Wine and histamine intolerance

Wine and histamine intolerance can be associated with an array of symptoms depending the degree of impairment of DAO (diamine oxidase) activity and the characteristics of the wine. (See the recent post on histamine intolerance for a more comprehensive review of the topic and a discussion of DAO and DAO testing.) A paper published in the International Archives of Allergy and Immunology presents bronchoconstriction as one manifestation of wine and histamine intolerance due to reduced DAO activity:

"A 38-year-old woman with a history of seasonal rhinoconjunctivitis reported repeated attacks of wheezing after drinking various alcoholic beverages. Two consecutive histamine provocations using two identical samples of red wine containing 200 micrograms histamine/l and 3,700 micrograms/l, respectively, were performed in a double-blind placebo-controlled fashion to assess a possible histamine-induced bronchoconstriction. Lung function, plasma histamine, skin temperature, pulse rate and symptoms were assessed. In 3 male controls, four consecutive wine tests were performed in a randomised double-blind placebo-controlled fashion. Drinking wine with 3,700 micrograms histamine/l caused coughing and wheezing with a decrease in lung function. Plasma histamine showed an increase at 10 and 20 min and decreased at 30 min both after histamine-rich as well as histamine-poor wine, reaching the peak increase after histamine-rich wine. Controls did not react and plasma histamine levels did not increase."

Note that in these subjects the decisive factor was not the amount of histamine in the wine but the ability to degrade it. This key element of wine and histamine intolerance is expressed in the authors' conclusion:

"Bronchoconstriction after wine or food rich in histamine seems to be caused by diminished histamine degradation on the basis of reduced activity of diamine oxidase. Histamine in wine may induce bronchoconstriction in patients suffering from histamine intolerance."

 Of course, patients exhibit a gradation of diminished DAO activity from mild to severe when tested. It stands to reason and is supported by experience that wines containing higher levels of histamine place more of a demand on DAO capacity. An interesting paper published in the Journal of Food Protection shows that malolactic fermentation in particular increases the histamine content of wine:

"Changes in biogenic amines (histamine, methylamine, ethylamine, tyramine, phenylethylamine, putrescine, and cadaverine) were monitored during the industrial manufacture of 55 batches of red wine. The origin of these amines in relation to must, alcoholic fermentation, malolactic fermentation, sulfur dioxide addition, and wine aging and the interactions between amines and their corresponding amino acids and pH were statistically evaluated in samples from the same batches throughout the elaboration process."

Malolactic fermentation which is used with most red wines and some whites such as Chardonnay was clearly the culprit:

"Malolactic fermentation was the main mechanism of biogenic amine formation, especially of histamine, tyramine, and putrescine. During this stage, the increase in these amines was accompanied by a significant decline in their amino acid precursors. Significant correlations between biogenic amine formation and the disappearance of their corresponding amino acids were observed, which clearly supports the hypothesis that malolactic bacteria are responsible for accumulation of these amines in wines."

And as would be expected due to the 'shutting down' of malolactic fermentation by the presence of sulfites...

"No increase in the concentration of biogenic amines was observed after SO2 addition and during wine aging, indicating that sulfur dioxide prevents amine formation in subsequent stages."

 What about the effects of sulfites themselves and problems from sulfite intolerance? Interestingly, a paper published in Annals of Allergy, Asthma & Immunology illuminates a mechanism by which sulfites elicit histamine release. Most readers will recall that histamine is released from mast cells and basophils by degranulation of the intracellular 'packets' in which they are stored. The authors were interested in examining how atmospheric sulfites cause bronchocontriction:

"To investigate the cellular responses of sulfite on cultured mast cells (rat basophilic leukemia [RBL-2H3] cells) and human peripheral blood basophils..."

They evaluated sulfite-induced mast cell degranulation and intracellular production of reactive oxygen species both with and without antioxidants present. They measured degranulation using β-hexosaminidase, serotonin, and histamine release assays and activation of free radicals (reactive oxygen species) with a redox-sensitive dye. Their results are significant for the role of sulfites in wine and histamine intolerance--and how to ameliorate it:

"Sodium sulfite induced degranulation and the generation of intracellular reactive oxygen species in RBL-2H3 cells. These responses were inhibited by the free radical scavenger tetramethylthiourea and the flavoenzyme inhibitor diphenyliodinium but not by depletion of extracellular calcium. Peripheral blood basophils also showed histamine release after exposure to sodium sulfite."

In other words, sulfites induce histamine release and antioxidants inhibit it. In their conclusion they note that it is not through a classical allergy immediate hypersensitivity (IgE-mediated) pathway:

"Sulfite, the aqueous ion of sulfur dioxide, induces cellular activation, leading to degranulation in mast cells through a non-IgE-dependent pathway. The response also differs from IgE-mediated degranulation in that it is insensitive to the influx of extracellular calcium. The putative pathway seems to rely on activation of the reduced form of nicotinamide adenine dinucleotide phosphate oxidase complex, leading to intracellular oxidative stress."

 This finding not only adds antioxidants to DAO supplementation to the resources for ameliorating histamine intolerance, but is fascinating to contemplate in consideration of the numerous patients who report better tolerance for 'old world' dry farmed wines versus 'new world' wines cultivated with drip irrigation. Briefly, the much larger root mass developed by vines that have to 'reach' farther through the soil in search of moisture also endows the fruit with richer 'minerality' and polyphenolic antioxidant compounds. Indeed, a study published in the Journal of Pharmacy and Pharmacology demonstrates that red wine polyphenolics ameliorate bronchoconstriction (which we have seen is induced by histamine).

"The aims of the study were to investigate the short and long-term effects of Provinol (red wine polyphenolic compounds) on tracheal smooth muscle reactivity using an in-vitro model of ovalbumin-induced airway inflammation in guinea-pig trachea, and to evaluate the role of nitric oxide (NO) in the bronchodilatory effect of Provinol."

The authors examined tracheal smooth muscle contraction in response to histamine and acetylcholine as mediators of bronchoconstriction and also to allergen (egg white protien), both with and without treatment with Provinol. They found that red wine polyphenolics do inhibit bronchoconstriction:

"Incubation of tracheal smooth muscle with Provinol decreased the amplitude of contraction in response to ovalbumin, histamine and acetylcholine. The non-selective NO synthase inhibitor L-NAME partially abolished the effect of Provinol on acetylcholine and ovalbumin-induced but not histamine-induced bronchoconstriction. A similar profile was observed after 14 days' oral administration of Provinol."

This implies that wine containing more polyphenolic compounds (generally speaking from vines cultured by dry farming methods rather than drip irrigation) contain within them more of the antioxidant compounds that can ameliorate wine histamine intolerance. A paper published in the International Journal of Immunopathology and Pharmacology discusses the mechanism by which flavonoid compounds in wine reduce histamine release:

"Flavonoids are low molecular weight compounds rich in seeds, citrus fruits, olive oil, tea and red wine, with potent antioxidant, cytoprotective and antiinflammatory activities... Particular hydroxylation patterns of the B ring of the flavones permit them to inhibit histamine, tryptase, interleukin-6 and interleukin-8 release from human umbilical-cord derived cultured mast cells, as well as from macrophages. The catechol (o-dihydroxy) group in the B ring as in quercetin confers potent inhibitory ability, while a pyrogallol (trihydroxy) group, as in myricetin, produces even higher activity."

Additionally...

"Inhibition of mast cell secretion was shown to be mediated by a 78-kD phosphoprotein which has been cloned and serves as a bridge between the cell surface and the cytoskeleton...These properties present unique opportunities for the synthesis of new compounds for the treatment of inflammatory and possibly proliferative disorders."

So for wine and histamine intolerance, the more polyphenolic and flavonoid compounds (which generally tend to be more highly concentrated in dry farmed wine) the better. Clinicians can be reminded of the excellent properties of quercitin in this context by a paper published in the Journal of Biological Regulators and & Homeostatic Agents:

"Quercetin is a bioflavonoid found in red wine, grapefruit, onions, apples, black tea, and, in lesser amounts, in leafy green vegetables and beans. Quercetin has an antioxidant and anti-inflammatory activity and prevents cancer. Quercitin inhibits the growth of certain malignant cells in vitro, and histamine and most cyclin-dependent kinases and also displays unique anticancer properties. Quercetin is a natural compound that blocks substances involved in allergies and is able to act as an inhibitor of mast cell secretion, causes a decrease in the release of tryptase, MCP-1 and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from few mast cell lines."

Practitioners expert in the use of nutraceuticals are aware of the various forms of quercitin for clinical use.

"Quercetin is a safe, natural therapy that may be used as primary therapy or in conjunction with conventional methods."

Clinical note: For patients whose presentation suggests histamine intolerance aggravated by wine, consider assessing DAO activity and compensating with supplemented DAO for impaired production if indicated; the use of flavonoid compounds, notably quercitin; and a suggestion to seek wines higher in polyphenolic and flavonoid compounds.