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Citric acid and histamine intolerance
08/22/2024 Food Intolerances
Look at online nutritional recommendations about histamine intolerance and almost every website or journal will have citric acid on a list of prohibited substances. The reasons for why it is not tolerated vary greatly, but common to all these sources of information is the lack of clarity over where this assertion about citric acid comes from. Since citric acid is used so commonly in our everyday lives, it’s worth taking a closer look at the current state of research.
Citric acid occurs naturally in many types of fruit and vegetable, and, as the name suggests, it is found in particularly high concentrations in citrus fruits. Citric acid (E 330) is now a widely used additive in many foods, drinks and even medicines. It gives these products a palatable, sour taste and has preservative qualities as well.
Originally, citric acid was extracted from lemons, but due to the high cost involved, a process was developed at the beginning of the 19th century to synthesize the acid microbiologically. It is now produced from glucose via fermentation using Aspergillus niger (a mold), before being carefully purified in a multi-stage process.
There is no chemical difference between natural and industrially produced citric acid. However, if you see citric acid on a list of ingredients, you can assume it is the industrially produced variant. Citric acid should not be confused with lemon juice concentrate, which is obtained from lemons (see Table 1).
▲ Table 1: Overview of assorted ingredients containing citric acid
Many online resources claim that citric acid would be unsuitable for people with histamine intolerance. It is sometimes speculated that it contains a high level of histamine due to the fermentation process. Additional claims will be made that how well or badly fruit and vegetables are tolerated depends on the citric acid content. Another theory is that citric acid is found in citrus fruits, which act as histamine liberators. However, since citric acid is synthesized and not extracted from lemons, this is nonsense anyway.
It seems that many authors don’t exactly know what the effect of citric acid on histamine intolerance may be. Unfortunately, more than a few websites give the impression that what is offered as “well-researched fact” is actually just wild speculation, and that even basic biochemical processes have not been understood by the authors. Moreover, there are generally no sources or citations to speak of. Overall, this doesn't inspire much confidence.
This question can be answered with an emphatic “No”. The production of citric acid is essentially based on the citric acid cycle, with the aid of microorganisms. Despite fermentation occurring, no histamine is formed. The end product of citric acid is purified after production and contains no significant amounts of biogenic amines.
There is a dearth of scholarly articles on this topic. The first of these dates from 1979, but it is our belief that the claim is broadly based on an article from 2018. This documented the experiences of four people who suffered from inexplicable symptoms after eating certain foods. These symptoms affected various parts of the body and included, for example, joint and muscle pain, shortness of breath, abdominal cramps, and debility.
The article points to artificially produced citric acid as a possible cause of these symptoms. Apparently natural citric acid did not result in any symptoms in those affected.
Based on these individual cases, it was claimed that the symptoms may have been due to production-related residues from the organism Aspergillus niger in the artificially produced citric acid. These fragments could have triggered mildly inflammatory processes in the body and thus, over time, potentially lead to sensitization.
Since Aspergillus niger has been used in microbiological production for over a century, it has never undergone modern-day safety testing. On the contrary, it has received the Generally Recognized as Safe (GRAS) rating from the United States Food and Drug administration (FDA), because no noticeable side effects have been observed with its use.
In principle, there is some merit to the hypothesis that residues from the production process could trigger a negative reaction in the body. Some molds are dangerous to humans. They produce harmful poisons (mycotoxins) and can cause diseases, allergies or infections. Genetic analyses have also shown that the organisms used for making citric acid can produce these mycotoxins. Some are so dangerous that they are monitored in food inspections.
It has furthermore been proven that molds killed by heat can trigger inflammatory reactions – even more strongly than living cells do. This is because the extermination of the mold releases the toxins stored inside the cell, where they are recognized more quickly by the immune system. A similar effect could also occur due to contamination in artificially produced citric acid.
However, this was only observed when molds of other strains were killed, and not with production residues in purified citric acid.
And what of the evidence that may refute the claim that that citric acid is intolerable?
The aforementioned article never clearly demonstrated that mold residues were actually the triggering factor. Instead, the ingredients of the foods believed to have caused the symptoms – energy drinks and ranch-flavored potato chips, for example – were examined for a common denominator that was also found in citric acid. This was, however, inconclusive. Those foods are highly industrially processed products with many ingredients that are difficult to trace, such as unspecified flavorings.
The manufacturing process using mold has been well researched and optimized over several decades to produce as few toxic byproducts as possible. The citric acid then undergoes a rigorous, multi-stage purification process that removes production residues very efficiently. Consequently, mold cells or even reproducible spores are not to be found in citric acid. At most, one might find small fragments of proteins or other cell components.
There are strict procedures in place to limit the production of mycotoxins as much as possible. In addition to citric acid manufacturers, food companies that use the acid also carry out quality controls. Furthermore, the requirements for the purity of citric acid in the pharmaceutical sector are even higher.
Regardless of this, not only would a detrimental effect on health be limited to any faint mold residues in citric acid, but foods on which mold or its spores grow could also cause problems in the body. And those substances are ubiquitous. You can find them in fresh and dried fruit, vegetables, grains, spices, nuts, pork and poultry, dairy products, coffee, and many other foods.
It is noteworthy that so little has been published on the intolerability of citric acid. If this were a widespread problem, one would reasonably expect to see a lot more research on the subject. However, there are individual cases that are credibly documented, and we can condense that research down into two attempts to explain the causes.
Hypothesis 1: Citric acid intolerance is independent of mold allergies
Citric acid intolerance without the involvement of mold allergies was documented in 1979, but no underlying pathomechanism could be identified. In more recent studies on the tolerance of additives, citric acid intolerance has also been observed, but this is very rare. There are, therefore, many question marks over this hypothesis.
Hypothesis 2: Citric acid intolerance is due to mold allergies
Far fewer questions abound here. There a voluminous body of data and research on illnesses caused by mold. It is established fact that people, especially those with weakened immune systems, can become seriously ill if exposed to large amounts of mold and its spores. Moreover, it has also been proven that mold allergy sufferers can react badly to production residues in citric acid.
A connection with histamine intolerance has not been investigated whatsoever. The acute lack of reliable data means there is no good reason to prohibit the intake of citric acid for this condition.
Nevertheless, it remains possible that some (few) histamine intolerance sufferers cannot consume industrially produced citric acid, either due to mold residues or other as yet unknown causes. If you are histamine intolerant and you experience reproducible reactions after consuming foods containing citric acid, consult a doctor immediately. If mold is indeed to blame, targeted treatment will be required.
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What is citric acid and where is it used?
Citric acid occurs naturally in many types of fruit and vegetable, and, as the name suggests, it is found in particularly high concentrations in citrus fruits. Citric acid (E 330) is now a widely used additive in many foods, drinks and even medicines. It gives these products a palatable, sour taste and has preservative qualities as well.
Originally, citric acid was extracted from lemons, but due to the high cost involved, a process was developed at the beginning of the 19th century to synthesize the acid microbiologically. It is now produced from glucose via fermentation using Aspergillus niger (a mold), before being carefully purified in a multi-stage process.
There is no chemical difference between natural and industrially produced citric acid. However, if you see citric acid on a list of ingredients, you can assume it is the industrially produced variant. Citric acid should not be confused with lemon juice concentrate, which is obtained from lemons (see Table 1).
| Ingredient | Source |
|---|---|
| Lemon juice concentrate | Lemons |
| Citric acid (E 330) | Aspergillus niger |
| Citrates (E 331–333) | Aspergillus niger |
What can we find online about citric acid?
Many online resources claim that citric acid would be unsuitable for people with histamine intolerance. It is sometimes speculated that it contains a high level of histamine due to the fermentation process. Additional claims will be made that how well or badly fruit and vegetables are tolerated depends on the citric acid content. Another theory is that citric acid is found in citrus fruits, which act as histamine liberators. However, since citric acid is synthesized and not extracted from lemons, this is nonsense anyway.
It seems that many authors don’t exactly know what the effect of citric acid on histamine intolerance may be. Unfortunately, more than a few websites give the impression that what is offered as “well-researched fact” is actually just wild speculation, and that even basic biochemical processes have not been understood by the authors. Moreover, there are generally no sources or citations to speak of. Overall, this doesn't inspire much confidence.
Is histamine formed during citric acid production?
This question can be answered with an emphatic “No”. The production of citric acid is essentially based on the citric acid cycle, with the aid of microorganisms. Despite fermentation occurring, no histamine is formed. The end product of citric acid is purified after production and contains no significant amounts of biogenic amines.
Where does the claim come from that citric acid is intolerable?
There is a dearth of scholarly articles on this topic. The first of these dates from 1979, but it is our belief that the claim is broadly based on an article from 2018. This documented the experiences of four people who suffered from inexplicable symptoms after eating certain foods. These symptoms affected various parts of the body and included, for example, joint and muscle pain, shortness of breath, abdominal cramps, and debility.
The article points to artificially produced citric acid as a possible cause of these symptoms. Apparently natural citric acid did not result in any symptoms in those affected.
Based on these individual cases, it was claimed that the symptoms may have been due to production-related residues from the organism Aspergillus niger in the artificially produced citric acid. These fragments could have triggered mildly inflammatory processes in the body and thus, over time, potentially lead to sensitization.
What is the evidence for this hypothesis?
Since Aspergillus niger has been used in microbiological production for over a century, it has never undergone modern-day safety testing. On the contrary, it has received the Generally Recognized as Safe (GRAS) rating from the United States Food and Drug administration (FDA), because no noticeable side effects have been observed with its use.
In principle, there is some merit to the hypothesis that residues from the production process could trigger a negative reaction in the body. Some molds are dangerous to humans. They produce harmful poisons (mycotoxins) and can cause diseases, allergies or infections. Genetic analyses have also shown that the organisms used for making citric acid can produce these mycotoxins. Some are so dangerous that they are monitored in food inspections.
It has furthermore been proven that molds killed by heat can trigger inflammatory reactions – even more strongly than living cells do. This is because the extermination of the mold releases the toxins stored inside the cell, where they are recognized more quickly by the immune system. A similar effect could also occur due to contamination in artificially produced citric acid.
However, this was only observed when molds of other strains were killed, and not with production residues in purified citric acid.
What is the evidence against this hypothesis?
And what of the evidence that may refute the claim that that citric acid is intolerable?
The aforementioned article never clearly demonstrated that mold residues were actually the triggering factor. Instead, the ingredients of the foods believed to have caused the symptoms – energy drinks and ranch-flavored potato chips, for example – were examined for a common denominator that was also found in citric acid. This was, however, inconclusive. Those foods are highly industrially processed products with many ingredients that are difficult to trace, such as unspecified flavorings.
The manufacturing process using mold has been well researched and optimized over several decades to produce as few toxic byproducts as possible. The citric acid then undergoes a rigorous, multi-stage purification process that removes production residues very efficiently. Consequently, mold cells or even reproducible spores are not to be found in citric acid. At most, one might find small fragments of proteins or other cell components.
There are strict procedures in place to limit the production of mycotoxins as much as possible. In addition to citric acid manufacturers, food companies that use the acid also carry out quality controls. Furthermore, the requirements for the purity of citric acid in the pharmaceutical sector are even higher.
Regardless of this, not only would a detrimental effect on health be limited to any faint mold residues in citric acid, but foods on which mold or its spores grow could also cause problems in the body. And those substances are ubiquitous. You can find them in fresh and dried fruit, vegetables, grains, spices, nuts, pork and poultry, dairy products, coffee, and many other foods.
What conclusions can we draw?
It is noteworthy that so little has been published on the intolerability of citric acid. If this were a widespread problem, one would reasonably expect to see a lot more research on the subject. However, there are individual cases that are credibly documented, and we can condense that research down into two attempts to explain the causes.
Hypothesis 1: Citric acid intolerance is independent of mold allergies
Citric acid intolerance without the involvement of mold allergies was documented in 1979, but no underlying pathomechanism could be identified. In more recent studies on the tolerance of additives, citric acid intolerance has also been observed, but this is very rare. There are, therefore, many question marks over this hypothesis.
Hypothesis 2: Citric acid intolerance is due to mold allergies
Far fewer questions abound here. There a voluminous body of data and research on illnesses caused by mold. It is established fact that people, especially those with weakened immune systems, can become seriously ill if exposed to large amounts of mold and its spores. Moreover, it has also been proven that mold allergy sufferers can react badly to production residues in citric acid.
There is a current debate about whether mold could be responsible for chemical sensitivity, in which various chemicals, foods, and medications trigger symptoms of intolerance. A recent study with over 10,000 participants examined possible triggers, and mold exposure, such as during home renovations, may explain up to 15% of cases. The remaining 85% can mainly be attributed to products from the petrochemical industry, such as pesticides or toxic combustibles.
How can these findings be applied to histamine intolerance?
A connection with histamine intolerance has not been investigated whatsoever. The acute lack of reliable data means there is no good reason to prohibit the intake of citric acid for this condition.
Nevertheless, it remains possible that some (few) histamine intolerance sufferers cannot consume industrially produced citric acid, either due to mold residues or other as yet unknown causes. If you are histamine intolerant and you experience reproducible reactions after consuming foods containing citric acid, consult a doctor immediately. If mold is indeed to blame, targeted treatment will be required.
In conclusion: considering the absence of data and the wide-ranging dietary consequences, we do not currently advise histamine intolerance sufferers to avoid consuming citric acid. In case of suspicion, it should be considered as an ingredient that has to be assessed individually, just to be sure.
Our price-winning "Food Intolerances" app helps you manage your diet. Available for iOS and Android. Check it out:Share article
Back to blog
Sources:
- D. Kregiel, Health Safety of Soft Drinks: Contents, Containers, and Microorganisms, BioMed Research International Volume 2015, Article ID 128697, 15 pages
- P. Show et al., Overview of citric acid production from Aspergillus niger, Frontiers in Life Science 8:3 (2015), 271–283
- I. Sweis et al., Potential role of the common food additive manufactured citric acid in eliciting significant inflammatory reactions contributing to serious disease states: A series of four case reports, Toxicology Reports 5 (2018), 808–812
- B. C. Behera, Citric acid from Aspergillus niger: a comprehensive overview, Critical Reviews in Microbiology, DOI: 10.1080/1040841X.2020.1828815
- S. Chacko et al., Comparison of pro-inflammatory cytokines (IL-6, IL-1 and IL-1) released by MPI and MARCO (-/-) knockout cells when stimulated by heat killed fungi- Candida albicans and Aspergillus niger, The Plymouth Student Scientist 9:1 (2016), 4–23
- G. Magureanu et al., Verfahren zur Gewinnung von Citronensäure (EP0151470B1), Europäisches Patentamt (1985), https://register.epo.org/application?number=EP85100995
- G. Perrone et al., Aspergillus Species and Their Associated Mycotoxins. Methods in molecular biology 1542 (2017), 33–49
- J. Friesvad et al., Fumonisin and Ochratoxin Production in Industrial Aspergillus niger Strains, PLoS One; San Francisco Bd. 6, Ausg. 8, (Aug 2011): e23496. DOI:10.1371/journal.pone.0023496
- C. Soares et al., Mycotoxin production by Aspergillus niger aggregate strains isolated from harvested maize in three Portuguese regions, Revista Iberoamericana de Micología 30(1) (2013), 9–13
- A. Waśkiewicz, Occurrence of fumonisins in food – An interdisciplinary approach to the problem, Food Control, Volume 26, Issue 2, 2012, 491–499
- BfR Bundesinstitut für Risikoforschung, Bewertung von „Candy Sprays“ mit erhöhtem Zitronensäuregehalt, Stellungnahme Nr. 015/2012 des BfR vom 14. Juli 2011, ergänzt am 21. Januar 2013
- I. Yoshioka et al., Non-production of mycotoxins by citric acid hyperproducer Aspergillus tubingensis (A. niger) WU-2223L: Evidence for its biosafety based on genome sequence and metabolite analyses, JSM Mycotoxins 72:2 (2022), 75–83
- E. Schuster et al., On the safety of Aspergillus niger – a review, Appl Microbiol Biotechnol 59 (2002), 426–435
- https://www.efsa.europa.eu/de/topics/topic/mycotoxins (abgerufen 01/2024)
- E. Książek, Citric Acid: Properties, Microbial Production, and Applications in Industries, Molecules 29:1 (2023), 22 ff.
- W. Walsh, Atopic dermatitis associated with citric and malic acid intolerance, Minn Med 62:9 (1979), 637–639
- B. Wang et al., Biomanufacturing of food-grade citric acid and comprehensive utilization of its production wastewater, Food Sci. Technol, Campinas 43 (2023), e110422
- T. Cairns et al., Something old, something new: challenges and developments in Aspergillus niger biotechnology, Essays in Biochemistry 65 (2021), 213–224
- G. Fuglsang et al., Prevalence of intolerance to food additives among Danish school children, Pediatr Allergy Immunol 4 (1993), 123–129
- C. Miller et al., What initiates chemical intolerance? Findings from a large population-based survey of U.S. adults, Environmental Sciences Europe 35:65 (2023), 1–19
Images:
Photo by Vidit Goswami on Unsplash
Photo by Sama Hosseini on Unsplash
Photo by Fulvio Ciccolo on Unsplash