467

HEPATIC COMABy J. M. WALSHE, M.A., M.R.C.P.

From the Medical Unit, University College Hospital Medical School

The Clinical SyndromeHepatic coma has been defined by Adams and

'Foley (1953) as ' a disorder of consciousness, i.e.a lack of awareness of stimuli and failure to respondaccompanied by a generalized disorder of move-ment. The derangement of consciousness presentsfirst as a mental confusion, with either increasedor decreased psychomotor activity, followed bystupor and coma.' Strictly it should be addedthat these symptoms and signs are associated withand are secondary either to a failure of liverfunction or to a gross disturbance of the portaland hepatic circulation.While hepatic coma should not be diagnosed

merely by a process of exclusion there is at presentno single physical sign or biochemical determina-tion which is by itself diagnostic of the condition.Clinically hepatic coma falls into three broadgroups, first the coma of acute hepatic necrosis,second the coma of chronic hepatitis with slowlyprogressive parenchymal cell failure and thirdcoma, associated with an apparently inactive andwell compensated cirrhosis, which has beenprecipitated by some abnormal biochemical loadupon the liver. It is in their mode of onset ratherthan in their fully developed form that thesediffer., Acute hepatic necrosis may result fromeither virus hepatitis or from poisoning by suchchemicals as the halogenated hydrocarbons,phosphorus, the toxin of the poisonous fungusamanita phalloides, and an increasing number ofdrugs in current use. It may develop at any timeduring the course of an attack of hepatitis, and ismost commonly found in young women of thechild-bearing age. Coincident with or precedingthe development of mental symptoms there isusually a deterioration in the clinical condition,nausea becomes intense and vomiting trouble-some; foetor hepatis is also to be expected. Inthe older age groups drowsiness and nightmaresare apt to be the first sign of nervous systeminvolvement, but in children and young adultsexcitement or frank mania may develQp. Thisphase of excitability may last a few hours orseveral days and if associated with fits of screamingmay present a real problem in sedation. Another

sign of impending coma is failure to recognise nearrelatives or confusion as to time or place. Physicalexamination of the nervous system at this stageshows that the tendon jerks are increased, ankleclonus is often present and, sometimes, extensorplantar responses. Flapping tremor of the handson sustained posture is also a valuable sign ofimpending coma and should be carefully andrepeatedly sought when this is suspected. Oncefully developed the coma of acute hepatic necrosisdiffers little if at all from other forms of hepaticcoma with the important exception that it has avery much higher mortality. After a few days theincreased muscle tone and tendon jerks give placeto flaccidity, the temperature and pulse begin torise and death is then imminent.

In chronic hepatitis, of the type described byAlsted (1947) in menopausal women, leading toactive progressive fibrosis and in patients withalcoholic cirrhosis there is seldom the phase ofexcitement seen in acute hepatic necrosis. Theonset of coma is much more insidious, the patientbecomes increasingly lethargic and drowsy andreadily falls asleep, but can at first be easilyroused. As the illness progresses some mildconfusion is to be expected. Finally a stage isreached, after days or perhaps weeks, in whichdrowsiness has become light coma, the patientwill respond readily to painful stimuli and theremay be frequent grimacing and pursing orsucking movements of the lips together with aflapping tremor, increased tendon jerks and ankleclonus. In the alcoholic, however, the tendonjerks are depressed or absent as peripheralneuritis usually precedes the development ofhepatic failure by months or years. Besides signsin the nervous system the classical signs of severechronic liver disease are to be expected, thoughjaundice is not necessarily always present andfoetor hepatis is less often found than in acutehepatic necrosis. After a few days in light coma thepatient may return to a state of confusion andeven normality and then relapse again into coma.This fluctuating course may last for weeks ormonths, but progressive mental deterioration canbe detected between the episodes of coma, and

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some of the physical signs, such as the flappingtremor of the hands, may never disappear com-pletely. Eventually deep coma will develop andonce the increased tendon jerks have given wayto flaccidity no recovery can be expected.

In patients with apparently well compensatedliver disease the reserve of function may be toosmall to handle any extra demands which it maybe called upon to meet. Of these the commonestare intercurrent infection, to which patients withliver damage are peculiarly susceptible, theinjudicious use of hypnotics, paracentesis, a highprotein diet, the administration of ammoniumchloride or ion exchange resins in the ammoniumphase (Gabuzda, et al., I952) and finally hae-morrhage from the upper gastrointestinal tract.Patients in whom large portal-systemic collateralveins are present, whether spontaneouslydeveloped or resulting from the surgical produc-tion of an Eck fistula, seem to be particularlysusceptible to the toxic action of a high proteindiet and methionine, or to the presence of bloodin the gut. Fully developed coma in these patientsis identical with that already described, but thestage of precoma may be very prolonged andreadily misdiagnosed, particularly in the Eckfistula type of patient in whom symptoms onlydevelop when protein tolerance is exceeded.Tremor of a Parkinsonian type, slurring of speechand confusion are the typical signs and may beremarkably chronic. Symptoms lasting as long astwo years have been described (Wilson andMcAlpine, I953; Sherlock, et al., 1954). It isprobable that a number of these patients mayfind their way into mental hospitals because oftheir confused mental state and often inappro-priate behaviour. Patients with portacavalshunts are peculiarly liable to this syndrome andit may prove to be one of the principal contra-indications to the operation.The Nature of the Biochemical Lesion

It is not possible in a short article such as thisto 'review fully the recent literature on the patho-genesis of hepatic coma. It is now, however,clearly established that the histological changeswhich are found in the brains of patients dying ofhepatic failure, characteristic though they are(Adams and Foley, 1953), cannot account for theclinical syndrome and that the underlying disordermust be due to a biochemical and not to a struc-tural lesion. Further it has been establishedthat the onset of coma is associated almostinvariably with a disturbance of nitrogen meta-bolism which leads to a rise in the concentrationof the blood ammonia (Van Caulaert and Deviller,1932; Schwartz, et al., 1953; McDermott andAdams, 1954, and many'other workers). There

is also some evidence that occasionally an abnor-mality of sulphur metabolism may be implicatedin the genesis of hepatic coma (Walshe, 1951;Challenger and Walshe, 1955; Phear, et al., I956).

In interpreting work on the correlation betweenan elevated blood ammonia and the developmentof coma it should be realised that the methods usedfor the estimation of blood ammonia will, in fact,determine all diffusible alkali that may be presentin blood or be liberated from shed blood under theconditions of the experiment; that is the additionof whole blood to strong alkali either in theConway micro-diffusion dish or the Seligsonmicro-diffusion bottle.

Moreover, results obtained by workers usingthese two techniques show certain importantdiscrepancies. For instance White, et al. (I955),confirmed Conway's original observation that,after shedding, the ammonia concentration ofblood rises with time and by extrapolation backto zero time found no ammonia present in normalblood. Bessman (1956), using the Seligsontechnique, reported that the concentration ofammonia in blood does not alter significantly withtime after shedding and he also found a highernormal blood ammonia than has been reported byworkers using the Conway technique. Theobvious conclusion to be drawn from these.observations is that these two methods aremeasuring not blood ammonia but some unstablecompound present in blood which is broken dowiiat a different rate under different experimentalconditions to liberate diffusible alkali. Whetherthe raised blood ' ammonia' reported in hepaticdisease is due to an increase in this unstablecompound or whether it is due to the failure astabilizing system normally presents remains to beseen. An alternative explanation favoured byBessman is that the Conway method gives a falselow result as part of the free ammonia is lost,either being used in carbamyl phosphate synthesisor by diffusion into cells. However, as bothtechniques under discussion use saturated potas-sium carbonate to liberate ammonia this explana-tion is hardly adequate. Finally the recent workof Bessman, et al. (I954 and 1955), and of Webster(1955), has shown that the 'ammonia' con-centration varies greatly depending upon the sitefrom which blood is drawn and peripheral vein'ammonia' may not truly reflect the concentra-tion of' ammonia ' reaching the brain, an observa-tion which necessarily throws doubt on thevalidity of all earlier work on the correlation ofneurological signs with blood ' ammonia' levels.

Despite these theoretical difficulties there isno doubt that, in patients with hepatic disease,coma can be precipitated by the oral administra-tion of ammonium salts (Van Caulaert, et al.,

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October 1956 WALSHE: Hepatic Coma 469

1933; Phillips, et al., 1952; White, et al., 1955),by ion exchange resins in the ammonium phase(Gabuzda, et al., I952) or by high protein diets(Schwartz, et al., 1954), and in all cases in whichthe syndrome is so induced the blood' ammonia'is elevated. Similarly in dogs with Eck fistulae aneurological syndrome can be produced by theadministration of ammonium salts or by forcedmeat feeding and the onset of symptoms is asso-ciated with a raised ' ammonia' concentration inthe blood (Riddell, et al., I954). In dogs, as inman, the normal blood 'ammonia' level isaround 50 [gg./Ioo ml., but symptoms of meatintoxication do not develop in the dog until theblood ' ammonia ' is over 700 tgg./ioo ml., whereasin man the syndrome of hepatic coma is usuallyassociated with a blood ' ammonia' of between150 and 250 tgg./Ioo ml., although higher levelshave been reported. Clearly it is dangerous toargue from the experimental animal to man. Insheep and cattle the normal jugular vein ammoniamay be as high as 200 to 300 tgg./Ioo ml. (Repp,et al., I955; Head and Rook, 1955) and the normalblood sugar is 30 to 40 mg./Ioo ml. (Reid, I950).In other words these biochemical findings, ifapplied to man, would indicate that the patientwas in the terminal stage of hepatic coma. Perhapsthey go some way to explain the intellectualpoverty of the sheep although it seems improbablethat a glucose and glutamate infusion wouldsignificantly improve its performance. In thesheep too a syndrome of urea toxicity has beendescribed and generally attributed to the liberationof ammonia by intestinal fermentation. Thepicture of urea toxicity in sheep is not in factreproduced by intravenous ammonium salts, butis closely mimicked by the oral or intravenousadministration of ammonium carbamate andHale and King (1955) have further shown thatideal conditions exist for the formation of thiscompound in the abomasum of the ruminatingsheep. This must seriously raise the question asto the role of this compound in the genesis ofhepatic coma in man when it is precipitated byoral urea or a high protein load in the gut.The difference between man and the experi-

mental animal was further emphasized by thefinding of Benitez, et al. (I954), of a normalcerebral ammonia concentration in dogs of360 ,±g./Ioo g., and that infusions of ammoniumsalts did not produce convulsions until theammonia concentration approached 5,oootg./Ioo g. It is difficult to interpret the reportedlevels for resting brain ammonia concentration asthis varies greatly with the method used forkilling the animal (Richter and Dawson, r948) andthese authors showed that brain can rapidlyliberate up to I,ooo pg. ammonia per Ioo g. on

stimulation. Weil Malherbe (I955) has alsopointed out that' brain tissue is capable of formingconsiderable amounts of ammonia in vivo andin vitro,' and that the quantity of ammonia soformed rises sharply after convulsions whetherproduced chemically or electrically. At presentthe question remains unanswered whether theammonia so liberated is the cause or the effect ofthe convulsion. In vitro inhibition of brainmetabolism is only produced by ammonia atconcentrations very much higher than thosereported in hepatic coma (Edson, I935; Findlay,et al., 1954). At high dilutions the ammonium ionclosely mimics potassium (Gore and McIlwain,1952; Mann, et al., 1939), and under these condi-tions will do so at concentrations which haveoccasionally been reported in man, that is around1,000 (zg./ioo ml.Bessman has attributed the toxic action of

ammonia to its ability to remove ketoglutaratefrom the Krebs cycle (Bessman and Bessman,1955), but this theory does not allow for thereplacement of C4 acids from glutamic acid bytransamination (Weil Malherbe, I952). Gluta-mate is present in the brain in high concentration(Weil Malherbe, 1950), is readily taken up bythe brain against the concentration gradient(Stern, et al., 1949) and can support respirationand response to stimulation of the human cerebralcortex when present as the only substrate(Mcllwain, I953). In the present state of know-ledge it is difficult to attribute the symptoms ofhepatic coma in man to ammonia at the concen-trations reported unless some other factor ispostulated such as a break down in the ammoniabinding mechanism of the brain of patients withsevere liver disease (Walshe, I955).

Certainly it is not possible to mimic the syn-drome of hepatic coma in man by givingammonium salts unless severe liver damage is alsopresent. Concentrations of blood 'ammonia' ashigh as i.8 mg.% were reached in some patientsof Seegmiller, et al. (1954), without the develop-ment of abnormal symptoms and in schizo-phrenics ammonium chloride infusions have beenused to produce convulsions (Ajmone-Marsan,et al., 1949), an extremely uncommon complicationof hepatic coma. Experimental studies on rats,using the standard Warburg technique, have lentsupport to the theory that, when liver damage ispresent, the brain handles ammonia in a mannerdifferent from that of the normal animal (Walshe,1956).

If the role of ammonia in the genesis of hepaticcoma is not yet satisfactorily defined there is noother theory that comes so near to conforming tothe observed facts. But brief mention must bemade of other clues which may eventually help

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towards the solution of the problem. The adminis-tration of methionine to patients with severehepatic disease can precipitate coma (Watson,i949; Phaer, et. al., 1955 and I956). Methioninesulphoxide, a glutamic acid antimetabolite whichmight interfere with ammonia binding in. thebrain, has been reported in the plasma and spinalfluid of patients in hepatic coma (Walshe, I951and 1953). Methyl mercaptan has been isolatedfrom the urine of a patient dying of acute hepaticnecrosis by Walshe and Challenger (i955) whopointed out that this was probably derived frommethionine by hydrolytic or reductive fission ofthe carbon sulphur bond, an alternative metabolicpathway which might be used when the normalprocess of transmethylation is interrupted.Although little is known of the pharmacology ofmethyl mercaptan it is potentially a toxic com-pound. Indole metabolism has not been closelystudied in patients with liver disease, but either afailure of the function of detoxification in theliver or the development of extensive portalcollateral veins might result in a raised concen-tration of these compounds reaching the arterialblood. In extremely high dilutions certainindoles can profoundly disturb consciousness;adrenochrome, lysergic acid diethylamide andserotonin (5 hydroxy tryptamine) are all indoliccompounds with an hallucinogenic action(Marrazzi and Ross Hart, I955). Using thestandard Warburg technique it can be shown thata number of simple derivatives of indole seriouslydisturb brain slice metabolism with a resultantmarked increase in ammonia production at con-centrations similar to those at which the knownhallucinogens are active in vitro (Walshe, 1956).The indoles are certainly formed in the gut bybacterial action and it is not improbable that alarge gastrointestinal haemorrhage or high proteinfeeding would result in increased production atthe same time as the ammonia formation increases.

Severe electrolyte disturbances will also resultin the onset of coma in patients with liver disease,though whether this is truly hepatic coma isdoubtful; this is, perhaps, a question of ter-minology into which I do not propose at presentto enter.

TreatmentWithout a certain understanding of the under-

lying metabolic lesion giving rise to hepatic comait is difficult to be dogmatic about the best form oftreatment. There are, however, certain generalprinciples which are applicable to the treatmentof all comatose patients and these should not beneglected in favour of attempts directly toinfluence the specific biochemical lesion ofhepatic coma.

These general principles include maintenance ofthe fluid and electrolyte balance, an adequatesupply of calories, prevention of infection and, asfar as possible, assurance of an adequate supply ofoxygen to the brain. I do not propose to deal indetail with all these points but only to referbriefly t6othe more controversial aspects.

Electrolyte disturbances are common in patientswith severe liver' damage. Fluid retention isoften associated with a low serum sodium (Hilton,1952; Schwartz, et al., 1953), and occasionallycorrection of deficiencies of either sodium orpotassium may be followed by a return of con-sciousness (Artman and Wise, 1953); certainlyserious deficiencies of either should be replacedwhen possible, though when oliguria is presentextreme care should be taken not to give excesspotassium. Salt poor human albumin has beenadvocated for the treatment of ascites when theplasma electrolytes are not greatly disturbed(Post, et al., I95i) but, as a powerful plasmaexpander, this is liable to precipitate dangeroushaemorrhage if portal hypertension is present.Under these circumstances the use of sodiumrestriction and mercurial diuretics are probablysafer and more likely to succeed (Hilton, 1952);ammonium chloride and diamox are, however,dangerous and should not be given. When severesodium depletion is associated with fluid retentionmuch benefit is sometimes obtained by giving300 ml. of 5%/ NaCl and following this withrestriction of fluids by mouth.The patient in coma will not need more than

1,000 calories daily unless fever is present. Thesecan be supplied easily as 25% glucose solutionwithout overloading the circulation with fluid. Toavoid venous thrombosis this should be given bypolythene catheter direct into the vena cava orinto a peripheral vein after addition of smalldoses of hydrocortisone to the infusion mixture(Polak, I956).

Prevention of infection will require the use notonly of an antibiotic but also expert nursing careahd the avoidance of unnecessary instrumentationof the urinary tract. As a covering antibioticpenicillin has many advantages and can bereplaced later by one of the tetracyclines if requiredto eradicate some specific organism. In patientswho appear likely to be unconscious for any lengthof time a tracheotomy reduces the risk of inhalationof gastric contents especially if it is decided to feedthem by stomach tube. Blood loss from thegastrointestinal tract should be carefully soughtand anaemia corrected either by whole blood orpacked cell transfusions. Haemorrhage fromoesophageal varices is a major emergency inpatients with severe liver disease and is a frequentprecipitating cause of coma.

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October 1956 WALSHE: Hepatic Coma 471Treatment of the specific biochemical lesion of

hepatic coma has been concerned mainly withattempts to correct the disordered nitrogenmetabolism and to promote glucose utilization.To achieve these results the following means havebeen used: protein withdrawal or the adminis-tration of glutamic acid, aureomycin, cortisone orlipoic acid (6.8 dithiol octanoic acid).The evidence for suspecting ammonia as a

causative agent in the onset of hepatic coma hasalready been considered; reduction of the proteincontent of the diet will reduce ammonia pro-duction by bacterial action in the gut. Thisundoubtedly leads to a marked improvement inmany cases of hepatic coma, particularly thosein which there are large portal collateral veins(McDermott and Adams, I954; Schwartz, et al.,1954; Sherlock, et al., 1954). During proteinwithdrawal calories can be supplied as glucoseonly; this is well tolerated for one or two weeks.If necessary protein can be given as small poolplasma, two bottles of which contain approxi-mately 45 g. As consciousness returns tube feedingbecomes safer and the problem less difficult butprotein should be restored only gradually to thediet. Aureomycin has been recommended in thetreatment of hepatic coma and Farquhar, et al.(1950), believed that the improvement theyobserved was due to a reduction in bacterialfermentation in the gut, and Phear, et al. (1956),have shown that it will reduce or abolish thesymptoms of methionine toxicity. Other workershave been less successful with this form of treat-ment (Shank, 1952; Patek, I954), and it has beenpointed out that large doses of aureomycin mightactually in themselves be hepatotoxic (Lepper,et al., I951; Rutenberg and Pinkes, 1952).

Glutamic acid plays a central part in theammonia binding mechanism of the brain (WeilMalherbe, 1950). Intravenous sodium glutamatehas been recommended in the treatment ofhepatic coma (Walshe, 1953), and there is nowmuch evidence that its use is indeed followedby a fall it the blood' ammonia' concentration(Riddell and McDermott, 1954; Sherlock, et al.,1954; McDermott, et al., 1955; Bessman andBradley, 1955; Webster and Davidson, 1956); insome cases this fall in the blood ' ammonia' levelhas been followed by a return of consciousness.Originally Walshe (1953) gave 23 g. of mono-sodium glutamate daily by vein but later suggestedgiving a mixture of the sodium and potassiumsalts, in a ratio of 3 to I, to avoid the hypokalaemiawhich may otherwise develop, particularly inview of the larger doses of glutamate which werebeing employed (Walshe, 1955). Very large doseshave been given by Webster and Davidson (1956)but the risk of overloading with sodium is great.

Cortisone, in doses' f5oo to i,ooo mg. a day, mayoccasionally be of value in patients with acutehepatic necrosis, a condition which otherwisehas such a high mortality (Ducci and Katz, 1952;Evans, et al., 1953). In chronic liver disease theresults have been rather disappointing (Sklar andYoung, 1955) and there is apparently a risk ofportal vein thrombosis in patients with portalhypertension (Eisenmenger, et al., 1952).

Lipoic acid is necessary for pyruvate to enterthe Krebs cycle; disturbances of keto acid meta-bolism have been reported in hepatic coma(Carafango, et al., 1953), and this suggested thatthe thiol groups in lipoic acid might be blocked orthat this co-enzyme factor itself might be deficient.Recently Lisan, et al. (1955), have reported goodresults following the use of this compound. Thesmall number of cases I have seen treated withlipoic acid have been less successful.

Vitamins have no curative role in hepatic comabut vitamin K should be given to lessen the riskof haemorrhage and also the B vitamins as patientsreceiving continuous intravenous glucose mayotherwise develop a conditioned B complexdeficiency.

In those patients who are noisy or excited inthe stage of impending coma sedation presents amost difficult problem. The long acting bar-biturates are handled largely by the kidneys anidare therefore the drugs of choice, but Sessions,et al. (I955), have recently published evidence toshow that even the quick acting barbiturates arehandled better by patients with liver disease thanwas previously thought to be the case.

In summary it may be said that careful attentionto the fluid and electrolyte balance and an adequatesupply of calories, preferably as intravenousglucose, are the corner stones on which the therapyof hepatic coma must be based. Of the variousforms of treatment aimed directly at correctingthe biochemical lesion causing coma, severerestriction or complete withdrawal of dietaryprotein and the use of glutamate are best in thecoma of chronic hepatic disease, while cortisoneshould be tried in large doses in acute hepaticnecrosis. In the latter condition, however, notherapy can hope to achieve a high cure rate untilan antibiotic active against the hepatitis virusbecomes available.

BIBLIOGRAPHYADAMS, R. D., and FOLEY, J. M. (I953), 'Metabolic and Toxic

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OBSTETRICS & GYNAECOLOGY(Postgraduate Medical Journal, July, 1954)

Price: 3s. 10d., post freeINTRODUCTORY PELVIC THROMBOSISCharles D. Read, F.R.C.S., F.R.C.O.G. J. Stallworthy, F.R.CS., F.R.C.O.G.RESPIRATORY HAZARDS IN THE THE EARLY DIAGNOSIS OF GENITALPREMATURE INFANT CANCER BY CYTOLOGY

Albert E. Claireaux, M.D., M.R.C.P. Erica Waechtel, M.D.

POSTMATURITY THE MENOPAUSES. G. Clayton, M.D., M.S., F.R.C.O.G. G. I. M. Swyer, D.M., M.R.C.P.

THE PLACE OF ULTRA-RADICAL SUR-THE RELATIVE MERITS OF THE VARIOUS GERY IN ADVANCED MALIGNANTBIOLOGICAL TESTS FOR PREGNANCY DISEASE IN THE PELVISH. P. Ferreira, M.D. J. B. Blaikley, F.R.C.S., F.R.C.O.G.

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