Download Review article: cinnamon‐and benzoate‐free diet as a primary

Alimentary Pharmacology and Therapeutics
Review article: cinnamon- and benzoate-free diet as a primary
treatment for orofacial granulomatosis
H. E. Campbell*, ,à, M. P. Escudier§, P. Patel–, S. J. Challacombe§, J. D. Sanderson*,– & M. C. E. Lomer*, ,–
*Diabetes and Nutritional Sciences
Division, King’s College London
(KCL), London, UK.
Department of Nutrition and
Dietetics, Guy’s and St Thomas’ NHS
Foundation Trust (GSTFT), London,
UK.
à
NIHR Comprehensive Biomedical
Research Centre at GSTFT and KCL,
London, UK.
§
Department of Oral Medicine, King’s
College London Dental Institute,
London, UK.
–
Department of Gastroenterology,
GSTFT, London, UK.
Correspondence to:
Dr M. C. E. Lomer, Kings College
London, Diabetes and Nutritional
Sciences Division, Room 4.103
Franklin Wilkins Building, Waterloo
Campus, 150 Stamford Street, London,
SE1 9NH, UK.
E-mail: [email protected]
Publication data
Submitted 4 November 2010
First decision 28 November 2010
Resubmitted 6 July 2011
Accepted 7 July 2011
EV Pub Online 4 August 2011
This uncommissioned review article was
subject to full peer-review.
SUMMARY
Background
Orofacial granulomatosis is a rare chronic granulomatous inflammatory
disease of the lips, face and mouth. The aetiology remains unclear but may
involve an allergic component. Improvements have been reported with
cinnamon- and benzoate-free diets.
Aims
To explore the prevalence of compound and food sensitivity and examine
the dietary treatments used in orofacial granulomatosis.
Methods
A comprehensive literature search was carried out and relevant studies
from January 1933 to January 2010 were identified using the electronic
database search engines; AGRIS 1991–2008, AMED 1985–2008, British
Nursing and Index archive 1985–2008, EMBASE 1980–2008, evidence based
medicine review databases (e.g. Cochrane DSR), International Pharmaceutical and Medline 1950–2008.
Results
Common sensitivities identified, predominantly through patch testing, were
to benzoic acid (36%) food additives (33%), perfumes and flavourings
(28%), cinnamaldehyde (27%), cinnamon (17%), benzoates (17%) and chocolate (11%). The cinnamon- and benzoate-free diet has been shown to provide benefit in 54–78% of patients with 23% requiring no adjunctive
therapies. A negative or positive patch test result to cinnamaldehyde, and
benzoates did not predict dietary outcome. The most concentrated source
of benzoate exposure is from food preservatives. Use of liquid enteral formulas can offer a further dietary therapy, particularly in children with
orofacial granulomatosis.
Conclusion
Management of orofacial granulomatosis is challenging but cinnamon- and
benzoate-free diets appear to have a definite role to play.
Aliment Pharmacol Ther 2011; 34: 687–701
ª 2011 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2011.04792.x
687
H. E. Campbell et al.
INTRODUCTION
Orofacial granulomatosis (OFG) is a chronic granulomatous condition characterised by disfiguring lip swelling
and oral involvement affecting all aspects of the oral
mucosa, but most often the buccal mucosa, gingivae and
sulcus.1, 2 Swelling and erythema are the most commonly
seen features but fissuring, ulceration, nodules, tags and
occasionally oral scarring from penetrating or prolonged
disease can also be present. OFG frequently exists as a
separate entity but is also commonly associated with
Crohn’s disease. The aetiology is unknown and no epidemiological studies have been carried out. However, the
largest reported population appears to exist in Glasgow.3
Historically, treatments often involved surgery4 but more
recently immunosuppressive medicines have been used
with success often seen with topical, intra-lesional and
systemic corticosteroids, thiopurines and occasionally
others such as clofazimine, thalidomide and anti TNF a
therapies.5–7
The experience of a combined oral medicine and gastroenterology clinic at a large teaching hospital in London, UK, exceeds over 200 patients for whom the
cinnamon- and benzoate-free diet has been used first line
in 86%.1 This diet requires avoidance of cinnamon, a
spice added to foods and hygiene products, benzoates
(which are salts and esters of benzoic acid) used as food
additives (E210–E219) and naturally occurring benzoic
acid sourced from some fruits and vegetables particularly
berries. The cinnamon- and benzoate-free diet is initially
used in isolation but some patients do not always benefit
from the dietary treatment and sometimes require
additional therapies. Symptom recurrence is common
and often unexplained. Moreover, the cinnamon- and
benzoate-free diet is complex requiring both dietetic
expertise and careful patient education and follow-up.
Practical information available to most practitioners
treating cases of OFG regarding the diet is scarce.
The objectives of this study were to explore (i) the
prevalence of compound and food sensitivity in OFG,
(ii) the dietary treatments used in OFG, (iii) dietary
sources of cinnamon and benzoates, (iv) other contributing factors in the dietary management of OFG and (v)
the current experience of the cinnamon- and benzoatefree diet in clinical practice.
METHODS
An extensive literature review was carried out. The
search strategy used the following databases; AGRIS
1991–2008, AMED 1985–2008, British Nursing and
Index archive 1985–2008, EMBASE 1980–2008, Evidence
688
based medicine review databases (e.g. Cochrane DSR),
International Pharmaceutical and Medline 1950–2008.
The search criteria included full journals as well as
abstracts from conference proceedings. Due to the rarity
of OFG, case studies were also accepted. Search terms
used included OFG, cheilitis granulomatosa, oral Crohn’s
disease, sarcoidosis, Melkersson-Rosenthal syndrome,
diet, atopy, allergy, sensitivity, cinnamon and benzoate.
Publications were excluded if there was insufficient detail
or if the results were not presented in English or could
not be translated sufficiently. References of retrieved
manuscripts were reviewed to identify further publications that may have been missed during the original
search.
RESULTS
Food and compound sensitivity in OFG
Since the 1980s, sensitivity to food in OFG has been
observed in almost a fifth of patients as a potential
aggravating factor.8, 9 The most frequently cited agents
include cocoa, cinnamaldehyde, cinnamon, toothpaste
with a range of foods including carrot, pork, apple juice,
orange juice, egg, cheese and tomato causing recurrence
of symptoms with a re-introduction programme following elimination of these foods.8
Patch testing is a commonly used method of identifying sensitivities in oral mucosal disorders and contact
dermatitis in oral medicine and allergy clinics. Patch
testing typically involves use of a standard battery of
patches containing individual compounds which are
placed on the skin, normally on the backs of patients
with suspected sensitivities. Contact urticaria is diagnosed when a reaction can be seen at 20 min after the
patches are placed. Delayed responses are seen at 24, 48
and 72 h following placement of the patches.
Two key studies initiated the concept of cinnamon
and benzoate sensitivity in OFG. In Belfast, in 1997,
Armstrong et al. 10 carried out cutaneous patch test studies in 48 patients with OFG. Twenty demonstrated sensitivity to one or more compounds, the most common
(18 ⁄ 20) being benzoic acid. This study also demonstrated
sensitivities to cinnamaldehyde, sorbic acid (a common
food preservative), fragrance mix, nickel sulphate and a
range of other compounds. In Glasgow, in 2000, a retrospective study on 264 patients with OFG assessed 48 different allergens using cutaneous patch tests which
included a modified standard European series, food additives, perfumes and flavourings and chocolate.11 Sixtytwo per cent were patch test positive to one or more
Aliment Pharmacol Ther 2011; 34: 687–701
ª 2011 Blackwell Publishing Ltd
Review: dietary treatment for orofacial granulomatosis
compounds with 122 (51%) and 97 (38%) demonstrating
sensitivity to benzoic acid and cinnamaldehyde respectively. A high incidence of patch test positive results to
other compounds such as fragrance mix, food additives,
perfumes and flavourings was also observed. Twenty
patients (8.2%) patch tested positive to chocolate which,
anecdotally, patients often cite as aggravating disease
symptoms. The authors reported an immediate response
(contact urticaria) at 20 min and a delayed response at
48 and 96 h. Contact urticaria to cinnamaldehyde (36%)
and benzoic acid (46%) were common but delayed
responses were less common [benzoic acid (7%) and cinnamaldehyde (4%)]. Delayed sensitivity to chocolate
(7%) was comparable to benzoic acid. Overall, 23 publications on food and compound sensitivity were identified
in this literature review, most of which were from the
UK or Ireland. The age of subjects ranged from 3 years
to 72 years. Table 1 summarises the data on sensitivity
testing in OFG. The primary methodologies used were
patch tests, often undertaken against a background of
Table 1 | Publications identified
Country of
publication
Methodology for
identification of
sensitivity
Number of
patients
Number of
patients with
identified
sensitivities
2008
England
Patch tests
1
1
Armstrong (10)
1997
N Ireland
Patch tests
48
20
Booth (104)
1997
England
Patch and blind oral
challenge
1
1
Cameron (18)
2003
England
Dietary exclusion
1
1
Chiu (105)
2008
Taiwan
Patch tests
1
1
Downs (106)
1998
England
Patch tests
1
0
Endo (107)
2007
Japan
Patch tests and dietary
assessment
12
12
Fitzpatrick (108)
2011
Ireland
Reference
(1st author
surname)
Publication
year
Alexandroff (103)
Patch tests
41
17
Urticarial patch tests
97
63
Gibson (109)
1996
Scotland
Patch tests
100
93
Guttman – Yassky (12)
2003
Israel
Patch tests
1
1
Khamaysi (110)
2006
Israel
Patch tests
13
6
Kiparissi (19)
2006
England
RAST and allergen
specific IgE tests
15
14
Lazarov (111)
2003
Israel
Patch tests
2
2
Mehta (112)
2003
England
Patch tests
1
1
Oliver (113)
1991
Australia
RAST and skin prick
1
1
Patton (9)
1985
Scotland
Patch tests and dietary
assessment
80
14
Pryce (13)
1990
England
Patch tests
1
1
Reed (114)
1993
Australian
Dietary exclusion
1
1
Sweatman (20)
1981
England
Allergen specific IgE,
diet assessment and
skin prick tests
1
1
Taibjee (88)
2004
England
Patch tests
1
1
Torgerson (115)
2007
US
Patch tests
13
4
White (17)
2006
England
Dietary exclusion
25
18
Wray (11)
1999
Scotland
Patch tests
264
192
RAST, radioallergosorbent test.
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689
H. E. Campbell et al.
clinical suspicion. Combining data for 386 patients with
OFG (Table 2) where specific sensitivities to one or more
compounds could be identified, 140 ⁄ 386 (36%) were sensitive to benzoic acid, 129 ⁄ 386 (33%) to food additives,
108 ⁄ 386 (28%) to perfumes and flavourings and 105 ⁄ 386
(27%) to cinnamaldehyde. Avoidance of oral mucosal
contact with many of these compounds through dietary
exclusion,8 removal of dental appliances,12 and even
removal of cobalt based ink pens in a boy with cobalt
sensitivity13 improved symptoms in OFG. It would therefore seem that where a compound sensitivity can be
readily identified, and regular contact with the lips and
oral mucosa is clear, removal or avoidance improves
symptoms in OFG. In contrast, a recent clinical review
of patch testing to the standard European series showed
only a small trend to increased response from a cinnamon- and benzoate-free diet in those that patch tested
positive.14 Furthermore 40% of patients who tested negative still responded to the diet (23 ⁄ 38 patch test positive
responded versus 20 ⁄ 50 patch test negative, P = 0.056).
Patch test results to benzoates, cinnamon and other
Table 2 | Identified sensitivities in orofacial
granulomatosis
n
Compounds
140
Benzoic acid
129
Food additives
108
Perfumes and flavourings
105
Cinnamaldehyde
68
Cinnamon
64
Benzoates
42
Chocolate
21
Nickel
12
Cow’s milk
7
Scorbic acid
6
Cinnamic alcohol
5
Gold sodium thiosulphate
4
Colbalt chloride, mercury
3
Fragrance mix, oak moss absolute, wheat,
toothpaste
2
Monosodium glutamate, salicylic acid, dairy,
colphony, formaldehyde
1
Piperitone, carvone, betal nut, peanut, potassium
dicanaurate, benzyl peroxide, dodecyl gallate,
sodium metabisulphate, glutamic acid, butylated
hydroxyanisole, eugenol, isoeugenol, kathon GC,
neomycin quaternium, balsam of Peru
n = number of patients with identified sensitivities.
690
related compounds were even less predictive of dietary
response. Unpublished data from our clinic in 38
patients with OFG also suggested that routine skin prick
testing (SPT) to cinnamon and benzoic acid was not predictive for dietary response. Nine of 13 patients who
were SPT positive for cinnamon responded to the diet
versus 12 ⁄ 25 who were SPT negative (P = 0.212). Five of
eight patients who were SPT positive for sodium benzoate responded to the diet versus 16 ⁄ 30 who were SPT
negative (P = 0.643).
In summary, a high rate of cinnamon and benzoate
sensitivity has been reported in patients with OFG but the
response to exclusion of cinnamon and benzoates is not
necessarily related. However, other compounds may also
cause sensitivity. Furthermore, in clinical practice, identifying the aggravating compounds and determining their
clinical relevance is challenging and often inconclusive.
Review of dietary management of OFG
Table 3 outlines the dietary intervention studies carried
out in patients with OFG. Two dietary therapies have
been assessed in the management of OFG comprising a
cinnamon- and benzoate-free diet14–17 or liquid enteral
nutrition.16, 18–20 The latter focused on using elemental
formula in preference to whole protein formula. These
studies were limited by their small sample sizes and retrospective nature which reflects the rarity of this disease.
Nevertheless, both treatments appear to offer beneficial
outcomes in OFG. Dietary benefit was not always clearly
defined but in most of the studies is measured through
improvement of signs and symptoms recorded on a disease severity scoring tool21 adapted specifically for
patients with OFG.17 This tool is available at http://
www.kcl.ac.uk/ofg. With respect to the cinnamon- and
benzoate-free diet, benefit is seen in 54–78% of patients
with OFG.14–17 Differences in these figures possibly relate
to differences in study methodologies. One used prospective methods 17 and the previously mentioned oral scoring tools to assess disease severity and activity.15–17 In
contrast, the largest study (n = 199) was a retrospective
notes review that used a more subjective assessment, and
the benefit observed was by clinical impression and could
not realistically take into account patient compliance.14
Despite the lower rate of benefit seen (54%), the strength
of this study was that it was more reflective of clinical
practice and demonstrated that nearly one quarter of
patients required no additional therapy, which was not
considered in the other studies. The diet appeared
marginally more beneficial to those without concurrent
Crohn’s disease but overall, there were no significant difAliment Pharmacol Ther 2011; 34: 687–701
ª 2011 Blackwell Publishing Ltd
Review: dietary treatment for orofacial granulomatosis
Table 3 | Publications investigating the dietary management of OFG
Study
Year
n
Study methods
Results
White (17)
2006
32
Prospective dietary intervention study
using the cinnamon- and benzoatefree diet in the treatment of OFG.
18 ⁄ 25 (72%) of patients demonstrated
benefit. 7 ⁄ 32 were excluded from the
data analysis for issues of non
compliance and incomplete data.
Nunes (16)
2008
57 (part 1)
12 (part 2)
Part 1; Retrospective review of dietary
management with a cinnamon- and
benzoate-free diet followed by part 2;
A dietary intervention study using
liquid enteral nutrition.
39 ⁄ 57 (68%) of patients benefited
from a cinnamon- and benzoate-free
diet with further improvement seen in
8 ⁄ 12 (67%) patients receiving liquid
enteral nutrition.
Kiparissi (19)
2006
14
Prospective intervention study using
elemental enteral nutrition in the
treatment of OFG in children.
10 ⁄ 14 (71%) complete remission. The
remainder benefited but required
additional treatments to induce full
remission.
Bogner (15)
2009
40
Retrospective assessment of the use
of the cinnamon- and benzoate-free
diet on disease sites.
31 ⁄ 40 (78%) demonstrated
improvement on the diet. The lips,
buccal mucosa and all other oral sites
improved significantly except the tongue.
Campbell (14)
2010
199
Retrospective analysis of use of the
cinnamon- and benzoate-free diet in
clinical practice
172 ⁄ 199 (86%) used the cinnamon- and
benzoate-free diet as the initial
treatment. 86 ⁄ 157 (55%) demonstrated
some benefit. 45 ⁄ 199 (23%) required
no adjunct therapies.
OFG, orofacial granulomatosis.
ferences between those with and without Crohn’s disease.14, 15, 17
Liquid enteral nutrition has been used to gain symptomatic relief in patients with OFG. One study (n = 12)
carried out over 6 weeks demonstrated benefit in eight
patients. Of these, six received an elemental formula
(Elemental 028 Extra; SHS International Ltd, Liverpool,
Meryside, UK) and two, a whole protein formula (Modulen IBD; Nestlé Nutrition, Croydon, Surrey, UK). Out of
the remaining 4 patients, 1 did not improve (Modulen
IBD; Nestlé UK) and three were unable to comply. A
paediatric study (n = 14) found similar success using an
elemental formula (Elemental 028 Extra; SHS) with 10
improving and four demonstrating some benefit but
requiring adjunct therapies.19, 22 Encouragingly, enteral
formula does appear to result in more rapid remission
with two case reports of improvement being seen in as
little as 2 days.18, 20
Immunological response to the cinnamon- and
benzoate-free diet
The mechanism for the observed dietary response to cinnamon and benzoate avoidance is not clear. Extrapolating
from other reports of hypersensitivity reactions (normally
asthma or allergic contact dermatitis) to benzoates used
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ª 2011 Blackwell Publishing Ltd
as food additives, some implicate a type 4 hypersensitivity
reaction which is mediated by lymphocytes and involves
activated T cells in response to antigens.22 This would
occur over a delayed period of 12 h or more as would be
illustrated by patch testing. Certainly this would be in
keeping with two studies in OFG patients where a T cell
response was implicated.23, 24 Delayed hypersensitivity to
benzoates has also been proposed in asthma and atopic
dermatitis, including possible late phase IgE dependent
responses associated with production of leucotrines and
other related arachidonic acid based reactions.22 Type III
reactions have also been proposed, which initiate the
complement system through means of circulating IgE
and IgM. An obvious argument is that these compounds
are too small to elicit such a response and that they
instead act as haptens binding to proteins (in particular
mucosal proteins within the mouth) which then trigger a
cell mediated response.25, 26 Interestingly, studies have
illustrated that sodium benzoate suppresses the Th1
pathway, hence altering the Th1 ⁄ Th2 balance permitting
a prominent Th2 response in the presence of a common
allergen.27–29 Hence, in OFG, sodium benzoate may not
itself be an allergen but in suppressing the Th1 pathway
in the oral mucosa it allows a significant Th2 response
whilst withdrawal of dietary benzoates re-dresses this
691
H. E. Campbell et al.
imbalance. Against this theory are the findings of Freysdottir et al. who identified a Th1 environmental profile
in the oral mucosa in OFG in keeping with that seen in
Crohn’s disease.30 Remarkably high rates of atopy are an
established observation in patients with OFG 31 which is
different to other chronic inflammatory disorders, for
example, rheumatoid arthritis and multiple sclerosis
where atopy rates appear reduced.32 Moreover, Patel
et al. recently discovered a novel population of sub- epithelial dendritic B cells in the oral mucosa of which a
subset, specifically in patients with OFG, expressed surface IgE implicating a likely IgE mediated response.33 It
is not clear if these cells are present as a consequence of
local inflammation or are resident prior to disease onset.
Benzoates are rarely implicated in IgE mediated reactions
although there have been some reports of anaphylaxis in
patients without OFG.34, 35 Additionally, in our specialist
OFG clinic, some patients (51 ⁄ 88) showed positive SPT
to sodium benzoate and cinnamon (54 ⁄ 88) although no
clear associations could be made with dietary response.
Immediate responses to cinnamaldehyde and benzoates
were also common in the Glasgow group.11
The true role of cinnamon and benzoates in the
immuno-pathogenesis of OFG remains unclear. However,
the prominence of allergic features, the evidence of type
I hypersensitivity and the likely abnormal T cell
responses suggest an intriguing and perhaps unique,
interplay between different immune pathways.
STRUCTURE AND PREVALENCE OF CINNAMON
AND BENZOATES
Cinnamon
Cinnamon is harvested from the bark of the cinnamon
tree and is naturally high in benzoates.36 True cinnamon
(Cinnamomum zeylanium N.) originates from Sri
Lanka.37 Many varieties exist and a close relative, Cassia
(Cinnamomum cassia Presi), originally sourced from
China, Indonesia or Vietnam, is often mistaken for cinnamon. Cinnamon oil makes up 1–8% of cinnamon and
provides the characteristic flavour. The pungent taste
and smell comes from cinnamaldehyde which has strong
antimicrobial activity.38 Cinnamaldehyde also occurs naturally in blueberries and cranberries.37 Other components of cinnamon and cassia include phenolic acids,
flavan-3-ols,39 proanthocyanidins,39, 40 cinnamyl alcohol,
terpenes, carbohydrates, coumarin and tannins.37 Cassia,
however, contains less cinnamaldehyde than cinnamon
but is high in coumarin, of which cinnamon contains
only a trace.41, 42
692
Both cinnamon and cassia are widely used in the food
and cosmetics industries as flavourings, preservatives and
perfumes. In a food ingredient label, where a spice makes
up <2% by weight of the food, cinnamon can be listed
under the generic title ‘spice’, ‘spices’ 43, 44 or mixed
spice.45 Cinnamon is often added to medicines, toothpaste and oral hygiene products, chewing gum, sweets,
soft drinks, chocolates, cereals, liquors, baked goods,
spicy savoury foods and cosmetics including perfumes,
creams soaps and balms. Both cassia and cinnamon are
predominant spices used in Asian cooking. There are no
official safety concerns regarding the use of cinnamon
which has been approved as a flavouring and perfuming
agent.37, 46, 47
Cinnamaldehyde and cinnamic acid have been cited
as irritants and patch test studies demonstrate positive
responses particularly in people with atopy and eczema.48
Cross reactions with balsam of Peru, the Myroxylon
pereirae tree extract commonly used as a fragrance, have
been demonstrated.49 In addition, there have been associated sensitivities between balsam of Peru and tomato, citrus fruits, spices, vanilla and cloves.49, 50 Toothpastes
and oral hygiene products with added cinnamon or cinnamon derivatives have been associated with oral intolerance resulting in gingivitis, glossitis, stomatitis and
perioral dermatitis.51–53 However, overall, reports of any
detrimental effects to health from cinnamon are rare.
Nevertheless, dietary studies quantifying cinnamon
intakes are limited. There is one study in children aged
between 2 and 5 years which demonstrated maximum
cinnamon intakes of 220 mg ⁄ kg body weight on peak
exposure days normally taken in rice pudding with
added cinnamon and sugar.54 These children were having cinnamon at least once every 6 days. This works out
at around 2.86 g of cinnamon for a 13 kg child which
equates to approximately one teaspoon per day. Longterm exposure of these children was calculated as
63 mg ⁄ kg body weight per day, assuming a 2 day per
week peak exposure of 220 mg ⁄ kg body weight.
Benzoates
Benzoates are known most commonly for their use as
antimicrobial preserving agents.55 Rich natural sources of
benzoates can be found in berries, prunes, tea, some
herbs and spices such as nutmeg, cinnamon, cassia,
cloves and in lower quantities, other foods such as milk,
cheese, yoghurts, soya, nuts and pulses.55, 56 The food
additives E210–219 are benzoate containing preserving
agents used in processed foods, for example soft drinks,
jams, sweets, chocolates, ice creams, pickles, baked
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Review: dietary treatment for orofacial granulomatosis
goods.57, 58 E216 and E217 have been banned in the
European Union (EU) following studies showing reduced
sperm counts in adolescent rats following ingestion of
the acceptable daily intake (ADI).59 Other sources
include the additive E928 (benzyl peroxide) which is not
listed for use in foods in the EU60 but is used in the cosmetics industry.61 E322 (lecithin) is an emulsifier used in
foods and medicines which, in some non-EU countries,
can be bleached with the use of benzyl peroxide. In the
EU however, hydrogen peroxide is now the only permitted bleaching agent for lecithin.60 Lecithin can also be
manufactured from soya which is a natural source of
benzoates.55 However, the dietary contribution of benzoates from soya lecithin is likely to be comparatively low.
Benzoates are added to cosmetics and pharmaceutical
products including creams, soaps, gels, oral hygiene
products, ointments and tablets.55, 61, 62 In 2003, an EU
directive was set up to ensure that ingredients previously
listed on labels as ‘parfum’ or ‘aroma’ would comply
with the regulations for listing the 26 likely allergens.58
This encompasses many cinnamon and benzoate derivatives. Oral hygiene products, in particular, tartar control
toothpastes and mouthwashes are common sources of
benzoates 55 and benzoic acid has been found to leach
from denture materials.63, 64 Benzoates have also been
found in oral dental impression materials used to create
moulds of teeth.65
The use of benzoates and quantities permitted in the
UK is controlled by EU regulations.57 A comprehensive
list of foods in which benzoates can be added is useful to
help identify potential benzoate sources but does not
necessarily mean that all these foods will contain added
benzoates. Furthermore, this legislation includes maximum permitted levels of benzoates often in combination
with sorbic acid rather than solely as benzoates.
For the general population, daily oral intake of benzoates is thought to be safe up to levels of 5 mg ⁄ kg body
weight at a concentration of 0.015–0.5%.55 A number of
nationwide population studies have demonstrated significant variation in benzoate intakes.55 These differences
have been attributed largely to variations in national legislation policing benzoate as an additive in different
countries.66 In the UK, a national survey analysed 250
samples of soft drinks and concluded that estimated benzoate intakes would be below the advised daily intake
(ADI) of 5 mg ⁄ kg body weight in line with the EU recommendations.67 This survey also demonstrated relatively low usage of benzoates as preservatives in soft
drinks. Of the 250 samples only four had levels above
the permitted level of 150 mg ⁄ L.
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ª 2011 Blackwell Publishing Ltd
Reports of benzoic acid toxicity are rare. Potential
toxic effects of sodium benzoate are thought to be similar to salicylic acid poisoning and generally non-specific
causing nausea, vomiting, malaise, irritability and hypoglycinaemia.68 Renal tubular dysfunction has also been
suggested secondary to therapeutic use of sodium benzoate in one case of hyperglycinaemia,68 a rare inborn error
of metabolism.
Despite the body of evidence surrounding the safety
of benzoates, public awareness has been raised with substantial negative press relating to a number of studies
implicating benzoates as having detrimental effects on
health.69, 70 Three key studies have contributed to this. A
study investigating the effects of weak organic acid food
preservatives (including benzoic acid) on yeast cells
found a pro-oxidant and mutagenic effect on the mitochondrial genome when exposed at very low levels.71
The authors extrapolated for the potential implicated
oxidative risks and mitochondrial damage these preservatives might be responsible for in humans. Further negative press ensued in 2006 when the soft drinks industry
was required by the Food Standards Agency (FSA) to
measure benzene levels in 230 soft drinks available in
the UK.72 Benzene is a carcinogen formed by the interaction of sodium benzoate and ascorbic acid.73 Only four
products were found to contain levels above the limit of
10 lg ⁄ kg and these were subsequently withdrawn from
the market. More recently, a study commissioned by the
FSA was conducted to investigate the influence of certain
food additives (food colourings and sodium benzoate) on
behaviour in children with Attention Deficit Hyperactivity disorder.73 The authors concluded that avoidance of
the additives used in the study might have some beneficial effects on behaviour. Some companies have consequently attempted to reduce their use of benzoates in
food products.74
Quantification of benzoates
Five papers were identified on the quantification of benzoates in foods. High performance liquid chromatography was the method used to quantify benzoate levels.
Two papers were German,36, 56 one was from Japan,75
one from China76 and one from New Zealand.77 Cinnamon contained the highest level of naturally occurring
benzoic acid with a mean of 33.6 mg ⁄ 100 g.36 Preserved
salted fish from Japan was very high in benzoic acid with
mean levels of 75.4 mg ⁄ 100 g.75 Other notably concentrated sources included soft drinks, mean levels of
14.4 mg ⁄ 100 g,77 nutmeg 4.41 mg ⁄ 100 g,36 ice cream
confectionery 10.7 mg ⁄ 100 g,77 ice cream toppings
693
H. E. Campbell et al.
5.6 mg ⁄ 100 g,77 soya sauce 5.1 mg ⁄ 100 g,75 cranberry
8.9 mg ⁄ 100 g,36 jams 7.1 mg ⁄ 100 g,75 and dried apricots
3.04 mg ⁄ 100 g.77 Comparatively, quantities of benzoates
obtained from preservatives are higher than natural
sources (Table 4).
A recent project set out to assess the levels of benzoates in processed foods, cosmetics and pharmaceuticals
by contacting UK manufacturers (n = 174).78, 79 Ninety
manufacturers responded but only 14 of these could provide quantitative data. The results demonstrated that benzoates are little used in the UK food industry and are
most commonly added to soft drinks. In the cosmetic
and pharmaceutical industries, benzoates are added more
significantly to a wide range of products, with two analgesics [Paracodal and Co-codamol effervescent (Bayer plc)]
containing as much as 120 mg per tablet. In addition,
soya flour added to bread is not sufficient (estimated benzoic acid values calculated as 0.0051 mg ⁄ slice) to merit
avoidance of breads containing soya flour. Similarly, soya
lecithin contains only trace amounts of benzoic acid at 2–
30 ppm and therefore need not be avoided. In addition,
rennet typically contains 0.4% sodium benzoate, and
6 mL of rennet are added per 100 L of milk in the production of cheese. Consequently the contribution of benzoates from rennet is minimal although the question of
naturally occurring benzoates in cheese and other milk
related products remains unclear.36, 80 Consideration of
natural sources of benzoic acid therefore remains important in patients with sensitivity to benzoates.
In summary, natural benzoate sources do contribute
to the overall exposure of patients to benzoic acid and a
cinnamon- and benzoate-free diet can be very restrictive
irrespective of the use of added benzoates. It is therefore
likely that in patients who respond well to dietary avoidance of cinnamon and benzoates, threshold tolerance levels are comparatively higher than those who partially
respond or do not respond to dietary treatment. It is also
reasonable to consider other sensitivities which may be
unrelated in these patients.
The relationships between cinnamon and benzoates
Cinnamon is a source of benzoic acid (Figure 1),36
cinnamaldehyde (see Figure 2) 81 and other phenolic
compounds.37, 40, 41, 81 Cinnamic acid (see Figure 3) is
found in cinnamon oil and is also readily oxidised from
benzaldehyde which is synthesised by gentle heating of
cinnamaldehyde.38 Cinnamic acid and benzoic acid are
structurally similar compounds classified as hydroxycinnamic acid and hydroxybenzoic acid respectively.82 Collectively, hydroxycinnamic and hydroxybenzoic acids are
known as phenolic acids. Phenolic acids make up
approximately one-third of a group of compounds
known as phenolics. Phenolic compounds are characterised by a phenol ring which is comprised of an aromatic
ring and at least one hydroxyl group (C6OH). There are
over 8000 phenolic compounds and there are many complex sub-classifications, the most well known being the
flavanoid (C6C3C6) group of which there are over 5000
83
and include mainly flavanols, anthocyanidins, flavones,
flavanones and isoflavones all of which can be further
sub-categorised. Cinnamon contains many phenolic comOH
O
Figure 1 | Benzoic acid.
O
H
Table 4 | Comparison of benzoate content of foods
Food
Quantity
(mg ⁄ 100 g)
Per portion
(mg)
Estimated
portion
Cinnamon
33.6
1.008
1 teaspoon (3 g)
Preserved
salted fish
(Japan)
75.4
37.7
50 g
Soft drinks
14.4
28.8
1 glass (200 mL)
Nutmeg
4.41
0.1323
1 teaspoon (3 g)
Cranberries
(fresh)
8.9
1.78
20 g
694
Figure 2 | Cinnamaldehyde.
O
OH
Figure 3 | Cinnamic acid.
Aliment Pharmacol Ther 2011; 34: 687–701
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Review: dietary treatment for orofacial granulomatosis
pounds including phenolic acids, phenolic volatile oils, 2hydroxycinnamaldehyde and cinnamaldehyde derivatives,
flavon-3-ols, catechin derivatives, 39 and proanthocyanidines.40 Phenolic compounds are recognised antioxidants
and cinnamon has a very high oxygen radical absorbance
capacity.84 The antioxidant capacity of cinnamic acids is
greater than in the homologous benzoic acid counterparts.85
Other contributing factors
Chocolate. Patients with OFG often associate symptoms
with chocolate consumption and indeed patch test studies
have demonstrated positive results to chocolate.11, 86–88
The largest patch test study demonstrated that, unlike
benzoic acid and cinnamaldehyde, a delayed response to
chocolate is more likely than contact urticaria.11 Furthermore, a case study reported recurrence of OFG symptoms
whilst undergoing a patch test study to cocoa, chocolate
and chocolate associated ingredients which involved no
oral mucosal contact with these compounds.88 In clinical
practice, symptom control of OFG can be achieved in
some patients with avoidance of only chocolate and few
other dietary limitations. Patients will often report a
delayed reaction with re-introduction of chocolate. The
relationship between chocolate and cinnamon and benzoates and the reason for sensitivity in OFG is not clear.
Chocolate can on occasion be flavoured with cinnamon
but is not a recognised source specifically of benzoic acid.
Cocoa does however contain phenolic acids89 and is a
rich source of proanthocyadinis 40, 90 as is cinnamon.91
Proanthocyadinis are degraded in the gut to smaller molecule phenolics and urinary phenolic acid excretion is
increased following a ‘chocolate meal’.92 Absorption of
some larger molecule phenolics have been demonstrated
in oral mucosal epithelium 93 but no studies exist specifically in relation to degradation and absorption of these
compounds in the mouth from chocolate.
Flavourings. There are approximately 2800 approved flavourings that can be added to foods in the UK.94 However, ‘flavourings’ or ‘natural flavourings’ labelled on
foods are not legally required to be specified on food
ingredient labels.43 Foods often contain such flavourings
and some derivatives are from cinnamon and benzoate.
It is not possible to identify the quantities used or what
the flavourings are unless they are stated. Consequently
this is another potential source of compounds that are
avoided on the cinnamon- and benzoate-free diet.
Tomatoes. Patients with OFG often complain of reactions to tomato and in particular cooked tomato. Tomato
contains small amounts of benzoic acid (mean levels
0.02 mg ⁄ 100 g, maximum levels 0.04 mg ⁄ 100 g.75 However, this is likely to be markedly increased in tomato
puree as much of the water content is removed as part
of the cooking process making it more concentrated.
Raw tomato contains 97% water compared with less than
1% water in tomato puree.95 Therefore, more concentrated tomato could exacerbate symptoms in sensitive
patients or there may be another tomato component that
contributes to symptoms. More recently, tomatoes have
also been discovered to contain cinnamic alcohol.96
Dermal exposure of benzoates and related compounds
Topically applied benzoic acid dissolved in acetone is
readily absorbed dermally with 43% subsequently
Table 5 | Practical considerations for the dietary management of orofacial granulomatosis
• The cinnamon- and benzoate-free diet is considered to be nutritionally adequate and indeed a recent service review in our own
clinic demonstrated nutritional adequacy for a selection of patients following this exclusion diet. However, it is not uncommon
for patients to have other food allergies ⁄ intolerances, or they may already have suspicions regarding certain foods which they
feel are contributing to their symptoms. They may therefore be already avoiding a number of foods and further dietary exclusion can lead to dietary inadequacy which can be avoided with a dietary assessment prior to intervention.
• Compliance can be an issue as the diet is challenging and lack of information on the cinnamon and benzoate content of foods
has undoubtedly contributed to this. Long-term avoidance is not possible and indeed, many patients will unwittingly eat foods
containing cinnamon and benzoates. The problem of symptom recurrence remains an ongoing issue in the clinical setting and
controlled re-introduction can be difficult. Non-response and frequent recurrence suggests that there are other factors to be
considered. Hence, it is not unusual for patients to complain of associations to other foods or compounds outside the spectrum
of the cinnamon and benzoate restricted diet.
• As quantitative information of foods in the UK is lacking, a re-introduction programme that does not specify foods but offers
guidance on controlled re-exposure and ways to identify and record foods that might induce recurrence is useful. Patients
should be advised to continue to avoid soft drinks, obvious sources of cinnamon and any foods they have associated previously
with symptoms with a view to these being re-introduced only if symptom resolution is maintained throughout the re-introduction phase.
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H. E. Campbell et al.
Table 6 | Dietary management of orofacial granulomatosis
Baseline assessment
Document oral lesions and site of presentation (see tool at www.kcl.ac.uk ⁄ ofg). Further assessment to include clinical photography (both portrait and profile), swabs of angles and fissures, inflammatory markers, haematinics (particularly if gastrointestinal
signs which might merit further investigation).
fl
Dietary assessment
• Check dietary exposure to cinnamon and benzoates. Rich sources are from preservatives normally in soft drinks ⁄ processed
foods and cinnamon used in spiced foods and bakery.
• Check for flavourings (mainly processed foods).
• Check for intake of chocolate.
• Check for intake of tomato, in particular tomato products which may contain tomato concentrate or puree.
• Consider other sources of cinnamon and benzoates (e.g. cosmetics, hygiene products and medicines).
• Consider potential contributing dietary deficiencies (e.g. anaemia related to iron, vitamin B12 or folic acid deficiency.116,
117
fl
Dietary exclusion
Commence dietary intervention for 12 weeks (see www.kcl.ac.uk ⁄ ofg for resources). Benefit is often seen within the first few
weeks but strict adherence is necessary and it can take much longer.
fl
Review
• Review at 4–6 week intervals and repeat objective oral assessment and dietary assessment. Consider that progression can be
slow and check for dietary compliance.
• After 12 weeks, if symptom improvement is not satisfactory, medical intervention can be considered. (Many patients use a less
strict version of the diet in addition to medicines to control symptoms).
fl
Dietary re-introduction
It is unrealistic to remain on a cinnamon- and benzoate-free diet indefinitely. Dietary re-introduction aims to minimise recurrence
and can also help patients identify specific foods they might relate to symptoms irrespective of the cinnamon and benzoate component. A re-introduction tool is available at www.kcl.ac.uk ⁄ ofg (it is common and achievable for patients to maintain their symptoms through avoidance of soft drinks, cinnamon and chocolate).
fl
Dietary failure
Improvement may not be seen from dietary exclusion. Consider other responsible compounds ⁄ foods or use of an elemental or
whole protein liquid diet (only with the support of a dietitian). Medical intervention may be required.
excreted in urine within 24 h.97 This can be increased to
61% absorption after 96 h when the dose is given in petrolatum.98 The absorption rate is site dependent with the
forehead being three times more absorptive than the
back.99 Ethnicity has little effect 100 but age does with
22–40 year olds having almost double the dermal
absorption of benzoic acid compared to those over
65 years of age.101 Balsam of Peru and fragrance mix
sensitivity are often implicated in contact dermatitis.50
The main chemical components include benzoic acid,
cinnamic acid, benzyl benzoate, benzyl cinnamate, cinnamyl cinnamate, vanillin and nerolidol amongst other
related phenolic compounds. Balsam of Peru is used in a
wide range of products including cosmetics and per696
fumes, pharmaceuticals, food flavourings, sweets, chocolates, drinks, pastries and cigarettes. Balsam of Peru
identifies fragrance sensitivity in 50% of patients with
fragrance sensitivity.49 Fragrance mix contains a mix of
oak moss cinnamaldehyde, cinnamic alcohol, alpha amyl
cinnamic alcohol geraniol, hydroxycitronellal, isoeugenol
and eugenol. Fragrance mix and balsam of Peru were
number 2 and 3 respectively of the top 10 positive patch
test compounds observed in 9948 patients with contact
dermatitis.102 Sensitivity to either balsam of Peru or fragrance mix is thought to be indicative of possible systemic contact dermatitis reactions to a range of balsam
cross reacting foods.96 These include citrus fruits, certain
flavouring agents, spices including cinnamon and cloves,
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Review: dietary treatment for orofacial granulomatosis
Table 7 | Available resources (www.kcl.ac.uk ⁄ ofg)
Simple dietary tool
• For use in chronic OFG where the disease is not severe.
(Some patients may require only minimal restriction).
• For clinicians to start a patient with dietary treatment prior
to referral to a dietitian.
• For maintenance of stable OFG which has previously
responded to a cinnamon- and benzoate-free diet.
Dietary tool for the management of OFG
• For use only after a full dietary assessment has been
undertaken by a dietitian.
• For use in severe OFG.
• For use in OFG which has been unresponsive to simple
dietary avoidance (1).
Controlled re-introduction programme
• For use following symptom improvement. May help identify
safe foods and tolerance levels.
Oral disease severity scoring tool
• Can be used to facilitate oral examination and monitor
disease progression.
OFG, orofacial granulomatosis.
vanilla, ketchups and other sauces ⁄ pickles, perfumed
teas, tobacco, chocolate, medicines, ice creams, cola and
other soft drinks, spicy foods and tomatoes.50 Many of
these foods are avoided on the cinnamon- and benzoatefree diet as are added food flavourings. The implication
of dermal absorption of cinnamates and benzoates from
cosmetics used on other parts of the body in OFG is
unclear. However, it is possible that people use their
hands to apply these products and subsequent hand to
mouth contact could therefore be a further source of
benzoate exposure. Thus avoidance of perfumed cosmetics or other topical products with added cinnamates or
benzoates, such as oral hygiene products is currently recommended in clinical practice.
DISCUSSION
Orofacial granulomatosis is a rare but distressing condition. The rarity of the disease has limited research and
consequently the aetiology remains unclear. However,
there is repeated and persuasive evidence that an allergic component may be involved and this is further supported by observed success with a cinnamon- and
benzoate-free diet. Patch testing is common to try and
identify sensitivities in OFG and both contact urticaria
and delayed hypersensitivity have demonstrated sensitivity to a range of compounds.11 Patch test sensitivity to cinnamon, benzoates and related compounds feature
repeatedly. However, the clinical relevance of these is not
always clear and a large proportion of patients have demonstrated benefit to a cinnamon- and benzoate-free diet
irrespective of patch test results. Whether this relates to
avoidance of cinnamon and benzoates specifically, or
other unidentified components of this restrictive diet is
not clear.
Immunosuppressive treatments are often beneficial but,
due to their side effects, are used reluctantly and, not
unreasonably, patients often prefer non-medicinal
options. The most obvious sources of cinnamon and benzoates tend to be cinnamon added to spiced foods and
bakery products and benzoates added as preservatives in
soft drinks. Chocolate appears to be a further common
trigger and also merits avoidance. The dietary programme
of avoidance of cinnamon and benzoates in clinical practice should be undertaken for a period of 12 weeks and is
likely to benefit over half of patients with one quarter
requiring no further intervention. Table 5 provides guidance on practical considerations for the management of
OFG and Table 6 illustrates an algorithm for the dietary
management of OFG. Table 7 provides a link for tools
which can facilitate this process and Figure 4 illustrates
the improvement observed in a patient with OFG who
was treated with a cinnamon- and benzoate-free diet.
Figure 4 | Photographs of pre and postdietary intervention with a cinnamon- and benzoate-free diet (patient consent
was obtained for publication of these photographs).
Aliment Pharmacol Ther 2011; 34: 687–701
ª 2011 Blackwell Publishing Ltd
697
H. E. Campbell et al.
Future work is required to further quantify cinnamon
and benzoates in foods, understand the relationships
between these dietary triggers and the potential immunological mechanisms responsible. In the meantime, the
cinnamon- and benzoate-free diet offers an appealing
non-medicinal treatment which benefits the majority of
patients and in a large proportion, may be the only
course of management required.
ACKNOWLEDGEMENTS
Declaration of personal interests: None. Declaration of
funding interests: Helen Campbell has received research
funding from the National Institute of Health Research
Comprehensive Biomedical Research Centre at GSTFT
and KCL, and the Foundation for Allergy Information
and Research.
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