Migraine and headaches caused by DAO deficiency

The deficiency in the enzymatic activity of the DAO should be treated as a trigger for migraine and the in vitro measurement of DAO activity and/or the genetic analysis of the DAO genotypes implied in DAO deficiency represent an opportunity today to the diagnosis and later dietary treatment of migraine.

Table of Contents

Migraine

Migraine is defined as a primary and disabling neurological disorder, in which the predominant symptom is the episodic and recurrent headache, being the main reason for consultation in a neurology service.

The main clinical characteristics of migraine, a part of the headache, often unilateral and throbbing, are nausea and/or vomiting, photophobia and phonophobia.

It is estimated that migraine affects approximately 12% of the population. The most recent epidemiological studies show that, about 16.6% of people over 18 years of age present migraine or other intense headaches throughout his life and in periods of 3 months. Of these, 11.7% have a diagnosis confirmation of migraine pain and the remaining 4.5% of probable migraine, giving a total prevalence that reaches the 16%.

The OMS, through its Global ranking Disease Burden in the year 2016 considers that migraine is the second human disease more disabling of all human diseases, given that a day of migraine is equivalent in disability to a day of blindness or paraplegia.

During the first years of life, the prevalence of this pathology is similar between the two sexes. These data changes radically with the onset of puberty, increasing the frequency three times in women after menarche and remained stable in the male population. In this way, women of childbearing age, they come to have an incidence of up to 25%, while in males is of 8%. This trend returns to match after the fifth decade of life.

Other evidence supporting a greater link with female gender is the existence of what is now called “menstrual migraine headache”, the improvement of symptoms during the second and third month of pregnancy, and the fact that contraceptives as the hormone replacement therapy can modify both the frequency and intensity of the crisis. Today we have the answer to everything without referring to the appellant “hormonal issue,” with the knowledge of the Diamine Oxidase enzyme (DAO) and the effects of its deficiency, how we will see further.

Cluster headache or “histaminic” cephalalgia

A cluster headache is a headache of vascular origin, (such as the migraine headache), which is also known as the headache of Horton, Cluster Headache or as ” histaminic cephalalgia”, although the mechanism of accumulation histaminic cephalalgia is more sudden than in the migraine because it attends a release of endogenous histamine.

Cluster headache or histaminic cephalalgia is characterized by attacks of severe pain, usually unilateral, which tend to be orbital orbital, supra, temporary, or in any combination of these sites, which last between 15 and 180 minutes and occur between two and eight times a day. The very intense pain, may be accompanied by tearing, nasal congestion, runny nose, forehead and facial sweating, miosis and/or eyelid edema and / or with concern or agitation.

During the worst attacks, the intensity of the pain is unbearable. In general, patients may not be able to lie down and, characteristically, move around the house.

The attacks can occur in a series of days or weeks. They can last for months when grouped periods and are spaced by periods of remission that can last for years. Sometimes, there may be a single annual periodic attack .

Only a 10% of patients are suffering from chronic cluster headache, i.e. without periods of remission.

The age of onset is usually 20-40 years. For unknown reasons, men have higher prevalence than women in proportion of 3 to 1.

Migraine and headaches: a public health, social and economic problem

In migraine, preventive treatment or prophylactic is a fundamental part in those patients presenting a high number of crisis or in those who have high intensity or duration, which leads to a substantial reduction in their quality of life, affecting their family, social and labor relationship.

A migraine attack lasts more than 24 hours in 50% of patients and 20-40% of patients exhibit more of one migraine attack a month with a peak of prevalence among 25 and 55 years of age, the most productive phase of life.

As a result, the migraine has a major economic impact. It is estimated that migraine is responsible for 112 million working days lost per year, assuming a cost in reduced productivity of 5-17 billion dollars in the United States. In addition, as a crisis has a maximum duration of 72 hours, usually do not have compensation on the part of the public health systems, supporting the cost of abstention enterprises.

On the other hand, 50% of patients with migraine self-medicate and half of the medicate are dissatisfied with the current treatments.

Background information on the pathophysiology of migraine and headaches

The pathophysiological mechanisms and systems involved in its genesis are several.

On one side we have a group of structures of the peripheral nervous system that include the trigeminal vascular system and its connections, and on the other the central structures composed of the trunk, diencephalon and the cerebral cortex.

The meningeal vessels are surrounded by a dense network of sensory fibers that comes from the first branch of the trigeminal nerve. This set formed by the meningeal vessels with their nerve branches form what we know as the trigeminal vascular system. Also a part of the the first cervical branches nociceptive fibers converge in the caudate nucleus of the trigeminal nerve.

The activation of this system, conveyed two main actions: the first, a transmission of pain into the caudate nucleus of trigeminal, and a second, the generation of a sterile meningeal inflammation. All of this results in a vasodilatation with protein extravasation, platelet aggregation, macrophage activation and release of serotonin known as neurogenic or aseptic inflammation.

After years of autopsy studies, resonance and brain scans, it has never been found an injury responsible for migraine. There is a high prevalence of patients in the same family and it is clear there is a genetic background in its genesis, which can now also have a response to mutations in the gene of the Diamine Oxidase (DAO) enzyme.

Among the different neuromodulators and substances that have been related in the pathophysiology of migraine is histamine.

The role of histamine and the deficit of DAO in migraine and headaches

Histamine is a biogenic amine widely distributed in the body and is involved in various processes within the normal functioning of the same, among which are digestive processes, vascular regulation, allergic reactions and inflammatory processes.

Histamine is a biogenic amine that can be found in several foods of daily diet, particularly can be found in high amounts in foods that have often pointed to as triggers of migraine in susceptible people.

And that is that the relationship between food and migraine/headache is widely referred to in the literature. In fact, decades included or considered the diet (or certain foods) as one of the causative agents or triggers of some headaches and migraine. According to some sources, the percentage of migraineurs patients that relate the onset of pain with the consumption of some food ranges between 12% and 60%. However, many other patients with migraine do not associate the triggering of migraine with food, given that there is a temporal relationship between ingestion and symptom.

The most cited as triggers of migraine or cluster headache are chocolate, cheese, citrus fruits, especially alcohol (wine and beer), meat products, dried fruits, coffee and certain additives.

Many of the foods implicated are potentially rich in biologically active amines: histamine, tyramine and others.

An excess of histamine, either by an excessive exogenous intake or by a defect in its degradation, cause an accumulation in plasma. The excess of this substance has been associated with digestive, cutaneous and neurological diseases specifically with migraine.

There is a high number of research words that point to the histamine as a mediator biochemist implicated in the pathophysiology of headache or migraine. Some others describe the headache as one of the main symptoms associated with high intake of histamine or other biogenic amines.

The role of histamine as a trigger for migraine or cluster headache has been confirmed by dose-response studies of oral administration of histamine in humans. In addition, the European Food Safety Authority, in its Scientific Opinion on the risk related to the biogenic amines from food published the year 2014, points out that the histamine from the diet is implicated in the pathogenesis of migraine in susceptible individuals who suffer deficiency of the diamine oxidase (DAO) enzyme activity.

Among the many types and classifications of headaches, the “Headache Classification Committee of the International Headache Society (IHS) includes the “Histamine-induced Headache” and considers how those headaches caused by acute exposure to histamine.

Key point in the metabolism of histamine, are their different pathways of degradation. The main enzyme responsible for this is the Diamine-oxidase (DAO), which is distributed in different tissues of the body. Transient or permanent reduction DAO activity gives rise to an accumulation of histamine and consequently the possible occurrence of symptoms of migraine.

Background in the diagnosis of migraine and headaches

There is no diagnostic method based on complementary examinations (resonances, analysis, etc.) to diagnose migraine. Recently, however, it has been shown that the measurement of DAO activity can prove to be a major  biological and genetic biomarker of migraine and other headaches.

Until recently the diagnosis has been fundamentally clinical, based on the criteria established by the “International Headache Society” (IHS) which are accepted by all the neurological societies in the world. The IHS classified into two main subgroups, migraine without aura and migraine with aura.

Migraine without aura

Recurrent idiopathic disorder of headache whose duration ranges from 4 hours to a maximum of 3 days. Is often characterised by a unilateral and throbbing headache but that sometimes it could affect the entire skull.

Typically it is moderate or severe intensity and characteristically suffers from a worsening to the match of head movements, which makes it difficult notably physical activities even the realization of any daily activity. Is often associated with other symptoms very typical and that configure the characteristics that allows its diagnosis as are the presence of nausea, vomiting, photophobia, phonophobia and sometimes osmofobia.

Diagnostic criteria for migraine without aura:

A. At least five crisis which meet the criteria B-D.

B. Headache episodes of between 4 and 72 hours duration (not treated or treated without success).

C. The headache presents at least two of the following four characteristics:

  1. Unilateral location.
  2. Pulsatile character.
  3. Pain of moderate or severe intensity.
  4. Worsened by or conditions the abandonment of routine physical activity (e.g., walking or climbing stairs).

D. At least one of the following during the headache:

  1. Nausea and/or vomiting.
  2. Photophobia and phonophobia.
  3. No better explanation by another diagnosis of the ICHD-III.

Migraine with aura

Typically in this phenomenon combine positive and negative symptoms, reversible type and are generally visual phenomena. Sometimes combined with the first symptoms are sensitive, usually unilateral. Being less common, some patients may experience transient alterations of language.

These phenomena are developed progressively in a time around the five minutes and its duration does not exceed an hour. These can be self-limited without symptoms, but more commonly during the aura or in term of its time of duration that do not exceed 60 minutes is accompanied by headache, with clinical features definable as migraine, though at other times the pain does not fully comply with these characteristics.

A. Diagnostic criteria for migraine with aura.At least two crises that meet the criteria B and C.

B. One or more of the following symptoms of aura completely reversible:

    1. Visual
    2. Sensitive
    3.  Speech or language.
    4. Motor
    5. Encephalic
    6. Retinal disorders.

C. At least two of the following four characteristics:

      1. Gradual progression of at least one of the symptoms of aura during a period of ≥5 min and/or two or more symptoms occur consecutively.
      2. Each symptom of aura has a duration of between 5 and 60 minutes.
      3. At least one of the symptoms of aura is unilateral.
      4. The aura is accompanied, or followed before 60 min, of headache.

D. No better explanation by another diagnosis of the ICHD-III and has been ruled out a transient ischemic attack.

Diagnostic criteria for cluster headache or “histaminic cephalalgia” according to the IHS:

A. At least five attacks fulfilling criteria of B and D.

B. Orbital Pain, supra orbital and / or temporary severe or very severe unilateral that lasts 15-180 minutes.

C. At least one of the following symptoms or signs, ipsilateral to the headache:

  • Conjunctival injection and/or tearing.
  • Nasal congestion and/or runny nose
  • Eyelid edema
  • Front and facial sweating
  • Miosis and/or ptosis
  • A feeling of restlessness or agitation

D. Occurs with a frequency of one on alternate days and 8 per day.

E. It is better explained by another ICHD-3 diagnosis.

Background in the symptomatic treatment of migraine and headaches

The treatment of the crisis has been imperative by the intensity and invalidating effects of the pain in most patients. The objective was to find the effectiveness with the least amount of side effects and the patient recovers its normal functional state with lower risk of relapse in the hours after. The majority of symptoms that accompany the pain were susceptible to complementary treatment except the aura.

It must be quick, and administered as soon as the patient identify the pain and migraine type, early treatment and optimal dose increases the effectiveness of the same. Once the crisis is advance, the pharmacological response is clearly lower, and even nil.

The symptomatic treatment of crisis is distinguished unspecified (with analgesics and non-steroidal anti-inflammatory drugs (NSAIDS)), specific (usually composed of ergot and triptans) and adjuvants (antiemetics, sedative and neuroleptics).

The repeated use of medication can lead to a situation of analgensic`s abuse, which can turn chronic the headache and cause a loss of pharmacological effectiveness. This condition we now know that is in part due to the possible inhibitor effect of drugs on the Diamine Oxidase (DAO) activity.

Drawbacks of the current pharmacological treatment

The pharmacological treatment that has existed until a few years ago for migraine and other headaches in the market offers a series of drawbacks:

  • Its mechanism of action on etiology of migraine is unknown.
  • They are usually drugs created for the treatment of other entities not related to migraine, such as depression, arrhythmias, or epilepsy, among others.
  • In spite of the efforts in research conducted over the past few years, all new drugs designed for this purpose, have failed, by suggesting that the therapeutic target chosen was erroneous.

New treatment and diagnosis of migraine and headaches: histamine and DAO treatment

Histamine in the nervous system

The relationship between the hypothalamus and migraine has been known for years. It is believed that different triggers of migraine can perform their initial action at this level. It has been suggested that the triggers of migraine activates the hypothalamus, the limbic areas and the cortical regions through common pathways.

Small structures of the brain may have areas in which you can avoid the blood-brain barrier . These structures would be in the circumventricular organs. Specifically around the third and fourth ventricles, which are richly vascularised, which are exposed to large amounts of substances circulating blood cells, such as histamine and other Biogenic Amines from the circulation.

Location of histamine and its relationship with migraine and headaches.

The histamine penetrates with difficulty from the bloodstream into the brain structures, and when it does its cumulative effects produce the crisis of migraine and other vascular headaches.

Mast cells liberators of histamine, belonging to peripheral tissues and that contribute to the generation of the inflammatory pain in multiple states, can penetrate quickly and cross the blood-brain barrier, especially in certain pathological conditions.

Ependymal cells and also cerebrovascular endothelium can produce histamine.

With regard to the systemic metabolism of histamine is produced by oxidation. The enzyme responsible for this process is the diamine oxidase (DAO). Small amounts of this enzyme have been detected in the brain of mammals.

The histamine has an imidazole ring and ethylamine as the basic structure that is shared with the neurotransmitters dopamine, norepinephrine and serotonin, and is synthesized by a variety of hematopoietic and neuroepithelial cells, so it has a wide range of features within and outside of the nervous system.

Mast cells, histamine, migraine and headaches

Mast cells are found in the dura mater next to the trigeminal nociceptive inputs. On the basis of the hypothesis that envisage a process of meningeal sterile inflammation, these cells and mediation by histamine may have an important implication in the pathogenesis of migraine and the rest of vascular headaches.

Have been showed increases in level of histamine in plasma and cerebrospinal fluid during the crisis of migraine. Other vasoactive peptides as the calcitonin gene-related peptide (CGRP) has been seen that its levels increased in plasma during the crisis of pain.

Both the substance P and CGRP are released by the meningeal activity of receptors, which would cause the release of mast cells which would be important in the second phase of the phenomenon, as it related to the presence of pain. Histamine causes a direct vasodilation of the harsh and active meningeal inputs without the liberation of CGRP, having an increase in cerebral blood flow.

Histamine, hypothalamus, migraine and headaches

It is estimated that the neurons with ability to synthesize histamine are approximately 64,000 and are in the rear-basal areas of the hypothalamus and in the tubero-mamilar cores.

The histaminergic neurons are among the mamilar core and the optic chiasm in the tuber cinereum. Similarly to other biogenic amines, the majority of the histaminergic terminations do not perform a close contact with the postsynaptic receptors (varicosites points).

The histaminergic varicosites seem to be in contact with blood vessels and cells of the glia and some of the ventral cells seem to have direct contact with the cerebrospinal fluid. The nuclei tubero-Mamilar receive inputs from other hypothalamic areas, basically orexinergic  and other including the serotonergic and noradrenergic. These are implicated in the pathophysiology of migraine, but his action is still not clear.

There seems to be a converged excitation of the dorsal raphe serotonergic neurons by orexinergic, noradrenergic, and histaminergic systems.

The heterogeneous response of histaminergic neurons has been documented and relates basically to stress reactions. Its activation in the states of consciousness is variable being absent during sleep, this being consistent with the clinical patterns of onset of symptoms to awakening.

In recent research, projections from the tuberomamilar nuclei to neurons of the trigeminal-thalamic-vascular have been involved showing that the central activity of histamine plays an important role in the beginning of the attacks by alterations in the rhythm of sleep, variations in the hours of food intake and emotional reactions.

Effect of the activation of histamine receptors in migraine and headaches

H1 receptors

This type of histaminergic receptors is widely distributed throughout the body, including the brain. Its central activation has been linked to processes with answers of depolarization and functions as the awakening, cycle of wakefulness and sleep and cognitive functions. Localization studies with tracers indicate that the largest proportion of these receptors are not related to neurons, but they are with vessels and cells of the glia.

The role of histamine can be related to functions of signaling to provide a greater contribution of blood glucose levels in an increase in neuronal activity. It is known for years the vasodilator effect of histamine and its effect on the production of headache.

When the H1 receptors in the endothelium of the intracranial arteries are stimulated, it activates the synthesis of nitric oxide (NO) and as a result causes vasodilation. This led to the formulation of the hypothesis of nitric oxide as a trigger, being the first phenomenon the vasodilation, all mediated by the H1 receptor located in cerebral vessels. Despite these descriptions, studies with drugs that act blocking H1 and H2 receptors does not have demonstrated efficacy in the treatment of migraine. This could be explained due to the fact that the blockade of histamine receptors affects a process that has already been unleashed and in which cannot be make a control through this route.

H2 receptors

This is postsynaptic receptors, as well as the previous, that potentiate excitatory inputs or mediate excitatory actions of neurons. Approximately a 40% show similarity with the H1 receptors, and its effects on the nervous system are less well-known, in part because of the increased difficulty of cross the blood-brain barrier of potentially antagonists.

Experimental studies show that brief exposures to H2 agonists can increase the activity of various types of neurons for a long period of time. This increase in neuronal responses can be seen in cortical neurons in response to sensory stimuli, whose appearance is believed to relate the thalamic inputs.

The drug with H2-antagonists effects most used is the cimetidine. Its use is with the aim of reducing stomach acid secretions. Studies such as preventive treatment in both migraine and tension-type headache in cluster does not have obtained positive results. Part of these results could be attributed to the fact that the cimetidine only manages to cross the blood-brain barrier in very high doses and through a intravenous administration.

H3 receptors

The histamine presents a great affinity for these receptors. In contrast to the effects of the activation of the H1 and H2, H3 have an inhibitory function on histaminergic neurons. They are found in presynaptic locations and present a low structural similarity with the H1 and H2 receptors. Are related to various functions of the brain, such as the modulation of the processes vigil-dream, cognitive processes, homeostatic regulation and inflammation.

There are several isoforms with distinct activities, which clearly shows the existing H3 receptor polymorphism in humans. The replacement of the amino acid 280 (alanine) by valine known as the H3R is considered a risk factor for migraine. This variant could lead to an increase of histamine due to inactivity of the autoreceptors.

H4 receptors

This receiver has a similarity of approximately 35% with the receivers H3, and has been localized mainly in peripheral tissues and mast cells. Currently, have been located in the cortical and subcortical regions of the brain structures.

Its exact role is unknown, but the activation of these receptors results in a hyperpolarization of neurons in the somatosensory cortex in rats. This process of cortical hyperexcitability, including the somatosensory cortex seems a fundamental process in the etiopathogenesis of migraine.

The similarity appreciated between the receivers H3 and H4 has caused that the interpretations of their activities in the clinic are difficult. The potential effect of cortical activation is reduced by the antagonistic effect of the H3 receptors. In a recent study, the intraventricular administration of an H4 receptor agonist induced an antinociceptive response. The use of an antagonist reversed this action.

Metabolism of histamine in migraine and headaches: deficit in the activity of the enzyme Diamino-Oxidasa (DAO)

The Diamine Oxidase (DAO) enzyme is one of the two enzymes responsible for the metabolism of histamine. The process causes an oxidative diaminacion, so that is also named this enzyme as Histaminase. It is stored in plasmatic vesicles of epithelial cells and secreted into the circulation secondarily to different stimuli.

It is therefore considered the DAO as the enzyme responsible for the metabolism of histamine that is found in the extracellular space.

In mammals is an expression of the DAO in intestine, ascending colon, placenta and kidney.

The gene that encodes the DAO is located on chromosome 7q35, composed of 10 pairs of Kilobases, 5 exons and 4 introns. It is a water-soluble glycoprotein, homodimeric with a molecular weight of 200,000, with subunits of 70-120 kilodaltons.

Is included in the group of amine oxidases and its active form is the active cofactor homodimeric with 2,4,5-trihidroxifenilalanine quinone.

Its kinetics is 20 mol/L for histamine, 350 mol/L for putrescine and 3mmol/L for spermidine.

Its optimal function is in pH of 7.2 and can be inhibited by chelating agents such as cianida reagents or carbonyl sulphide as the aminoguanidine.

Activity of the diamine oxidase: migraine and headaches caused by deficit of DAO

Not all individuals have the same enzymatic DAO activity. This is also not remains constant in each individual, because it can be conditioned by a variety of factors that cause a blockage of the same or that there is a situation of excess of histamine that motivates an overall decrease of its activity on a temporary basis.

Some studies have shown an increase in DAO activity during the crisis of migraine what could be interpreted as a defense mechanism for the removal of excess histamine.

Outside these specific situations we have studied various mutations that are causing a decline in the DAO activity in serum of patients with different pathologies related to an increase in the plasma concentration of histamine. It has been recently published that people who are carriers of mutations rs10156191 and rs2052129 of the gene that encodes the DAO, and cause a decrease in its activity, present a higher risk to suffer from migraine that those who do not.

On the other hand it has been reported that a 87% of patients with diagnosis of migraine, present DAO activity deficiency, which improve their symptoms using a dietary treatment supplemented with exogenous enzyme DAO.

Taking into account these data, the deficiency in the enzymatic activity of the DAO should be treated as a trigger for migraine and the in vitro measurement of DAO activity and/or the genetic analysis of the DAO genotypes implied in DAO deficiency represent an opportunity today to the diagnosis and later dietary treatment of migraine. The supplementation with exogenous DAO enzyme, is the new option in the dietary treatment and prevention of migraine. Since this is a dietetic food for special medical purposes and be a protein of animal origin the risk of adverse side effects to this treatment is minimal or non-existent.

In patients with cluster headache or “histaminic cephalalgia”, the determination of the DAO activity can be a good biomarker of diagnosis, although usually present an enzymatic activity at levels above the threshold of normality, so it is a good idea to measure pre-emptively also the concentration of circulating histamine with some frequency. The study of the genotypes of the DAO can contribute to a good diagnosis too.

With regard to the diet it is appropriate to review especially those foods that, not having a high concentration of histamine, are liberators of endogenous histamine, as a recurrent consumption can cause accumulation of histamine by a non-metabolic pathway.

  • Maintz et al. Histamine and histamine intolerance. Am J Clin Nutr 2007; 85:1185-1196.
  • Jarisch et al. Histamin-Intoleranz. Histamin und Seekrankheit, 2 edn. Stuttgart, Germany: Georg Thieme Verlag KG, 2004.
  • Izquierdo-Casas et al. Low serum diamine oxidase (DAO) activity levels in patients with migraine. J Physiol Biochem 2018;74(1):93-99.
  • García-Martín et al. Diamine oxidase rs10156191 and rs2052129 variants are associated with the risk for migraine. Headache 2015;55(2):276-86.
  • A.Duelo et al. Low-histamine diet supplemented with exogenous diamine oxidase enzyme is useful for treating migraine in patients with DAO Deficiency. Ann Nutr Metab 2018;73 (suppl 2); 1-93
  • Izquierdo-Casas et al. Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial. Clin Nutr. 2018 Feb 15. pii: S0261-5614(18)30014-1
  • Maintz et al. Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy 2001; 66:893-902.
  • Steinbrecher and Jarisch 2005, Histamine and headache. Allergologie 28: 85-91
  • Music et al., 2013, Serum diamino oxidase activity as a diagnostic test for histamine intolerance. Wien Klin Wochenschr 125: 239-43
  • Manzotti et al., 2015, Serum diamine oxidase activity in patients with histamine intolerance. International Journal of Immunopathology and Pharmacology
  • Maintz et al., 2006, Evidence for a reduced histamine degradation capacity in a subgroup of patients with atopic eczema. J Allergy Clin Immunol, 117,1106–12.

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