Thorax (1966), 21, 577.

Cholesterol pleural effusion in rheumatoidlung disease

G. C. FERGUSON

From the Chest Clinic, Dundee, and the Department of Tuberculosis, University of St. Andrews

Cholesterol pleural effusion is a rare condition.According to Moll and Fowweather (1940),Malaguti collected 44 cases from the literatureup to 1929. However, I have been able to readonly 39 case reports since the original by Churtonin 1882, the majority being in the non-Englishliterature. This paper describes a further twopatients, who are of particular interest in that forthe first time there is in one case a full post-mortem report with histological appearances and,in both, evidence that rheumatoid lung disease wasan aetiological factor.

CASE I

P. D., a 39-year-old man employed as a semi-skilledloom mechanic, or tenter, developed rheumatoidarthritis in 1938. Two months before the onset of hisarthritis he was said to have had a right-sidedpneumonia. In 1951 he was admitted to Bridge ofEarn Hospital for further treatment of the arthritisand was found to have a right-sided pleural effusion.Aspiration of this revealed numerous cholesterolcrystals, the cell count being 65% lymphocytes and35% polymorphs, while the fluid was sterile onculture and negative for Mycobacterium tuberculosis.His condition settled and he was allowed home. (Abrother suffered from pulmonary tuberculosis andrheumatoid arthritis.)He remained well until 1956, when he was

admitted to Ashludie Chest Hospital with a sixmonths' history of tiredness, productive cough, andexertional dyspnoea. Clinical examination revealedlow-grade fever, severe rheumatoid deformity affect-ing the hands, elbows, shoulders, and knees, and aright-sided pleural effusion.

Investigations were as follows: Haemoglobinconcentration 13 g./ 100 ml. (88%), W.B.C. 10,000/mm.3 with normal differential count. E.S.R. 25mm./first hour. Serum albumin 3 g., globulin 2-9 g.,cholesterol 110 mg./100 ml. Sputum culture on fouroccasions was negative for Myco. tuberculosis. Achestradiograph revealed reticulation in both lung fieldsand a small right pleural effusion (Fig. 1). Thepleural effusion was white and opalescent and con-

tained numerous cholesterol crystals but no cells. Itwas sterile and negative on culture for Myco.tuberculosis on two occasions. Treatment consistedof various antibiotics plus repeated aspiration, andthe fusion cleared almost completely.

In 1957 he was admitted to Maryfield Hospital witha two weeks' history of productive cough and breath-lessness. A chest radiograph revealed a fresh inflam-matory lesion at the right base which responded topenicillin and tetracycline. He was followed up as anoutpatient, and in 1958 his condition deterioratedwith wheezing and worsening of his joint symptoms.Treatment with phenylbutazone and prednisone, 5mg. b.d., for two months produced considerableimprovement.

In 1959 he was readmitted to Maryfield Hospitalon two occasions. The first was in June with ahistory of severe chest pain, and a diagnosis ofbilateral bronchopneumonia with basal effusions andearly cardiac failure was made. He responded totreatment with tetracycline and mersalyl and was dis-charged, but was readmitted in October with furthersevere chest pain and breathlessness. A diagnosis ofmyocardial infarction was made; anticoagulant treat-ment was started but he died three days later.Post-mortem examination showed a recent myo-

cardial infarct involving the septum and a healedinfarct in the postero-lateral wall of the right ven-tricle. The left coronary artery was grossly narrowedand the right occluded by thrombus 4 cm. from itsorigin. The trachea and bronchi contained pus. Thelungs, which were fibrotic and showed markedirregular emphysema, felt nodular, and in the rightlower lobe nodules were visible, one of which showedcentral calcification. A long-standing pleural effusionwas present on the left side, and the visceral pleurawas coated with a thick layer of fatty material.The histological appearances were strongly sugges-

tive of rheumatoid lung disease (Fig. 2). There wasa widespread granulomatous process with round cellinfiltration, areas of necrosis, and palisading of histio-cytes. Lymphoid follicles were conspicuous and therewas thickening and round cell infiltration of the wallsof the arterioles. The pleura was greatly thickenedby a deposit of fibrinoid material probably represent-ing the organization of fibrin, and containingnumerous cholesterol clefts (Fig. 3).

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FIG. 1. Case L. Chest radiograph in 1956 shows bilateral reticulationaffecting mainly the lower zones and a small right pleural eJffusion.

CASE I I

T. B., a 54 year-old man employed as a semi-skilleddraughtsman or stock-tracer, was discovered onroutine miniature radiography in February 1965 tohave a left-sided pleural effusion. He gave a historyof mild rheumatoid arthritis affecting the hands in1962, which improved after a short course of phenyl-butazone. In January 1965 he had sustained a minorinjury to the left chest, but there was no history ofchest illness, and a previous miniature film in 1963had shown only minimal pleural thickening at theleft base. There was no family history of arthritis orchest trouble.On admission to hospital he was found to be obese

and to have minimal finger clubbing, but he wasafebrile and had no joint abnormalities. There weresigns of a left pleural effusion but no other abnormalphysical signs, and a chest radiograph was normal

apart from the effusion (Fig. 4). Investigations: Man-toux 100 T.U. 15 mm. induration. E.S.R. 21 mm.first hour (Westergren). Laryngeal swabs negative forMyco. tuberculosis on three occasions. Blood count.serum proteins, and electrophoresis were all normal,and serum cholesterol was 275 mg./100 ml. R.A. latexand L.E. latex tests were negative and no L.E. cellswere found in the peripheral blood, but subsequentlythe R.A. latex test was positive on three occasionsand the Rose-Waaler test was positive at a titre of 1in 8. The pleural fluid was opalescent and shimmer-ing and contained numerous cholesterol crystals. Itscholesterol content on three occasions was 248, 105,and 120 mg./100 ml., and it also contained albumin3 g. /100 ml. and globulin 3 g./ 100 ml. Culture wassterile and negative for Myco. tuberculosis on threeoccasions. The deposit also contained polymorphs,lymphocytes, and serosal cells, but no malignant cellswere found despite three separate examinations.

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FIG. 2. Case L. Section of lung showing granuloma with necrotic focus surrounded by lymphocytes andpalisading of histiocytes with plasma cells in the walls of the arterioles. Arterioles show thickening andlymphocytic infiltration. x 120.

41,

FIG. 3. Case L. Section of lung showing markedly thickened pleura with cholesterol clefts.

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FIG. 4. Case I. Chest radiograph in February 1965, showing left pleuraleffusion but otherwise clear lung fields.

FIG. 5. Case II. Chest radiograph in November 1965, showing almostcomplete resoluitioni with steroid therapy.

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Cholesterol pleural effusion in rheumatoid lung disease

Pleural biopsy showed a chronic inflammatory pro-cess suspicious of tuberculosis. Repeated aspirationproduced partial resolution and he was allowed home.

In May 1965 it was found that the effusion hadrecurred to its former size. Aspiration was repeatedand again no malignant cells were found on cyto-logical examination. The effusion recurred again inJuly and treatment was begun with cachets giving atotal daily dose of 12 g. P.A.S. plus 300 mg. isoniazid.There was no improvement by October 1965, so theanti-tuberculous chemotherapy was discontinued andprednisolone, 20 mg. daily, was started. A monthlater the chest radiograph showed that the effusionhad almost completely resolved (Fig. 5). This improve-ment has been maintained following discontinuationof the steroid therapy.

DISCUSSION

The first recorded case was that of Churton in1882, summarized as 'Double haemorrhagicpleurisy. Degeneration of cells with formation ofcholesterine; subsequent empyema on right side,operation and recovery; followed by empyema onleft side, septicaemia and death'. Later cases havepresented a fairly uniform picture. The effusionis chronic, benign, and recurrent, without fever ortoxaemia, the symptoms being generally limitedto slight cough, chest discomfort, or exertionaldyspnoea. The fluid itself, which may be clear,turbid, or haemorrhagic, nevertheless has acharacteristic opalescence or sheen which in con-trast to chylous effusions fails to clear with alkalior ether. Microscopy reveals numerous typicalpolyhedric crystals of cholesterol. Cells may benumerous, scanty or degenerate, and culture isusually sterile. The true incidence of theseeffusions may be greater than is usually accepted,as chest aspirations are frequently entrusted tothe most junior medical staff, who may not un-naturally fail to recognize the unusual characterof the fluid.There are only two previous post-mortem

reports, those of Churton (1882) and Stein (1932),but in neither is there any mention of the histo-logical appearances. Both emphasize the grosspleural thickening with calcification and suchrigidity that the pleural sac could be removed likea cast. In the latter case the cause of death wastuberculous meningitis.

In general, repeated aspiration has been theonly treatment, but one case (Frew and Campbell-Fowler, 1956) is said to have improved on anti-tuberculous chemotherapy. The commonest asso-ciated condition is active pulmonary tuberculosis,which was present in 14 out of the 39 casesreported in the literature. In the rest, no definite

TABLE

Pleural FluidAge Effusion Asoitd Chol-

Author and History Csodcited esterolSex (yrs) ons (mg. _G

100 RatioMl.)

Stein (1932) 45 M

Durham andDiamond(1939)

Moll andFowweather(1940)Erwin (1941)

Evander(1946)

38 M

27 M

19 M

23 F

20 F

Stein (1947) 49 M

Curran(1946-8)

Sossi (1951)

Frew andCampbell-Fowler(1956)

Presentcases

43 M

45 M

40 M

60 M

25

4

10

2

4

9

23

7

13

13

35

61 M Notknown

33 M Notknown

39 M

54 M

Notknown

<2

Pneumonia witheffusion at age20; died of T.B.meningitis

Pulmonary tuber-culosis treatedwith artificialpneumothorax

None

Pulmonary andlaryngeal tuber-culosis

Healed primarycomplex

Pulmonary tuber-culosis treatedwith artificialpneumothorax

Apical tuberculo-sis. Tuberculouseffusion 23 yearspreviously.Meningovascu-lar syphilis

Pulmonary tuber-culosis treatedwith artificialpneumothorax

Pulmonary tuber-culosis. A.P.

?Tuberculouseffusion

Long-standing effu-sion. Later died? renalamyloidosis

'Pneumonia' 17years previously

Pleurisy and pneu-monia at age 10.R. cholesteroleffusion with Iacid alcohol fastbacillus onsmear but nega-tive culture.

Squamous carci-noma L. mainbronchus

'Pneumonia' 2months pre-viously. Severerheumatoidarthritis 13years. ? Rheu-matoid lung

Mild rheumatoidarthritis 3 yearsearlier

2,353 _

133

260

180

300

342

224

400

0-88

1 8

1 75

3.3

0-8

1-0

factor was incriminated, but in the present twocases there is evidence to suggest that the under-lying process was rheumatoid lung disease. Bothhad clinical and serological evidence of rheuma-toid arthritis, and in case I the radiological appear-ances were compatible with and the histologystrongly suggestive of 'rheumatoid lung'. In caseII the effusion could have been tuberculous, butthere is no evidence to support this, and the occur-rence of isolated pleural effusions as a manifesta-

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G. C. Ferguson

tion of rheumatoid disease is now well recognized(Ward, 1961).So far as the actual mechanism of cholesterol

deposition is concerned, Weems (1918) consideredthat ageing or chronic effusions produced grosspleural thickening which reduced the resorptivepower of the pleura and allowed cholesterol toaccumulate. Desbordes (1938) and Desbordes andLevy (1938), investigating the cholesterol contentof various pathological fluids, found that theycould cause precipitation of cholesterol by decreas-ing the albumin/globulin ratio to less than unity.Moll and Fowweather (1940) in their case foundan albumin/globulin ratio of 0-88 and applied thistheory to cholesterol effusions, but it has not beenborne out by subsequent experience (see Table).These authors have also postulated that contactwith a subpleural caseous focus containingcholesterol would help to cause precipitation.

Other authors have considered the cholesterolto be a breakdown product, whether of tuberclebacilli, red cells, or lymphocytes. It seems unlikelythat tubercle bacilli would be present in suffi-ciently large numbers, and although the chole-sterol/cholesterol ester ratio in the effusionsresembles that of red cells, the haemorrhage insuch cases would have to be gross. A lympho-cytic origin seems the most likely, and this con-clusion was reached by a recent Italiansymposium (Candela, 1958).

All authors are agreed that these effusions arenot associated with any alteration in the serumcholesterol level or clinical evidence of disturbedcholesterol metabolism such as xanthomata.The Table shows that in most cases of chole-

sterol effusion there is a long effusion history, andchronicity is probably the most important singlefactor leading to their formation, whatever theactual mechanism. With the decline of tuber-culosis the aetiology of chronic pleural effusionshas become more varied, and the cases presented

here are a reflection of the increasing importanceof rheumatoid disease in this field.

SUMMARY

Two cases of cholesterol pleural effusion aredescribed, in both of which it is probable thatthe underlying condition was rheumatoid lungdisease. The literature is reviewed and the con-clusion is reached that the main aetiological factoris chronicity of effusions from whatever cause.

I wish to thank Dr. Helen L. Duguid and Dr.William Guthrie, who carried out the pathologicalstudies in the first case, and Dr. R. N. Johnston forhelp and advice in the preparation of this paper.

REFERENCES

Candela, A. (1958). La pleurite colesterinica. Lotta c. Tuberc., 28, 997Churton, T. (1882). Double haemorrhagic pleurisy: Degeneration of

cells with formation of cholesterine; subsequent empyema onright side, operation and recovery; followed by empyema onleft side, septicaemia and death. Trans. clin. soc. Lond., 15, 19.

Curran, T. M. (1946-8). Cholesterol pleural effusion. Trans. TubercSoc. Scot., p. 51.

Desbordes, J. (1938). Sur le m4canisme de solubilisation ou deprecipitation du cholest4rol dans le strum ou les liquides patho-logiques (pouvoir cholesterolytique). C.R. Soc. Biol. (Paris), 127,869.- and Levy, D. (1938). Sur le taux prot5ines et l'Nquilibre s4rine

globuline dans divers liquides d'epanchements (liquide d'ascite,liquides pleuraux). Ibid., 127, 494.

Durham, W. R., and Diamond, S. (1939). Cholesterol pleurisy. Med.Bull. Veterans' Adm. (Wash.), 16, 12.

Erwin, G. S. (1941). Cholesterous pleural effusion. Brit. J. Tuberc.,35, 25.

Evander, L. C. (1946). Cholesterol pleural effusion. Amer. Rev.Tuberc., 54, 504.

Frew, H. W. O., and Campbell-Fowler, C. (1956). Cholesterolpleural effusion. Practitioner, 176, 416.

Moll, H. H., and Fowweather, F. S. (1940). Cholesterol pleuraeffusion. J. Path. Bact., 61, 37.

Sossi, 0. (1951). Considerazioni su alcuni casi di pleurite colesterinica.Ann. Inst. Forlanini, 13, 247.

Stein, H. F. (1932). Cholesterol-thorax in tuberculosis (Cholesterolpleurisy). Arch. intern. Med., 49, 421.

(1947). Cholesterol pleural effusion. Amer. Rev. Tuberc.,56, 305.

Ward, R. (1961). Pleural effusion and rheumatoid disease. Lancet, 21336.

Weems, B. F. (1918). Cholesterohydrothorax. Amer. J. med. Sci.,156, 20.

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