Despite all the promises of how beneficial a paleo-esque diet will be, there are those individuals who remain with lingering health issues. These could be anything from persistent skin problems, to gastrointestinal issues, headaches, cardiovascular problems such as arrhythmias, menstrual irregularities, etc. The trap for practitioners promoting a paleo-type diet (of any brand), when any of these issues are in existence prior to intervention, is to over-promise what a paleo diet can do to help. This inevitably leads to a degree of disappointment if these issues do not resolve, with the introduction of a paleo diet, to the extent that everyone had hoped… a situation made worse when others do experience a full resolution and want to sing the praises of the diet from the roof tops.
Whilst the exclusion of grains, sugars, and vegetable oils (in my experience) has lead to a vast improvement in the health of many individuals, there has to be the understanding that the restriction/exclusion of these ‘neolithic agents of disease’ is not going to be the answer to everything. And as much as we would like to believe otherwise, there may be aspects of a paleo diet (particularly if interpreted and applied in certain ways), which may cause problems that didn’t previously exist or may worsen existing conditions.
If an individual interprets a paleo diet as ‘eat as many fruits & vegetables as you like’, and as a result, significantly raises their fruit intake (because fruit is paleo, after all), they may find themselves having issues with fructose intolerance.
[Sidebar: I commonly see this in individuals afraid of the eating of saturated fat – they invariably feel hungry all the time and continually reach for multiple pieces of fruit as a convenient, healthy, and paleo snack food (and/or nuts)]
The persistence of gastrointestinal and/or skin conditions can lead one to chase shadows if they cannot get beyond a gluten-causes-everything mantra. Has there been some cross-contamination? Can gluten make it into grain-fed meat? You can really end up chasing your tail on it.
The fact remains that there are many reactions that can occur to foods (particularly plant-based foods), be they paleo or otherwise. I have worked with people who, after shifting over to a paleo diet and increasing their egg intake, have discovered that they do not tolerate eating large amounts of eggs all the time without suffering gastrointestinal and/or skin reactions. I have already mentioned fructose which, when consumed in excessive amounts [which in a paleo context typically comes from eating too much fruit or coconut cream], can overwhelm the carrier in the gut lining that absorbs fructose. The fructose not absorbed travels to the colon where it can be fermented by the intestinal bacteria here, producing gas, bloating, pain, and diarrhoea.
Histamine intolerance is another example of the body being overwhelmed by a chemical that, in the case of histamine, it cannot metabolise to a more inert form. Histamine levels can them build up and trigger issues, potentially in multiple systems, around the body. Few people are aware of histamine, what it is, and what it can do, despite its ubiquitous nature. And as I hope to be able to show, there is perhaps a link back to our neolithic agents of disease that may exacerbate the multiple systemic effects of histamine.
The following is a nice easy introduction to the difference between food intolerance and allergy – something I hope to blog on more in the future…
What is food intolerance?
Countless numbers of people suffer from food sensitivity and intolerance – often without being aware of it. Effects can range from common digestive system problems including abdominal pain and spasms, diarrhoea, constipation, and flatulence, to headaches, to skin rash and eczema – all due to the body’s inability to thoroughly digest food caused by the lack of proper amounts of certain enzymes.
Many food intolerances are confused with food allergies and are caused by elevated levels of histamine in food. These elevated histamine levels can make eating foods, such as pizza, fish, wine, beer, and many other foods a miserable experience.
Food intolerance versus food allergy
It is important to recognize the difference between food intolerance and food allergy. Non-allergenic histamine food intolerance is mostly brought on by foods not processed properly in the intestinal tract. Food intolerance is a digestive system response to the inability to digest particular ingredients in food that does not involve the immune system. In contrast, a food allergy is an abnormal response to food triggered by the body’s immune system. Reactions to histamine found in foods are not food allergies, though the symptoms can look and feel the same. Furthermore, the severity of the food intolerance symptoms is dependent on the ingested amounts of histamine-rich food.
Whilst drawing on multiple sources for the information in this post, there is one main paper that I will be drawing on most heavily;
From Allergy UK:
Histamine is a chemical which occurs naturally in certain foods. This is also one of the chemicals that is released in the body as part of an allergic reaction, causing the typical ‘itching, sneezing, wheezing, swelling’ allergy symptoms. We all have an enzyme (Diamine oxidase [DAO]) which breaks down any histamine that we absorb from a histamine-containing food, so when we eat a food which contains histamine it does not affect us. However some people have a low level of this enzyme, and when they eat too many histamine-rich foods, they may suffer ‘allergy-like’ symptoms such as headaches, rashes, itching, diarrhoea and vomiting or abdominal pain. This is called histamine intolerance. Some studies have also suggested links between histamine intolerance and urticaria, asthma, eczema and anxiety and panic attacks.
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.
It is found in virtually all animal body cells.
Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury – the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.
Histamine can also occur within foods, or certain foods are able to stimulate the body’s own natural release of histamine. The sharp-minded amongst you are perhaps already starting to string a few things together, as here we have a compound that can be released from multiple sites, with multiple targets and functions (including neural signalling), and that can also be obtained from the diet or stimulated by certain foods or food groups. If something was to go wrong with the regulation of the body’s concentrations of this compound, you can realistically expect to see multiple systems show signs of dysfunction. And indeed, this is what we see with cases of histamine intolerance.
Histamine exerts it effects by binding to one of four types of receptors (often referred to H1, H2, H3, or H4 receptors). When one experiences all the symptoms of an allergic response to airborne triggers, (headache, flushing of the skin, runny nose & eyes, welts forming on the skin, etc) such as pollens for example, one might take antihistamines. The action of these antihistamines is to block the histamine receptors, preventing histamine from initiating the symptom profile typically seen. This blockade is typically of H1 receptors, but some H2 receptor antagonists are also available.
Depending on the target receptor, the binding of histamine may cause smooth muscle contraction, vasodilation, increased vascular permeability (blood vessels become a bit leaky), mucus secretion, rapid heart rate, changes in blood pressure, arrhythmic heart rates, the stimulation of stomach acid secretion, and an increased response from pain fibres.
This diagram offers a good summary of the multiple targets and effects of histamine.
|Histamine-related symptoms. Maintz, L. et al.|
Histamine intolerance results where there is an imbalance between the build up and breakdown of histamine. Histamine can be metabolised by two pathways;
- Diamino oxidase enzyme (DAO)
- Histamine-N-methyl transferase enzyme (HNMT)
In simple terms, DAO can be considered responsible for the extracellular breakdown of histamine, for example, in the gut and bloodstream, whereas HNMT inactivates histamine intracellularly. Therefore it is the DAO enzyme that plays a key role in metabolising dietary sources of histamine and histamine that are released from inside cells into extracellular spaces such as the gut and bloodstream. Indeed, the tissues with the highest activity if DAO include the intestines, placenta, and kidney. It is the activity of DAO that, when insufficient, leads to the majority of the symptoms associated with histamine intolerance. The activity of DAO may be deemed to be insufficient when it is unable to match the concentrations of histamine contained in histamine-rich foods, when its activity is blocked by alcohol, when histamine liberating foods or medications are consumed, or when DAO blocking medications are taken.
Sources of Histamine
Histamine and its precursor, histadine (along with other bioactive substances) are present in almost all foods in varying concentrations. However, foods that have been matured or fermented tend to have higher histamine contents. This is due to the bacteria and yeasts that are involved in this maturation and/or fermentation process have the HDC enzyme required for the conversion of histadine (an amino acid – contained in any food with a significant amount of protein) to histamine. High histamine concentrations are found in microbiologically produced foods such as mature cheese, sauerkraut, wine (particularly reds), or microbially contaminated protein-rich food such as fish, meat, and sausages.
Red wine offers a double whammy as it is both histamine-rich and a potent inhibitor of the DAO enzyme responsible for histamine metabolism. The rise in plasma histamine that can occur whilst consuming red wine can account for the reactions often seen in those consuming it – sneezing, flushing of the skin, headache, and asthma attacks. Other compounds within wine are also able to trigger similar reactions (such as sulphites and the by-products of alcohol metabolism).
Whilst some foods do not naturally contain histamine, they are able to function as histamine liberators, whereby they encourage the release of stored histamine from the various cells around the body, e.g. citrus fruits. Various medications may also do the same.
Histamine is not the only bioactive substance that can lead to histamine intolerance. Other compounds of the same class (biogenic amines) are able to interact with the enzymes responsible for metabolising histamine (particularly in the gut), further reducing the concentration of enzymes available to interact with histamine and effectively increasing the histamine concentrations.
Therefore, increased histamine concentrations may be achieved via food by any combination of the following;
- histamine in food,
- histamine liberators in food,
- DAO blockers in food,
- DAO competitors in food.
Histamine levels will vary based on the maturation process and the degree of freshness. The longer food is stored or left to mature, the greater its histamine content and the more problematic it can be for individuals with food sensitivities and intolerance.
Fresh meat contains no or very little histamine. However, when meat is processed further, the maturation process results in the accumulation of biogenic amines.
The same is true for fish. Fresh fish contains no or very little histamine. However, fish spoils very easily and this leads to a rapid accumulation of histamine due to bacteria. Further processing, which includes salting, smoke-drying, marinating and preservation, may increase the histamine content.
Examples of foods/substances that may increase histamine levels resulting in symptoms including digestive problems, headaches and skin rashes are:
- Alcohol, particularly red wine and champagne. Also white wine and beer.
- Aged, smoked, canned fish and fish sauces. Tuna fish, mackerel, sardines, anchovy, herring, catfish, salmon.
- Smoked and processed meats such as salami, ham, bratwurst and bacon
- Certain vegetables: tomato, spinach, eggplant, avocado, mushrooms and canned vegetables as well as commercially prepared salads
- Certain fruits: strawberries, bananas, papayas, kiwi, pineapple, mango, tangerines, grapefruits, red prunes, pea
- Red wine vinegar, balsamic vinegar
- Soy sauce
- Sunflower seeds
- Coffee, black tea
- Some fruits: citrus, bananas, strawberries, red prunes, pears, kiwi, raspberries, papaya
- Bread and confectionery made with yeast
- Peanuts, cashews, walnuts
Drugs/Substances that may block intestinal DAO
- N-Acetyl Cysteine
- Amino guanidine
As you can see, within this list there are still plenty of foods that might be considered ‘paleo’ and with the withdrawal of other foods some of these things may see a significant increase in their consumption.
From the Maintz paper;
Foods with potential histamine-releasing effect
- Citrus fruits
Symptoms of Histamine Intolerance
It is thought that approximately 1% of the population suffer from histamine intolerance (with 80% of these being middle-aged women), similar numbers to what is commonly seen with the likes of food allergies, celiac disease, etc. As with these other reactions however, it is thought that this number might be an underestimation, particularly in light of most individual’s likely lacking awareness of histamine and its potential effects.
I have not read anything (though my literature search has been far from exhaustive) that specifically suggests why it is such a female-dominated condition, though reasons may include that women are less inclined to put up with the symptoms and will seek medical help more so than men, and women may have more of a sensitivity to histamine, perhaps having more histamine receptors than men? In doing a search, I came across this recent (and timely for my post) article on histamine intolerance in the UK’s Daily Mail, which provides a great insight of a woman who has suffered with histamine intolerance. Her story very much mirrors my own case studies with the people I have worked with.
The primary symptoms of histamine intolerance are:
- low blood pressure (fainting, dizziness ; hypotension) is the common symptom of histamine intolerance, especially when young.
- headache which aggravates when moving (in contrast with tension-type headache),
- heart rhythm problems (cardiac arrhythmia),
- acid reflux from stomach,
- running nose (rhinitis),
- asthma, chronic cough
- hives (urticaria),
- itch (pruritis),
- painful periods (dysmenorrhoea) ,
Symptoms often occur with some delay to the trigger. After the primary symptoms of histamine intolerance have subsided, there may be secondary symptoms which include:
sleep disturbance (being awake, insomnia),
anxiety and panic attacks
Your body reacts to high histamine levels by producing adrenaline to increase the blood pressure. Adrenaline is causing these secondary symptoms of histamine intolerance.
The Maintz paper notes the typical clinical picture;
Even healthy persons may develop severe headache or flushing due to ingestion of massive amounts of histamine as is known from studies of scromboid poisoning.
In histamine-sensitive patients with reduced DAO activity, symptoms occur even after the ingestion of the small amounts of histamine that are well tolerated by healthy persons. Symptoms can be manifest via the abovementioned actions of histamine in multiple organs, such as the gastrointestinum, lung, skin, cardiovascular system, and brain, according to the expression of histamine receptors. Typical symptoms of histamine intolerance include gastrointestinal disorders, sneezing, rhinorrhoea and congestion of the nose, headache, dysmenorrhoea, hypotonia, arrhythmias, urticaria, pruritus, flushing, and asthma.
The headaches induced by histamines are largely vascular in nature, with histamine triggering the release of nitric oxide from the vascular walls, opening up the large intracranial arteries and increasing blood pressure to the brain. It is noted too, that migraine sufferers show a reduced activity of the histamine-metabolising enzyme, DAO. It has also been noted that women who suffer migraines experience a degree of remission during pregnancy due to the higher levels of the DAO enzyme being released from the placenta.
My most recent case study began with an investigation into a woman’s ongoing dysmenorrhoea. This woman tended to suffer headaches, some respiratory effects, ongoing itchy skin, arrhythmia, gastrointestinal symptoms (IBS-C & D in nature), and had a very irregular menstrual cycle ranging from 2 weeks to 6 weeks, with no set pattern. She was on an oestrogen-dominant OCP and is a confirmed coeliac. I had wondered whether damage to the absorptive surface of her gut wall meant she was absorbing an inconsistent dose of the OCP and this was causing fluctuations in her hormone profile.
After a literature review for causes of dysmenorrhoea, I came across the information on histamine intolerance and trialled a low histamine diet. Problem solved, with the added bonus that the last remaining eczema-like skin problems resolved, as did the best part of the remaining gastrointestinal symptoms. Symptoms return when too many histamine containing foods begin to creep back into the diet.
The following quote shows why high levels of histamine can cause dysmenorrhoea, potentially exacerbated by the use of oral contraceptives;
In the female genital tract, histamine is produced mainly by mast cells, endothelial and epithelial cells in the uterus and ovary. Women with histamine intolerance often suffer cyclical headache and dysmenorrhoea. In addition to a contraction promoting effect, this is attributable to the fact that histamine, via the H1 receptors, increases oestradiol production markedly, but progesterone production only mildly (e1). The painful uterine contractions associated with dysmenorrhoea are caused by an increased production of prostaglandin F2a in the endometrium, which is promoted by oestrogens and inhibited by progesterone.
Histamine can therefore intensify dysmenorrhoea via an increase in oestrogen production. Conversely, oestrogen can affect histamine activity: the cyclical rise in plasma oestrogen was shown to be associated with a larger skin weal in skin prick tests (e2).
One of the issues with diagnosis of histamine intolerance is that the symptomology is diffuse and often points to other conditions, especially in the minds of clinicians who may not even be aware of histamine intolerance (note the comment in the Daily Mail article of the doctor who had never heard of histamine intolerance and who could not find a dietician to refer to who had either). I found the following study on PUBMED which highlights, to an extreme, how histamine intolerance may manifest and be diagnosed as something else;
Histamine intolerance mimics anorexia nervosa
Histamine intolerance is a clinically heterogeneous disease. We present a woman who suffered from weight loss, diarrhoea, abdominal pain, headache, flushing and bronchial asthma for several years. When placed on a histamine-poor diet, she experienced weight gain and improvement of other all signs and symptoms, supporting the diagnosis of histamine intolerance. Therefore, this disease should be included in the differential diagnosis of anorexia nervosa.
Causes of Histamine Intolerance
Whilst in simple terms histamine intolerance can be considered a straight forward imbalance between histamine intake/liberation and histamine metabolism, it would seem that there are several underlying conditions that can alter the capacity of the DAO enzyme and therefore reduce histamine metabolism. It is at this point that we begin to see some overlap with some of the inflammatory gut conditions which, as we know, are heavily influenced by our modern inflammatory dietary agents – grains, sugars, and vegetable oils. Could it be possible that many of the symptoms that we often associate with say, gluten intolerance, are actually as a result of gluten causing a degree of gut inflammation and this reducing the histamine-metabolising DAO capacity?
From the Maintz;
Histamine intolerance can develop through both increased availability of histamine and impaired histamine degradation. Underlying conditions for increased availability may be an endogenous histamine overproduction caused by allergies, mastocytosis, bacterias, gastrointestinal bleeding, or increased exogenous ingestion of histidine or histamine by food or alcohol. Other biogenic amines, such as putrescine, may also be involved in displacing histamine from its mucosal mucine linkage, which results in an increase of free absorbable histamine in circulation. However, the main cause of histamine intolerance is an impaired enzymatic histamine degradation caused by genetic or acquired impairment of the enzymatic function of DAO or HNMT. Gastrointestinal diseases with altered enterocytes also may cause decreased production of DAO.
It would seem, in much the same way that fructose intolerance can be increased when the fructose transporters are damaged by gut inflammation, that this same damage to the cells of the gut (enterocytes) can lead to an increasing intolerance to histamine. Other factors can either separately or (more likely in the context of a standard western diet), concurrently reduce the capacity of DAO. Other biogenic amines, alcohol, and medications can competitively inhibit the breakdown of histamine by DAO.
Where histamine intolerance is acquired by dietary and lifestyle factors, it may be reversed by addressing these factors (low histamine diet, removal of known inflammatory agents to the gut, removal of DAO-blocking medications, etc). However, there also looks likely to be a genetic cause to reduced histamine breakdown. Interestingly, polymorphisms in the expression of the DAO enzyme have also been associated with inflammatory and neoplastic diseases.
Various single-nucleotide polymorphisms (SNPs) in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy, gluten-sensitive enteropathy [coeliac disease], Crohn’s disease, ulcerative colitis, and colon adenoma.
…histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO, but the high inter-individual variations in the expression of DAO in the gut and the association of SNPs in the DAO gene with gastrointestinal diseases provide evidence for a genetic predisposition in a subgroup of patients with histamine intolerance.
The accurate diagnosis of histamine intolerance is going to be heavily reliant on the clinician’s familiarity with the signs and symptoms of histamine intolerance, and the patient’s ability to adhere to a low histamine diet. Whilst some clinical testing may be available, it might not be readily accessible if the clinician that can refer through to this testing is ignorant of this condition. As with many other conditions, diagnosis is often via a process of elimination/exclusion.
What is of paramount importance from a clinical standpoint is the taking of a detailed and accurate history and including food and symptom diaries. When interpreting the health history, it is helpful to look at the complete picture rather than simply focus on system by system symptoms. In other words, if the presentation is headaches, eczema, and dysmenorrhoea, look to see what links can be drawn between these three symptoms rather than just approaching them as having distinct and mutually exclusive causes.
The author of the Maintz paper offers the following in a similar paper angled more toward addressing histamine intolerance in clinical practice;
The diagnosis of histamine intolerance is made in the presence of at least two typical symptoms, improvement on a histamine free diet and antihistamines, and a reduced DAO level and/or raised histamine level. These findings should be tested using a placebo controlled histamine provocation test. The keeping of food diaries and dietary advice have proven helpful in many patients. These mechanisms allow the documentation of symptomatic improvement through compliance with a histamine reduced diet and recurrent symptoms where there have been dietary lapses.
Blood tests tend to focus on DAO activity, with <3 U/mL strongly suggestive of histamine intolerance, and <10 U/mL making it probable. It is said that an activity >10 U/mL makes the diagnosis unlikely. Plasma histamine levels can also be measured and may be useful if the clinical picture points directly to histamine intolerance but it is not supported by DAO activity tests. Given the general lack of recognition of histamine intolerance, and therefore a low number of labs available to run this testing, the gold standard of a diagnosis is an elimination-provocation test (preferably double-blind & placebo-controlled).
Given the associations with other inflammatory states, including neoplastic conditions, it may be prudent, if a diagnosis of histamine intolerance is made, to also look for these underlying conditions (coeliac disease, Crohn’s disease, ulcerative colitis, colonic adenoma). It also pays to assess for some of the nutritional cofactors that are either involved with normal DAO activity (vitamin B6, copper), or histamine breakdown (vitamin C).
|Diagnostic flow diagram for use in suspected histamine intolerance. Maintz, L. et al.|
The main treatment is adherence to a low histamine diet. This is quite a separate entity to a histamine-free diet which would be practically impossible to adhere to, nor is it required for the patient to enjoy relieve from the typical symptoms of histamine intolerance. The key is to identify low histamine-containing and inducing foods and to bulk up the diet with these foods. I advise people to run a three day rolling average with their histamine loads. This allows a degree of freedom to perhaps consume some higher histamine foods, e.g. bacon, but still stay on top of histamine levels overall.
Once awareness is created around which foods are highest in histamine, constructing a low histamine ‘paleo’ diet is actually relatively easy to do. It is also important to recognise that a degree of additional tolerance is gained by removing the major inflammatory agents from the diet (grains, sugars, & vegetable oils) – something that should already be taking place within the context of a paleo diet and which may explain either the full or partial relief people experience when they begin eating such a diet.
Where high histamine foods are unavoidable (e.g. you want to drain a bottle of red one night), then prophylactic dosing with antihistamines may buy you a bit of extra breathing space. However, in the general run of things, the taking of antihistamines appears to not add any additional benefit over the adherence to a low histamine diet. If an individual has been following a low nutrient diet for some time, then perhaps additional vitamin B6, copper, and vitamin C may be of benefit. Diet should be assessed to ensure it is providing these nutrients in adequate amounts moving forward.
It is useful to assess all medications that are being used, including the oral contraceptive. It is quite on the cards that many of the medications that might be in play and which may interfere with histamine metabolism, are being used to treat individual symptoms of histamine intolerance, e.g. blood pressure medications, anti-depressants, and (ironically) histamine antagonists.
For those who, despite a low histamine diet, or who are reluctant to use antihistamines when they know histamine intake is likely to creep up, there are DAO capsules available that can boost histamine clearance capacity.
This post possibly takes the award for my longest single post to date but it has been one that I have wanted to write for a few weeks now. I see histamine intolerance (and likely some of the similar food chemical sensitivities) as perhaps the missing link for those individuals for whom the paleo diet hasn’t quite provided the full relief they had hoped. As you have hopefully seen, adhering to a Paleo 2.0 type of diet, free of inflammatory agents, has an important part to play in providing relief from some of the symptoms caused by a lack of histamine-metabolising capacity. However, it also needs to be recognised that it isn’t a solution to everything in and of itself, and indeed, a poorly (or ignorantly) constructed paleo diet may lead to either a continuation or worsening of an individual’s symptoms.
There is a lot more to this histamine story to be threshed out yet… just not in this post!