In the 1960s it was postulated that dietary biogenic amines such as histamine might cause adverse reactions such as migraine headaches. Subsequently a number of adverse reactions have been ascribed to dietary biogenic amines, including hypotension or low blood pressure, facial flushing, nasal congestion and/or gastrointestinal and respiratory distress. The foods implicated in these adverse reactions were cheese, chocolate, fish and fermented foods such as wine (Morrow et al. 1981, Askar and Treptow 1986, Malone and Metcalf 1986).
An adverse reaction to a food can either be a food allergy or a food intolerance. An immune or IgE-mediated allergy occurs on subsequent exposure of an individual to an allergen, such as a food protein, where the sensitised mast and blood basophil cells release histamine and other anaphylaxis-associated chemicals. In Australia, similar to the USA, approximately 2.5% of the population has a food allergy, and specifically, 4-8% of children under three years of age and 1-2% of the adult population have a food allergy. A food intolerance, on the other hand, is a form of hypersensitivity and is not mediated by the immune system. A relatively large amount of a food is needed to trigger a histamine induced food intolerance in contrast to a small amount needed to trigger an IgEmediated food allergy. After the oral ingestion of histamine, however, a food intolerance can be indistinguishable from a food allergy since histamine is also a mediator in a food allergy.
Accordingly, those individuals who experience an adverse reaction when consuming wine frequently attribute their reaction to the histamine content of wine. The current scientific literature suggests, however, that there is no correlation between wine intolerance and the histamine content of wine (Dahl et al. 1986, Kanny et al. 1999, 2001) although wine may contain histamine releasing compounds.
What is histamine?
The biogenic amine, histamine, is an endogenous compound. It is produced in the body by both mast cells and their related blood basophils. The lungs produce the highest concentration of histamine.
Histamine exerts its effects or adverse reaction by interacting with receptors on cellular membranes; there are H1 and H2 receptors, which have different effects on the body. These receptors are also located in more than one organ of the body, which explains why histamine is responsible for numerous symptoms. In the cardiovascular system, histamine interacts with both H1 and H2 receptors. Interaction with H1 receptors causes dilatation of extravascular or peripheral blood vessels, capillaries and arteries, which results in hypotension, facial flushing and headache. Interaction with H2 receptors, however, causes contraction of cardiovascular smooth muscle that accelerates heart rate (Beavan and Horakova 1978, Taylor 1985). In the gastrointestinal system, histamine interacts with H1 receptors to contract intestinal smooth muscle, which results in nausea, abdominal cramps, vomiting and diarrhoea (Taylor 1985), and in the lungs to contract bronchial smooth muscle, which results in bronchospasm. Histamine also interacts with H2 receptors in the parietal cells of the stomach, which regulate gastric acid secretion (Taylor 1986). In addition, histamine acts as a neurotransmitter in the central nervous system to stimulate motor and sensory neurons, which result in urticarial lesions (Taylor 1986). Other cutaneous or skin reactions are rash, edema and localised inflammation.
Histamine is metabolised or broken-down in the human body primarily by two enzymatic pathways. The first pathway is methylation by histamine N-methyltransferase, which is followed by either oxidation by monoamine oxidase enzymes and/or by acetylation by diamine oxidase. Both pathways are present in the gastrointestinal tract and liver (Granerus 1968, Taylor and Lieber 1979, Hui and Taylor 1985, Taylor 1986). Putrefactive amines (putrescine and cadaverine) and other biogenic amines such as tyramine, tryptamine and phenylethylamine, inhibit the metabolism of histamine (Voigt et al. 1974, Summer and Taylor 1979, Taylor and Lieber 1979, Lyons et al. 1983, Hui and Taylor 1985, Taylor 1986). These other amines, which are also observed in wine, compete with histamine for metabolism in the gastrointestinal tract, which results in an increased intestinal uptake and urinary excretion of unmetabolised histamine.
Histamine is also involved in IgE-mediated allergic reactions. For example, on contact with, or ingestion of, a substance (antigen) to which an individual is ‘allergic’, histamine is released from mast cells and basophils as the antigen attaches to, and cross-links with, the IgE molecule (antibody) which is bound to the surface of the mast cell. This results in exocytosis, which is the discharge of histamine-containing granules from the cell. These granules circulate throughout the body to cause different reactions. Histamine is, however, readily metabolised and excreted in urine from the body.
It is often postulated, therefore, that the ingestion of foods that contain histamine can result in symptoms similar to an allergic reaction. Furthermore, foods, including wine, can inhibit the monoamine oxidase enzyme and hence delay the metabolism of histamine, and increase the concentration of histamine in blood. In addition, the ethanol and acetaldehyde constituents of wine can stimulate the release of endogenous histamine (Lowenberg et al. 1981, Zimatkin and Anichtchik 1999).
Which foods contain histamine?
Histamine, in addition to other biogenic amines, is present in measurable quantities in: aged cheese; fish such as mackerel and tuna; meat; yeast extract and products; vegetables such as egg plant, spinach and tomatoes (Malone and Metcalf 1986); and wine (Ough 1971, Subden et al. 1979, Buteau et al. 1984, Baucom et al. 1986). In particular, foods that have been exposed to microorganisms during ripening, processing or storage can contain a relatively high concentration of histamine and other biogenic amines.
Histamine occurs naturally in these foods and wine, and is generated by the bacterial and microbial decarboxylation of the amino acid L-histidine. Approximately 5 to 80mg/L of L-histidine is present in grapes and juice depending on the grape variety (Rankine 1989, Spayd and Andersen-Bagge 1996, Gloria et al. 1998, Stines et al. 2000). It is hypothesised that bacterial growth, during the alcoholic or malolactic fermentation of the winemaking process, is responsible for the decarboxylation (Cilliers and van Wyk 1985, Vidal-Carou et al. 1989). It has been established that there is generally a greater concentration of histamine in red wine than in white wine, which may be partly attributed to the greater susceptibility of red wine to malolactic fermentation (Zee et al. 1983, Vidal-Carou et al. 1990, Radler and Fäth 1991, Costello et al. 1993, Costello et al. 1996, Jarisch and Wantke 1996).
How much histamine is in wine?
The amount of histamine in foods commonly consumed is generally ten-fold more than that measured in wine (Malone and Metcalf 1986, Mahendradatta and Schwedt 1996). The concentration of histamine in wine has generally been observed to be less than 5mg/L; the average concentration in Australian wine is generally less than 1mg/L (Costello et al. 1993, Costello et al. 1996, unpublished data). Wines that exhibit significant spoilage, however, may have a higher concentration of histamine.
Where does the histamine in wine come from?
Biogenic amines, including histamine, are primarily produced by both indigenous and commercial strains of lactic acid bacteria (LAB) in wine (Lonvaud-Funel and Joyeux 1994, Coton et al. 1998, Soufleros et al. 1998, Coton et al. 1999, Lonvaud-Funel 2001). The bacteria enzymatically decarboxylate the amino acid, Lhistidine, to the amine, histamine. The ability of different LAB genera to produce histamine varies significantly. For example, detectable histamine (greater than 0.1mg/L) was produced by nine of 22 Leuconostoc and Oenococcus spp., four of nine Lactobacillus spp. and all seven Pediococcus spp. examined by Costello et al. (1993, 1996 and unpublished data). The maximum concentration of histamine produced by LAB strains isolated from wine was 3.8mg/L for Leuconostoc and Oenococcus and 2.4mg/L for Lactobacillus and Pediococcus. Histamine was also produced by four of seven commercial Oenococcus oeni (formerly Leuconostoc oenos) strains; the maximum concentration of histamine produced was 1.5mg/L, although some strains have been reported to produce histamine at concentrations up to 33mg/L (Guerrini et al. 2002). The production of biogenic amines in wine can, therefore, be limited and minimised by restricting bacterial activity to strains selected for their inability to produce them.
In addition to a difference in the susceptibility of red and white wine to undergo malolactic fermentation, the difference in histamine concentration between red and white wine may also be attributed to different winemaking practices. Contrary to white wine, red wine vinification is usually carried out in the presence of grape skins and pulp, which enables extraction of a higher concentration of L-histidine into the must (Quevauviller et al. 1969, Meléndez et al. 1999, Stines et al. 2000). Furthermore, only white wines are generally clarified/fined with bentonite at doses
greater than 50g/hL, which may remove biogenic amines from wine (Kállay and Szalkai 1996). The difference in histamine concentration may also be attributable to the antimicrobial use of sulfur dioxide during vinification. For example, less sulfur dioxide is generally added to red wine. Consequently bacterial growth and the bacterial formation of amines is more prevalent in red rather than white wine (Plumas 1970, Coton et al. 1999).
In addition to bacteria, the yeasts used in alcoholic fermentation are also responsible for the production of histamine but to a lesser extent (Vidal-Carou et al. 1989, Torrea et al. 2001, Caruso et al. 2002, Torrea et al. 2002). The autolysis of yeast cells can release cellular amines, including histamine, into wine (Blackwell et al. 1969).
In 1992, a pilot study was undertaken at The Australian Wine Research Institute where Riesling and botrytised Riesling juices were fermented with 12 Saccharomyces cerevisiae yeast strains under controlled laboratory conditions. While there was only a small difference between the histamine concentration of the juice and resultant wine for both the botrytised and non-botrytised Riesling (0.47 ± 0.01mg/L and 0.60 ± 0.12mg/L, respectively and 0.069 ± .007 and 0.064 ± 0.012mg/L, respectively), there was a tenfold difference between the botrytised and non-botrytised Riesling juice and wine (The Australian Wine Research Institute; unpublished data). This implies that the majority of this small amount of histamine was present in the juice prior to the addition of yeast, and may also indicate that some histamine was produced prior to alcoholic fermentation. In addition, this suggests that there was some microbial activity on the vine, although it has not been confirmed whether Botrytis promotes decarboxylation of amino acids in the berry and juice (Ribéreau-Gayon 1988).
Furthermore, there was no significant difference between the 12 different S. cerevisiae strains in their ability to promote histamine production (Australian Wine Research Institute; unpublished data). This implies that these 12 particular S. cerevisiae strains contributed little to histamine production under the experimental conditions employed. Such an observation is also in accordance with the data of Ough et al. (1987), Torrea et al. (2001) and Caruso et al. (2002), which indicates that the amino acid decarboxylase enzymes are not uniformly distributed amongst S. cerevisiae and other yeast strains.
The significance of histamine in wine
Histamine, when administered intravenously, can briefly cause vasoactive symptoms such as facial flushing and mild headaches, and asthma. These symptoms can occur at a concentration in blood of 0.1mg, but when ingested with food, the effect of histamine is considerably reduced.
On ingestion, histamine is readily metabolised by the enzymes in the gastrointestinal tract and liver (Malone and Metcalf 1986). As a result, a significantly decreased concentration is available to circulate in the bloodstream. An adverse reaction generally occurs only when a large amount exceeding the normal dietary intake of histamine is ingested, for example, greater than 25 to 250mg. While these amounts are far in excess of those observed in wine, individuals ‘intolerant’ or ‘sensitive’ to histamine will exhibit an adverse reaction from the ingestion of wine containing a significantly lower concentration of histamine (Wantke et al. 1994, Jarsich and Wantke 1996, Wantke et al. 1996).
Three primary hypotheses have been proposed to explain why the occasional consumer’s adverse reactions to wine may be attributed to the histamine in wine. First, it has been suggested that the ethanol constituent of wine may accelerate the absorption of histamine. Second, as previously stated, ethanol, and in particular its primary metabolite acetaldehyde, which is a known monoamine oxidase enzyme inhibitor, may delay the metabolism of histamine in the liver. This delay would increase the plasma concentration of histamine and the amount of time that histamine circulates in the blood stream, consequently potentiating its adverse effects.
Third, it has been suggested that gastrointestinal diamine oxidase activity may be significantly reduced in ‘intolerant’ individuals compared to that in ‘tolerant’ individuals (Sattler et al. 1988, Sattler et al. 1989, Lessof et al. 1990, Sattler and Lorenz 1990, Wantke et al. 1993, Wantke et al. 1994, Jarsich and Wantke 1996, Wantke et al. 1996, Raithel et al. 1998a, 1998b). Genetic polymorphisms or differences for diamine oxidase have been identified between intolerant and tolerant individuals (Petersen et al. 2003, Schwelberger et al. 2003). Gastrointestinal histamine-Nmethyltransferase activity may also be significantly reduced in intolerant individuals (Kuefner et al. 2004). Indeed, after consuming wine containing a 20mg/L of histamine, healthy tolerant individuals have been observed to have a significantly increased plasma concentration of diamine oxidase, and there was no change in their plasma histamine concentration (Wantke et al. 1999). In addition, no change was observed in the plasma concentration of histamine of healthy tolerant subjects consuming wine containing 22.8mg/L histamine. No change also was observed in the concentration of histamine and its primary metabolite methylhistamine in their urine, and no subject exhibited an adverse reaction (Kanny et al. 1999).
While an intolerant individual, after consuming wine containing as little as 0.2mg/L and 3.7mg/L of histamine, has been observed to have a significantly increased plasma histamine concentration and exhibited facial flushing and bronchoconstriction (Wantke et al. 1996), this has not been consistently observed in other studies. For example, in a clinical study by Kanny et al. (2001) approximately 90% of wine ‘intolerant’ subjects exhibited an adverse reaction after consuming wines containing 0.4mg/L and 13.8mg/L histamine, respectively. No corresponding increase, however, in the plasma and urine concentration of histamine and methylhistamine was observed up to 45 minutes after consumption of the wine.
Wine has also been implicated in the aetiology of migraine headaches (Trethewie and Khaled 1972, Mariné et al. 1986) and the histamine H2 receptor antagonist, cimetidine, has been observed to block the headache provoked by the ingestion of red wine (Glaser and de Tarnowsky 1983). No relationship between histamine ingestion and migraine headaches, however, was observed when histamine-spiked beverages were administered (Lüthy and Schlatter 1983).
These observations support the emerging evidence, which suggests that there is no relationship between an intolerance to wine and the concentration of histamine in wine (Jansen et al. 2003). Clinical studies suggest, therefore, that an intolerance to wine is not related to the concentration of histamine in wine, but that a substance other than histamine or biogenic amines in wine may be involved, such as a ‘histamine-releasing’ substance (American Academy of Allergy and Immunology Committee on Adverse Reactions to Foods 1984, Dahl et al. 1986, Kanny et al. 1999, 2001, Zuberbier et al. 2002). Indeed, the involvement of the histamine-releasing acetaldehyde in wine intolerance has previously been suggested (Lowenberg et al. 1981, Shimoda et al. 1996, Zimatkin and Anichtchik 1999), in particular for consumers who have significantly reduced acetaldehyde dehydrogenase activity (Harada and Agarwal 1981).
Much anecdotal evidence, which forms the basis of the many articles and comments in the media, points to histamine as the ‘culprit’ in wine causing headache and other adverse reactions.
While it is accepted that the excessive consumption of alcohol will cause adverse reactions, research, however, clearly demonstrates that histamine is a minor constituent of wine and that there is no relationship between its concentration in wine and histaminemediated adverse reactions in either healthy tolerant or wine intolerant consumers.
A fourth and final hypothesis is that although the amount of histamine in individual foods is below the amount generally thought necessary to induce an adverse reaction, consumption of multiple histamine-containing foods on an occasion may result in ingestion of sufficient histamine to produce symptoms as the body’s capacity to metabolise histamine is exceeded (Chin et al. 1989).
A full set of references will be published on the AIM gateway in March 2005. For a copy please contact alison.rees@AIM-Digest.com
Creina Stockley is a member of the AIM Council.