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Clinical Perspectives of Food Intolerances – Lactose, Fructose and Histamine

The term “food intolerance” is an umbrella term for all unwanted symptoms or diseases associated with the consumption of specific food items. It is not synonymous with the term food allergy. Food intolerance is defined here as an adverse reaction to a food chemical for which no immunological mechanism has been demonstrated or suspected. These non-immunological reactions make up the major proportion of all adverse reactions to food. Either they are the result of an enzyme deficiency, where amines or carbohydrates contained in the food are not adequately digested, or their cause lies in an absorption (malabsorption) or transport dysfunction, whereby specific carbohydrates are absorbed only to a limited extent in the small intestine. In both cases, carbohydrates or amines find their way into the deeper part of the intestine where they can lead to a myriad of symptoms and cause bacterial decomposition and yeast overgrowth.


Enzymes are protein molecules that act as biological catalysts, chemical substances that accelerate a reaction without being changed or diminished. They are generally specific to one correct substrate and recognize the reactant by its shape and the position of the bonding site and in turn bind to the substrate at its active site. Upon attachment, the substrate undergoes an enzyme-catalyzed reaction.


Food intolerance from an enzyme deficiency can affect any system of the body. The most common symptoms include irritable bowel1, 2, headaches, migraines, fatigue, behavioral problems3, 4, 5, 6, 7, or urticaria8. Asthma symptoms can also be triggered in some patients9 and, occasionally, anaphylactoid reactions occur10.


Besides toxic reactions (food poisoning, etc.) and digestive disorders with structural cause, for targeted diagnostics in the case of food intolerances, a differentiation must first be made between immunological and non-immunological reactions. For most North Americans and Europeans, the most common non-immunologic food intolerances associated with the digestion and absorption of amines and carbohydrates are lactose, fructose, and histamine intolerance.


Reactions are dose dependent and tend to be delayed (hours to days), making it difficult to identify the cause. This article will be confined to lactose, fructose, and histamine intolerance.


Lactose Intolerance


Lactose (milk sugar) intolerance is very common. In fact, it is thought to affect around 75% of the world's population.11 Lactose is a disaccharide, meaning that it consists of two sugars. These sugars are normally broken down into their components - glucose and galactose - in the small intestine by the enzyme lactase, also known as lactase-phlorizin hydrolase or LPH. Only when broken down can these monosaccharide molecules be absorbed through the wall of the small intestine. If the enzyme lactase is deficient, lactose cannot be broken down and therefore cannot be absorbed. The lactose then ends up in the colon undigested, where it is fermented by intestinal bacteria, resulting in fermentation products such as carbon dioxide (CO2), short chain fatty acids, hydrogen and methane. The lactose molecules are also active osmotically causing an influx of water into the colon. This abnormal fermentation may cause gas, bloating, diarrhea and cramping like pain. The reduced absorption of glucose in the small intestine can also temporarily induce hypoglycemia bringing about fatigue and headaches.12



Lactose intolerance is therefore due to an enzyme deficiency (more formally referred to as an enzymopathy) and should not be confused with milk protein allergy, where the immune system reacts to components in milk such as casein and beta- and alpha-lactalbumins.


There are three main types of lactase deficiency: primary, secondary and congenital. Primary lactase deficiency is the predominant cause of intolerance worldwide. This is caused by an inherited genetic fault carried through families. Secondary lactase deficiency is a shortage of lactase from an issue with the small intestine. This can result at any age and may be a result of certain medication including chemotherapy or damage to the intestine. This type of deficiency is sometimes temporary, although it may also be a permanent condition. Finally, congenital lactase deficiency is a rare condition that is also genetic based and is found in newborn babies. It is an inherited fault that causes newborns to produce little or no lactase. It is passed on as an autosomal recessive inheritance pattern, whereby both parents must have a copy of the gene to pass the condition on to the offspring. With lactose intolerance, the genetic primary form and the form that is acquired secondarily must be differentiated to be effectively treated.


Lactose is also found in breast milk, and almost everyone is born with the ability to digest it. It is not common to see lactose intolerance in children under the age of five (but it does occur). As with all mammals, the production of lactase in humans decreases after weaning through the withdrawal of the mother’s milk. In populations that carry out intensive dairy/goat farming, protective mutations developed approximately 7,500 years ago, ensuring lifelong lactase persistence for the mutation carrier.13, 14


Primary lactose intolerance is an autosomal recessive disorder. Individuals who have a cytosine nucleotide close to the lactose gene do not produce lactase in adulthood, which makes them lactose intolerant. Those who can consume lactose can do so as a result of a single point mutation in their DNA near the lactase gene that replaces a cytosine nucleotide to a thymine and a further replacement of a guanine to an adenine in a similar location. The alterations, cytosine to thymine and guanine to adenine, located at positions -13910 and -22018 on the MCM6 gene respectively, have both been linked to lactase persistence.




The above diagram demonstrates the location of the lactase (LPH) and MCM6 genes on chromosome 2. It also demonstrates the location of the C/T and G/A swaps on the MCM6 gene, which lead to lactose persistence. For individuals who do not carry this protective mutation, lactase production continues to decrease.


With the secondary form of lactose intolerance, the production of lactase is not reduced because of genetics, but the result of another underlying disease. A secondary lactase deficiency can manifest itself in damage to the epithelium (lining) of the small intestine (the place where lactase is synthesized) e.g. when antibiotic treatment is given, or when patients have celiac disease or an inflammatory bowel disease such as Crohn’s disease.


Genetic testing can be used to differentiate between primary and secondary lactose intolerance. Potential causes of secondary lactase deficiency, apart from allergies to milk products and dysbiosis, chronic inflammatory bowel disease should be ruled out. If Crohn’s disease or ulcerative colitis is suspected, determination of the genetic markers NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) and ATG16L1 (Autophagy related 16 like 1) can be helpful. ASCA (Anti-Saccharomyces cerevisiae antibodies) that accumulate with Crohn’s disease and pancreatic acinar cell antibodies or the goblet cell autoantibodies associated with ulcerative colitis can also be determined through laboratory tests.15




Generally, a lactase deficiency with a secondary cause is only temporary and is reversible after the intestinal epithelium is regenerated. The intestine is one of the most highly regenerative organs in the human body, regenerating its epithelium every five to seven days. Continual cell renewal allows the epithelium to withstand the constant wear and tear it suffers while breaking down food, absorbing nutrients, and eliminating waste. Numerous products are available to assist in the repair of the epithelium, such as probiotics, omega-3 supplements, the amino acid glutamine and zinc.


Rice milk, almond milk, hemp milk and other nut and bean beverages are good alternatives to dairy milk. Purchasing lactose-reduced or lactose-free dairy products is another option. These products are available at most supermarkets and health food groceries in the refrigerated dairy section. Also, using lactase enzyme tablets (Dairy Ease, Lactaid, others) may assist in digestion of lactose in dairy products. Consuming these tablets just before a meal or snack is best; however, not everyone with lactose intolerance is benefited by these products. Bear in mind that lactose-free dairy and lactase enzymes will not help with an immunological reaction to milk proteins. Recombinant bovine growth hormone (rBGH) is a synthetic (man-made) hormone that is marketed to dairy farmers to increase milk production and should be strictly avoided.




Fructose Intolerance


Dietary intolerances to fructose and fructans are common, yet poorly recognized and managed. Fructose is a hexose sugar that is now commonly consumed in the Western diet. It is often used as a sweetener or as high fructose corn syrup (HFCS) in soda, fruit juices, or candy, and is naturally present in such fruits as apples, peaches, pears, oranges, etc.17 A fructan is a polymer of fructose molecules. Fructans with a short chain length are known as fructooligosaccharides. Over the last decade, fructose intolerance has come to the forefront because of new knowledge on the mechanisms and treatment of these conditions. With fructose intolerance, a differentiation must be made between genetically determined enzyme deficiency (hereditary fructose intolerance, HFI) and a fructose transport defect (fructose malabsorption). Targeted diagnostics can be carried out for both forms and clarification of the causative pathological mechanism using differential diagnosis is of therapeutic relevance.


Patients with these problems often present with unexplained bloating, belching, distension, gas, abdominal pain or diarrhea. One study showed that two thirds of patients with irritable bowel syndrome (IBS) have fructose intolerance.16


With the exponential increase of high fructose corn syrup in the North American diet, an increased prevalence of fructose intolerance has occurred as well as increased obesity. Babies often exhibit clinical abnormalities after they are weaned and fed with baby food that contains fructose. There may be pronounced hypoglycemia with vomiting, attacks of sweating, neurological symptoms and even seizures, lethargy, and failure to thrive. As adults, people with undetected HFI suffer with complex symptoms such as diarrhea, pain in the upper abdomen, bloated stomach, and there is risk of irreversible liver and kidney damage.




Fructose Metabolism


Fructose from the ingestion of food is metabolized in the liver. There, it is first converted to fructose-1-phosphate. The enzyme aldolase B is responsible for the next conversion stage. This enzyme is in the cells of the liver, kidney and mucous membrane of the small intestine, and cleaves the fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate. If the aldose B enzyme is impaired due to genetics, this leads to an accumulation of fructose-1-phosphate in the cells with a serious toxic effect. Furthermore, the increased fructose-1-phosphate level inhibits glycolysis. In this situation, chronic exposure to fructose can lead to liver enlargement and progressive liver insufficiency.18


Detecting Hereditary Fructose Intolerance (HFI)


Mutations in the aldolase B gene can result in an enzyme deficiency. This can be identified through a molecular fructose intolerance genetic test. The mutations A149P, A174D, and N334K are some of the most common defects that occur and are responsible for approximately 85% of all patients with HFI. The other 15% carry rarer mutations of the aldose B gene.19


So, if fructose intolerance is suspected, the test for the three most common mutations of the aldolase B gene (A149P, A174D, and N334K) is conducted first. If two mutations are found, HFI is proven. If none of these more common mutations is detected, however, the probability of an HFI is low. If a single heterozygous mutation is found, then a search is carried out for other rarer mutations in the remaining areas of the aldolase B gene. A second mutation would then confirm the suspected diagnosis of an HFI.20


Fructose Malabsorption


It is believed that up to 36% of the European population has fructose malabsorption in a more or less severe form, and approximately one-half of affected individuals are symptomatic.21 When ingested in small quantities, most dietary fructose is completely absorbed. However, free fructose has limited absorption in the small intestine, with up to one half of the population unable to completely absorb a load of 25g. Fructose and fructans are not hydrolyzed or absorbed in the small intestine. Unlike glucose, which has an active transport mechanism and is completely absorbed, fructose is absorbed in the small intestine through facilitative diffusion, and its absorption capacity is limited.22, 23, 24

Fructose deposited (not absorbed) in the intestine binds to tryptophan from food, which blocks tryptophan’s absorption.25 An insufficient supply of tryptophan causes a reduction in the synthesis of serotonin, leading to depression and sweet cravings. Studies have shown that a fructose-reduced diet can improve early signs of depression.26, 27




Additionally, the physiological consequences of fructose malabsorption include increased osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. Thus, if unabsorbed, fructose may serve as an osmotic load that draws fluid into the intestinal lumen. This may cause distention of the small intestine and lead to such symptoms as abdominal pain, bloating, and discomfort. Furthermore, after reaching the colon, unabsorbed fructose may be fermented by the anaerobic colonic flora, producing excessive amounts of hydrogen, methane, carbon dioxide, short chain fatty acids, and other gases. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. Furthermore, untreated fructose malabsorption leads to a proliferation of intestinal bacteria and yeast, which metabolize the fructose. This worsens the symptoms over time.




Managing an issue with the breakdown of fructose typically includes elimination of the sugar. Eliminating foods that contain high levels of fructose is a good place to start. These include:


  • sodas

  • certain cereal bars

  • certain fruits, such as prunes, pears, cherries, peaches, apples, plums, and watermelon

  • apple juice and apple cide

  • rpear juice

  • sugar snap peas

  • honey

  • desserts such as ice cream, candy, and cookies containing fructose sweeteners


Aside from a reduction of sugar and fruit consumption, when reading labels, there are many ingredients to look out for when trying to manage fructose malabsorption. Be mindful of the following:


  • high fructose corn syrup

  • agave nectar

  • crystalline fructose

  • fructose

  • honey

  • sorbitol

  • fructooligosaccharides (FOS)

  • corn syrup solids

  • sugar alcohols


Patients with fructose malabsorption also exhibit significantly lower levels of folic acid.28 A significant link to fructose malabsorption has also been shown for a zinc deficiency.29 Folic acid deficiency, like vitamin B6 and B12 deficiencies, may increase concentrations of homocysteine, which is known to be an additional risk factor for cardiovascular disease. It is therefore recommended for patients with fructose malabsorption to monitor trace elements, test for homocysteine and include supplemental zinc as part of a supplemental regime.


Histamine Intolerance


Histamine is an organic nitrogenous compound (a biogenic amine) involved in local immune responses, as well as in regulating numerous physiological functions. Histamine is also a neurotransmitter in the central nervous system (i.e. it relays messages between cells), where it’s involved in many brain functions such as arousal, pituitary hormone secretion, suppression of eating and cognitive functions. So, we very much need a certain amount of histamine for the body to function well on many levels. The highest concentrations of histamine in the body are found in the tissues most exposed to the outside world such as the skin, mouth, sinuses, digestive tract and the lungs.


It is a part of the immune response to foreign pathogens and is produced by white cell basophils and by mast cells. It also occurs to various degrees in many foods.30 Histamine is involved in the inflammatory response and plays a dominant role in allergic diseases such as rhinitis allergic (hay fever), allergic bronchial asthma and urticaria.


Histamine intolerance results from a disequilibrium of accumulated histamine and the inability to break down histamine.31 In other words, histamine intolerance is characterized by histamine levels exceeding a person’s histamine tolerance threshold. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity.32


Specifically, the terms “histamine intolerance” or “enteral histaminosis” are used to explain a variety of symptoms that appear to be caused by dietary histamine upon ingestion of food with a high histamine content, such as fish, cheese, meat products, and alcoholic beverages. Histamine present in food is usually associated with other pharmacologically active biogenic amines and is produced from the amino acid L-histidine by microorganisms possessing histidine decarboxylase activity in the course of food processing or spoilage.33, 34, 35


Though histamine intolerance is not nearly as common as lactose or fructose intolerance, histamine intolerance affects at least 1% of the population, if not more. Most people with histamine intolerance generally go undiagnosed, so the actual prevalence is probably much higher.36, 37


Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. DAO breaks down extracellular (free) histamine and is mainly produced by intestinal mucosal cells. With reduced DAO activity, histamine also accumulates in the blood. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. The lack of DAO can have primary or secondary causes.


Additionally, histamine N-methyltransferase (HNMT) is another important enzyme inactivating histamine. HNMT is a cytosolic protein that can convert histamine only in the intracellular space of cells. HNMT degrades intracellular histamine mainly in the liver, kidney, bronchial mucosa and in the central nervous system. Activity reduction of this second histamine degrading enzyme HNMT may also increase the symptoms. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. For histamine to cause adverse reactions and symptoms it must be resorbed in the intestine and transported via the bloodstream without being inactivated by the enzymes DAO and HNMT present in intestinal epithelial cells.


Histamine intolerance can also clinically manifest if the body is loaded with so much histamine that despite normal activity, the DAO cannot adequately metabolize the histamine load. The excess histamine may be exogenous in origin (through ingestion of food) or it may be due to excessive levels of endogenously produced (mast cell-associated inflammation, allergy). Histamine is produced in foods, especially when bacterial enzymes convert the histidine in the diet to histamine. Therefore, the histamine content increases with increased storage time. Histamine cannot be destroyed by deep-freezing or heating due to its stability. Since histamine formation is caused by bacteria, large amounts of histamine are found mainly in microbially produced or fermented foods (cheese, sauerkraut, wine) as well as in protein-rich food (fish, meat) depending on the storage period. In case of reduced DAO activity, the consumption of histamine-rich food can lead to the already mentioned intestinal as well as systemic symptoms.




Since histamine receptors are found in almost all organ systems, the symptoms of histamine intolerance are very heterogeneous and can manifest in many ways. Histamine intolerance symptoms tend to appear very soon after eating a high-histamine food, typically within less than two hours. Symptoms typically disappear in a matter of hours and rarely last longer than 24 hours. DAO breaks down the histamine in food, as well as the histamine of allergic processes occurring at intervals. This explains why in addition to the classic acute symptoms flush, nausea, headache, feeling hot and shortness of breath, and especially diarrhea may occur. However, skin eczema, rhinitis, urticarial attacks, hypertension, colitis and asthma are also described. Instead, an HNMT deficiency has more of an effect on the breakdown of the comparatively constant intracellular body histamine. This causes more chronic forms of histamine intolerance, which often affects the nervous system.38




The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by certain foods and supplements that assist in breaking down histamines.


Selection of appropriate foods is often difficult, because manufacturers do not usually detail the amounts of histamine in foods. With diagnosed histamine intolerance, it is therefore necessary to follow general suggestions. Some types of food contain naturally high amounts of histamine (cocoa, spinach, tomatoes). A high content of histamine is also present in foods which originate by fermentation, either spontaneous or targeted (fermentation of alcoholic beverages -- beer, wine; fermented vegetables, cheeses, meat, soy, yoghurt). A more complete diet is shown below.


Because exposure to histamine exists beyond diet, total avoidance of histamines is not entirely attainable. Furthermore, it is important to limit the intake of substances which either directly cause or stimulate endogenous histamine release and inhibit activity of DAO and HNMT. In particular, many medications interfere with histamine metabolism and should be avoided if at all possible wherever they are suspected of playing a role in causing or maintaining histamine intolerance. Common painkillers such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), some diuretics, antibiotics and antidepressants are among the medications that can affect the functioning of DAO.


Several supplements assist with histamine breakdown. Because histamine is synthesized from the amino acid histidine by pyridoxal -5- phosphate (Vitamin B6), it has been proposed that supplemental P-5-P helps with histamine overload. Supplementation of zinc, copper, and vitamin C also act as cofactors for DAO and may be supplemented to improve function. Histamine-degrading probiotics are also beneficial.39 Histamine-degrading bacteria include bifidobacteria species, particularly Bifidobacterium infantis, Bifidiobacterium breve, Bifidobacterium longum, and Lactobacillus Plantarum, Lactobacillus rhamnosus, Lactobacillus salivarius, and Lactobacillus gasseri.


Both DAO deficiency and excessive levels of histamine can be determined through laboratory tests. Genetic analysis of DAO differentiates between primary or secondary DAO deficiency. Genetic variants of the AOC1/ABP1 gene can affect how much DAO enzyme is produced, and HNMT variants can cause variations in the production of that enzyme also. Additionally, diagnosis is made by detecting a genetic variant (C314T) that reduces HNMT activity by 30-50%. This genetic variant is closely associated with histamine-associated diseases such as asthma and atopic dermatitis. On the other hand, it is not possible to measure intracellular HNMT, which is localized above all in the liver; here, the determination of an activity-reducing genetic variant is available. However, HIT does not only occur due to reduced histamine degradation. It may also manifest clinically if there is a histamine excess that cannot be sufficiently degraded at present despite normal DAO activity.


In order to avoid unnecessary lifelong diets, it should be clarified in the case of existing DAO deficiency whether it is a primary genetic or a secondary caused DAO deficiency, because this result has therapeutic consequences. In a primary DAO deficiency, genetic variants (polymorphisms) lead to a reduced activity of the DAO enzyme. Genetic analysis is indicated in patients with diminished DAO activity in the blood and the associated clinical symptoms to distinguish between a genetic or a secondary and thus causally treatable reversible form of histamine intolerance.


In summary, food intolerances are generally not as serious as food allergies. Digestive symptoms occur after a certain amount of a food has been consumed. Although the symptoms may be extremely debilitating at times, food intolerances are not life threatening. Food intolerances can be caused by a variety of conditions such as an enzyme deficiency, where amines or carbohydrates contained in the food are not adequately digested, or their cause lies in an absorption (malabsorption) or transport dysfunction, where specific carbohydrates are absorbed only to a limited extent in the small intestine. Fortunately, there are laboratory tests for lactose, fructose and histamine intolerance that help clarify treatments.



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©2019 James P.M. Odell, OMD, ND, L.Ac.


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