PF and Food Triggers

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Diet and Pemphigus
In Pursuit of Exogenous Factors in Pemphigus and Fogo Selvagem
Ethel Tur, MD; Sarah Brenner, MD
Individuals with a genetic predisposition to pemphigus will develop the disease only when one
or more additional factors are present. The nature of these factors is as yet unknown, but our
starting point was that certain drugs (penicillamine, captopril, and rifampicin) are recognized
as such factors. Since some nutrients have chemical compositions similar to these known causative
drugs, these nutrients may act similarly and, therefore, nutritional factors should also be suspected.
As when drugs are involved, elimination of the inciting ingredients may be crucial for management
of the disease. This article discusses the possible role of nutritional ingredients in the disease
process of pemphigus, including fruit, leaves, roots, seeds, and even water. Possible causative candidates
are thiol, thiocyanate, phenols, and tannins. Arch Dermatol. 1998;134:1406-1410
Because the variability in the incidence and
age of onset of pemphigus cannot be explained
by genetics, environmental factors
are implied. Susceptibility to autoimmune
diseases is multifactorial1; not all
individuals with a proven susceptible genotype
will develop autoimmunity. In many
diseases, it appears that autoimmunity is
preceded by some environmental insult.
Tissue damage may be the key event that
either allows for release of sequestered antigens
from immunologically privileged
sites or causes local inflammation resulting
in lymphokine release and subsequent
expression of antigens, or both.
Sinha et al1 note that perhaps the biggest
challenge in the future will be the search
for the environmental events that trigger
self-reactivity.
It has been established that exogenous
factors in the form of drugs, in particular
thiol-containing drugs,2,3 play a role
in the induction of pemphigus. This points
to the possibility of finding other offenders,
such as food products with chemical
compositions similar to these drugs.4-9 We
suggest that diet factors are involved in the
pemphigus disease process and that, potentially,
morbidity can be reduced if these
factors are identified and avoided.
DIETARY FACTORS
IN PEMPHIGUS
Thiol
When a thiol group is included in the molecular
structure of a drug, the drug is capable
of inducing pemphigus. Thiol groups
are part of the molecular structure of certain
plants; therefore, when these plants are
ingested, they may have the same effects as
thiol-containing drugs. Indeed, 3 compounds
of garlic (allylmercaptan, allylmethylsulfide,
and allylsulfide) were shown to
induce acantholysis in vitro.5 Garlic belongs
to the Allium group of plants, as do
onion, shallot, chive, and leek, all of which
also contain a thiol group. In the mountainous
(Himalayan) zones of India there are
many wild species of Allium L, and these appear
at tribal markets.10 Evidence for involvement
of thiol-containing foods in autoimmunity
is provided by case reports
indicating induction of pemphigus by garlic7
and leek.6 Elimination of these foods
from the diet induced remission, and readministration
caused exacerbation.
Isothiocyanates (Mustard Oils)
A distinct group of thiol-containing plants
comprises those with thioglucosides—
isothiocyanate-producing glucosides (by
From the Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv
University, Sackler School of Medicine, Tel Aviv, Israel.
ARTICLE
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enzymatic hydrolysis). They are of the mustard family
of plants that includes 3200 species in 375 genera and is
of worldwide distribution.11 Mustard (Brassica nigra) is
a member of the Cruciferae family, as are horseradish,
winter cress, turnip, broccoli (which contains both mustard
oils, namely, isothiocyanates and allyl isothiocyanates),
radish, cabbage, brussel sprouts, and cauliflower.
The seeds of mustard (containing 30% fat) are
used in French mustard, spices, and oils, and seed and
root extracts yield allergenic mustard oils—isothiocyanates.
12 Depending on the chemical structure, the compounds
are immunologically reactive (allyl and benzyl
isothiocyanate) or irritants (phenyl isothiocyanate): they
may either cause antibody-mediated acantholysis or be
incorporated into the epidermis leading to nonimmunologic
biochemical acantholysis in a manner similar to thiolbearing
drugs.13
The caper family (Capparidaceae), a tropical relative
of the mustard family, is another source of thioglucosides.
12 Usually, several thioglucosides coexist in a single
plant, and they are distributed throughout the plant in
varying amounts during its growth cycle. Synthetic oil
of mustard contains allyl isothiocyanate as the principal
ingredient. Allyl isothiocyanate is widely used for flavoring
of food products, especially seasoned sauces. It
is an irritant to mucous membranes and produces blisters
if left in contact with the membranes long enough.14
Phenols
Pemphigus may be topically induced as well: pemphigus
erythematosus has been induced by allergic contact
dermatitis caused by tincture of benzoin,15 and contact
with chromate has also caused pemphigus.16 The possibility
of induction of pemphigus by contact with phenols
has been described.17 Some phenolic compounds such
as phenylisothiocyanate contain sulfur, and others do not.
Following our previous publications,4-9 we received several
letters from patients with pemphigus who experimented
with foods and experienced variations in the
symptoms of their disease with elimination or readministration
of phenol-rich foods.
Urushiol. The mechanism by which urushiol elicits allergic
contact dermatitis probably begins with covalent
binding of the pentadecylcatechols to skin proteins.18 A
similar reaction might be the first step in the sequence
of events leading to acantholysis. Plants containing urushiol
(39,59-pentadecylcatechol) belong to the Anacardiaceae
family that includes the genus Toxicodendron (poison
ivy, poison oak, and poison sumac), the most
prominent genus in causing allergic skin reactions. There
are many related cross-reacting species such as mango,19,20
pistachio, and cashew that belong to the same family.
Other Phenolic Compounds. Aspartame, an artificial
sweetener, is a phenolic compound, as are many other
food additives such as preservatives, colorings, and flavorings.
Sodium benzoate, tartrazine (yellow dye No. 5),
vanillin, eugenol, caffeic acid, vitamins C and E, and cinnamic
acid are all phenols. Cinnamic acid is present in
apple, grape, orange, pineapple, and tomato juices. Cinnamon
spice is derived from the inner bark of Cinnamonium
zeylanicum, the phenol-containing cinnamon tree,
and many other species of Cinnamonium are also used as
spices. Eugenol, for example, an oil distilled from
Cinnamonium green leaves, is used as a flavoring for sweets
and foods.
Pinene, another phenol-containing substance, is used
to flavor baked goods, beverages, candy, condiments,
chewing gum, and ice cream. It is also found in tomatoes,
potatoes, mangoes, and bananas. Phenol-containing
piperine constitutes 5% to 9% of the content of
black pepper. Firewoods used for smoking and grilling
foods are another source of phenol. Ingested phenolics
are secreted in the milk and therefore appear in cows’ milk.
For example, gossypol is a phenolic constituent of cottonseed,
and when cows are fed cottonseed, this fatsoluble
compound appears in all the milk-fat products
made from those cows’ milk. Indole is another phenol
found in milk.
Tannins
Tannins are naturally occurring plant polyphenolic compounds
with considerable biologic activity. The astringency
of many fruits during the early part of growth is
due to high tannin content that declines as the fruit ripens.
Certain woods, root materials, barks, leaves, and even
hairs are also sources of tannin.
Previously, we pointed out the possible role of tannins
in the induction or promotion of pemphigus.8 Some
of the possible effects of tannins are listed below:
Precipitating interaction with proteins Alveolar macrophage stimulation
Interaction with drugs Platelet activation
Effect on nutrition Enzyme inhibition
Release of neutrophil chemotactic factor Metal ion deprivation
There is also evidence suggesting that tannins inhibit copper
utilization.21 Interestingly, the well-known pemphigus
inducer penicillamine is a chelating agent for copper.
Polyphenols induce apoptosis.22 Tannins also induce
binding of IgA paraprotein to red blood cells in a manner
analogous to tanning (waterproofing and preserving
animal skins to make leather) with phenolic plant extracts.
Tannins react with structures on or in the red blood
cell membrane.23 Tannin is frequently used as a crosslinking
agent,24 and similar cross-linkage in the epidermis
may possibly be the mechanism through which these
compounds induce pemphigus. Similarly, the first step
in drug-induced acantholysis involves binding of the drug
to the cell membrane.
Tannic acid has often been used in electron microscopy
as a stain for carbohydrate-rich cell surfaces. Tannic
acid stains the cell surface and intercellular material
in squamous epithelium and the desmosomes.25 Tannins
may activate platelets and are implicated in the
epithelial injury of bronchi by cotton dust. Some are carcinogens,
linked to nasal sinus cancer in woodworkers,
squamous cell carcinoma of the oral mucosa, and gastrointestinal
malignancies. Tannin has been shown to
produce a cytotoxic effect on human peripheral blood
lymphocytes in vitro, although this effect is dependent
on increasing concentrations and time of exposure.26
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Other factors affecting tannin activity include the
steric structure of both the tannin and the protein, absorption,
and the composition and size of the protein on
which the tannins act. Temperature, pH, and the presence
of metal ions, calcium, and other chemical compounds
will also influence tannin activity.
Intake of Tannins. Examples of Foods Containing Tannin.
Cassava (Manihot esculenta Crantz), also known as
manioc, mandioca, Brazilian arrowroot, and yucca, is an
important dietary staple in many forms for more than 500
million people in South America, Africa, and Asia.27 Cassava
roots and leaves contain cyanogenic and noncyanogenic
glycosides. Cassava leaves (both red and white
varieties) also contain condensed tannins. The tannin content
of oven-dried (70°C for 3 days in an air oven) cassava
leaves is from 0.2 to 3 g/100 g, depending on the
variety of cassava, and that of blanched leaves (100°C for
5 minutes) is 0.15 to 0.22 g/100 g.28
Mango also contains high amounts of tannin in the
pulp and skin, though this varies with the different kinds
of mango. India is the largest producer of mango, with
over 60 varieties grown there. The cashew tree produces
apples (not a true fruit botanically) in addition to
the nuts, and these apples are rich in tannins and are used
to make juice and alcoholic drinks in Brazil.
The guarana plant is a perennial climbing shrub
native to Brazil and other wooded Amazon regions. In
recent years, products manufactured from guarana have
been imported into the United States. The fruit is reddish
and contains glossy brown seeds. Some Indian
tribes grate fresh seed and swallow it with water, and
some make a fermented drink. Sometimes it is dry
roasted and then ground with cassava. This mixture of
2 high-tannin foods might have important implications.
The greatest use of guarana presently is as a soft drink,
which is imported to the United States. Guarana contains
a high caffeine level as well as tannin. The total
tannin content of air-dried guarana is 12.1% (proanthocyanidins
and prototannins).29 The seeds before any
treatment contain 6% tannin.
Fruits such as the kola nut, betel nut, black walnut,
raspberry, cherry, cranberry, and blackberry are all
high in tannin content. Avocado, banana, apple, and pear
are also rich in tannins, as are peach, persimmon, eggplant,
and grape skins. Coffee and cocoa seeds and the
roots of ginger, ginseng, and garlic are tannin rich, as are
the leaves of cassava, tea, mate´, and rosemary, the stems
of vanillin, and the shells of carob. Provisions such as beer,
wine, and soft drinks contain tannin additives. Tannin
is also added to candy, ice cream, baked goods, and even
nutritional supplements.
Stimulants and Masticatories. Certain plants that are
used for recreational and social ingestion and also as aphrodisiacs
and medications are rich in tannins (Table 1).
To this category belong the guarana from Brazil, betel nut
or areca nut (Areca catechu) from Malaya, which is popular
in India and in many other countries in that region
and in South Africa, and the kola nut from west Africa.
The appeal of exotic products has led to their spread to
North America as well, where they are now sold in sundries
shops and grocery stores. Guarana and kola nut are
also rich in caffeine and are used as stimulants.30 Chewed
betel nuts release tannins and thiocyanate. Immature nuts
contain 38% to 47% tannin, mainly polymerized leukocyanidins,
but the percentage decreases as the fruit matures,
and processing reduces the level to 8% to 15%.
Betel nut addiction afflicts at least 10% of the human
race.30 The betel quid is a package of fresh betel leaf
(Piper betle vine), the undersurface of which is smeared
with lime, containing pieces of betel nut and tobacco.
Spices are sometimes added too, as well as mustard. The
leaves that are used for chewing contain 1% to 1.3% tannin
and other phenols. The leaf yields 0.62% to 2.4% volatile
oil, which is 75% phenolic.30
The nut itself, aqueous extracts of it, and specific
constituents in the nut can be mutagenic and carcinogenic.
31 Several phenolics from the chewed plant products
can generate free radicals that can exert a cytotoxic
effect on the oral mucosa.32 It is a common practice to
keep pieces of the nut or betel quid in the mouth for prolonged
periods of time. Betel nut constitutes 50% of the
betel quid by weight, and a person may consume the
equivalent of 20 to 30 nuts and 200 leaves of betel vine
per day.
One method of preservation of the fresh betel nuts
involves blanching them in boiling calcium chloride. The
calcium (lime) component of the betel quid may take part
in pemphigus pathogenesis because the reaction of pemphigus
autoantibodies is enhanced by calcium supplementation.
Another ingredient of the betel quid, katha, is derived
from the heartwood of the cutch tree (A catechu),
and contains 11.7% to 14.2% tannin. It is a potent tanning
agent; 0.45 kg of cutch is equal to 3.2 kg to 3.6 kg
of oak bark for tanning purposes. It is also used as an
antioxidant in vegetable oils. An aqueous solution of A
catechu bark containing catechin and tannin, prepared
as a tincture or powder, has been used in the United States
as an astringent coloring in liquors, soft drinks, ice cream,
candy, and baked goods.
The expression of antigens that are markers of epithelial
differentiation may be regulated by substances such
as retinoic acid or calcium. Moreover, these antigens may
be involved in cell-to-cell adhesion in the epidermis.33
Thus, the same food compounds that play a role in car-
Table 1. Tannin and Caffeine Content of Some Masticatories
and Stimulants*
Substance
Tannin
Content
Caffeine
Content
Guarana 12 3-5
Coffee beans 0.7 1-2
Roasted coffee beans 1.7 . . .
Dry tea leaves 3.7 1-4
Kola nuts (Cola nitida, Cola acuminata,
family Sterculiaceae)
3.9-4.4 1.5-3.2
Mate´ 7-11 1.0-1.5
Betel nut (Areca catechu L) 8-15 Negligible
Betel leaf (Piper betle) 1.0-1.3 Negligible
Katha (derived from catechu) 11.7-14.2 Negligible
Cassava leaves 0.15-3.0 Negligible
*Tannin and caffeine contents are measured as a percentage of dry
weight. Ellipses indicate not available.
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cinogenesis of the mouth may play a role in cell-to-cell
adhesion leading to the development of pemphigus. However,
a combination of factors is needed: carcinogenicity
has been shown to occur as a result of chewing a mixture
of pepper leaf, betel, and lime but not the betel nut
without lime.30
Interestingly, chronic exposure to cashew nut oil has
been shown to cause oral carcinoma in women who refrain
from tobacco and betel nut habits.34 In addition, oral
submucous fibrosis, a precancerous condition, is prevalent
among cashew workers in south India.35 Chromosome
breakage observed among betel nut chewers has
been attributed to the joint action of betel nut–derived
alkaloids, polyphenols and/or tannins, and nitrosamines
in the saliva.
Kola nuts (Cola nitida and Cola acuminata, family
Sterculiaceae) were carried to America from Africa with
the slave trade in the 17th century30 and spread due to
the reputation of the seeds as stimulants. Tannin levels
in C nitida are 3.9% to 4.4%, and total polyphenol levels
are 6.7%, particularly catechol and epicatechol. Kola nuts
are consumed fresh wherever they are grown throughout
the world, and aqueous extracts or concentrates are
used as flavorings in soft drinks, particularly with extracts
of coca leaves.
Nuts such as peanuts and pistachios may contribute
to pemphigus induction because people who eat them
have a habit of sucking the shells. These shells have high
tannin content.
Drinks. Tannin is the main component of tea,36 and
coffee also contains a substantial amount of tannin.37 Mate´,
also called yerba mate´, Brazilian tea, or Paraguay tea, is
a tealike beverage popular in many South American countries.
It is brewed from dried leaves of an evergreen tree,
Ilex paraguarensis, and contains caffeine (1%-1.5%) and
tannin (7%-11%). The plant grows wild in southern Brazil,
where pemphigus is endemic in the Parana and Paraguay
river basins.38
Fruit juice, beer, wine, and liquor are all sources of
tannin. Tannins are used in the clarification of wine and
beer. Distilled liquor contains spices and flavoring agents
such as vanillin and cinnamon that contain tannins. But
the most intriguing issue is water. Possible constituents
and effects of water have been discussed in detail in a previous
publication.9 South American pemphigus foliaceus
(endemic pemphigus, fogo selvagem) affects individuals
of all ages and has a familial prevalence where it
is endemic in areas of Brazil. This has prompted a search
for environmental factors.33
Most patients with fogo selvagem live in close proximity
to rivers. Many of these rivers contain high levels
of tannin caused by decomposing leaves and other vegetable
matter from the lush surrounding forests. Along
these rivers, fogo selvagem occurs in regions where the
weather is hot and humid. These conditions are needed
for tannins to decompose, fitting our hypothesis that tannins
in the water are an important factor in pemphigus.
The number of new cases of fogo selvagem is highest
at the end of the rainy season and lowest during the
dry summer. Rainfall causes a rise of the waters; large
quantities of organic materials are then carried by the
stream, and the amount of tannins dissolved in the water
increases. Furthermore, variations of annual rainfall
result in differences in the tannin content, and this may
account for the observation that new fogo selvagem cases
occur in clusters.39
A possible lead toward a means for controlling pemphigus
lies in the fact that chlorination of water results
in the formation of the hypochlorite ion that combines
with phenolic compounds even in high dilutions. This
might account for the disappearance of fogo selvagem following
urbanization, which usually involves treating of
the water.
Spices. Spices have a high tannin content, ranging
from 0.12 g/100 g to 1.26 g/100 g (Table 2). Spices of
the Umbelliferae family (ajowan, coriander, and cumin)
and black pepper have the highest content of tannin. All
over India, where pemphigus is prevalent, spices constitute
an important part of the daily diet.40 Among spices,
red chillies account for the highest daily tannin
consumption by individuals in India, followed by coriander,
cumin seeds, black pepper, and garlic. It is noteworthy
that patients showing positive skin-prick test results
to fresh fruits and vegetables also exhibited positive
skin-prick reactions to spice (mustard included).41
Calcium ions are necessary for the reaction of tannins,
tannins’ action resulting in elevated intracellular calcium
ion concentration. Interestingly, dry ginger, ajowan,
and asafoetida, which are spices with high tannin
content, also have high calcium levels.41
Food coloring. Several food coloring products have
high tannin content. Mangosteen, a tropical fruit that originated
in Southeast Asia, was introduced into the Americas
centuries ago. Its skin contains 13% tannin and is used
Table 2. Tannin and Calcium Content in Spices, and Average Daily Consumption per Individual in India
Spice Tannis, g/100g Calcium, g/100g Spice Consumed, g/d*
Tannins Consumed
in Each Spice, mg/d
Garlic (Allium sativum) 0.12 0.11 2.49 ± 2.78 3.0
Dry ginger (Zingiber officinale) 0.54 1.47 0.04 ± 1.31 0.2
Red chillies (Capsucum annum) 0.90 0.06 3.08 ± 2.06 24.6
Asafortida (Ferula foetida) 0.80 1.01 0.06 ± 0.10 0.5
Coriander (Coriandrum sativum) 0.82 0.65 1.37 ± 1.30 11.3
Cumin seeds (Cuminum cyminum) 0.90 0.92 0.80 ± 0.77 7.2
Black pepper (Piper nigrum) 0.94 0.38 0.33 ± 0.30 3.1
Ajowan (Carum copticum) 1.26 1.26 0.11 ± 0.17 1.4
*Values are expressed as mean ± SD.
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as a coloring for food. The use of the catechu bark as
food coloring was discussed earlier. It is also used as an
antioxidant in vegetable oils.
Nutritional Supplements. Several popular nutritional
supplements contain high concentrations of tannins.
Some preparations are bark extracts containing
proanthocyanidins and other polyphenols. There are
also grape seed extracts containing flavonoids, tea extracts
with high levels of tannins, and mixtures of
extracts with high tannin levels.
CONCLUSIONS
In summary, inferences that diet plays a role in pemphigus
induction may be drawn from a wide variety of facts:
(1) The molecular structure of many food ingredients is
similar to that of known pemphigus-inducing drugs. (2)
Case reports6,7 indicate the connection. (3) Tannins and
phenols are known to interact with proteins. (4) Seasonal
variations in pemphigus incidence coincide with seasonal
tannin variations in diet. (5) Yearly variations in pemphigus
outbreaks coincide with yearly tannin variations.
(6) Incidence of fogo selvagem drops as populations move
into urban areas with chlorinated water supplies.
Finding the exogenous stressors is the first step toward
their elimination. The second step is unfolding the
sequence of events and the interaction between these
stressors. The task is enormous and includes many variables,
as even changes in the mode of preparation of the
same foods might eliminate the deleterious effects of certain
constituents.
We suggest that foods containing thiol, phenolic
compounds, and polyphenols have a role in pemphigus.
But which of the multitude of these compounds are involved,
their mode of action, and under what conditions
their effect is exerted still remains to be unveiled.
Accepted for publication August 17, 1998.
Corresponding author: Ethel Tur, MD, Department of
Dermatology, Ichilov Medical Center, 6 Weizman St, Tel
Aviv, Israel 64239 (e-mail: tur@eng.tau.ac.il).
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