Irritable Bowel Syndrome, Gastrointestinal Disorders, and Histamine Sensitivity

Dr Janice Joneja looks at the malabsorption problems which so often lead to a diagnosis of IBS, and how they can be managed.

Acute or chronic abdominal pain with diarrhea or constipation is a common and widespread condition worldwide.  Typical symptoms in the gastrointestinal (digestive) tract include:

Abdominal pain
Bloating
Burping
Constipation
Diarrhea
Flatulence
Heartburn
Nausea
Vomiting

When the most frequent pathologies such as gastroenteritis, inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, short bowel syndrome, surgery in the gastrointestinal tract, drugs, infections of all types (viral, bacterial and parasitic), celiac disease and tropical sprue have been ruled out by appropriate tests, a diagnosis of irritable bowel syndrome (IBS) is usually offered to the afflicted patient.

IBS is often referred to as a “functional gastrointestinal disorder” (FGID), or “functional bowel disorder” (FBD). These medical terms indicate that the condition impairs the normal function of a bodily process, but every part of the body looks completely normal under examination, dissection or even under a microscope. FGIDs are one of the most common reasons for seeking healthcare, and they are associated with poor health-related quality of life and substantial costs to society. (1)

The physiological mechanisms underlying these disorders are incompletely known, but several causes for the conditions have been suggested, including: low-grade inflammation; the speed at which food passes through the digestive tract (intestinal motility) (2); microorganisms in the digestive tract (the intestinal microbiome) (3); and psychosocial factors, such as stress, anxiety and depression. (4) “Disturbed sensation” can also be a factor; this is where the patient’s nervous system is not working correctly, leading the brain to receive incorrect messages, including an increased perception of pain, or lowered pain threshold. (5)

However, several disorders within the digestive tract are frequently overlooked when causes for the condition are being considered, namely: carbohydrate malabsorption and histamine intolerance.  Malabsorption of the carbohydrates lactose, sucrose and maltose is typically due to deficiencies in enzymes that break down these sugars; fructose malabsorption is usually a result of a defect in the transporter molecule, named GLUT5, that moves fructose molecules across the intestinal epithelial cells into circulation; and histamine intolerance is frequently caused by a deficiency in the enzymes that break down excess histamine. All of these conditions can result in the IBS symptoms listed above. Here we shall look at these conditions and examine their diagnosis and management.

Lactose Malabsorption or Intolerance

Lactose intolerance or malabsorption (LM) results from a reduced production or impaired activity of the enzyme lactase in the epithelium of the small intestine. LM can result from an inherited deficiency of the enzyme or from damage to the intestinal cells that produce the enzyme. As a result the disaccharide lactose cannot be cleaved into the absorbable monosaccharides glucose and galactose.  Consequently, undigested lactose moves into the lower bowel where it causes a change in osmotic pressure, resulting in fluid being drawn into the bowel and retained within it.  This, and the products of fermentation of the lactose by microorganisms in the area, leads to the symptoms typical of lactose intolerance, which include diarrhea, bloating, flatulence, pain and occasionally nausea and vomiting. 

Sucrose and Maltose Malabsorption

Sucrose and maltose malabsorption are usually the result of inherited deficiencies in the sucrase/isomaltase enzymes, which impairs the individual’s ability to break down sucrose, maltose, short 1–4 linked glucose oligomers (chains of glucose molecules), branched (1–6 linked) α-limit dextrins (chains of glucose in a specific formation linked through carbon atoms in the 1 and 6 positions in the glucose molecule), and starch.   

Sucrase cleaves the disaccharide sucrose into its constituent monosaccharides, glucose and fructose.  When the enzyme is deficient, intact sucrose moves into the lower bowel where it causes an increase in osmotic pressure and forms a substrate for microbial fermentation, resulting in the same symptoms as lactose malabsorption, listed above.

Similar enzymes, collectively called dextrinases, break up chains of glucose in maltose and other glucose polymers (several molecules bonded together) so that free glucose is released and absorbed into circulation.  Deficiency in the enzymes leads to glucose chains entering the bowel, again causing an increase in osmotic pressure and microbial fermentation.

These conditions, termed primary enzyme malabsorption, are quite rare and typically diagnosed in early childhood. (6)  However, recent research studies are indicating that secondary sucrose and maltose malabsorption can result from damage to the intestinal enterocytes when there is significant injury to the cells as a result of conditions such as the villous atrophy seen in celiac disease. (7) [Intestinal villi are small projections from the intestinal wall that increase the surface area of the intestine to facilitate optimal absorption of nutrients from the digestive lumen.  Villous atrophy occurs when conditions, such as celiac disease, damage the cells].

Whether due to a primary (genetic) or secondary (acquired) deficiency, absent or diminished enzyme activity allows undigested sugars to accumulate in the lumen of the small intestine, resulting in the clinical effects of sucrase/isomaltase deficiency. (8) The osmotic effect of malabsorbed sugars contributes to watery diarrhea. Subsequently, other symptoms such as bloating, flatulence and abdominal pain are caused by the fermentation of undigested carbohydrate by colonic bacterial microflora which release methane, hydrogen, and carbon dioxide causing bloating and abdominal pain. In secondary lactase, sucrose and isomaltase deficiency symptoms are usually temporary, with enzymatic activity gradually returning to normal or near normal as the underlying disorder is successfully resolved.

Fructose Malabsorption

Fructose in food is absorbed into the body by a process known as facilitated diffusion by the major transporter protein GLUT5.  Fructose intolerance or malabsorption (FM) is caused when the GLUT5 protein is unable to move all of the fructose in the digestive tract across the cells lining the small intestine (the intestinal epithelium) into circulation. The undigested and unabsorbed fructose moves into the large intestine, where the colonic bacteria ferment the sugar molecules, causing symptoms such as abdominal pain, bloating, flatulence and diarrhea. (9)  GLUT5 protein is produced on the apical border of enterocytes (intestinal cells) in the small intestine, so damage to these cells, such as inflammation, reduces the amount of the protein produced and therefore decreases the amount of fructose absorbed.  The production of GLUT5 is often decreased in people with diabetes, obesity and hypertension (high blood pressure), so in these conditions it is not unusual to see the typical symptoms of fructose intolerance.

Histamine Intolerance

What is not so well-known is that symptoms of IBS are also symptoms of histamine intolerance (HI). (10)  HI results from an excess of histamine in the body as a result of the reduced capacity of histamine degrading enzymes, diamine oxidase (DAO) and N-methyl transferase (HNMT), resulting in an excess of histamine.  A lower than normal level of serum DAO (less than 10 U/mL), which is the main enzyme for the metabolism of histamine present in the diet, causes insufficient histamine breakdown in the GI tract, (11) leading to absorption of an excessive quantity of histamine into circulation.

DAO is produced by mature apical enterocytes which are located in the upper intestinal villi. (12) It is continuously released from the intestinal mucosa and also transported to the blood circulation.

Effects of Malabsorption

When considering the above, it becomes evident that malabsorption of several different dietary components can result in the symptoms of IBS.  All of the conditions discussed share the common finding that the deficient agents responsible for the intolerance or malabsorption are produced in the cells lining the small intestine, namely the enterocytes.  Logically, if these cells are damaged, the enzymes and proteins necessary for efficient digestion and absorption of the nutrients involved will be adversely affected.

This effect was demonstrated by a laboratory study on rats in 1980. (13) With increasing damage to the epithelial cells, there was a progressive decrease in the enzyme activities studied; first, lactase levels fell, then maltase and sucrase, and finally mucosal and plasma diamine oxidase activity.  The decrease in plasma diamine oxidase reflected the degree of mucosal damage.  The authors suggest that diamine oxidase activity is unique among intestinal mucosal enzymes studied to date in that circulating levels can serve as a marker of mucosal maturation and integrity. Furthermore, the order in which the enzymes were damaged probably reflects their situation on the intestinal villi:  lactase would be expected to be produced at the tip of the villus, followed in order by maltase, sucrose, and lastly diamine oxidase.  The investigations involved digestive enzymes, so the fructose GLUT5 protein, which is not an enzyme, but a transporter molecule, was not included in these studies.

A study in Austria in 2016 (14) investigated the prevalence rates of lactose malabsorption (LM), fructose malabsorption (FM) and histamine intolerance (HI) in 439 patients with gastrointestinal symptoms in the absence of diagnosed intestinal pathology. Hydrogen breath tests for lactose and fructose intolerance identified 241 (54.9%) patients with LM and/or FM, of which 89 (36.9%) individuals were also diagnosed with HI. Specifically, 94 (21.4%) of the patients were only lactose intolerant; 31 (7.1%) showed only fructose malabsorption; and 100 (22.8%) were only histamine intolerant.  However, 116 (26.4%) individuals showed intolerance of more than one of these conditions concomitantly: 52 (11.8%) were both lactose and histamine intolerant; 23 (5.2%) were fructose and histamine intolerant; and 14 patients were afflicted with all three conditions (LM, FM and HI), while 98 (22.3%) of the test subjects were negative for all three.

The authors suggest that these findings demonstrate that multiple combinations of carbohydrate malabsorption with HI may be associated with GI disorders.   An important extension of a follow-up study would include tests for sucrose and maltose malabsorption as both conditions may be responsible for similar symptoms in some individuals in the study population.

Nevertheless, the recognition that histamine intolerance can play a significant role in gastrointestinal conditions that until now have defied conventional testing and therapy is an important step forward in management of IBS and related diseases.

This seems a great challenge for clinicians in view of individualized treatment requirements. Research studies show that a proper diagnosis and effective dietary intervention significantly reduces the severity and frequency of gastrointestinal symptoms in IBS. Thus, diagnosis of malabsorption of carbohydrates in IBS using specific breath tests, and tests for HI are very important for the proper treatment of IBS patients.

Diagnosis

In practice, it is not easy to diagnose each of the conditions individually.  The most frequently used test for carbohydrate malabsorption is the hydrogen breath test. (15)  After taking a specified amount of the sugar, the amount of hydrogen in the patient’s breath is measured. Hydrogen is one of the products of fermentation of the unabsorbed sugar by microorganisms in the large bowel.  The hydrogen is absorbed into circulation and eventually reaches the lungs, where it is expelled in breath. An abnormal amount of hydrogen indicates malabsorption of the sugar.  Unfortunately, the test is not entirely accurate. Sometimes the hydrogen actually arises from fermentation of carbohydrates in the GI tract other than, or in addition to the one tested.

In some cases, especially congenital sucrase/isomaltase deficiency, the condition may be confirmed by disaccharidase assay of duodenal or jejunal mucosa obtained endoscopically.  An endoscope tube is inserted into the upper intestine and a biopsy sample taken.  Testing of the sample for the suspect enzymes will determine a deficiency.  However, the technique is very invasive and normally used to diagnose congenital (primary) SI malabsorption.  The test would be used only in exceptional cases of secondary disaccharidase deficiency.

To complicate the situation, the patient may be unable to absorb multiple carbohydrates, and it is the combination of the sugars which leads to the symptoms.  For example, in the reports cited above, some individuals showed malabsorption of both lactose and fructose, while others were intolerant to both sugars and histamine.  When significant damage to the intestinal villi occurs, which could be due to a number of GI tract disorders such as celiac disease, gastroenteritis, inflammatory bowel disease, and other causes of inflammation, several of the epithelial enzymes may be deficient, resulting in malabsorption of multiple carbohydrates, as well as increased uptake of histamine from the diet as the damaged cells are unable to produce sufficient DAO to break down the excess.

Diagnosis of histamine intolerance is difficult because standardised diagnostic tests for HI are still lacking. Measurement of serum diamine oxidase levels and a positive response to a histamine-restricted diet form the basis of HI diagnosis at the present time.   However, histamine intolerance should be suspected when symptoms occur in organ systems throughout the body, in addition to those in the GI tract.  While symptoms of carbohydrate malabsorption are confined to the GI tract, symptoms caused by histamine excess may be experienced in the skin, as hives (urticaria), angioedema (swelling in deeper layers within the skin, facial and oral tissues), flushing and reddening (erythema); the upper respiratory tract as nasal congestion (rhinitis) and runny nose (rhinorrhea); the eyes as irritation, watering and reddening (conjunctivitis); the nervous system as headache, fatigue, confusion, irritability, and rarely,  momentary loss of consciousness; and occasionally more alarming signs such as increased heart rate (tachycardia), chest pain, and feelings of anxiety or “panic”. (10)

Following available testing, which would include hydrogen breath tests for the unabsorbed sugar, and assay for DAO where available, confirmation of the conditions may be obtained from exclusion diets.  If symptom relief is achieved following removal of the suspect components from the diet for a trial period, a fairly definitive diagnosis of carbohydrate and/or histamine intolerance can be assumed. 

Management

Management of carbohydrate malabsorption and histamine intolerance is optimally achieved by avoidance of the offending foods.  However, in many cases where there are several concomitant deficiencies, avoidance of all of the foods containing the offending components while ensuring complete balanced nutrition from those allowed can be extremely challenging.  The aid of a registered dietitian is essential in the process.

In some cases, the deficient enzymes may be available as supplements which act in the digestive tract to “pre-digest” the problem dietary components.

Lactase (beta-galactosidase) enzyme is available as a supplement, marketed variously as “Lactase enzyme”, Lactaid® and Lacteeze®.  As with other such enzymes, the supplement must be taken with the food containing the offending ingredient, in this case most milk or milk products.  Lactose-free milk and milk products in which the lactase has been broken down by lactase before packaging are available commercially.

Sucrase/isomaltase (SI) deficiency may be managed with the enzyme sacrosidase, which is available commercially as Sucraid®, a yeast-derived enzyme that has been used effectively in patients with congenital SI deficiencies. (6)  A 2012 study of six patients with congenital sucrose/ isomaltase deficiency showed little improvement following advice regarding dietary management, but experienced a marked reduction in symptoms with sacrosidase administration; no adverse events were reported. (16)

Diamine oxidase is available as a supplement, marketed as Umbrellux™ and Histame™.  The supplemental enzyme should be taken immediately prior to a meal containing histamine ingredients so that it mixes with the food as it passes through the digestive tract and metabolizes the histamine before it can be absorbed into circulation.

Fructose malabsorption may be improved by the use of the enzyme xylose isomerase. (17) The enzyme converts dietary fructose to glucose by a biochemical process known as isomerisation.  Glucose does not require the GLUT5 transporter molecule exclusively to reach circulation, so when GLUT5 is deficient, glucose can still move across the epithelium into the blood stream. Xylose isomerase is available commercially as FructosAid® in North America and Xylosolv™ in Europe. However, using xylose isomerase to convert fructose to glucose cannot be used in cases where excess glucose needs to be avoided, such as diabetes, because the process results in an increase in the amount of glucose absorbed.

Prognosis

When deficiencies in the digestive enzymes or transport proteins discussed in this article are due to an inherited (congenital) defect (primary deficiency), there is no evidence that the situation will change over time.  However, when a secondary deficiency is the result of an underlying pathology such as an inflammatory process from a variety of causes, normal function may be restored when the factors causing damage to the enterocytes are identified and treated or eliminated.  Examples of treatable conditions include celiac disease, which is managed by gluten avoidance; mast cell activation disorders such as mastocytosis when mast cell stabilizers reduce the amount of histamine released; bacterial and parasitic infections when the causative organism is identified and eliminated by appropriate antibiotics.

Of particular interest is a 2013 study (18) from Slovenia on 316 histamine-intolerant patients, which reported that as a result of the histamine-restricted diet not only did the majority of the symptoms disappear but that the patients’ level of serum DAO increased significantly.  Further research on this observation would be expected to identify how histamine interacts with the DAO-producing enterocytes, or whether this phenomenon has its origin in mechanisms involving histamine regulation.

Summary

IBS and other similar digestive tract conditions may be caused or exacerbated by frequently underdiagnosed conditions of carbohydrate malabsorption and histamine intolerance.

Diagnosis of the deficiencies responsible for these conditions is difficult.    Tests, limited by reliability and availability, may reveal the underlying physiological defects.  Dietary exclusion diets, followed by challenge of the suspect food ingredients may support the results of the tests.

In some cases supplements may provide symptomatic relief.

Exclusion diets, appropriate supplementation by deficient factors and introduction of nutrients of equivalent nutritional value are, at present, the most effective ways of managing the conditions.

April 2018

Further information on all topics discussed can be obtained in Dr. Joneja’s publications:

Lactose, Fructose, Sucrose/Isomaltose Malabsorption:

Joneja J Vickerstaff. The Health Professional’s Guide to Food Allergies and Intolerances. Academy of Nutrition and Dietetics. October 2012  ISBN 978-0-88091-453-6
Can be purchased from the Academy on-line.    

Joneja, J.M.Vickerstaff. Digestion, Diet and Disease: Irritable Bowel Syndrome and Gastrointestinal Function. Rutgers University Press, Piscataway, New Jersey. August 2004 ISBN 0-8135-3387-2
Can be purchased from the publisher, or a free copy available here.

Histamine intolerance

Dr. Janice Joneja.  The Beginner’s Guide to Histamine Intolerance.  Sep 27 2017 from Amazon - Paperback - EBook

Dr. Janice Joneja. Histamine Intolerance: A Comprehensive Guide for Healthcare ProfessionalsNov 27 2017 E book From Amazon: Canada; USA; UK

References

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(2) DuPont AW, Jiang ZD, Harold SA, Snyder N, Galler GW, Garcia-Torres F, DuPont HL.  Motility abnormalities in irritable bowel syndrome. Digestion. 2014;89(2):119-123

(3) Sundin J, Öhman L, Simrén M. Understanding the gut microbiota in inflammatory and functional gastrointestinal diseases. Psychosom Med. 2017 Oct;79(8):857-867.

(4) Fond G, Loundou A, Hamdani N, Boukouaci W, Dargel A, Oliveira J, Roger M, Tamouza R, Leboyer M, Boyer L. Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2014 Dec;264(8):651-660.

(5) H Mertz. Role of the brain and sensory pathways in gastrointestinal sensory disorders in humans. Gut 2002;51(Suppl I):i29–i33

(6) Treem WR (2012) Clinical aspects and treatment of congenital sucrose/isomaltase deficiency. J Pediatr Gastroenterol Nutr 55:S7–S13

(7) Cohen SA. The clinical consequences of sucrase-isomaltase deficiency. Mol Cell Pediatr. 2016 Dec;3(1):5-8 

(8) Naim HY, Roth J, Sterchi EE, Lentze M, Milla P, Schmitz J, Hauri HP (1988). Sucrase-isomaltase deficiency in humans. Different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme. J Clin Invest 82:667–679

(9) Jones HF, Butler RN, Brooks DA. Intestinal fructose transport and malabsorption in human.  American Journal of Physiology Gastrointestinal and Liver Physiology 2011;300(2):G202–G206

(10) Maintz L, Novak N. Histamine and histamine intolerance. American Journal of Clinical Nutrition 2007;85(5):1185-1196.

(11) Manzotti G, Breda D, Di Gioacchino M, Burastero SE. Serum diamine oxidase activity in patients with histamine intolerance. International Journal of Immunopathology and Pharmacology 2016;29(1):105–111

(12) Ji Y1, Sakata Y, Li X, Zhang C, Yang Q, Xu M, Wollin A, Langhans W, Tso P.   Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release. Am J Physiol Gastrointest Liver Physiol. 2013 Apr 15;304(8):G732-G740.

(13) Luk GD, Bayless TM, Baylin SB. Diamine oxidase (histaminase). A circulating marker for rat intestinal mucosal maturation and integrity.  J Clin Invest. 1980 Jul;66(1):66-70.

(14) Enko D, Meinitzer A, Mangge H, Kriegshäuser G, Halwachs-Baumann G, Reininghaus EZ, Bengesser SA, Schnedl WJ. Concomitant Prevalence of Low Serum Diamine Oxidase Activity and Carbohydrate Malabsorption.  Can J Gastroenterol Hepatol 2016  Volume 2016, Article ID 4893501, 4 pages 

(15) Rana SV, Malik A. Breath tests and irritable bowel syndrome. World Journal of Gastroenterology June 2014;20(24):7587-7601

(16) Puntis JW, Zamvar V. Congenital sucrase-isomaltase deficiency: diagnostic challenges and response to enzyme replacement therapy.  Arch Dis Child. 2015 Sep;100(9):869-871.

(17) Komericki P, Akkilic-Materna M, Strimitzer T, Weyermair K, Hammer HF, Aberer W.  Oral xylose isomerase decreases breath hydrogen excretion and improves gastrointestinal symptoms in fructose malabsorption - a double-blind, placebo-controlled study.  Aliment Pharmacol Ther. 2012 Nov;36(10):980-987. 

(18) Mušič E1, Korošec P, Šilar M, Adamič K, Košnik M, Rijavec M. Serum diamine oxidase activity as a diagnostic test for histamine intolerance. Wien Klin Wochenschr. 2013 May;125(9-10):239-243.

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