Clinical and Laboratory Investigations Dermatology 1992;184:98-102
Department of Dermatology, General University Hospital. Faculty of Medicine. Salamanca. Spain
Key Words Silica Trichloroethylene Induced progressive systemic sclerosis Induced systemic scleroderma
Silica and TrichloroethyleneInduced Progressive Systemic Sclerosis
Abstract Several environmental factors and chemicals have been described as being able to induce systemic scleroderma and scleroderma-like diseases. The present work reports 2 male patients with progressive systemic sclerosis and pulmonary silicosis. Both patients had occupational histories of exposure to silica and one of them of handling trichloroethylene as a degreasing agent. The clinical and analytical findings could not be distinguished from those present in idiopathic systemic scleroderma with the exception of interstitial images with calcified hilar lymph nodes in the chest X-ray suggestive of pulmonary silicosis.
Introduction Among the pathologies of the connective tissues where occupational hazards play an important role, progressive systemic sclerosis (PSS) occupies one of the first places. Pulmonary silicosis has been described in systemic lupus erythematosus, although currently it remains unclear whether this is a coincidence or whether there is any patho genic connection. The association of certain occupations with PSS has been known for some time. In 1914, in a series of 9 patients with PSS. Bramwell [ 1] found 5 stone masons; he wrote: ‘in the last three cases I have correctly suggested the occupation of the patient as soon as I saw and felt the hands before I asked him a single question’. Since then, and parallel to industrial development, numerous chemicals and products responsible for scleroderma-like diseases have appeared, sometimes identical to idiopathic systemic scleroderma. Recognition of these would help to prevent this disease by avoiding exposure of workers to these agents, although it might be very difficult to determine the true cause of such conditions because several different sub
Received: A p ril S. 1991 Accepted: Julv 9. 1991
stances may be involved. It is likely that as new products appear and are described, some cases of systemic scler oderma considered as being idiopathic may be withdrawn from this category of diseases.
Case Reports Case I. A 65-ycar-old man had been working in a lead mine for more than 10 years. He had been diagnosed as suffering from pulmo nary silicosis 7 years previously. In the 5 years prior to presenting he had displayed Raynaud's phenomenon, dysphagia for solids, arthromyalgias and dyspnea upon medium effort. He displayed cutaneous sclerosis on the trunk, malar telangiectasia, sclerodactyly and trophic lesions on his hands. There was an erythematous-edematous zone on his left hand with a small ulcer, exuding a whitish substance. Upon auscultation, basal crepitations were observed in the medial field of both lungs. Blood pressure findings and the rest of the exploration were normal. The following analytical results were of interest: eryth rocyte sedimentation rate 52; 13.200 leukocytes (60% segmented) with normal erythrocyte and platelet counts; urea 149 mg/dl: creati nine 1.56 mg/dl: creatinine clearance 68 ml/min: alkaline phosphatase 463 mg/dl: gammaglutamyltrar.speptidase 209 mg/dl. The rest of the
S. Yanez Diaz M unoz T o rrc ro . 14—IS. 5 °C E-37007 Salamanca (Spain)
© 1992 Karger A G . Basel 1018-8665/92/1842 4 K)98 $ 2.75/0
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S. Yanez Diaz M. Moran P. Unamuno M. Armijo
analytical findings, including calcium, phosphorus, creatine phosphokinasc, and immunoglobulin quantification, were normal. Latex, complement and cryoglobulins were normal or negative. Antinuclear antibodies 1/640 (mottled pattern). anti-DNA, and anti-RNP antibod ies were negative. In the study of lymphocyte populations a decrease was observed in the hclpcr/suppressor ratio (1.09). HLA determina tion: Alt). B12, B17. DR5. Serologies for the determination of syphi lis. hepatitis A. B. and C. Brucella and Rickettsias were negative. The tests for tuberculosis in sputum and cultures on Ldwcnstcin-Jenscn medium were negative No evaluable alterations were found in the electrocardiogram. Basal gasometry and post-effort findings were as follows: desaturation upon effort. Chest X-ray: calcified hilar lymph nodes and an interstitial pattern (fig. I). The X-ray findings of the patient's hands revealed calcinosis but with no bone alterations. The esophagogastroduodenal study revealed esophageal apcristaltism. Ultrasonography of the liver revealed hepatic calcifications suggestive of granulomatose hepatitis of probable silicotic origin. Skin biopsy pointed to a thickening of the dermal collagen compatible with PSS. Case 2. A 39-year-old male patient had been working in a company dedicated to the maintenance of central heating systems using trichlo roethylene as a degreasing agent and fiber glass as an insulator. The patient complained of recent dyspnea upon effort and Raynaud's phe nomenon that had been present for several years. The patient had sclerosis with diffuse cutaneous hyperpigmentation, areas of hypopig mentation. alopecia and sclcrodactyly with trophic lesions (fig. 2). There were no signs of muscular weakness, no neurological signs, nor alterations upon physical exploration other than signs of basal crepita tion in both lungs. Blood pressure was 100/60. The analytical findings were as follows: erythrocyte sedimentation rate 67. polyclonal hyper gammaglobulinemia. antinuclear antibodies 1/160 (mottled pattern). anti-DNA. anti-RNP antibodies, cryoglobulins, complement, anti smooth muscle antibodies, renal and hepatic function and other anal yses were normal. Lymphocyte populations were normal. HLA: A2 A2a. B12. DR7. The electrocardiogram was normal. The csophagoduodcnal study revealed a decrease in esophagic peristalsis. Arterial gasometry was normal. Spirometry showed a moderate restrictive dis turbance. The tests for the presence of Mycobacteria and culture in Ldwenstein-Jensen medium were negative. The chest X-ray disclosed calcified hilar lymph nodes, with a predominantly basal interstitial pat tern (fig. 3). Gammagraphy with " Ga disclosed a deposition in the posterior fields. Skin biopsy pointed to hyalinization, a thickening and homogenization of the collagen with marked atrophy of the dermal appendages, compatible with systemic scleroderma.
Discussion
Fig. 1. Calcified hilar lymph nodes. Interstitial pattern. Fig. 2. Sclerodactyly with trophic lesions.
99
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The term scleroderma includes a heterogeneous group of processes that exhibit cutaneous induration as a common denominator. Among their clinical aspects are PSS, the localized forms of scleroderma, systemic scleroderma and scleroderma-like diseases due to challenge by chemicals, eosinophilic fascitis and pseudosclerodermas. The prev alence of PSS in white males has been estimated at between 0.3 and 0.5/1 ()().()()(). Women arc affected at a rate some 3-6 times higher [2|. Like other diseases of the connective tis sues. genetic, environmental, toxic and infective factors
Table 1. Inducing factors for PSS and scicrodcrma-likc diseases
Silica Vinyl chloride Aromatic hydrocarbons Aliphatic hydrocarbons Epoxy resins: bis|4-amino-3-mcthylcyclohexyl]mcthanc Paraffin, silicone Bleomycin, pentazocine, penicillamine Aniline /.-Tryptophan
S i0 2
Skin
Vessels
Lung
IL-1
T-Helper cell
stimulation Skin Lung -«------Vessels MAF macrophages macrophages macrophages IL-1
1
IL-1
IL-1
1
1
B cell stimulation
Fibroblasts Increased collagen production
Scleroderma
Vascular occlusion
Silicosis Lung fibrosis
Immune phenomena
Fig. 4. Mechanism of action of silica; modified from Haustcin ct al. (5). IL-1 = Interleukin I; MAF = macrophage-activating factor.
100
Yäricz Diaz/Moran/Unamuno/Armijo
Trichloroethylene-Induced PSS
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Fig. 3. C alcified hilar lymph nodes. Basal interstitial pattern.
have been implicated in itsetiopathogenesis. Different sub stances able to induce systemic scleroderma and scleroderma-like changes have been described (table 1). With the exception of silica, which produces systemic scleroderma identical to the idiopathic forms, the rest produce sclero derma-like diseases that arc occasionally reversible when exposure is interrupted. Since the original description by Bramwcll 11]. silica has been the substance most related with these processes. Cowie [3] studied the incidence of PSS in black South Afri can males, finding 8.2/100.000 among miners and 0.3/ 100.000 among nonminers. In 1982. in a study carried out in East Germany, it was found that 77% of all males with PSS had been exposed to silica dust and that half of these had associated pulmonary silicosis [4|. It has been calcu lated [5] that the likelihood of developing PSS in male patients older than 40 with silicosis is approximately 190 times that found for males without silicosis and some 50 times higher in those exposed to silica dust than the male population not exposed. In contrast with this. Ructtner [6], in Switzerland, found 4 cases of PSS in 2.000 patients with silicosis and none in 650 autopsies of silicotic patients. Since 1974 in South Africa and 1978 in Germany these systemic sclerodermas have been recognized as occupa tional diseases without it being necessary for the patient to have associated pulmonary silicosis simultaneously. In some cases silicosis developed first, as in the case of our first patient, in others the skin disease developed first anti then pulmonary silicosis, and in others both diseases appeared simultaneously [7]. Although with a lower frequency than in miners. PSS has also been described in other professional workers exposed to silica dust such as in sand blasting, glass and ceramics workers, quarry workers, sculptors and den tal technicians [8], The mechanism of action of silica is summarized in figure 4. Crystals of silica of less than I urn arc phagocytosed by macrophages and arc transported to the regional
Table 2. Vinyl chloride [CH, = CHCI| disease
Acro-osteolysis Raynaud's phenomenon Fibrotic skin Fibrosis and angiosarcoma of the liver Pulmonary fibrosis Paresthesias Esophageal disturbances Thrombocytopenia Splenomegaly
bons, trichloroethylene and perchloroethylene are widely used as solvents, cleaners and adhesive agents. They are volatile substances, the most volatile being trichloroeth ylene. which was formerly used as an anesthetic. Apart from being inhaled they also enter the skin, causing irrita tive dermatitis. These chlorinated hydrocarbons give rise to disorders similar to the disease caused by vinyl chloride (table 2). Additionally, reports have been made of psychic altera tions. liver toxicity, renal and cardiac affectation, neuropa thy, cosinophilia, aplasic anemia, facial flushing and intol erance to alcohol and fats. Fundt-Hansen and Isager [13] described 2 patients employed in the cleaning of metals and high tension cables who had scleroderma-like diseases and who were exposed to aliphatic hydrocarbons. The same year Saihan et al. [14] published the case of a patient, a mechanic with prolonged exposure to trichloroethylene, who had scleroderma, a malabsorption syndrome. Raynaud's phenomenon, impotency. gynecomastia, pigmentation, lymphadenopathv and peripheral neuropathy. Generalized morphea due to expo sure to trichloroethylene in laundry workers, carpenters, laboratory personnel and painters has been reported 115]. The epoxy resins [16] and the toxic-oil syndrome have also been related to generalized morphea. The mechanism of sclerosis induced by aliphatic hydro carbons is not known. It is interesting that, like trichloro ethylene and perchloroethylene, vinyl chloride is also an aliphatic hydrocarbon. Unlike these substances, the aro matic hydrocarbons (benzene, gasoline, xylene) induce scleroderma-like diseases limited to the zones of contact and do not cause systemic alterations. Our second patient referred to episodes of sleepiness after exposure to trichlo roethylene, but did not display other alterations reported in patients exposed to this compound. It is likely that many symptoms, as has been reported for neuropathy [14], are due to contaminants.
101
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lymph nodes. Since silica is a chemically inert but toxic sub stance for macrophages, the latter attribute depending on the dose, when the macrophage dies the silica is released and is phagocytosed again, thus constituting a permanent stimulus for fibroblasts, which increase their production of collagen, leading to cutaneous sclerosis, vascular occlusion and pulmonary fibrosis. Some studies [5, 9] on patients with PSS and silicosis have shown that there arc no differences with idiopathic PSS from the clinical, immunological and serological points of view, as in the present cases. With only exposure to silica Rustin et al. [9] found 22 miners without either PSS or sili cosis and with a mean of 5 years of exposure; these were antinuclear antibodies - positive in 3 cases, and in 9 of them there were increased levels of factor VIII R Ag as a marker of endothelial damage. These authors concluded that the formation of immune complexes, antinuclear antibodies and damage to endothelial cells occur following exposure to silica. Exposure to silica dust has been related to ultrastructural alterations of the endothelium resembling those found in PSS. Fibrosis of the intima of small arteries was reported by Fleischmajer et al. [10]. Apart from PSS and silicosis, exposure to silica has been related to rheumatoid arthritis, glomerulonephritis, tubular-interstitial nephropa thy and bronchopulmonary carcinoma. Apart from the lung, nodes of silica arc also found in the spleen, bone marrow and liver [6]. The hepatic calcification observed in our first patient probably corresponded to cal cified silicotic nodules. More recently, cases of PSS have appeared [11, 12] years after breast implant using paraffin and silicone. It appears that silicone is converted into silica which when phagocytosed by macrophages would follow the mech anism described in figure 4. Apart from PSS. different dis eases of the connective tissues have been associated with augmentation mammoplasty and. as in the case of the cases of PSS in miners induced by silica, it is not known which patients of those exposed to such procedures will develop the diseases. After withdrawal of the prosthesis the disease may remit [12], and hence it is crucial to evaluate this ante cedent, which is not usually mentioned in the interview with the women who have undergone this kind of mammo plasty. There is therefore a variable proportion of persons exposed to silica that develop PSS, and although it has been suggested that the intensity of exposure would be more important than its duration, a complex, as yet not under stood, interaction among environmental factors and the host seems to be involved. The second of our patients was exposed to trichloro ethylene over a period of 7 years. The aliphatic hydrocar-
In conclusion, we believe that consideration of the occu pation of a patient and detailed research into the sub stances handled by a patient presenting with a sclerodermalike disorder will eventually lead to the knowledge of new agents able to induce these processes. Some cases of sys temic- scleroderma will not continue to be called idiopathic
and it will be possible to avoid the exposure of the patients to these products and to gain further insight into the étio pathogénie mechanisms of the disease. It will also be possi ble to develop therapeutic strategies for a disease that cur rently cannot be treated efficiently.
References
102
7 Haustein UF. Ziegler V: Environmentally induced systemic sclerosis-like disorders. Int J Dermatol 1985:24:147-151. 8 Zschunke E. Ziegler V. Haustein UF: Occupa tionally induced connective tissue disorders: in Adams RM (ed): Occupational Skin Dis ease, cd 2. Philadelphia. Saunders. 1990. pp 172-183. 9 Rustin MHA. Bull HA. Ziegler V. Mehlhorn J. Haustein U-F. Maddison PJ. James J. Dowd PM: Silica-associated systemic sclerosis is clin ically. serologically and immunologically indis tinguishable from idiopathic systemic sclerosis. Br J Dermatol 1990:123:725-734. 10 Flcischmajer R. Pcrlish IS Duncan M: Sclero derma; a model for fibrosis. Arch Dermatol 1983:119:957-962. 11 Spiera H: Scleroderma after silicone augmen tation mammoplasty. JAMA 1988:260: 236-238. 12 Sahn EE. Garen PD. Silver RM. Maize JC: Scleroderma following augmentation mammo plasty. Arch Dermatol 1990:126:1198-1202.
Yáñez Díaz/Morán/Unamuno/Armijo
13 Fundt-Hansen 11. Isager H: Scleroderma after occupational exposure to trichlorethylcnc and trichlorethane. Acta Derm Vencrcol (Stockh) 1987:67:263-264. 14 Saihan EM. Burton JL. Heaton KW: A new syndrome with pigmentation, scleroderma, gynaecoinastia. Raynaud's phenomenon and peripheral neuropathy. Br J Dermatol 1978; 99:437-440. 15 Yamakage A. Ishikawa II: Generalized mor phea-like scleroderma occurring in people exposed to organic solvents. Dermatológica 1982:165:186-193. 16 Yamakage A. Ishikawa H. Saito Y. Ilattori A: Occupational scleroderma-like disorder occur ring in men engaged in the polymerization of epoxy resin. Dermatológica 1980:161:33-44.
Trichloroethylene-Induced PSS
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1 Bramwell B: Diffuse scleroderma: Its fre quency. its occurrence in stone-masons, its treatment by fibrinolysin injections, elevations of temperature due to fibrinolysin. Edinb .1 Med 1914:12:387-401. 2 Mcdsger TA. Masi AT: Epidemiology of sys temic sclerosis. Ann Intern Med 1971:74: 714-721. 3 Cowie RL: Silica dust-exposed mine workers with scleroderma (systemic sclerosis). Chest 1987:92:260-262. 4 Ziegler V. Pampel W. Zschunke E. et al: Kri stalliner Quarz (eine) Ursache der progres siven Sklerodermie? (abstract). Dermatol Monatsschr 1982:168:398-401. 5 Haustein UF. Ziegler V. Herrmann K. Mehl horn J. Schmidt C: Silica-induced sclero derma. J Am Acad Dermatol 1990:22: 444-448. 6 Silicosis and Silicate Disease Committee: Dis eases associated with exposure to silica and nonfibrous silicate minerals. Arch Pathol Lab Med 1988:112:673-720.
Department of Dermatology, General University Hospital. Faculty of Medicine. Salamanca. Spain
Key Words Silica Trichloroethylene Induced progressive systemic sclerosis Induced systemic scleroderma
Silica and TrichloroethyleneInduced Progressive Systemic Sclerosis
Abstract Several environmental factors and chemicals have been described as being able to induce systemic scleroderma and scleroderma-like diseases. The present work reports 2 male patients with progressive systemic sclerosis and pulmonary silicosis. Both patients had occupational histories of exposure to silica and one of them of handling trichloroethylene as a degreasing agent. The clinical and analytical findings could not be distinguished from those present in idiopathic systemic scleroderma with the exception of interstitial images with calcified hilar lymph nodes in the chest X-ray suggestive of pulmonary silicosis.
Introduction Among the pathologies of the connective tissues where occupational hazards play an important role, progressive systemic sclerosis (PSS) occupies one of the first places. Pulmonary silicosis has been described in systemic lupus erythematosus, although currently it remains unclear whether this is a coincidence or whether there is any patho genic connection. The association of certain occupations with PSS has been known for some time. In 1914, in a series of 9 patients with PSS. Bramwell [ 1] found 5 stone masons; he wrote: ‘in the last three cases I have correctly suggested the occupation of the patient as soon as I saw and felt the hands before I asked him a single question’. Since then, and parallel to industrial development, numerous chemicals and products responsible for scleroderma-like diseases have appeared, sometimes identical to idiopathic systemic scleroderma. Recognition of these would help to prevent this disease by avoiding exposure of workers to these agents, although it might be very difficult to determine the true cause of such conditions because several different sub
Received: A p ril S. 1991 Accepted: Julv 9. 1991
stances may be involved. It is likely that as new products appear and are described, some cases of systemic scler oderma considered as being idiopathic may be withdrawn from this category of diseases.
Case Reports Case I. A 65-ycar-old man had been working in a lead mine for more than 10 years. He had been diagnosed as suffering from pulmo nary silicosis 7 years previously. In the 5 years prior to presenting he had displayed Raynaud's phenomenon, dysphagia for solids, arthromyalgias and dyspnea upon medium effort. He displayed cutaneous sclerosis on the trunk, malar telangiectasia, sclerodactyly and trophic lesions on his hands. There was an erythematous-edematous zone on his left hand with a small ulcer, exuding a whitish substance. Upon auscultation, basal crepitations were observed in the medial field of both lungs. Blood pressure findings and the rest of the exploration were normal. The following analytical results were of interest: eryth rocyte sedimentation rate 52; 13.200 leukocytes (60% segmented) with normal erythrocyte and platelet counts; urea 149 mg/dl: creati nine 1.56 mg/dl: creatinine clearance 68 ml/min: alkaline phosphatase 463 mg/dl: gammaglutamyltrar.speptidase 209 mg/dl. The rest of the
S. Yanez Diaz M unoz T o rrc ro . 14—IS. 5 °C E-37007 Salamanca (Spain)
© 1992 Karger A G . Basel 1018-8665/92/1842 4 K)98 $ 2.75/0
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 8/24/2018 9:42:15 AM
S. Yanez Diaz M. Moran P. Unamuno M. Armijo
analytical findings, including calcium, phosphorus, creatine phosphokinasc, and immunoglobulin quantification, were normal. Latex, complement and cryoglobulins were normal or negative. Antinuclear antibodies 1/640 (mottled pattern). anti-DNA, and anti-RNP antibod ies were negative. In the study of lymphocyte populations a decrease was observed in the hclpcr/suppressor ratio (1.09). HLA determina tion: Alt). B12, B17. DR5. Serologies for the determination of syphi lis. hepatitis A. B. and C. Brucella and Rickettsias were negative. The tests for tuberculosis in sputum and cultures on Ldwcnstcin-Jenscn medium were negative No evaluable alterations were found in the electrocardiogram. Basal gasometry and post-effort findings were as follows: desaturation upon effort. Chest X-ray: calcified hilar lymph nodes and an interstitial pattern (fig. I). The X-ray findings of the patient's hands revealed calcinosis but with no bone alterations. The esophagogastroduodenal study revealed esophageal apcristaltism. Ultrasonography of the liver revealed hepatic calcifications suggestive of granulomatose hepatitis of probable silicotic origin. Skin biopsy pointed to a thickening of the dermal collagen compatible with PSS. Case 2. A 39-year-old male patient had been working in a company dedicated to the maintenance of central heating systems using trichlo roethylene as a degreasing agent and fiber glass as an insulator. The patient complained of recent dyspnea upon effort and Raynaud's phe nomenon that had been present for several years. The patient had sclerosis with diffuse cutaneous hyperpigmentation, areas of hypopig mentation. alopecia and sclcrodactyly with trophic lesions (fig. 2). There were no signs of muscular weakness, no neurological signs, nor alterations upon physical exploration other than signs of basal crepita tion in both lungs. Blood pressure was 100/60. The analytical findings were as follows: erythrocyte sedimentation rate 67. polyclonal hyper gammaglobulinemia. antinuclear antibodies 1/160 (mottled pattern). anti-DNA. anti-RNP antibodies, cryoglobulins, complement, anti smooth muscle antibodies, renal and hepatic function and other anal yses were normal. Lymphocyte populations were normal. HLA: A2 A2a. B12. DR7. The electrocardiogram was normal. The csophagoduodcnal study revealed a decrease in esophagic peristalsis. Arterial gasometry was normal. Spirometry showed a moderate restrictive dis turbance. The tests for the presence of Mycobacteria and culture in Ldwenstein-Jensen medium were negative. The chest X-ray disclosed calcified hilar lymph nodes, with a predominantly basal interstitial pat tern (fig. 3). Gammagraphy with " Ga disclosed a deposition in the posterior fields. Skin biopsy pointed to hyalinization, a thickening and homogenization of the collagen with marked atrophy of the dermal appendages, compatible with systemic scleroderma.
Discussion
Fig. 1. Calcified hilar lymph nodes. Interstitial pattern. Fig. 2. Sclerodactyly with trophic lesions.
99
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The term scleroderma includes a heterogeneous group of processes that exhibit cutaneous induration as a common denominator. Among their clinical aspects are PSS, the localized forms of scleroderma, systemic scleroderma and scleroderma-like diseases due to challenge by chemicals, eosinophilic fascitis and pseudosclerodermas. The prev alence of PSS in white males has been estimated at between 0.3 and 0.5/1 ()().()()(). Women arc affected at a rate some 3-6 times higher [2|. Like other diseases of the connective tis sues. genetic, environmental, toxic and infective factors
Table 1. Inducing factors for PSS and scicrodcrma-likc diseases
Silica Vinyl chloride Aromatic hydrocarbons Aliphatic hydrocarbons Epoxy resins: bis|4-amino-3-mcthylcyclohexyl]mcthanc Paraffin, silicone Bleomycin, pentazocine, penicillamine Aniline /.-Tryptophan
S i0 2
Skin
Vessels
Lung
IL-1
T-Helper cell
stimulation Skin Lung -«------Vessels MAF macrophages macrophages macrophages IL-1
1
IL-1
IL-1
1
1
B cell stimulation
Fibroblasts Increased collagen production
Scleroderma
Vascular occlusion
Silicosis Lung fibrosis
Immune phenomena
Fig. 4. Mechanism of action of silica; modified from Haustcin ct al. (5). IL-1 = Interleukin I; MAF = macrophage-activating factor.
100
Yäricz Diaz/Moran/Unamuno/Armijo
Trichloroethylene-Induced PSS
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Fig. 3. C alcified hilar lymph nodes. Basal interstitial pattern.
have been implicated in itsetiopathogenesis. Different sub stances able to induce systemic scleroderma and scleroderma-like changes have been described (table 1). With the exception of silica, which produces systemic scleroderma identical to the idiopathic forms, the rest produce sclero derma-like diseases that arc occasionally reversible when exposure is interrupted. Since the original description by Bramwcll 11]. silica has been the substance most related with these processes. Cowie [3] studied the incidence of PSS in black South Afri can males, finding 8.2/100.000 among miners and 0.3/ 100.000 among nonminers. In 1982. in a study carried out in East Germany, it was found that 77% of all males with PSS had been exposed to silica dust and that half of these had associated pulmonary silicosis [4|. It has been calcu lated [5] that the likelihood of developing PSS in male patients older than 40 with silicosis is approximately 190 times that found for males without silicosis and some 50 times higher in those exposed to silica dust than the male population not exposed. In contrast with this. Ructtner [6], in Switzerland, found 4 cases of PSS in 2.000 patients with silicosis and none in 650 autopsies of silicotic patients. Since 1974 in South Africa and 1978 in Germany these systemic sclerodermas have been recognized as occupa tional diseases without it being necessary for the patient to have associated pulmonary silicosis simultaneously. In some cases silicosis developed first, as in the case of our first patient, in others the skin disease developed first anti then pulmonary silicosis, and in others both diseases appeared simultaneously [7]. Although with a lower frequency than in miners. PSS has also been described in other professional workers exposed to silica dust such as in sand blasting, glass and ceramics workers, quarry workers, sculptors and den tal technicians [8], The mechanism of action of silica is summarized in figure 4. Crystals of silica of less than I urn arc phagocytosed by macrophages and arc transported to the regional
Table 2. Vinyl chloride [CH, = CHCI| disease
Acro-osteolysis Raynaud's phenomenon Fibrotic skin Fibrosis and angiosarcoma of the liver Pulmonary fibrosis Paresthesias Esophageal disturbances Thrombocytopenia Splenomegaly
bons, trichloroethylene and perchloroethylene are widely used as solvents, cleaners and adhesive agents. They are volatile substances, the most volatile being trichloroeth ylene. which was formerly used as an anesthetic. Apart from being inhaled they also enter the skin, causing irrita tive dermatitis. These chlorinated hydrocarbons give rise to disorders similar to the disease caused by vinyl chloride (table 2). Additionally, reports have been made of psychic altera tions. liver toxicity, renal and cardiac affectation, neuropa thy, cosinophilia, aplasic anemia, facial flushing and intol erance to alcohol and fats. Fundt-Hansen and Isager [13] described 2 patients employed in the cleaning of metals and high tension cables who had scleroderma-like diseases and who were exposed to aliphatic hydrocarbons. The same year Saihan et al. [14] published the case of a patient, a mechanic with prolonged exposure to trichloroethylene, who had scleroderma, a malabsorption syndrome. Raynaud's phenomenon, impotency. gynecomastia, pigmentation, lymphadenopathv and peripheral neuropathy. Generalized morphea due to expo sure to trichloroethylene in laundry workers, carpenters, laboratory personnel and painters has been reported 115]. The epoxy resins [16] and the toxic-oil syndrome have also been related to generalized morphea. The mechanism of sclerosis induced by aliphatic hydro carbons is not known. It is interesting that, like trichloro ethylene and perchloroethylene, vinyl chloride is also an aliphatic hydrocarbon. Unlike these substances, the aro matic hydrocarbons (benzene, gasoline, xylene) induce scleroderma-like diseases limited to the zones of contact and do not cause systemic alterations. Our second patient referred to episodes of sleepiness after exposure to trichlo roethylene, but did not display other alterations reported in patients exposed to this compound. It is likely that many symptoms, as has been reported for neuropathy [14], are due to contaminants.
101
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lymph nodes. Since silica is a chemically inert but toxic sub stance for macrophages, the latter attribute depending on the dose, when the macrophage dies the silica is released and is phagocytosed again, thus constituting a permanent stimulus for fibroblasts, which increase their production of collagen, leading to cutaneous sclerosis, vascular occlusion and pulmonary fibrosis. Some studies [5, 9] on patients with PSS and silicosis have shown that there arc no differences with idiopathic PSS from the clinical, immunological and serological points of view, as in the present cases. With only exposure to silica Rustin et al. [9] found 22 miners without either PSS or sili cosis and with a mean of 5 years of exposure; these were antinuclear antibodies - positive in 3 cases, and in 9 of them there were increased levels of factor VIII R Ag as a marker of endothelial damage. These authors concluded that the formation of immune complexes, antinuclear antibodies and damage to endothelial cells occur following exposure to silica. Exposure to silica dust has been related to ultrastructural alterations of the endothelium resembling those found in PSS. Fibrosis of the intima of small arteries was reported by Fleischmajer et al. [10]. Apart from PSS and silicosis, exposure to silica has been related to rheumatoid arthritis, glomerulonephritis, tubular-interstitial nephropa thy and bronchopulmonary carcinoma. Apart from the lung, nodes of silica arc also found in the spleen, bone marrow and liver [6]. The hepatic calcification observed in our first patient probably corresponded to cal cified silicotic nodules. More recently, cases of PSS have appeared [11, 12] years after breast implant using paraffin and silicone. It appears that silicone is converted into silica which when phagocytosed by macrophages would follow the mech anism described in figure 4. Apart from PSS. different dis eases of the connective tissues have been associated with augmentation mammoplasty and. as in the case of the cases of PSS in miners induced by silica, it is not known which patients of those exposed to such procedures will develop the diseases. After withdrawal of the prosthesis the disease may remit [12], and hence it is crucial to evaluate this ante cedent, which is not usually mentioned in the interview with the women who have undergone this kind of mammo plasty. There is therefore a variable proportion of persons exposed to silica that develop PSS, and although it has been suggested that the intensity of exposure would be more important than its duration, a complex, as yet not under stood, interaction among environmental factors and the host seems to be involved. The second of our patients was exposed to trichloro ethylene over a period of 7 years. The aliphatic hydrocar-
In conclusion, we believe that consideration of the occu pation of a patient and detailed research into the sub stances handled by a patient presenting with a sclerodermalike disorder will eventually lead to the knowledge of new agents able to induce these processes. Some cases of sys temic- scleroderma will not continue to be called idiopathic
and it will be possible to avoid the exposure of the patients to these products and to gain further insight into the étio pathogénie mechanisms of the disease. It will also be possi ble to develop therapeutic strategies for a disease that cur rently cannot be treated efficiently.
References
102
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