Document 6wLb23jdabwLo2ne62O3kZXY3

r &S 109326 SI-K^ICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 ___Duplicate in all cards:--?' /?& 68 69 , 76 *j p G G 219 /6& year as-1961- Pile number [Sight justify [Numeric only] Author(s), as Last Name PS (No Punctuation) and coden for journal as JAKA preceeded -by. one blank space 1 Ai /\7 M/luJAfone. C.l `20:21 VL*&u 1 ' 1 EC. . 40 41 ! 1 1 Sub-Inc er: Code 60 61 62 [u 12 113 Title of P-enort; end vith space--hyphen-hyphehyspace. Follow vith Index Terrs, separated from each other with -coisaa-spaca. Avoid other punctuation* ' 12 !_ ( do'not abbreviate. 11iur V . (jLh * '"`iPO, / . f Uje( i*jCJT /o m */'fh . \* . 7"a fy o/fly I- C/ tort-'i d-p_. 61 v62 21TM 22 23 - 24 Source (Journal, Vol., Number, Pages,Bate) 12 ...........; ` ' ' Q-p C.Qv> <* ajc.**-^ **^.1 tap______ {Jof- J2 3C- f3~> 61 62, 31 /L8~ /37A 32 /. , * Brief Sunnary' 61 62 61 62 63 64 \I^l*- -l Reprinted from the Journal of the American Medical Association September 2Qf^iJf76j)7olume 236 Copyright 1976, American Medical Association R&S 109327 Capillary Abnormalities in Polyvinyl Chloride Production Workers Examination by In Vivo Microscopy Hildegard R. Maricq, MD; Maurice N. Johnson, MD; Charles L. Whetstone, MD; E. Carwile LeRoy, MD ' Examination by wlde-fleld capillary microscopy of the hands of 152 workers In vinyl chloride (VC) polymerization plants demonstrated scat tered, scleroderma-like mlcrovascular abnormalities In 21 workers and iso lated capillary abnormalities In 27, as compared with only three Isolated ab normalities in 50 manual workers not exposed to vinyl chloride. Thirteen of 17 VC workers with objective evidence of VC-associated abnormalities (an giosarcoma or fibrosis of liver, acroosteolysls, or scleroderma-like skin le sions) were observed to have mlcrovascular abnormalities. If prospective studies confirm the implications of this study, capillary mi croscopy may become a useful mass-screening procedure In the early de tection and prevention of VC-associated disease. (JAMA 236:1368-1371, 1976) INITIAL reports of human disease in which vinyl chloride (VC) has been implicated as pathogenetic were lim ited to descriptions of such peripheral changes as distal phalangeal resorp tion, ie, acroosteolysis (AOL).15 Re cently, a systemic effect of VC has been suggested by an unusual pat tern of hepatic portal, intralobular, and capsular fibrosis; angiosarcoma of the liver; and pulmonary functional abnormalities suggesting early pul monary fibrosis, all of which occur more frequently among workers em ployed in polyvinyl chloride produc tion plants than among the general population.*-10 Furthermore, animal From the Division o( Rheumatology and Im munology, Department of Medicine. Medical University of South Carolina, Charleston (Drs Maricq and LeRoy): The B. F. Goodrich Com pany. Akron. Ohio (Dr Johnson); and Continen tal Oil Company. Ponca City. Okla (Dr Whet stone). Reprint requests to Division of Rheumatology and Immunology, Department of Medicine. Med ical University of South Carolina. 80 Barre St. Charleston. SC 29401 (Dr Maricq). experiments have demonstrated that VC can produce a variety of tumors in rodents.11-12 There are several similarities be tween VC disease and scleroderma (systemic sclerosis): Raynaud phe nomenon is prominent among the symptoms associated with AOL3 5 0 013; localized scleroderma-like lesions have been reported in some patients with AOL513; and, in both VC-associ ated disease and scleroderma, smallblood-vessel lesions and interstitial fibrosis are thought to be important in pathogenesis.,',, l` In scleroderma, changes in small blood vessels of the skin have been observed in vivo by capillary micros copy.1516 Using the technique of widefield capillary microscopy, distinctive abnormal capillary patterns in the fingers of patients with Raynaud syn drome and scleroderma have been demonstrated.16 Furthermore, a posi tive correlation is noted between the severity of capillary pattern abnor malities and multisystem involve ment in these connective-tissue dis orders.17 The possibility that VCassociated disease might be charac terized by microvascular abnormal ities similar to those observed in scleroderma led to the present study of VC workers, using techniques of wide-field capillary microscopy. The specific questions of this study were the following: (1) Do symptomatic VC workers have finger-skin-capillary abnormalities? (2) Are the abnormal ities similar to or different from those seen in patients with idiopathic scleroderma and Raynaud syndrome? (3) Are microvascular abnormalities related to the type of VC-associated abnormality (peripheral vs systemic), especially liver abnormalities? (4) Are microvascular abnormalities related to the nature and duration of VC-exposure? (5) Are microvascular abnor malities found in a control group of manual workers not exposed to VC? SUBJECTS VC Workers Selected by Symptoms (n = 44).--The 44 subjects in this group gave a history of symptoms and signs possibly related to VC exposure. They were 31- to 57-year-old men (mean age, 42 years) who had worked in the polyvinyl chloride industry for 5 to 28 years (mean, 15 years). A history of past reactor-cleaning experience (ranging from 0.2 to 8 years; mean, 2.5 years) was present in 35 of 44 workers. Table 1 shows the com plaints and the pathologic findings in group 1. VC Workers Selected by Question- 1368 JAMA, Sept 20. 1976-Vol 236, No. 12 Capillary Abnormalities--Maricq et al / naire (n -108).-These subjects were selected on the basis of their answers to a" questionnaire used in the poly vinyl chloride production plant to de tect early AOL. All available subjects who had given one or more affirma tive answers to the questionnaire (Q + ) were examined, a total of 66 subjects. Seventy-one subjects were examined from a random selection of those who had given negative an swers to all questions (Q-). Data on 29 of the 137 subjects examined were excluded because of unreliable obser vations caused by skin' injuries or deep pigmentation, leaving 108 em ployees (50 Q+ and 58 Q-) in this group. Control Manual Workers (n = 50).-- The possibility that repeated minor injuries associated with manual labor might contribute to the abnormal findings seen in VC workers led to the examination of workers from compa nies making neither VC nor polyvinyl chloride and hospital employees work ing as carpenters, truck drivers, and maintenance men, a total of 50 work ers. All were men and ranged in age from 19 to 62 years (mean age, 43 years). METHODS Wide-field Capillary Microscopy.--The technique of wide-field capillary micros copy as previously reported"* consists of the observation of selected skin sites under immersion oil, using a stereo wide-field mi croscope at magnification x 12. Wide-field microscopy permits the detection of microvascular patterns, such as' the presence and distribution of dilated or deformed mi crovessels and the absence of capillary loops, without attempting to measure ab solute vessel dimensions. The technique is rapid and suitable for mass screening. Twelve standard sites were examined in each subject: four nailfolds and two each of the following sites: dorsum of the distal phalanx other than the nailfold, dorsum of the middle phalanx, dorsum of the proxi mal interphalangeal joint, and the finger pad. Photography of Microvessels.--The widefield photographic technique as previously described" was used to photograph at least one finger of each subject. All photographs were coded for blind comparison of capil lary findings in VC workers and control subjects. Clinical and Occupational Data.--All sub jects were interviewed as to length of em ployment, job assignment, general state of health, presence or absence of Raynaud phenomenon, and smoking and drinking Table 1.--Clinical Findings and Complaints of Group 1 Vinyl Chloride Workers* No. of Subjects^l No. of Sub With Capillary jects Examined Changesf Severe AOL with Raynaud phenomenon 64 Scleroderma-like skin lesions with Raynaud phenomenon 54 Liver abnormalities^ 65 Subtotal 17 13 Healed AOL with Raynaud phenomenon 60 Heated AOL without Raynaud phenomenon 10 Raynaud phenomenon alone 93 Nonspecific skin rashes without Raynaud phenomenon 7 1 Miscellaneous complaints 40 Subtotal 27 4 Total 44 17 *AOL indicates acroosteolysis. fOf 17 subjects with abnormal capillaries, ten had scattered changes (8/13 and 2/4 of the two groups above) and seven had isolated changes. Two patients with angiosarcoma of the liver and one each with (1) portal fibrosis and en larged spleen, (2) portal fibrosis with early cirrhosis and fatty metamorphosis, (3) thrombosis of the splenic vein, mild liver damage, and reticuloendothelial cell hyperplasia, (4) fatty metamorphosis with focal capsular and subcapslilar fibrosis and splenomegaly with vascular congestion. Table 2.--Comparison of Capillary Observations Between VC Workers and Controls* Scattered capillary abnormalities Abnormal capillaries present, but few In number No capillary abnormalities seen Total , Employees of VC Industry 11 27 70 108 Manual Workers Not Exposed to VC 0 3 .. 47 50 J | *VC indicates vinyl chloride. Difference In the prevalence of capillary abnormalities be tween VC workers and controls Is statistically significant (xs = 1S.50, P<.001). habits. A limited physical examination was performed. All data were coded for later analysis and were unknown to the capil lary observer and photographer. RESULTS Group 1 (VC Workers Selected by Symptoms).--Examination of group 1 subjects showed scattered capillary abnormalities similar to those found in scleroderma (Fig 1 and 2). Defi nitely dilated capillary loops were seen in the nailfold and in other fin ger sites, contrasting with the sur rounding normal vasculature. Pale avascular areas were frequently ob served. The capillary abnormalities were usually more discrete and less numerous than those seen in most pa tients with scleroderma. They were seen more frequently in subjects with severe AOL, liver abnormalities (as defined in Table 1) and sclerodermalike lesions (13/17) than in those with healed AOL, nonspecific skin rashes, or Raynaud phenomenon alone (4/27; X! = 14.21, P < .001). Moreover, 5 of 6 subjects with liver abnormalities ver ified by biopsy specimens had microvascular abnormalities (Table 1). In a few subjects, lesions resem bling mini versions of clinically vis ible papular skin lesions were ob served microscopically (Fig 3, left). In two subjects with active AOL, capil lary hemorrhages were observed un der the proximal nail plate in addi tion to the common type of "splinter hemorrhages" under the distal nail plate (Fig 3, center). Group 2 (VC Workers Selected by Questionnaire).--Dilated capillaries were observed in 38 of 108 group 2 workers; both the number and distri bution of dilated capillaries differed from those observed in most sclero derma patients. Many group 2 work ers had isolated, extremely dilated capillaries (Fig 3, right and Table 2). No correlation was found between the length of time employed as a reactorcleaner (or the length of time ivitld the company) and thecapillary abnor" malities. Office and supervisory per sonnel who had never been produc- JAMA. Sent 20. 1976-Vol 236. No. 12 Capillary Abnormalities--Maricq et a! 1369 Fig 1.--Top left, Wide-field view of nailfold area in normal sub ject. Bottom left, Nailfold capillaries of patient with sclero derma. Bottom right, Nailfold capillary pattern in worker of polyvinyl chloride production plant. Note similarity with pat tern seen in scleroderma patients. R&S 109329 Fig 2.--Left, Dorsum of middle phalanx in normal subject. Center, Cluster of dilated capillaries in same anatomical site in patient with scleroderma. Right, Vinyl chloride worker with pattern similar to that seen in scleroderma. Fig 3.--Left, Miniplaque on dorsum of distal phalanx in VC worker with acroosteolysis (AOL). Cen ter, Capillary hemorrhages under both distal and proximal nail plate in a vinyl chloride (VC) worker with AOL. Right, Single extremely dilated capillary in nailfold of VC worker with liver abnormalities. 1370 JAMA. Sept 20. 1976-Vol 236, No. 12 Capillary Abnormalities--Maricq et al t tion workers had fewer microvascular tified photographs of VC workers abnormalities (3/22) than production were mixed with 136 photographs of workers (35/86, x! = 4-49, P<.05); control subjects and 130 photographs however, production workers showed of patients with scleroderma and re no differences in capillary abnormal lated diseases; all photographs were ities according to job category. There rated for the presence of capillary was no significant difference (x13d4,2=5 6 7 abnormalities. The results demon 1.32, P>.5) between employees who strated that significantly more VC had been classified as Q+ or Q-- on workers (39/152) than control sub the basis of the questionnaire. It was jects (3/50) had capillary abnormal noted, however, that there was little ities (xJ = 7-69, F<.01). Although ob or no correlation between the re jective, for technical reasons, sponses regarding Raynaud phenom photographs are slightly less sensi enon obtained from the questionnaire tive than direct observations in de and those obtained from the inter tecting capillary abnormalities. view at the time of examination. Physical examination disclosed two COMMENT workers with AOL (one "active" and The results of this study demon one "healing" by roentgenographic strate that capillary abnormalities examination) and papular skin le seen in the finger skin by in vivo mi sions, and ten workers with hepato croscopy are present in VC workers megaly (4 cm or more below the right more frequently than in control sub costal margin). The subject with ac jects. These capillary abnormalities tive AOL showed scattered capillary are not exclusively related to pe changes, the subject with healing ripheral pathological conditions such AOL had a "normal" capillary exami as AOL, scleroderma-like lesions nation. There was no correlation be of hands, and Raynaud phenomenon, tween hepatomegaly and capillary but are also found in subjects with findings. liver abnormalities (as defined in Comparison of VC Workers With Table 1) and in subjects who have Control Subjects.--Capillary abnor papular lesions elsewhere on the malities in group 2 VC workers were body. Microscopic papular or fibrotic significantly more frequent than in lesions can also be observed in VC the control manual workers examined workers. In 33% of the subjects who (x'= 15.50, P < .001) (Table 2). show any capillary changes, the pat Analysis of Photographic Data.-- tern appears similar to the micro- Three hundred seventeen uniden vascular changes seen in scleroderma; in the remaining majority, changes consist of a few dilated capillaries only; very few control subjects show even these minimal capillary abnor malities. Since microvascular change occur more frequently than overt VCassociated pathologic conditions in VC workers, they may represent an early manifestation of the VC effect. More work is needed to determine the nature and evolution of such mi crovascular abnormalities, their rela tionship to VC-associated disease (as opposed to a transient reaction to VC exposure), and their relationship to the subject's susceptibility to VC dis ease. Further studies are also needed to compare the capillary changes re ported here with those seen in small blood vessels and endothelia of ani mals exposed to VC." Capillary mi croscopy might then be used as a re producible, noninvasive technique to monitor VC workers and to identify VC-associated peripheral and visceral disease in susceptible individuals at an early and possibly preventable stage. This investigation was supported in part by the Charlotte and Sidney Lifschultz Foundation National Institutes of Health grant AM 18904 the South Carolina State appropriation for re search, and the RGK foundation. Irving J. Selikoff, MD, supplied 24 control industrial workers for capillary examination. Karen Menth, Eleanor Gattoni, and Villu Maricq provided technical assistance. 1. Harris DK, Adams WGF: Acro-osteolysis occurring in men engaged in the polymerisation of vinyl chloride. Br Med J 3:712-714, 1967. 2. Wilson RH, McCormick WE, Tatum CF, et al: Occupational acroosteolysis: Report of 31 cases. JAMA 201:577-581, 1967. 3. Dinman BD, Cook WA, Whitehouse WM, et al; Occupational acroosteolysis: I. An epidemio logical study. Arch Environ Health 22:61-73, 1971. 4. Falk H, Creech JL, Heath CW, et al: He patic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63, 1974. 5. Lange CE, Juhe S, Stein G, et al: Die sogenannte Vinyl-chlorid-Krankhcit-cine be- rufsbedingte Systemsklerose? Int Arch Arbeitsmed 32:1-32, 1974. 6. Litis R, Anderson H, Nicholson WJ, et al: Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sci 24622-41, 1975. 7. Marsteller H J, Lelbach WK, Muller R, et al: Unusual splenomegalic liver disease as evi- * References denced by. peritoneoscopy and guided liver biopsy among 'polyvinyl chloride production workers. Ann NY Acad Sci 246:95-134, 1975. 8. Miller A, Teirstein AS, Chuang M, et al: Changes in pulmonary function in workers ex posed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 246:45-52, 1975. 9. Suciu I, Prodan L, Ilea E, et al: Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sci 24653-69, 1975. 10. Thomas LB, Popper H, Berk PD, et al: Vinyl-chloride-induced liver disease: From idio pathic portal hypertension (Banti's syndrome) to angiosarcomas, N Engl J Med 292:17-22, 1975. 11. Viola PL, Bigotti A, Caputo A: Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Rea 31:516-522, 1971. 12. Maltoni C, Lefemine G: Carcinogenicity bioassays of vinyl chloride: Current results. Ann NY Acad Sci 246:195-218, 1975. 13. Markowitz SS, McDonald CJ, Fethiere W, et al: Occupational acroosteolysis. Arch Derm 106:219-223, 1972. 14. Rodnan GP: Progressive systemic sclerosis (scleroderma) and calcinosis,' in - Hollander JL, McCarty DJ Jr (eds): Arthritis and Allied Conditions, ed 8. Philadelphia, Lea & Febiger, 1972, pp 962-1005. 15. David E, Landau J; Clinical Capillary Mi croscopy. Springfield, 111, Charles C Thomas Pub lisher, 1966. 16. Maricq HR, LeRoy EC: Patterns of finger capillary abnormalities in connective tissue dis ease by widefield microscopy. Arthritis Rheum 16:619-629, 1973. 17. Maricq HR, Spencer-Green G, LeRoy EC: Relation entre la distribution des capiltaires anormaux et le degrf d'envahissement systmique dans la sclCrodermie (progressive gCnSralis4e), J Sci Med Lille 93:283-286, 1975. 18. Maricq HR: "Wide-field" photography of nailfold capillary bed and a scale of plexus visu alization scores (PVS). Microvasc Res 2:335-340, 1970. R&S 109330 JAMA. Sept 20, 1976-Vol 236. No. 12 Capillary Abnormalities--Maricq et al 1371