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Pemphigus and Diet: Does a Link Exist?

By Vincenzo Ruocco, M.D., Sarah Brenner, M.D., and Eleonora Ruocco, M.D., from the Department of Dermatology, 2nd University of Naples, Naples, Italy, Department of Dermatology, Tel-Aviv Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Correspondence: Vincenzo Ruocco, MO, Department of Dermatology, 2nd University of Naples, Via Sergio Pansini, 5, 1-80131 Naples, Italy.

Introduction

In dermatology, there are typical examples of disorders related to dietary factors. The pathogenic, links between nutritional factor(s) and skin disease may be different.

Nutrient deficiency and nutrient excess are the simplest causes of specific diet-related cutaneous changes: scurvy (vitamin C deficiency) and acrodermantis enteropathica (zinc deficiency) are examples of the first type, and caronenoderma (carotene excess) is an example of the second type. Genetic metabolic defects or enzyme deficiencies, although subtle, may pave the way for the onset of diet-related skin disorders, where a toxic effect is exerted by the dietary factor(s): alcohol intake is responsible for porphyria curanea tarda, and the ingestion of choline- and lecithin-containing foods is the cause of eccnine bromhidrosis, with the typical “fishyodor that features trimethylaminuria. More often, an immune (and complex) mechanism is involved in the pathogenesis of strictly diet-dependent skin disorders, e.g. atopic dermatitis and food-induced urticaria (related to several foods), dermatitis herpetiformis (gluten), and allergic contact dermatitis (nickel). Finally, cutaneous disorders exist where the pathogenic interference of dietary factors has repeatedly been advocated, but without convincing evidence: psoriasis, seborrheic dermatitis, and acne are the commonest examples of this type.


Concerning pemphigus, although the medical literature is replete with reports and references to numerous factors that can favor or trigger this disease, dietary factors are only rarely mentioned as possible pemphigus inducers. In recent years, however, epidemiologic, clinical, and experimental data have been collected on the subject, thus allowing the inclusion of nutritional factors into the ever growing list of exogenous agents capable of inducing pemphigus in genetically predisposed individuals.

Epidemiologic data

Amazonian Brazil and India are vast territories where pemphigus is endemic, but with striking clinical differences: the Brazilian foliaceus variant (fogo selvagem) vs. the vulgaris form that prevails in India. A common denominator for this clinically different endemic behavior in two countries that are so distant and whose inhabitants have such a different genetic background may exist (as demonstrated by the earlier age of onset of pemphigus in both populations), and may lie in certain enviromnental and nutritional peculiarities of the resident populations.2, 4

In the Amazonian water basins, which directly serve the natives for drinking, fishing, and bathing, the continuous rotting of an enormous quantity of tropical vegetation results in an increased amount of tannins dissolved in the water system, to such an extent that the high tannin content gives the water a black color and the river its name, i.e. Rio Negro (Black River).2 Tannins are naturally occurring plant polyphenolic compounds that have many biological properties,2, 4 some of which (binding to the cell surface of squamous stratified epithelia, enzyme inhibition, metal ion deprivation) are shared with penicillamine, the drug most involved in pemphigus induction.5, 6 Tannins are also important constituents of guarana, a plant which spontaneously grows in the Amazonian territory and which is commonly employed by the local inhabitants to prepare very popular drink, also called guarana, largely used as a stimulant.3

All over India, there is a wide consumption of spices (garlic, mustard, red chillies, black pepper, coriander and cumin seeds) not only for culinary purposes, but also for cosmetic uses. For instance, body massaging with mustard oil and its topical application on scalp hair are extremely common practices in India.3 Most of these spices are rich in thiols and isotbiocyanates, substances with a chemical structure (-SH groups) shared with the drugs most involved in pemphigus induction (penicillamine, captopril),3 as well as with tannins. By studying the distribution of pemphigus in the different Indian ethnic groups, a high incidence of the disease has emerged among Sikhs.7 Although this group constitutes only about 2% of the whole Indian population, about 25% of the Indian cases of pemphigus affect Sikhs, who consume a large amount of garlic for culinary, religious, and local medical traditions. In India, there is also a large consumption of tea, a beverage with a very high tannin content, and the Hindu cultural and religious tradition makes betel quid chewing a widespread habit.3, 4 The betel quid is a package of fresh betel leaf, soaked with lime, catechu, tobacco and several spices (chiefly mustard), which is either chewed or kept in the mouth for prolonged periods of time (sometimes overnight) to form a bolus with stimulating properties. In particular, betel nut addiction seems to be the most common remedy for the pangs of hunger among the poorest native population. Chewed betel nuts release conspicuous quantities of tannin, phenol, and thiocyanate compounds.3, 4

Both in Amazonian Brazil and in India, the dietary staple is cassava (Manihot esculenta), also know as manioc, mandioca, tapioca, Brazilian arrowroot, and yucca.3, 4 This plant is the major food source of carbohydrates in the poorer section of Kerala (a south west coastal state of tropical India). Cassava leaves contain condensed tannins and cyanogenic glucosides, the main cyanide metabolite of which is thiocyanate.3 Other food habits shared by Brazilian and Indian populations concern the large consumption of mango, cashew, and coconut, the edible components of which are rich in tannins and other long-chain phenols.3, 4 In this respect, it is noteworthy that many of the pemphigus-inducing drugs contain a phenol group in their molecule.8

Clinical data

Patients who have had pemphigus related to dietary factors have been well documented. For example, a Neapolitan woman, who was affected by pemphigus vulgaris, received conventional treatment and remained healthy for some years. Then, an abrupt relapse of the disease (in the form of the erythematosus variant) occurred a few days after a fish and shellfish-based meal heavily spiced with garlic.5 Superficial pemphigus appeared in a 49-year-old man who admitted to consuming daily a large amount of garlic. In the absence of conventional treatment and on a garlic-free diet alone, the disease cleared for several months. Soon after an unintentional dietary test with a strongly garlic-spiced fish meal, the pemphigus recurred.9 A similar observation was reported in a Polish woman suffering from pemphigus vulgaris. Her diet consisted mainly of leek, which suggested that this vegetable could play a role in the maintenance of the disease. Indeed, withdrawal of leek from the diet produced a remission, coinciding with a considerable fall of the pemphigus antibody titer. Conversely, leek challenge induced oral lesions along with an increase in her antibody titer.10

Experimental data

An experimental study has shown that certain allyl compounds (allylmercaptan, allylmerhylsulfide, and allyl-sulfide), found in plants belonging to the genus Allium, i.e. garlic, leek and onion, can provoke acantholysis in normal human skin cultured in vitro at concentrations less than or equal to 6 mM. The acantholytic effect is more prominent in samples taken from a donor with a pemphigus-prone antigen, i.e. DR4, in her human leukocyte antigen (HLA) phenotype.11 This indicates that certain histocompatibility antigens that predispose to pemphigus can exert their action not only immunologically, as already well known, but also bio-chemically, possibly by rendering the antigen structure, i.e. Malpighian epithelia, more vulnerable to chemical acantholysis-inducing factors. A more recent investigation has shown that tannic acid, when added to normal human skin cultured in vitro, at concentrations ranging from 0.1 to 2. mM, causes different cytotoxic effects, the most prominent of which are acantholytic changes. Interestingly, the concentrations needed to exert this effect varied remarkably among the subjects who provided explants, thus indicating a high interindividual variability in susceptibility to tannin acantholysis.12

Both allyl compounds and tannins are immunologically reactive. In particular, a protein fraction from aged garlic extract enhances cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A.13 Garlic is also considered to be both a type I and type IV allergen.14 Tannin has been shown to produce a cytotoxic effect on human peripheral blood lymphocytes in vitro: this effect is dependent on concentration and time of exposure.15 Tannins are also known to enhance the release of neutrophil chemotactic factor.2, 14

Taken together, these experimental findings can suggest possible pathomechanisms involved in cases of pemphigus linked with certain diet ingredients. In genetically pemphigus-prone subjects, the abundant ingestion of allyl compounds and/or tannins may cause acantholytic lesions directly, indirectly, or in a combined manner. These substances may either be incorporated into the Malpighian epirhelia, leading to nonimmunologic biochemical acantholysis, or may release sequestered antigens from immunologically privileged sites and also interfere with the immune balance, leading to antibody-mediated immunologic acantholysis. The combined mechanism is also possible, as has been considered for the induction pemphigus by thiol drugs.16

Table 1: Chemical compounds with acantholytic potential, together with some nutrients in which they are present.

Thiol allyl compounds Garlic, onion, leek, chives
Isothiocyanate-producing glucosides Mustard, horseradish, radish, turnip, cabbage, cauliflower, Brussels sprouts, broccoli
Phenols Mango, cashew, pistaschio, black pepper
Tannins Cassava, red chillies, tea, red wine, cherry, raspberry, cranberry, blackberry

Conclusions

Although several factors have been reported to be responsible for the induction of pemphigus, dietary factors are only rarely mentioned. Their role in the induction of disease seems to be underestimated.1 A growing body of evidence supports the possible etiologic role of dietary factors in the development, maintenance, and/or exacerbation of the disease. Among the enormous variety of chemical compounds that are present in the diet, thiols, isothiocanates, phenol and tannins seem to be responsible for pemphigus induction. All of these substances are largely represented in the dietary habits of populations with a high incidence of pemphigus (Amazon Brazilians and Indians). Some of these substances (thiol allyl compounds) have been identified as inducing factors in well-documented cases of diet-related pemphigus. Both thiol allyl compounds and tannins have proven to be capable of provoking acantholytic changes in normal human skin cultured in vitro. In this respect, it should be pointed out that the use of dietary ingredients rich in thiols, isothiocyanates, phenols, and tannins is widespread in the eating habits of most countries4 (Table I). Therefore, the seemingly harmless nature of the diet in patients with pemphigus might be misleading, and the possibility of pemphigus induction by nutrients in genetically predisposed subjects should be considered. In this light, several cases of so-called idiopathic pemphigus could in fact be related to food components. Waiting for future studies and investigations to shed light on the matter, it is advisable for pemphigus patients to reduce the consumption of foods and drinks with a high content of thiols, isothiocyanates, phenols and tannins (Table I).

References

1. Brenner 5, Wolf R. Possible nutritional factors in induced pemphigus. Dermatology 1994; 189 337-339.

2. Tur E, Brenner S. The role of the water system as an exogenous factor in pemphigus. Intl Dermatol 1997; 36: 810-816.

3. Tur E, Brenner S. Contributing exogenous factors in pemphigus. IntJ Dermatol 1997 36: 888-893.

4. Tur E, Brenner S. Diet and pemphigus. In pursuit of exogenous factors in pemphigus and fogo selvagem. Arch Dermatol 1998; 134: 1406-1410.

5. Ruocco V, Pisani M. Induced pemphigus. Arch Dermatol Res 1982; 274: 123-140.

6. Bialy-Golan A, Brenner S. Penicillamine-induced bullous dermatoses: a review. I Am Acad Dermatol 1996; 35: 732-742.

7. Kanwar AJ, Kaur S. Pemphigus. in Sikhs (Letter to the Editor). Dermatologica 199I; 183: 53.

8. Goldberg I, Kashman Y, Brenner S. The induction of pemphigus by phenol drugs. IntJ Dermatol ~ 38: 888-892.

9. Ruocco V, Brenner S, Lombardi ML. A case of diet-related pemphigus. Dermatology 1996; 192:. 373-374.

10. Chorzelski TP, Hashimoto T, Jablonska S et al. Can pemphigus vulgaris be induced by nutritional factors? Eur J Dermatol 1996; 6: 284-286.

11. Brenner S, Ruocco V, Wolf R, et al. Pemphigus and dietary factors. In vitro acantholysis by allyl compounds of the genus Allum. Dermatology 1995; 190 197-202.

12. Brenner 5, Ruocco V, Ruocco E, et al. In vitro tannin acantholysis. IntJ Dermatol 2000; 39: 738-742.

13. Morioka N, Sze LL, Morton DL, Irie RF. A protein fraction from aged garlic extract enhances cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A. Cancer Immunol Immunother 1993; 37: 316-322.

14. Jappe V, Bonnekoh B, Hausen BM, Gollnick H. Garlic-related dermatoses: case report and review of the literature. Am J Contact Dermatitis 1999; 10: 3 7-39.

15. Vincenrini-Diaz VEP, Takahashi CS. Action of an extract of Stryphnodendron obovatum Benth seed on rat bone marrow and human lymphocytes. Rev Bras Genet 1993;16: 175-185.

16 Ruocco V, de Angelis E, Lombardi ML. Drug-induced pemphigus. II. Parhomechanisms and experimental investigations. C/in Dermatol 1993; II: 507-513.

Reprinted with the permission of the International Journal of Dermatology 2001, 40, 161-163 and ©2001 Blackwell Science Ltd. All rights reserved.

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