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S3 Occupational Acroosteolysis III. A Clinical Study Vernon N. Dodson, AID; Bertram D. Din man, AID; Walter AI. Wkitehouse, AID; Ahmed N. AI. Nasr, AID, PhD; and Harold J. Alagnuson, AID, AIPH, Ann Arbor, Alich Four subjects with acroosteolysis were studied clinically. Alt had osteolytic lesions, especially in the distal phalanges of the hands, and Raynaud's phenomenon. All had worked as polyvinyl chloride reactor-vessel cleaners, with hand scraping being the common mode of operation. Raynaud's phe nomenon anteceded osteolytic lesions. One of the subjects was in negative calcium and phosphorus balance. Plethysmographlc abnormalities were present in three. Esophageal motility was normal. Scintiscans of the hands using sodium fluoride labelled with radioactive fluorine (1!F) revealed variable uptakes in the fingers which correlated with the radiographic lesions. A wide variety of clinical laboratory parameters were normal. Occupational acroosteolysis (aol> consists primarily of Raynaud's phenome non and osteolysis of the distal phalanges in the hands. Suciu et al first described Ray naud's phenomenon in polyvinyl workers in 1963.1 Osteolytic lesions were reported in other cases.1-7 Other associated clinical fea tures such as hepatomegaly, the cutaneous stigmata of scleroderma, hypothroid param eters, and numerous abnormal laboratory tests have been reported.17 Epidemiologically, patients with AOL are associated with the manufacture of vinyl chloride polymers, more specifically with the hand cleaning of the polymerization reactors. This paper reports the results of intensive clinical investigation of four patients with AOL. These four patients were selected from those employees of 32 plants engaged in the manufacture of vinyl chloride poly mers throughout the United States. Methods Each patient was admitted to the Clinical Research Unit, University of Michigan Hospi tal, for a two-week period where detailed medi cal histories were investigated and physical examinations performed. Details of the work histories and environmental exposures were de rived from in-plant epidemiological studies car ried out jointly by the Institute of Environ mental and Industrial Health of the University of Michigan and the Manufacturing Chemist*' Association. Table 1 lists the laboratory param eters applied. In addition, calcium and phos phorus balance studies were carried out, using a dietary history to establish a constant cal cium-phosphorus intake to which each patient was accustomed. Daily 24-hour urine specimens were collected, and stool specimens were pooled every three days for calcium and phosphorus determinations. Appropriate correctional com putations for uneaten foods were made. Cate cholamines and 5-hydroxyindole acetic acid were determined on 24-hour urine collections, often partitioned by six-hour units and usually collected on days of provocative cold stresses during plethysmographic determinations. Numerous roentgenographic techniques were introduced, ranging from skeletal survey films to barium swallow radiographs and bone xerog raphy. Scans of the hands and sacral regions, using sodium floride labelled with radioactive fluorine (1#F), were undertaken in two of the patients. Plethysmography of the forearms and hands, using the method of Zweifler et al, was employed.* Esophageal motility studies were made, using Snladin et al's technique.* Results Submitted for publication Fab 9, 1970; accepted March 24. From tha taction of Occupational and Environ mental Medicine and tha Department of Internal Medicine (Dr. Dodson), and the Institute of Envi ronmental and Industrial Health (Dr*. Dinmen and Nasr), tha Department of Environmental and In dustrial Health, School of Public Health (Dr. Msgnuson), and the Department of Radiology (Dr. Whitehouse). University of Michigan. Ann Arbor. Reprint requests to Institute of Environmental and Industrial Health, University of Michigan, Ann Arhor, Mich 48104 (Dr. Dinman). History.--Blanching of the hands was the first sign of AOL. In two of the men, the onset was gradual over a few weeks, and in two it was abrupt, as shown in Table 2. Cold was the inciting factor in all cases. The blanching was associated with either tin gling of the hands or tenderness of the fingertips. The polyvinyl work exposure-tofirst-blanching ranged from one to 23 Atch Eiwhon II--*ol 22, tjcifi 1271 i t j. t OLI 2300 i \ Fig 1.--Note transverse defects In distal phalanges of fingers one to four on left hand and fingers one to three on right hand. Marginal defect is present in distal portion of distal phalanx of right fifth finger (case 1). Table 1.--Laboratory Investigation of AOL Patients Biochemistry Sodium Calcium Potassium Phosphorus Carbon dioxide Cholesterol Chloride Glucose (fasting) Bilirubin direct/total Urea nitrogen Creatinine Total serum protein Electrophoresis serum Albumin <*1 <*2 0 y Magnesium Lipids Phospholipids Triglycerides Catecholamines Norepinephrine Epinephrine ______________ _____________Serum Enzymes Alkaline phosphatase Threonine aldolase Acid phosphatase Malic dehydrogenase Serum glutamic oxaloacetic transaminase Glutamic dehydrogenase Serum glutamic pyruvic transaminase Leucine aminopeptidase Lactic da hydrogenase isogram Aldolase 5 'Nucleotidase Creatine phosphokinase Serine dehydrotase Isocitrate dehydrogenese Immunological Tests Venereal Disease Research Antinuclear factor Laboratory Cryoglobulins LE ceil Immunophorasis Direct Coomb's IgA Latex-rheumatoid factor IgM Cold agglutinins IgG months. The length of the interval bore no relationship to the mode of onset or the severity of the symptoms. A summary of the habits and dietary history of these patients is detailed in Table 3. Three of the four men were cigarette smokers with smoking histories of nine (case 1), 15 (case 4), and 25 (case 2) pack-years. Half drank coffee (three or nine cups per day). All were casual tea drinkers. Three drank between three and 18 bottles of beer each month. One (case 4) drank 120 cans of beer per month but no whiskey while the others consumed less than four Fla 2.--Hand* show further resorption of bone, resulting in shortening of terminel phelanges of all fingers except left fifth end right fourth, letter having developed transverse defect. Right fifth fbtgar hat shown additional resorption of distal phalangeal tip. Soft-tissue clubbing is related to Shortened phalanges (case 1). .......... 1> L"].| lie,................ IP |I"|W pw f O LI 2301 OCCUPATIONAL ArROOSTEOLYSlS~nODE''N ET AL 85 ounces of whiskey per month. Table 2.^Clinical Features of Patients With AOL at Onset Three of the mm rarely drank milk, and the other (case 4) averaged two glass es each day. Dietary histor ies indicated calcium ink kes between 1,000 mg and 1,800 mg/day except for one pa tient (case 2) whose usual intake was 518 mg/day. This patient's normal dietary in take of phosphorus averaged 2,400 mg/day while the oth ers took in between 1,500 and 1,800 mg/day. None had unusual food cravings or aversions. Clinical Features Blanching, Onset precipitated by cold Associated symptoms: Fingertip tenderness. Tingling of the hands, Joint pain Case 1 Case 2 Sudden Gradual ++ + Elbows + -- Coccyx Low back Joint stiffness Subcutaneous nodules Hands -- Muscle swelling Exposure-to-first blanch interval 1 mo Intermittent tinnitus + Palpitations with exertion Hands Knees 6 mo + + Case 3 Gradual + + -- Hand Knees + 18 mo -- Case 4 Sudden + -- + 1 hip, 1 wrist. 1 knee, hands Low back Sacro-iliac -- -MB 23 mo + - Some details of family his tory are recorded in Table 4. Table 3.--Habits and Dietary Histories of Patients With AOL A firm history of hyperten Features sion was present in either the Cigarette smoking (pack-yr) Case 1 9 Case 2 25 Case 3 0 Case 4 15 father or the mother in three Average coffee consumption of the four patients, and one (cups/day) 93 half also had immediate fam Alcohol per month Beer (12-04 unit) 3 13 ily members with diabetes Whiskey (os) 14 00 8 120 08 mellitus though none per Milk (glasses/day) Rarely Rarely Rarefy 2 sonally evidenced the dis Calcium intake (mg/day) ease. Notably, the fathers of Phosphorus intake (mg/day) 1,045 1,519 518 1,587 1.327 2.457 1,096 1,797 all four men had heart dis eases. Tabla 4.--Diseases In Family Member of Petient With AOL The associated symptoms Family and signs of joint involve Member Case 1 Cese 2 Case 3 Case 4 ment are listed in Table 5. Intermittent transient ortho static tinnitus was mentioned Father Diabetes mellitus Heart disease Heart disease. Chronic lung disease Congestive 4 heart failure. Hyperlipemia, Hypertension by three of the four patients. This occurred upon rising from * mg or recumbency. Mother ... Brother Emphyseme Hypertension, Obesity Hypertension Obesity The one patient not having tinnitus (case 3) had chronic poetnasal drip, nasal stuffiness, and a prior history of child hood bronchia] asthma. Physical Examination.--The major physi cal findings were restricted to the skin and joints, as shown in Table 5. Synovial and skin thickening were observed by two or more clinicians independently. Dupuytren's contractures were present bilaterally in one patient (case 1). The extensor ligaments of the wrist were thickened in another (case clinical laboratory parameters depicted in Table 1 were found to be essentially normaL All four men vacillated between negative and positive calcium balances day-to-day during the two-week period. Except for one patient (case 2), all averaged a positive balance ranging from 33 to 246 mg/day. This patient managed a deficit of 27 mg/ day, which was primarily a function of renal excretion. All had positive phosphorus balances except this patient, whose phosphoturia always accounted for more than his 2). The distal phalanges of the hands of one stool losses. patient (case 3) were shortened. Five-hydroxyindole acetic acid determina Laboratory Parameters.--The numerous tions were performed on 24-hour urine spec- Arch Environ Health--Vol 22, Jan 1971 OX.X 2302 SG OCCUPATIONAL ACROOSTEOLYSIS DODSON ET AL Table 5,--Physical Findings on Patients With AOL imens which were sometimes Physical Findings Skin Dorsal-thickening Case l Case 2 Case 3 Case 4 partitioned in six-hour incre ments (Table 6). One pa tient's third-period value of hands Blanching Without cold With cold + _ + +* + 2.8 occurred during a cold _ stress while plethysmogra ++ + + + phy was being done (case 1). Joints Synorial thickening Incidental pipt mp; Knees Dupuytren's contracture Finger R 2 and 3 L 3 and 4 Also fingers, t Proximal interphalangeal. j Metacarpophalangeal. pipt -- _ -- Thickening of wrist extensors Shorten ing of finger tips _ -- Another patient's third value of 1.6 did not increase under similar cold stress (case 2). Plethysmographic studies revealed normal pulse vol umes in all but one patient (case 2). All patients ex cept one (case 3) showed di minished pulse volumes with cold stress typical of the Raynaud's phenomenon observed in other dis eases. Esophageal motor activity a normal in all subjects as shown by barium fluoro t .. scopy and Saladin's et al motility technique. Radiological Findings.--The radiographic findings of the four patients analyzed are summarized in the case reports. Report of Cases _ _ _ _ _ _ _ _ -J Fig 3.--Erosive and sclerotic changes in sacro-iliac joints bilaterally (case 1). Fig 4.--Erosive lesions of os calcis posterior to bony spur (case 1). Case 1.--X-ray films made elsewhere prior to the patient's hospitalization at the University of Michigan exhibited normal hands on Oct 20, 1966, and, in 1967, showed marginal bone de fects of the right third and left second, third, and fourth distal phalanges and distal fragmen tation of the distal phalanx of the left first digit. On Aug 8, 1967, transverse defects were noted on the distal phalanges of the left fingers one to four and right one to three, with resorp tion of the distal portion of the distal phalanx of the right fifth finger. The appearance of the hands on Oct 13, 1967, when the patient was first seen, is shown in Fig 1. Some reparative changes were noted in comparison with the previous films, with persistent transverse de fects in fingers one to four on the left and one to three on the right, with a marginal defect in the distal portion of the distal phalanx of the right fifth finger. Further check-up examination was obtained on Jan 9, 1969, and Oct 24, 1969, the latter being shown in Fig 2. During this period of time, there has been further resorption of bone, resulting in shorten ing of the termii. il phalanges of all fingers except the left fifth, which has remained unin volved, and the right fourth, which has main tained its length but has developed u transverse Arch Environ Health--Vol 22, Jan 1971 OLI 2303 Fig 6.--Sacro-iliac Joint* show erosive and sclerotic change*, more marked on left <ca*a 2). & $ u{ 1. / V: Arch Environ Health--Voi 22, Jan 1971 OLI 2304 88 OCCUPATIONAL ACROOSTEOLYSIS--DODSON ET AL Table 6.--Five-hydroxyindole Acetic Acid and Catecholamine Studies in Patients With AOL Case 1 Case 2 Case 3 Case 4 Unnary Excretion Five-hydroxylndole acetic acid 8am-2pm 2pm-8pm 8pm-2am 2am-8am Total (1) Total (2) Total (3) Catecholamine Epinephrine Norepinephrine Urine Creat* Urine Creat Urine Creat- Urine Creat Mg Volume inine Mg Volume inine Mg Volume mine Mg Volume inine 0.78 0.92 2.80 0.89 5.39 5.8 4.0 7.6 390 460 730 140 1,720 2,170 1.720 0.36 0.42 0.62 0.12 1.52 1.47 1.46 2.0 265 0.59 2.2 240 0.54 1.2 300 0.69 1.6 210 0.48 7.0 1.015 2.30 23.6 6.1 390 lt208 416 430 2,444 0.30 0.97 0.33 0.34 1.94 ... ... defect. The right fifth finger has shown addi tional resorption of the phalangat tip. Softtissue clubbing is noted in the shortened phalanges. Some sclerosis is noted along the margins adjacent to the transverse defects. This patient also showed extensive erosive and scle rotic changes in the sacro-iliac joints, as seen in Fig 3. An erosive lesion was also found in the plantar surface of the os calcis, as depicted in Fig 4. Case 2.--This patient had an extensive skele tal survey on Feb 8, 1968, with positive findings limited to the hands and pelvis. As shown in Fig 5, the left hand revealed a marginal defect at the tip of the distal phalanx of the second finger while the third finger showed a transverse defect in the distal pha lanx. At the same time, the right hand present ed transverse lytic defects in the distal pha langes of the second and third fingers and an additional distal marginal defect of the second finger. Figure 5 compares a typical sodium fluo ride t*F scintiscan of the bands and the corre sponding roentgenograms. A slight increase in sodium fluoride 13F uptake is seen in the distal phalanges of the left third and right second and third fingers while the uptake is - diminished over the distal phalanges of the left fifth and right fourth and fifth fingers. Generally, up takes over the remaining bones of the hands are uniform. The sacro-iliac joints also displayed extensive erosive and sclerotic change, more marked on the left, as shown in Fig 6. Case 3.--Extensive skeletal survey on this Fig 7.--Hands show shortening and widening of distal phalanges of all fingers, with resultant clubbing of soft tissues (case 3). Arch Environ Health--Vol 22, Jan 1971 OLI 2305 OCCUPATIONAL ACROOSTF.O LYSIS-- DODSON ET AL S9 patient on March 18, 1968, showed shortening and widening of the distal phalanges of all tinges (Fig 7), with resultant clubbing of the soft tissues. These changes were interpreted as the end stages of healing of AOL. The sacro-il iac joints showed erosive and sclerotic changes, i more marked on the right (Fig 8). Review of previous x-ray films made else where indicated that some sacro-iliac joint changes were present on April 8, 1959, and that the hands had not changed in appearance since October 1965.' CASE 4.--Review of previous x-ray films made of this patient indicated that no abnor mality of the hands was present on Feb 20, 1967, or Jan 23, 1968. On July 15, 1968, films of the sacro-iliac joints exhibited erosive and scle vC \ Fig 8,,__ Sacra rhac joint* show erosive and sclerotic changes. more marked on right (case 3). rotic changes, and the hands revealed marginal defect of the distal phalanges of the left third and the right fourth fingers, slight irregularity of distal phalanx of the right fifth finger, and transverse defects of the distal phalanges of the thumbs bilaterally. Skeletal survey on Oct 20, 1968, noted sepa ration of the tip of the styloid process of the right ulna, marked resorptive and sclerotic changes of the sacro-iliac joints (Fig 9), and some progression of the hand involvement, with transverse defects now involving the distal phalanges of the left digits one to three and Fig 10.--Hands show transverse defects in distal phalanges of left fingers one to three and right fingers one and four, with an additional marginal defect of left second finger (case 4). C . _ J i Fig 9.--Sacro-iliac joints show erosive and sclerotic changes bilaterally (case 4). _____ f Arch Environ Health--Vol 22, Jan 1971 I OLI 2306 90 OCCUPATIONAL ACROOSTEOLYSIS--DODSON ET AL right digits one and four and an additional marginal defect of the left second digit (Fig 10). Irregularity of the lower pole of the right patella was also noted. Comments Raynaud's phenomenon was the first manifestation noted by these subjects and in the majority of the cases reported. Harris and Adams* reported one case in which distal digit shortening occurred first, while Wilson et al4 noted this in five of his 31 cases. This suggests that the vascular lesion tends to antecede the bone changes in most individuals. None of these patients exhibited Raynaud's phenomenon of the feet, which confirms Wilson et al's experience. All of these individuals had been ``reactor clean ers" ie, they spent some hours each week cleaning the polyvinyl chloride polymeriza tion kettles shortly prior to or at the time of the onset of their disease. No consistent relationship was found between the occur rence of severity of either Raynaud's phe nomenon or the osteolytic lesions and those habit patterns which have been shown to influence vascular reponses, eg, cigarette smoking and the ingestion of alcohol, coffee, or tea. Likewise, neither the bone lesions nor Raynaud's phenomenon seemed to cor relate with the daily consumption of milk or dietary calcium. Dallas and Nordin10 have shown that while dietary deficiencies or cal cium may or may not potentiate osteoporo sis of various types, an adequate calcium Intake of 15 mg/kg is protective. Only one patient (case 2) had less than this amount (5.8 mg/kg). Since such dietary histories have been shown to be quite reliable,11 their habitual calcium intakes do not appear to be a consistent causative factor in their cases, likewise, the calcium-phosphorus balance studies on these men reveal no clear-cut ' abnormality or pattern. This result might be anticipated since these men have been away from reactor cleaning for several months, and the mass of involved bone is slight compared to the entire skeleton. However, it should be pointed out that a two-week bal ance period is a short observation period though they were placed on calcium and phosphorus intakes comparable to their usu al eating habits to obviate disruption of their "steady state." At first glance, it appeared that there was a rich history of heart disease or hyperten sion or both in the parents of these men. Comparison of them with healthy male chemical workers not involved in polyvinyl chloride manufacture and matched in age suggests a significant correlation by the x2 test, using Yate's correction. Whether such an observation suggests a hereditary frailty to explain the susceptibility of those individ uals developing AOL is speculative. The number of observations is too small to sup port seriously such a contention at this time. The extent and character of other muscu lar skeletal findings such as tendon and synovial thickening confirm the findings of others. We are able to offer no suitable explana tion for the frequent episodes of intermittent orthostatic tinnitus described by three of these men. Suciu et al described liver enlargement, various vague asthenic symptoms, and mani festations of hypothyroidism. Such findings were not present in these men or had they been in the past. The radiological findings in occupational AOL have been reviewed recently on the basis of the epidemiological investigation of the polyvinyl chloride industry. Workers in other countries have described lytic lesions in the distal phalanges of the hands, styloid processes of the ulna and radius, and the sacro-iliac joints.1* These four patients demonstrate the en tire spectrum of radiographic hand changes in occupational AOL from the earliest mar ginal erosion of the distal phalanx through the extensive transverse defect, with ulti mate healing resulting in a short and wide phalanx. The fact that all four showed sac ro-iliac involvement suggests that the inci dence of involvement at this site is probably higher than previously suspected. The additional smaller abnormalities found in the ulnar styloid, os calcis, and lower pole of the patella suggest that these areas might well be evaluated in other cases as they appear in order to get a more accur ate estimate of their incidence. The sodium fluoride '*F scintiscan data suggests that the more advanced osteolytic changes with transverse defects at this time were picking up more fluorine and probably Arch Environ Health--Vol 22, Jan 1971 OLX 2307 OCCUPATIONAL ACROOST EO LYSIS-- DODSON ET AL 01 calcium, indicating active remineralization. would be wise to exclude any individual That the digits with marginal defects picked with Raynaud's phenomenon from reactor up less than the normal bones implies some cleaning. Since seniority practices usually type of uptake block or active demineraliza remove workers from reactor cleaning with tion. If the latter is true, it is all the more the passage of time, such excluded workers interesting that different bone lesions ap probably would not return to this particular pear to be mineralizing and demineralizing job. In view of the low prevalence of this in the same individual, even the same hand. disease, we believe that permanent restric The etiological agent or agents responsible tion of these few workers from this job does and the pathogenical mechanisms remain not pose any undue administrative burden. obscure. Until more is known of the natural history Medical Prevention.--The interval be of this disease, prudence would dictate the tween the beginning of reactor cleaning and course as here recommended. the onset of AOL appears highly variable, ie, one to 23 months. Accordingly, the fre quency with which one examines reactor This investigation was supported by Public Health Service grant 2M01 RR-42 and a grant from the Manufacturing Chemists* Association. cleaners has no rational basis. By contrast, the occurrence of Raynaud's phenomenon References should serve as a sufficient warning for fur 1. Suciu I, Drejman I, Valeslcai: Investigation of ther inquiry. This is not to suggest that prudent medi cal practice does not require periodic exami nation of reactor cleaners and other groups of workers in whom AOL occurs. These groups should be surveyed periodically by use of hand roentgenograms and medical questionnaires. The form the latter might take has been discussed in the epidemiologi cal segment in this series. But we would emphasize that prevention of AOL also re quires the cooperation of supervision. This group should be alerted as to the possible significance of Raynaud's phenomenon in relation to AOL. Upon the discovery of any case of AOL among workers at risk, such individuals should be removed from the job. X-ray films of the hand, back, and knees should be obtained. A medical history questionnaire, similar to those used in the epidemiological survey reported here, should also be pro cured. A medical evaluation for other causes of Raynaud's phenomenon is in order. In view of the unpredictable course of AOL, it the diseases caused by vinyl chloride. Med Intern 15:967-978,1963. 2. Cordier JM, Fievez C, LeFevte MJ, et el: Acroosteolysis and skin lesions among worker* en gaged in cleaning reactors. Cah Med Travail 4:14- 19, 1966. 3. Chatelain A, Motilon P: A syndrome of acrooe- teotysis of occupational origin: Heretofore not iden tified in France. J Radiol Electr 48:277-280,1967. 4. Wilson RE, McCormick WE, Tatum CF, et el: Occupational acroosteolysis. JAMA 201:577-581, 1967 5. Harris DK, Adaroa WGF: Acroosteolysis oc curring in man engaged in the polymerization of vinyl chloride. Brit Med J 3:712-714,1967. 6. Benoit JP: Aeroosteolytie of occupational ori gin, thesis. Lyon, 1968. 7. Hess EV, Schneider H, Roush G: Clinical studies in occupational acroosteolysis: A new dis ease. Read before the 40th meeting of the Central Society for Clinical Research, Chicago, 1967. 8. Zweifler AJ, Cushing G, Conway FJ: The relationship between pulse volume and blood flow in the Anger. Angiology 18:591-598.1967. 9. Saladtn TA, French AB. Zarafonitis Cl, et al: Esophageal motor abnormalities in scleroderma and related diseases. Amer J Dig DU 2:522-635,1966. 10. Dallas 1, Nordin BEC: The relation between calcium intake and roentgenologic osteoporosis. Amer J Clin Nutr 11:263-269,1962. 11. Becker BC, Indik BP, Beeuwkes AM: Dietary Intake Methodologiee: A Review, technical report. Ann Arbor. Mich, University of Michigan, I960, pp 55-57. Arch Environ Health--Vol 22, Jan 1971