Absence of Skin Sensitivity to Oxides of Aluminium, Silicon, Titanium Or Zirconium in Patients With

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Gut1996;39:231-233 231 Absence of skin sensitivity to oxides of aluminium, Silicon, titanium or zirconium in patients with

Crohn's disease Gut: first published as 10.1136/gut.39.2.231 on 1 August 1996. Downloaded from

J C W Lee, S Halpem, D G Lowe, A Forbes, J E Lennard-Jones

Abstract obstructive lymphadenopathy. It has been Background-Some metallic compounds, proposed that this is caused by fibrosis of the especially of zirconium, can cause cell afferent lymphatics as a result of absorption of mediated granulomatous inflammation of microparticles of silica and alumino-silicates the skin. Pigment granules containing through the skin where people walk barefoot compounds of aluminium, silicon, and on certain types of soil. Particles containing titanium have been observed within silica, titanium, and aluminium are present in macrophages in the wall of the small microgranulomata within inguinal lymph intestine in health and in Crohn's disease. nodes of sufferers.6 Granulomata also develop Zirconium compounds can be ingested in in response to intradermal injection ofcolloidal toothpaste. silica in healthy subjects but these are foreign Aim-To determine in a pilot study if body granulomata and are clearly distinguish- granulomatous sensitivity can be detected able from the cell mediated response to small to compounds of these metals or silicon quantities of zirconium lactate.7 after injection into the skin of patients As metals and minerals are ubiquitous in the with Crohn's disease. community, a hypersensitivity to these sub- Subjects-Eight patients with Crohn's stances in some people rather than a direct disease known to have had granulomata in toxic effect is the most probable pathogenetic the intestine and not currently treated mechanism by which they may contribute to with corticosteroids, and two healthy disease. Experiments with metal compounds controls. by skin testing provide a useful model for the Method-Two intradermal injections each study of the evolution of granulomatous of 0.1 ml of a 002% suspension of one of lesions in hypersensitive people. After intra- the compounds made in the abdominal dermal injection of small quantities of http://gut.bmj.com/ wall of each subject. The site was marked zirconium lactate or beryllium oxide, a distinct and full thickness skin biopsy performed epithelioid cell granulomatous reaction can be six weeks later. found in sensitive subjects compared with a Result-A foreign body granuloma was foreign body reaction to larger amounts in observed on histological examination of non-susceptible subjects.2 8 two biopsy specimens but no evidence of a The gastrointestinal tract is exposed daily to celi mediated response in any subject. metallic compounds from diverse dietary on September 24, 2021 by guest. Protected copyright. Conclusion-No support was found for the sources, either intentionally as with food hypothesis that Crohn's disease is due to a additives, or unintentionally via cooking uten- specific sensitivity to ingested metallic or sils. Small amounts of toothpaste, containing silicon compounds. zirconium compounds, may be swallowed. (Gut 1996; 39: 231-233) Interestingly, toothpaste has been postulated as a possible cause of CD.9 Keywords: Crohn's disease, skin sensitivity, A black granular pigment containing aluminium, silicon, titanium, zirconium. aluminium, silica, and titanium has been described within the intestinal wall of adults, St Mark's Hospital, including those affected by CD. The pigment London An in J C W Lee increase the incidence of Crohn's disease is found in macrophages concentrated in the A Forbes (CD) in the developed world and reports of lymphoid aggregates of the small bowel, and in J E Lennard-Jones clustering of cases in some geographical some cases also in the mesenteric lymph regions suggests that 11 Departments of environmental factors nodes.'0 Dermatology contribute to disease pathogenesis. Inorganic We have tested the hypothesis that patients S Halpem substances may be one such factor. with CD are sensitive to certain metal com- Metallic compounds or minerals have and Histopathology pounds or to the mineral silica by conducting D G Lowe been implicated as the cause of some human intradermal skin testing on patients in a pilot diseases. Zirconium lactate, when applied to the study. St Bartholomew's skin can cause a specific cell mediated granulo- Hospital, London matous reaction in a few subjects.' 2 Pulmonary Correspondence to: granulomatous lesions are associated with Methods Professor J E Lennard-Jones, St Mark's Hospital, occupational exposure to compounds of titan- Northwick Park, Watford ium, beryllium, and aluminium.5 Road, Harrow, Middlesex Subjects studied HA1 3UJ. In podoconiosis, an endemic but non-filarial Eight patients (seven men and one woman) Accepted for publication form of elephantiasis, there is severe oedema with CD and two healthy male subjects volun- 19 January 1996 of the lower limbs as a consequence of teered for the study. The duration in time since 232 Lee, Halpern, Lowe, Forbes, Lennard-j7ones

CD had been diagnosed ranged from four to Results 27 years, with a median of 13.5 years. Terminal ileum involvement by CD had been Patients with CD reported in all of the patients. In seven Except for a short period of localised pain at patients, surgical resection of diseased bowel the time of injection, no patient reported any had been required in the past, including six other side effect. There were no visible nor Gut: first published as 10.1136/gut.39.2.231 on 1 August 1996. Downloaded from with two or more resections. The median palpable papules at the injection sites for the time interval between surgical removal of duration of the study prior to skin biopsy. bowel, in which histological evidence of granu- Serial sections from each biopsy specimen lomata within diseased intestine was found, were examined under light microscopy. and skin testing was five years and ranged from Histological evidence of a loose granuloma one to 10 years. For the remaining patient around foreign material (silica) was observed who had not required operative treatment, as the only significant abnormality in one of 16 granulomata had been found in colonic sites tested. There was no evidence of an biopsy specimens obtained during endoscopy inflammatory response or other reaction to the 12 years previously. Six patients were injected metals in the other biopsy sites tested. receiving maintenance treatment with Inorganic material was not identified in any of mesalazine or sulphasalazine and one also with the histological sections in the remaining azathioprine. Two patients were not receiving biopsy sites under light microscopy. any specific treatment for CD. None of the patients studied required treatment with corticosteroids for at least two months prior Controls to and during the study. The study was Of the two control subjects studied, a foreign approved by the district research ethics com- body type granuloma (to zirconium oxide) was mittee. present in one of four skin sites tested. As with CD patients, there were no side effects except for minor localised discomfort at the time the Choice ofsubstances used and theirphysical compounds were injected intradermally. characteristics Four inorganic substances were selected for testing - zirconium oxide (ZrO2), titanium Discussion oxide (TiO2), aluminium oxide (A1203), and The aim of the study was to identify whether silica (SiO2), obtained from Degussa specific granulomatous sensitivity to inorganic (Cheshire, UK). The first three were chosen substances exists in patients with CD. The because of the known association of com- results have not provided evidence that

pounds of these metals with diseases charac- patients with CD are prone to develop skin http://gut.bmj.com/ terised by granulomatous hypersensitivity granulomata after intradermal exposure to reactions and the presence of two of them in inorganic substances. Compounds of the three pigment within intestinal wall. Silica was used metals used are known to be associated with a as a non-specific substance, which can cause a granulomatous reaction in human tissue, -6 granulomatous skin response. and appropriately we have used elements that The compounds had a purity greater than are found in the granular pigment identified

96% and the average sizes of the primary parti- within diseased bowel wall.10 11 Furthermore on September 24, 2021 by guest. Protected copyright. cles were 12 (SiO2), 13 (A1203), 21 (TiO2), compounds of these elements are likely to be and 30 nm (ZrO2). Although their crystal ingested in small quantities: aluminium (from structures vary, they never exist as isolated cooking utensils, anti-caking agent), titanium primary particles, tending to form aggregates (artificial colouring), silica (thickening and and agglomerates (technical information anti-caking agent), and zirconium (tooth- supplied by Degussa). paste). 12 Elias and Epstein demonstrated, by intradermal skin testing of minute quantities of Preparation and intradermal injection of zirconium lactate and beryllium oxide, that inorganic substances only people known to be sensitive to these A 0.02% (w/v) suspension (1 in 5000) of metals developed a distinct epithelioid each substance (4 mg of compound diluted granulomatous reaction, whereas a non- in 20 ml sterile water) was autoclaved for specific foreign body inflammatory response 20 minutes at 121 °C before use. Each was seen in non-sensitive subjects when subject was tested with two substances. A injected with larger doses.8 A granulomatous volume of 0.1 ml of each suspension was skin reaction has also been described in certain injected intradermally at separate sites on subjects after injections ofvaccine that contain the anterior abdominal wall, which were an aluminium compound.13 It may be that if tattooed with India ink for future iden- inorganic substances have a part to play in the tification of the area. After six weeks the pathogenesis of CD, only a few members ofthe skin test sites were biopsied under local anaes- general population are sensitive. In this study, thesia with a standard disposable punch we were careful in our selection of patients, biopsy instrument of 4 mm diameter, and ensuring all had histological evidence of examined for histological evidence of a granulomata within their diseased intestine. granulomatous reaction. In two patients Furthermore, as corticosteroids may influence biopsies were done after seven and nine weeks the immune response, no patient had required respectively. treatment with systemic corticosteroids for at Absence ofskin sensitivity to oxides ofaluminium, silicon, titanium or zirconium in patients with Crohn's disease 233

least two months, and in most instances should be noted these foreign particles were longer, before the test injection. fed to the animals daily, in comparatively large As the alimentary tract is exposed con- quantities, and all animals developed macro- tinually to ingested substances, the possibility scopic and histological lesions. Thus this is that one or more of these is responsible for CD probably not a hypersensitive reaction, but a is plausible. Dark pigment containing metal non-specific toxic response. Gut: first published as 10.1136/gut.39.2.231 on 1 August 1996. Downloaded from particles in the bowel wall are found in The results of our study do not suggest that macrophages within Peyer's patches, which specific skin sensitivity to the three metals mediate sampling and processing of inert compounds tested or to silica is present in CD particles from the lumen of the bowel. patients. As skin biopsy is invasive we did not Experiments in animals have shown that in- test further patients in this pilot study. soluble polystyrene particles of 50 nm to 3 ,um The presence of metallic particles within are taken up mainly by Peyer's patches, trans- diseased bowel wall most probably results from ported to the serosa, and thence by mesenteric intestinal absorption, but without pathological lymphatic vessels to lymph nodes14; particles of consequence, as it also occurs in health. titanium 500 nm in diameter are handled We are grateful to Degussa, Cheshire, UK, for supplying the similarly. There is some evidence to suggest inorganic metal compounds used in the study. that intestinal permeability is increased among CD patients and their healthy relatives, 1 Shelley WB, Hurley HJ. The allergic origin of zirconium suggesting this could be an important initiating deodorant granulomas. Br Jf Dermatol 1958; 70: 75-101. factor in the pathogenesis of CD.15 2 Epstein WL, Skahen JR, Krasnobrod H. Granulomatous Skin testing may not be the most appro- hypersensitivity to zirconium: localisation of allergen in tissue and its role in formation of epithelioid cells. J Invest priate method to test for suspected sensitivity Dermatol 1963; 38: 223-32. as the immunological and inflammatory 3 Kriebel D, Brain JD, Prince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis 1988; 137: response to foreign substances by the skin is 464-73. probably different from that in the gastro- 4 Chen W, Monnat RJ, Chen M, Mollet NK. Aluminium induced pulmonary granulomatosis. Hum Pathol 1978; 9: intestinal tract. However, it would be difficult 705-11. and perhaps potentially harmful, to test human 5 Shigemtsu N, Matsuba K, Watanabe K, et al. A granulomatous lung disease produced by titanium. In: Jones- subjects by requesting them to ingest metallic Williams W, Davies BH, eds. Sarcoidosis and other compounds for a period before intestinal granulomatosis diseases. Cardiff: Alpha Omega, 1980: 728-33. biopsies. 6 Price EW. Podoconiosis: non-filarial elephantiasis. Oxford: The concentration of the suspensions we Oxford University Press, 1990. 7 Shelley WB, Hurley HJ. The pathogenesis of silica granulo- tested and the duration oftime they were left in mas in man: a non-allergic colloidal phenomena. J Invest situ before the skin sites were biopsied may be Dermatol 1960; 34: 107-22. 8 Elias PM, Epstein WL. Ultra-structural observations on important determinants of the response. A experimentally induced foreign-body and organised 0.02% suspension (1 in 5000) of the com- epithelioid cell granulomas in man. Am J Pathol 1968; 52: http://gut.bmj.com/ 1207-16. pounds was used and this is comparable to 9 Sullivan SN. Hypothesis revisited: Toothpaste and the published concentration of 1 in 10000 and cause of Crohn's disease. Lancet 1990; 336: 1096-7. 10 Shepherd NA, Crocker PR, Smith AP, Levison DA. 1 in 1000, which have evoked a specific Exogenous pigment in Peyer's patches. Hum Pathol 1987; granulomatous response in zirconium lactate 18: 50-4. 11 Powell JJ, Ainley CC, Kendall MD, Dhillon AP, Sankey sensitive subjects, within six weeks of EA, Thompson RPH. Specific inorganic microparticles in intradermal testing.' 8 More concentrated gut tissue may initiate Crohn's disease. Gut 1991; 32:

A572. on September 24, 2021 by guest. Protected copyright. preparations of 1% to 4°/0 produce a foreign 12 Hanssen M. E for additives. London: Thorsons, 1987. body type ofresponse. We are not aware of any 13 Fawcett HA, Smith NP. Injection-site granuloma due to aluminium. Arch Dermatol 1984; 120: 1318-22. guidelines recommended for intradermal test- 14 Jani P, Halbert GW, Langridge J, Florence AT. ing with compounds ofaluminium, titanium or Nanoparticulate uptake by the rat gastro-intestinal mucosa: quantitation and particle size dependency. silicon. J Pharm Pharmacol 1990; 42: 821-6. In animal experiments, dogs fed on a daily 15 May GR, Sutherland LR, Medding JB. Is small intestinal permeability really increased in relatives of patients with ration of finely divided sand or talcum powder Crohn's disease? Gastroenterology 1993; 104: 1627-32. developed intestinal inflammation with pro- 16 Chess S, Chess D, Olander G, Benner W, Cole WH. Production of chronic enteritis and other systemic lesions nounced lymphoedema and pathological by ingestion of finely divided foreign material. Surgery features similar to regional ileitis. 16 However, it 1950; 27: 221-34.