11 million visits.2 In 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.4

Functional Bowel Disorders

Irritable 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.5 IBS is a similar issue globally in both developed and developing countries.6 Chang et al estimated that in 1 year, IBS accounted for 500,000 inpatient hospital stays.7 Women reported an incidence of 2:1 compared to men.5 Triggers for IBS include stress, hormonal fluctuations, and certain foods, including chocolate, alcohol, carbonated beverages, fruits, and vegetables.5,8 Diagnosis is predominantly based on symptoms, defined as abdominal pain and altered bowel activity with no organic origin.5

IBS 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 5 treated with antispasmodics, opioids, 5-HT3 antagonists, and/or anticholinergics.

Recurrent Abdominal Pain: RAP 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.9 For 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.9 Approximately 11% of the children met the criteria for RAP. Another study conducted by Hyams et al evaluated 507 adolescents in an American suburban area.10 Of 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.11 Many pediatricians treat RAP predominantly with emotional support and reassurance for the family that no serious disease is present.12

Fructose Malabsorption

One area gaining interest with those who study FBD is fructose malabsorption, a condition characterized by gas, bloating, discomfort, nausea, disturbed bowel function, and occasionally gastroesophageal reflux (TABLE 1).13 During 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.14 This 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.15-17

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 (TABLE 2). Prior to the advent of food-processing technology in the 1960s, honey and fruits were the main dietary sources of fructose.18 Since that time, technology has led to the use of alternatives, including sucrose (a disaccharide of fructose and glucose commonly known as table sugar) and high-fructose 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.19,20

The availability of inexpensive, tasty, fructose-laden products makes reducing or eliminating fructose from the diet difficult. According to the U.S. Agriculture Fact Book, HFCS consumption increased from 16% to 42% of total sweetener consumption between the years 1978 and 1999.21,22 In 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).23 Furthermore, the authors discovered a decrease in postprandial glucose and insulin response following fructose consumption. These findings confirm that side effects of long-term, sugar-sweetened beverage consumption can be attributed to specific properties of fructose.23,24

Pathophysiology of Fructose Malabsorption

Fructose 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 (TABLE 1).25 This 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.19

Assessment of Dietary Fructose Intake

The hydrogen breath test is the foundational diagnostic assessment for identification of dietary fructose malabsorption.26 One description of this test comes from a study conducted by Choi et al of 183 patients with unexplained chronic abdominal pain.27 Subjects 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.28 A 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.27

The 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.14 In 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.27 To 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 IBS

One 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 (TABLE 1), the perception that fructose does not play a major role in patients with IBS often leads to a lack of treatment.19

Fructose-Restricted Diet

International consensus on treatment of traditional IBS starts with increased fiber intake as first-line therapy.29 However, there are no published guidelines to assist the patient with fructose malabsorption in constructing a manageable diet.11

Despite 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.19,30,31 For 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.27

In 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.32

These two studies demonstrate positive impact on clinical symptoms with dietary intervention.27,32 Lack of guidelines on fructose restriction in patients suffering from fructose malabsorption should not deter pharmacists from making such dietary recommendations.

Role of the Pharmacist

As 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.19,33 Although 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.12,19 Recommendations to substitute foods and beverages containing high amounts of fructose for those containing lower amounts (TABLE 3) can be helpful to patients suffering from fructose malabsorption symptoms. Pharmacists should encourage patients to focus on food alternatives. Realistic goals can positively impact symptoms and improve quality of life.27 Patients should be encouraged to consult with a registered dietitian if they are unable to self-manage dietary needs.

REFERENCES

1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480- 1491. 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;106:130-138. 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;133:799-807. 4. Lembo AJ. The clinical and economic burden of irritable bowel syndrome. Pract Gastroenterol. 2007;31(suppl)3- 9. 5. Grundmann O, Yoon SL. Irritable bowel syndrome: epidemiology, diagnosis and treatment: an update for health- care practitioners. J Gastroenterol Hepatol. 2010;25:691-699. 6. Tally NJ. Functional gastrointestinal disorders as a public health problem. Neurogastroenterol Motil. 2008;20(suppl 1):121-129. 7. Chang JY, Locke GR, McNally MA, et al. Impact of functional gastrointestinal disorders on survival in the community. Am J Gastroenterol. 2010;105:822-832. 8. Chang L. The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome. Gastroenterology. 2011;140:761-765. 9. Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children. Arch Dis Child. 1958;33:165-170. 10. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents: a community-based study. J Pediatr. 1996:129:220-226. 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;5:959-963. 12. Weydert JA, Ball TM, Davis MF. Systemic review of treatments for recurrent abdominal pain. Pediatrics. 2003;111:e1-e11. 13. Piche T, Des Varannes SB, Sacher-Huvelin S, et al. Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease. Gastroenterology. 2003;124:894-902. 14. Gibson PR, Newnham E, Barrett JS, et al. Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther. 2007;25:349-363. 15. Wong D. Hereditary fructose intolerance. Mol Genet Metab. 2005;85:165-167. 16. Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998;35:353-365. 17. Bouteldja N, Timson DJ. The biochemical basis of hereditary fructose intolerance. J Inherit Metab Dis. 2010;33:105-112. 18. Hanover LM, White JS. Manufacturing, composition and applications of fructose. Am J Clin Nutr. 1993;58(suppl):724S-732S. 19. Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management. J Am Diet Assoc. 2006;106:1631-1639. 20. Skoog SM, Bharucha AE. Dietary fructose and gastrointestinal symptoms: a review. Am J Gastroenterol. 2004;99:2046-2050. 21. Agriculture Fact Book 2000. Washington, DC: U.S. Department of Agriculture; 2000:314. www.usda.gov/news/pubs/ fbook00/factbook2000.pdf. Accessed September 9, 2011. 22. Marriott BP, Cole N, Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr. 2009;139:1228S-1235S. 23. Stanhope KL, Bremer AA, Medici V, et al. Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women. J Clin Endocrinol Metab. 2011;96:E1596-E1605. 24. Hu FB, Malik VS. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav. 2010;100:47-54. 25. Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocriol Metab. 2008;295:E227-E237. 26. Romagnuolo JM, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterological practice: an evidence based review of indications and pitfalls in interpretation. Am J Gastroenterol. 2002;97:1113-1126. 27. Choi YK, Johlin FC, Summers RW, et al. Fructose intolerance: an under-recognized problem. Am J Gastroenterol. 2003;98:1348-1353. 28. Jones HF, Butler RN, Brooks DA. Intestinal fructose transport and malabsorption in humans. Am J Physiol Gastrointest Liver Physiol. 2011;300:G202-G206. 29. DecisionBase. Irritable Bowel Syndrome: A New Therapy for Non-Constipation-Predominant IBS With Greatly Improved Efficacy Will Reach Near-Blockbuster Status. Decision Resources. Inc. March 2010. http://decisionresources.com/ Products-and-Services/Report? r=dbaspd2510. Accessed September 9, 2011. 30. Choi YK, Kraft N, Zimmerman B, et al. Fructose intolerance in IBS and utility of fructose-restricted diet. J Clin Gastroenterol. 2008;42:233-238. 31. Johlin FC Jr, Panther M, Kraft N. Dietary fructose intolerance: diet modification can impact self-rated health and symptom control. Nutr Clin Care. 2004;7:92-97. 32. Fernandez-Banares F, Rosinach M, Esteve M, et al. Sugar malabsorption in functional abdominal bloating: a pilot study on the long-term effect of dietary treatment. Clin Nutr. 2006;25:824-831. 33. Nutrition Data Laboratory. USDA. www.nal.usda.gov/fnic/ foodcomp/search/. Accessed September 9, 2011

Fructose malabsorption

Fructose malabsorption

Classification and external resources

Fructose

ICD-10 E74.3

ICD-9 271

OMIM 138230

Fructose malabsorption, formerly named "dietary fructose intolerance" (DFI), is a digestive disorder[1] in which absorption of fructose is impaired by deficient fructose carriers in the small intestine's enterocytes. This results in an increased concentration of fructose in the entire intestine. Occurrence in patients identified to be suffering symptoms of irritable bowel syndrome is not higher than occurrence in the normal population. However, due to the similarity in symptoms, patients with fructose malabsorption often fit the profile of those with irritable bowel syndrome.[2] A small proportion of patients with both fructose malabsorption and lactose intolerance also suffer from celiac disease. Fructose malabsorption is not to be confused with hereditary fructose intolerance, a potentially fatal condition in which the liver enzymes that break up fructose are deficient. Pathophysiology Fructose is absorbed in the small intestine without help of digestive enzymes. Even in healthy persons, however, only about 25–50g of fructose per sitting can be properly absorbed. People with fructose malabsorption absorb less than 25g per sitting.[3] In the large intestine, fructose that has not been adequately absorbed reduces the absorption of water osmotically and is metabolized by colonic bacteria into short chain fatty acids, producing the byproduct gases hydrogen, carbon dioxide and methane.[citation needed] This abnormal increase in hydrogen is detectable with the hydrogen breath test. The physiological consequences of fructose malabsorption include increased osmotic load, rapid bacterial fermentation, altered gastrointestinal motility, the formation of mucosal biofilm and altered profile of bacteria. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. The clinical significance of these events depends upon the response of the bowel to such changes. Some effects of fructose malabsorption are decreased tryptophan,[4] folic acid[5] and zinc in the blood.[5] Restricting dietary intake of free fructose and/or fructans may provide symptom relief in a high proportion of patients with functional gut disorders.[6] Symptoms

 Bloating (from fermentation in the small and large intestine)  Diarrhea and/or constipation  Flatulence  Reflux  Stomach pain (as a result of muscle spasms, the intensity of which can vary from mild and chronic to acute but erratic)  Vomiting (if great quantities are consumed)  Early signs of mental depression[7]  Nausea Diagnosis The diagnostic test, when used, is similar to that used to diagnose lactose intolerance. It is called a hydrogen breath test and is the method currently used for a clinical diagnosis. Treatment There is no known cure, but an appropriate diet and the enzyme xylose isomerase can help. Xylose isomerase Xylose isomerase acts to convert fructose sugars into glucose. Dietary supplements are limited in the amount of fructose they can convert, thus the amount of fructose in a meal must be estimated and an appropriate dosage taken to work.[citation needed] Diet Foods that should be avoided by people with fructose malabsorption include:

 Foods and beverages containing greater than 0.5 g fructose in excess of glucose per 100 g and greater than 0.2 g of fructans per serving should be avoided. Foods with >3 g of fructose per serving are termed a 'high fructose load' and possibly present a risk of inducing symptoms. However, the concept of a 'high fructose load' has not been evaluated in terms of its importance in the success of the diet.[8]  Foods with high fructose-to-glucose ratio. Glucose enhances absorption of fructose, so fructose from foods with fructose-to-glucose ratio <1, like white potatoes, are readily absorbed, whereas foods with fructose-to-glucose ratio >1, like apples and pears, are often problematic regardless of the total amount of fructose in the food.[9]  Foods rich in fructans and other fermentable oligo-, di- and mono-saccharides and polyols (FODMAPs), including artichokes, asparagus, leeks, onions, and wheat-containing products, including breads, cakes, biscuits, breakfast cereals, pies, pastas, pizzas, and wheat noodles.  Foods containing sorbitol, present in some diet drinks and foods, and occurring naturally in some stone fruits, or xylitol, present in some berries, and other polyols (sugar alcohols), such as erythritol, mannitol, and other ingredients that end with -tol, commonly added as artificial sweeteners in commercial foods. Foods with a high glucose content ingested with foods containing excess fructose may help sufferers absorb the excess fructose.[10] The role that fructans play in fructose malabsorption is still under investigation. However, it is recommended that fructan intake for fructose malabsorbers should be kept to less than 0.5 grams/serving,[11] and supplements with inulin and fructooligosaccharide (FOS), both fructans, should be avoided.[11] Foods with high fructose content[edit] According to the USDA database,[12] foods with more fructose than glucose include:

Food Fructose (grams / 100 grams) Glucose (grams / 100 grams)

Sucrose 50 50 (for reference)

Apples 5.9 2.4

Pears 6.2 2.8

Fruit juice e.g. Apples, 5–7 2–3 Pears

Watermelon 3.4 1.6

Raisins 29.8 27.8 Food Fructose (grams / 100 grams) Glucose (grams / 100 grams)

Honey 40.9 35.7

High fructose 42–55 45–58

corn syrup

Mango 4.68 2.01

Agave nectar 55.6 12.43

The USDA food database reveals that many common fruits contain nearly equal amounts of the fructose and glucose, and they do not present problems for those individuals with fructose malabsorption.[13] Some fruits with a greater ratio of fructose than glucose are apples, pears and watermelon, which contain more than twice as much fructose as glucose. Fructose levels in grapes varies depending on ripeness and variety, where unripe grapes contain more glucose. Dietary guidelines for the management of fructose malabsorption[edit] Researchers at Monash University in Australia developed dietary guidelines[11] for managing fructose malabsorption, particularly for individuals with IBS. Unfavorable foods (i.e. more fructose than glucose)[edit]

 Fruit – apple, pear, guava, honeydew melon, nashi pear, pawpaw, papaya, quince, star fruit, watermelon;  Dried fruit – apple, currant, date, fig, pear, raisin, sultana;  Fortified wines  Foods containing added sugars, such as agave nectar, some corn syrups, and fruit juice concentrates. Favorable foods (i.e. fructose equal to or less than glucose)[edit] The following list of favorable foods was cited in the paper: "Fructose malabsorption and symptoms of Irritable Bowel Syndrome Guidelines for effective dietary management".[11] The fructose and glucose contents of foods listed on the Australian food standards[14]would appear to indicate that most of the listed foods have higher fructose levels.

 Stone fruit: apricot, nectarine, peach, plum (caution — these fruits contain sorbitol);  Berry fruit: blueberry, blackberry, boysenberry, cranberry, raspberry, strawberry, loganberry;  Citrus fruit: kumquat, grapefruit, lemon, lime, mandarin, orange, tangelo;  Other fruits: ripe banana, jackfruit, kiwi fruit, passion fruit, pineapple, rhubarb, tamarillo. Food-labeling Producers of processed food in most or all countries, including the USA, are not currently required by law to mark foods containing "fructose in excess of glucose." This can cause some surprises and pitfalls for fructose malabsorbers. Foods (such as bread) marked "gluten-free" are usually suitable for fructose malabsorbers, though sufferers need to be careful of gluten-free foods that contain dried fruit or high fructose corn syrup or fructose itself in sugar form. However, fructose malabsorbers donot need to avoid gluten, as those with celiac disease must. Many fructose malabsorbers can eat breads made from rye and corn flour. However, these may contain wheat unless marked "wheat-free" (or "gluten-free") (Note: Rye bread is not gluten-free.) Although often assumed to be an acceptable alternative to wheat, spelt flour is not suitable for sufferers of fructose malabsorption[citation needed], just as it is not appropriate for those with wheat allergies or celiac disease. However, some fructose malabsorbers do not have difficulty with fructans from wheat products while they may have problems with foods that contain excess free fructose.[citation needed] There are many breads on the market that boast having no high fructose corn syrup. In lieu of high fructose corn syrup, however, one may find the production of special breads with a high inulin content, where inulin is a replacement in the baking process for the following: high fructose corn syrup, flour and fat. Because of the caloric reduction, lower fat content, dramatic fiber increase and prebiotic tendencies of the replacement inulin, these breads are considered a healthier alternative to traditionally prepared leaveningbreads. Though the touted health benefits may exist, sufferers of fructose malabsorption will likely find no difference between these new breads and traditionally prepared breads in alleviating their symptoms because inulin is a fructan, and, again, consumption of fructans should be reduced dramatically in those with fructose malabsorption in an effort to appease symptoms. New research Fructose and fructans which are polymers of fructose are FODMAPs (Fermentable Oligo-, Di- and Mono-saccharides and Polyols) known to cause gastrointestinal discomfort in susceptible individuals. A low FODMAP diet has widespread application for managing functional gastrointestinal disorders such as IBS.[8] See also

 Hereditary fructose intolerance  FODMAP  Gastroenterology  Hydrogen breath test  Invisible disability  Food intolerance  Irritable bowel syndrome  Malabsorption References

1. MayoClinic.com 2. Ledochowski M, et al. (2001). "Fruktosemalabsorption". Journal für Ernährungsmedizin (in German) 3 (1): 15–19. 3. http://www.uihealthcare.com/kxic/2008/06/fructose.html 4. Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D (2001). "Fructose malabsorption is associated with decreased plasma tryptophan". Scand. J. Gastroenterol. 36 (4): 367–71. doi:10.1080/003655201300051135. PMID 11336160. 5. ^ Jump up to:a b Ledochowski M, Uberall F, Propst T, Fuchs D (1999). "Fructose malabsorption is associated with lower plasma folic acid concentrations in middle-aged subjects". Clin. Chem. 45 (11): 2013–4. PMID 10545075. 6. Gibson PR, Newnham E, Barrett JS, Shepherd SJ, Muir JG (2007). "Review article: fructose malabsorption and the bigger picture".Aliment. Pharmacol. Ther. 25 (4): 349– 63. doi:10.1111/j.1365-2036.2006.03186.x. PMID 17217453. 7. Ledochowski M, Sperner-Unterweger B, Widner B, Fuchs D. (2010). "Fructose malabsorption is associated with early signs of mental depression.". European Journal of Medical Research 3 (6): 295–8. PMID 9620891. 8. ^ Jump up to:a b Gibson PR, Shepherd SJ (2010). "Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach". Advances in Clinical Practice 25 (2): 252–8. doi:10.1111/j.1440-1746.2009.06149.x. PMID 20136989. 9. http://www.healthsystem.virginia.edu/internet/digestive-health/nutrition/BarrettArticle.pdf 10. Skoog SM, Bharucha AE (2004). "Dietary fructose and gastrointestinal symptoms: a review". Am. J. Gastroenterol. 99 (10): 2046–50.doi:10.1111/j.1572- 0241.2004.40266.x. PMID 15447771. 11. ^ b c d Shepherd SJ, Gibson PR (2006). "Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management" (PDF). Journal of the American Dietetic Association 106 (10): 1631–9. doi:10.1016/j.jada.2006.07.010.PMID 17000196. 12. USDA National Nutrient Database Release 20, September 2007 13. Sugar Content of Selected Foods: Individual and Total Sugars Ruth H. Matthews, Pamela R. Pehrsson, and Mojgan Farhat-Sabet, (1987) U.S.D.A. 14. "NUTTAB 2010 Online Searchable Database". Food Standards Australia New Zealand. Archived from the original on 2012-03-24. Retrieved 7 July 2013.

Use and abuse of hydrogen breath tests M Simrén and P‐O Stotzer

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This article has been cited by other articles in PMC.

Abstract

Within the field of gastroenterology, the majority of symptoms cannot be explained by structural abnormalities detected on routine investigations.1 Many of these symptoms are clustered together forming the functional gastrointestinal disorders, as defined by the Rome II criteria.2,3 The pathophysiology behind these disorders is still incompletely known.4 In the search for possible pathophysiological factors of functional gastrointestinal disorders, several authors have used different hydrogen breath tests in recent years to detect various abnormalities, such as carbohydrate malabsorption5,6,7 and small intestinal bacterial overgrowth (SIBO).8,9 However, these tests are indirect, with several drawbacks and pitfalls. In this article, we will review the literature on the use of hydrogen breath tests to detect carbohydrate malabsorption and SIBO, and highlight the controversies and inconsistencies in the interpretation of these tests, especially regarding the relevance of fructose malabsorption and SIBO in patients with functional gastrointestinal disorders.

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Hydrogen breath tests

Hydrogen breath tests are based on the fact that there is no source for hydrogen gas in humans other than bacterial metabolism of carbohydrates.10 For these tests different carbohydrates are administered orally and the concentration of hydrogen is measured in expired air. When defective sugar absorption is present, unabsorbed sugars are available in the colon for bacterial fermentation, and in the case of SIBO the bacterial population migrates proximally in the small intestine gaining access to the sugars. When exposed to bacteria in the bowel, the substrate will be metabolised to hydrogen, which is quickly absorbed, expired, and possible to measure in expired air (fig 11).). The different tests are performed in the fasting state after at least one day of a low fibre diet. Smoking raises and exercise lowers hydrogen concentrations and is therefore not allowed during the test.11 Glucose12,13 or lactulose14 are the most commonly used substrates for diagnosis of SIBO whereas the different sugars tested for carbohydrates malabsorption are given to detect these disorders.15

Figure 1 Schematic drawing showing the principles behind breath tests.

“Hydrogen breath tests are based on the fact that there is no source for hydrogen gas in humans other than bacterial metabolism of carbohydrates”

The hydrogen breath test depends on the presence of hydrogen producing bacteria. However, a considerable proportion of non‐hydrogen producing bacteria, which can yield false negative results, has been observed in some12,16,17 but not all studies.18,19,20 Several other potential sources of error exist, such as carbohydrate malabsorption in chronic pancreatitis and coeliac disease, with false positive tests for SIBO due to colonic fermentation and gas production,20,21,22,23 and gastrointestinal motor disorders, where delayed gastric emptying may cause false negative tests24 and rapid transit through the small bowel will produce false positive breath tests.22,25,26,27 False positive results may also be due to the oral bacterial flora and if the subject has failed to adhere to a low fibre diet the day before the test.

Go to: Carbohydrate malabsorption

Carbohydrate digestion and absorption

Almost all carbohydrates from the diet are large polysaccharides or disaccharides. In order to be adequately absorbed from the intestine into portal blood, poly‐ and disaccharides must undergo digestion in order to become absorbable monosaccharides (glucose, galactose, and fructose). For this, different enzymes are required, such as pancreatic amylase and intestinal epithelial enzymes (that is, lactase, sucrase, and maltase). Absorption is mainly an active transport, with selectivity for specific monosaccharides and competition between different sugars. Therefore, the composition of the diet influences the efficiency of carbohydrate absorption and the amount of carbohydrates that reaches the colon unabsorbed.

Carbohydrates that reach the colon unabsorbed are fermented by bacteria and have been proposed to be of importance for symptoms such as bloating, abdominal distension, and diarrhoea. In particular, lactose,7,28,29,30 fructose, and sorbitol5,31 has been extensively studied in patients with functional gastrointestinal disorders but more complex carbohydrates that escape small bowel absorption may be of even greater importance.32

Lactose malabsorption Lactose absorption

Lactose, found in milk, is a disaccharide composed of galactose and glucose. It is digested by lactase, which is found on the brush border of small intestine epithelium, into glucose and galactose, and these monosaccharides can then be absorbed. Lactose maldigestion is the incomplete hydrolysis of lactose due to lactase deficiency, which may occur as a primary disorder33 or secondary to another disorder of the small intestinal mucosa, for instance coeliac disease.34 The vast majority of patients with the primary form have an acquired deficiency (that is, enzyme activity is normal during the first years of life but then declines with ageing). Because lactose cannot be absorbed it passes into the colon and through increased fluid secretion and gas production it can lead to gastrointestinal symptoms referred to as lactose intolerance. There are marked racial differences in the prevalence of lactase deficiency, with the prevalence being 3– 8% in Scandinavia and Northwest Europe, increasing to close to 100% in Southeast Asia. In Europe, the frequency increases in southern and eastern directions, reaching 70% in southern Italy and Turkey.15 Testing for lactose malabsorption

The most common test today to diagnose lactose malabsorption is the lactose hydrogen breath test. Breath hydrogen is measured following ingestion of 25–50 g lactose dissolved in 100–500 ml of water, and after intake hydrogen concentration in end expiratory air is determined at 15–30 minutes intervals for 4–5 hours. The definition of a positive test has varied but a rise of 10–20 ppm over basal values is usually considered to indicate lactose malabsorption. The rise should be detected in more than one breath sample. A positive test indicative of lactose malabsorption usually peaks at 2–4 hours (fig 22),), while an early peak (within one hour of ingestion) may reflect rapid small bowel transit, SIBO, or substrate fermentation by the oral flora. The appearance of gastrointestinal symptoms during the test is also assessed to evaluate the presence of subjective lactose intolerance. However, this is usually done with the patient knowing that he/she has ingested lactose, which makes the usefulness of this information unclear. Importantly, there are great discrepancies between the presence of lactose maldigestion and symptoms of lactose intolerance,35,36 and lactose maldigesters can usually tolerate small amounts of lactose, up to 240 ml of milk (12.1 g lactose) daily according to one study, with minimal or no symptoms.35,37

Figure 2 Schematic drawing of hydrogen breath tests (fructose with or without sorbitol and lactose) indicating carbohydrate malabsorption.

Lactose malabsorption in functional gastrointestinal disorders

The importance of lactose malabsorption for gastrointestinal symptoms in irritable bowel syndrome (IBS) and other functional gastrointestinal disorders is controversial. The majority of studies, including a recent large survey of more than 1000 IBS patients, found the prevalence of lactose malabsorption in IBS subjects to be virtually the same as in the normal population.28,30,36,38,39 As stated previously, the prevalence of lactose maldigestion differs widely between different countries but the prevalence of IBS has not been found to differ substantially between countries with low versus high prevalence of lactose maldigestion.28,30,38 The importance of lactose malabsorption in IBS is therefore questionable, and the association between these two conditions is probably a coincidence because both are common and would be expected to occur together.40 However, in some studies, lactose malabsorption has been reported to be of great relevance for patients with IBS, and a positive effect on symptoms after lactose restriction has been demonstrated.7,29 Moreover, subjective lactose intolerance might be more prevalent in IBS patients due to increased sensitivity to lactose maldigestion in some, and to yet unresolved issues in others.7,36,29,41

“The importance of lactose malabsorption for gastrointestinal symptoms in IBS and other functional gastrointestinal disorders is controversial”

The importance of factors other than maldigestion of lactose behind subjective lactose intolerance is supported by the fact that self reported milk intolerance in IBS patients does not help in identifying lactose malabsorbers.42,43 Moreover, the majority of patients with lactose malabsorption can consume a considerable amount of lactose before having symptoms,35 and the use of lactase treatment seems to be of limited value.44Therefore, subjective lactose intolerance is probably relevant only for a subgroup of IBS patients, especially in those consuming large amounts of dairy products. In these patients a lactose reduced diet might have a positive effect on some of the symptoms, especially diarrhoea and gas/bloating, but the general impression is that the importance of lactose malabsorption in IBS has been overestimated during the past, and that dietary lactose exclusion rarely ameliorates the symptoms to any large extent in these patients.40

Fructose malabsorption Fructose absorption

Fructose is a ketohexose occurring naturally in its free form or as sucrose (glucose+fructose). It is widely used as a sweetener in different foods, beverages, and candy, and it is also present in fruits such as apples, peaches, cherries, and pears.45 It is absorbed by carrier mediated facilitated diffusion and results indicate that the capacity for fructose absorption is small compared with that for sucrose and glucose.46 The absorptive capacity for fructose varies greatly, but as high as 30–80% of healthy individuals tested with a hydrogen breath test demonstrated incomplete absorption of a 10% solution of 50 g of fructose.47,48,49 These studies also demonstrated that the absorptive capacity was unrelated to age or sex but that it was dose and concentration dependent. To put this dose into perspective, mean daily intake of free fructose (sucrose excluded) in the US population has been found to be 16 g/day but “heavy” consumers may reach 60–100 g/day.50 Testing for fructose malabsorption

When testing for fructose malabsorption, 25–50 g of fructose dissolved in 150–250 ml of water have been used. Methodology and interpretation of results is otherwise similar to lactose, as described above (fig 22).). It is unclear what the optimal dosage of fructose is to detect clinically meaningful malabsorption. Another unresolved issue is how symptoms should be assessed during the test and to what extent these are reliable, as very few blinded studies have been performed and the majority of studies are also uncontrolled. Of great importance is also the fact that simultaneous ingestion of glucose increases fructose absorption,48,49 and the majority of dietary sources of fructose also contain glucose. On the other hand, simultaneous ingestion of sorbitol, a naturally found sugar alcohol often used as a “sugar free” sweetener by the food industry, increases malabsorption of fructose.51 Therefore, breath testing of fructose alone probably does not reflect fructose ingestion in everyday life, making interpretation of the test extremely unreliable from a clinical point of view. Fructose malabsorption in functional gastrointestinal disorders

A controversial issue is the importance of symptomatic malabsorption of fructose and/or sorbitol in IBS and other functional gastrointestinal disorders. Based on the few direct comparisons existing in the literature, malabsorption of fructose and/or sorbitol is not more frequent in IBS patients than in healthy subjects.6,31,52,53 However, one study demonstrated that IBS patients with incomplete absorption of fructose had significantly more severe symptoms after ingestion of fructose than IBS subjects without malabsorption, and the symptoms were enhanced by adding sorbitol, supporting the role of symptomatic fructose‐sorbitol malabsorption in IBS.5 A subsequent large study reported a similar proportion of fructose‐sorbitol malabsorption in IBS patients with and without symptoms after intake of fructose and sorbitol, opposing the view of an important role for fructose‐sorbitol malabsorption in IBS.31 A Spanish study found more severe symptoms after intake of a fructose‐sorbitol mixture in patients with functional gastrointestinal disorders than after intake of sucrose as a control solution6whereas we found similar symptoms in IBS patients with subjective fruit intolerance after intake of a fructose‐sorbitol mixture versus glucose (control), irrespective of the presence of fructose malabsorption.54

“Malabsorption of fructose and/or sorbitol is not more frequent in IBS patients than in healthy subjects”

As stated in a recent review, there is need for controlled studies clarifying the relation between incomplete fructose absorption and symptoms, and also assessing the effects of co‐ingestion of other sugars on fructose absorption.55 Until we have this information the role of fructose malabsorption tests in clinical practice remains uncertain. For IBS patients ingesting large amounts of fruits and/or products where artificial sweeteners are used, diets where fructose is empirically restricted might be tested.

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Small intestinal bacterial overgrowth

SIBO is a condition caused by an abnormal number of bacteria in the small intestine. Symptoms related to bacterial overgrowth in the small intestine are diarrhoea, weight loss, anaemia, and malabsorption.56,57,58,59SIBO is a common cause of malabsorption and malnutrition,56,60 especially among the elderly61,62 and in patients with blind loops,59 stenosis,63 diverticula,64,65 and motor disorders.66,67 Recently, SIBO has been suggested to be associated with a large number of different conditions, such as coeliac disease,34 chronic pancreatitis,68,69 hypothyroidism,70 Parkinson's disease,71 and fibromyalgia.72 However, the proposed contribution of SIBO to IBS has received the greatest attention, with studies demonstrating prevalence values of 38–84% of SIBO in IBS,8,9,72,73,74 but these studies have been heavily criticised,75,76,77,78,79 and contradictory results exist.80,81 In most cases the diagnosis of SIBO has been established by the use of hydrogen breath tests, usually with glucose or lactulose. However, the use of breath tests and interpretation of the result require knowledge about these tests. In some studies discussion around possible sources of errors with the test has been very sparse, as well as alternative interpretations of the results.68,82,83,84,85 “SIBO is a condition caused by an abnormal number of bacteria in the small intestine”

Normal bowel flora

The concentration of bacteria in the gastrointestinal tract increases in a caudal direction (table 1 1).). The stomach is almost sterile and the upper part of the small bowel contains only small numbers of bacteria. The flora consists mainly of Gram positive bacteria. Strictly anaerobes are rare. In the distal part of the small bowel, the flora more resembles that of the large bowel but the ileocaecal valve acts as a barrier, with an increase in bacteria concentration distally to the valve. Gram negative aerobes predominate and strictly anaerobes are common. In the colon, anaerobes outnumber aerobes.86,87 There is large interindividual variability but within individuals the intestinal flora remains fairly constant over time.86

Table 1 Concentration of bacteria in different parts of the gastrointestinal tract (bacteria/ml)

Definition of SIBO

For several reasons the stability of the bowel flora can become disturbed so that bacterial overgrowth may occur. In the context of SIBO, this usually means abnormal numbers of normal inhabitants of the gastrointestinal tract. As the normal upper small bowel harbours less than 104 colony forming units/ml and the vast majority of these bacteria are Gram positive aerobes, it is possible to define SIBO as conditions differing from this (for example, a total growth of >104 bacteria and/or growth of Gram negatives or anaerobes). This definition can be acceptable in a strictly microbiological context but for clinical use it is of limited value as symptoms of SIBO correlate poorly with this definition. SIBO is usually defined as a total growth of >105 colony forming units/ml intestinal fluid.13,16,25,88,89,90 However, this definition is also insufficient as a substantial part of overgrowth with this definition consists of Gram positive flora. Gram positive overgrowth is mainly due to upper respiratory flora and is a frequent finding in the upper part of the small bowel of healthy elderly people91 and has not been correlated with symptoms of SIBO.92,93,94,95Growth of colonic‐type bacteria (mainly Gram negatives, strictly anaerobes and enterococci) correlates with symptoms of SIBO.56,57,60 Furthermore, these bacteria possess certain properties such as the ability to deconjugate bile salts, affect the binding capacity of intrinsic factor, and reduce the absorptive function of enterocytes,87,96 mechanisms closely related to the symptoms of SIBO. A definition of SIBO as >105colonic‐type bacteria therefore seems to be more clinically relevant. Tests for SIBO Small intestinal culturing

Culture of small bowel content is the most direct method for diagnosing SIBO and culture of jejunal aspirate is by many considered to be the gold standard. However, there are several difficulties associated with culturing. Obtaining aspirate for cultures is cumbersome and results of culturing are not always representative. It is a common belief that cultures are often false negative, especially concerning obligate anaerobes.60,97 Furthermore, only the upper part of the small bowel is accessible for culturing and bacteria have been proven to grow only at the actual location of the predisposing abnormality.98 On the other hand, false positive cultures due to contamination, mainly from the oral flora, are also believed to be common.99 Breath tests

Because of the disadvantages with cultures, different breath tests have been developed. All of these are indirect tests based on certain metabolic characteristics unique for bacteria. There are three main types of breath tests used for diagnosing SIBO. The original breath test for diagnosing SIBO was the bile acid breath test,100,101 depending on the ability of many types of bacteria to deconjugate bile acids,56 but this test is rarely used today. In the 1 g 14C‐D‐xylose breath test,102,103 patients are given 1 g of 14C labelled xylose which after absorption is normally secreted through the kidneys with only minor endogenous metabolism. In the case of bacteria in the small 14 bowel, xylose is metabolised to CO2 which is absorbed and expired and thus possible to detect with a breath test (fig 11),), with an earlier peak implying jejunal overgrowth and a somewhat later peak more distal overgrowth (fig 33).

Figure 3 Examples of test results from glucose and xylose breath tests, indicating jejunal and ileal bacterial overgrowth, respectively, as well as a normal test.

“Hydrogen breath tests, using glucose or lactulose, are the most commonly used tests for SIBO today”

Hydrogen breath tests, using glucose12,13 or lactulose,14 are the most commonly used tests for SIBO today, and therefore the rest of the article will focus on these tests. Glucose is normally given in a dose of 50–75 g dissolved in water and lactulose in a dose of 10 g. H2 in end expiratory breath samples are thereafter measured every 15 minutes for up to three hours. Abnormal versus normal results

Definitions of normal and abnormal results of breath tests are even more variable than for cultures. The lack of generally accepted definitions raises a situation where you can almost choose the test and definition that best suits your purpose. It is not uncommon to see the same authors change their definitions of a positive test in different papers.8,9,72 Only a few papers have described adequately their reasons for choosing a certain cut off point.23,24,25,104

Glucose is readily absorbed in the proximal small bowel, and in the absence of severe transit abnormalities it rarely reaches the colon,26,105 making it an attractive substrate to detect at least proximal SIBO. The glucose hydrogen breath test is considered positive if there is a clearly recognisable hydrogen peak, exceeding 10–20 ppm (fig 33).12,13,89 High fasting concentrations may be due to SIBO but this is a very unspecific finding which may also be due to slow intestinal transit leaving a residue of poorly absorbable carbohydrates remaining in the colon.16 Mostly, however, high fasting concentrations occur when the instruction to follow a low fibre diet before the test not has been followed.

Lactulose passes unabsorbed through the small bowel and into the colon. Therefore, apart from detecting SIBO, it can also be used as a measure of orocaecal transit.106 The original definition of a positive lactulose test (that is, indicating SIBO) was an easily detected early hydrogen peak (>20 ppm), due to small intestinal bacteria, occurring at least 15 minutes before the later prolonged peak, corresponding to the passage of the remaining lactulose into the colon (fig 4 4).14 However, in some of the more recent studies, other less restrictive definitions, such as a rise 9,72,74 in H2 within 90 minutes, have been used, which should be compared with the fact that the mean orocaecal transit time assessed with lactulose breath testing in healthy controls is slightly above 90 minutes.106,107 Therefore, using this definition, 50% of healthy controls would be expected to suffer from SIBO!79

Figure 4 A positive lactulose hydrogen breath test indicating small intestinal bacterial overgrowth with an easily detected early peak due to small bowel bacteria, clearly distinguishable from the later prolonged peak corresponding to the passage ...

“The sensitivity and specificity of the lactulose hydrogen breath test in detecting SIBO has been reported to be only 68% and 44%, and for the glucose breath test 62% and 83%”

Moreover, without a clear second peak in the lactulose breath test, it is impossible to distinguish SIBO from colonic fermentation, often caused by rapid transit,81,108 and importantly lactulose itself accelerates small bowel transit.107 However, not even detection of two easily distinguishable hydrogen peaks is a safe criterion as it has been shown in transit studies that a bolus can reach the caecum, imitating the first peak followed by the body of lumen contents, producing a second peak, yielding false positive lactulose tests.108,109 Therefore, it is not surprising that the sensitivity and specificity of the lactulose hydrogen breath test in detecting SIBO has been reported to be only 68% and 44%, and for the glucose breath test 62% and 83%.16 Which test should be used?

There is no general agreement as to which breath test is preferable.25,88,89,104 In some investigations the 1 g 14C‐D‐xylose breath test has shown excellent results but this has not been confirmed in more recent studies.23,25,104 However, as stated above, the hydrogen breath test with lactulose was found to have both lower specificity and sensitivity than other breath tests.16,89 Although sensitivity in general is acceptable, because of the low specificity for diagnosing SIBO compared with jejunal cultures, it has even been questioned if breath tests are useful at all for diagnosing SIBO.16,20,23,24,81,90,104,108

Is there a link between SIBO and IBS?

Recent studies suggest a strong link between SIBO and IBS, using the lactulose breath test,8,9,72,74,110 but others, using lactulose, glucose, and xylose breath tests, as well as jejunal cultures, have failed to confirm these findings.80,81 It has been proposed that the reason for the poor concordance between the lactulose breath test and jejunal cultures and the other breath tests is that lactulose is not absorbed in the small bowel. Because of this, the lactulose breath test is thought to be superior in detecting ileal bacterial overgrowth.8,9As this part of the small bowel has other functions than the upper part, bacterial overgrowth of the distal small bowel may also cause different symptoms. Theoretically, it is possible that distal bacterial overgrowth would not cause malabsorption, but instead IBS symptoms. However, evidence of the existence of culture proven ileal bacterial overgrowth is lacking.

“Recent studies suggest a strong link between SIBO and IBS, using the lactulose breath test, but others, using lactulose, glucose, and xylose breath tests, as well as jejunal cultures, have failed to confirm these findings”

Pimentel et al have shown that the lactulose hydrogen breath test is often positive in IBS patients8,9,72 and that treatment with antibiotics or a low fibre diet in patients with IBS and a positive lactulose hydrogen breath test improves symptoms and reduces breath hydrogen concentration.9,111 Are these results really explained by the presence of SIBO? An alternative interpretation is that the positive breath test is due to hydrogen production by colonic bacteria and that treatment reduces the number of bacteria and their production of hydrogen. This is supported by preliminary findings from King and colleagues of abnormal colonic fermentation in IBS112 and a more recent study from the same group113 where they demonstrated that treatment of subjects with IBS with metronidazole or a low fibre diet improved symptoms, reduced gas excretion, and produced a corresponding decrease in the concentration of faecal bacteria. The studies by Pimentel and others have paved the way towards studying alterations in the gut flora of IBS and other functional gastrointestinal disorders. The story of SIBO and IBS has not come to an end and hopefully future studies will be performed using appropriate methods and correct interpretation of the results.

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Conclusion

Hydrogen breath tests are simple and safe, providing us with an easy tool to unravel the pathophysiological alterations behind symptoms difficult to explain. However, these tests have a number of limitations. The importance of SIBO and bacteria in other parts of the gut for functional gastrointestinal symptoms remains to be determined, and breath tests used wisely can be important together with other techniques in future studies. Today, regular use of the lactulose breath test in clinical practice in the evaluation of symptoms in patients with suspected functional gastrointestinal disorders cannot be recommended. The relevance of maldigestion of specific carbohydrates, such as lactose and fructose, in functional gastrointestinal disorders is probably overestimated. However, in some patients with a large intake of products containing these sugars, a hydrogen breath test, followed by dietary restriction of the sugar in case of a positive test, may be advised. Hopefully, the occasional abuse of hydrogen breath tests seen today can be turned into proper clinical and scientific use in the future.

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Abbreviations

SIBO - small intestinal bacterial overgrowth

IBS - irritable bowel syndrome

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Footnotes

Conflict of interest: None declared.

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FOFMAPs to the rescue Today I have a very specific topic about how I have been feeling and what I am going to do about it. I don’t know if everyone is aware of or has heard about FODMAPs before. It is an elimination diet that is very useful to those with any IBS/IBD symptoms or diagnosis. FODMAPs are carbs that are high in sugars but not all carbs are FODMAPs. They are fructose, lactose, fructans, galactans,and polyols.

Now I have already been tested positive for fructose intolerance and know dairy fat bothers me as well as whole eggs but 1. I have done an awful job really limiting fructose and 2. my stomach still hurts on an almost daily basis. This isn’t always a I have a tummy ache hurt but the symptoms include: gas, bloating, cramping, constipation and diarrhea. I experience most of these and the cramping is often the worst symptom of all. It is a sharp pain in my left side that causes me to lean over a little when it happens and hold my breath.. safe to say these are not pleasant symptoms when trying to live a “normal” life like going out with friends, enjoying meals, and working out.

My symptoms had eased up a lot during the last couple months but started to get worse again and there is no real way to pinpoint why. It is very frustrating when you don’t know what to change or why you feel so awful. So now that I am home for two weeks I am going to fully commit to the FODMAPs ‘diet.’ This is for my health and not weight reasons and I will say I am not googling my symptoms and making these decisions based off half credible sources but that my GI doctor, the nutritionist I saw, and the dietitian that did my fructose intolerance testing all have told me I really need to do this in order to pinpoint irritants and help with my gut healing so I don’t have to deal with this for the rest of my life. The reason I did not do it a year ago when I was first told about this was 1. because I was intimidated by this disease I found out I had, a food intolerance, and no reason for me getting it all and 2. because as a college student it is hard to cut out so many foods and still get a variety of nutrients for collegiate training and 3. not wanting to waste my meal plan and spend all my money on groceries.

I am going to do a 6 week elimination period starting today and then reintroduce foods one at a time afterwards. I am really not a fan of cutting out whole food groups but I would much rather figure this out for good and not feel so awful all the time. After looking at the do’s and don’ts I do not think it will be as hard as I originally thought. I can still eat my blueberries, bananas, some nuts, fish and egg whites, oatmeal, nut butter, gf flour, lettuce, yams, squash, quinoa, and coffee! Plus some others, but no froyo but I will make sure to buy some lactose free ice cream at the grocery store and probably save a lot of money not going so often.

It really helps to be home at the start of this to be able to have access to more foods and hopefully get into the habit of not eating the other things. It also helps that i have limited those items with fructose for the last year so it will not seem like too many more things off the list.

I look forward to hopefully feeling 100x better and being more comfortable going out in public and being with people. I know this is the best decision for me after having multiple creditable sources recommend it.

Here are some of the resources I am using to figure out what to eat and not eat and focus on what I like that I can have! http://stanfordhospital.org/digestivehealth/nutrition/DH-Low-FODMAP-Diet-Handout.pdf http://www.ibsgroup.org/brochures/fodmap-intolerances.pdf