The spectrum of common atrioventricular orifice (canal)

Clinical pathologic

N. H. G. A. B. C.

conference

Simon, M.D. Cohen, M.D. Glick, M.D. Kanter, M.D. Levin, M.D. L. Pirani, M.D. Chicago, Ill.

Case history G. Y., a 25year-old Japanese man, was admitted for the fifth and last time to Michael Reese Hospital because of shortness of breath. In 1950, at the age of four, the patient was first given a diagnosis of systemic lupus erythematosus (LE) at Children’s Memorial Hospital and was started on steroids. In 1956 he underwent bilateral iridectomies because of cataracts and glaucoma. In 1960 he was noted to develop generalized osteoporosis with compression fractures of the vertebral bodies and aseptic necrosis of the left talus over a period of two years. These complications were attributed to steroids, which were discontinued in 1962. In April, 1965, at the University of Illinois, a renal biopsy was done for the first time and showed moderately severe diffuse membranous glomerulonephritis without vascular or proliferative changes. He was treated with azathioprine at this time and was continued on this for two to three years when his disease was thought to be inactive. He was followed in the clinic and was described as having done quite well, being active both at work and in school. In August, 1969, he was first admitted here with the acute onset of right-sided flank pains and lower limb swelling following a four-hour automobile trip. I’hlebograms confirmed the presence of inferior vena cava obstruction at the level of the fourth lumbar vertebra; clots were also found in the left femoral, left external iliac, and common femoral veins. The patient was treated with bishydroxycoumarin. Upon discharge heavy proteinuria continued with evidence of lupus activity.

He was readmitted a second time in November 1969. At this time there was evidence of lupus with positive LE preparations, positive antinuclear antibodies, BrC complement of 55 (range 145 * 22), presence of cryoglobulin, active sediment with 50 RBC’s (red blood cells), 30 WBC’s (white blood cells) per high-power field with doubly refractile oval fat bodies and 1.014 Gm. of proteinuria in 24 hours. The BUN (blood urea nitrogen) was 40 with a creatinine of 1.1 mg. per 100 ml. A renal biopsy was done, revealing active lupus, and, compared to the 1965 biopsy, revealed more focal and segmental proliferative and sclerosing features with occasional crescent formation. Inferior vena cavagram revealed partial recanalization and Coumadin was continued. To treat the active lupus, a course of nitrogen mustard was given and the patient was begun on prednisone, 25 mg. daily. The cholesterol was then 340 mg. per 100 ml. and albumin 2.1 mg. per 100 ml. In April, 1971, the patient was admitted for the fourth time with an acute myocardial infarction complicated by multifocal ventricular premature beats and congestive heart failure requiring lidoCaine, digitalis, and quinidine therapy. At this time, he was also found to have hyperlipidemia with Type II electrophoretic pattern; with cholesterol of 280, a low-cholesterol diet was begun. Other laboratory data included an albumin of 1.9 Gm. per cent; urinalysis revealed active sediment, oval fat bodies, and 3.8 Gm. proteinuria during 24 hours. LE preparations were negative three times and B,C complement was normal twice. Coumadin, which the patient had stopped taking before admission,

From

the Department of Medicine (Dr. Simon). Northwestern Ilniversity Medical School, the Cardiovasrular Institute (Drs. Cohen and Glick). rind the Renal Division (Dr. Kanter) of the Department of Medicine, Departments of Diagnostic Radiolwy (Dr. Levin) and Pathology (Dr. Pirani), Michwl Reese Hospital and Medical Center and Pritzker School of Medicine, 1Iniversity of Chicago, Chicago, Ill. Received for publication Nov. 2. 1972. Reprint requests to: Dr. G. Glick. Cardiovascular Institute, Michael Reese Hos:>ital and Medical Center. 29th St. and Ellis Ave.. Chicago, III. 60616.

1’01. 86. No. 4. fi1”. 139-552

Octohrr,

1973

American

Heart

Journal

539

In july. 1971, he ~-as admitted for the fifth .llrd last t&e with a two-day history of pro~:reAvr shortness of breath, increasing leg swelling. fever, tachycardia, and coughing. He denied any chest pain or hemoptysis and there was no ahnormal bleeding. His cough was productive of whitish sputum. He also complained of pain in his testicles for about three days. Physical esanzination on admission The patient appeared Cushingnoid and was in moderate respiratory distress. Vital signs included blood pressure of 116/80 mm. Hg, pulse 110 per minute with occasional premature beats, respirations 40 per minute and labored, and temperature was 102” I;. The skin was warm with good turgor. There was a dry, scaly, slightly red, maculopapular rash over the face with butterfly distribution and well-delineated horders; similar lesions appeared on the dorsum of both hands and in the groin areas, with strikingly welldelineated borders. .\cneiform eruptions were present in the neck, chest, and hack. The head was normocephalic. The eyes showed bilateral iridectomy scars and absent left lens. The fundi showed fat discs with arteriolar narrowing and A-V nicking; no hemorrhages, exudates, or cytoid bodies were seen. The neck was supple with moderate jugular venous distention at 45”. The hepntoju~ular reflrts was positive. The chest expanded symmetrically without splinting; there w:lq diffuse wheezing with bilateral basilar r;iles. There was no evidence of consolidation or effusion. The point of masimum cardiac impulse was not palpable or visible. The heart tones were of yood quality: S, and Sz lvere normal, S, was intermltlently heard at the alxs, and S., was present. No murmurs or rubs were heard. The abdomen was distended ; no fluid waves could be elicited. There were numerorlh venous collaterals seen on the abdominal wall. The liver sl~n v,xs 12 cm. with a smooth, nontender edge. The spleen was not felt. There was bilateral pedal edema. There was no evidence of thrombophlebitis; Homan’s sign was negative. There was no clubhin~. ‘I’he nail’; xvere pink-white and scaly. The right cpididymi\ was markedly swollen and inflamed, and extremely tender to palpation. The neurological examination revealed no abnormalities. Laboratory data. The hemoglobin was 14.5 Gm. per cent; hemntorrit, 44.7 per cent; and RBC count, 4.5 million per cubic millimeter. WBC count was 8,600 per cubic millimeter with a differential of 78 neutrophils, 1 band, 15 lymphocytes, 6 monocytes. platelets. Crinnlysis showed a pII and numerous of 6; specific gravity, 1.005; a large amount of ljrot&n; and negative for sugar and acetone. There were seven to fifteen RBC’s and two to five \\‘RC’s per high-power field. Alqo. the urinalysis showed ;I few bacteria and was poiitivc for doubly refractilc fat- bodicb. The chest s-r,>? showed cardiome~al\ with l)ulmonxy v.~~ular congehtinn. :ln ECG (elertn,c.lrdiocr;lIll) showed old 1)oxteroinferior myocardial infarction with frequent PVC’S (prem;lture ventricular contractions). Sodium was 148; pot,lhsium, 4.3; chloride, 9.5; and CO?, 2.1 mI
ri.11 blood g:;,seh \howed ,S 1311 of i.-lic, A f’(.ibLt (II !o. and i, J’o: of 139 mm. II 4 nhile the paticlit \\,I- I-CI~eivilq oxygen by na~.~l ~YI~~III:I. .f‘he .SGO’I‘ ~VI-LII~I glutamicosnlncetic tr.lll-;amin.~xe) wai .i.5; %;I’1 (serum ~lutamic pyruvic. tr,rni.lminas~), 42 ; l.I)fl (lactic dehydrogennse). 357; Cf’li (crentine ljhos7 units. Srri.ll examinations of these phokinase), enzymes did not show any significant increase. The alkaline phosphntase was 2.5 Rodansky units. The total bilirubin was 0.3; direct, 0.2 mg. per 100 ml. Total protein was 5.3 Cm. per cent, with albumin of 2.4 Gm. The serum cholesterol was 220 and triglycerides 89 mg. per 100 ml. Serum romplement done on July 23, 1971, was 80 rng. per 100 ml., on July 29, 1971, 120 mu:. per 100 ml. The TgG was 1,000; IgA, 210; IghI, 3.50 mg. per 100 ml. Cryoglobulin was present. A 24 hour urine protein showed 2.23 Gm. per 24 hours. The R.4 factor was negative. The first two LE preparations were negative, but later these became positive. The prothrombin time was 22.8 seconds; PTT was 46.6 seconds, with a control of 39.0. Blood and sputum cultures for acidfast bacilli were negative. :\ urine culture was also negative as well as stool cultures. Skin lesioll< on the face, hands, and groin showed m>-celium and spores on the potassium hydroxide smears. Hospikd rourse. The patient 1~~s extremely anxiorls and acutely short-of breath. EIe was thought to be in congestive heart failure and treatment was begun with diuretics, d,isjtalis, and sedation, with xood response. The posslbllity of pulmonary embolization was strongly suspected; heparin theral)y was started. AI\ emergent)1~11~ SC;LII showed evidence only of pulmonary congchtion and other non~pecilic tinding<. Cardiologic a11t1 c.lrdiovascrllx c.onsrllt;ltion srlgK:ested that conserv.rtive mnnagemellt without further diagnostic. studies was indicated. By evening the patient had markedly improved, and coml)lained only of paints in his right testicle Lvhich subsequently subsided with annl~esics, tetrxycline, and local heat. The temperature was elevated for two days but came down with improvement of the epididymitis. On the second hoqjital day, while being weighed, he developed sudden xvere sub sternal chest pain tvith shortnebs of brent h, dial)horesis, and transient hypotenAon. Physical esllmin,ltion was unrevealing and the ECG’s remained u+ changed. IIe resllonded readily to oxygen and morl,hinc. He was then kept at coml~lete bed rest and hepnri~~, prednisone, and quinidine were continrlcd. 1Ie then stabilized. r)ermatology c.onsult.lnt\ diasnosed fungal infection5 of the skin and nails by potassium hydroxide smcal-b. Therapy \vith Tinnctin was followed by marked imlxovement. >le;rnwhile, renal function was slightly deteriorating, Lvith creatinine of 3 and RITN of 80 mc. per 100 ml. The proteinuria, however, ;tt most \v.,s 2.5 mq. per 24 hours. On the seventh hobl)it,tl day el&odes of minor chest pain ag:;lill occurred. with Fhortnexq of tlrenth. Seri,lt ECG’s showed persistent elevation of S-T begmen&, suggestive of an active myocardi;~l and/or Ixzricnrdial procea. On the tenth hosl)it.ll AI)- more severe chest pain occurred with shortness of breath, sweating, br;tdycardia, and hypotension; the pat irnt was transferred to the coron~rr!-survcill~~~~(~e unit with a diagnosis of ncllte myocardi:ll inf.lrt,tioll, nl-

Clinical

though serial ECG’s and enzymes were not diagnostic. Five days later the patient was discharged from the coronary-surveillance unit. On the seventeenth hospital day, seven days after the presumed infarct, a pericardial friction rub was heard, with a low-grade fever which then disappeared spontaneously. On the twenty-fifth hospital day a holosystolic murmur was first heard in the apex with radiation to the axilla. The heart tones were noted to be muffled and distant. The patient, however, was improving clinically. There was no evidence of congestive heart failure and chest pains were less frequent, although the ECG’s continued to show a possible active myocardial or pericardial process. On the tenth and twenty-first hospital days LE preparations were positive and on the thirtieth hospital day the B1C was 72 mg. per 100 ml. On the twenty-fifth hospital day azathioprine was started because of the possible activity of the disease and in an effort to be able to reduce the steroid dose of 30 mg. prednisone daily. By the thirtieth hospital day the patient was completely asymptomatic. The renal status was stable and he was gradually ambulating without any problems. On the thirtv-third hospital dav ~ the oatient . was discharged. . Two days after discharge from the hospital the patient died.

Discussion DR. IZZY SOMMERS (MODERATOR) : The case for discussion today is that of a 25year-old man who presented with systemic lupus erythematosus (SLE) and the nephrotic syndrome. We are privileged to have with us, to solve the problems of this case, Dr. Norman nI. Simon, Associate Professor of Rledicine at Northwestern University RIedical School. DR. N. M. SIMON: The case presents an unusual challenge in that the diagnosis of SLE appears to be well established. The course is an extended one and my task is to sort out the nature and extent of the systems involved by the SLE process and to determine whether other significant diseases also were present. The patient was a 25year-old Japanese man. In our experience at Northwestern TTniversity 1Iedical Center, we have noted an increased prevalence of people of the Oriental race in patients with SLE.’ He was found to have SLE at the age of 4 years and was started on corticosteroid therapy. Two years later he first showed renal -involvement, manifested 1-1~ the nephrotic syndrome. Slll)sequently, he developed a numl~er of serious complications related to steroids, nhich I\-ere discontinued after a treatment period of eight years. The first renal I)iopsy was performed nine years

pathologic conference

541

after the onset of renal disease, and the tissue was reported to show diffuse membranous glomerulonephritis. This is one type of renal lesion found in SLE. Involvement of the kidneys is common in lupus, occurring in 50 to 80 per cent of patients, generally early in the clinical course. The renal lesions of SLE have been well defined hy Pollak and Piran? and Baldwin and co-workers.3 In addition to meml)ranous glomerulonephritis, these include a mild alteration labeled as minimal glomerular involvement or focal glomerulonephritis and a severe abnormality described as active or diffuse glomerulonephritis. Each lesion appears to have its own natural history and there is little tendency for one to progress into another. The patient was then started on treatment with azathioprine, which was continued for several years until the disease was inactive. He returned a year or two later with signs of acute occlusion of the major veins of the left leg, extending into the inferior vena cava. The occurrence of right flank pain suggests involvement of the renal veins as well, which might account for the observed increase in proteinuria. Indeed, it is possible that renal vein thrombosis may have been the underlying disorder from the very beginning. The renal biopsy finding of meml~ranous glomerular changes is compatible with this speculation. However, there are alternative explanations to account for thromhotic venous disease in this patient. First, SLE is a vasculitis which may affect veins as \vell as arteries. Second, significant al)normalities in blood coagulation are found in patients with the nephrotic syndrome regardless of etiology.4 These include increased levels of plasma fibrinogen, factors V, coml)ined VI I and X, VIII, and platelets, and accelerated thromhoplastin generation. The coagulation abnormalities disappear as the neohrotic syndrome goes into remission. As’infection formerly was a major threat to nephrotic patients Ijefore the introduction of antiljiotics, tl~roml~oen~l~olism now stands as a serious complication of their disease. The patient was started on treatment with oral anticoagulants, \)ut required readmission to the hospital a short time later with evidence of active disease. A large

1tililtI~~‘r of t-ccl I~lootl cx4ls \\ilS IlotcYl ill lll(~ ttt~ustt:tl in paticn!5 \\.itlt ttrinc, a titiding t~~eniln-atious glom~rular disease ;LIICI perhaps related lo nnticwagril~itit tltc:r;tp~.. A repeat renal I)iopsy \vas performed :tt this time and revealed cltanges suggestive of active glor~icrulonepltritis. A Iransitioti of one l-ype of renal lesiott into mother is very unusual in patients u.itli SLII, in terms of l,oth our own experience’ and that of otheri; L .z,3 Two years later the patient presented with another major catastrophe, an acute myocardial infarction, at the retnarknl~ly young age of 21 years. A Type II Ityperlipoproteinemia and persistent almorrnalities of the nephrotic syndrome were found, hut there were no itiin~unologic signs of active disease. Holy can \ve explain the occ-ttrrence of acute inyocardial infarction in this patient? X13 may produce ;1 v;tsmlitis, involving the coronary arteries. I Iowever, large coronary artery oc~c~lrtsion with frank ntyocardial infarction is tlistinrtly ~inusml.“~~ The patient Itad It?;percltolestcrolen~ia and ‘rype I I ltyperlilmproteincnlin. Serum lipid ;tImorntalities at-t’ associated aith the ncpllrotics)--ndromc regardless of etiology.7 Levels of cholest-erol and triglyceride arc increased due lo cmIlanced hepatic s)~ttthcsis of these lipids and retarded ca~;tlmIisnt. ‘I‘l;pcs I I :tntl IV lipoprotein almorni~tlities are most coiiitnonly found. There is ai incrensecl risk of atl~eroscleroticocclusive events in patients \vitlj the nephrotic syndrontc. Of 36 patients \z.itli nietnl~rmoits glonnerulonepl~ritis at ottr own institution. four devclopcd fatal n~~ocnrdial infarc-tion at n relatively young ~tgc.~ Ijerlyne and 1lallicl;” estimated that the risk of fatal infarction MXS increased 35 times in neplirotic patients. No\\- \ve cotnc to the last admission. I le re-entered the Itospital in Jrtly, 1971, \\;ith symptoms of congestive heart failure and testicular pain. Physical findings revealed a skin rash, more likely dttc to a superficial mycosis than to %,I<, signs of congestive failure lvitli an SzI and S, gallop, and epidid>rtnitis. \lav \\c rcsvic\\ tltc Ec‘( i’s and x-t-a)‘5 at this ;ititeY! DR. II. u)IIRN: The first availal)le IX‘(; on this patient was on Nov. 5, 1969 (Fig. 1). It is n,itllin normal limits. On April 9, 1971, slurred Q I\-rives have developed in

I,c~~itls I I, I I I, ;ttltl \ ti. ‘l‘ll(~ QRS c~ottll~leu is now tminly itiverlc~tl in I,cadh I ;1ti(1 \. j ;ttttl l)iplm+ic in a\‘~,. S-‘I‘ wgnletl (c, at-e c~l~\~tted in I,wds I I, III, and 1‘:: tltrcwgli \‘,;, :tntl I‘ waves arc itivertctl in tlies~ 1e;tcls. ‘l‘l~esc clianges are contpatil~le \vit~li ;111 :tctlte posteroapical tuyoc;trtlial infarction, proI)aljly \vtth some loss of lateral myocnrdittm as w:ell, accounting for the slight rigli t axis deviation. Almost four months later, on July 29, 1971, QKS complexes have Imane widened and slurred, especially in Leads I, V;, and \,‘6. Q a-aves are no longer seen in Leads II, I:;, and Vg. ‘The ‘I‘ uaves are no longer inverted, Imt S-T segments remain elevated in Leads II, 11 I, and the tnidprecordial leads. Thus an incomplete left hndle branch l)lock has olwured part of the features of the ntyocardial infarction. In addition, S-T segment deviation has occurred partly lwcattse of the left Imndle branch I)lock, and partly I)ecause of digitalis effects, aliic-Ii may elevate S-T segtiterits in right precordial leads as \vcll as in leads reflecting ntyoc-ardinl infarction, st~ch as Leads I I md III in this case. 1,eft Imndle Iu-anch I)lock disappears 1)~ the time of the next tracing (Aug. 2, 1971) and Q waves are again clearly seen in Lead I I, SO that the inferior myocardial infarction is more olwiotts. In addition, T \vnvcs have I)ecome inverted itt the tnidprecordial leads. This suggests at1 active process in the anterior tnyocardiutn. This process ma> or may not Iw isclientic in nature. Also, cctopic ventricular I)eats have developed. TIIC last t\vo tracings, on Aug. 11 and 1X, 197 1, SllO\\ a stalk pattern of inferior ntyocardial infarction, digitalis effects, the development of left ventricular liypert roplly, and lvaxing and mating of anterior iscliettlia-like alterations. I feel that the deviation of the S-T segttlents is still on the Ihs of digitalis effects and left ventricular liypertropliy; if there is a pericarclitis here, I ant rttial)le to recognize it as ntainly I~ccnuse of ~~l~~iicc of the such, cqw-ted evolution and presence of other auses for the contour alterations. [)I(. sowfEw: TItanI; you 1 jr. (‘olicti. 1)it. 1%. i.trvm: I-irst, films of Imny strttcture demonstrate \\.ltat is noted in the protocol, that is, the steroid effects on the Imnes, dentineralizntion, and cnmprwsion of the dorsal and Ir~ti~lm- vcrtcl~r:tl Imdies.

Clinical pathologic conference

I l/5/69

4/9/i?

7/29/71

B/2/71

8~~71

543

8/18/71

I

Fig. 2. Phlebogram of Aug. 18, 1969, showing occlusion of left femoral vein and of inferior vena cava at the level of the fourth lumbar vertebra. There are small thrombi in the right femoral vein and extensive collateral veins.

Fig. 29,

1. ECG’s taken on Nov. 5, 1969, April Aug. 11, and Aug. 18, 1971 (see text).

9, July

The chest film at the time of the first admission showed the heart size to be normal. The first phlebogram, on Aug. 18, 1969 (Fig. 2), showed almost complete occlusion by a large thrombus in the left femoral vein, and this is seen to extend upward into the vena cava with occlusion of the vena cava at the level of the fourth lumbar verteljra. There is extensive collateralization of the veins in the perivertebral plexus. There are small clots in the right femoral vein. The examination was repeated al)out three months later, on Nov. 5, 1969 (Fig. 3). It is evident that the clots in the right femoral vein have disappeared l)ut there is essentially no difference in the left femoral vein tlirombus. There continue to I)e extensive venous collaterals. Chest films showed that the patient uent on to develop cardiac enlargement and infrapulmonary effusion, both of \vhich improved in response to treatment prior to the patient’s death. DR.

SIMON:

of the renal DR. IXVIN:

WerC

there

veins? I cannot

SignS

Of

tell whether

OCdUSiOn

or not

Fig. 3. Phlebogram of Nov. 5, 1969. The thrombi in the right femoral vein are no longer present. The status of the left femoral vein and of the inferior venn cnva is essentially ‘unchanged.

the renal veins are thrombosed. The contrast medium did not reach the height of the renal veins so I cannot tell whether there is washout by the blood coming from the renal veins to the vena cava; nor was there any attempt to catheterize the renal

.I
veins. Of interest, tllcillgll, i5 111;iL 01) tiri;C stud), 1 neglected to point out that \\ c do see the calyceal system of lwth l~iclneys and the\, look intact. The kidneys, ho\\-ever, are somewhat enlarged, measuring 15 cm. in length. One fan set here the calyceal system on the left side and on the right side. They appear grossly normal except that the kidneys are large. DR. SIMON: Laboratory studies initially suggested inactive disease, but immunologic parameters of activity later became abnormal. The hospital course was characterized by recurrent episodes of shortness of breath, chest pain, transient hypotension, the appearance of a pericardial friction rub, and deterioration of renal function, suggesting a relentless downhill course. However, his condition improved after treatment with digitalis, diuretics, and heparin to the point where he \vas able to leave the hospital only to die suddenly two days later. It appears that we must focus on the nature of the cardiac involvement in this patient with SLE. In view of the history of previous myocardial infarction, coronary atherosclerosis comes to mind first. But in spite of the stormy course in the hospital, serial ECG’s and serum enzyme studies failed to establish the occurrence of fresh infarction. Therefore, 1 doubt that coronary atherosclerosis could account for the sequence of events during the last hospital admission. I’ulmonary enil~olisni is, of course, possil)le and was a source of serious concern to his physicians, especially in view of the history of thrombosis of the inferior vena cava and leg veins. Although it Tvould 1)e difficult to exclude pulmonary emlwlism, significant findings are not compatil)le jvith this diagnosis-the pericardial friction rub and negative lung scan. In one report on pulmonary embolism, positive lung scans were ol stained in all patients.“’ Finally, 1l.e may consider direct involvement of the heart l’y SLE. There may I)e endocarditis, affecting the valve leaflets, papillary muscles, and mural cndocardium, initially described by Lil)man and Saclts.” Although endocarditis may produce systolic and diastolic murmurs, it rarely is of sufficient hemodynamic consequence to result in congestive heart failure. In addi-

.i ,:I;.:

~l\~r~artli;~l danl;lK:t: ma)- wcur in SL13..1,’ ‘I’llis-is due to vasculitis of the sniall coronary arteries rather tlian to priniar), iiivolvernent of m?;oc;lrdial filwrs;. I Io\vever, clinical evidence of franI< myocardial infarction is unusual. The findings and course in the patient under discussion are entire11 compatible with active lupus myocarditis. Pericarditis is the most common manifestation of cardiac involvement in SLE,“,” although not always evident clinically. The patient presented today did have a pericardial friction rul). Other alterations which contribute to cardiomegaly and congestive heart failure in patients witli SLE are systemic hypertension, pulmonary hypertension from parenchymal or small vessel involvement in the pulmonary tree, anemia, and fever. Therefore, I would conclude that the patient had systemic lupus erythematosus, active, primarily involving the heart and the kidneys. The cardiac involvement \vas in the form of pericarditis and myocardial damage due to coronary vasculitis superimposed on atherosclerosis of the coronary arteries. Examination of the kidneys will slio\v membranous glomerulonephropathy \vitli an unusual transition to an active glomerulonephritis. As to the immediate cause of death, one can only speculate, since the patient \\a5 not tinder oljservathat the mechanism \vas an nrtion, rhytlimia or pulmonary eiiilwlisni. UK. SOMMI312S: 1)r. Simon, that \\‘a~ the most lucid discussion that \ve have heard in man) a year. 1 wonder if an)’ of the people involved in the care of this patient before his demise lvould care to make a comment. DK. .a. KANTICK: I enjoyed your discussion very much, Dr. Simon. I n-ould like to linow if you have any thoughts as to \\.llat \ve might have done during that lasl admission to determine the etiology. of his cardiac disease. DR. SIMON: I \Yill ans\Yer that after the pathologic report. DK. G. GI,ICE;: I also enjoyed very much your discussion, L)r. Simon. Just on the basis of this protocol, I would think that coronar\ _ atherosclerosis ma\. Iw the primary reason for the patient’s death. I

Clinical pathologic conference

Fig. 4. First renal no hvoercellularitv. x49d.j

biopsy (April, 1965). Representative glomerulus showing Small interstitial infiltrates of round cells were also

suggest this possibility for several reasons. The description of the initial examinaticn during his admission in July indicates that the heart tones were of good quality and no murmurs were heard. On the last admission he was admitted for congestive heart failure, which was managed easily with the usual regimen of diuretics, digitalis, and salt restriction, since he improved greatly within one day. On the second hospital day, however, he developed severe substernal chest pain with associated shortness of breath, diaphoresis, and transient hypotension. The situation seemed to have been uncertain enough so that he was admitted to our coronary-surveillance unit with the presumptive diagnosis of a possible acute myocardial infarction. He then developed a pericardial friction rut) \vhich certainly could be due to lupus pericarditis, but is very commonly seen about a week after myocardial infarction in patients \vith myocardial infarction on an atherosclerotic basis alone. In addition, his heart tones now lvere noted to be muffled, lvhereas, as I pointed out before, on admission they were well heard. Furthermore, he developed a holosystolic murmur that was not present on admission. Llnder these circumstances, \\-e usually ascribe the holosystolic murmur that results from infarc-

diffuse present.

membranous (Hematoxylin

545

changes, but and eosin;

tion or ischemic injury to either papillary muscle dysfunction or the development of a ventricular septal defect. The patient was discharged three weeks after this possible myocardial infarction. We do not know the level of his activity after discharge, hut the two- to three-week period after myocardial infarction, if you will grant the possibility of an acute myocardial infarction, is the time when \\-e see myocardial ruptures or development of further infarction xvith arrhythmias and sudden death. So, although I think your diagnosis is very \vell taken, I would consider strongly the possibility of coronary atherosclerosis. DR. KANTER: The protocol nas somewhat unfair in that it failed to state that the patient had persistent angina pectoris between the second and final hospitalizations. He may not have reported this to the house staff. He \\-a~ a very frightened young man xvho knew he \vas going to die. The diagnosis of his initial myocardial infarction \vas not easy. It ~2s the fact that patients lvith long-standing nephrotic syndrome are predisposed to arteriosclerotic disease and myocardial infarction whicl~ influenced our admitting diagnosis. He presented \vith none of the classical features of infarction, having developed al)dominal distress during a fight \vith his mother and girl friend.

He ~vas admitted to tllc hospital despite t11c protestations of the lior~sc staff, \vlio attrihted his conlplaints to anxiet~~ follmving n family argunient. Of umrse, the EC(; settled the matter. DR. C. I,. PIRANI : ‘his case \\:a~ selected for a CI’C first I,ecauz+2 of its long and iri-

teresting history and second I,ecause all the ni;ljor c-linical manifestations of this patient’s illness were satisfactorily explained l,y the postnlortcm examination. Ih-. Simon 11;~s:given LIS a very lucid presentation nicely correlated \vith possil)le pathologic findings and this \I-ill rnnk~ In> task m11(~11 easier.

Clinical

pathologic conference

547

Fig. 7. Second renal biopsy. Electron micrograph of a glomerular ca~)illnry. There were extensive electron-dense subepithelial deposits (arrows). Smaller deposits were also present within the basement membrane proper (BM) and in the mesnngial areas (A[). The capillary lumen (L) is narrowed by the swollen endothelial cells (EN). (x 8,400.) First, I will present the findings of the two renal biopsies. One was obtained in 196.5 at the I.Jniversity of Illinois. It was an adequate biopsy and all glomeruli showed essentially the same changes, namely, a diffuse thickening of the capillary wall with normal cellularity and patent. capillary lumens (Fig. 4). In periodic acidL Schiff and better in silver methenamine preparations, a true thickening of the leasement meml~me and some irregularity of its contour could I)e seen (Kg. 5). There \vas a mild increase of mesangial matrix, hut this \\‘as not thought to I)e significant. Under oil immersion it was possil)lc to recognize projections or spikes from the memlu-ane. outer aspect of the I)asenient In trichrome preparations under oil immersion the I)asement mcml)rane and its projections from the outer aspect \vere I)lue. Separating the spikes \vere fuchsino-

philic red areas corresponding to immune deposits. In brief, the histologic pattern of the first biopsy was quite consistent with either that of idiopathic membranous glomerulopathy or that of the membranous form of lupus nephritis.2s’3 The second renal I)iopsy was obtained ahout four years later. The disease appeared to be more active. The glomerular changes were similar to those of the first biopsy except for an occasional small epithelial crescent (Fig. 6). There was now an interstitial infiltrate of inflammatory cells, for the most part lymphocytes and plasma cells, which should be interpreted as a sign of activity of lupus nephritis. There IIXS nlore interstitial edema and filjrosis as \vell and in the glomerular capillaries fe\v trapped leukocytes could he seen. We must keep in mind that at this time the patient had also a reasonably

Fig. 8. Cross-section thrombus is present.

through the right renal vein near (Hematoxylin and eosin; X40.)

Fig. 9. At autopsy, moderate membranow either in the tubules or in the interstitium.

changes were (fIematoxylin

well-documented episode of renal vein thrombosis which may have I)een responsible for the prominent interstitial edcma.r4 Electron microscopy of the seroncl 1)iopsy revealed the capillaries of all glomeruli studied to have a very thick 1)asement membrane with electron-dense deposits, primarily in a subepitlielial position l)ut

the inferior

vena

cavn.

I)resent ill all &merrtli. rind e&n; X200.)

A well-organized

No changes

and recanalized

of note were

see11

also Lvitliin the basement memln-ane proper. Electron-dense deposits were also seen in the niesangial areas. I5 The visceral epithelial cells showed villous transformation and the foot processes were generally fused (Fig. 7). The endothelial cells were often swollen and occasionally were found to contain

viruslike

inclusions

in

tlieir

cyto-

Clinical

plasm-a common finding in SLE.16 In brief, the electron microscopic studies confirmed the diagnosis of lupus nephritis, membranous type. At the time of autopsy, the external examination revealed a maculopapular skin lesion which histologically was found to be due to a mycotic infection, probably trichophytosis, and which we thought to be related to the low immunologic resistance of this patient. There was a moderate amount of aortic atherosclerosis, especially in the abdominal segment. The inferior vena cava below the renal veins presented an irregular intimal surface due to a web of fibrous tissue. The right renal vein also contained some bands of fibrous tissue. However, the lumen of both these vessels was adequately patent. Histologically, these bands were obviously part of a recanalized thrombus (Fig. 8). The kidneys were large and had a smooth surface. Histologically, the renal changes were quite similar to those observed on the second renal biopsy, except that all evidence of active disease was no longer present. Actually, the tubules were well preserved and there was little interstitial edema or fibrosis (Fig. 9). There was, however, a mild to moderate degree of nephrocalcinosis in the renal medulla. This almost certainly was related to corticosteroid therapy as was the extremely severe osteoporosis seen in sections from the vertebrae confirming the x-ray findings. As we have occasionally seen in patients with osteoporosis, even with normal serum calcium levels, there was a mild degree of parathyroid hyperplasia. However, no changes of osteitis fibrosa or of increased osteoclastic activity were seen. The spleen showed atrophic lymphoid tissue and the adrenal cortices were somewhat reduced in size, both changes obviously secondary to corticosteroid therapy. The heart \z:eighed 470 grams, much of this increased \\-eight due to the abundant subepicardial fat. Thus hypertrophy \vas considered to be only mild to moderate. On cross-section, the right coronary artery, a few centimeters from its orifice, uxs seen to be occluded by a recent throml~us. Histologically, the thrombus could be seen to have formed over an atheromatous plaque (Fig. 10). The left circumflex coronary artery \vas completely occluded l)y an old athero-

pathologic conference

549

Fig. IO. Cross-section through the right coronary artery showing extensive atheromatous changes and a superimposed recent thrombus. (Hematoxylin and eosin;

X65.)

sclerotic process with calcification. Other coronary arteries presented considerable atherosclerosis. There \\-as a rather large infarct, in part old and in part recent, involving primarily the posterior aspects of the interventricular septum and of the left ventricular wall. The left papillary muscles all the way to their apex mere involved by fibrosis and by very recent ischemic necrosis, probably no more than t\vo days old (Fig. 11). Tllis lesion n-as almost certainly responsible for the holosystolic murmur heard a few days 1)efore death. A small organizing mural thrombus \vas attached to the area of infarction in the left posterior \\;a11 which \vas estimated to be six to eight jveeks old. To complicate matters, in the periadrenal adipose tissue a few small arteries presented the classic changes of acute arteritis, a possibility that Dr. Simon mentioned. The inflammatory cells consisting of polymorphonuclear leukocytes, Iympllocytes, and plasma cells extended through the entire thickness of the \vall, in which fibrinoid changes I\-ere alsa, present (Fig. 12). No microorganisms were seen with the use of special stains. The possi-

Clinical

aggravated the renal disease only temporarily. This may have been due to the prompt diagnosis and treatment of this complication. As a result of the nephrotic syndrome and persistent hyperlipidernia, severe atherosclerosis, particularly of the coronary arteries, developed early in the life of this patient and led to the occlusion of two major coronary arteries and extensive myocardial infarction. The possibility that periarteritis may have facilitated the development of atherosclerosis does not seem likely. The isolated periadrenal arteritis remains unexplained I)ut there was no evidence of either old or recent arteritis in the coronary arteries. DR. SIMON: I steered away from the diagnosis of coronary atherosclerosis as the primary cardiac lesion I)ecausc of the finding of a pericardial friction rub and the aljsence of confirmatory evidence of myocardial infarction. This line of thinking was Ijastd on the assumption that the presence of a pericardial friction rul) in a patient \vitll myocardial infarction would indicate a transmural infarct, which should be reflected in diagnostic EC(; and serum enzyme changes. It is soljering to realize that our constrictive ways of thinking are not ala-ays valid and that lDr. Glick’s summation ~42s more accurate than my own. An important issue raised I)y this case is the need to alter our approach to the patient \vitll tile neplirotic syndrome in that attention must I)e paid not only to the kidneys Ijut also to the significant lipid and coagulation al~normalities that are present nith the enhanced risk of atlierogenesis and throml)otic events. If treatment of the underlying renal lesion produces a remission of proteinuria, we mav expect resole t ion of the associated lipid snd clotting al)norm;ilities. I lo\\-ever, if treatment is unsuccessful in altering proteinuria, tlien direct tllcrnpeutic efforts at lo\vering serum lipids 1)). dift and drugs antl preventing tlironil~osis tlirougll the use of nnticoaguIants sl~ould Ix strongly considered. In a recent report, arteritis of a large coronar>artery \vitll occlusion and myocardial infarction \vas dclnonstratcd in a 16.year-old girl \vitll SLIS.‘? In addition, nngiograpllical)normnlitics of nlajor corennry

vessels

\vere

forlnd

in

three

otlier

pathologic conference

551

young women. All had angina pectoris and two sustained myocardial infarctions. DR. s. KAMNS: I just want to ask I)r. (Glick wIletIler, somewhere in the last month or so before he died, this patient migllt have heen a candidate for coronary angiograpliy or coronary bypass surgery? Dn. GLICK: The answer to both questions is yes. I would have considered him a candidate for both angiography and surgery. However, I have great doulrt that either of these procedures would have been carried out. We do coronary angiography only when we think corrective surgery is in the cards, and in view of his primary disease, 1 doubt that we would have thought that surgery would have been helpful. DR. SOMMEKS: Any more comments or questions from the audience? If not, thank you very much.

REFERENCES 1.

2.

3.

4.

~5 6.

7.

8. 9.

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12.

Simon, N. M., Werner, W. J., Franklin, W. A., and Potter, E. V.: Comparison of steroid and combined steroid-immunosuppressive treatment of lupus erythematosus nephritis, Ann. Intern. Med. 74:842, 1971. I’ollak, V. E., and Pirani, C. L.: Renal histologic findings in systemic lr~pr~s erythematosus, Mavo Clin. Proc. 44:630. 1969. Baliwin, I). S., I.owenste’in, J., Rothfield, N. F., Gnllo, G., and McCluskey, Ii. T.: Clinical course of proliferative and membranous forms of Iul,us neljhritis, Ann. Intern. Med. 73:929, 1970. Kendall, A. G., Lehmnnn, R. C., and Dossetor, J, B.: Nephrotic syndrome: a hypercoagulable state, Arch. Intern. Med. 127:1021, 1971. Shenrn, RI. A.: The heart in systemic lupus erythematosus, AM. HEART J. 58:452, 1959. Brigden, I$‘., Bywaters, E. G. I,., Lessof, M H., and Ross, I. I’.: The heart in systemic lupus erythematosus, Br. Heart J. 22:1, 1960. Simon, N. hil., and del Grero, F.: Lipid abnormalities in renal disease. Ann. Clin. Lab. Sri. 2:186, 1972. Enrle, 1). I’.: Glomerulonephritis: clinical aspects, Bull. N. Y. Amd. Med. 46:749, 1970. Berlvne. G. M.. and Mnllick. N. I’.: Ischemic hear;-disease ai a complicn;ion of nephrotic syndrome, I.nncet 2:399, 1969. Szucs, M. M., Jr., Brooks, II. I,., Grossman, W., Banns, J. S., Jr., Meister, S. G., Dexter, I,., and I )alen, J. \\‘.: IXagnostic sensitivity of Iaboratory findings in acute pulnion:~ry embolism, Ann. Intern. Med. 74:161, 1971. I,ibman, E., an11 Sacks, B.: A hitherto undescribed for-m of valvular and mur,d endocarditis, Arch. Intern. Med. 33:701, 1924. Ronlicjio, 1‘. A.. Ilotti, 1~. E., and Hagstrom, J. \V C.: Coronary arteritis, occlusion, and

13.

14.

myocardial infarction due to lupus erythematows, AK HEART J. 83:153, 1971. Ehrenreich, T., and Churg, J.: Pathology of membranous nephropathy, in Sommers, S. C., editor: Pathology annual, New York, 1968, Appleton-Century-Crofts, vol. 3, p. 145. Rosenmann, E., Pollak, V. E., and Pirani, C. L.: Renal vein thrombosis in the adult: A clinical and pathologic study based on renal biopsies, Medicine 47:269, 1968.

15.

16.

Dujovne, I., Pollak, 1’. E., Pirani, C. I.., and Dillard, M.: The distribution and character of glomerular deposits in systemic lupus erythemntows, Kidney Intern. 2:33, 1972. Gyorkey, F., Min, K. \\‘., Sinkovics, J. G., and Gyorkey, I’.: Systemic lupus erythematosus and myxovirns, N. Engl. J. Med. 280:33, 1969.