Aota Pathl. J p . 33(6): 1223-1231, 1983

GENERALIZED FIBROSIS ASSOCIATED WITH PULMONARY ASBESTOSIS

Hiroshi KOBAYASIXI, Akiharu OKAMURA, Yoshihiaa OHNISHI, Ariyoshi KONDO,* Toshio YAMAMOTO,** Hidehiro OZAWA,**

and Takashi MORITA*** Departmente of Pathology and * Internal Medicine, NiiQata Univer&ty SG?WOt

of Medicine +* D e p a r t d of Anatomy, NiiQata University &lml of DerJietry

*** Department of Pathology, Shinrahn Hoepitid, NiiQata

An autopsy case of pulmonary asbestosis with fibrosis of various organs was reported. Pulmonary carcinoma and glomerulonephdtis were com- plicated. Asbestos bodies (ABs) and fibers (AFs) were identified in the organs with fibrosis such as the lung, liver, kidney, heart, and thyroid gland by electron microscopy and digestion method. Moreover, we identified AFs in the spleen by electron microscopy which had been resected due to idiopathic portal hypertension six years previously. It is suggested that AFs can be transported to various organs and persist for a long period of time to cause pathological changes there. ACTA PATHOL. JPN. 33: 1323-1231, 1983.

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Pulmonary asbestosis was reoognized as a clinical entity in 19272, and the h t case of bronchogenic carcinoma was described in 1936.8 WAGNER et al?5 demonstrated an increased incidence of pleural mesothelioma in South &&an asbestos workers in 1960. Since then, various gastrointestinal malignancies with asbestosis have been discussed. 6,10,13

But other diseases related to asbestosis have been rarely mentioned. LYNSCH and S m 8 showed an autopsy cases of pulmonary asbestosis with which myocarditis, portal cirrhosis, and splenitis were accompanied, but they could not find any asbestos bodies (ABs) and asbestos fibers (AFs) in the extrapulmonary organs except an asbestosis-like body in the spleen. While some investigators reported that they found ABs and AFs in various organs by extraction method',' and an e~periment,~ they did not refer to any pathological changes of the extrapulmonary organs.

We autopsied a case of pulmonary asbestosis with pulmonary carcinoma and fibrosis of various organs such as the liver, kidney, and thyroid gland. Additionally ABs and AYs were detected in each organ not only by digestion method'% but also by electron microscopy. Such a case seems not to have been reported.

Accepted for publication November 30, 1988. ++# fB, FUH WE?, kB SA, ZaW t E F , I.LI* a%, d\W %%, %El f& Mailing address; H. KOBAYASHI, Dept. of Pathology, Niigata University School of Medicine, Asahimachi-dori 1-767, Niigata City 951, JAPAN.

1224 QENERALIZED ASBESTOSIS Acta Pathol. Jpn.

Case Report

A patient, 53-year-old man, was referred to Niigata University Hospital for evaluation of hepatosplenomegdy in Januwy, 1973. Two months prior to admission he had been pointed out hepatosplenomegaly a t periodic medical examination. In his past history he had been admitted to a medical center for hepatomegaly and proteinuria in 1963, but the details were obscure. Significantly he had had a temporary job of asbestos spraying at a construction company from 1962 to 1971. And he had smoked a half pack of cigarettes per day.

On physical examination, the spleen was palpable four finger-breadths below the costal margin and the liver, three finger-breadths on the right midclavicular line. Laboratory data revealed a hematocrit value of 31%, a red blood cell count of 330 x lo4/ cmm, white blood cell count of 6,800/ cmm with normal differential counts and a platelet count of 21.8 x 104/cmm. Liver function test did not reveal any abnormalities. Hepatitis B antigen and antibody were negative. Portal pressure was 290 mmH,O. A chest X-ray film already revealed moderate pulmonary fibrosis, but the details of his job could not be attained. So the clinical diagnosis was idiopathic portal hypertension. A splenectomy and wedge biopsy of the liver were done on July 20, 1973. The resected spleen weighed 840 g and histologically showed moderate congestion and slight perivascular fibrosis without fibroadenia nor sinus hyerplasia. The biopsied liver revealed portal fibrosis (Fig. 1).

In December, 1974, the serum potassium and blood urea nitrogen became to increase slightly. In December, 1976, laboratory data revealed a serum creatinine of 2.2 mg/dl, blood urea nitrogen of 51 mg/dl, uric acid of 12.0 mg/dl, sodium of 136 mEq/

1, potassium of 6.1 mEq/l, and chloride of 113 mEq/l. The serum total protein was 7.2 g/dl with albumin of 3.9 g/dl. Im- munoelectrophoresis showed IgG of 2,58Omg/dl, IgA of 368mg/ dl, and IgM of 151 mg/d . An- tinuclear antibody was negative. Total complement titer was within normal limits. The titer of antistreptolysin-0 was less than 100 Todd units. Urine protein excretion was 1.1 g/day. Urinalysis revealed (+) protein

~-

Fig. 1. Portal fibrosis of the biopsied liver. H.E., xl8.

and negative sugar. So he was diagnosed as suffering from chronic renal failure. Though he had been treated only by dietary cure, the urinary protein had been controlled about 1 g/day and blood urea nitrogen and serum potassium had decreased to 30 mg/dl, 4.9 mEq/l, respectively.

33(6): 1983 H. KOBAYASHI d d. 1226

In December, 1978, dyspnea on exertion appeared. And thechest X-ray film showed diffuse reticular shadows and pleural efi3ions. Anoxia and emmiation increased gradually. He died of respiratory failure in Juxe, 1979.

Autopsy Findings Macroswpiml F a i n g s

The pleural cavities contained much effusions (left; l,OoOml, right; 200ml; bloody). Pleural coverings were thickened over the entire surface of both lungs and adhered to the chest wall. The lungs were firm and showed marked fibrosis (left; 326 g, right; 640 g). Additionally in the left lower lobe some, up to 1 ~ 0 . 8 om sized, white nodules were noted.

The heart showed marked fibrous pericarditis partidy with calcareous deposits and was slightly hypertrophic (410 g). Coronary arteries revealed moderate athero- sclerosis.

The liver weighed 1,200g and slight perihepatitis was noted. On cut surface diffuse fibrosis without regenerative nodules was revealed.

The kidneys were slightly contracted (left; 130g, right; l06g). The fibrous capsules were adherent. The surfaces were finely granular with scattered small cysts. On cut surfaces cortices were atrophic and cortico-medullary junctions were obscure.

The thyroid gland weighed 10.6g and was firm in consistency. On cut surface it showed moderate fibrosis and decrertse of colloid.

The cervical, paratracheal, subcarinel, and pulmonary Mar lymph nodes were moderately swollen with moderate deposition of anthracotic pigments. Mesenteric and retroperitoneal lymph nodes showed moderate swelling with brown-red discoloration.

Bone marrows were red cullular and had firm consistency in examined lumbar vertebrae, rib, sternum, and left femur.

Mioroscqzrical Findings

The pleurae showed fibrino-fibro-purulent pleuritis. The lungs showed diffuse lesions composed of marked interstitial fibrosis mainly around the bronchioles and alveolar ducts with many anthracotic pigments (Fig. 2). The bronchioles were markedly ectatic and in some areas purulent bronchitis was noted. High power magnifica- tion revealed many asbestos (ferruginous) bodies in the fibrotic lesions extraoellulary or in macrophages. By polarized light microscope some needle-shaped substances showed birefringence. Sections taken from the white nodular lesions in the left lower lobe disclosed well differentiated adenocaminoma with no metastasis.

The pericardium showed marked hyalinized thickening, and with polarized light microscope a few birefringent substances were identified in the same arem. Irregular fibrosis without cellular reaction was seen in the myocardium.

The liver demonstrated portal fibrosis that had not so progressed since the time of splenectomy. The liver capsule showed fibrous thickening with small round cell

1226 OENEBbLIZED ASBEST08IS Ada Patlrol. Jpn.

Fig. 2. Pulmonary fibrosis. H.E., x7 . Fig. 3. Nodular lesion of the glomerulus. PAM stain, ~ 3 7 . Fig. 4. Fibrosis of the thyroid gland. H.E., x 7. Fig. 5. Bone marrow( vertebra) showed peritrabecular fibrosis and increased hematopoiesis.

H.E., x16.

infiltrate. Additionally under polarized light microscope birefringent substances were identified in the wedge biopsy as well as that of necropsy.

The kidneys showed generalized glomerular lesion ; hypercellularity and swelling with distinctive lobulation and sclerosis of the glomerular tufts. Additionally, glomerular capillary walls were often double contoured by periodic acid methenamine silver or PAS stains. Sclerotic nodules very similar to those of Kimmelstiel-Wilson disease were found in some glomeruli (Fig. 3). Some tubules were atrophic and some minute adenomatous lesions of the tubules were identified. In the interstitium moderate infiltration of chronic inflammatory cells and focal fibrosis were also noted.

The thyroid gland showed moderate fibrosis with some birefringent long substances and infiltrations of chronic intlammatory cells (Pig. 4).

Bone marrows revealed slight fibrosis of the peritrabecular areas (Fig. 6) . Other hematopoietic parenchyma represented moderate to severe hypercellularity.

Lymph nodes; Pulmonary Mar, subcarinal, and paratracheal nodes had several ABs, but cervical, mesenteric, and retroperitoneal nodes represented no ABs nor fibrosis.

33(6/: 1983 H. KOBAYASXI d d. 1227

Fig. f3a. AB (Ab) and many short AFa (arrow heads) in the phagocytic cell of the lung. x 3,660. 6b. AF (arrow heads) in the meeangiel area of the glomerulus. P, Podooyte; BM, besement membrane. x 13,320. 6c. AF in the interntitiurn of the renal cortex. x 17,000. 6d. AF in the thyroidgland. x 8,900 6e. AF in the reseoten8pleen. x 8,900.

1228 OENEBALIZED ASBESTOSIS Acta Pathl. Jpn.

Electron Mkosmpkal Findings

In the lung many ABs and AFs were distinctively detected not only in the fibrotic areas but also in the phagocytic cells (Fig. 6a). In the liver, several AFs were identified in the portal areas. In the kidney, some AFs were identified in the glomeruli, the site of which was probably mesangial area, and in the interstitium (Figs. 6b, 613). However, electron dense deposit in the glomerular basement membrane was not revealed. We also identified several AFs in the fibrotic foci of the heart as well as the thyroid gland (Fig. 6d).

These AFs were straight and had light and dark bendings that appeared to cross the fiber axis a t the right angles4 and had no tubular structure. And of interest was the fact that several AFs were identified in the paraffin embedded spleen which had been resected in 1973, six years prior to the patient's death (Fig. 6e).

Extradon of ABs

By the digestion methodla, we examinedrandom portions of 10% formalin fixed lung, heart, liver, kidney, pancreas, stomach, colon, regional and distant nodes.

Specimens of 5 g were taken from each of these organs.

ABs were present in all or- gans except the colon. Much more ABs, however, were identi- fied both in the lung and in regional nodes than in other or- gans. The number of ABs in the lung was more than lo4, and that in the regional nodes was about 1,600. In other organs several to more than ten ABs were present.

Enkction of AFs

The sediments obtained by the same method12 were added to by a drop of distilled water and

to electron microscope grids cover- ed with carbon films. As control

study, we examined the routinely used formalin solution and distilled water. AFs were present in all examined organs (Fig. 7), but in the formalin solution and

distilled water any APs were not detected. There were innumerable fibers in the lung and regional nodes. Much less AFs were present in the extrapulmonary organs. AFs

Fig. 7. Extracted AF of the kidney. ~6,120. Inset were shows extracted AB of the kidney. ~90.

33(6): 1983 H. EOBAYASHI d d. 1229

Fig. 8a. X-ray energy spectra of crocidolite had distinct peaks for silicon and iron, and low peaks for magnesium and sodium. 8b. X-ray energy speotra of amosite had no peak for sodium.

Fig. 9a. Diffrsction pattern of amosite. Fig. 9b. Diffraction pattern of anthophyllite.

had various lengths (mean value 6.1 p, n=100). However, their diameters were almost constant (mean value 0.16 p, n=100).

Adytiml Ekctrm Microscopy

Several 0 s which had been identified in each examined organ of Epon embedded specimens and extracted specimens for AE's were reexamined by analytical electron microscopy.

On X-ray energy spectra (Figs. 8a, 8b) and &&action patterns (Figs. 9a, 9b), three kinds of amphiboles; crocidolite(riebeckite) , amosite ( p e r i t e ) , and ferroanthophyllite were detected. But we could not h d any chrysotile asbestos.

LKwtmbn Asbestosis is regarded as an occupational disease by inhalation of AF's which

leads to progressive fibrosis and scarring of the lung. The correlation of pulmonary carcinoma and mesothelioma with asbestosis appears to have been established, and moreover a relationship between asbestosis and gastrointestinal malignancies has been d i s c ~ e d ~ J 0 ~ 1 3 But, as far aa we know, other diseases associated with asbestosis have been rarely reported.

Our case of asbestosis showed peculiar changes in various organs. One of them was portal fibrosis of the liver. We identified AFs in these fibrotic foci by electron microscopy and both AJ3s and AFs by digestion method. Since AE's are well known as

1230 QENEEALI!&ED ASBESTOSIS A& Pathol. Jpn.

fibrogenetic substance, it may be acceptable that when they migrate to some organs they act as a fibrogenetic agent. Indeed the migration to various organs of AFs was identified by a few a ~ t h o r s . ~ ~ ~ On the other hand, we could deny toxic chemicals, viral or alcoholic hepatitis, parasites, and malnutrition as the causes of portal fibrosis on account of the clinicopathological data. So in this case portal fibrosis may be due to asbestos.

There have been several reports on the presence of AFs and/or A3s1,7,11 in the kidney, but any renal changes have not been described. Although there is no direct proof of causative relationship between asbestosis and the renal changes, absence of electron dense deposits and similarity of focal lesions to Kimmelstiel-Wilson nodules without evidence of diabetes mellitus are unusual findings of idiopathic membranopro- liferative glomerulonephritis. Similarity to diabetic glomerulosclerosis, which was found in toxic glomerulopathy such as carbon disulphide poisoning,@ and identification of AFs in the mesangium may suggest the possible participation of AFs in development of the glomerular lesion.

The thyroid gland of the case revealed a chronic thyroiditis with moderate fibrosis. ATs were identified by electron microscopy and digestion method. The thyroid lesions could be differentiated histopathologically from Hashimoto’s thyroiditis and Riedel’s struma. In this case we might believe AFs in the thyroid were irritating mechanically and chemically resulting in fibrosis.

Bone marrow showed slight to moderate peritrabecular fibrosis and moderate to severe hyperplasia of hematopoiesis. Moreover, AFs were identified by the digestion method. SELLIKOFF~~ discussed the presence of AFs in the bone marrow. And GERBER~ reported 5 cases of asbestosis with tumors of hematopoietic system; i.e. multiple myeloma, myeloproliferative disorders, and lymphoproliferative disorder (atypical macroglobulinemia). In this case, when we considered the concomitance of peritrabecular fibrosis and AFs, we might believe the role of asbestos as the causal genesis.

AFs have been shown in pleural plaques. The route of AFs arriving to the parietal pleura has been a subject of speculation. TIxoMso~~~ suggested sharp AFs passed directly through the pulmonary tissue and got to the pleura. He also supposed the direct penetration through the diaphragma. Pericarditis and perihepatitis as well as pleuritis of our case might be caused by AFs, because AFs were identified in these lesions.

Additionally, in the spleen resected six years previously t o the patient’s death, several AFs were identiiled by electron microscopy. This wi l l confirm the presence of AFs in the body at least for more than six years. Conversely splenectomy may have facilitated the migration of AFs to various organs, since the spleen is a major organ of the reticuloendothelial system.

Finally, we could suppose from these pathological changes that AX’S had streamed in the blood and lymph and persisted in the body for a long period of time to cause the fibrosis of various organs. But the number of AFs and ABs are extremely less in

33(6): 1983 H. EOBAYASHI el d. 1231

the extrapulmonary organs than in the lung. experimental background will be needed to establish the causal genesis.

So more accumulation of cases and

Aekmledgernent: We thank Dr. Junji h~ (Faculty of Science, Niigata University) for his valuable contribution of determining asbestos fibers. We also thank Mr. Tomiph i HASEQAWA, Mr. Kazumasa SATO, Mr. Susumu MOMOZAEI, and Mrs. Michiko TANABE for their technical assistance.

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11. Smmom, I.J.: Discussion. Ann. NY Acctd. Sci. 132: 596, 1965. 12. SMITH, M.J. and NAYLOR, B.: A method for extracting ferrugioua bodiea from sputum and

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Pneumoconiosis, Proceedings of international conference, Johannesberg, 1962. Cape Town, Oxford University Press, p. 138, 1970.

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