High Serum Transaminase Activity in Heart Disease

High Serum Transaminase Activity in Heart DiseaseCirculatory Failure and Hepatic Necrosis

By THOMIAS KILLIP III, M.D., AND MARY ANN PAYNE, M.D.

IN THE PAST few years, determination ofthe serum or plasma activity of predomni-

nantly intracellular enzyme systenms has be-come a valuable adjunct in the study ofdisease. Since the original report of LaDueet al.1 many groups have investigated the lev-els of serum glutamic oxalacetic transaminaseactivity in a wide variety of conditions. Bothmyocardiuni and liver contain high concen-trations of this enzyme, and clinical experi-enee has demonstrated the value of repeateddeterminations of blood transamiliase activityin the diagnosis and evaluation of myocardialinfaretion and liver disease.2

In animals an uncomplicated acute meyocar-dial infaretion is associated with inereases inserum glutamic oxalacetic transaminase activ-ity that correlate roughly with the amount ofinfarcted muscle.3-6 In the majority of pa-tients sufferilng from an acute myocardial in-faretion, the changes in blood enzyme activityresemble those produced in the experimelntalanimal; after the first day, the level increases,usually to less than 400 units. and then grad-uallv falls to normal within a 3- or 4-day pe-riod.7 Infrequently, however, the blood enzymeactivity soars to very high levels followiing anacute myocardial infaretion. In animal ex-periments, such high levels of enzyme activi-ty have been recorded only in instanees ofvery large infarets.3 6 Occasional patientshave been cited with very high seruiii levelsof glutamic oxalacetic transaminase activityprior to death from a myocardial infaretion,and autopsy disclosed central necrosis of theliver.7' 8 It has been postulated that the livernmay contribute to these unusual levels ofblood enzymne activity.8' 9 There has lnot, how-ever, been ani extensive clinical survey of thisproblemn.

From the Department of Medicine, The New YorkHospital-Cornell Medical Center, New York, NT. Y.

646

Recently we observed a young man withadvanced rheumatic heart disease and tightaortic stenosis who developed progressive he-patic dysfunetion (fig. 1) during his finalillness and showed a rise in serum glutamicoxalacetic transaminase activity to 1,912 units(W.D., table 1). At postmnortem examinationthere was severe acute central nlecrosis of theliver (fig. 2). Coincidentally there was a re-port of a similar patient with a very hightransaminase activity in whom a clinicaldiagnosis of hepatitis had been consideredalthough hepatic central necrosis was dem-onstrated at autopsy.10 These observationsstimulated an extensive review of our experi-ence at The New York Hospital with patientshaving cardiac disease and high levels ofserum glutaimic oxalacetic transaminase activ-ity, and this review formns the basis of thepresent report.

Materials and MethodsThe records were reviewed of every patient who

had a serumii glutamic oxalacetic transaminase ac-tivity (SGOT) greater than 500 units per milliliterper minute as determined in the Liver Laboratorvof The New York Hospital fromti January 1956through July 1958. The records of those patientswho had primary cardiovascular disease and highlevels of enzyvme activity were selected for specialstudy. No patients with clinically evident viralhepatitis, toxic hepatitis, cirrhosis, or biliary tractdisease were included.The recorded clinical informiiation was scruti-

nized for evidence of heart failure and hypoten-sion. Right heart failure was diagnosed when thevenous pressure was elevated and the liver wasenlarged and tender. The level of venous pressurewas measured by direct saline manometry andreferred to the estimated level of the right atrium,or was estimated bv inspection of the neck veins.Hypotension was diagniosed when the systolicblood pressure was 20 mmn. Hg below the pre-viously recorded levels on 2 or more consecutivebedside determinations. A diagnosis of clinicalshock was made when specific comments indicated

Circulation, Volume XXI, May 1960

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SERUM TRANSAMINASE IN HEART DISEASE

the presence of severe hypotension, cold wet skin,and peripheral eyanosis, usually accompanied bychanges in mentation.

In those cases in which an autopsy had beenperformed, the sections of the liver and othertissues were carefully reviewed. The microscopicappearance of the hepatic sections was categorizedas follows: normal, central congestion, centralhepatic cord atrophy, central fibrosis, acute centralnecrosis. A careful attempt was made to distinguishbetween chronic or long-standing and acute changesin the hepatic architecture. Central fibrosis or

atrophy was interpreted as evidence of chronicchange. Central atrophy was diagnosed when theplates or cords of hepatic cells radiating towardthe hepatic vein were thin, often not reachingthe central vein, without evidence of acute necrosis,and the sinuses were dilated. In evaluation ofacute central necrosis the criteria described byOsserman and Ellenbergo" were utilized: eosino-philic staining of the central area sharply con-

trasting with the basophilic stain of the normalliver cells; nuclear changes including pyknosis,fragmentation, occasional large pale nuclei, andoccasional free nuclei; invasion by polymorpho-nuclear leukocytes; more or less architectural dis-ruption depending on the age of the lesion. Cen-tral congestion, though often present, was notconsidered essential for a diagnosis of acute cen-tral necrosis.

Further to evaluate the clinical and autopsycorrelations that became apparent among thosepatients with high transaminase activity, a secondseries was accumulated from the autopsy files ofThe New York Hospital. This group will betermed a "Control Series," since it was selectedwithout regard for the level of SGOT activity.The records of all patients who died primarilyfrom cardiac disease and were autopsied duringthe 30-month period from January 1956 to Julyl1958, and who had SGOT activity determinedwithin 30 hours before death, were reviewed.Eighteen patients met these criteria, none of whomhad clinical or autopsy evidence of primary he-patic disease, and constitute the "Control Series."Serum transanminase activity was determined by

a modification of the method of Karmen12 andwas reported as units per milliliter of serum per

minute (hereafter abbreviated to units). Bloodsamples showing hemolysis were routinely dis-carded.

ResultsDuring the 30-month period covered by this

study, 12,566 glutamic oxalacetic transami-nase determinations were performed upon

4,761 patients in the Liver liaboratory of TheNew York Hospital. In 157 patients, at least


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Figure 1Clinical course of case 3. Hepatic and renal in-sufficiency accompanied progressive circula,toryfailure from multivalvular rheumatic heart disease.

1 determination was above 500 units; mostof these had liver disease. In 17, however7 thehigh SGOT levels occurred in patients suffer-ing from cardiac disease without evidence ofprimary liver or biliary tract involvement(table 1). Eleven of these 17 patients wereoriginally admitted because of an acute trans-mural myocardial infarction proved by thedevelopment of a Q-wave and RT-segmentelevation in certain leads of the electrocardio-gram. The 6 other patients were admitted fortreatment of severe heart failure due to vari-ous causes. Ten patients died after the SGOTelevation was recorded; 5 of these had myo-cardial infaretion and 5 had severe failurewithout recent myocardial infaretion. Post-mortem examinations were performed in 8 ofthese patients; 4 had myocardial infaretion,4 did not (table 2).The maximum transaminase levels recorded

in each patient ranged from 524 to 6,570units. Five patients had peak levels of more

647

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4 8000

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I::lx"I"I



KILLIP, PAYNE

Table 1Clinical Data in Seventeen Patients -with Heart Disease and Seraum Glutanmic OxalacetiTrawsaminase Activity >5900 Units

Case Clinical diagnosis

W.T. HCVD, acute MI,CHFE, aortic dissection

D.O. Acute MIW.D. RHD, CHFH.S. HCVD, arrhythmias, CHFC.L. Acute MII.I. ASHD, previous MII, CHFR.L. Acute MI

HCVD, acute MIAcute MIASHD, CHFRHD, CHFAcute MIRHD, CHFHCVD, acute MIAcute MIAcute MIAcute MI

Right heartfailure

0

++++

++: ++

+

++

+

+

++

+

+V-H

++

H-+++F-+-++

24328

12

24

148

>86

>6>6>8>6

8

Abbreviations: SGOT, serum glutamic oxalacetic transaminase;

Outcome

6570 Died, autopsy3850 Died, autopsy191I2 Died, autopsy1588 Died, autopsy12'56 Survived954 Died, autopsa870 Died suddenlv

2 weeks later,autopsy

760 Survived736 Died, autopsy734 Died, autopsy653 Died568 Survived554 Survived550 Survived546 Survived526 Died5224 Survived

HCVD, hypertensive cardio-vascular disease; MI, myocardial infaretion; CHF, congestive heart failure; RHD, rheuasatieheart disease; ASHD, arteriosclerotic heart disease; +, present, moderate; +++, preselit,severe.

thani 1,200 units, and only 1 of these survived.Although the nunmber of patients involved issmall, table 1 indicates that the higher theSGOT in patients with cardiac disease, theworse is the prognosis. Five of 7 with SGOTbetween 500 and 700 unlits survived, whereas8 of 10 with levels greater than 700 uniits died.Serum transamlinase activitv usually fell

sharply after the peak level and was oftennornial within a week ini those patients whosurvived the initial episode (fig. 3). In W.T.,in whom shock persisted for 10 days despitevigorous treatment, the tranisaminiase activityfell from a peak of 6,230 niiits to 200-350units durinig a 4-day period and remaiiied atthat level until death.The clinical association between the peak

seruii transamiiiase activity and the level ofblood pressure was striking. In all 17 patielnts,the elevation of SGOT to more than 500 unlitswas preceded by a fall in blood pressure pro-

dueinig significant hypotelnsion or overt clin-ical shock (table 1). The duratiotn of thehypotensioni could not alwavs be determninedprecisely from the available record, but inthose patients from whom adequate data were

available hypotension had beeni present for atleast 6 hours prior to the SGOT elevation.Sixteeln of the 117 patieiits also had right heartfailure of varying severity. The hypotension,heart failure, and very high transamiuiaselevel oceurred in differen-t settings: as a di-rect complicatioll of acute myocardial infare-tion, in association with severe m-yocardialfailure, and secondary to a rapid arrhythmiain a patient with a diseased heart.

Liver-function tests were frequently abnor-mal when SGOT activity rose to high levels.Serum bilirubins were elevated in 7 of 8 pa-

tients in whoin the determination was avail-able. Four patients had excessive inereases inprothrombin time (over 60 seconds bv the


Hypotension precedingSGOT determination Peak

>500 u. SGOTDuration activity,

Severity hours units

N.S.A.T.A.G.J.C.L.G.H.P.E.K.D.D.'W.S.W.L.

648



SE t I1- ArlANSAMXINA\E IN HEART DISEASE 4

QuicAk 1stage inetiodi) followinig the adiniini>s-Iratio of usual (loses of eoniad(lin -derivative(ajiticoagtlatit s tmid reqiiiredl tre atment witlN.italaini l1 In 3 otlher patienfts- antie.oagrulantswxere administered wvitlhout diftieiiltv. Five pi-t ellits x-itfliout atitimoagulanllt therapy hladtrothrotiilit time dleterminatiot(is m1ore than2 set(onds albov thleicoitrol. Serum alkalilnelplhosl)haltase aet- ix itvx' a-ntIItdloeeld ation] teStsweTr nontutII(I-]. lBrmIIslflsNIeinIIIt ltaIIlII'ill test s

xvere0 tiot ])etfot'ned.

PathologyIieviexew of thle pt-.otoeols1 .111d histolog-ic lma

term] froimi the S aii1topislcd j)tiellits recNyvealei1 colmltol p)atlholog-ic. fillillg -cute ceiitraln1e( r'osis of the lix Fo.Fiot of thie patients alsohad r.-eceut nvocardiall infarctionI, a111(1 I oft.lhese had a recent dissection of the aorta.

Necrosis iii other or(g tis xx as ntot observed.rTlius in 4 of thle -iutopsied palticitits nlecrosis

itllnin tIe liver xvas fthe oalnt sour(.,e iceidtifiediftlllt collld have beel lesl)oIisible for the ele-va(itioti of the S( ( )T activity.When the liver sectiotis xvere (raded ac-

t,01ing to thie detlree of cent rla areniteetuiralcollapse, loss of hIcpatie-ell outlilles, andatnonint of 1iver cell regen-o-erlation, the apparlcut ag,e of the lesion correlated Ax-itlh thle timlieIfrotn peak trnainase actitvit u.1titlda.1'I0i kfelalt'l!s11ill8Si cll4;ix,\ Iti deatli.

-fit })tients T1.8., A.T., aid DIO., in all ofwho]i)eaktperiak si ninise ac-tivity was rc-

(corded ixxthiii 24 bonus before dea-tth, the ccen-t crl liver cells xx rer acutelv niecr-otic buit thecrds(I,; extelnl.ded to thle cet itrl veint and1 theatchit-e.cturc ix-as intact (figo. 4). Tn W.D. and(IW\`.T., in wlhoio p)ak(S(OT activity occurredS to 10 days lpriol to deatb, tbe central bepaticcells hac-d disintegratedltdlted thlic cellcetral strolmnxxas comprssesd (fig. 22). lTlie cenutral spaceswvere filled Axxithp. inorpl leuko-c ytes, proteitiaccous debris, red bloo1 (1cells,atM111 o0casclsiottlaj fre'e ulci. ''1e xNval1s calsofibroblastic )101o ifert ion.

Patient L.L. wxas unusual in tliat the cvi-deuee for (central. nero sil IxsN'i thle reg-etiIe1-tiotu of the cells arointidth'ecentral veins a-isitidicated by\ larg-e., pale, double nuclei with)ale-stamining cytoplasm. r1'}iis observation.

Circulation, Volutme XXI, May 1960

974 4-½

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'(v1).ef*'tElf t CS

144s P 4~~~~~~~<%¾~j ;;t' c

iv ~ ~ t

101)

i Set((01 o

°if fit N 0IRf)10 tOIst 4l/1)teii/ ta (tCastrc) 10'f7J816 Ofl't t

us o /oo eta/vte(ol}e'iRto (CV).t'X((1005s. Bottont. JJiyht p00-vowf/ some suf (jo)lt ofitvvs. fI tea so'vofitdoay11isZ J<* et t/to fi IlJ{to ottts '8isload-s of Ite>lvlie csells, 10(611(1{ {(tells, pl/11001'j}l)ho-1 t Zleazr I'lel:o<Jleyts, pro'0teJioaRetl00, debis f i. No ])(5 )S-

ereotioOlt of b qt8)/u'f a#>l1 2sto1totd portlfet (2e104 (PT).lI1emoltosc lia1 <ttit (0611/7 sf tain.

hoxvvcre0(t? ')rrcl1ate(t xvith[ thIe c inzical1 datal(fig. 3) of a1 tranlsientt SOOTrSalise to) high ac-tivTitx- afterl ati ep:isode oft hypoTteteisioti folloxvcdthx\ cliniCcal rgecovelry for- 2) xvcckfs utitil a18.1ttcti tLtt(l Unexllceted dea\(lthl.

[ix patienits WA.D.n lit,? andl I I-. thlerle xverecentral atroj)llv andf somne cenitral fibi losis finaddlitionl to r}ecctt cenltral nlecrosis inl the) liver.rThe(se find{ingcs eorrlale:ftcdl xxithi thle clincl (d1ata, sin(ew alll 3 hadl( loltigstaiidiiig card(iacdisease withl mulltiple ep)isodles of righst h1eartfai1lure p}riol to tbewir finlal adlmissions.

6;49



KILLIP, PAYNE

Table 2Autopsy Data in Eight Patients with Heart Disease Who DiedOxalacetic Transaminase Activity Exceeded 500 Units

Time frompeak SGOT

after Serum Glutamic

Autopsy findings

Patient to death General

W.T. 10 days ASHD, HCVYD, recenit -I, LVH, recentaortic dissection

D.O. 24 hours ASHD, HCVD, acute MI, LVH, intercapillaryglomeruloselerosis, ilninimal microseopicpancreatic necrosis

W.D. 8 days RHD, LVH, RVH, aortic and nmitral stelnosis,mnitral and tricuspid insufficiency

H.S. 24 hours HCVD and ASHD with myocardial fibrosis,LVH, chronic cholecystitis, cholelithiasis

I.R. 3 hours ASHD, old MI, LVH, RVH

R.L. 15 days Receint -MII, ASHD, small renal infarcts

A.T. 24 hours ASHD, acute MIA.G. 24 hours ASHD, LVH, RVH

Liver

Acute central necrosis

Acute central necrosis

Acute centiral necrosis,central fibrosis

Acute ceiitral necrosis

Acute central necrosis,central fibrosis

Recent central necrosiswith regeneration

Acute central necrosisAcute central necrosis,

central fibrosis

Abbreviations: ASHD, arteriosclerotic heart disease; HCVD, hypertensive cardiovasculardisease; RHD, rheumatic heart disease; MI, myocardial infaretion; LVH, left ventricularhypertrophy; RVH, right ventricular hypertrophy.

A few selected cases are presented to illus-trate the clinieal and pathologic correlationsencountered in this group of patients withheart disease and high SGOT activity.

Case ReportsCase 1

D.O., a 62-year-old woman, known to havemild diabetes and hypotension, was admitted toThe New York Hospital 6 hours after the onsetof severe crushing precordial pain. Physical ex-an-ination revealed hypotension, shock, a pulseof 20 per minute, pulmonary congestion, dis-tended neck veins, edena, and an enlarged liver.The hematocrit value was 27 per cent, a whiteblood count 30,400 per ,I,,i,.3 with 93 per centpolymorphonuclear leukocytes. A blood urea nitro-gen was 108 lmg. per cent. An electrocardiogramxshowed complete heart block and an acute posteriortransmural myocardial infaretion.

Twenty-four hours after admuission SGOT activ-ity was 3,850 units and a total bilirubin was 1.2lg. per cent, with 1.0 miig. in the direct fraction.During the seciond day her blood pressure roseto 160 70 and the rhvthnm becaime normal at 80per iminute. Despite gradual imuprovement, shedied on the third hospital day. Three hours beforedeath, SGOT activity was 1,400 units.

Postm-lortem exaniination revealed a large, acuteposterior infaretion of the left ventricle extendinginto the intraventricular septum, right ventricle,and right atrium. There was an extensive aeute

central necrosis of the liver involving approxi-nmately 60 per cent of each lobule. Other findingswere intereapillary glonmerular sclerosis and patchyfat necrosis in the pancreas.

CommentHigh SGOT activity in this patient was

associated with a large myocardial infaretioncomplicated by severe heart failure, completeheart block, and prolonged shock. Autopsyrevealed in addition to the myocardial infare-tion an extensive central niecrosis of the liverof recent origini. If the sections viewed underthe microscope are representative a large pro-portion of the liver was necrotic. Althoughthere was extensive destruction of heart mus-cle, leak of enzymes from the necrotic livercells must have contributed in large part tothe very high levels of serum transaminaseactivity recorded prior to death.Case 2A 47-year-old iman, R.L., was admitted to The

New York Hospital 6 hours after the onset ofsevere precordial pain. During the 18 monthsprior to admission he had occasional attacks ofangina pectoris, and his physician had recordedblood pressures of 150 to 170/80 to 110.On admission he had a blood pressure of 120/90

mm. Hg and a regular pulse of 100 per minute.There were basal rales, distended neck veins, and

Circulation, Volume XXI, May 196o

650




an enlarged, tender liver. The venous pressurewas 145 mm. of saline. An electrocardiogramshowed a recent transmural anterior myocardialinfaretion.SGOT activity 8 hours after the onset of chest

pain was 77 units. Twelve hours after admissionhis blood pressure fell to 100/70 mm. Hg, with-out signs of clinical shock, remained low for 24hours, and then gradually rose to 120/80. SGOTactivity 8 hours after the onset of the hypotensionhad increased to 870 units (fig. 3). The patientimproved until the sixteenth day after admission,when he suddenly had a recurrence of his chestpain and died.Postmortem examination revealed a recent occlu-

sion of the circumflex branch of the left coronary

artery with an infaretion of the anterior wall ofthe left ventricle estimated to be 2 weeks old. Amural thrombus was adherent to the infaretedarea, and there were several small infarets of thekidneys. Microscopic sections of the liver showedactive regeneration of the hepatic cells aroundthe central vein with large, pale, reduplicatednuclei.

Comment

High SGOT activity in this patient oc-

curred after an acute myocardial infarctionwas complicated by heart failure and hypo-tension. The serum transaminase activityseveral hours after the fall in blood pressure

was considerably higher than that usually en-

countered in patients with an uncomplicatedmyocardial infarction. The regeneration ofliver cells around the central vein demon-strated at postmortem examination 2 weeksafter the infaretion is interpreted as evidenceof an acute but limited hepatic central necro-

sis that was undergoing repair. The hepaticinjury was probably secondary to the fall inblood pressure that occurred shortly afteradmission and was undoubtedly an importantfactor in the high level of SGOT activity thatoccurred at that time. The renal infaretionswere quite small and most likely did not con-

tribute significantly to the SGOT elevation.Case 3

W.D., a 43-year-old man was admitted to TheNew York Hospital complaining of orthopneaand jaundice. Physical examination revealed deepjaundice and eyanosis with severe respiratory dis-tress. Although he had profuse diaphoresis, coldskin, and an almost imperceptible pulse, his bloodpressure was 120/95 mm. Hg. The cardiac rhythm


I

I

I

II

I'

+t

2 3 4 5 6 7 8 9 l0 12 13 14 15 16 17 18

rigure 3Clinical course of case 2. An acute myocardialinfarction was complicated by right heart failure,hypotension, and high SGOT activity. Recoverywas uneventfu4l until sudden death on eighteenthday.

was atrial fibrillation at a rate of 90 per minute.He had physical findings of aortic stenosis andinsufficiency, mitral stenosis and insufficiency, andtricuspid insufficiency. There were bilateral pleuraleffusions, rales over both lung fields, an enlargedtender liver, and ankle edema.

Shortly after admission SGOT activity was1,206 units, a blood urea nitrogen was 45 mg.per cent, and a serum bilirubin was 4.9 mg. percent (fig. 1). Two days later the blood pressurefell and became unobtainable for 32 hours, despiteintermittent norepinephrine therapy. The rhythmthen reverted spontaneously to normal at a slowrate and the blood pressure was maintained at110/80 mm. Hg. On the fourth day the serumtransaminase activity was 1,912 units, the serumbilirubin was 15.0 mg. per cent, with 9.2 mg. inthe direct fraction, and the blood urea nitrogenwas 105 mg. per cent. Five days after admissiona venous blood ammonia was 190 gamma per cent(normal <100). He died oln the thirteenth hospitalday.At autopsy the heart weighed 700 Gmn. There

was tight aortic stenosis, imioderate mitral stenosisand insufficieney, and a widely dilated tricuspidvalve. Both ventricles were hypertrophied. Therewas no evidence of necrosis in the myocardium orin any other organ but the liver. Sections of theliver demonstrated acute central necrosis involvingabout 40 per cent of the hepatic lobule engraftedon chronic central fibrosis and atrophy (cardiaccirrhosis) of moderate degree (fig. 2). The kid-neys were hvperemuie but otherwise unremarkable.Comment

In this patient very high transaminase lev-els were associated with heart failure, shock,

.M

651



KTTiTITP, PAYNE

Figure 4Tol ). Section o l(((' l/(0 1l ( O(( i s bo(('i((y

acute necrosis of| h(1pj)Ofic NO+ 0-oundig( cen

Veins (CV) (f b of u'iiotolc 'c7cst0) ft f

"entral ar' a('S. BOttomli. IHJigfher1' ower fs](i(( Swc-

tion of liver. Cel alu Vi ontlOin( aro'i0id cenlti/'t il6ih

barely discerni.ible. 1ilr(asio0 ('ol(1l(1 thcls' a1(1i

polylmorphoInu'lea(r Il( /((A Ic(N15'. ttf intw(1 c/rv1(

near portal triad (PT). IIe m((to,to l/Jill eo,0(0

stain.

ailli piog'O IIssix'e lhepatic alill renal iisulffi-

cilex'jT.The slhar1p) redletioni in liepatic bloo)d(flmov' associated itli the shock pIrodneed Ii ie'l

failure, extcnsix'se lepatie eentral necrosis,very highl SQ 01' activity, 7 )0l lbsixe bili.rubi-

eneia, and elevated blood amonlOIlia. AIltlholilcenal. function also (leteriorated secoiidarv to

Ithe reduced blood floxv, hlistolog.ic chagllello s IlI

the kidnevs- Nwere ininilnial. rfleoTily possible

source founid( at auitopsy for the gr-eat increasein SGOOIT was the recenit necrosis of hepaticparenclbvinal cells aroni the entral veins,.

Tlhis ease pirovides a1 strikina il lust ration of

tihe effect of pjlro(giessive eireilctttoix failure oniliver.| func.tion and st intutre. Several extiel(edl cliiical observetrs wer-e of thle opifnionthat thelie tifclit 1had deelleloed a Vrial blepa-titis. A ease presentin simila clinical mallii-festationIs ali(l (liagnostie (difficullties hIs beect'receinlyreporItted.I")0-1. Iatas IIot leeli genera1y1reeogn izd thliat prolonged ciurclatory failureiaiiifestedl by bypotellsioll, may lea{d to 1iias-siellvepaf lepdihy l destrmctionil .1liver failure.

Case 4At .8 \eai'0(1 1i01t 11.-8.,e xlas alliiid tte(l to The

Ncix Yiork Hospital, June 22, 1957, bec(~ause (Vfproge.s;ivte (1dspnena. 1 his b)100(1 pressure Xvls160.094 1mi1. Ig-, 011(1 the pulse wans 1:30 pcei miniiitc.There were 1).ns.il1sOltils, an1 1ciihi r-ed tetndei' liver,an111d perilhei01 dilciiiThf(} nlifx alter :dmiissidoii 1blOOd ureaN- nitrogen01 was 1 moe. per celit andSGQOP aetixvitx' wvas 15 units. HI d(vel(op)ed sililUstelhiAcl]\rdi.a witlh rntcbletXweeii 13.5 ;nd 15( pci'iinutc -with :f rtqueiit atrial lp)l'el(ituire m(((tractiols,

then a1 triail fibrilla tion with a xvltri'ulj.la r rte (o.f195 per minute aind lanter aitrial' fluttel (fig. 5).Ilis blood pleissurI1i -ws unobtainainble for 12h1oun1's. Following- (liili(ilne1th1er(<pv, ni(1'1011l silill

rhiythm returniid aidi his b)11o(d p)l(siii'( io'( to1:30 0T, but he died '2 (layvs l Ttci'w.Ixlxe 1 (01'safter the ilset of lhy l(tellsi((i1 his 1blood( 1urea litio-,"(lI lhad riseln to 6t6 oIn. pir' a S(celtaindeGOtix--it)' AX (s 'I,58 units.

At atoltls>!; thle w101tiXei lld 790 Gmn. Bth1cont ii l eS AXer dila ted :111d1 lix)yrti'(jlliedl. Thereweric scattered sioa'll ro.as oflox1vocai?dial fibrosis..blit no(I'01011(,ioclitio11:s 01'm,X(t0Vtidial ilifllr-tioIl. 2ecti(ns' of the lix reve''dled extellsix c.acute (enitlrl necrosis nix'olx'ine' aIbout -10 perl (ccit(If vzlh hiepa ltic lobule (fig. 4). lh iiectrotic (,(,]Iwrsr demniarcafted flow the 1 oj11(d livec'cell>, hut theI ()Xve-1111aIri'iitcctiirillur iattern( AXtSf

Xw ell pei'sei'xdl xithlollt fillosis, inidicntiii-' recentlii juixv. The ksidneps AXere normnl]. Te-re wVOSlalsoC'1oilii ( 110Tc stitis1 ehcholcllitn;,lis AX ithout cx-i-(lenec (,f rleent acuto iilfl:lllllntitni.

tor ( (I 11fsii thlis patient~)log'ie.ssxeB mx oc ididal fail-

mre ail(l au vel xr rapid. velm.itricular tate Axxereassociated xx itlh lo'- blood piess,lile ian highSGO)T acftivtity. Thle bvi-poteiisiOli wN-as alniiostcertainlyr a ianlifestaitilon of a very low eayr-diac outpiut with a (-oneomitait reduietion. illhepati: pIerfuIsioilI.T11 ecittial mitciosis(f)I-' thleliver AXvas thlei oilxtmi (I idemtifified att post

C'ircalatiu, Aolc( IAl, Mat'1;9

52



SERUAI TRANSAMINASE IN HEART DISEASE

180f

. 11 L-.E

E 120

0) 900

60a

cc 30

z 200a1-

75

w

150

r

125

0

Da10

--SINUS TACHY.-I APCs - AF I-FLUTTER-I-

4D A Y S

Figure 5Clinical course of case 4. High SGOT activity and hepatic necrosis occurred in settingof heart failure, arrhythmias, and hypotension.

mortem examiination for the iniereased SGOTprior to death.

Control Series. The clinical and autopsydata from the control series confirm anidamplify the correlations noted in the groupof patients with high transaminase activity.SGOT activity ranged from 17 to 408 unitsin the 18 patients of the eontrol series.

Seven patients had normal SGOT activityprior to death (table 3). In none was centralnecrosis of the liver demonstrated at autopsy,and none had hypotension or shock prior todeath. Four of these patients died during about of right heart failure, and in 3 the fail-ure was severe. Noteworthy is case 3, whodied from cor pulmonale associated withkyphoscoliosis, severe right heart failure (ve-iious pressure greater than 300 mm. saline)anld deep evanosis. Despite these abniormali-ties the blood pressure was mnaintained andSGOT activity was normal 16 hours before


death. At postmortem examiniationi the livershowed central congestion without necrosis(fig. 6). In case 4, SGOT activity was normal4 hours prior to death from advanced rheu-matic heart disease with severe right and leftheart failure without hypotension. Autopsyrevealed a severely congested liver withoutevidenee of acute necrosis (fig. 7). From thissmall group of patients it may be concludedthat venous hypertension alone is probablynot associated with either acute central necro-sis of the liver or elevation of the SGOT ac-

tivity.The data from the 11 patients with elevated

SGOT activity (table 3) provide further con-firmation of the relationships noted previous-ly in the group of patients with very highserum enzyme activity. All 5 of the patientswith hepatic central necrosis had hypotensionfor more than 6 hours prior to death. In allbut 2 of the patients with elevated SGOT ae-

653

r

_



KILLIP, PAYNE

Table 3Control Series. Clinical and Autopsy Data in Eighteen Patients Who Died of HeartDisease and Had Serum Glutamic Oxalacetic Transamninase Activity Determined withinThirty hours befoire Death

Hypotension Acute centralRight heart

failure Pri

1-7 3-68-12 8, 11, 12

13-1516-18

13-1518

>6 hours necrosis Myocardialior to SGOT prior to death of liver necrosis

8, 9, 10 8, 9, 10 8, 9, 10 10, 12

16, 17, (18l) 16, 17, 1814, 15

16, 18 16, 17

tivity, the increased enizyme activity could berelated to either myocardial necrosis or acutehepatic neerosis or both. Of the 2 withoutevident tissue necrosis at postmortem exam-ination, 1, case 13, died of a saddle embolus.The other, ease 11, died of rheumatic heartdisease and failure. One patient, case 17, diedafter prolonged hypoteinsion, but did liot havecentral necrosis. Precise correlation of thelevel of SGOT activity with the hepatic archi-tecture and the degree aiid duration of thehypotension was not possible because of thevariation in the time blood samples were ob-tainied for enzyme activity determinations.

DiscussionThis study has demonstrated that a group

of patients suffering from heart disease withvery high levels of SGOT activity had severalfactors in common: right heart failure, hypo-tension or shock preceding the SGOT eleva-tion, and, in those autopsied, central necrosisof the liver. All 8 patients who came to au-

topsy had acute central necrosis of the liver,which appeared to be related in time to theelevated serum transaminase activity. Clinicaland laboratory data from the 9 patients whowere not autopsied were essentially similarto those from the autopsied group, and it isreasonable to assume that they also had an

acute central necrosis of the liver at the timeof the high SGOT activity. In no patient was

there clinical, laboratory, or pathologic evi-dence of either hepatitis or active biliary tractdisease. In none could other causes of elevatedtransaminase such as pulmonary infarction,skeletal muscle injury, brain injury, acutepancreatitis or drugs2 be incriminated.

In 11 patients the acute central necrosis ofthe liver was related to circulatory changesassociated with an episode of acute myocar-dial infaretion. Necrosis of both the heart andthe liver undoubtedly contributed to the ele-vated SGOT activity in this group, but thelevel of activity was considerably higher thanthat usually associated with an uncomplicatedmyocardial infaretion. In 6 patients, 4 ofwhom were autopsied, there was no evidenceof infaretion of the heart and the very highlevels of transaminase activity were probablyrelated to liver necrosis aloiie.Although both Popper13 anid Sherlock14

have emnphasized the difficulties in interpret-ing postmortenm sections from the liver, theacute hepatic necrosis encountered in thisstudy is clearly a reflection of antemortemevents. Acute central necrosis is not an in-variable finding at autopsy, even in patientswith severe heart disease,"1 and was not en-

countered in the 7 patients from the controlseries who had niornmal SGOT activity priorto death.

It may be concluded, then, that irrespectiveof whether or not recent myocardial infarc-tion be present, very high levels of SGOTactivity (>500 units) in patients with cardio-vascular disease and circulatory failure whodo not have primary liver disease are a reflec-tion of an acute necrosis of hepatic cells sur-

rounding the central veins. Presumably lossof hepatic cellular integrity results in leakof the intracellular enzymes into the periph-eral circulation and very high serum activity.Since current technics for enzyme assaynieasure the activity of the enzyme system,not the coneentration, it cannot be stated with


Casenumber

SGOTlevel, units

Normal46 - 100

101 - 200201 - 500

654



SERUlTRANSAM I NASE IN II ERT 1)I SEASE 655

certaint thatant increase in blood enizy-ieactivity mneanms an incease in blood enizvym-eroiieiit.rationi. '1'Iie possibility that the chanoesin bloo(o enz-yme ac(tivity aIre Secondarv to(deianges in Inhibitors or activators c.,annot ber'uled out completely.

Thline (lata fronlt the (coiitiol Series, selectedwitlhoLt reg00a,r(l :f r the level of serumii enzymineativityv, reinforce the oiserx aloniVIl that, in pa-tienlts Awitih h.e,art (Ilsease, centrattl inecrosis ofthe liver is a-Issoctiate.d ix it t elevate(l SGOTactivilty 11(lldhyv)oteisioll. Vellou's hyperten-sioni alone was; niot associated with either in-creased SOT activity or acuite centralnRecrosis of the: livrL iii the a,iseiicc of a fallin blood ])ressure. That piroloniged hyp}oten-sioni does not inivariably lead to hepatie ieero-sis or el-evated SOOT is indieate(I by7 ease 17of: the control series. We have too feW oliser-va,tiolls inl jpatienits with prololllypjhiotell-Sion anld 110 right hiecairt failure to (Iraw firmiliconc.lusion.s. Melhy (t al. have reported inod-erate inc(reaNses ill SOOT()r aetivitv ill hypoten-sionl (dulle to (edlot-oxill,1.5 a conidit-ioni niot usuiallyc pOifll)amlie(I by hleart failure. 1'lasnia(OaT

activity inre a"'ses to ery lligh levels in (log'ssubjeeted to hemorrhagcic shock, and(l the liveris a major sourtc1e1 of tlis inerease.1" Aniv formnof periph eral Circulatory failure, if severeellnoug, can probatbly pro(luce deficient lie-jpatic lperfllsion and hepati,e entral necrosis

itit inIcreaUsed SGOT activity.lsolatctd instances of acute ecntral necrosis

of tie liver:ii patients with high SOOT activ-ity hative been previous'ly reported.8' 1, isPubli,shed protocols indicate that m1tost pa-tiets Wilthliaeute utiyocar(lial inifarctioii anidvery high serum t ransaiunase levels havTebeell hypotenlsive. (Chinsky et aClt. pr-esenited aPatient wvitlh high SO-OT activity anid centralnecrosis of the lixvrc following a, prolongedarr1mVytUi:isa, alLl post ulated tlhatl the fiypoten-sio81lassociated with thie arrltitlminia prodlucedtile liverl'(1lamage.

Tulle ptllogienesis of acm te eentral nic"rs-is-of tile IiVer has been the subljeet of speculationsincee F. 1B. Mallory first described th1e histo-logic (letails more than 50h years ago..19-21 He

Circulatton, Voltunme XXI, May 1960

Figure 6Sec tion of liver front pat icnt who dlicci of ovrpulmnonacle witht secete rcc 310o hqpertensi on, normalblood1 cicssu nornoil SOT at ictcit el. Note intensecon gestioni about centrcial coin with thinning f hopatio cords and pg!Jnotict nuctieci. There is zo cci-delice of acute hep(ttic necrosis. Control seriesicase 3. Hematoxglin! and eo0si sintin.

wN-Cas areftil to (lifferemitiale t his lesi.oni fr oichronic imassive conestiontofthe' liv,er,Iamidinterplreted the acutte necrosis as (dnciiei Canacute tox:il state ' ill th1 amlltelllortell periotl.M:lain volrkers have hdl( thliat aculte necrossiis caused( by acute congestion (if thle, lifver.Baltont and Zimnimiermnami aid( JlillsnJI 8llpro(lleed central necrosis by coinplete or par-tial oceilusioll of the thloracic iifelrior Venlacava. Althoug(-h the lfisLtologic lesoions ini theli\er Aiwere interpiet(ldas secomlar-v to aecute(:t11< ( t iO l

Ib( ire xlt 1)i

l l

e if-8( I 1(.

)rIo(,/edur ('

l

spressur'e)7, thejir e.xperlimlenltal l)rocedulresmul1lst also liave s;eelye:l- com-promlised liepatieblood floxy and(l oxygen su)ply.

Experiences dturingr World AW"ar 11 indi-cate(l that acute eentral niecrosis of the liveicoul (levelop ill )rCeviously healthy patientsfollowingr prolonged shock.24, 2112 a detailedstudy of central nicerosis llamlnert anid Alli-SonI'26 hia(d jirobably recogttized this samiie fac-tor wlhent they state(l that the ''only com-istantetiolo(ical factor inii cases of hemorrhagienecrosis is a severle cirlculatory (listurbaiiee.7In a recent study of centriloulmlar n-werosisfollowillng 1m1yocarlal 1- infarction, Clarke27fouinid 8 of 9 Iafticits iwithi centrdl nlecrosishiad developed shock after the imiyocardial in-

.



KIILIP, PAYNE

>iiiezl: st}'))l{ iihotXt ersi.(#Si. ~t'f.3' 4.tS'.'ealSyi an1eselsz

*t;- o e tla"t 4:lle *illo;kV

s- . A 1Cv _4

Fiur 7

t¾l lie}8'l'iltl r fr-rn jutite nt(with severe rightli}1tiIto/lititl f t'itniel bloo pressurle, utorralSOOT/ hun litolfin t iii tit otek indt)enel creentrallt'ii2I}iiiit iiid aiophot withou ctt'tte ((CCtra nrosis.Cotl

\t a};v+(s;thXe valse:riof the eati lsinElenbergta)ellssiermail-u amliie aIdV soextened wthiO(lIt.iIO->ti 'I lClO;illtlicciwof20uselleted antop--i'-.ltolO:it:'(l]'Tho+'k hadul be ten presenltine3

\ote\xortix'> wast(llirebobsel rva-Slonrortthasevr

ii}ti2tasi^tI s;eril'il- trarisantiirislse activity, onlyIidce1B\Cloped( overt^ colinlical shlock. Tihat mtoredid oat't haxe\Tt c8lassicj cMl inlica8l shlock is probably

'eia1ti'd I o a)eItlea'slt 2)fa1't ois. First, a diagnusisit1 shockt' wat-s predica*(tedt on1 rigid cr1iteria.Scowl.{ the a hslrrXlte' level of blood pressureis not ar1 letaccurte- measulre of the absolutehexltci o sxs->ternici or regionlal bllood flow, andhiha}lt1er arc: implortanlt iii the iiroductionl of

at iolit <'crAatt n1]lecr:osis; of thle liver.lii pa)tfienlts xxitli ad{vancedf hleart disease and

:eVc'e<Xt hlearit failurle, a1 decline in blovod pres-sale^ s gIenerally an1 indeication that cardiaciirrti)riEt hasfaSl'lenIti to) sulch a low level thateiir1iget>Xsi )ill lpeihral vascX'ular resistancee areiinlsrr1ftii eiiej1|t 1( llto c-mn irviaj the previous levels of<Xieterial l:pe^ssure. Although it has been ar-

gued, particularly in referenee to the hypo-tension of acute myocardial infaretion, thatthe low blood pressure is largely the result ofani iniadequate adjuLstnment of peripheral vas-cular resistance,28 the weight of the evidenceeat the present timne favors the view that aniniadequate cardiac output is a primary fault.In patiernts with advanced aortic or mitralstenlosis and reduced arterial pressures, dataobtainied at cardiae catheterization haveshown a low cardiac output anid hig,h periph-eral resistaniee.291 30 Rapid arrhythmuias arefrequen-tly accompanied by a fall in cardiacoutput anid arterial pressure.31 Several stud-ies have deimonstrated that the bypotension ofacute myocar dial infaretion is accompaniedby a fall in cardiac output; resistance changesare variable.32 3 It seems reasolnable, thenl, toassumlie that the hypotension encountered inthe 17 patients with very high transaminiaseactivity reflected a significanlt drop in cardiacoutput.

It lhas been shown that hepatic blood flowparallels the level of cardiac output in pa-tienits with chronic heart failure and that theproportion of systemic flow diverted throughthe splanchuie bed remainis essen-tially con-stant.35 ,3m Sinmilarly, in burni shock37 anidhlemorrlhagric shock38 hepatic blood flow de-elines in proportion to the chaniges ini cardiacoutput. Cardiogen:ie shock :mlust also be ac-companied by severe restriction of hepaticblood flow and very low oxyg,eni colntent inthe hepatic veilns. ITepatic alnd mneseniterieoxygenation arie maintainied during shock byalnl increase in oxyoen extraction per unitof flow producing, a widened arterioveniousoxygen difference.38 39 Under sueh circuin-stances, those liver cells farthest fromrl the ar-terial and portal s-upply anid closest to theeentrtal veinis arc bathed in blood almost de-pleted of oxygen and other nutrients. Atsome critical point the vitality of the centralcells is compromised and necrosis and loss ofintracellular enzynles follow. If the circula-tory reductioni is prololnged, cells more andmrlore distal to the central vein beginr to dete-riorate, produeint, a picture of massive neero-


636




sis such as was encountered in W.T., D.O.,W.D., and H.S.

In several cases with extensive central nie-crosis, there was a bridging of necrotic cellsfrom one central area to another (fig. 4). Ifa patient should survive under such condi-tions, it is not difficult to visualize an exten-sive network of fibrous tissue eventually link-ing one hepatic lobule with another and re-sulting in a cardiac cirrhosis. The bridgingbetween the central necrotic areas is com-pletely in accord with Rappaport 's experi-mental evidence that the terminal branches ofthe hepatic inflow circulation arborize notonly around the central vein but also in theborder area between the lobules equidistantfrom the hepatic triads.40 These bridges ofnecrotic tissue, therefore, are further evidenceof the role of circulatory changes in the path-ogenesis of acute central necrosis.Although all but 1 of the 17 patients with

high SGOT activity had right heart failure, itis unlikely that venous hypertension alone pro-duces either aeute central niecrosis or highlevels of transaminase activity.8' 41 We havestudied 8 patients with proved chronic con-strictive pericarditis and severe elevation ofvenous pressure; SGOT activity was normalin all. Four patients in the control series diedfrom heart failure with severe venous hyper-tension, and although all had varying degreesof atrophy and fibrosis around the centralvein, none had either acute central necrosisor elevated SGOT activity prior to death. Thechronic reduction in oxygen tension in theterminal branches of the hepatic veins asso-ciated with right heart failure42 may set thestage, however, for the rapid deterioration ofthe central cells after the development ofcardiogenic shock and thus be synergistic withthe acute reduction in hepatic blood flow.The patients with high SGOT activity and

myocardial infaretion had extensive myocar-dial necrosis by electrocardiographic criteriaand at autopsy. In the experimental animalthe level of SGOT activity correlates wellwith the size of the infarct.3-6 At least oneof the experimental technics utilized to pro-

Circulation, Volume XXI, MPa 1960

duce myocardial necrosis, however, is asso-ciated with proloniged cardiogenie s'-iock.3 4:It is possible that in som-le exl)erilnelts thehigh SGOT activity eflected both inyocardialand hepatic necrosis. A correlation betweenthe size of the myocardial infaretioni ancd thelevel of SGOT activity has liot beeln estab-lished in man.The association of high levels of tran1sami-

nase activity and a poor progniosis il p)atielltswith cardiac disease has beei iiote'l by othersparticularly with invocardial inifaretioni.7. 8

Since this study has demonistrated that a highilevel of SGOT activity in such patients im-plies hepatic necrosis, the correlationi betweenserum enzyme activity anid prognosis is proba-bly not related strictly to the aiio-iiit of lnyo-cardial tissue damage, but rather to the ftune-tional consequence of a giveni itnfaretioni. It iswell known that myocardial infaretioni associ-ated with shock carries a grave progOnosis.44 Inlterms of the function of the cardiovascularsystem, high levels of SGOT activity have thesame clinical significance as shock and there-fore signify a poor prognosis. Such high val-ues, however, are more sensitive indieators ofthe level of hepatic perfusion than the bloodpressure. This information mnay be useful atthe bedside. Very high levels of SGOT inpatients with cardiovascular disease shouldbe an indication for vigorous attempts to treatthe eirculatory inadequacy whether or nlotovert clinical shock be present.

There is one final iiiplicatioii of this studythat merits mention. Changes in blood enzyvmeactivity are widely utilized to eo-roborate adiagnosis of myocardial infaretion. Not in-frequently if neither the elinical history northe electrocardiogram is diagnostic, the in-terpretation of the changes in blood activityof SGOT or soime other non-organ-specificenzyme such as lactic dehydrogeinase nmay de-termine whether or not a patient is treated foracute myocardial infarction. If, as we ha edemonstrated, severe acute central necrosisof the liver produces striking elevation ofserum enzyme activity, it is not unlikely thata minor degree of hepatic necrosis following

657



KILLIP, PAYNE

acute circulatory changes may result in lesserelevations and indeed produce an activitycurve mimicking that seen in myocardial in-faretion. We have recently observed 2 elderlypatients with complete heart block who hadtransaminase activity curves typical of myo-cardial infaretioni when their ventricular rateslowed and blood press)ure fell for severalhours. In one the bradyeardia was secondaryto high potassium and in the other to over-digitalization. In neither was there clinical orother laboratory evidence of acute myocardialinfaretion. The implication is clear: SGOT-activity changes similar to those of myocar-dial infaretion may occur secondary to centralnecrosis of the liver unrelated to a myocardialinfaret. Caution should be used in interpret-ing seruin transamiinase changes in patientswith cardiac disease without diagnostic electro-cardiographic or clinieal abnormalities. De-termination of glutamic pyruvic transaminaselevels may be helpful in such situations, sineeelevation of the serum activity of this enzymeappears largely to reflect liver necrosis and isunusual in uncomplicated myocardial infare-tion.

SummaryA survey of all patients with very high

serum glutamic oxalacetic transaminase ac-tivity encountered during a 30-month periodat The New York Hospital revealed 17 pa-tients with cardiac disease who had 1 or moreserum giutamic oxalacetic transaminase (SG-OT) determinations exceeding 500 units.None had clinical evidence of primary liveror gallbladder disease. Eleven were admittedwith acute myocardial infarctioni, 6 withsevere heart failure. All 17 developed hypo-tension or shock and all but 1 right heart fail-ure prior to high SGOT activity.

Several patients had abnormalities of liverfunction when SGOT activity was very high.In 4 there was an excessive increase in pro-thrombin time following administration ofanticoagulants.

In the 8 patients who came to autopsy therewas histologic evidence of acute hepatic cen-tral necrosis. In 4 there was necrosis of bothheart and liver, in 4 necrosis of liver alone.

Clinical and autopsy data from a controlseries of patients with heart disease selectedwithout regard for the level of SGOT activitycorroborate the association between hypoten-sion, central necrosis of the liver, and in-creased SGOT activity. Inerease in venouspressure in the absence of hypotension wasnot associated with acute cenitral necrosis orelevated SGOT activity.

It-is concluded that very high SGOT ac-tivity (>500 units) in patients with heartdisease is at least in part caused by acutehepatic central niecrosis secondary to a dropin cardiac output and reduced hepatic bloodflow. Caution is urged in the interpretationof increased blood activity of intracellularenzymne systenis as evidence for myocardialnecrosis. Acute circulatory changes may re-sult in hepatic necrosis and increased bloodenzyme activity without myocardial infare-tion.

AcknowledgmentWe wish to express our gratitude to Dr. Henry R.

Erle for invaluable assistance during the collectionof the transaminase data and to Dr. John T. Ellis,who reviewNed the pathologic material.

AddendumSinee this manuscript was submitted for publica

tion a similar study has been published, which alsodemonstrates a correlation between very high levels ofSGOT and central hepatic necrosis in patients withheart disease. The authors concluded, however, thatacute right heiart failure was the precipitating causeof the liver necrosis. (Bang, N. U., Iversen, K., Jagt,T., and Tobiassen, G.: Serum glutamic-oxaloacetictransaminase activity as an index of eentrilobular livercell necrosis in cardiac and circulatory failure. Actamed. Seiandinav. 164: 385, 1959.)

Summario in InterlinguaUn revista de omne le patientes con elevatissime ac-

tivitates de transaminase glutamico-oxaloacetic delsero, incontrate al Hospital New York in le cursode un periodo de 30 menses, resultava in un lista de17 casos con morbo cardiac in que un o plure determi-nationes de transaminase glutamico-oxaloacetic delsero (TGOS) monstrava valores de plus que 500 uni-tates. Nulle patiente in iste serie exhibiva signosde un morbo primari del hepate o vesica biliari. Dece-un habeva essite hospitalisate a catisa de acute infarei-mento myocardial, 6 a causa de sever discompensationcardiac. Omne le 17 disveloppava hypotension o choce omnes, con un exception, habeva discompensation

Circulation, Votume XXI, May 1960

658




dextero-cardiac ante le accusation del elevate activi-tate de TGOS.

Plure patientes habeva anormalitates del functionhepatic quando le activitate de TGOS esseva multoelevate. In 4, un excessive augmento del tempore deprothrombina esseva notate post le administration deanticoagulantes.

In le 8 patientes presentate al necropsia, provashistologic de acute necrosis central del hepate essevaconstatate. In 4 il habeva necrosis del hepate e delcorde, in 4 solmente del hepate.Datos clinic e necroptic ab un serie de controlo de

patientes con morbo cardiac sed seligite sin reguardoal nivello del activitate de TGOS supporta le associa-tion inter hypotension, necrosis central del hepate, eaugmento del activitate de TGOS. Augmento deltension venose in le absentia de hypotension nonesseva associate con acute necrosis central o elevationdel activitate de TGOS.

References1. LADUE, J. S., WROBLEWSKI, F., AND KARMEN, A.:

Serum glutamic oxaloacetic transaminase activ-ity in human acute transmural myocardial in-farction. Science 120: 497, 1954.

2. AGRESS, C. M.: Evaluation of the transaminasetest. Am. J. Cardiol. 3: 74, 1959.

3. -, JACOBs, H. I., GLASSNER, H. F., LEDERER, M.A., CLARK, WV. G., WROBLEWSKI, F., KARMEN,A., AND LADUE, J. S.: Serum transaminaselevels in experimental myocardial infaretion.Circulation 11: 711, 1955.

4. NYDICK, I., WROBLEWSKI, F., AND LADUE, J. S.:Evidence for increased serum glutamic oxal-acetic transaminase (SGO-T) activity follow-ing graded myocardial infarcts in dogs. Circu-lation 12: 161, 1955.

5. RUDOLPH, L. A., SCHAEFER, J. A., DUTTON, R. E.,JR., AND LYONS, R. H.: Seirum glutamic oxal-acetic transaminase in experimental tissue in-jury. J. Lab. & Clin. Med. 49: 31, 1957.

6. RUEGSEGGER, P., NYDICK, I., FREIMAN, A., ANDLADUE, J. S.: Serum activity patterns of glu-tamic oxaloacetic transaminase, glutamic pyru-vie transaminase and lactic dehydrogenase fol-lowing graded myocardial infaretion in dogs.Circulation Research 7: 4, 1959.

7. LADUE, J. S., AND WROBLEWSKI, F.: The signifi-cance of the serum glutamic oxaloacetic trans-aminase activity following myocardial infarc-tion. Circulation 11: 871, 1955.

8. CHINSKY, M., SHMAGRONOFF, G. L., AND SHERRY,S.: Serum transaminase activity: observationsin a large group of patients. J. Lab. & Clin.Med. 47: 108, 1956.

9. -, WOLFF, R. J., AND SHERRY, S.: Serum trans-aminase activity: A comparison of the pyruvicand oxalacetic transaminases. Am. J. M. Sc.233: 400, 1957.


10. Case Records of the Massachusetts General Hos-pital (Case 44212): New Eng. J. Med. 258:1058, 1958.

11. ELLENBERG, M., AND OSSERMAN, K. E.: The roleof shock in the production of central liver cellnecrosis. Am. J. Med. 11: 170, 1951.

12. KARMEN, A.: A note on the spectrophotometricassay of glutamic oxalacetic transaminase inhuman blood serum. J. Clin. Invest. 34: 131,1955.

13. POPPER, H.: Significance of agonal changes inhuman liver. Arch. Path. 46: 132, 1948.

14. SHERLOCK, S.: The liver in heart failure. Rela-tion of anatomical, functional, and circulatorychanges. Brit. Heart J. 13: 273, 1951.

15. MELBY, J. C., EGDAHL, R. H., BOSSENMAIER, I. C.,AND SPINK, W. W.: Suppression by cortisol ofincreased serum-transaminase induced by endo-toxin. Lancet 1: 441, 1959.

16. KILLIP, T., AND PAYNE, M. A.: Unpublished ob-servations.

17. CHINSKY, M., AND SHERRY, S.: Serum trans-aminase as a diagnostic aid. Arch. Int. Med.99: 556, 1957.

18. DURANT, J. R., BOWERS, G. N., AND TWADDLE,P. I.: Observations on the behavior of variousdiagnostic aids in myocardial infarction. Am.J. M. Se. 235: 644, 1958.

19. MALLORY, F. B.: A histological study of typhoidfever. J. Exper. Med. 3: 611, 1898.

20. : Necrosis of the liver. J. M. Research 6:264, 1901.

21. : Chronic passive congestion of the liver. 5.M. Research 24: 455, 1911.

22. BOLTON, C.: The pathologic changes in the liverresulting from chronic passive venous conges-tion experimentally produced. J. Path. & Bact.19: 258, 1915.

23. ZIMIMERMAN, HT. M., AND HILLSMAN, J. A.:Chronic passive congestion of the liver; an ex-perimental study. Arch. Path. 9: 1154, 1930.

24. DARMAANDY, E. M.: Renal anoxia and the trau-matic uraemia syndrome. Brit. J. Surg. 34:262, 1947.

25. BYWATERS, E. G. L.: Anatomical changes in theliver after trauma. Clin. Sc. 6: 19, 1948.

26. LAMBERT, R. A., AND ALLISON, B. R.: Types oflesions in chronic passive congestion of theliver. Bull. Johns THopkins Hosp. 27: 350,1916.

27. CIARKIE, W. T. W.: Centrilobular hepatic necrosisfollowing cardiac infarction. Am. J. Path. 26:249, 1950.

28. AGRESS, C. M.: Management of coronary shock.Am. J. Cardiol. 1: 231, 1958.

29. GORLIN, R., HTAYNES, F. W., GOODALE, W. T.,SAWYER, C. G., Dow, J. W., AND DEXTER, L.:Studies of the circulatory dynamics in mitral

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KILLIP, PAYNE

steiiosis. II. Alteredl dylyanaies at rest. AIm1.Heart J. 41: 30, 1951.

30. -, MCMILLAN., I. R., MEDD, W. E., MATHERIS,-M. B., AND D ALEY, R.: Dy1 aim-ies of the eircu-1-tion of aortic valvular clisease. Ani. J. ALed.18: 855, 1955.

31. WEGRIA, R., FRANK, C. W., WA NG, H., AND

LAAMMERANT, J.: The effect of atrial and venltricular tachiveardia oni candiae output, coronary

blood flow and mean arterial pressure. Circu-lation Research 6: 624, 1958.

32. FRIEISS, E. D., SCHNAPER, IH. W., JOHNSON, R.L., AND SCHREINER, G. E.: Heinodylyina-ie al-

terations in acute inyocitrdial infarction. I.

Cardiac output, mean arterial pressure, totalperipheral resistanice, "'central" amid totalblood voliimies, venious pressure aind average

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Hemodynamic studies of patients w ith vo-

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Neuroses of the HeartAngina Pectoris

Stenocardia, or the breast-pang deseribed by Heberden, is not an inidependent affection,but a symulptonIi associated with a nuiumber of muorbid conditions of the heart and vessels,miiore particularly with sclerosis of the root of the aorta and changes in the coronary

arteries. True angina, whieh is a rare disease, is characterized by paroxysms of agonizingpain in the region of the heart, extending into the arms and neck. In violent attacks thereis a senisation of impending, death.-WIILIAM OSLER, M.D. The Principles and Practiceof Medicine. New York, D. Appleton & Comiipany, 1893, p. 655.


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THOMAS KILLIP III and MARY ANN PAYNEHepatic Necrosis

High Serum Transaminase Activity in Heart Disease: Circulatory Failure and

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