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Postgrad Med J: first published as 10.1136/pgmj.34.391.262 on 1 May 1958. Downloaded from 262

BERYLLIUM By I. B. SNEDDON, M.B., Ch.B., F.R.C.P. Consultant Dermatologist, Rupert Hallam Department of Dermatology, Sheffield

It is opportune in a symposium on monary berylliosis which fulfilled the most to discuss disease because it mimics so stringent diagnostic criteria. closely the naturally occurring Boecks sarcoid and A beryllium case registry set up at the Massa- yet carries a far graver prognosis. chusetts General Hospital by Dr. Harriet Hardy Beryllium was first reported to possess toxic had collected by 1956 309 examples of the disease, properties by Weber and Englehardt (I933) in of whom 84 had died. The constant finding of Germany. They described and acute beryllium in autopsy material from the fatal cases in workers extracting beryllium had proved beyond doubt the association between from ore. Similar observations were made by the granulomatous reaction and the metal. Marradi Fabroni (I935) in Italy and Gelman It is difficult to reconcile the paucity of accounts (I936) in Russia. Further reports came from of beryllium disease in this country with the large Germany in I942 where beryllium poisoning was amount of beryllium compounds which have been recognized as a compensatable disease. Towards used in the last ten The in the end of World War II the production and use years. only reports the medical literature are those of Agate (I948),copyright. of beryllium salts increased greatly in the United Sneddon (i955), and Rogers (1957), but several States, and in 1943 Van Ordstrand et al. reported others have reached public notice in the daily the first examples of chemical in men press by reports of coroners' inquests and medico- extracting from ore in Ohio. In legal actions. It is possible that there are others addition to the acute respiratory disease, it had undiagnosed which are at present labelled Boeck's also been recognized that an acute contact derma- sarcoidosis. titis and ulcers resembling chrome ulcers occurred workers in extraction amongst beryllium plants, http://pmj.bmj.com/ but it was not until 1946 that the first examples Pathology of delayed chemical were described The basic pathological change seen in material by Hardy and Tabershaw. from three autopsies by Chesner (1950) was an They drew attention to a slowly progressive intra-alveolar nodular granulomatous lesion which sarcoid-like change which involved the lungs, involved all the lung fields. The nodules were and other organs in workers who had been composed of a preponderance of large endothelial exposed sometimes for a very short time to cells with plasma cells, mononuclears and lympho- beryllium compounds. The striking feature of cytes. There was no caseation at any stage. on September 28, 2021 by guest. Protected the condition was the long latent period between Giant cells of both foreign body and Langhan's exposure to beryllium and the onset of symptoms. type were seen in large numbers. Inclusion This delay at first lead to doubt that beryllium bodies were seen within the giant cells in some itself was responsible for the pathological changes but not all cases. Spread occurred by aggregation and even as recently as I95I an annotation in the of nodules in a more diffuse fashion throughout Lancet suggested that the case against beryllium the alveolar septa. The diffuse reaction was at was not proven, though this was later contradicted first a polymorphous cellular one with later by Harriet Hardy (1951) who has so vigorously and hyalinization. campaigned for better recognition of the danger. Hilar lymph nodes were invariably affected by It is in deference to her that the condition is the same granulomatous process. The liver was called beryllium disease in this article. involved in two of the three cases, but there were Since that time more and more cases have been no other visceral lesions. Similar granulomatous described in the United States of America. In reactions have been described in skin lesions I953 Denardi et al., in an authoritative review of associated with beryllium disease of the lung by the subject, reported 35 examples of chronic pul- Grier et al. (I948), who also gave the first account Postgrad Med J: first published as 10.1136/pgmj.34.391.262 on 1 May 1958. Downloaded from May 1958 SNEDDON: Beryllium Disease 263 of skin nodules due to accidental implantation of when attempting to differentiate the two con- beryllium in the skin. ditions. Lederer and Savage (1954), who have described Equally, respiratory function studies which the only example of beryllium of the show diminished vital capacity and slowing of skin in this country, noted pathological changes alveolar diffusion in beryllium disease are merely indistinguishable from sarcoidosis in part of the a measurement of the severity of the lung damage. lesion but extensive caseation in other areas. Impairment of respiratory function is, however, Although most investigators have failed to pro- found earlier and is more severe in beryllium duce pulmonary granulomata in animal experi- disease than in sarcoidosis. ments with beryllium compounds, Davies and Wilson (1948) has described the radiographic Harding (1950) succeeded in causing pulmonary appearance of the lungs as being in three stages: granulomata in rats after intra-tracheal injection (I) A fine ground-glass granularity through the of a mixture cf beryllium oxide and manganese whole of the lung fields; dioxide. (2) A superimposed recticular pattern; and (3) Very characteristic nodulation. The nodules Clinical Features varying in size from small to quite large, but not Symptoms may arise after a latent period from all cases progress through these stages. the last exposure to beryllium, of a few months Hilar gland enlargement does occur but never to over ten years, and the exposure time need without densities in the lung fields. It is note- only be a few weeks. Although the majority of worthy that the early changes may be so finely patients have worked in contact with beryllium granular that miniature mass radiography may compounds, Sterne and Eisenbud (I951) have not show them. recorded beryllium disease in residents in the near Many of the American articles do not refer to neighbourhood of beryllium extraction plants the results of tuberculin skin tests, but Hardy where the air contained less than ix±g. of beryllium states that in her series of cases, in contrast to million and was as low as sarcoidosis, the responses have not differed from per parts probably those of the On the other o.I ,ug. per million. The disease has also affected general population. copyright. relatives of beryllium workers whose only contact hand, Agate's patient showed a change from a was with soiled working clothes. positive Mantoux reaction of I/I,OOO to negative The onset is insidious with dyspnoea on exer- during the course of the illness, and in Rogers' tion, one of the first complaints. A dry paroxysmal (1957) patient and in two of the author's cases the , fatigue and loss of weight associated with Mantoux test was negative. anorexia are usual and periods of may occur. The has only been performed on a As in sarcoidosis, quite advanced changes may few patients with beryllium disease, and the be present in the lungs without symptoms, and results have either been negative or a non-specific http://pmj.bmj.com/ such cases are discovered on routine chest radio- foreign body reaction. graphy. Biopsy of the liver may reveal a sarcoid-like Physical signs are usually minimal though club- granulomatous reaction indistinguishable from bing of the fingers and crackling rales throughout sarcoidosis. both lung fields and pleural friction have been The Differential described. Enlargement of the liver and spleen Diagnosis be but The differential diagnosis of beryllium disease may found, enlarged superficial lymph on September 28, 2021 by guest. Protected glands are very rare. Skin nodules of the same includes miliary , miliary carcino- type as those seen in sarcoidosis have occurred matosis, and haemosiderosis, but occasionally, and in the author's case linear sarcoid above all else it resembles Boeck's sarcoidosis and infiltrations in the site of previous skin damage the majority of reported cases were first thought by beryllium copper strip were a presenting and to be that condition. unusual feature. There are some differences between the two. For instance, no lesions of the eye, parotid or tonsil have been found in beryllium disease, and Investigative Procedure cervical and axillary node enlargement is rare. As Hardy (1956) has pointed out, many of the No cystic bone changes have ever been reported. laboratory procedures such as total serum proteins The course of beryllium disease tends to be more and globulin, electrophoretic pattern of serum, rapidly downhill than that of sarcoidosis, but these liver function studies, urinary and serum calcium slight differences are not of sufficient importance and urinary steroids may show abnormalities in to tip the scale when faced with a patient. beryllium disease just as they may in sarcoidosis, The original criteria of diagnosis of beryllium and therefore they are of little or no assistance disease established by American workers were: Postgrad Med J: first published as 10.1136/pgmj.34.391.262 on 1 May 1958. Downloaded from 264 POSTGRADUATE MEDICAL JOURNAL May 1958 (I) History of exposure to dusts and fumes of beryllium compounds. (2) Clinical course of the pulmonary syndrome including studies of pulmonary function. (3) Radiographic evidence of granuloma of the :":,;;.....::.,.. lung. (4) Lung biopsy and analysis for beryllium. In 1953, Denardi et al. reported the reliability of skin patch tests carried out with dilute solutions of beryllium salts in distinguishing between * ...... beryllium disease and other conditions which simulate it. They obtained an eczematous reaction beneath the patch tests in 12 cases and a negative response in five other patients with various lung including sarcoidosis...... Van Ordstrand (i954) confirmed the reliability ..... of this method and stated that so far he had no knowledge of a false positive result. In the patient I described in I955 markedly intense eczematous reactions were obtained by ...... patch tests with I per cent. and 2 per cent. solu- tions of beryllium sulphate and nitrate. Usually in epidermal hypersensitivity, positive eczematous patch test reactions subside within a few days, but in this patient an inflammatory reaction was present three weeks later. The skin still showed copyright. and a erythema, scaling, perceptible infiltration; Fic. i.-Positive patch test to beryllium salts after biopsy from the inflamed area revealed pronounced three weeks showing infiltration and pseudo-tuberculous reaction in the dermis, but scaling. insignificant epidermal changes. In order to confirm that this was a specific test, hazardous for a patient so sensitive to again similar patch tests were carried out on over Ioo handle beryllium. normal controls and all were negative. Negative Estimation of in the urine reveal beryllium may http://pmj.bmj.com/ tests were obtained on 30 patients suffering from its presence years after exposure since beryllium sarcoidosis (Geraint James, 1956). is stored in the bones and only very slowly ex- Since that time I have repeated the test on a creted. A positive finding only demonstrates second case of beryllium disease, and I have that the patient has had contact with beryllium knowledge of a third positive patch test which and does not prove that it is the cause of the remained visible for some weeks but in which no patient's disease. biopsy was performed (Jordan, I957). Van Ordstrand reports that beryllium was found This modification of the original patch test in I,ooo urine specimens from healthy present and on September 28, 2021 by guest. Protected appears to be a valuable diagnostic method though former beryllium workers. A negative finding it must be admitted that there is a risk of activating does not exclude beryllium disease, but one iso- the disease by introducing fresh beryllium into lated 24-hour specimen is not sufficient and the patient. repeated tests should be carried out. Even after The importance of obtaining an accurate diag- repeated examinations it has not been possible to nosis would appear to justify this slight risk, and demonstrate the metal in the urine in every case. it is a simpler and even safer method of con- It may be possible to demonstrate beryllium in firming the diagnosis than lung biopsy. skin granulomata and it is usually present in lung It should be understood that patch tests should tissue if a lung biopsy is carried out. It was not be used on any patient who is likely to come found in four out of five lung biopsies performed in contact with beryllium again because Curtis by Denardi et al. (I953). (I951) has shown that it is only too easy to sensi- In the case in which the beryllium was not tize normal individuals. Eight out of I6 of his found the skin patch test proved positive, and control subjects develops eczematous reactions they therefore considered the patch test has super- one to two weeks later. It would be doubly seded lung biopsy as a diagnostic test. The Postgrad Med J: first published as 10.1136/pgmj.34.391.262 on 1 May 1958. Downloaded from lMay I958 SNEDDON: Beryllium Diease 265 patch test has the advantage that it shows the patient has had previous contact with beryllium and that the patient has actually become sensitized. Course and Treatment In to contrast sarcoidosis, the prognosis in ... beryllium disease is not good. Until the intro- duction of steroid treatment reported mortality :r1 was 35 per cent., the patients dying of progressive and cor pulmonale. A few patients have had spontaneous remissions, but A·· some symptoms and radiographic changes re- mained and roughly 50 per cent. of patients have ·;iiii:i4 been left moderately or severely disabled. Recent figures from the Progress Report of the Beryllium Case Registry are more encouraging as ~6· there have been only two deaths amongst ioi cases treated with steroids in I954 and I955. It is believed that the decline in fatality rate can largely be ascribed to the steroid therapy though the decline had begun earlier and may be partly due to the recognition of more early and mild cases. 'rreatment with corticotrophin or cortisone, though not invariably successful, is the only treat- ment of proven benefit. Rogers (1957) has recently reviewed the published accounts of the copyright. use of steroids which are in the main favourable, and describes the in the FIG. 2.- Histological changes of patch test skin showing improvement general sarcoid reaction and no epidermal change. Magni- condition of one case when given short courses of fication times corticotrophin. My patient (Sneddon, I955) has 40. been treated with cortisone, at first ioo mg. daily Neon sign manufacturing. and latterly a maintenance dose of'50 mg. daily. Beryllium alloy manufacturing. Her general condition has improved and the skin Accidental and unforeseen contact may occur, http://pmj.bmj.com/ lesions have disappeared, but there has been no such as the possibility that refuse collectors and radiological improvement. scrap dealers may come in contact with broken Fortunately tuberculosis does not complicate fluorescent tubes or copper alloys of beryllium. beryllium disease, and there has been as yet no It is vital that industry should be aware of the report of tuberculsis in a case treated with steroids. risks of beryllium so that preventive measures may be taken. It was possible to control the Industrial of Beryllium acute pneumonitis caused by beryllium when it Since one of the important criteria of diagnosis became realized that there was a clear-cut relation- on September 28, 2021 by guest. Protected is a knowledge of exposure to beryllium, it is im- ship between the incidence of the disease and the portant to establish those industrial processes concentration of beryllium in the air. which carry the . The following table The prevention of chronic beryllium disease is (Hardy, I956) lists the known risks: not so simple since the amount of beryllium Beryllium metallurgy. necessary to cause the disease may be fantastically Ceramic operations. small. Nor is the incidence amongst those exposed Radio tube manufacturing. high; Sterner and Eisenbud (I95I) quote six cases Atomic energy development. amongst I,700 workers at risk, an incidence of Neighbourhood contamination. only 0.3 per cent. It appears from this low Use of alloys containing more than 4 per cent. incidence and the way the disease behaves that it beryllium. is an allergic reaction rather than a true toxic Extraction of beryllium. process. This seems even more probable in view Fluorescent powder manufacturing. of the evidence in proven cases of skin hyper- Fluorescent lamp manufacturing. sensitivity to beryllium. Fluorescent lamp salvage. Until I955 it had been supposed that beryllium Postgrad Med J: first published as 10.1136/pgmj.34.391.262 on 1 May 1958. Downloaded from 266 POS'IGRAI)UATE MEDICAL JOURNAI, May 1958 copper alloy and she occasionally scratched her hands on this. No evidence of a source of beryllium contamination of the air could be dis- '::.:: :.·::}: covered in the workshop. After leaving this work in 1952 she did only housework and thus had no contact with ::}: beryllium :: for five years before the first skin lesions appeared. ·(.~~}·i··::~·~~ .i On examination in ii .S.;;i:·: .··· June 1957 the only abnor- mality detected was the skin eruption which con- E·:. .· sisted of linear infiltrated reddish blue papules on ..:i the backs of both hands and the sides of several fingers. There were also brownish flat papules .. I to 2 mm. diameter on the flexor aspect of both wrists and some of these were arranged in linear distribution. No abnormal physical signs were found in the chest and there was no enlargement of liver, spleen or lymph glands. ii '':.....i:.· Investigations .wi.· i.. Histological examination of a papule from the right hand showed aggregation of tubercle-like follicles around a larger area of fibrinoid necrosis. No acid-fast or doubly refractile materials were seen. Radiological examination of the chest showed miliary pinhead shadows distributed throughout both These are rather and coarser

lungs. larger copyright. than those seen in our previous cases of beryllium disease. There is also some enlargement of the FIG. 3.- of the case of beryllium hilar glands. disease showing miliary pin-head shadows through- A tomograph confirmed enlargement of the out both lung fields and hilar gland enlargement. hilar lymph nodes. No bony change was present in the hands and feet. alloys containing less than 2 per cent. beryllium Mantoux I/Io,ooo and I/Ioo were negative. these can E.S.R. was in a were safe, but from my experience even 17 mm. one hour and complete http://pmj.bmj.com/ give rise to beryllium disease. The following blood count was normal. brief report of a hitherto unpublished case is in- A patch test, using I per cent. beryllium sul- cluded because it underlines so many features of phate, gave an intensely positive response in 48 the disease, including the mystery of how the hours and a control test with i per cent. lithium patient contracted it. sulphate was negative. The patch test site be- A married woman of 38 developed several came infiltrated and scaly and five weeks later painless red papules on the backs of the hands was easily visible. A biopsy performed at that and fingers and was referred to hospital in June time showed an intense sarcoid granulomatous on September 28, 2021 by guest. Protected 1957. The papules had appeared six months infiltration extending down to the subcutaneous previously. At times they had become ulcerated. fat. For the last two years she had also noticed short- This therefore is another example of beryllium ness of breath on exertion but had otherwise felt disease in a woman whose only contact was with well and had not lost weight. 2 per cent. beryllium copper alloy some three years before she developed symptoms. By the Occupational History time skin lesions took her to her doctor quite From October 1950 to December I952 she had advanced lung changes were present. The diag- been employed by the same firm of precious nosis appears definite in view of the history of metal smelters where my previous case of beryl- contact with beryllium; the lung changes, the lium disease had worked. Her job consisted of histology of the skin lesion and the patch tests drying sheet metal which had been washed in results. plain water in a trough containing sawdust; this she brushed off with a small hand brush. Some Summary of the sheet metal was 2 per cent. beryllium The history and main features of beryllium Postgrad Med J: first published as 10.1136/pgmj.34.391.262 on 1 May 1958. Downloaded from MayT195 SNEDDON: Beryllium Disease 267 disease are described and illustrated a hitherto JAMES, D. GERAI NT (1956), personal comlmulnication. by JORDAN, W. (1957), personal communication. unpublished case report of beryllium disease in a Lancet Annotation (1951), i, 1357. woman whose only contact with beryllium was LEDERER, H., and SAVAGE, J. (I954), Brit. J. industr. Me.l. II, 45. handling 2 per cent. beryllium copper alloy sheets. LLOYD-DAVIES T. A., and HARDING ,H. E. (1950), Ibid. 5, 671. BIBLIOGRAPHY MARRADI FABRONI, S. (1935), Med. d. Lavoro, 26, 297. Progress Report of the Beryllium Case Registry for 1956, Massa- AGATE, J. N. (1948), Lancet, ii, 530. chusetts General Hospital, Boston 14. CHESNER, C. (I950), Ann. intern. .Med., 32, I028. ROGERS, W. N. (1957), Lancet, ii, 267. CURTIS, G. H. (I951), Arch. I)erm. Svph. (A.M.A.), 64, 470. SNEDDON, I. B. (1955), Brit. med. J., i, 1448. DENARDI, J. M. VAN, ORDS'RAND, H. S., CURTIS, ;. H., STERNER, J. H., and EISENBUD, M. (1951), Industr. Hilth and ZIELINSKI, J. (I953), Arch. industr. Hvg., 8, i. Monthly, iI, 104. (ELMAN, I. (I936), .. industr. Hyg., i8, 371. VAN ORDSTRAND, H. S., HUGHES, R., and CARMODY, GRIER, R. S., NAISH, P., and FREIMAN, D. (. (1948), Ibid., M. G. (1943), Cleveland Clin. Quart., 10, io. 30, 228. VAN ORDSTRAND, H. S. (1954), Arch. industr. Hvg., 9, 232. HARDY, H. L., and TABERSHAXW, I. R. (1946), Ibid., 28, 197. \WEBER, H. H., and ENGLEHARDT, W. E. (1933), Z. (;ewHi\'., HARDY, H. L. (1951), Lancet, ii, 448. 10, 41. IHARDY, H. I,. (I956), Amer. Rev. Tuberc., 74, 885. \VILSON, S. A. (1948), Radiology, 50, 770.

RUTHIN CASTLE, NORTH WALES A Clinic for the diagnosis and treatment of Internal Diseases (except Mental or Infectious Diseases). The Clinic is provided with a staff of doctors, technicians and nurses. The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual rainfall is 30.5 inches, that is less than the average for England. The Fees are inclusive and vary according to the room occupied.

For particulars apply to THE SECRETARY, Ruthin Castle, North Wales. copyright. Telegrams: Castle, Ruthin Telephone: Ruthin 66

Bibliography continued from page 247--Professor Niels Danbolt, M.D. BIBLIOGRAPHY KVEINM, A. (1941), Nord. IMed., 9, 196. BESNIER, E. Ann. Derir. (1898), Syph. (Paris), 10, 333. KUTZNITZKY, E., and BITTORF, A. (1915), 11. rced. H'schr., http://pmj.bmj.com/ BOECK, C. (I899), .7. cultan. Dis., 17, 543. 62, I349. BOECK, C. (I916), Arch. Dernm. Syph. (Wien), 73, 71. I,()FGREN, S. (1953), Acta med. scand., 145, 424. BRUINS SLOT, W. J., GOEDBLOEI), J., and GOSLINGS, J. RICKER, WX., and CI,ARK, M/. (1949), Amer. 7. C'lin. Path., (1938), Acta mned. scand., 94, 74. I9, 725. DANBOLT, N. (1954), 'Sarcoidosis, in MacKenna: Modern 'lrends in Dermatology,' London. QUINQUAUD (1892), Antln. Dermr. .Syph. (Paris), 3, 1142. DANLOS (I901), Ann. Dermr. S'vph. (Paris), 2, 576. RIEDER, H. (190o), Fortschr. Rontgenstr., 15, 125. I)ARIER, J., and ROUSSY, G. (1904), Ibid., 5, 144. SAI,VESEN, H. A. (1935), Acta nmed. stand., 86, 127. IHEERFORDT, C. F. (1909), Arch. f. Ophthalm., 70, 254. SCHAUIANN, J. (1936), Brit. J. Dermi., 48, 399. IIUTCHINSON, J. (i898), ' Archives of Surgery,' Hutchinson, TENNESON, NM. (1892), Ann. Derm. ,Syph. (Paris), 3, 1142. 9, 307. \V!I,LIA'MS, R. H., and NICKERSON, D. A. (1935), Proc. Soc. on September 28, 2021 by guest. Protected JIANGLIN(;, 0. (1io9), Fortschr. Ri;ntgenstr., 27, 375. exp. Biol. (N.Y.), 33, 403.

Bibliogvrnalt,Iv colnihlef(ronm tba,e^;8--Loui VSilt-hbachE. lA .D NICKERSON, D. A. (194)), cited by Appel, B., Arch. Derm. Syph. SANDS, J. H., PALMER, P. P., MAYOCK, R. I,., and ('REGER, (Chicago), 43, 172. W. P. (1955), Amer. .. Mled., 9, 401. NITTER, L. (1953), Acta radiol. (Stock/l.) (Suppl.), 105, 1-202. SCADDING, J. G. (1956), Tubercle, 37, 371. PEPYS, J. (1955), Amer. Rev. Tuberc., 71, 49. SCHIER, W. W., ROTH, A., OSTROFF, (., and SCHRIFT, PUTKONEN, T. (1943), Acta derm.-renereol. (St,ckh.) (Suppl.), M. H. (1956), Amer. J. Med., 20, 94. 23, I-I94. SEEBERG, G. (I951), Acta derm.-venereol. (Stockh.), 3I, 426. QUINN, E. L., BUNCH, D. C., and YAG(EI,, E. M. (1955), SILTZBACH, L. E., and EHRLICH, J. C. (1954), Amer. .Med., J. invest. Derm., 24, 595. I6, 790. REFVEM, 0. (I954), Acta med. scand. (Suppl.), 294, 1-146. SILTZBACH, I,. E. (1957), Ibid., 22, 841. REID, J. D. (1956), N.Z. med. J., 55, 275. SONES, M., and ISRAEL, H. L (1954), Ann. intern. MIed., 40, 260. ROGERS, F. J., and HASERICK, J. R. (1I54), J. inrest. Derm., SONES, M., ISRAEL, H. ,., KRAIN, R., and BEERMAN, H. 23, 389. (1955), J. invest. Ierm., 24, 353. ROSTENBERG, A., SZYMANSKI, F. J., BREBIS, G. J., TEILUM, G. (1948), Amer. .7 Path., 24, 389. HAEBERLIN, J. B., and SENEAR, F. E. (1953), Arch. Derin. ZETTERGREN, T,. (1954), Acta ,Soc. Med. upsalien. (Suppl.), Syph. (Berl.), 67, 306. 5, I-I8o.