November 1974 The Journal oJ" P E D I A T R I C S
Complete left bundle branch block in idiopathic pulmonary hemosiderosis The case of a young boy is reported in whom proved pulmonary hemosiderosL~ of unknown etiology was associated with disease of the myocardium and of the conducting system, as evidenced by complete LBBB and by elevation of left ventricular end-diastolic pressure. This appears to be the eleventh case of this ill'understood association, and the third case with a diagnosis" of LBBB. The suggestion is advanced that the factor which could account for the involvement of both the heart and the lungs in this disorder may be a structural abnormafity of the capillaly walls.
W. E. Gaum, M.D.,* and K. Aterman, M.D., D.Sc., F.R.C.Path., Halifax, N. S., Canada
I D I O P A T H I C p u l m o n a r y h e m o s i d e r o s i s is a wellk n o w n entity. Its association w i t h cardiac disease, however, has only infrequently been reported. It was, t h e r e f o r e , c o n s i d e r e d o f i n t e r e s t to describe s u c h a case, in w h i c h t h e r e was E C G e v i d e n c e of c o m p l e t e LBBB associated with t h e typical picture of p u l m o n a r y h e m o siderosis, a n d to review s o m e o f the o t h e r p u b l i s h e d reports of this association.
CASE REPORT Clinical history and findings. In March, 1972, a 15 8/12-yearold boy was referred to the cardiac service of the Izaak Walton Killam Hospital for Children for the investigation of cardiomegaly. In December, 1970, he had sought medical attention elsewhere because of fatigue, pallor, and "spitting up" of blood. He also complained of a persistent cough. Although neither the pattern nor the occurrence of the abdominal pain, of which he complained at the time, was typical, a barium study had suggested the presence of a duodenal ulcer, and his anemia was attributed to bleeding from it. He was treated by transfusion and placed on a bland diet with supplemental iron. In the spring of 1971, however, he required another blood transfusion. In September of that year he complained of increasing shortness of From the Depco'tments of Pediatrics (Cardiology) and Pathology, Dalhousie University. and the lzaak Walton Killam Hospital for Children. *Reprint address:Department of Pediatrics, lzaak Walton Killam HospitalJbr Children, 5850 UniversityA re., Halff'ax, N~ S., Canada, B3J 3G6.
breath with exertion, orthopnea, and "hemoptysis" of about 4 oz/day. Physical examination. At the time of admission to this hospital the patient still complained of dyspnea, cough, and occasional spitting of blood. He could climb only one flight of stairs. His height was 150 cm; weight, 39 kg. The chest was clear. The pulse was 52 beats/min, with occasional ectopic beats. The blood pressure was 90/60 mm Hg. The apica ! impulse was slightly displaced to the left. A paradoxically split $2 with a soft systolic ejection murmur at the apex could be heard. There was no sign Abbreviations used ECG: electrocardiogram VCG: vectorcardiogram Hgb: hemoglobin WBC: white blood cell BUN: blood urea nitrogen LBBB: left bundle branch block PAS: periodic acid-Schiff of heart failure, and no significant changes were found in other organ systems. The chest roentgenogram (Fig. 1) showed slight left ventricular prominence. There were bilateral pulmonary opacities in the mid-lung zones, with the apices and bases relatively clear. R0entgenograms of nasal cavities showed them to be clear. ECG (Fig. 2) and VCG showed left atrial enlargement and complete LBBB. Laboratory data. On admission the Hgb was 9.6 gm/100 ml, the hematocrit 30.7%. The red cells showed slight hypochromia, anisocytosis, and poikilocytosis. The reticulocyte count was 3.2%. The serum iron was 56 p,g/100 ml, the iron-binding
Vol. 85, No. 5, pp. 633-638
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The Journal of Pedia(rics November 1974
Fig. 1. Roentgenogram of chest showing left ventricular prominence and a reticulo-nodular interstitial pattern,
Fig. 2. ECG showing complete left bundle branch block. capacity 380 txg/100 ml. WBC, 7,400 ( n e u t r o p h i l s 66%, eosinophils 2%, l y m p h o c y t e s 30%, m o n o c y t e s 2%). The eosinophil count was variable, with a maximum of 10% out of 6,900. The bone marrow showed slight erythroid hyperplasia With normoblastic maturation. Iron stains were negative. The sedimentation rate was 14 mm/hr. Stools gave a negative reaction for occult blood. Urinalysis was normal. BUN, 13 rag/100 ml; serum creatinine, 0.8 rag/100 ml; cold agglutinins, 1:128 (increased). Gastric washings showed moderate numbers of hemosiderin-laden macrophages. Serum samples were submitted for fluorescent antibody determinations. They gave negative results for antithyroid, anti-nuclear, and antimyocardial antibodies. Cardiorespiratory findings. Cardiac catheterization performed prior to lung biopsy showed moderately elevated left ventricular end-diastolic (20 mm Hg) and pulmonary artery wedge pressures (a, 23 mg Hg; "v;" 28 mm Hg). Left ven-
triculography revealed a dilated and poorly contractile left ventricle. Oxygen saturations and cardiac output were normal (Fick). Pulmonary function studies were within normal limits. In summary, there was evidence of left ventricular disease by clinical examination, ECG, VCG, catheter data, and angiography. The presence of a complete LBBB and the elevation of left ventricular end-diastolic pressure indicate disease of both the conduction system and the myocardium. Diffuse myocardial fibrosis could have accounted for both these changes. Biopsy of the Lung. An open biopsy of the lung was performed and a fragment of lung, 1.0 by 0.5 by 0.5 cm, was submitted for h!stologic examination. It had a peculiar slate-gray color with a distinct brownish tinge. An imprint of the specimen yielded a large number of fairly uniform-appearing macrophages containing numerous granules of hemosiderin. On frozen section these cells could be seen to fill the respiratory spaces Of the lung. A Prussian blue reaction performed on a thin slice of the specimen gave a distinct blue color indicative of hemosiderosis. Permanent sections of the lungs confirmed this impression (Figs. 3 to 5). They showed many of the features which have been described in pulmonary hemosiderosis. 13 In several areas the alveolar septa were seen to be still thin and delicate (Fig. 3), but the capillaries were distinctly distended, and extravasations of red cells into the alveolar spaces were not uncommon. Throughout the lungs the alveolar lining ceils were distinctly prominent, in contrast to the flat lining cells of the capillaries and vessels. In most of the respiratory spaces aggregates of variable numbers of large mononuclear cells containing fine and coarse granules of brown pigment were present (Figs. 3 and 4). With stains for iron (Fig. 5) these granules were shown to be hemosiderin. These stains also demonstrated a focal iron incrustation of basement membranes and of the walls of some vessels, which in these areas showed fragmentation of the elastic fibers and some focal intimal proliferation. In addition to these changes a marked interstitial fibrosis of the lungs (Fig. 4) resulted in thickening of the alveolar septal wails and in accentuation of the connective tissue framework. This was caused by the deposition of a distinctly fibrillar, but rather avascular, connective tissue without demonstrable elastic fibers. As in many other processes characterized by phagocytosis, PAS stains demonstrated a saliva-resistant, PAS-positive material in many of the pigment-laden macrop hages and alveolar lining cells (Fig. 4). No giant cells, nuclear or cytoplasmic viral inclusions, or aggregates of inflammatory cells were seen. The pleura showed distinct thickening with a deposition of brownish granular pigment. The bronchi and bronchioles were normal and, apart from the focal intimal proliferation and iron incrustation already mentioned, the pulmonary vessels did not present significant changes. A diagnosis of pulmonary hemosiderosis of unknown origin was made. The patient Was treated with prednis0ne (10 mg twice a day) before discharge and continued on digoxin (0.125 mg twice a day). Symptomatically he is now much improved. One year after discharge he has had no new pulmonary symptoms. His cardiac physical findings, ECG, and chest roentgenogram, however, remained unchanged.
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LBBB and pulmonary hemosiderosis
Fig. 3. Microphotograph of section from lung biopsy, to show some thin alveolar septa, extravasated red cells, and pigment-carrying mononuclear cells. (10% buffered formalin, 7 ~,, hematoxylin and eosin~ x 510.)
DISCUSS.ION Although idiopathic pulmonary hemosiderosis had apparently been noted already by Virchow, it was only in 1921, when Ceelen described two instances, that this d i s o r d e r was clearly recognized, k < s It is not widely known, however, that Ceelen 4 was also the first person to draw attention to changes in the heart occurring in this condition. In m o s t instances in which cardiac m a n i f e s t a t i o n s have been m e n t i o n e d since t h e n in idiopathic pulmonary hemosiderosis, either clinically or at necropsy, attention was paid mainly to the enlargement of the heart, 6 particularly to the degree of right ventricular hypertrophy, dilatation, and failure, 3 which were interpreted as a consequence of the pulmonary changes. 2 "Changes are confined to, or maximal in, the lesser circulation. Myocardial changes, if present, are insufficient to account for the pulmonary lesions. ''l Soergel and Sommers, 2b however, stressed that pulmonary hyp e r t e n s i o n and cor p u l m o n a l e appear to be " r a r e features" of pulmonary hemosiderosis and Otto 3 considered that the pathogenesis of the cor pulmonale was still unclear. Occasionally degenerative, mainly fatty, changes of the myocardium have been mentioned, 2~,b, < 7-9presumably a consequence of the anemia occurring in pulmonary hemosiderosis. Ceelen's 4 findings, however, were different. He noted on microscopic examination of the heart of his second patient that the myocardium con-
tained foci of lymphocytic and polymorphonuclear aggregates which w e r e " . . , in no way sufficient to explain the extraordinarily pronounced induration of the lungs" (our translation). Ceelen 4 was also the first worker to point out that none of the other organs examined contained deposits of i r o n . a finding amply confirmed since then i, s, 10, n In 1939 Gellerstedt5 reported the necropsy findings in a boy age 15 yr who, in addition to the pulmonary changes of hemosiderosis, also had a "subchronic myocarditis o f i n f l a m m a t o r y c h a r a c t e r , " although Waldenstrom, 12 Who later described the clinical aspects of this case, stated that ECG's about 8 mo before death were normal. Gellerstedt 5 suggested that the common factor in the lesions found in his case may well have been an agent "damaging the heart as well as the p u l m o n a r y c a p i l l a r i e s " (our translation), p e r h a p s , in view of the periodic occurrence o f a p e r i p h e r a l eosinophilia, "a type of allergic reaction by endogenous antigens." Shortly afterward, Glanzmann and Walthard 7 described a young girl who, at the age of 6 yr, had suffered from scarlet fever and who was found at necropsy, 7 yr later(to have focal embolic nephritis, severe pulmonary hemosiderosis, and a moderately pron o u n c e d " m y o c a r d i t i s interstitialis c h r o n i c a . " A few years later Scheidegger and Dreyfus 13also reported, in a girl aged 1 yr, pulmonary hemosiderosis with myocardial changes of fat deposition, focal lymphocytic and histio-
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The Journal of Pediatrics November 1974
Fig. 4. Another field from the same section as Fig. 3, to show extensive fibrosis and massive accumulation of phagocytic mononuclear cells. (10% buffered tbrmalin, 7 /~, periodic acid--Schiffstain; x 190.)
cytic cell infiltrates, and slight scar tissue formation. They considered these changes to be similar to those reported by Ceelen 4 and Gellerstedt, s but Soergel and Sommers 2b viewed them as "acute, diffuse, nonspecific myocarditis." The next report was stated by Soergel and Sommers 2b to be the case of Halm~gyi and associates, 14 but these workers spoke only of "cot pulmonale" and nowhere mentioned the presence of myocarditis, so that their clinical study cannot be included in this review. In 1957 Soergel, 1~however, described two cases, one of which was that of a girl aged 13 yr, who died of acute heart failure and who was found to have a "mild, focal, subacute and chronic myocarditis," Soergel's l~ second case was that of a boy, anemic from the age of 5 yr, who had at necropsy 10 yr later a slight left ventricular hyp e r t r o p h y and a "nonspecific, subacute, and chronic myocarditis with focal fibrosis of the myocardium and endocardium." Campbell and Macafee, 11 however, rightly pointed out that a detailed histologic description of these changes was not given by Soergel. ~~They ~ themselves presented another, beautifully illustrated, case of a 14-yr-old boy who was first seen at the age of 7 yr. The heart was enlarged, with right ventricular hypertrophy, and with left ventricular dilatation with patchy fibrosis and focal endocardial thickening. The myocardium cont a i n e d infiltrates of p o l y m o r p h o n u c l e a r leukocytes, some eosin0phils, lymphocytes, and large mononuclear
cells. C a m p b e l l and Macafee, H therefore, s p o k e o f a "severe myocarditis." Murphy 6 similarly concluded that an "active myocarditis with considerable areas of scarring" was present in his case of a young man in whom a diagnosis of diabetes was made when he was 19 yr old. Two years later a roentgenogram of the chest showed "miliary nodutation." Another 2 yr later hemoptysis and anemia developed, with a transient eosinophilia and an intermittent right bundle branch block which finally disa p p e a r e d , although tracings later s h o w e d f r e q u e n t episodes of 2:1 heart block. A year later the diagnosis of pulmonary hemosiderosis was confirmed by lung biopsy. A n E C G showed complete heart block with LBBB. A t necropsy the heart presented fibrosis of the posterior wall extending up to the endocardium, and a cellular infiltrate of polymorphonuclear leukocytes and of eosinophils, particularly in the subendocardial tissue of the left ventricle and atrium. Murphy's 6 case is noteworthy because it appear s to be the first instance in which cardiac manifestations other than acute heart failure have been noted clinically. In other cases quoted so far evidence of myocardial involvement was found only at necropsy. Of additional interest is the occurrence of LBBB in Murphy's 6 case, since this sign was also observed in the case presented here and in the case reported by Brune et al. 15These workers described a 20-yr-old man with clinical and radiographic
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LBBB and pulmonary hemosiderosis
Fig. 5. Stain for iron in the same section as Figs. 3 and 4, demonstrates the extensive deposits of hemosiderin. (10% neutral buffered formalin, 7 t~, Prussian blue reaction; x 190.)
evidence of primary pulmonary hemosiderosis of about 289 yr standing, who also had a gallop rhythm, a large cardiac silhouette on roentgenograms, and E C G and V C G evidence of incomplete LBBB with frequent extrasystoles, attributed to a cardiomyopathy of unknown etiology. Unfortunately, as in our case, no histologic heart findings were available. The authors, however, pointed out that the signs of.pulmonary hemosiderosis were present some time before cardiac manifestations became apparent, and emphasized this point by quoting a n o t h e r case r e p o r t e d by M o n n e t and associates. 16 These workers described a child aged 13 yr who had signs of pulmonary hemosiderosis followed 5 yr later by cardiac failure. The necropsy findings confirmed the diagnosis o f p u l m o n a r y h e m o s i d e r o s i s associated with fibrosis o f the m y o c a r d i u m , p a r t i c u l a r l y o f the left ventricle. There are thus 11 published instances in which an association of pulmonary hemosiderosis with myocardial changes has been established. In three of these LBBB was demonstrated during life, A n involvement of the left bundle or of the myocardium in general by the hemosiderotic process itself cannot be postulated, since there appears to be general agreement that iron has not been demonstrated in the myocardium in any of the instances of idiopathic pulmonary hemosiderosis studied so far., No explanation of the observed association of
these myocardial changes with idiopathic pulmonary hemosiderosis can, in fact, be given at this stage. Elliot and Kuhn 17 had at one time suggested that there existed in pulmonary hemosiderosis widespread abnormalities of the pulmonary capillaries in the form o f damage to the basement membrane, presumably caused by the deposition of i m m u n e complexes. Since their case subsequently turned out to be an unusual instance of disseminated lupus erythematosus, 18 their findings cannot be applied to the defect in idiopathic pulmonary hemosiderosis in general. An ultrastructural abnormality of the basement membrance of an alveolar capillary has, however, been described by Hyatt and associates ~9in the case of a young child suffering from idiopathic pulmonary hemosiderosis. The authors attributed the leakage of capillary contents into the alveolus to this defect in the capillary basement membrane. No deposition of protein in the basement membrane suggestive of immune complexes was found, in keeping with the absence of demonstrable serum antibodies. This observation is of interest in view of the failure to demonstrate antinuclear or antimyocardial antibodies in the case presented here. Gellerstedt's6 pioneering suggestion of a possible allergic reaction due to endogenous antigens has, therefore, so far not been substantiated. It would, however, be tempting to postulate a common link between the pulmonary and myocardial changes in pulmonary hemosiderosis in
Gaum a n d A t e r m a n
the form of more widespread capillary damage involving both organs, as Ceelen 4 a n d Gellerstedt 6 had already suggested. This a s s u m p t i o n of a c o m m o n vascular factor would still not explain why the deposition of hemosiderin is so p r o m i n e n t in the lungs b u t absent in the myocardial lesion, but it offers the possibility of a unifying hypothesis which should be confirmed or refuted by ultrastructual studies in future instances. We should like to thank Dr. K. E. Bove, The Children's Hospital, Cincinnati, Ohio, for the determination of antibodies. The illustrations were prepared by the audio-visual department of Dalhousie University.
The Journal o f Pediatrics November 1974
1. Wyllie, W. G., Sheldon, W., Bodian, M., and Barlow, A.: Idiopathic pulmonary hemosiderosis (essential brown induration of the lungs), Quart. J. Med. 17: 25, 1948. 2a. Soergel, K. H., and Sommers, S. C.: Idiopathic pulmonary hemosiderosis and related syndromes, Am. J. Med, 32: 499, 1962(a). 2b. Soergel, K. H., and Sommers, S. C.: The alveolar epithelial lesion of idiopathic pulmonary hemosiderosis, Am. Rev. Resp. Dis. 85: 540, 1962. 3. Otto, H.: Die Atmungsorgane, in Altmann, H.-W., et al., editors: Handbuch der allgemeinen Pathologie, vol. 3: part 4, Die Organe, Berlin, 1970, Springer Verlag, p. 1. 4. Ceelen, W.: Die Kreislaufstoerungen der Lungen, in Henke, F., and Lubarsch, O., editors: Handbuch der speziellen pathologischen Anatomie und Histologie, Atmungswege und Lunge, vol. III. part 3, Berlin, 1931," Springer Verlag, p. 1. 5. Gellerstedt, N.: Ueber die "essentielle" anaemisierende Form der braunen Lungeninduration, Acta Pathol. Microbiol. Scand. 16: 386, 1939. 6. Murphy, K. J.: Pulmonary hemosiderosis (apparently idiopathic) associated with myocarditis, With bilateral penetrating corneal ulceration, and with diabetes mellitus, Thorax 20: 347, 1965. 7. G l a n z m a n n , E., and Walthard, B.: Idiopathische progressive braune Lungeninduration im Kindesalter mit
hereditaerer Haemoptyse, intermittierunder sekundaerer Anaemie und Eosinophilie und embolischer Herdnephritis, Monatsschr. Kinderheilkd. 88: 1, 1941. Wigod, M.: Idiopathic pulmonary hemosiderosis: Report of a case in early childhood with severe anemia, N. Engl. J. Med. 253: 413, 1955. Florian, J.: Zur Klinik der idiopathischen Lungenhaemosiderose der Erwachsenen, Munch. Med. Wochenschr. 98: 1597, 1956. Soergel, K. H.: Idiopathic pulmonary hemosiderosis: Review and report of two cases, Pediatrics 19: 1101, 1957. Campbell, S., and Macafee, C. A. J.: A case of idiopathic pulmonary hemosiderosis with myocarditis, Arch. Dis. Child. 34: 218, 1959. Waldenstrom, J.: Relapsing, diffuse, pulmonary bleeding or hemosiderosis pulmonum--a new clinical diagnosis, Acta Radiol. 25: 149, 1944. Scheidegger, S., and Dreyfus, A.: Braune Lungeninduration des Kindes mit sekundaerer Anaemie, Ann. Paediatr. (Basel) 165: 2, 1945. Halmfigyi, D., Felkai, B., Soev6nyi, E., Weber, A., Czipott, Z., Kov~ics, G~, and Steiner, B.: Der kleine Kreislauf bei essentieller Lungenhaemosiderose, Z. Kreislaufforsch. 45: 40, 1956. Brune, J., Viala, J.-J., Dorsit, G., Rousset, H., and Galy, P.: Une observation d'h~mosiderose pulmonaire probablement primitive avec myocardiopathie, Lyon Med. 223:. 427, 1970. Monnet, P., Larbre, F., Verney, R., and Besset, A.: Hgmosiderose pulmonaire idiopathique avec importantes lgsions myocardiques, Pediatrie 16: 194, 1961. Elliot, M. L., and Kuhn, C.: Idiopathic pulmonary hemosiderosis--Ultrastructural abnormalities in the capillary walls, Am. Rev. Resp. Dis. 102: 895, 1970. Kuhn, C.: Systemic lupus erythematosus in a patient with ultrastructural lesions of the pulmonary capillaries previously reported in the Review as due to idiopathic pulmonary hemosiderosis, Am. Rev. Resp. Dis. 106: 931, 1972. Hyatt, R. W., Adelstein, E. R., Halazun, J. F., and Luken, J. N.: Ultrastructure of the lung in idiopathic pulmonary hemosiderosis, Am. J. Med. 52: 822, 1972.