J Neurogastroenterol Motil 2014; 20(2): 228-235  https://doi.org/10.5056/jnm.2014.20.2.228
Unclear Abdominal Discomfort: Pivotal Role of Carbohydrate Malabsorption
Miriam Goebel-Stengel1,*, Andreas Stengel2, Marco Schmidtmann1, Ivo van der Voort1, Peter Kobelt2, and Hubert Mönnikes1
1Department of Internal Medicine, Institute of Neurogastroenterology and Motility, Martin-Luther Hospital, Academic Teaching Institution of Charité - University Medical Center, Berlin, Germany; and 2Charité Center for Internal Medicine and Dermatology, Division of General Internaland Psychosomatic Medicine; Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
Correspondence to: *Correspondence: Miriam Goebel-Stengel, MD, PhD, Department of Internal Medicine, Institute of Neurogastroenterology and Motility, Martin-Luther Krankenhaus, Caspar-Theyβ-Str. 27-31, 14193 Berlin, Germany. Tel: +49-30-8955-3111, Fax: +49-30-8955-4554, E-mail: miriam.goebel-stengel@gmx.de
Received: November 19, 2013; Revised: February 26, 2014; Accepted: February 27, 2014; Published online: March 28, 2014.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Background/Aims

Carbohydrate malabsorption is frequent in patients with functional gastrointestinal disorders and in healthy volunteers and can cause gastrointestinal symptoms mimicking irritable bowel syndrome (IBS). The aim of this study was to investigate the prevalence of symptomatic lactose and fructose malabsorption in a large population of patients with IBS-like symptoms based on Rome II criteria.


Methods

Patients with unclear abdominal discomfort (n = 2,390) underwent lactose (50 g) and fructose (50 g) hydrogen (H2) breath tests and depending on the results further testing with 25 g fructose or 50 g glucose, or upper endoscopy with duodenal biopsies. Additionally, this population was investigated regarding the prevalence of small intestinal bacterial overgrowth (SIBO) based on glucose breath test and celiac disease.


Results

Of the 2,390 patients with IBS-like symptoms, 848 (35%) were symptomatic lactose malabsorbers and 1,531 (64%) sympto-matic fructose malabsorbers. A combined symptomatic carbohydrate malabsorption was found in 587 (25%) patients. Severe fructose malabsorbers (pathologic 25 g fructose test) exhaled significantly higher H2 concentrations in the 50 g test than pa-tients with negative 25 g fructose test (P < 0.001). Out of 460/659 patients with early significant H2 increase in the lactose and fructose test who underwent a glucose breath test, 88 patients had positive results indicative of SIBO and they were sig-nificantly older than patients with negative test result (P < 0.01). Celiac disease was found in 1/161 patients by upper endoscopy.


Conclusions

Carbohydrate malabsorption is a frequent but underestimated condition in patients with IBS-like symptoms although diagnosis can be easily confirmed by H2 breath testing.(J Neurogastroenterol Motil 2014;20:228-235)

Keywords: Breath tests, Fructose, Hydrogen, Irritable bowel syndrome, Lactose
Introduction

Recurrent or chronic abdominal discomfort is a common condition in the health care setting. Most patients have had prior medical evaluation that did not yield a satisfactory diagnosis. Common organic causes of chronic abdominal pain and discomfort encompass peptic ulcer disease, postoperative adhesive bands or gynaecologic disorders. However, the irritable bowel syndrome (IBS) and carbohydrate malabsorption are also frequent in patients with unexplained gastrointestinal symptoms.

Lactose, a disaccharide composed of galactose and glucose, is cleaved into absorbable monosaccharides by the enzyme lactase which is found in the epithelium of the small intestine. Lactose intolerance results from a lack of lactase often referred to as lactase deficiency.1 The non-digested lactose cannot be absorbed in the small intestine and thus reaches the colon. For the monosaccharide fructose, the glucose transporter (GLUT)-5 protein of the enterocytes is the preferred transport system out of the small intestinal lumen.2 A lack of this transporter and/or a shortened small intestinal transit time result in an exceeding transport capacity for fructose.3,4

At their onward transport, fructose and lactose that remain in the lumen of the small intestine subsequently reach the colon and are fermented by resident bacteria.5?7 Degradation products of the bacterial metabolism are hydrogen (H2), carbon dioxide, hydrogen sulfide, methane and short chain fatty acids.5,6,8 While hydrogen is partly absorbed and exhaled and does not lead to osmotic diarrhea which is caused by short chain fatty acids and undigested oligodisaccharides,5?7 it may, similar to other gaseous metabolites, cause bloating and abdominal distension resulting in abdominal discomfort and cramps, especially in individuals with visceral hypersensitivity. Altogether, these symptoms can imitate IBS.9,10

Hydrogen breath tests offer an excellent non-invasive method to detect excessive production of hydrogen as seen in fructose and lactose malabsorption. The disability to sufficiently cleave lactose accompanied by clinical symptoms is referred to as symptomatic lactose malabsorption while the lack of clinical symptoms is referred to as lactose malabsorption. After infancy, most mammals, including humans, lose the intestinal enzyme lactase and thus the ability to digest lactose.11 Due to a genetic mutation, others keep the ability and worldwide, the persistence of the lactase gene is the most common enzymatic variant. Interestingly, this highly penetrant autosomal-dominant genetic polymorphism obeys a characteristic geographic distribution increasing from North to South, which is underlined by data showing that in Scandinavian countries only 3?8% of the population lack lactase,12 while the prevalence in the Austrian study group is around 20%,13 in China about 28%,14 in the Mediterranean up to 70% and in equatorial Africa even up to 98%.15 One has to consider that due to migration the number of people experiencing nutritional problems due to lactase deficiency in Europe steadily increases.

Lactose malabsorption has already been well recognized as a cause of non-specific gastrointestinal (GI) symptoms.16?18 On the contrary, malabsorption of fructose is less well studied but has recently received growing attention through the fact that restricting rapidly fermentable oligo-, di- and monosaccharides and polyols (FODMAPs) is beneficial in controlling symptoms of abdominal discomfort.19,20 Indeed, 2 studies reported a prevalence of fructose malabsorption in functional dyspepsia or unexplained GI symptoms of 40?55% and 73%, respectively.10,18 Therefore, it seems to be reasonable to perform routine fructose H2 breath tests in patients with unexplained abdominal symptoms who have had an unremarkable medical check-up including laboratory tests, physical examination, ultrasound and endoscopy and in the absence of “red flags” (e.g., unintended weight loss, rectal bleeding, fever, severe diarrhea or vomiting, persistent pain in the upper or lower right abdomen, family history of inflammatory bowel disease or colon cancer).

The gold standard to detect small intestinal bacterial over-growth (SIBO) is the culture of jejunal aspirates. However, in clinical practice the H2 breath test with glucose is often preferred.4 In healthy subjects, glucose is completely absorbed in the proximal small intestine, while in SIBO glucose is fermented by bacteria before absorption resulting in an early or late rise of H2 levels from the dysbiosis of the jejunum or ileum, respectively.

Up to now there is a lack of studies describing the role of carbohydrate malabsorption in patients with IBS-like symptoms in large study populations. Therefore, in a retrospective analysis, we characterized 2,390 patients with unclear abdominal discomfort with regards to occurrence, prevalence and severity of carbohydrate malabsorption, SIBO and celiac disease which may also lead to abdominal discomfort and IBS-like symptoms.

Materials and Methods

Patient Population Characteristics

The documentation and archive system of the gastroenterological unit of the Charit? Medical Center has been used as study entry database. Patients were outpatients or admitted from other departments of the Charit? Medical Center for hydrogen breath testing due to their GI symptoms in the years from 2000 to 2006. All patients consented to their data analysis for study purpose. They were asked about GI infections, antibiotics use or colonoscopy within the last 4?6 weeks. The breath tests were only performed 4?6 weeks after such an event. All subjects who presented with unclear abdominal discomfort (e.g., IBS-like symptoms) had unremarkable physical examination, lab results, ultra-sound and endoscopy in the absence of “red flags” (e.g., unintended weight loss, rectal bleeding, fever, family history of inflammatory bowel disease and colon cancer, persistent pain in the upper or lower right abdomen, severe diarrhea or vomiting). All subjects who had taken 2 H2 breath tests, with 50 g lactose and fructose, respectively, were included (n = 2,390).

Abdominal IBS-like symptoms were assessed once at the first contact with patient by a GI symptom questionnaire that is routinely used by the outpatient clinic at the Charit? Medical Center for functional GI and motility disorders. This questionnaire has not been validated yet but was used before21 and can group patients according to Rome II criteria.

Hydrogen Breath Test

The H2 breath tests all followed the same regimen. After an 18-hour overnight fast (water only), an end-expiratory breath sample was collected from the patients into a syringe. The breath sample was immediately analyzed by the use of a GMI Exhaled Hydrogen Monitor (GMI Medical, Renfrew, UK; measurement range 0?250 parts per million [ppm], sensitivity 2 ppm, measurement accuracy ± 2%, ± 1 ppm for values < 50 ppm) and the result of the measurement was documented. First, 2 baseline values for H2 were determined in the end-expiratory exhalation air. Only patients who showed a starting value of ≤ 20 ppm were included. After an oral load of the relevant carbohydrate in 200 mL water, according to the current German guidelines,4 further breath samples were obtained every 10 minutes over the measurement period of 180 minutes. An increase of the end-expiratory H2 concentration > 20 ppm above average baseline within 180 minutes was defined as significant/pathologic rise. The time until the first significantly increased value, time and value of the maximum H2 concentration as well as the concurrent abdominal symptoms under the carbohydrate load were documented.

Definitions and Measurements

Lactose hydrogen breath test

Patients received a solution consisting of 50 g lactose in 200 mL water. An H2 increase without typical abdominal symptoms was defined as lactose malabsorption. Patients with a pathologic H2 increase in combination with abdominal symptoms were defined as symptomatic lactose malabsorbers.

Fructose hydrogen breath test

The German guideline on clinically relevant breath tests in gastroenterology recommends the performance of hydrogen breath tests with 50 g fructose (in 200 mL water) first and an additional test with 25 g fructose (in 100 mL water) in case of a positive result to rule out fructose malabsorption.4 The term fructose intolerance describes a genetic disorder (deficiency of aldolase B due to ALDOB gene mutation). Analogous to lactose indigestion, we use the term fructose malabsorption to describe intestinal fructose malabsorption expressed by an H2 increase without corresponding symptoms and symptomatic fructose malabsorption for patients who present with symptoms in addition to their malabsorption. Patients with a pathologic H2 breath test with 50 g fructose and a normal H2 breath test with 25 g fructose are defined as moderate symptomatic fructose malabsorbers, whereas patients showing pathologic results in both H2 breath tests are classified as severe symptomatic fructose malabsorbers.

Glucose hydrogen breath test

An early pathologic increase in hydrogen levels (≥ 20 ppm above baseline during the first 60 minutes of the measurement period) in both lactose and fructose breath tests is suggestive of SIBO. Patients with suspected SIBO underwent the additional breath test with 50 g of glucose in 200 mL water.

Upper endoscopy

Patients with positive fructose and lactose breath tests are suggestive for celiac disease that often presents with secondary carbohydrate malabsorption due to duodenal atrophy. Therefore, these patients were asked to undergo upper endoscopy with duodenal biopsies.

Statistical Methods

Data are expressed as mean ± SEM and analyzed by ANOVA followed by all pair-wise multiple comparison procedures (Tukey’s post hoc test); P < 0.05 was considered significant.

Results

Study Population

Overall, 2,390 patients with unclear abdominal discomfort performed both H2 breath tests with 50 g lactose and with 50 g fructose. Of these, 1,548 were female and 806 were male. The mean age was 49.6 years. The majority of patients was Caucasian (n = 2,132), followed by Arabians (n = 128), Mediterraneans (n = 116), Asians (n = 12) and Africans (n = 1).

Prevalence of Carbohydrate Malabsorption

In the H2 breath test with 50 g lactose, 1,023/2,390 patients showed a significant H2 increase corresponding to a prevalence of lactose malabsorption of 42.8%. Of these, 848 patients additionally reported abdominal symptoms, indicating a prevalence of lactose intolerance of 35.5% of the whole study population. Of these, 554 were female and 294 were male. Additionally, 365 patients reported symptoms although no H2 increase was seen, while in contrast, 175 patients showed an H2 increase but reported no symptoms (Table 1). Of the 848 symptomatic lactose malabsorbers, 679 (80.1%) were of Caucasian, 93 (11.0%) of Arabic, 65 (7.7%) of Mediterranean and 11 (1.3%) of Asian origin. The one African reported symptoms but did not have a corresponding H2 increase. On the contrary, the prevalence of symptomatic lactose mal-absorption according to ethnicity was 91.7% in the Asian population, 72.7% in the Arabian, 56% in the Mediterranean, and 31.8% in the Caucasian population, respectively.

In the breath test with 50 g fructose 1,818/2,390 patients had a significant H2 increase, which translates into a prevalence of fructose malabsorption of 76.1%. Of these, 1,531 patients were symptomatic fructose malabsorbers and reported abdominal symptoms indicating a prevalence of moderate symptomatic fructose malabsorption of 64% of the whole study population. Another 172 patients reported abdominal symptoms but had no H2 increase, while in contrast, 287 patients showed an H2 increase but reported no symptoms (Table 1). Of the 1,531 symptomatic fructose malabsorbers, 1,367 were of Caucasian, 82 of Arabic, 74 of Mediterranean, 7 of Asian and 1 of African origin.

The prevalence of symptomatic fructose malabsorption according to ethnicity was 64.1% in the Arabian and Caucasian, 63.8% in the Mediterranean and 58.3% in the Asian population, respectively.

Of all patients, 829 subjects showed a significant increase in both H2 breath tests. Of those, 587 additionally reported symptoms corresponding to a prevalence of combined symptomatic carbohydrate malabsorption of 25% of the whole study population.

Severity of Symptomatic Fructose Malabsorption

To assess the severity of fructose malabsorption, in case of a pathologic H2 breath test with 50 g fructose (n = 1,818) an additional H2 breath test with 25 g fructose was conducted (Table 1). This breath test was performed in 552 patients. Of these, 226 patients had a significant H2 increase. Of these, 170 patients reported abdominal symptoms, thus defined as severe symptomatic fructose malabsorbers. Abdominal symptoms without H2 increase were reported by another 97 patients, while in contrast, 56 patients showed an H2 increase but reported no symptoms.

Correlation of Maximal H2 Increase and Severity of Fructose Malabsorption

The comparison of maximal H2 concentrations in the H2 breath test with 50 g fructose showed that patients with pathologic H2 breath test with 25 g fructose, classified as severe fructose malabsorbers, exhaled significantly higher H2 concentrations than patients with negative H2 breath test with 25 g fructose, defined as moderate fructose malabsorbers (123.6 ± 4.9 vs. 90.1 ± 2.9 ppm, P < 0.001).

Small Intestinal Bacterial Overgrowth

In 460/659 patients with early H2 increase in the fructose and lactose breath test, a H2 breath test with 50 g glucose was performed (Table 2). A significant H2 increase, indicative of bacterial overgrowth was detected in 88 patients. A total of 123 patients indicated abdominal symptoms. In this subgroup 44 patients did not show a significant H2 increase, whereas 61 patients had a significant H2 increase. Of all 88 patients with significant H2 increase, 85 showed an early H2 increase, which is indicative of SIBO. Three patients had a late increase indicative of terminal ileum dysbiosis. The comparison of age between patients with positive and negative glucose breath test indicated that patients with positive glucose breath test were significantly older than patients with negative test (54.8 ± 1.8 vs. 49.4 ± 0.8 years, P < 0.01).

Tables

Prevalence of Symptomatic Lactose and Fructose Malabsorption

Breath testLactose (50 g)Fructose (50 g)Fructose (25 g)
Performed2,3902,390552
Abdominal symptomsoverall1,2131,703267
without H2 increase36517297
with H2 increase8481,531170
H2 increaseoverall1,0231,818226
without abdominal symptoms17528756

H2, hydrogen.

Data are presented as number of patients.


H2 Breath Test for Small Intestinal Bacterial Overgrowth (Glucose)

Glucose (50 g)
Performed (N)460
Abdominal symptoms overall123
Abdominal symptoms without H2 increase44
Abdominal symptoms with H2 increase61
H2 increase overall88
H2 increase without abdominal symptoms17
No H2 increase, no abdominal symptoms277
Early H2 increase (SIBO)85
Late H2 increase (Dysbiosis of the terminal ileum)3

Patients with early significant hydrogen (H2) increase in the fructose and lactose test (n = 659) were asked to take the glucose breath test to exclude small intestinal bacterial overgrowth (SIBO).

Data are presented as number of patients.


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