Scientific Research

Dr. John Kamsteeg: The Association between Histamine level, Sun sensitivity and Age in HPU-patients



There is a strong association between histamine level and age; as age increase the histamine level decrease. Also between sun sensitivity and histamine level there is a strong association. The lower the histamine level the higher the percentage of sun sensitivity patients. This suggests there should be a metabolic explanation for the association between histamine level, sun sensitivity and age. In this report we try to give a explanation for sun sensitivity in HPU-patients.


Looking at the results over the past ten years, the one association that is striking, is the inverse relationship between histamine level and age. This is not a new finding. But within the group of HPU-patients it is clear from the present study that this relationship is much stronger in a statistical sense than in open population.
Looking at a sub-group of controls, almost all of the people with very low histamine levels had poor folic acid status. Even where this did not show as a low red-cell folate, there was an increase in FIGLU-excretion (Formiminoglutamic acid) after histidine loading. When the really low folate controls are removed from the forementioned statistics, the relationship between histamine and age strengthens to a very high statistical significance.
Further investigation according to Howard MacLaren Howard (pers. comm.), although it is so far that the complete research has been carried out on a relatively small group, shows that extreme low histamine level and FIGLU excretion correlates very well for around 85% of the patients. In general, as FIGLU increases (reflecting poor folate status) histamine decreases.
It is very clear from the findings that the poor folate status is not be the only reason for low histamine levels. FIGLU excretion after amino acid loading, being the most reliable predictor of folate deficiency and low histamine is only true for young female patients with very low hitamine levels. However, the relationship between the age of the patient, poor folate status and lowered histamine is statistically of very high significance. On the other hand high copper levels tends to decrease the histamine levels too. Copper tends to activate MAO and DAO enzymes that will break down histamine. This shows to be the other main reason for low histamine levels in HPU-patients. This is not influenced by using a copper containing birth control device.

Histamine is formed from histidine by histidine decarboxylase. All decarboxylation reactions are pyridixal-5-phosphate dependent. Because of the deficiency of pyridoxal-5-phosphate in HPU-patients histidine is not converted to histamine but the concentration of histidine is increased. This histidase is both induced by high histidine levels, hormones like estrogens and other porfyrinogens. Histidine will be converted, as age increases, very rapidly in urocanic acid.

The pathway of FIGLU-formation

If histidine is not converted to histamine by decarboxylase, histidine will converted to FIGLU and if there is no folate deficiency into glutamic acid and formyl-THFA. The first reaction in this pathway is the nonoxidative deamination of L-histidine to trans-urocanic acid by histidase (histidine ammonia-lyase). In this reaction ammonia is released.1,2 This enzyme is expressed with high activity in the liver and in the skin.3,4 Histidase is regulated in a complex developmental, hormonal, and tissue-specific manner.5-8
In contrast, hepatic activity is not detectable until four days after birth, and subsequently increases gradually until puberty. Adult females have a twofold higher level of hepatic histidase than males, owing to estrogen induction.5-7 Other hormones, including glucocorticoids, glucagon, and triiodothyronine, also regulate hepatic histidase, albeit to a lesser extent than estrogen.5,6,8 Dietary regulation of hepatic histidase has been demonstrated. High-protein diet show increased hepatic histidase activity.9,10
However, the differences between the developmental programs of histidase in liver and epidermis could reflect differences in the metabolism of urocanic acid in these two tissues. In the liver, urocanic acid is an intermediate in the conversion of histidine to glutamic acid, whereas in the epidermis, it accumulates and may be both a UV protectant and an immunoregulator.
Urocanase catalyses the nonoxidative conversion of trans-urocanic acid to imidazolonepropionic acid. Imidazolonepropionic Acid Hydrolase converts imidazolonepropionic acid to formiminoglutamic acid (FIGLU), an important intermediate that links histidine catabolism to folate metabolism. FIGLU is a donor of formyl groups to tetrahydrofolic acid and is a marker for folic acid deficiency.11
Formiminotransferase catalyses the formation of formiminotetrahydrofolic acid from FIGLU. Tetrahydrofolic acid is required for this reaction, and glutamic acid is liberated. Folic acid deficiency results in a strikingly increased excretion of FIGLU in response to loading with L-histidine, presumably due to the reduction in available tetrahydrofolic acid.12 Trans-urocanic acid is formed from the deamination of L-histidine by histidase in the liver and in the stratum corneum.13 In the epidermis, trans-urocanic acid (lmax = 275 nm) undergoes an isomerization to cis-urocanic acid in UV light,14 the proportion of cis and trans isomers varying according to the UV light exposure.15,16
Epidermal urocanic acid probably acts as natural sunscreen17,18 led to the hypothesis that the deficiency of urocanic acid in the skin causes more sensitivity to sunlight and more susceptible to sunburn than others. The ability of urocanic acid to protect skin from sunburn has been demonstrated by a number of investigators.19-23 A study of skin erythema in histidinemic children suggested increased sensitivity to UV light.24 Urocanic acid in the skin may also reduce photomutagenesis, since the absorption spectra of both the cis and trans isomers of urocanate overlap with the absorption spectrum of DNA.14


In HPU-patients the histamine level is not only decreased because of the deficiency of folic acid by also by the induction of the enzyme activity of MAO and DAO enzymes by copper. Even more than in open population the association between age and histamine level is very strong. But even at very young age (18-25 years) some women with HPU shoes markedly decreased histamine levels. In almost al these patients a certain amount of sun sensitivity excists.
In HPU-patients which strongly decreased histamine levels, histidase activity is strongly increased. This probably shows an induction mechanism on liver histidase. This is not only caused by estrogen in birth control pills, but also by porfyrinogenic substances with cannot be excreted by HPU-patients.Birth control pills are used on very young age (from 13 years and older) because of the severe menstrual problems which starts because of the deficiency of pyridoxaal-5-phosphate. Estrogen happens to be one of the main porfyrinogens in these young girls. Histadine levels are in fact low in plasma and urine of HPU-patients. HPU-patient are sun sensitive as well. In the questionnaires of HPU-patients there was a striking association between sun sensitivity and low histamine levels. Probably there is hardly enough histidine in the epidermis to be converted by the epidermal-histidase in the skin in trans-urocanic acid. That’s why the UV-screen is hardly build up and probably sun sensitivity develops.

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