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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.

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



Lactose intolerance (clinical symptoms or positive load test)

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.



lactose intolerance cartoon

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.



High Fructose Corn Syrup Consumption and Obesity Rates in the US

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



Fructose deposited (not absorbed) in the intestine binds to tryptophan from food, which blocks tryptophan’s absorption.

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.