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THE DIAGNOSIS OF INFECTIVE HEPATITIS ANDITS SEQUELAE

By G. A. ELLIOTT, O.B.E., M.D., F.R.C.P.Professor of Medicine, University of the Witwatersrand, Johannesburg, South Africa

The object of this presentation of a well-knownand frequently documented -subject is to emphasizethe diagnostic difficulties of the clinical picturespresented by infective hepatitis. From the pointof view of diagnosis, consideration must be givento the following stages of the disease, the differ-entiation into stages clearly not being absolute

A. Acute Infective Hepatitis(i) The pre-icteric phase, with pyrexia and

intestinal manifestations dominating the picture.(ii) The icteric phase, with jaundice as the

dominant manifestation. The type varies fromthe fulminating to the average type of case withjaundice lasting two to three weeks.

(iii) The post-hepatitis syndrome, the stage ofsymptoms without signs.

(iv) Infective hepatitis without icterus.(Homologous serum jaundice and post-

arsphenamine jaundice are included for the pur-pose of discussion under the heading of acuteinfective hepatitis.)

B. Chronic (Post-Infective) HepatitisThis includes the ' inactive hepatitis' of

Barker3, the ' peri-acinar' or ' cholangitic' typeof Eppinger"5, and the ' cholangiolitic' type ofWatson and Hoffbauer54. The clinical picturesmay be persistent hepatomegaly with or withoutsymptoms, or recurrent jaundice of all grades ofseverity with or without symptoms, or a combina-tion of these manifestations.

C. Post Infective Hepatitis CirrhosisEach of these phases will be considered as a

diagnostic problem in itself in which the clinicalpicture, the biochemical tests of liver function, andliver biopsy will be considered in their relation todiagnosis. It is not the purpose of this paper togive a critical evaluation of all liver function tests,on which subject many reviews and standard bookshave been written. Recent reviews by Osgood42and Stein5' offer a fair assessment.

The Pre-Icteric PhaseIn the majority of cases infective hepatitis at

this stage presents as a' P.U.O.' with anorexia and

nausea as the prominent symptoms, to which maybe added myalgic pains and the other usual accom-paniments of any pyrexial illness.. This pyrexialphase may last from a day or two to a week ortwo. Many cases in military practice were dis-charged from hospital with the diagnosis of' short term P.U.O.' only to return a few dayslater with jaundice'4. During the pre-ictericphase, a minority of cases may experience severeabdominal pain suggesting the diagnosis ofcholecystitis or appendicitis, and laparotomy mayappear to be indicated. The normal white cellcount of infective hepatitis is a valuable aid in thediagnosis. The milder cases may in the pre-icteric phase be apyrexial and complain only ofanorexia and nausea with possibly some vomiting,and a complete absence of physical signs onexamination. Such cases are apt to be labelledneurosis' or ' gastritis '-diagnoses frequently

proved wrong by the later appearance of jaundice,the vanity of the doctor possibly suffering morefrom such error than the welfare of the patient.

Physical signs apart from the pyrexia in thepre-icteric phase are conspicuous by their absencealthough there may be some hepatic tenderness onpalpation or ' fist ' percussion. Special investiga-tions of the blood at this stage are of somediagnostic value. The total leucocyte count isnormal or reduced. There is a relative lympho-cytosis, a feature common to many other virusaffections such as influenza and sandfly fever.Atypical mononuclear cells such as are found ininfective mononucleosis may be seen in anappreciable number of cases, reaching as high as6o per cent. of the total white cell count2. Hepatitismay complicate infective mononucleosis' and thediagnostic difficulties in such an instance areobvious. Heterophil antibodies have not been re-ported in infective hepatitis. Their presence orabsence is, however, neither diagnostic nor ex-clusive of infective mononucleosis. At this stageof infective hepatitis the blood sedimentation rateas a rule is normal2. The urine may or may notshow excessive quantities of urobilinogen. Uro-bilinuria is not a reliable diagnostic aid2 54 since itis frequently absent at this stage of infectivehepatitis and present in many other conditions of

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short term fever. Bilirubinuria at this stage maybe detected by chemical analysis a day or so beforeits presence is clinically suspected, the methyleneblue test'9 being a simple and useful routine,particularly where the disease is epidemic andcoincident with other epidemic pyrexial diseasessuch as influenza or sandfly fever.

Tests of hepatic function at this stage may beabnormal. According to Barker and others2 thecephalin cholesterol and bromsulphthalein testsshow a defect in 50 to 75 per cent. of cases. Otherreports confirm the finding of abnormal liver func-tion tests. Other infections may show defectivehepatic function tests at this stage41, but in suchcases the abnormality is in single tests rather thanin batteries of tests. It would appear then, thattests of hepatic function in the diagnosis of in-fective hepatitis at the pre-icteric stage, have onlya limited value. Examination of liver histology bybiopsy at this stage has not been reported onextensively, but Mallory32 describes grades andquality of histological change in the pre-ictericstage indistinguishable from the changes which areseen during the icteric phase.

The Icteric PhaseOnce hyper-bilirubinaemia becomes apparent,

either by noticeable jaundice or by darkening ofthe colour of the urine, it is clearly necessary todecide whether the condition is one of intra-hepatic (hepatocellular, toxic, or infective) jaun-dice, extra-hepatic obstructive (surgical) jaundice,or haemolytic jaundice. Under the heading ofhepatocellular jaundice, in which condition anobstructive element of greater or less degree isalways present, must be considered diseases inw-hich hepatitis is a usual accompaniment of thecondition, e.g. infective hepatitis, homologousserum jaundice, post-arsphenamine jaundice, theacute infections of yellow fever and Weil's disease,chemical and vegetable hepatotoxins; and thediseases in which hepatitis is an occasional ac-companiment e.g. the very important condition ofmalignant tertian malaria with hepatic involve-ment, and infectious mononucleosis or pneu-monia. Under the heading of extra-hepaticobstructive jaundice must be considered in par-ticular stone in the common duct with its eventualcholangitic hepatitis of Himsworth25, and malig-nant obstructions. Haemolytic jaundice can bereadily differentiated from the other two types ofjaundice by its haematological characteristics.The haemolytic jaundice of malignant tertianmalaria and of the sulphonamides are two con-ditions that must be considered in the diagnosis ofany case of haemolytic jaundice. In the differentialdiagnosis of jaundice the value of an accurateclinical history and examination cannot be over-

emphasized. In very few cases will biochemicaltests or study of liver cell structure by biopsy domore than confirm the clinical diagnosis. Never-theless such tests are of value in assisting not onlyin diagnosis but also in prognosis, and, as in thecase of plasma prothrombin estimations, in theassessment of fitness to undergo operations.

Hepatocellutlarjaundice and extra-hepatic obstruc-tive jaundice. First must be considered the dis-tinction between hepatocellular jaundice with itsobstructive element, e.g. infective hepatitis, andextra-hepatic obstructive jaundice such as that dueto gall stones or carcinoma. All important in thedifferential diagnosis is the clinical history- andpicture. In case of stone in the common duct, thehistory or observation of pyrexial attacks with dis-comfort or actual pain may be helpful, but thesemay be absent, and furthermore in surgically orpost-mortem proved cases of hepatocellular jaun-dice, including occasional chronic forms of in-fective hepatitis, episodes of pyrexia occur withsevere right upper abdominal pain. Watson andHoffbauer54 report one case in which an initialattack of infective hepatitis occurred in I912, thepatient eventually dying with cirrhosis of theliver in I945, three laparotomies having been per-formed in the previous I3 years in the search for astone in the common duct on account of painfulpyrexial 'episodes and recurrent obstructive jaun-dice. Liver biopsy in a jaundiced period duringI932 showed normal liver cells and some slightperiportal fibrosis. Neither at laparotomy noreventually at post-mortem following a fatal haema-temesis was any organic cause of chronic recurrentobstructive jaundice found.

Contrariwise, jaundice due to stone in thecommon duct may simulate hepatocellular jaun-dice. In one's own recent experience there is a caseof a woman aged 57 admitted to hospital in Novem-ber, I946, with jaundice of obstructive type ofsome six weeks duration, pruritus, right upperabdominal discomfort, the patient showing at thetime of admission to hospital defective hepaticfunction tests (cephalin cholesterol, thymol tur-bidity, hippuric acid). Biopsy at that time was notdone. Within six wee'ks of the time of admissionthe condition improved and the patient was dis-charged from hospital free of jaundice andsymptoms. A year later there was a recurrence ofobstructive jaundice of mild and varying degree,pruritus, and slight upper abdominal discomfortwith occasional pyrexia over a period of someweeks. Biochemical tests again showed deficientliver function. Laparotomy was performed and astone was found obstructing the common duct;there was macroscopic and microscopic evidenceof hepatic cirrhosis. The diagnosis of chronichepatitis of cholangio-hepatitic type was correct,

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but the primary cause was the obstruction causedby the stone.

Hepatic function tests may be of some value inthe differentiation of extra-hepatic obstructivejaundice and intra-hepatic hepatocellular jaundiceif carried out early in the disease. There is greatdifference of opinion regarding the relative meritsof these tests, vide Cantarow and Trumper8. Allagree that more than one of the many availabletests must be applied in each case. Sherlock46 47correlates biopsy studies with hepatic functiontests and concludes that a single specimen ofvenous blood examined for bilirubin, alkalinephosphatase, and serum albumin content gives in-formation regarding diagnosis and extent of liverdamage as adequately as more complicatedbatteries of tests. Serum bilirubin increases pro-portionately to the extent of liver cell damage inacute hepatitis ; phosphatase is rarely above 30King-Armstrong units in hepatocellular jaundiceand often up to go units in obstructive jaundice;and serum albumin reduction is proportionate toliver cell defect in acute hepatitis and cirrhosis.Sherlock48 points out the unreliability of thehippuric acid test unless the renal function hasbeen shown to be normal. All authors agree that,apart from the serum bilirubin level, whichmerely reflects the degree of jaundice, tests ofliver function carried out early are of some value indistinguishing the two conditions of hepatocellularand extra-hepatic obstructive jaundice, hepato-cellular function being normal in early extra-hepatic obstructive jaundice. In the course of afew weeks, however, the function tests in obstruc-tive jaundice become abnormal due to the as-sociated cholangio-hepatitis3' 25. Himsworth, inemphasizing the parenchymal damage that super-venes sooner or later on obstruction, and afterdiscussing liver function tests, concludes that thereis yet no test which approaches in value a carefulclinical assessment. Liver biopsy is of value ifundertaken at an early stage of the jaundice. Ininfective hepatitis, homologous serum jaundice andpost-arsphenamine jaundice, a characteristic pic-ture is seen13 31 32 43 47 whereas in the early stagesof extra-hepatic obstructive jaundice, the livercells are normal. It is pointed out, however3' 47 49,that in as short a time as two to three weeks fromthe onset of extra-hepatic obstruction, liver cellnecrosis and periportal fibrosis may appear andare indistinguishable from the post-infectivehepatitis picture. It is essential, therefore, thatliver biopsy as an aid in differentiation be carriedout at an early stage of the jaundice.With all modern aids, however, one can but

agree with Lipp and his co-workers27 who, afterreviewing 412 cases ofjaundice in their clinic, con-cluded that careful evaluation of the clinical history

and the findings on clinical examination gave acorrect diagnosis in go per cent. of cases ofjaundice, and in the majority of -this group of casesdthe laboratory findings supported the diagnosis.In the remaining io per- cent. of their cases,however, both the clinical and the laboratoryevidence were inconclusive, and in all cases ofobstructive jaundice of obscure aetiology lapar-otomv was regularly advised in order to avoidoverlooking a possible extra-hepatic surgical lesion.In this connection Himsworth25 in discussingcholangio-hepatitis (ascending cholangitis) withits eventual parenchymal failure and cirrhosis ofthe biliary (Hanot) type consequent upon obstruc-tion, concludes that it is impossible to be certainthat extra-hepatic obstruction is absent and advisesthat cases diagnosed as cholangio-hepatitis shouldbe surgically explored. His emphasis on carefulclinical assessment in the diagnosis has alreadybeen mentioned.Having considered the differences between

extra-hepatic obstructive jaundice and intra-hepatic hepatocellular jaundice, it is necessary todiscuss the various types of hepatocellular jaun-dice. The first consideration is whether the threeconditions of infective hepatitis, homologousserum jaundice and post-arsphenarmine jaundice,are the same or different conditions, and ifdifferent whether they can be differentiated.Homologous serum jaundice. This is generally

regarded as being due to a virus infection butwhether this is identical with the virus of in-fective hepatitis is in dispute. The disease hasfollowed prophylactic inoculations in which thevirus is a part of the inoculated material, as in thecase of yellow fever vaccine, or in which the virusis conveyed from one individual to another by themultiple dose, per syringe technique of givingprophylactic inoculations, as in the epidemicspread by tetanus toxoid inoculations described byCapps, Sborof and Scheiffley10. Therapeutic con-valescent serum, transfusions of plasma or wholeblood, and imperfectly sterilized syringes used invenereal and diabetic clinics have spread the in-fection. As little as o.oi cc. of infected plasma orserum is sufficient to convey the virus 28 32.The clinical picture of homologous serum

jaundice is indistinguishable from infectivehepatitis unless it be true as is claimed byMcMichael31 and Ginsburg20 that homologousserum jaundice tends to be more severe than in-fective hepatitis, a difference of little value whenconsidering individual cases. Biochemical hepaticfunction tests in the various stages of the two con-ditions are identical. Thus, Neefe and co-workers4' report defective liver function tests inthe pre-icteric stage between the time of the ex-perimental inoculation of volunteers with infected

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plasma and. the onset of the jaundice, as well asduring the icteric phase. In their experience,serum bilirubin level, cephalin flocculation, brom-sulphthalein excretion, plasma vitamin A andplasma prothrombin activity were found both inthe pre-icteric and the later stages to detecthepatic disturbances more consistently andpromptly than did estimates of urobilinuria,serum albumin and globulin, serum alkaline phos-phatase, hippuric acid excretion and blood sedi-mentation rate. They noted that bilirubinuria wasobserved early and, furthermore, before anysignificant increase in serum bilirubin level.Serum bilirubin became increased above normalafter the cephalin cholesterol and other hepaticfunction tests had shown dysfunction, In some ofthe cases, all tests except the serum and urinarybilirubin were abnormal, these being obviouslycases of hepatitis without jaundice. The brom-sulphthalein excretion they considered to be re-liable as a guide to recovery as it was the last testto return to normal and was specially valuable infollowing cases without jaundice. Control seriesof tests on disorders such as influenza not usuallyassociated with clinically detectable liver abnor-malitv showed occasional single test deviationsfrom the normal, but never was the whole batteryof tests abnormal as in hepatitis.

According to Dible and others'3, Mallory82 andother observers, liver biopsy does not assist in thedifferentiation of homologous serum jaundice frominfective hepatitis and for that matter from post-arsphenamine jaundice.The incubation period is said to differ, being 6o

to I20 days in homologous serum jaundice andone-half to one-third of this time for infectivehepatitis, this being used as evidence that theviruses are of a different type. Such argument isnot necessarily correct as it is known that a com-bination of virus and immune body increases theincubation period of any virus, and in the case ofhomologous serum jaundice the virus, being con-tained in the serum, is of necessity injected alongwith immune body. In this connection it isinteresting to note the incubation period of thejaundice induced by Gardner and others'8 whoinoculated over 300 volunteers suffering fromrheumatoid arthritis with serum from cases of in-fective hepatitis. The incubation period from thetime of inoculation to the appearance of thejaundice in the io per cent. of volunteers who de-veloped jaundice was from 27 to I3I days.Cameron7 reported incubation periods of up tosix months in volunteers inoculated with infectivehepatitis serum but the subjects of his experimentwere living in an area where infective hepatitis wasendemic. It has also been suggested by Havens24,Neefe"l and others, that the portal of entry of a

particular virus may determine differences in itsincubation period. Neefe and others4' indicatethat in their nine volunteers inoculated with yellowfever vaccine or with plasma, 12 to 35 dayselapsed from the date of the inoculation to thefirst biochemical or clinical manifestations ofhepatitis, 65 to iio days elapsing before jaundicewas added to the picture. They remark withoutcomment that the period of I2 to 35 days is theaccepted incubation period of infective hepatitis.

It has not been finally decided if a crossimmunity between homologous serum jaundiceand infective hepatitis exists. Neefe and co-workers39 in a small but well-controlled series ofhuman volunteer experiments found results whichstrongly suggested a lack of cross immunity. Theynoticed in their series furthermore, that infectivehepatitis serum given parenterally to volunteersfailed to cause jaundice, whereas orally ad-ministered infective hepatitis virus in the form offiltrates of faeces did cause jaundice; on the otherhand serum from homologous serum jaundicecases administered parenterally was followed byjaundice. Havens23 reported human volunteerexperiments which suggest that no cross immunityexists. Gould2l studied the incidence of infectivehepatitis and 'yellow fever homologous serumjaundice in the armed forces, and found that theincidence of infective hepatitis in subjects withprevious homologous serum jaundice was ratherhigher than in those who had not had homologousserum jaundice. His findings, furthermore,suggested that clinical and subclinical infectivehepatitis conferred immunity against a furtherattack of infective hepatitis.

Contact infection from homologous serumjaundice has not been confirmed, while it is, so faras is known, the common mode of spread in in-fective hepatitis. Findlay and Martin'7 are amongthe few who have claimed to transmit homologousserum jaundice following yellow fever immuniza-tion by intra-nasal instillation of virus. Neefeand others38 40 failed to cause jaundice in I9volunteers within a two to four month periodafter ingestion of filtrates of faeces from cases ofhomologous serum jaundice whereas filtrates offaeces from infective hepatitis cases taken bymouth caused jaundice in 26 days in six out ofI2 volunteers.

It remains uncertain whether the two viruses ofhomologous serum jaundice and of infectivehepatitis are identical or separate entities. Havens22reviews his own and other extensive studies andsums up with the statement: 'It is not yetdetermined whether the differences in route ofinoculation, length of incubation period, dis-tribution of virus, period of infectivity and lackof cross immunity are representative of the

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activities of actually different viruses or of anti-genic differences of various strains of one virus.'One must therefore conclude that there are nomethods, clinical, chemical or histological, ofdistinguishing homologous serum jaundice frominfective hepatitis, nor is there any definiteevidence to decide whether one or two viruses areimplicated.

Post-arsphenamine jaundice. In the humansubject this should not be called arsenical hepatitissince there is little evidence that arsenic directlycauses the hepatitis. The vast majority of suchcases occur between the fifteenth and twentiethweeks of arsenical treatment33, but cases may de-velop later in the course of treatment or after thecompletion of treatment. Delay in the appearanceof jaundice after completion of arsenical treatmentdoes not exclude all relationship between arsenicand jaundice since it is known that delayed hepaticdamage, the 'massive hepatic necrosis ' of Hims-worth, may occur months after removal of thepatient from contact with the so-called hepato-toxins, such as T.N.T. or cincophen26. Casesoccur after the first or second injection of arsenic,and such cases have beeh claimed, not necessarilyjustifiably, to be due to the arsenic, on the groundsthat a virus conveyed by syringe could not haveincubated in so short a time5. Although it isaccepted that jaundice can occur as part of aHerxheimer reaction between the fifth and thetwenty-fifth days of treatment44 it is also possiblethat early jaundice is an example of biotropismwith the arsenic sensitizing the liver to invasionby the virus of infective hepatitis which is lyinglatent in the body awaiting an opportunity toattack. That factors other than a hepatotoxin- arenecessary before such toxin can exert its action onthe liver is a reasonable hypothesis. In animalexperiments such factors, in the case of chemicaltoxins, are locality52, climatic factors of tempera-ture and barometric pressure 35 36 37, and diet,which subject Himsworth25 reviews very ade-quately. By analogy, if the virus of infectivehepatitis is regarded as an hepatotoxin, it seems,for instance, possible that the high mortality of themalignant type of infective hepatitis described inCopenhagen by Bjorneboc and others4, in which37 per cent. of a series of 303 cases were dead in amatter of months, could have been due to theassociation of a standard infective hepatitis virusacting in conjunction with some other factor, forexample malnutrition. Attempts to induce jaun-dice by oral administration of faeces and naso-pharyngeal washings from post-arsphenaminejaundice cases failed, whereas inoculation ofserum (sero-negative) from such cases was followedby jaundice (MacCullum29).

Dible and McMichael12, in a liver biopsy study

of 35 cases of post-arsphenamine jaundice, offeredthe opinion that post-arsphenamine jaundice, in-fective hepatitis, and homologous serum jaundicewere one and the same disease, and that post-arsphenamine jaundice was not due to the arsenic.They pointed out that in animals jaundice isproduced by arsenic after doses I5 times themaximal equivalent dose administered to humancases of syphilis. The histological picture in thethree conditions is described as an hepatic in-flammation of varying intensity and distributionwhich is common to post-arsphenamine jaundice,infective hepatitis, and homologous serum jaun-dice12 13 32The facts that massive mapharside treatment

consisting of 1,200 mgm. of the drug given infive days can be carried out without any demon-strable defect of hepatic function53, that jaundiceis rare under massive arsenotherapy, and that manycases are reported of arsenical administration beingcontinued during post-arsphenamine jaundicewithout adverse effect on the jaundice or thepatient34 hardly support the supposition thatarsenic has a direct hepatotoxic action. Cormiaand Blauner1' reported six cases of jaundiceamongst 500 syphilitics treated by massive arseno-therapy over a period of two years, and remarkedthat the six cases occurred in a short circum-scribed period during which there was a generalincrease in infective hepatitis amongst the popula-tion. , They suggested that infection was at least afactor in the production of post-arsphenaminejaundice. Nevertheless the majority of venere-ologists advise withholding arsenic for threemonths after the post-arsphenamine jaundice hasdisappeared. The clinical picture and course inthe individual case of post-arsphenamine jaundicediffer in no significant manner from infectivehepatitis. Acutely fatal cases occur, mild averagecases, and cases leading to chronicity. Such casesof post-arsphenamine jaundice are infrequentlyassociated with other manifestations of arsenictoxicity such as dermatitis or peripheral neuritis34.Collective studies, however, do show a differentcourse and prognosis. In Borensztejn's series5 of226 post-arsphenamine jaundice cases there were40 deaths, a percentage of deaths far exceedingthe under i per cent. mortality of infectivehepatitis. Of 36 deaths from acute liver necrosisin the Middle East14 I2 were receiving arsenic priorto death, the incidence of post-arsphenaminejaundice to infective hepatitis at the time beingI to 13.

Biochemical studies of hepatic function inpost-arsphenamine jaundice differ in no way fromthose found in infective hepatitis. The incidenceof post-arsphenamine jaundice varies from clinicto clinic, from o.6 per cent. to 40 per cent. and

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more of cases under treatment, this aspect of thesubject being reviewed by Marshall33 and others.There is little evidence to support syphiliticdisease of the liver as the cause ofjaundice. Thereis therefore no method of differentiating post-arsphenamine jaundice from infective hepatitisnor is there evidence that they are differentdiseases. The concensus of opinion is that post-arsphenamine jaundice is a virus jaundice ofhomologous serum type.

Specific types of infection. Specific types of in-fection with liver affection as a dominant con-comitant must clearly be considered as a cause ofacute hepatocellular jaundice. Weil's disease andyellow fever in particular require mention; 'thelatter in view of present day air travel facilities no.longer remains a disease to be considered only inendemic tropical areas. The clinical and bio-chemical picture in both these conditions is that ofan acute hepatocellular jaundice with parenclhymalhepatic failure of all grades, but the specificcharacter of the disease is diagnosed only by thefeatures of epidemiology, the general clinicalcharacters, and specific immunological investiga-tions. Malignant tertian malaria must be con-sidered in all cases of acute pyrexial illness withjaundice. The jaundice can be hepatocellular orhaemolytic or of both types. Any practitioner inmalarious countries has had experience of casesdiagnosed and treated as infective hepatitis that inreality were malignant tertian malaria, such errorsarising through not carrying out the simple pro-cedure of a blood examination. Patients con-tracting malarial infection in endemic areas cannowadays. reach non-mLarial parts of the worldquite readily within the incubation period of thedisease.

The Post-Hepatic SyndromeThis special heading connotes a not at all un-

common clinical problem. The syndrome con-sists of symptoms of lassitude, anorexia, dyspepsia,occasional diarrhoea, and a lack of interest in theeveryday things of life. On clinical examinationthere are no abnormal physical findings, and bydefinition hepatocellular tests, if carried out, arenormal; biopsy of the liver shows none of thedescribed features of infective hepatitis. On thistype of evidence it is tempting to label such a casepsychoneurotic and indeed this may be correct.Sherlock and Walshe50 describe 20 cases of thistype in which the hepatic function tests favouredby Sherlock were applied and correlated withliver biopsy findings. In 'these patients hepaticfunction tests were normal, liver -biopsy wasnormal, with the exception that in three of thecases there was residual portal scarring, and in i6the liver was palpable. The authors suggested

that these patients had learned how to push theirlivers down by diaphragmatic action and theyregarded them all as psychoneurotic. Onehesitates to accept normal hepatic function testsand even normal liver histology by present dayhistological techniques as proving the absence of

,all hepatic disease. It is known that hepaticfunction tests (apart from a raised serum bilirubin)and biopsy may be normal in the face of persistentrelapsing jaundice and eventual -portal cirrhosisfollowing infective hepatitis5. We accept thediagnosis of infective hepatitis, acute and chronic,in the absence of jaundice and raised serumbilirubin, but with abnormalities in function testsother than estimation of serum bilirubin. Itseems that a combination of normal histology,normal serum bilirubin, and normal hepatocellularfunction tests is not incompatible with a disturbedhepatic function that could serve as a basis ofsymptoms. Physical signs such as a tender liver,enlarged or not, or even a recurrence of jaundice,may be induced in such cases after strenuousexercise or by a long jolting ride in a vehicle overrough roads, indicating the, organic basis to thesymptoms3 14.The post-hepatitis syndrome may be due to

other complicating diseases. In areas whereamoebiasis is endemic, the differential diagnosisbetween amoebiasis and the post-infective hepatitissyndrome is important on account of the specifictreatment required for amoebiasis, particularly thehepatic forms. The differential diagnosis of thesetwo conditions will be discussed later. Duodenalulcer and cholecystitis are amongst the conditionsthat must be excluded in- this post-!hepatitissyndrome.

Infective Hepatitis without JaundiceEppinger" in 1937 drew attention to the post-

mortem findings of severe liver damage compatiblewith the findings of infective hepatitis, wherethere had been no jaundice during life. Neefe4and others have studied cases of homologousserum hepatitis induced in volunteers and in someof these cases serial biochemical liver functiontests were abnormal without the development ofjaundice at any stage. MacCallum and Bauer30reported the same experience. Mallory32 describedappearances in liver cells indistinguishable fromthe appearance of infective hepatitis in cases withno jaundice, .and Capps9 agreed with the existenceof such an entity. Barker3 described cases Qfchronic hepatitis in which tender hepatomegalywith defective hepatic function: but withoutjaundice persisted after infective hepatitis. Popperand Franklin43 have reviewed the recent literatureon this subject.The symptoms in such cases are general fatigue

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with or without' pyrexia, dyspepsia, occasionallydiarrhoea, and on examination there is hepato-megaly after if not before exercise, and livertenderness. Clinical jaundice, bilirubinuria andhyperbilirubinaemia are absent. Hepatocellularftinction tests show abnormalities in the majorityof cases. The white cell count is normal or low asin infective hepatitis "with jaundice. The con-dition'may be acute or-chronic. Clearly such anentity as infective hepatitis without jaundicepresents difficulties in diagnosis, particularly if theliver is not palpable at the time of the examination,and such cases are likely to be labelled psycho-neurotic. Where the liver is palpable and tender,hepatic amoebiasis, either diffuse or with abscessformation, must be considered. One has per-sonally seen cases of hepatic amoebiasis presentingwith this very same clinical picture in which restin bed alone without emetine has produceddramatic temporary improvement even whereabscess formation was later proved, the temperaturesubsiding, the white cell count returning to normal,and the symptoms being relieved, this improve-ment lasting for a matter of weeks. 'Clearly in-fective hepatitis with rest in bed could follow thesame course. In the case of amoebic hepatitisthere is eventually a recurrence of symptoms, andthe abscess if present will at some time becomemanifest. In amoebiasis the hepatic function testsare usually normal, and liver biopsy material,unless-the needle happens to strike an abscess, isnormal and- fails to show the appearances ofinfective hepatitis.

Chronic HepatitisChronic hepatitis following infective hepatitis

may present itself as a persistent hepatomegalywith or without defective hepatic function tests, oras a chronic, recurring, mild or severe obstructivetype of jaundice, with greater or less degrees ofill health in any of these types of case.. We areindebted to Barker and others3 for emphasizing thechronic stage of infective hepatitis, which in somedegree follows about io per cent. of cases of acuteinfective hepatitis.' Th6-'dauthors-' describedchronic cases as compla'ining of lassitude,dyspepsia with discomfort, particularly in theright hypochondrium, anorexia, bouts of diarrhoea,and showing, on examination, hepatomegaly anddefective hepatic function tests, the latter beingcommon though not invariable. The testscarried out by Barker and his co-workers includedestimation of serum proteins, plasma prothrombin,bromsulphthalein excretion, serum cholesterol,serum alkaline phosphatase and serum bilirubin.Over a per-iod- of- I2 months the authors notedimprovement in many of these cases. The de-fective tests were not consistently related to the

presence or severity of the symptoms. The urinein these chroniecases sometimes showed excessiveurobilinogen, the results being too variable to beof value. Barker considered the bromsulphthaleintest to be of greater value than other tests in thefollow up of such cases. The blood sedimentationrate was reported as frequently normal; this is inagreement with the findings of Stein51. Theauthors moreover drew attention in passing tocases presenting mild recurrent jaundice with orwithout defective hepatocellular function and oftenlasting years with more. or less good health, theperiods of poor health occurring during the periodsof mild jaundice. Such cases are more fullydescribed by Watson and Hoffbauer54. 'Inactivehepatitis' is a term suggested by Barker andreserved for those cases of post-infective hepatitichepatomegaly without symptoms.Watson and Hoffbauer54 investigated cases pre-

senting recurrent obstructive jaundice, corres-ponding to one clinical type referred to by Barker,and also corresponding to Eppinger's second type.Eppinger15 considered that there were two typesof catarrhal jaundice clinically and anatomicallydistinct, the first being the hepatocellular typewhich is the average case of infective hepatitislasting three or four weeks and clearing completely,and the periacinar or cholangitic type, with moresevere jaundice of longer duration (two to fourmonths), palpable liver and spleen, sometimesascites, acholic stools, and urobilinogen absent inthe urine, at least for long periods. Such* casesmay be laparotomized for surgical causes of ob-struction with negative results. Watson andHoffbauer's cases showed in general prolonged re-current regurgitation jaundice following an attackof infective hepatitis with pruritis, hyperbili-rubinaemia and bilirubinuria, increased serumalkaline- phosphatase, normal or almost normalhepatocellular function tests, and liver usually en-larged but not necessarily tender. Urobilinuriawas intermittently present. Biopsy revealed nomechanical causes of obstruction to the bilechannels, there being some periportal fibrosis in afew of the cases, but the liver cells were normalapart from the presence of occasional multi-nucleated cells which were regarded as evidence ofhepatic cell regeneration. Details of one of theircases have been outlined in an earlier paragraph.Because of the absence of mechanical obstruction,in this and other cases, the authors postulated afunctional change in the permeability of the bilecanaliculi (cholangioles), likening it to the func-tional change in the renal glomerular epitheliumin orthostatic albuminuria, and gave the name' cholangiolitic hepatitis' to the condition. Thelater cirrhotic stage they call ' cholangioliticcirrhosis.' Whether the opinion is right or wrong,

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the authors certainly did draw attention to theclinical syndrome of-this type of case. Sherlock46stated that she has not seen the type of casedescribed by Watson and Hoffbauer. One has,however, had personal experience of two cases ofthis type both with mild recurrent jaundice,usually subclinical, following infective hepatitis,the attacks being associated with mild ill health.Both cases had normal hepatocellular functiontests and normal appearance of liver cells onbiopsy at the last examination which was threeyears after the initial attack of infective hepatitis,and both cases are leading normal sedentary typesof life.

In chronic hepatitis, the presence of fattychanges in the liver cells seen in biopsy sections isagainst the diagnosis 'of 'a ''stage of -infectivehepatitis. Popper- and' Franklin43 found thechanges-described in infective hepatitis by-Sher-lock47, McMichael31 and Mallory32, and pointedout that in what they call the toxic variety and inmalnutrition, fatty changes were common. Theydescribed 2I cases of the toxic variety, the toxinsbeing arsenic, cincophen, that of pneumonia andthyrotoxicosis, and they stated that fatty changeswere present in three of these cases. Unfortunatelythey did not specify which toxins were causativein these three cases. This should be considered inrelation to the findings of Dible and his co-workers13 and Sherlock 47, that post-arsphenaminejaundice is indistinguishable. from infectivehepatitis under the microscope. In cases ofchronic hepatitis, cholecystograms may be abnor-mal due to defective hepatic excretory function,and' it is tempting to regard such cases as chole-cystitis with stone formation and recurring ob-structive jaundice, and to advise operation. As inthe case of the icteric phase, laparotomy may benecessary in the full knowledge that no surgicalobstruction may be found, but it must be reiteratedthat in certain cases there are no means of ascer-taining without laparotomy whether surgical ob-struction is present or not.

Post-Infective Hepatitis CirrhosisThere seems little doubt that post-infective

hepatitis portal cirrhosis occurs, indistinguishableclinically and pathologically from other types ofportal cirrhosis such as alcoholilz or malnutritionalcirrhosis. Statistically, only a small percentage ofcases of portal cirrhosis give a previous history ofjaundice, the figures varying from 5 to I5 per cent.in different published series. Sherlock46 afterreviewing the literature adds nine cases of her own,showing on serial biopsy the gradual developmentof periportal fibrosis in which portal cirrhosis couldreasonably be attributed to the preceding acutehepatitis. Of these cases, six were infective

hepatitis and three were post-arsphenaminejaundice. In one case death from haematemesistook place due to cirrhotic portal hypertension twoand a half years after the attack of acute infectivehepatitis, and in another a period of six yearselapsed between the infective hepatitis and themanifestations of portal cirrhotic hypertension. Itis of value to refer again to the case of Watson andHoffbauer54 which showed normal liver cells andsome slight periportal fibrosis and cellular infiltra-tion at the time of the first liver biopsy 13 yearsbefore death from haematemesis due to advancedportal cirrhosis, and 24 years after the attack ofinfective hepatitis. Sheldon and James45 describedtwo cases of cirrhosis three years after the actualattack of infective hepatitis, the picture being inthese cases identical with the picture described as' toxic or post-necrotic cirrhosis' or 'healedyellow atrophy ' of Mallory. Sherlock noted thatshe has not seen nodular hyperplasia after in-fective hepatitis as described by Sheldon andJames. King26 reported a case of infectivehepatitis aged I9, who, after partial clinical re-covery, eventually died of acute hepatic failureten months after the attack of infective hepatitis.During the partial recovery phase he suffered fromgqneral feelings of ill health, and hepatic functiontests showed deficiencies. Biopsy at the secondmonth showed greatly thickened portal tracts withliver cells showing only slight abnormalities, and arepeat biopsy at the sixth month showed completedistortion of normal hepatic structure with verycellular fibrous tissue and islands of proliferatingliver cells. At post-mortem examination, therewas a dearth of liver cells and great increase inportal fibrous tissue. Fernando and others16describing 102 cases of cirrhosis in Ceylon drewattention to a nodular cirrhosis that followedcontinuously upon or after an interval following anattack of jaundice, differing from the Laennec typeof cirrhosis which in their series was not precededby jaundice. They offered no 'explanation for the~cause of the jaundice. Dible'3 described residualscarring after infective hepatitis under twoheadings, firstly, fibrosis confined to the anatomicalportal tracts, without functional hepatic dis-turbance, and which may disappear with thepassage of years, and secondly, severer cases wherethe reticulum framework of the lobule is destroyedthrough loss of liver cells, fibrous tissue con-densing in the spaces previously occupied by theliver cells, and in such cases followed by per-manent cirrhosis. They considered that only inthe latter tvpe of case will portal hypertensiondevelop. Cameron and Karunaratue6 poisonedrats with carbon tetrachloride and producedcirrhosis which resolved to normal with dis-appearance of the cirrhotic fibrous tissue on

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December I948 ELLIOTT : Diagnosis of Infective Hepatitis and its Sequelae 635

stopping the administration of the carbon tetra-chloride. This reversibilitv of fibrosis noted bothexperimentally and in human cases, is obviouslyimportant in considering prognosis and assessingsymptoms in relation to anatomical defects.

It has been pointed out by McMichael3" andothers that study of cirrhotic liver structure bybiopsy may give false results, and this conforms toone's own experience, the biopsy needle failing tocut a true section of liver structure, travellingbetween fibrous bands and removing nothing morethan a few liver cells. In one example in my ownexperience, a case of Banti's disease with normal:liver function tests was reported as having histo-logically normal liver cells obtained by liverbiopsy. Splenectomy was advised but abandoned'after opening the abdomen, on account of grossmacroscopic hepatic cirrhosis, confirmed histo-logically. Evidence is strong that portal cirrhosiscan follow an attack of infective hepatitis. Histo-logically such cirrhosis in its end result is in-distinguishable from cirrhosis due to many othercauses. The mechanism whereby chronic pro-gressive disease of an organ such as the liver can beinitiated by an acute virus affection of that organ isunknown.' King26 suggested the possibility thatprimary damage to liver cells initiates an abnormalauto-antibody production which gives rise tosecondary and progressive liver damage. Casesare recorded and have been quoted in whichcirrhosis with portal hypertension has developedin as short a time as two and a half years after theacute attack, or as long as 33 years after the acuteattack. In cases of portal cirrhosis, the causativeaction of infective hepatitis can but be'hazarded onthe past history of an attack of jaundice. In con-Esidering the prognosis of infective hepatitis thedevelopment of cirrhosis in a small percentage ofcases must be remembered.

General CommentsInfective' hepatitis in its various stages can

simulate many diseases of the liver. The lesscommon pictures such as chronic hepatitis with orwithout jaundice, acute hepatitis without jaundice,or the post-hepatitic syndrome, must not, however,be used as scrap heaps on which to throw allobscure cases of hepatomegaly with a vaguesymptomatology. It is not proposed to list all thepossible conditions which may simulate these lesscommon forms of infective hepatitis. A pyrexialillness with hepatomegaly is always a challenge tothe diagnostician. The following is a selection ofcases in my own experience that have presentedsuch difficulties and in which a final answer wasobtained

i. A male, aged 45, complained of recurrentattacks of ill health with pyrexia over a period of

five years with occasional jaundice, and withperiods of good health between the attacks. Theonly finding on examination was a moderatehepatomegaly. After prolonged medical treatmentand many investigations, laparotomy revealed thecase to be one of an hydatid cyst with a low gradeinfection iin it.

2. A patient of 25 was pyrexial for four weekswith no focal sign other than a palpable liver.Biopsy revealed tuberculous foci. The case diedlater of miliary tuberculosis. All investigations,including X-ray of the chest up to the time of thebiopsy, had been negative.

3. A patient of 52 with right upper abdominalpain for two months with intermittent pyrexia wasoperated on as a case of cholyecystitis and noabnormality was noted. Fourteen days after theoperation a pleural effusion developed at the rightbase, amoebiasis was obviously suspected, but aliver biopsy revealed actinomycosis.

4. A military officer, aged 28, had a temperaturefor four weeks with hepatomegaly and someglandular enlargement in the neck. All investiga-tions as to cause were negative until sternalpuncture revealed kala-azar.

5. A Bantu male subject of 32 had a pyrexialillness lasting some five weeks with tender hepa-tomegaly as the only focal sign on examination.Biopsy revealed primary carcinoma of the liver,the commonest form of carcinoma in the maleBantu.

6. A girl of 15 complained of upper abdominaldiscomfort as a rule after exercise, and on examina-tion she was found to have a tender liver with threeinches enlargement. There was no jaundice. Allexaminations were reported negative but it wasnoted that the venous pressure in the neck wasincreased and after investigation the case wasfound to be one of constrictive pericarditis.

Until specific immunological reactions andbacteriological procedures become available foruse in the diagnosis of infective hepatitis in allits stages, the condition will continue to causedifficulty in diagnosis.

SummaryThe subject of infective hepatitis has been re-

viewed with particular attention to the diagnosticdifficulties that may arise in the different stages ofthe disease from the pre-icteric to the chronic, andincluding cases without jaundice and cases endingin portal cirrhosis.The relative merits of the clinical picture, bio-

chemical tests of hepatic function, and liverbiopsy studies are -discussed with regard to theirvalue in diagnosis, and it is pointed out that carefulclinical assessment remains the most importantsingle diagnostic aid.

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