Thorax 1990;45:899-901 899 Short reports Thorax: first published as 10.1136/thx.45.11.899 on 1 November 1990. Downloaded from

system.' Except for isolated cases of lung Lung fibrosis induced cancer,26 the lungs have not been considered to be specifically injured by Thorotrast. We by Thorotrast report a case of lung fibrosis causing death 45 years after thoracic fistulography with Thorotrast. P De Vuyst, P Dumortier, P Ketelbant, J Flament-Durand, J Henderson, Case report J C Yernault At the age of 18, in 1940 during the second world war, our patient sustained extensive shrapnel wounds to the back of her chest. She Abstract required drainage of bilateral haemothoraces A 63 year old women developed progres- and during her hospital stay an unknown sive shortness of breath, pulmonary amount of Thorotrast was injected to outline hypertension, and respiratory failure thoracic fistulas. She recovered fully and led a and died from pulmonary fibrosis 45 normal life in Canada from 1945 until 1977. years after thoracic fistulography with She smoked about 20 cigarettes a day and Thorotrast. Bouts of acute respiratory worked as a bank employee. Since 1978, failure occurred with features of non- however, she had increasing dyspnoea and cardiogenic pulmonary oedema. Lung reduced effort tolerance and in 1983 was tissue obtained by biopsy and at admitted to hospital in Vancouver with severe necropsy showed abundant radioactive breathlessness and hypoxaemic respiratory particles of thorium dioxide in the lungs. failure. Chest radiographs showed transient The particles were congregated in the alveolar infiltrates and Kerley B lines, consis- walls of blood vessels and in perivascular tent with pulmonary oedema. fibrous zones, consistent with a causal On her return to Belgium in September role of Thorotrast in the development of 1983 physical examination showed bilateral lung fibrosis. It is suggested that the posterior thoracic scars and inspiratory basal fibrosis was due to the combined effects crackles. Chest radiographs showed radio- of alpha radiation on the interstitial opaque tracks of blind fistulas in the mid

perivascular zones and of recurrent pul- zones and a diffuse reticular pattern http://thorax.bmj.com/ monary oedema due to endothelial predominant in the lower lung fields (fig 1). damage. Lung function tests showed a restrictive ven- tilatory defect-forced vital capacity (FVC) 1A44 (predicted 2-73) litres, total lung capacity Thorotrast, which contains radioactive (TLC) 3 02 (predicted 4 36) 1-and a low thorium dioxide and was used formerly as a single breath carbon monoxide transfer factor contrast material, has been shown to cause of 2 8 (predicted 7 7) mmol min-' kPa-' 1-'. Arterial blood gas tensions in room air were: malignant tumours and fibrotic lesions at the on September 30, 2021 by guest. Protected copyright. sites of injection and in the reticuloendothelial pH 7*37, carbon dioxide tension 5-3 kPa, oxygen tension 7-3 kPa. Right heart catheter- isation showed an increased pulmonary artery .ilE iSh pressure (45/20, mean 35 mm Hg) with a -S - *,,_ normal wedge pressure and cardiac output. Chest Department .. s Bronchoalveolar lavage yielded 38 7 x 106 PDeVuyst P Dumortier cells with a normal differential count. There J C Yemault had been no chronic drug intake, no Pathology occupational dust exposure, and no domestic Department, Erasme exposure to birds or moulds. Other investiga- Hospital, Free University of Brussels, tions (including tests for autoantibodies) gave Brussels, Belgium normal results apart from a haemoglobin con- J Flament-Durand centration of 18 2 g/dl and a serum potassium P Ketelbant concentration of 3-3 mmol/l. In autumn 1983 Department of the patient had a sudden exacerbation with Medicine, Ottawa General Hospital and hypoxaemia and radiographic signs of pul- University of Ottawa, monary oedema. At open lung biopsy through Ontario, Canada a left thoracotomy almost complete pleural J Henderson fusion was noted. Histological examination Address for reprint requests: ...... in Dr P De Vuyst, Service de showed subpleural fibrosis, particularly Pneumologie, H6pital relation to blood vessels within the lung Erasme, Route de Lennik 808, B-1070, Bruxelles, parenchyma (fig 2a). Transparent refractile Belgium. Figure I Chest radiograph showing a radio-opaque irregular particles were easily detected in the Accepted 20 June 1990 track in the right mid zone. fibrous zones (intermingled with anthracotic 900 De Vuyst, Dumortier, Ketelbant, Flament-Durand, Henderson Yernault

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,. X a Figure 2 (a) Histological section ofthe lung biopsy specimen showing perivascular and interstitialfibrosis with particulate deposits (scale bar 100 gm). (b) Histoautoradiograph of the lung biopsy specimen showing short and straight tracks indicating alpha emnissionfrom particles of thorium dioxide.

pigment) and in the walls of small vessels in alpha particles in great quantities over pro- both giant cells and endothelial cells, suggest- longed periods."' Fibrosis has also been ing that they had passed through the vessels. found frequently near the injection sites as a The pulmonary arteries had normal or mildly result of extravasation in subcutaneous tissue8 thickened media but no signs of veno- as well as in the reticuloendothelial system. occlusive disease, our presumed diagnosis. Thus liver cirrhosis, fibrosis of the spleen, and Only supportive treatment was given. myelofibrosis may occur.9 The patient returned to Canada and died in Our patient died from lung fibrosis 45 years October 1985. Necropsy confirmed severe after the injection of Thorotrast into her pulmonary fibrosis, with acute bilateral thoracic fistulas. Several features are consis- pneumonia as the immediate cause of death; tent with a causal role of thorium in the mild hepatic cirrhosis was also present. induction of her lung fibrosis. The first is the Mineralogical and autoradiographic studies presence of abundant thorium dioxide parti- were performed on a lung biopsy sample and cles in the lung sections, particularly in the http://thorax.bmj.com/ on lung, liver and sleen necropsy samples. In fibrous zones and in the vascular walls. the lung biopsy specimen histoautoradio- Histologically, the perivascular fibrosis sug- graphy showed abundant short and straight gests that the offending agent may have tracks typical of alpha emission from the entered the lungs via the bloodstream. It is refractile particles (fig 2b). These were iden- conceivable that radioactive thorium particles tified as thorium particles (0-1-20 ,um in within the endothelial cells of the pulmonary diameter) by analytical electron microscopic capillaries could lead to modification of their studies using an x ray dispersive spectrometer. permeability, and thus explain the episodes of on September 30, 2021 by guest. Protected copyright. Autoradiography of digested necropsy non-cardiogenic pulmonary oedema. Lung samples showed 131 370 emissions of radio- fibrosis may result from chronic or recurrent activity a day per gram of dry lung tissue, pulmonary oedema, as in mitral stenosis.'° 135 822 from liver tissue, and 577 548 from In addition, radiation is a well known cause spleen tissue. A cumulative radiation dosage of lung fibrosis and Thorotrast has been was extrapolated from these data on the fol- implicated in the development of fibrosis in lowing basis:7 an energy value of 4 MeV for other organs. Determination of the radiation alpha emission by thorium, a quality factor of dose to a target tissue is difficult,5"' and cal- 15 for alpha emission, a conversion factor of culation of the total cumulative radiation dose 624210 for the transformation of MeV into to the lungs is impossible because the initial rads, an exposure of 16 425 days (45 years), injected doses and the change in thorium and a dry:wet weight ratio of 0-1. The cal- dioxide concentration in the lung parenchyma culated dose is about 210 rem (2-1 Sv), or 14 over 45 years are not known. The doses to rad (0-14 Gy). tissues adjacent to the surface of Thorotrast aggregates, however, are considered to be very high,'2 and this is supported by the appear- Discussion ances of the autoradiographs of the lung sec- Thorotrast has been associated with long term tions from our patient. complications, particularly malignant tumours There were no occupational, environmen- developing either near injection sites (thoro- tal, or drug related causes for lung fibrosis and trastomas) or in the reticuloendothelial sys- no apparent systemic disease. We infer there- tem. Thorium dioxide is retained in the reti- fore that Thorotrast was the cause of the lung culoendothelial system, from which it emits fibrosis. We can find no previous reports of Lungfibrosis induced by Thorotrast 901

lung fibrosis due to Thorotrast despite the We thank Mr J Bette for his help in calculating the radiation dosage; Professor C A Wagenvoort for reviewing the tissue many thousands of patients injected with it.239 sections; Professor D V Bates, who referred the patient; and The type of injection (thoracic fistulography), Dr M Jane Thomas for the necropsy report.

however, appears to have been rare. Among Thorax: first published as 10.1136/thx.45.11.899 on 1 November 1990. Downloaded from 168 patients described by Boyd et al3 who received Thorotrast, 141 had intra-arterial 1 Abbatt JD. History of the use and toxicity of Thorotrast. injections and 27 cerebral ventricular or sub- Environ Res 1979;18:6-12. arachnoid injections. 2 Janower ML, Miettinen OS, Flynn MJ. Effects oflong-term Thorotrast eposure. Radiology 1972;103:13-20. Particles were found in the liver and spleen 3 Boyd JT, Langlands AO, Maccabe JJ. Long-term hazards of of our patient and microscopy of the lung Thorotrast. Br Med J 1968;ii:517-21. tissue suggested transendothelial passage. 4 Mori T, Maruyama T, Kato Y, Takahashi S. Epidemiological follow-up study of Japanese Thorotrast Probably thorium particles were resorbed by cases. Environ Res 1979;18:44-54. lymphatics from the tissue around the fistulas 5 Looney WB. An investigation of the late clinical findings following Thorotrast (thorium dioxide) administration. and passed into the bloodstream. The AJR 1960;83:163-85. presence of thorium particles in the blood 6 Abrahamson L, O'Connor M, Abrahamson M. Bilateral vessel walls suggests that this "embolisation" alveolar lung carcinoma associated with injection of Thorotrast. Ir J Med Sci 1950;6:229-35. process was continuing at the time of lung 7 International Commission on Radiological Protection. biopsy, which is consistent with the episodes Individual monitoringfor intakes of radionuclides by work- our ers. Report of a task group. Oxford: Pergamon Press, of pulmonary oedema that characterised 1988:201-7. (ICRP publication 54.) patient's illness. It is also possible that 8 Dahlgren S. Effects of locally deposited colloidal thorium thoracic lymphatic drainage was impaired by dioxide. Ann N Y Acad Sci 1967;145:786-91. 9 da Silva Horta J. Late effects of Thorotrast on the liver and adhesions between the parietal and visceral spleen, and their efferent lymph nodes. Ann N Y Acad Sci pleura, and by obstruction due to thorium 1967;145:676-99. 10 Fraser RG, Pare JAP. Diagnosis ofdiseases ofthe chest. Vol 2. induced fibrosis'3 in thoracic lymph nodes, 2nd ed. Philadelphia: Saunders, 1978:1217-27. thus reducing the clearance of lung particles 11 Grillmaier R, Muth H. Radiation dose distribution in lungs and increasing their retention in the inter- of Thorotrast patients. Health Phys 1971;20:409-19. 12 Kaul A, Foll U, Haase V, Palme G, Riedel W, Stoepmann stitium of the lung. HJ. Microdistribution of Thorotrast and dose to cellular We conclude that lung fibrosis should be structures. Environ Res 1979;18:13-22. 13 Bensinger TA, Keller AR, Merrell LF, O'Leary DS. considered as a late complication of thoracic Thorotrast-induced retriculoendothelial blockade in man. fistulography with Thorotrast. Am J Med 1971;51:663-8.

Thorax 1990;45:901-2 tion of a mass in the right lung. Preoperative Adult respiratory pulmonary function tests showed a one second

forced expiratory volume (FEVy) of 0-96 litres http://thorax.bmj.com/ distress syndrome after (60% predicted) and a forced vital capacity (FVC) of 1-62 1 (70% predicted). When she limited resection of was breathing air her pH was 7 40, arterial carbon dioxide tension (Paco2) 4-0 kPa, and adenocarcinoma of the arterial oxygen tension (Pao2) 8 5 kPa. No evidence of mediastinal disease was seen on a lung chest computed tomogram or at mediastino-

scopy. Right upper and middle lobectomies on September 30, 2021 by guest. Protected copyright. were performed. She was extubated without Sherif El Bayadi, David B Ettensohn, difficulty two days later. On the third post- John Yashar operative day she developed mild dyspnoea. This rapidly progressed in severity and diffuse bilateral alveolar infiltrates were noted on her chest radiograph. Abstract Her temperature was 38°C and white blood Brown University Two cases of the adult respiratory dis- cell count 12 2 x 109/1 (90% segmented Program in Medicine, tress syndrome developed after limited forms, 4% lymphocytes, 3% band forms, and Roger Williams resection for lung carcinoma. No other 3% monocytes). Arterial blood gas analysis General Hospital, Memorial Hospital of known precipitants were evident. The while she breathed oxygen (fractional inspired Rhode Island, adult respiratory distress syndrome is a oxygen (FIo2) 60%) showed: pH 7 40, Paco2 Providence, Rhode clinical expression of acute lung injury' 5-3 kPa, and Pao2 4-9 kPa. She was intubated; Island, USA were and S El Bayadi that may arise from various insults and urine, blood, and sputum cultured; D B Ettensohn include air and blood borne factors.2 empirical treatment with gentamicin and Department of Tumour related blood borne factors may mezlocillin was started. Pulmonary capillary Surgery have contributed to lung injury in these wedge pressure was 8 mm Hg and cardiac J Yashar cases. output was 5 90 1/min. Bronchoscopy showed Address for reprint requests: scanty mucus in the left lower lobe bronchus Dr David B Ettensohn, Division of Pulmonary and an intact anastomotic site. She did not Medicine, Memorial Case reports respond to treatment and died on the seventh Hospital of Rhode Island, Pawtucket, Rhode Island CASE 1 postoperative day. At necropsy the lung 02860, USA. A 71 year old woman with a history of showed changes consistent with the adult Accepted 20 June 1990 obstructive airways disease underwent resec- respiratory distress syndrome with no