Document dQRKM94k7D5MLwnXkqJkxD8N6

Unicoi and Exptrimental Dermatology (1977) 2, 17. Original article* A connective tissue disorder similar to vinyl chloride disease in a patient exposed to perchlorethylene G. P. SPARROW Department of Dermatology, Guy's Hospital, London SEi 9RT Accepted for publication 5 July 1976 Summary atient is reported who had a connective tissue type of disease clinically similar to vinyl Heride disease. It is suggested that this may have been caused by abnormal sensitivity to rchlorethylcne to which he was exposed in his occupation. Case report* A 19-year-old Caucasian male complained of constant coldness of the hands and feet for 3 months. On exposure to low temperature, his fingers and distal parts of his feet would develop white and blue discolouration, but would not become red on rewanning. Soon after wards it involved all his fingers, the distal half of the palms, the feet, knees, elbows and even the tongue on very cold days. For the same period of time he had noticed weakness, stiffness and aching of the muscles of his arms, shoulders and legs, especially in the morning. Weights which he had previously lifted with ease seemed too heavy, and he could not stand from a squatting position. His fingers had become swollen and he could no longer grip tightly. He also developed impotence. He had had alopecia areata intermittently since the age of 5 years, and at 14 developed alopecia totalis which persisted for 5 years before almost complete regrowth took place spon taneously. He had never been jaundiced. His paternal grandfather had symptoms suggestive of Raynaud's phenomenon, and his paternal uncle had had alopecia as a child. Reprint requests to: Dr G.P. Sparrow, Department of Dermatology, St Helier Hospital, Carshalton, SurTey SM5 iAA. Case presented at the St John's Hospital Dermatological Society Clinical Meeting on 6 December 1975- 18 G. P. Sparrow I When he left school aged 15 years, he worked in a dry cleaning business. Most of the tir I was spent in pressing clothes, but once a week he assisted in cleaning the drums which h contained solvent (perchlorethylene). During this activity, which lasted a few minutes, , described heavy exposure to the fumes, which often left him lightheaded, dizzy and ve sleepy after work. Others employed at work had experienced symptoms like this. The wo premises were examined by the factory inspectors, who found on a random visit that ti ambient levels of perchlorethylene were within safe limits. However measurements we not made during or shortly after drum cleaning. Other workers there were not examine. On examination his hands and feet were markedly cold with variable mottled pallor ar cyanosis. The lower legs and arms were involved to a lesser extent, and transient pallor of or side of his tongue was observed on exposure to cool external temperature (ioC). The ski of the hands was diffusely swollen and thickened, but changes suggestive of systemic sderos such as tapering of the fingers, telangiectasia and loss of finger pulps and skin appendag :v ; s were absent. Multiple nail fold haemorrhages were prominent. His scalp hair was normal, bt '7-r- there was some patchy hair loss on the limbs. There was an area of depigmentation on th '' "! scrotum. Peripheral pulses were normal. No other abnormality was detected in the cardio vascular system, or in the respiratory, gastro-intestinal, genito-urinary or central nervou ; r system. There was considerable muscular weakness, with some wasting and tendemes particularly of the proximal limb muscles. Inability to flex or extend the fingers fully wa combined with some loss of power in the grip. Muscle tone and co-ordination were normal as were the tendon reflexes, and there was no fasciculation. Investigations The chief abnormalities were found in the patient's immune system, hepatic and musculo skeletal functions. Antinuclear factor was strongly positive on several occasions, titre 1 in to, 240, with s speckled pattern of fluorescence. Plasma protein electrophoresis was normal, but immuno globulin levels showed a borderline high IgG at 1700 mg/ml (normal range 800-1700), absent IgA (140-400) and normal IgM at 120 mg/ml (50-200). No LE cells were found and no cold agglutinins, cryoglobulins, smooth muscle or antimitochondrial antibodies could be demon strated. Circulating immune complexes were also not found. Levels of C3, C4 and DNA binding were normal. Although serum bilirubin and alkaline phosphatase were normal, the serum gammaglutamyl transpeptidase level was raised at 751.U./litre (normal level < 54); bromsulphthalein retention was increased being 21% at 25 and 45 min; the prothrombin time was 16 secs (control 12) and the kaolin cephalin time 41 s (control 34). This was taken to be indicative of a mild hepatitis. Liver biopsy was performed at the same time but appeared normal histo logically. Electromyography showed evidence of a myopathy. Serum creatine phosphokiaase levels were increased, ranging from 117 to 162 units/litre (normal <90). Aluscle biopsyshowed a lymphocytic infiltrate between the muscle bundles. The urinary hydroxyproline excretion was raised at 55 mmol/mol creatinine (normal <39) suggesting a possible increase in collagen turnover. A right brachial arteriogram showed occlusion of the palmar digital Connective tissue disorder similar to vinyl chloride disease 19 artery adjacent to the 2nd metacarpal. Histological examination of a skin biopsy taken from an affected finger showed some blood vessels to have mildly oedematous walls and to be surrounded by a sparse round cell infiltrate. There were no changes of scleroderma present. Other normal findings included: Blood: haemoglobin, white cell differential, platelet count, ESR (5-10) urea, electrolytes, calcium, phosphate, sugar, uric acid, Coombs' test, latex test, TPHA, RPR, fibrin degradation products. Urine: Urinalysis, creatinine clearance. X-rays: Chest, abdomen, hands, feet, sacroiliac joints, barium swallow. Treatment and progress A trial of tolazoline and later phenoxybenzamine, did not lead to any clinical improvement, nor did a period of 6 weeks off work. Prednisolone 20 mg daily led to a rapid increase in well being, disappearance of myalgia, improvement in muscle power and a decrease in swelling of the fingers. The serum creatine phosphokinase and liver function tests returned to normal. There was, however, no improvement in the Raynaud's phenomenon. 'iscussion s young man had an 18-month history of polymyopathy, severe acrocyanosis and a mild hepatic disorder. It would appear that his clinical features fall within the broad category of collagen disorders, but do not conform exactly with any of the classical patterns; in particular it was unlike systemic sclerosis in many respects. The features were similar to those of`mixed connective tissue disease', (Sharp et al., 1972) and the high titre of antinuclear antibody show ing a speckled pattern was in favour of this. However, in this condition joint symptoms are prominent, and there are typical sclerodermatous skin changes. Raynaud's phenomenon is usually not as severe as in this case and lymphadenopathy and oesophageal involvement are common. Standard biochemical tests demonstrated an abnormality of liver function. Chronic active hepatitis was considered as a cause, but was thought to be unlikely in view of the normal liver biopsy. Perchlorethylene may have been responsible as it is known to be hcpatotoxic (Von Oettingen, 1964; Meckler & Phelps, 1966). A number of workers engaged in the polymerization of vinyl chloride to polyvinyl chloride (PVC) have been observ ed to develop a syndrome, the main features of which are Raynaud's phenomenon, skin changes and osteolytic lesions chiefly in the fingers. For some years it was called `occupational aero-osteolysis', but recently this term has been abandoned in favour of `vinyl chloride disease' as it has been shown to be a multisystem disorder in which the bones are not necessarily affected (Lange et al., 1974). Involvement of the liver, lungs and muscles has been reported and there is also evidence of an immune disturbance. Angiosarcoma of the liver, which occurs in vinyl chloride workers, does not affect this particular group of patients. Hitherto this syndrome has not been found in workers in other industries. In this condition changes in the skin of the hands may be striking, with diffuse thickening id an inability to flex or extend the fingers fully, combined with severe, but variable acro^nosis. Dermal nodules have been described, but true sclerodermatous changes are absent. ncii 20 G. P. Sparrow Histological examination of the skin may show thickening of collagen bundles and di organization of elastic fibres, or merely a perivascular lymphocytic infiltrate in early cas< (Walker, 1976a). Lange's (1974) scries of patients bad thrombocytopaenia, splenomegal abnormal liver function with periportal fibrosis and pulmonary insufficiency. Osteolytic lesioi of the terminal phalanges of the hands and sometimes of the feet and pelvic bones wet previously thought to be an essential feature of the syndrome, but in Walker's series of 5 patients, only two had this change (Walker, 1976b). Her patients also had undue fatigue, lim pains, dyspnoea and impotence. Brachial arteriograms showed narrowing of digital vessel: cryoproteins were common, and .creatine phosphokinase was sometimes raised (Walke: 1975, 1976a). Further studies on the same group of patients have led to the suggestion tht vinyl chloride may alter IgG molecules, allowing them to become antigenic with subsequer. antibody production and complex formation (Milford Ward et al., 1976). Vinyl chloride disease is almost entirely restricted to those who clean the reactors ii which polymerization takes place, but the incidence is low, for example, only 3% in the stud; of Wilson et al. (1967). This may be partly a dosage effect, but there is also some evidence 0 personal idiosyncrasy. Although over 200 different compounds including perchlorethylent (Moulin et al., 1974) may be used or produced during the course of FVC formation, it i' now thought that vinyl chloride itself is the actiological agent. However, it is impossible tc completely exonerate other chemicals and Dinman et al. (1971) suggested that the disease might be caused by several agents, each producing a component of the clinical picture. The most striking similarity between our patient and those with vinyl chloride disease was the severe acrocyanosis and changes in the skin ofthe hands. Polymyopathy, mild hepatitis and impotence were also common features, as was the immunological disturbance. Anti nuclear antibody has sometimes been reported as positive in vinyl chloride disease, although not in such a high dtre. Arteriograms in both cases have shown narrowing of digital vessels. Among clinical differences were the lack of osteolytic lesions, the presence of multiple nail fold haemorrhages and the absence of circulating cryoproteins. Our patient had never been exposed to vinyl chloride, but the chemical likeness between vinyl chloride (CH2 CHC1) and perchlorethylene (CC12 = CC12) suggests that the latter may have some of the actions of the former. Although vinyl chloride is a very reactive chemical and perchlorethylene a relatively inactive one, these and other small chlorinated hydrocarbons have certain toxic effects in common. They are anaesthetics and are hepatotoxic (Rowe et al., 1952; Browning, 1965). Experimentally, they cause damage to peripheral nerves (Rumsby & Finean, 1966). Perchlorethylene is regarded as relatively free from these toxic actions, but chronic exposure has been shown to damage the liver and nervous system. Colcr & Rossmiller (1953) found definite evidence of abnormal liver function in 4 of 7 workers in a degreasing plant using perchlorethylene. The Threshold Limit Value which indicates acceptable con centration has been reduced from 200 to 100 parts/106 in Great Britain, and in other countries is as low as 37 parts/106 (Czechoslovakia) and 7 parts/io6 (USSR). (American Conference of Industrial Hygienists, 1974). One of Lob's (1957) nine cases of chronic perchlorethylene poisoning had certain clinical features similar to our own. This patient had fatigue, myalgia, variable cyanosis of the finger tips (Raynaud's phenomenon) and biochemical evidence of hepatic dysfunction. Another Connective tissue disorder similar to vinyl chloride disease 21 similar case was that of Rein] (1957). This was a young woman who had been exposed to trichlorethylene for 2 years, when she developed Raynaud's phenomenon and later sclero dermatous changes on the skin of the face and limbs with inability to extend the fingers. The paucity of reports of cases similar to our own does not exclude our patient being abnorm ally sensitive to perchlorethylene, for example through an idiosyncrasy in biochemical handling or through a pre-existing abnormality of his immune system. The latter is suggested by his long-standing alopecia areata and vitiligo and absent IgA, which may be associated with auto immune disease (Hobbs, 1968). Although halogenated hydrocarbons have not been reported as causing a lupus erythematosus-like syndrome, this can give a picture very like that of our case, with myalgia, hepatitis, Raynaud's phenomenon and antinuclear antibodies (often in high titre). In procainamide-induced LE and in vinyl chloride disease it has been suggested that the chemicals in question combine with body proteins to render them antigenic (Blomgren, Condemi & Vaughan, 1972; Milford Ward et al, 1976). We suggest that perchlorethylene may have caused or exacerbated our patient's disease, possibly by an alteration of his immune system. Acknowledgments My thanks to Dr W.N. Mann for permission to study the patient, and Dr A.G. Thomson of the Employment Medical Advisory Service for his help with industrial aspects of the case. Also to the Central Toxicology Laboratory, Imperial Chemicals Industries Ltd, who gave assistance with the toxicology and to Dr R.S. Wells and Dr Anne Walker for their advice d encouragement. Refer nces American Conference of Governmental Industrial Hygienists Documentation of Threshold limit Values for Substances in the Workroom Air. 1974 Edn. Blomgren, S.E., Condemi, J.J., Vaughan, J.J. (1972) Procainamide--induced lupus erythematosus. American Journal of Medicine, 52, 338-348. Browning, E. (1965) Toxicity and Metabolism of Industrial Solvents, pp. 213-219. Elsevier, Amsterdam. Coler, H.R. & Rossmjller, H.R. (1953) Tetrachlorethylene exposure in a small industry. Archives of Industrial Hygiene and Occupational Medicine, 8, 227-233. Dinman, B.D., Cook, W.A., Whitehouse, W.M., Magnuson, H.J. & Ditcheck.T. (1971) Occupational acroosteolysis. x. An epidemiological study. Archives of Environmental Health, 32, 61-73. Hobbs, J.R. (1968) Immune balance in dysgammaglobulinaemia. Type IV. Lancet, i, no-114. Lange, C.E., Juhe, S,, Stein, G. fit Veltnam, G. (1974) Vinyl chloride disease. International Archives of Occupational Health, 3a, 1-32. Lob, M. (1957) Les dangers du perchlorethylene. Archivfur Gewerbepathologie und Gesierbehygiene, 16, 45-52Meckler, L.C. & Phelps, D.K. (1966) Liver disease secondary to tetrachlorethylene exposure. Journal of the American Medical Association, 197, 662-663. Milford Ward, A., Udnoon, S., Watkins, J,, Walker, A.E. & Darke, C.S. (1976) Immunological mechanisms in the pathogenesis of vinyl chloride disease, British Medical Journal, i, 936-938. Moulin, G., Rty, J. Pailard, P., Vouillon, G. & Guttin, G. (1974) Aspects sclcrodermiques de l'acro-osteolyse professionelle. Annales de Dermatologic et de Syphiligraphie, 101, 33-44. RfiNL, W. (1957) Scleroderma caused by trichlorethylene ? Bulletin of Hygiene, 34, 678-679. Rowe, V.K., McCollister, D.D., Spencer, H.C., Adams, E.M., Irish, D.D. (1952) Vapor toxic of tetrachlorethylene for laboratory animals and human subjects. Archives of Industrial Hygt and Occupational Medicine, 5, 566-579. Rumsby, M.G. & Finean, J.B. (1966) The action of organic solvents on the myelin sheath of peripht nerve tissue. III. Chlorinated hydrocarbons. Journal of Neurochemistry, 13, 1513-1515. Sharp, G.C., Irwin, J.S., Tan, E.M., Gould, R.G. & Holman, H.R. (1972) Mixed connective tis< disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody extractable nuclear antigen. American Journal of Medicine, 52, 148-159. Von Oetttngen, W.F. (1964) The Halogenated Hydrocarbons of Industrial and Toxicological Importan pp. 271-283. Elsevier, Amsterdam. Walker, A.E. (1975) A preliminary report of a vascular abnormality occurring in men engaged in t manufacture of polyvinyl chloride. British Journal of Dermatology, 93, Supplement 11, 22-23. Walker, A.E. (1976a) Clinical aspects of vinyl chloride disease: skin. Proceedings of the Royal Socu of Medicine, 69, 286-289. Walker, A.E. (1976b) Personal communication. Wilson, R.H., McCormick, W.E., Tatum, C.F. & Creech, J.L. (1967) Occupational acro-osteolys Journal of the American Medical Association, 201, 577-581.