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Clinico- Pathological Conference

A male with rheumatic mitral stenosisTHE POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION

AND RESEARCH, CHANDIGARH

THE CASEA 45-year-old man was admitted to the PostgraduateInstitute of Medical Education and Research (PGI),Chandigarh in 1980 and diagnosed to have rheumaticheart disease. He was put on digoxin, lasix and potassium.supplements, his salt intake was restricted and he wasprescribed prophylactic penicillin. His condition deteri-orated to class III (by the New York Heart Associationclassification). Subsequently, he was advised a mitralvalve replacement in 1981, but he did not comply.

In December 1988he was admitted for cardiac catheteri-zation and angiography. By this time he had progressedto class IV symptoms and had episodic streaky haemoptysisand paroxysmal nocturnal dyspnoea. The catheterizationprocedure was uneventful except that he developed a mildhypersensitivity reaction to the injected radiologicalcontrast. After this he was given a date for operation.

He was admitted on 23 March 1989, for surgery. Soonafter admission he developed left-sided pleuritic chestpain, fever, cough and mucoid expectoration.

Examination at admission revealed a middle-aged manof average build and nourishment. There was no pallor,cyanosis, clubbing, pedal oedema or jaundice. The pulserate was 100/minute and it was irregular. The jugularvenous pressure was 4 em above the clavicle with a sharpv-y collapse and the blood pressure 100/70mm Hg. Therewere no peripheral signs of rheumatic activity or infectiveendocarditis. The precordium was pulsatile and the apexbeat felt in the left 6th intercostal space in the axillaryline. It was left ventricular in type with a moderate leftparasternal heave. The P2and the main pulmonary arterypulsations were palpable and S, was loud and variable.The S2was loud and P2 louder than A2. An opening snapand a mid-diastolic murmur were present at the apex. Agrade IIINI pan-systolic murmur was heard at the apexradiating to the axilla. There was a short systolic murmurin the tricuspid area increasing with inspiration. Onauscultation of the lungs there were vesicular breathsounds with bilateral basal crepitations. The results ofinvestigations over his three admissions are in Table I.

At admission he was being treated with digoxin,frusemide, potassium chloride and isoptin for congestivecardiac failure and control of the ventricular rate. He wasalso given co-trimoxazole and deriphylline. During hishospital stay his dyspnoea worsened and he developed aleft-sided chest pain without haemoptysis and there wastachypnoea of 56/minute. He was thought to have

pulmonary embolism and was started on heparin. How-ever, his. condition continued to deteriorate and hedeveloped hypotension and died.

CLINICAL DIAGNOSISChronic rheumatic heart disease with mitral stenosis andregurgitation, pulmonary venous and arterial hypertension,atrialfibrillation (fast ventricular rate). Congestive cardiacfailure (partially controlled) and possibly pulmonaryembolism.

DIFFERENTIAL DIAGNOSISDR RAMESHKUMAR:This patient had heart disease andrenal failure. I willstart by discussingeach ofthese problemsand then speculate on the terminal events.

He had classical physical signs of dominant mitralstenosis (MS), regurgitation (MR) and congestive cardiacfailure (CCF). The echocardiogram showed a thickenedmitral valve with paradoxical motion ofthe posterior leaflet,a large left atrium and a mitral valve orifice of 1.0 cm-,Cardiac catheterization revealed an end-diastolic gradientbetween the left atrium and ventricle of 18-20 mm Hg.These findings confirm the diagnosis of severe MS. Theleft ventricular angiogram showed opacification of the leftatrium during ventricular systole, thus establishing thepresence of MR as well. The doppler study excluded anyassociated aortic regurgitation. The aortic root angiogramcould not be done as the patient developed hypersensitivityto the contrast..

The pulmonary artery pressure was 43/30 mm Hg witha mean of 36 mm Hg, confirming the diagnosis of severepulmonary arterial hypertension (PAH). In view of themitral valve thickening, paradoxical movement of theposterior mitral leaflet and a past history of rheumaticfever, the aetiology was probably rheumatic.

In addition to rheumatic valvular heart disease thispatient also had azotaemia with a good urine output.Since his serum creatinine was normal in December 1988his renal failure was probably of recent origin. In theabsence of a urine examination and other relevant investi-gations I would consider the first possibility to be infectiveendocarditis. The patient had fever, CCF and renalinvolvement and the diagnosis of infective endocarditisshould be considered in every patient with fever and aheart murmur. So, I strongly suspect it in this patient. Theglomerulonephritis in infective endocarditis is 01 threetypes.

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TABLE I. Results of clinical tests

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March 1989Clinical tests November 1980 December 1988

Haemoglobin (g/I00ml)Total white cell count (cmm)Differential white cell countESR (first hour)UrineSerum Na+/K+ (mEq/L)Urea/creatinine (mg/dl)Alkaline phosphataseChest X-ray (Fig. 1)

ELEcrROCARDIOGRAM (FIG. 2)

ECHOCARDIOGRAPHY (FIG. 3)LVID(D) (ern)LVID(S)(cm)AO(cm)LA (cm)

14.09800

P70, L26, E3, Ml32

Normal132/4.25111.2

14.67200

P79, L20, E220

RBC5-6/HPF138/3.663/1.3

16.05050

P68,L3230

Not done137/4.9120/4.0

30 king Angstrom unitsCardiomegaly, left atrial appendageenlarged. Left and right atriumenlarged. Prominent main pulmonaryartery and upper lobar veins.

20 December 1988

5.03.13.06.0

Thickened mitral valve with paradoxical motion ofposterior mitral leaflet. No calcification. Normaltricuspid and aortic valves. Pulmonary valve showedflattening of slope, no a 1 wave, mid-systolic notchsuggestive of severe pulmonary arterial hypertension.'Doppler showed no aortic regurgitation. Large LAthrombus.

Atrial fibrillation with fast ventricularrate. Prominent R wave in VI sugges-tive of right ventricular enlargement

22 December 1988

4.63.52.36.5

Same as on 20 December 1988 except mitral valvesubvalvular apparatus thick. Mitral valve area = 1.0crn-. Doppler showed mitral regurgitation and no aorticregurgitation.

LYID(D) Left ventricular internal diameter (diastole) LYID(S) Left ventricular internal diameter (systole) AO Aorta LA Left atrium

1. Focal and segmental proliferative glomerulonephritiswhich presents as mild proteinuria, microscopichaernaturia with or without azotaemia. '

2. Diffuse proliferative glomerulonephritis withazotaemia.

3. Crescentic glomerulonephritis manifests as rapidlyprogressive renal failure with severe azotaemia andoliguria.

In addition to these lesions, one may also encounter mildto severe endarteritis on renal histology. In this patient, Iexpect to see diffuse proliferative glomerulonephritis withor without crescents.

A low cardiac output state secondary to CCF may causemild prerenal azotaemia but this patient never hadhypotension or oliguria except terminally. Alternatively,the kidneys may have been involved by multiple renalinfarcts secondary to embolization from the heart. Athrombus in the left atrium in one of the echocardio-graphic studies suggests this possibility. Since the serumcreatinine was 4 mg/dl, it would be expected that thispatient had large bilateral renal infarcts. However, thetotal absence of gross haematuria in such a situation is

unusual. Hence I will not consider this possibility seriously.Coming to the terminal event, this patient had chest

pain, tachypnoea and hypotension-symptoms whichsuggest pulmonary thromboembolism in a bed-riddenpatient with CCF.

DR RAMESH KUMAR'S DIAGNOSIS-Chronic rheumatic heart disease, mitral stenosis (severe),mitral regurgitation (moderate), atrial fibrillation,pulmonary arterial hypertension and congestive cardiacfailure.-? Infective endocarditis with diffuse proliferativeglomerulonephritis.-? Pulmonary thromboembolism.

CLINICAL DISCUSSIONDR K. S. CHUGH:This is a very thoroughly investigated

and followed up case and there seems to be no doubtabout the cardiac condition.

DR H. N. KHATTRl:There are two aspects of this casethat need to be discussed. The patient had severe mitralstenosis, mitral regurgitation, fast ventricular response

CLINICO-PATHOLOGICALCONFERENCE

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atrial fibrillation and was in congestive heart failure for 6to 7 years. What was the cause of his sudden deteriorationwhen he developed tachypnoea with worsening of thecongestive cardiac failure? Did he have a pulmonarythromboembolism? I think he had. The left atrium wasreported to contain a large thrombus, but a repeatechocardiogram two days later showed no such thrombus.Did he develop multiple renal thromboemboli leading tomultiple renal infarcts which caused acute renal failureand worsening of his condition?

DR HARJINDERSINGH:This patient came for surgery verylate. We did not seriously think of infective endocarditis.We were planning a closed mitral valvotomy but he wentinto hypotension and we strongly suspected that he hadhad a pulmonary thromboembolism.

DR R. DHAND:Iwould like to reinforce the commentsmade by Dr Khattri. I think the pulmonary thrombo-embolism was not the only final episode but there isevidence of repeated emboli since November 1988.

DRH. N. KHATTRJ:Ido not think that would be correct.The catheter data of December 1988 showed elevation ofthe pulmonary arterial pressure with near equalization of

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FIG 1. Chest X-ray

FIG 2. Electrocardiograph

FIG 3. Left ventricular angiogram

the pulmonary artery diastolic and wedge pressures.There was no evidence of pulmonary thromboembolismat that time.

DR B. K. SHARMA:Dr Ramesh Kumar has suggestedthe diagnosis of multiple renal infarcts to explain the renalfailure. However, even in December 1988, there wassome borderline elevation of the blood urea and serumcreatinine and there were red cells in the urine. A smallembolization to the kidney even at that time cannot beruled out. My main suggestion is that there is no way toexclude the possibility of prerenal factors being responsiblefor this kind of renal failure. A patient with congestivecardiac failure who is receiving a lot of diuretics can easilyshow this degree of azotaemia.

DR K. L. GUPTA:I feel that the possibility of multiplethromboemboli to the kidney as suggested by Dr Sharmaon the basis of a few red blood cells in the urine is notreally tenable and cannot explain the present renal in-sufficiency since there is no history of frank haematuria.This patient is more likely to have had a glomerulonephritisdue to infective endocarditis.

DRK. S. CHUGH:Ialso do not think that the renal picture

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is one of thromboembolism. The puzzling aspect of thiscase is the left atrial thrombus. Are we dealing with athrombus that has disintegrated and disappeared?

DR P. L. WAHl:Dr Chugh's question is clearly a loadedone. It is certainly possible to have systemic thrombo-embolism and no thrombus visible in the left ventricle onechocardiography (this may have moved into the systemicvascular circulation) or alternatively one may visualize thethrombus in the left atrium but there may not be systemicemboli. However, the situation is a peculiar one. Athrombus was seen but two days later it had disappeared.I find that some doubt has been expressed in both thereports and we should keep these doubts in mind.

DR RAMESHKUMAR:Actually on the basis of the firstechocardiographic visualization of the thrombus thepatient was put on heparin. Two days later, after a repeatexamination, heparin was withdrawn as the cardiologistswere not quite certain whether or not the thrombus waspresent and the patient was being prepared for a surgicaloperation.

DR K. S. CHUGH:This patient therefore had rheumaticheart disease with mitral stenosis and regurgitation and noaortic regurgitation. We are handicapped as far as thekidney lesion is concerned due to a lack of urine examina-tion. There is a possibility of glomerulonephritis but I donot think there was a terminal thromboembolism. I nowrequest Dr C. K. Banerjee to present the autopsy findings.

PATHOLOGICAL DISCUSSIONDR C. K. BANERJEE:A partial autopsy was performed.The brain was not examined. The serous cavities did notcontain any excess of free fluid. As the heart was the mainconcern of the treating consultants as well as the topic ofdiscussion now, I will start there. It was overweight (500 g)and enlarged. Both atria were hugely dilated and the mitralvalve cusps were thickened. The edges were rolled andcommissures fused (Fig. 4). The chordae tendinae werealso thickened and only marginally shortened. The leftventricle was not very dilated and showed only borderlinehypertrophy. The aortic valve cusps, tricuspid. valve andpulmonary valve were all normal. The right ventricle wasdilated and its wall was hypertrophied. Histologically asection from the mitral valve showed vascularization andthe myocardium showed many Aschoff bodies (Fig. 5).There were no morphological features of pulmonaryhypertension in the lung vessels and the liver showed nofeatures of passive venous congestion.

The second pathology, which was responsible for hisfatal outcome was in the lungs. The two lungs were massive,weighing more than 1 kg each. The pleura were mildlythickened. The cut surface showed almost total replace-ment of the lung parenchyma with miliary tubercles whichwere diffusely present in both lungs (Fig. 6). A small hilarlymph node also showed caseation. Histologically the lungshowed features of confluent caseous bronchopneumonia.Granulomas were scanty (Fig. 7). Ziehl-Nielsen stainingshowed a large number of acid-fast bacilli in areas of acuteinflammation in the lungs. Miliary tuberculosis was presentin the myocardium (Fig. 8), liver (Fig. 9), spleen (Fig. 10),kidneys, adrenals and pancreas. The small and large

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FIG 4. Photograph of the heart showing a dilated left atrium anda thickened mitral valve. The left ventricular cavity is ofnormal size.

FIG 5. Photomicrograph showing Aschoff body in the myocardium(H&E, x 120)

FIG 6. Photograph of slices of lungs showing extensive miliarytubercles

CLINICO-PATHOLOGICAL CONFERENCE

FIG 7. Miliary tubercles with Langhans giant cell in the lung(H&E, x 120)

FIG 8. Miliary tubercle in the epicardium (H&E, x 120)

FIG 9. Tubercles in the liver (H&E, x 120)

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FIG 10.Miliary tubercles in the spleen with a large area of caseation

FIG 11. Stress ulcers in the stomach and large linear ulcers in theduodenum

FIG 12.Hyphae of candida in one of the gastric ulcers (PAS, X480)

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intestines also showed miliary tuberculosis.The stomach and duodenum showed superficial ulcers

(Fig. 11). Histologically these were acute ulcers withnecrosis of the mucosa and a mild inflammatory cellinfiltrate. One of the duodenal ulcers had perforated, thebase of the ulcer being formed by the pancreas. The gastriculcer and the duodenal ulcers showed superadded Candidainfection (Fig. 12).

AUTOPSY DIAGNOSIS~hronic rheumatic heart disease with mitral valvulitisproducing predominantly mitral stenosis and mild mitralregurgitation.-Disseminated tuberculosis involving the lungs, hilarlymph nodes, heart, liver, spleen, kidneys, gastrointestinaltract, adrenals and pancreas.-Stress ulcers in the stomach and duodenum withsuperadded candidiasis. Sealed perforation of duodenalulcer.

CONCLUDING DISCUSSIONDR K. S. CHUGH:We have a surprise element which was

not at all suspected during the life of the patient and Inotice that everybody is trying to re-read the old chestX-rays to see if miliary tuberculosis was really missed.

DR P. L. WAHl: This case illustrates that even in anapparently open and shut case the pathologist may stillfind something unsuspected. This highlights the importanceand need for more autopsies in this country. Even closescrutiny ofthe chest X-ray done in December 1988 does notshow any tuberculosis. A more recent X-ray is not availableand it seems no X-ray was done in April 1989. Regardingthe left atrial thrombus suspected on echocardiographicexamination, one should note that the angiographycarried out soon after this examination in April does notshow any space-occupying lesion in the left atrium. Attimes in a large left atrium a whirlpooling of blood may bemistaken for a thrombus.

DR K. S. CHUGH: Dr Ramesh Kumar confirms that nochest X-ray was done during the second admission. Couldthe pathologist tell us if the lesions of tuberculosis can bedated? We know of course that these must have developedbetween December 1988 and April 1989.

DR S. SUR!: I would also like to record my surprise thateven though the patient had fever, expectoration and wasdue to have surgery no chest X-ray was done. Tuberculosiscould certainly have developed in the 4 months betweenDecember 1988 and his death in April 1989.

DR B..K. SHARMA:We thought his fever might be due

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to infective endocarditis but the tests excluded this possib-ility. If you read the clinical protocol it says 'fever occurredduring the last few days'.

DR S. K. JINDAL: Tuberculous granulomas can form in3 weeks. In this case the miliary spread may have originatedfrom a tuberculous mediastinal lymph node which wasperhaps present for a longer period.

DR N. K. GANGULY:I would like to make a commentregarding the 'laboratory diagnosis of infective endocarditis.Not only should the bacterial culture be done but bacterialteichoic acid and anti-teichoic acid antibodies should alsobe looked for. Also the levels of serum complement areraised in rheumatic heart disease as well as in tuberculosisbut fall as infective endocarditis develops. This is parti-cularly useful when there is renal involvement and one hasto choose between embolism and an immune complexmediated renal lesion .

DR C. K. BANERJEE:The duration of onset of tuberculosishas probably been the 4 months between December 1988and March 1989. Granulomas take about three weeks todevelop and massive caseation may occur in 6 weeks.Therefore, in this case, I think, the tuberculous lesionslook about 6 to 8 weeks old. I agree that the initial lesionwas in a hilar lymph node.

DR B. N. DATTA: In the non-sensitized host a tuberclemay take 3 to 6 weeks to develop but in a sensitizedpatient caseation and a tuberculous reaction develop veryquickly, sometimes within days. The Aschoff bodies inthe heart are usually a part of rheumatic heart disease butthese can be stimulated by any toxic condition such asinfective endocarditis or even, as in this case, bygeneralized and myocardial tuberculosis.

DR K. S. CHUGH: In conclusion, this case once againproves that because of the milieu in which we live, tubercu-losis should be suspected in any patient with a history offever, cough and expectoration and that a chest X-ray isstill very important.

CompiledbyDRB. N. DATTA

ParticipantsC. K. BANERJEE:Department of PathologyK. S. CHUGH:Department of NephrologyB. N. DAITA: Department of PathologyN. K. GANGULY:Department of Experimental MedicineK. L. GUPTA:Department of NephrologyS. K. JINDAL:Department of Chest DiseasesH. N. KHAITRI:Department of CardiologyRAMESHK.UMAR:Department of Internal MedicineB. K. SHARMA:Department of Internal MedicineHARJINDERSINGH:Department of Cardiothoracic SurgeryS. SURI:Department of RadiodiagnosisP. L. WAHl: Department of Cardiology