childhood cirrhosis

VENO-OCCLUSIVE DISEASE OF THE LIVER AND INDIANCHILDHOOD CIRRHOSIS

BY

DERRICK B. JELLIFFE, GERRIT BRAS AND KANAI L. MUKHERJEE

From the Department of Tropical Medicine, Tulane University of Louisiana, New Orleans, U.S.A.*, the Departmentof Pathology, University College of the West Indies, Jamaica, and the Calcutta School of Tropical Medicine, Calcutta,

India

(RECEIVED FOR PUBLICATION APRIL 24, 1957)

Cirrhosis of the liver is rare in childhood in thetemperate zone and it is then usually due to somespecific and traceable cause, such as Rhesus incom-patibility, galactosaemia, congenital syphilis, inassociation with congenital abnormalities of thebiliary apparatus, or following infective hepatitis.In most of the subtropics and tropics-at leastaccording to present probably incomplete evidence-cirrhosis in childhood is somewhat more common,but it is still infrequently seen, despite the fact thatthe condition may have a high incidence amongstadults.

There appear to be only two widely separatedregions of the world from which cirrhosis in child-hood has been commonly reported in the medicalliterature-the West Indian island of Jamaica andthe subcontinent of India, especially the easternStates of Madras and Bengal.As it has recently been possible for the writers

collaboratively to have had experience in bothregions, the present paper has been written in orderto compare clinical and histological features ofcirrhosis in childhood as seen in both Jamaica andCalcutta, West Bengal.

VENO-OCCLUSIVE DISEASE OF THE LIVERAwareness that cirrhosis was common enough to

be a public health problem among Jamaican childrenin the lower socio-economic groups was initiated bythe original clinical accounts of McFarlane andBranday (1945), Roys (1948) and Waterlow (1948).The work of Hill, Rhodes, Stafford and Aub

(1953) clarified the clinical picture, initiated theinvestigation of the histology and suggested possibleaetiological factors. More recently, Bras, Jelliffeand Stuart (1954) demonstrated the predominantrole of an obliterating process in the hepatic vein

* Late of the Section of Maternal and Child Health, All-IndiaInstitute of Hygiene and Public Health, Calcutta, India.

radicals in the morphogenesis, so that the conditionwas designated 'veno-occlusive disease of the liver'(V.O.D.).

Clinical Picture. The clinical picture has beendescribed by Jelliffe, Bras and Stuart (1954a, 1954b),and may be summarized in the following three, oftenill-defined, overlapping stages (Fig. 1): (1) Acutehepatomegaly (2 to 10 cm.) developed suddenly infive to 10 days, mainly in young children of from18 months to 3 years of age, often with ascites,frequently after non-specific upper respiratory tractinfection and often subsiding with or without treat-ment in four to six weeks. (2) Subacute, persistent,firm hepatomegaly, with or without recurrent ascites,may occur spontaneously or after the acute stage;it may subside clinically, with a high protein diet orpass into the chronic state (Fig. 2). (3) Chronic, theclinical picture of cirrhosis, is shown in Fig. 3.

Recently, veno-occlusive disease has been shownto occur, although less commonly, in Jamaicanadults (Stuart and Bras, 1955), while it has also beendiscovered in another West Indian island, Barbados(Stuart and Bras, 1956).

Morbid Anatomy. The sequence of histologicalchange, as demonstrated by both liver biopsies andnecropsies, has been described by Bras et al. (1954),by Bras and Watler (1955) and more recently it hasbeen summarized by Bras and Hill (1956).The initial lesion in the acute stage is a sub-

endothelial intimal thickening, with partialocclusion of the lumen, in small and medium sizedbranches of the hepatic vein, associated with centri-lobular congestion. If the condition persists,atrophy and loss of liver cell cords occurs followedby a centrilobular (non-portal) fibrosis. The intimalthickening in later stages is composed of fibroustissue. The liver in chronic cases is diffusely, finelygranular and macroscopically indistinguishable from

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ARCHIVES OF DISEASE IN CHILDHOOD

CompleteRecovery

/7!(a) ACUTE V.O.D.

ClinicalRecovery

(I(Sudden hepatomegaly,often ascites, usually (directly)in adequately nourishedchildren 1' to 3 years)

Rapid Death ? Coi(increasing jaundice,

cholaemia)(eithe

witt

b) SuB-AcUTE V,O.D.

(persistent firmhepatomegaly, with (dirctly;or without recurrent

ascites)

'4,Kmplete Recoveryr spontaneously orh treatment)

(C) CHRONIC V.O.D.

(Cirrhosis of liver,No clinicallypathognom on ic

features)

ClinicalImprovement

E(b) & (c) may be present with no

clinical history of preceding illness..

FIG. 1.-Diagram of the clinical natural history of veno-occlusive disease.

early Laennec's cirrhosis, although histologically thecirrhosis is clearly not portal.

Aetiology. It has been postulated tentatively thatveno-occlusive disease in Jamaican children may bedue to the effect of an as yet unidentified toxin on theliver of undernourished children. The nature of thistoxin is unknown, but the frequent association ofcases of acute veno-occlusive disease with precedingrespiratory tract infections, including whoopingcough, may be significant, while the practice ofdrinking over 200 different varieties of home-prepared herbal infusions, known as 'bush-teas', mayalso be relevant (Asprey and Thornton, 1953). Thelatter hypothesis has received support from therecent report of the condition in a cow in Jamaica(Bras and Berry, 1956), and direct attempts to

ik reproduce the disease in experimental animals fedon bush-teas have supported this theory. More-over, Selzer and Parker (1951) described an outbreakwhich began as acute Chiari's syndrome caused byeating bread made from inadequately winnowed

FIG. 2.-A Jamaican girl with subacute veno-occlusive diseaseshowing symptomless hepatomegaly only.

FIG. 3.-Jamaican boy with chronic veno-occlusive disease showing1 I(r. 3, the picture of fully developed cirrhosis.FIG. 2.

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INDIAN CHILDHOOD CIRRHOSIS

wheat contaminated by a species of senecio, orragwort, a common wild plant, while, even earlier,Davidson (1935) had demonstrated that retrosine,one of the alkaloids of senecio, produced an endo-thelial proliferation in the central and sublobularveins as its primary effect.

Recent studies (Bras, Berry and Gyorgy, 1957)on experimental animals have shown that histo-logical lesions identical to those of veno-occlusivedisease can be reproduced in the livers of cattle andhorses by feeding them with certain toxic plants.

INDIAN CHILDHOOD CIRRHOSISSince its original description as a clinical entity

by Sen (1887), it has been recognized that cirrhosisof the liver in young children is a not uncommoncondition in various parts of India, and a consider-able, somewhat repetitive literature has grown upon the subject, almost entirely confined to Indianmedical journals (Radakrishna Rao, 1934). Anauthoritative review of the present situation has beenpublished recently by the Liver Diseases Sub-Committee of the Indian Council of Medical Research(I.C.M.R.) (1955).

NomenclatureA variety of different names have been employed

at different times by various authors, includingbiliary cirrhosis (Gibbons, 1888), infantile cirrhosisof the liver (Lahiri, 1936), hypertrophic or biliarycirrhosis (Brahmachari and Brahmachari, 1938) andsubacute toxic cirrhosis of infants (RadhakrishnaRao, 1935). None of these seem entirely satis-factory and; as the disease appears to affect youngchildren rather than infants exclusively, the non-committal term 'Indian childhood cirrhosis' (I.C.C.)will be used in the present account.

Present CasesDiagnostic Criteria. Precise criteria for case

selection were difficult to formulate. As the earlysymptoms are indeterminate and non-specific,children were selected initially by finding a firm orhard hepatomegaly, after exclusion as far as possibleof other known causes of liver enlargement, such askwashiorkor, malaria, kalar azar, infective hepatitisand congenital syphilis. Associated splenomegaly,the development of a collateral circulation, ascitesand jaundice were regarded as corroborativeevidence, but not necessary for diagnosis.

This classification is obviously unsatisfactorywhen it is recalled that knowledge of thepathology of Indian children is rudimentary,especially as post-mortem examinations are rarelyperformed. It is quite probable that there are as yet

unrecognized causes of hepatomegaly in early child-hood in India, as for example, visceral larva migransdue to ingestion of ova of the dog or cat roundworm(Toxocara canis, T. cati) (Beaver, Snyder, Carrera,Dent and Lafferty, 1952), or even perhaps as aresult of the continuous transhepatic migration oflarvae of A. lumbricoides, an almost universalparasite in children in some parts of India.

In the present series, liver biopsies were under-taken whenever possible, although this was oftennot feasible. Of the first 13 cases, nine were biopsiedwith a modified Vim-Silverman needle, and, of these,four showed no abnormality histologically and onedemonstrated only moderate fatty change. All fiveof these children showed only a moderate, firmenlargement of the liver, with no corroborativeevidence of cirrhosis. In view of these negativefindings, together with the present somewhat con-troversial and uncertain evidence of any early orspecific histological lesions in this condition, it wasdecided not to include these five cases and to selectcases more rigidly in future.The present series is, therefore, composed of 15

children seen at either the Out-patient Clinic of theCalcutta School of Tropical Medicine or at theChild Welfare Clinic of the All-India Institute ofHygiene and Public Health. They were admitted tohospital for full investigation whenever possible, butthis was often not practicable as parents refused toallow their children to be admitted or beds were notavailable in the always busy and overcrowded ward.

Cases were only included if they showed thetentative diagnostic criteria of hepatomegaly, aspreviously described, together with at least onedefinite physical sign probably corroborative ofcirrhosis, such as splenomegaly, dilated collateralcirculation, ascites or jaundice, and/or histologicalevidence of hepatic fibrosis at liver biopsy ornecropsy. It is realized that this classification is alsoopen to criticism, especially as it excludes early casesabout which very little is known.

Age Incidence. The average stated age at whichchildren were brought to the clinic in the present smallseries was 3 years 5 months, with a range of from 11months to 8 years 10 months. Apart from possibleinaccuracies due to incorrect ages given by parents,it will be appreciated that this cannot be taken as.an index of age of onset, as several children at leasthad previously attended other hospitals, privatescientifically trained physicians or Ayurvedic healers.

Sex IncidenceAs noted in the Indian Council of Medical

Research report (1955), a number of workers have

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remarked on a higher incidence in male children,while others found no difference in sex distribution(Achar and Raju, 195 1, quoted by the Indian Councilof Medical Research, 1955). In the present group,seven children were girls (47 %), while the remainder(53 %) were boys.

Family History. It has often been noted thatmore than one sibling in a family may be affected,and estimates of the frequency of familial incidencevary from about 20 to 40%. In the present group,only one child (7 %) had a family history suggestiveof fatal cirrhosis in an older sibling.

Signs and Symptoms. All patients had a slowand insidious onset, which is in agreement withthe literature. In no instance was this abruptas in acute veno-occlusive disease, and there wasnever any preceding history of jaundice. Parentsof affected children reported that the illnesshad begun with the gradual onset, over periodsvarying from 4 months to 3 years, of the followingclinical features: abdominal enlargement in twochildren (13 %), general ill-health and lassitude in

EIi;. 5.

!FIG. 4.-In(in a Bengaclinical ciimegaly, di]

a:

FIG. 5.-Inin a Bengaclinical cirhard hepaicollateral

two (13 %), vague upper abdominal discomfort infour (27 %), poor appetite in five (33 %), loss ofweight in eight (54 %), loose stools in six (40%)and dimness of vision in one child (7 %).

Clinical examination revealed the followingfeatures in addition to a firm to hard hepatomegaly:splenic enlargement in eight children (54 %), ascites,varying from just detectable to tense distension ofthe whole abdomen in eight (54 %), a conspicuouscollateral circulation in seven (47 %), jaundice ineight (54 %), clubbing of the fingers in two (13 %)and oedema in one child (7%) (Figs. 4 and 5). Inaddition the following general features were noted:probable malnutrition (as evidenced by stunting,poor muscle tone) in six children (40 %), obviouswasting of muscles and subcutaneous fat in six(40 %), clinical anaemia in five (33 %), rachiticstigmata in one (7 %), follicular keratosis in two(13), Bitot's spots in one (7%) and bleeding gumsin one child (7 %).

Laboratory Data. The following average resultswere obtained for the 11 children who were admittedto hospital: Haemoglobin 9 3 g. per 100 ml. (range

6- 9 to 1 I * 6); blood filmsfor malarial parasites nega-tive in all cases; Rhesusfactor positive in five children

,_ tested; Wassermann reactionnegative in all cases. A whiteblood count gave 11,000 perc.mm. (range 8 to 16,000),neutrophils 64% (range 50to 74 0) plasma proteins(total) 6-0 g. per 100 ml.(range 4- 5 to 7- 5); albumin2-8 g. per 100 ml. (range18 to 3 8), globulin 4 0 g.per 100 ml. (range 2-0 to5 2). The following liver func-tion tests were carried out:serum bilirubin, thymol tur-bidity, alkaline phosphatase,gamma globulin, serumcholinesterase. Abnormal re-sults were found in at least oneof these in each case, but no

dban cirrhosis of childhoodlii girl, early in the stage of definite pattern emerged, exceptrrhosis, showing hepato- that advanced cases showed alated collateral circulation definitely raised serum bilirubin

level.diancirrhosisof childhood Helminth ova were presentli girl late in the stage ofrrhosis showing cachexia, in the stools of nine childrentomegaly, ascites, marked (hookworm four, roundwormcirculation and spleno- t

megaly. three and both, two).

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Course. The 11 children admitted to the wardwere treated with a high-protein-high-vitamin diet,with added polyvitamin capsules. Associated infec-tions were dealt with, if present, and ascites tapped,if needed. No other specific treatment wasattempted.The following results were obtained with treat-

ment periods of from four to 10 weeks in these 11clear-cut cases of cirrhosis: slightly improvedgenerally (with no obvious effect on hepatic condi-tion (four), no change (one), deterioration and takenhome (three), died in hospital (three) (two incholaemia and one with bronchopneumonia). Casescould not be followed up in the Out-patient Depart-ment or at home.

Socio-economic Background. This was consideredas follows:

(1) PLACE OF RESIDENCE. According to theparents, the majority (66 6%) of the children hadalways lived in Calcutta City. Of the other five,three lived in adjacent rural West Bengal, while twohad recently come from Amritsar, East Punjab, andLucknow, Uttar Pradesh, respectively.

(2) RELIGION AND CASTE. Twelve of the 15children (80 %) were Hindus, while two wereMuslims and one was a Sikh. Of the Hindus, fourwere Brahmins and the remaining eight were ofnon-Brahmin castes.

(3) ECONOMIC STATUS. This was very difficult toascertain with any precision and even harder todefine. However, three came of what can be called'lower middle class' families, that is, with fathersworking as clerks, small shop owners, etc. Themajority were from lower socio-economic groups,such as vegetable sellers, unemployed, bidi (localcigarette makers), doorkeepers, etc. None, it mustbe stressed, came from the most abjectly im-poverished bustee (slum) dwellers.

(4) DIET. Dietetic histories varied greatly andwere never obtained with any degree of accuracy.Affected children were usually being fed on breastmilk (up to about 2 to 3 years), a very little dilutedcow's milk, some rice or barley, dhal (legumes) andoccasionally fish. Older children were receiving someof the family masala (curry sauce). Depending uponthe parents' financial status, goat's milk or driedpowdered milk might also be added, althoughsometimes all milk might have been stopped in amistaken attempt at dietetic treatment. Basically,then, the diet consisted of small quantities of milktogether with mainly carbohydrate foods.

(5) ToxIC FACTORS. Enquiries were made to ascer-tain if any of the children had been receiving possibly

toxic herbal remedies, and the use of Ayurvedic *medicines before the illness was admitted by sixparents (400%), although no child was reported tohave been given castor oil. Antecedent febrileillnesses were inquired about, in view of thepossibility of the toxin of an infectious disease beingaetiologically involved. In only one child was therea history of 'measles' just before the probable dateof onset of the hepatic disorder.

Morbid Anatomy. Histological examination wasundertaken in six of the total of 15 cases, four byliver biopsy and two following 'local' post-mortemexaminations.

Results are summarized in the Table, and, as w'illbe noted, the histology was similar to that seen inchronic veno-occlusive disease in all cases, especiallyin Nos. 3 to 6.

TABLESUMMARY OF MAIN HISTOLOGICAL FINDINGS IN SIX

CASES OF INDIAN CHILDHOOD CIRRHOSIS

Case No. Source Main Histological Findings

XS/55/54 Needle biopsy Advanced cirrhosis involving portaltriads and branches of hepatic veins.

XS/55/149 Needle biopsy Advanced cirrhosis, apparently in-volving portal triads and branches ofhepatic veins.

XS/55/150 Needle biopsy Marked fibrosis showing veno-occlu-sion of branches of hepatic veins.

XS/55/151 Needle biopsy Fibrosis, apparently involvingbranches of hepatic veins.

XS/56/103* Necropsy Advanced cirrhosis with markedveno-occlusion of branches of hepaticveins.

XS/56/236 Necropsy Fibrosis mainly centrilobular andinvolving hepatic veins with thickenedwalls.

* Case of Manik Das-full details given in text.

Typical Case SummaryClinical History. Manik Das (XS/55/54), a Bengali

boy, aged 3 years 9 months, was admitted with an eight-month history of the gradual onset of abdominalswelling, 'low fever' and general ill health. He hadalways lived in Calcutta and was a Hindu of the Sudracaste. The boy's father owned a small shop, allegedlyearning R. 150 (f.11.5 or $32.20) monthly. There was nohistory of antecedent illness, and no Ayurvedic medicinesor other herbals were stated to have been given. Therehad been two female siblings: one, aged 7 years, wasalive and well, while the other was reported to have diedsix years previously of 'liver' when aged 4 years. Detailsof the past diet could not be obtained. The present dietconsisted of a little breast milk, cow's milk i seer

* Ayurveda ('health from the Vedas') is the traditional indigenoussystem of medicine employed in India. A wide variety of pre-dominantly herbal remedies are used.

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(16 ounces) daily, together with a little barley, rice andfish occasionally.

Examination showed a thin, chronically ill boy withascites, moderate jaundice and some dilated veinsrunning upwards across the epigastrium. The liver wasenlarged 5 cm. below the costal margin, and was hardand not grossly irregular. There was no clubbing. Thespleen was enlarged 2 cm. Follicular keratosis waspresent on the elbows, while the tongue showed super-ficial ulceration.

Laboratory Investigations. Haemoglobin was 9 3 g.per 100 ml.; the white blood count 13,000 per c.mm.(neutrophils 58 %O lymphocytes 37 %). The Wassermannreaction was negative. Plasma proteins were 4-5 g. per100 ml. (albumin 1-5, globulin 3-0). A blood film formalaria parasites was negative. The child was Rhpositive. The stools showed no ova or parasites.

Course. The subsequent course in hospital wasrapidly downhill and the child died 10 days afteradmission. Permission for a partial necropsy wasobtained.

Necropsy Findings. The peritoneal cavity was foundto be filled with slightly bile-stained fluid, and the wholeliver was removed. The liver was finely nodular over theentire surface (Fig. 6) and the cut section showed fibroussepta and was slightly greenish.The histological examination showed advanced

cirrhosis with much fibrosis present in the form of septacausing pseudo-lobulation, but also there was a consider-able increase of connective tissue inside the pseudo-lobules; while, in addition. there were further dense areasof fibrosis throughout the liver. The dense areas offibrosis and the fibrous septa included portal triads aswell as hepatic veins. The pseudo-lobules showedregeneration of liver cells as evidenced by liver cell cordsof two or more cell layers in thickness.

There was much eosinophilic degeneration of thecytoplasm of the liver cells, many of which were seen tobe disintegrating and polymorphonuclear leucocytes invarying number were present in such areas (Fig. 7). Theliver cell nuclei showed polyploidy. The larger bile ductsin the portal triads were unaffected, while there was muchproliferation of smaller bile ducts in the liver lobules inthe areas of fibrosis. Some of these proliferated bileducts contained bile. The interstitial tissue showed manycells, mainly polymorphonuclear leucocytes and lympho-cytes (Fig. 8). The bile capillaries between the liver cellswere clearly visible and occasionally markedly dilated.The hepatic artery and portal veins showed no changes,

but many of the hepatic veins were partially cr com-pletely occluded by subendothelial connective tissueformation (Figs. 9, 10, 11).

In comparing the appearance with chronic veno-occlusive disease, it can be said that the hepaticvenous occlusion is about equal in extent, but thatin chronic condition in Jamaica there is usually less

involvement of the portal tracts. The histologicalpicture, such as found in Fig. 12, obtained from acase of chronic veno-occlusive disease in a Jamaicanchild, and leaving many portal tracts free, cannotbe matched in this liver. In veno-occlusive diseasethere is no marked bile duct proliferation such ashere, while inflammatory cells are not pronounced.This condition, as initially described by Gibbons(1888), was indeed marked in this case.

Comparison with Cases Reported in the LiteratureOnset. As noted earlier, all 15 cases in the

present small series gave a history of gradual,insidious onset and progressive course, and this isin agreement with all previous accounts, althoughit is of interest to note that Achar and Chacko (1954)found that a quarter of a large group of cases inMadras were preceded by an attack of jaundice.

It is difficult to compare ages of the present caseswith other reports, as it is sometimes not clearwhether the ages recorded refer to the onset ofsymptoms or to attendance at hospital, quite apartfrom such well-known difficulties as inaccuraciesand approximations in the figures given by theparents. However, according to the I.C.M.R. report(1955), the majority of reported cases have beenbetween 1 and 3 years of age, so that the presentgroup seem to be somewhat older than is usual.

Signs and Symptoms. In the literature cirrhosisin Indian children is classically considered as havingthree clinical stages: (1) Early (or stage of onset),(2) intermediate, (3) late. These have been termedprecirrhotic, compensated and decompensated cir-rhosis by Chatterjee (1940).For the first or early stage, descriptions are

extremely vague and non-committal, and vary con-siderably according to different authorities. Clinicalfeatures considered to be attributable to this stageof the disease are such protean ones as generalill-health and lassitude, altered appetite (eitheranorexia or increased), constipation or diarrhoea,low or occasional fever, flatulence and minorabdominal distension. According to some, the liveris just palpable, while the stools may be pale.

In the second or intermediate stage, children arealleged to be peevish and irritable, and to haveprotuberant abdomens, livers definitely enlargedwith a sharp, 'leafy' edge, together with somesplenomegaly and dilated superficial abdominalveins. Ascites and some ankle oedema may bepresent, while the sclera are subicteric and thestools pale.

In the third or final stage, the picture is that ofclinically obvious cirrhosis. The child is wasted,usually icteric and with a prominent abdomen, due

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FIG. 6.-Picture of liver at necropsy in a case of Indian cirrhosis of childhood showing a finely nodular surface (Manik Das).

i 1-. I i4

FIG. 7.-Nodule of regenerated liver cells, with many cells visible in the centre undergoing eosinophilic degeneration with necrosis (Caseof Manik Das). Haematoxylin and eosin x 340.


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376 ARCHIVES OF DISEASE IN CHILDHOOD

FIG. 8.-Liver showing bile duct pro-liferation with 'thrombus' in the bileduct at arrow, and marked infiltrationwith polymorphonuclear leucocytes andlymphocytes in the intestinal tissues(Manik Das). Haematoxylin and eosin

x 450.

FIG. 9.-Occlusion of branches of the hepatic vein (Manik Das). Reticulin X 60.


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FIG. 10.-Liver showing almostcomplete occlusion of a branchof the hepatic vein (Manik Das).

FIG. 11.-Occluded branch ofthe hepatic vein, showing smallblood vessels (? recanalization)(Manik Das). Mallory trichome

x 170.

Fir,. 10.

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to ascites, smooth or finely irregular, hard hepato-megaly and, usually, definite splenomegaly. Markedengorgement of the collateral circulation will bevisible. The urine will be scanty, and may containalbumin, bile pigments and salts.Two-STAGE CLASSIFICATION. In view of the

apparent present confusion and lack of specificityof alleged early features (i.e., general ill-health,flatulence, pale-coloured stools, etc.), many of whichcan be seen in a percentage of Indian childrenattending paediatric out-patient or child welfareclinics, the following 'two-stage' classification issuggested tentatively as a practical, more easilydefinable and standardized system of identifica-tion, at least until further knowledge of the naturalhistory of the disease is acquired. It must bestressed that these two stages overlap and merge intoone another.

(i) Stage of Hepatomegaly. It is generally agreedthat the most suggestive clinical sign, both earlyand late, is a firm or hard, painless enlargement ofthe liver, coming on insidiously, and in India, youngchildren, especially in the first five years of life,should be suspected of having early cirrhosis, ifother causes of hepatic enlargement-such as

malaria, kala azar, kwashiorkor, congenital syphilisand congenital lesions of the bile ducts-can beexcluded. (It is realized that at present there isno proof that all cases pass through a stage of

FIG. 12.-Jamaican child withchronic V.O.D. in whom the liver

E; N1ES > Fd1 E showed non-portal cirrhosis.

hepatomegaly early in their evolution to frankcirrhosis. Nevertheless, this concept of a stage ofhepatomegaly, based on the consensus of practicalexperience and clinical evidence, may be used atleast temporarily until the acquisition of newerknowledge permits of more specific diagnosticcriteria.)

In addition, the physiologically palpable soft liverfound in many young children in the first few yearsof life, especially if exaggerated by chest deformitiessuch as occur in rickets, will have to be borne inmind as will the transient soft hepatomegaly whichis considered by some to occur as a temporaryphenomenon in young children during any acutefebrile illness. The acute tender liver of amoebichepatic involvement can be mentioned, but shouldpresent no diagnostic problem.The diagnosis of probable early I.C.C. depends,

therefore, as judged by present knowledge, simplyon finding a definite firm or hard hepatomegaly forwhich no other explanation can be discovered.Other variable and apparently entirely non-specificfeatures may be present, such as general ill-health,low fever, etc. Chaudhuri (1944) says that theremay be complaints of a general nature vaguelyreferable to the digestive system.

Clinical diagnosis at this stage can only bepresumptive until the development months later ofdefinite cirrhotic features. A positive family history

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is suggestive, but gives no scientific proof. Specificlaboratory biochemical tests do not at present exist.Liver biopsy would appear ultimately to offer thebest possibility of early diagnosis, but much furtherwork is needed to investigate the histopathology ofwhat may well be a heterogenous group andespecially to delineate the specific changes of earlyI.C.C.-a difficulty increased by present incompleteknowledge of the morbid anatomy of the liver ofnormal, but undernourished, Indian children. Inthe specimens discussed in the I.C.M.R. report(1955), initial changes consisted of patchy, but fairlywidespread, degeneration of liver cells, associatedwith mild reactive change in and around Glisson'scapsule and in the sinusoids. However, as thisCommittee themselves imply, these findings cannotbe accepted as universally applicable as definitehistological criteria suitable for use in earlydiagnosis.The difficulty of making a diagnosis on clinical

grounds alone is clearly shown, when, in the earlystages of the present investigation, five children withmoderate firm hepatomegaly were found, at least inthe small fragment of liver available following needlebiopsy, to have apparently normal histology (four)and moderate fatty change (one). Similarly, asnoted in the I.C.M.R. Report (1955), a number ofchildren in Achar's large-scale investigation inMadras in South India were found to show noabnormality at liver biopsy, despite their havingwhat were considered to be abnormal palpablelivers.

(ii) Stage of Clinical Cirrhosis. At this stage, adiagnosis is usually relatively simple on clinicalgrounds. All the children in the present small seriesof 15 fell into this category. Affected children showa hard, smooth or finely granular enlargement of theliver, together with some or all of the followingfeatures of hepatic disease: ascites, icterus, spleno-megaly, dilated collateral circulation. Loss ofweight and anaemia are usual. Ankle oedema isnot uncommon. The stools are clay-coloured andthe urine is dark, containing bile pigments and salts,and, occasionally, albumin. Moderate intermittentfever is usual. Laboratory tests have not beensufficiently investigated, but a raised serum bilirubinlevel, some degree of anaemia and a variable patternof abnormal liver function tests are seen. Leuco-cytosis is often present, but may well be ratherrelated to intercurrent infection, especially of therespiratory tract. The histology of the liver, asshown by biopsy and at necropsy, is that of a diffusefibrosis, details of which will be given later.As to differential diagnosis, other forms of

cirrhosis must be excluded, including those

associated with congenital syphilis, Rhesus incom-patibility, post-hepatitic scarring, and, in younginfants, congenital atresia of the bile ducts. Thesecan usually be excluded by the history and laboratoryinvestigations.

In West Bengal, Cooley's anaemia presentingwith jaundice and hepato-splenomegaly can bedifferentiated by the marked anaemia, characteristicskull shape, and other haematological investiga-tions.

Socio-economic Background. This was consideredunder specific headings:

(1) GEOGRAPHICAL INCIDENCE. According to theavailable medical literature, I.C.C. has only beenreported from India, with the exception of the fewcases described from Colombo, Ceylon, byKarunaratne (1951) and by Fernando (1954).Within India, the disease has been reported from allStates, with the apparent exceptions of the EastPunjab and Pepsu. The condition has always beenmost commonly recorded in Madras and WestBengal, especially Calcutta. It is of interest-andmay be of aetiological significance-that this typeof childhood cirrhosis does not seem to have beendescribed from other parts of south-east Asia.

Information regarding the public health signific-ance of I.C.C. is meagre. No statistics are availablesummarizing the incidence of the disease in thepopulation as a whole in any part of the country.As the I.C.M.R. report (1955) observes, most serieshave been from quite unrepresentative populationsamples, that is, from hospitals in large towns. Thereappears at the moment to be an impression amongstsome experienced clinicians in larger Indian citiesthat the condition is seen less frequently nowadaysthan it was 15 years ago.

(2) RELIGION AND CASTE. As has been stressedby all observers, the disease occurs most commonlyin Hindus, often of the Brahmin caste. However,it must be realized that Hindus form the vastmajority in most areas of India. That I.C.C. occursamongst non-Brahmins is clearly shown by even thepresent small series where eight were so classified.Similarly other workers have shown that the con-dition does affect Muslims, Anglo-Indians and otherminority groups. The I.C.M.R. (1955) summarizesthe situation accurately when it says : 'It isimpossible to say on the basis of available informa-tion whether the observed predominance among theHindus is merely a reflection of their numericalsuperiority in the country or whether they are moresusceptible to the disease than others.'

(3) ECONOMIC STATUS. It has long been remarkedthat I.C.C. does not primarily affect the very lowest

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and most impoverished socio-economic groups, asdoes kwashiorkor, for example. As Prabhu (1940)rightly observes: 'Curiously enough, the poorestclasses seem to be exempt from it. It is hardly everfound among sweepers, rickshaw-pullers, labourersor in vagrant classes or in slum areas, among whomdiseases attributable to malnutrition are found.'While this was certainly so in the present small

series, as the I.C.M.R. (1955) report stresses, thisdoes not necessarily mean that malnutrition playsno part in the aetiology, 'for it is well known thatthe diet of some of the middle and even upper classesmay be unbalanced and qualitatively unsound,although quantitatively adequate'. (In Calcuttathis was certainly observed to be correct in anothercontext, in that rickets was found to occur muchmore commonly amongst the children of strictlyvegetarian Marwari merchants of considerablewealth.)

Morbid Anatomy. Despite the recent increasedinterest in the pathology of I.C.C. and theconsequent intensification of active research, com-paratively few necropsies have been reported,probably not more than 40 in all, and these have allbeen in advanced cases dying in the final phases ofthe stage of clinical cirrhosis. Thus, Bhende andDeoras (1954) stress that the records of only ninenecropsies were available to them from the period1926 to 1954, in the archives of a leading hospital inMadras.

All accounts are in general agreement as to thegross appearance of the liver in advanced cases thatcome to necropsy.

'The organ is usually shrunken, stained greenwith bile, of normal shape with sharp margins andfirm consistency. The capsule is thick and some-what opaque white in colour and free from adhesionsor exudation. The capsular surface may be eithersmooth with indistinct lobular markings, or may beuneven, granular or flatly nodular, particularly onthe under-surface. The sectioned surface is greenishin colour with obliteration of the normal lobularpattern by a diffuse fibrosis. It presents either asmooth greyish-green surface finely mottled withsmall scattered dark-green areas or a finely granularsurface with a diffusely spread greyish-green fibrousnetwork enclosing small rounded islands ofregenerating parenchyma' (I.C.M.R., 1955).

Gibbons (1888) compared the bile-stained areasof regenerating hepatic tissue to 'mustard seedgranules'; while the surface of the liver has beenconsidered to have a 'morocco leather' appearance.

Findings at the two partial necropsies in thepresent series agreed completely with this generalnaked-eye description. A comparison of thehistological changes found at necropsy and at liverbiopsy in the present cases and by other workers is

made later in this paper, when these are also com-pared with the morbid anatomical findings ofveno-occlusive disease in Jamaican children.

Treatment and Course. There is general agree-ment that the prognosis of I.C.C., in what has herebeen termed the stage of clinical cirrhosis, is usuallyhopeless, in that, after a period of months, or evena few years, deterioration occurs and death resultsfrom cholaemia, secondary infection, or, lesscommonly, oesophageal haemorrhage. The situa-tion does not seem to have altered since 1890 whenSen (quoted by Krishna Rao, 1950) noted that theestablished disease was 'more certain of its victimsthan the dreaded cholera or smallpox'.A large number of different, often bizarre forms

of treatment, usually based on a particular worker'stheoretical concept of the aetiology, have been triedat various times and cures claimed. Inspection ofsuch claims invariably shows a lack of precise criteriafor initial diagnosis, absence of control cases,inadequate follow-up and small numbers of cases.Many children allegedly cured may not have beensuffering from the condition at all. The I.C.M.R.report again accurately summarizes the situation:'No convincing evidence has so far been producedto show that the natural course of the disease is inany way modified by the several regimes which havebeen advocated enthusiastically from time to time.'One difficulty, at least in West Bengal amongst

'lower middle class' parents, is the fact that thereis a wide awareness of cirrhosis as a serious, oftenfatal childhood disease-often known locally by theEnglish word 'liver'. The anxiety of parents of thistype provides a fertile field for quacks and for widelyadvertised proprietary and Ayurvedic 'liver cures',such as those containing extract of Kalmej (Andro-graphus paniculata).Not infrequently 'liver' is diagnosed in Bengali

children on the basis of such common and non-specific features as lassitude, fairly loose, rather palestools and slight fever, together with physiologicallypalpable liver in a flabby, somewhat anaemic child.

In view of the present ignorance of the cause ofI.C.C., therapy is empirical with a high-protein, high-vitamin diet, together with plenty of added sugarand supplementary polyvitamins, and the treatmentof associated infection. Terminally, protein shouldbe reduced, in view of the known toxic effect on thecentral nervous system in cases of liver damage ofprotein breakdown products (Sherlock, Summerskill,White and Phear, 1954).When considering the present-day treatment of

I.C.C., and especially some of the complex regimesthat have from time to time been advocated, it is

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IN-DIAN CHILDHOOD CIRRHOSIS

perhaps salutary to consider the original form oftherapy advocated by Sen (1887): 'Muriate ofammonia, iodide of potassium, nitro-hydrochloricacid, taraxacum, ipecacuanha and rhubarb in a mildbitter infusion were administered internally, whilesmall mustard plasters, iodine ointment, tincture ofiodine and nitro-hydrochloric acid baths were usedexternally.'

INDIAN CHILDHOOD CIRRHOSIS AND VENO-OCCLUSIVE DISEASE OF THE LIVER COM-

PARED

Clinical PictureThe clinical picture of veno-occlusive disease of

the liver as seen in Jamaican children and that ofIndian childhood cirrhosis present many similaritiesand certain apparent differences.

Economic StatusIn both conditions, affected children do not come

from the very lowest socio-economic groups. How-ever, in India, it is well known that cases also occurin 'upper middle class' families as, for example,where the father is a physician or merchant. Thisis unknown in Jamaica.

Diet and NutritionApart from the study by Rhodes (1952) in Jamaica,

when she found that affected children were havinga diet low in protein, detailed dietetic investigationsdo not appear to have been carried out on eithergroup. However, in both conditions it is probablethat the diet is usually inadequate, and that this isreflected in the children's nutritional status. In theearly stages of both diseases, children are usuallyundernourished without showing evidence of grossmalnutrition, while in the final cirrhotic stage,cachexia develops as a result of the chronic illness.

Onset and Clinical FeaturesJamaican children first presenting with either the

subacute or chronic stages of veno-occlusive diseasevery much resemble the usual picture of I.C.C.They are usually brought in by parents with com-plaints of abdominal swelling, due to ascites and/oran enlarged liver. Following this, both groups showthe same progressive downhill course over monthsor years, sometimes with long clinically latentperiods, but eventually terminating fatally incholaemia, oesophageal haemorrhage or intercurrentinfection.

Personal experience and descriptions in themedical literature give the impression that both earlymarked dilatation of the collateral circulation and

haemorrhage from oesophageal varices are com-moner in veno-occlusive disease, while jaundiceseems to occur earlier and in a higher percentage.In addition, Indian children with childhood cirrhosisare reported to show more general features of ill-health, such as loose stools, poor appetite, etc.An important difference between veno-occlusive

disease in Jamaica and I.C.C. is that cases of theformer may present as acute veno-occlusive disease,that is, with an initial acute episode of hepatomegalyand ascites, during which the histological picture ofacute exudative subendothelial thickening of smalland medium sized branches of the hepatic veins canbe found in liver biopsy material. In addition, anumber of cases of veno-occlusive disease presentingin the subacute or chronic stage have a past historysuggestive of a possible acute episode of hepaticveno-occlusion. As far as can be discovered byperusal of the literature, by discussion with experi-enced clinicians and as a result of personal observa-tion, this type of initial acute episode has never beenreported from India.

If the ages of onset of cases of Jamaican veno-occlusive disease presenting in the subacute orchronic stages are compared with the present series,it will be seen that the range is very similar, that is,from about 1 to 9 years. However, in most accountsof I.C.C. the main incidence is given as between1 and 3 years, so that most evidence points towardsthe Indian variety of cirrhosis usually manifestingitself some two or three years earlier than iscustomary in Jamaican cases. Finally, as a point ofsimilarity, both conditions may often show a familialincidence.

TROPICAL CHILDHOOD CIRRHOSIS INOTHER AREAS

Although not as commonly reported, nor, appar-ently, such a public health problem as in Jamaicaand India, cirrhosis of childhood has also been thesubject of investigation in certain other tropicalregions.

In Egypt, where cirrhosis in children and adultsis usually considered to be mainly the result ofcombined malnutrition and schistosomiasis, Hashem(1948) has also described what he terms 'a variantof subacute portal cirrhosis encountered in Egyptianchildren', which is unrelated to bilharzial infection.This condition, which occurs mainly in childrenbetween the ages of 8 months and 7 years, is ofunknown aetiology. The main clinical featuresappear to be the fairly rapid onset of cirrhosis, witha very enlarged, firm liver and dilated, tortuousthoraco-abdominal veins. Oedema of the lowerlimbs is a frequent finding, and the spleen is enlarged

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in one-third of cases. Haematemesis is not reported.The syndrome is of especial interest as, as will benoted later, the liver histology very much resemblesthat of veno-occlusive disease.

Walters and Waterlow (1954) have reported animportant and broad-based investigation into thepathogenesis of hepatic fibrosis in African childrenand young adults in the Gambia. In these cases,the main features appear to be general ill health,distended abdomens and ascites. Jaundice wasunusual, and dilated collateral circulation andhaematemesis were not noted. Anaemia was oftena conspicuous feature. No history of previous acuteepisodes was mentioned.

HISTOLOGICAL FINDINGSRadhakrishna Rao (1935, 1954) described histo-

logical studies in I.C.C. when widespread obliterativelesions of the smaller divisions of the hepatic venoustree were found and appeared to be playing animportant part in the evolution of the cirrhosis.Of the many articles from India, it has becomeevident that histological study of I.C.C. has beenrelatively limited because of the difficulty of obtain-ing necropsy and other 'material. Bhende andDeoras (1954) summarized the various reports onthe pathological findings as follows. Necrosis ofliver cells uniformly distributed throughout theorgan, but varying in degree in different areas, hasbeen observed by most writers. Fibrous bands, aswell as diffuse fibrosis throughout the liver, havebeen reported; this fibrosis includes portal triads,but, according to some writers, may also originatefrom and include branches of the hepatic vein whichmay or may not show thickening of their wallsand/or obliteration of their lumina. Dr. Y. M.Bhende of Madras has kindly allowed us to studyagain the histology of seven of his cases and we con-firm his findings that, in several of the sections, thereis very marked obliteration of the hepatic veins(Figs. 13, 14). It should be noted that, in the paperby Bhende and Deoras (1954), the nine casesexamined histologically represent hospital necropsymaterial collected over a period of 25 years and itmust have been difficult to establish that thesechildren did, in fact, all belong to the same clinicalentity. On the whole, authors other than Radha-krishna Rao (1935, 1954) and Ramachandra Rao(1935) have not been much impressed by theobliteration of the branches of the hepatic veins.Nodules of regeneration have been found to beabsent or not very marked. The biliary tree wasreported to be normal by Radhakrishna Rao (1935,1954), but bile duct proliferation in varying degreeswas remarked by several authors. Several of the

Indian author's have felt that the histologicalpicture of I.C.C. was that of toxic cirrhosis.Achar and Chacko (1954) examined material from

10 necropsies and 75 liver biopsies from cases which'clinically looked like infantile biliary cirrhosis'.They paid special attention to the hepatic venoustree and could not demonstrate any obliteration.Srivastava and Aikat (1954) studied the histology ofliver biopsy specimens in 45 cases and, on the whole,confirmed the findings of earlier writers; they donot comment on the hepatic veins.The Liver Diseases Sub-Committee (I.C.M.R.,

1955) reported on a careful study of a total of60 cases in various stages of the disease. Theyconcluded that the basic alteration in the liver inI.C.C. is diffuse liver cell damage and replacementfibrosis. This fibrosis was portal in origin, butmight go on to form bands which would then dividethe liver into pseudo-lobules, while these pseudo-lobules would in their turn be invaded by fibroustissue. In other cases, the fibrosis remained diffusewithout any attempt at pseudo-lobulation. Occlu-sion of the hepatic veins was not a feature.Fernando (1954) describes eight cases with the

clinical picture of I.C.C. from Ceylon. Thehistological appearances were those of intralobularcholangiolitic biliary cirrhosis. Karunaratne (1951)had earlier reported three cases observed in Ceylonand concluded that fibrosis did not originate in theportal tracts.From Egypt, Hashem (1939) reported a special

form of cirrhosis of the liver in children. Patho-logical findings in three-cases were described: acutehaemorrhagic necrosis associated with phlebitis andthrombosis of the smaller divisions of the hepaticveins was noted and was a prominent feature in theacute and subacute cases. This was followed byfibrosis and cirrhosis.From West Africa, Walters and Waterlow (1954)

have described fibrosis of the liver observed inGambian children, of which the aetiology wasunknown. The authors suggested the possibility ofa dual lesion and a dual aetiology, viz., (a) a nutri-tional or metabolic lesion of the parenchyma, and(b) the development of hyper-reactive mesenchymalelements as a result of malaria. A severely fattyliver characteristic of kwashiorkor was never seen,neither was there frank necrosis of parenchymalcells.

In South Africa, Higginson (1956) has recentlyreported that he has observed four cases of veno-occlusive disease. Suckling and Campbell (1957)have reported from South Africa that the develop-ment of a cirrhosis could not be established in afive-year follow-up study of previously treated

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kwashiorkor patients. The generaltendency at present is to considerthat malnutrition and kwashiorkorper se are not in themselves responsiblefor a subsequent fibrosis or cirrhosisof the liver-a view also expressed onthe basis of observations in Jamaicaninfants and children (Bras, 1955).l

In Indonesia, Lie and Tjokronegoro(1954) found fibrosis and cirrhosis of 4

the liver relatively frequently inchildren in Java with or withoutmalignant malnutrition. The mal-nutrition was apparently not a factorin the production of the fibrosis. Theyconcluded that viral hepatitis or adisease clinically consistent with virushepatitis might be one of the causes ofcirrhosis in this country. One of thepresent authors (G.B.) has been in theposition to study some of their materialand shares the opinion expressed by 4these authors that the histologicalpicture also is not like that of veno-occlusive disease.

Blankhart (1953) reported therelatively frequent occurrence of , -cirrhosis of the liver in the island ofSangir, lying to the north of Celebes.This condition was clinically diagnosed

Nou. 13.

FIG. 13.-Marked sub-endothelial collagen-ous thickening ofhepatic vein branch.Mallory trichome

41-~~~~~~~ -x 340. (Slide of Dr.Y.Bhende of Madras.)

FIo. 14.-Branch of* ~~the hepatic vein

markedly narrowed;two blood channels

_ lined by endotheliumare visible (? re-canalization) x 340.(S ide of Dr. Y. Bhende

of Madras.)

FIG. 14.


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in 32 children under 15 years of age, but was not seenin those younger than 5 years. Histology was difficultto obtain, but whilst working in Indonesia one of thepresent writers (G.B.) was able to examine some ofBlankhart's material. The cirrhosis seen was histo-logically well advanced and, although occasionallyveno-occlusion of branches of the hepatic vein wasobserved, it could not be excluded that this was asequel to the cirrhosis rather than a primary lesion.From Europe, a condition of obliteration of

hepatic veins, named endophlebitis hepatica obli-terans, occurring in infants and children, has beenreported. Wurm (1939) reported eight cases at theage of 3 months, all ending fatally. A bacterialtoxic aetiology through artificial feeding wasincriminated. Burkhardt (1938) saw this conditionin a 2-year-old child for which he postulated anallergic cause. Konig (1943) observed the conditionin a newborn child and postulated intoxication bythe transplacental route.A number of other conditions leading to occlusion

of the hepatic veins have been reviewed in a previouspublication (Bras et al., 1954). Various conditionsof the liver giving rise to fibrosis and/or cirrhosis inchildren have been described, such as syphilis andthe more obscure types exhaustively reviewed byRbssle (1930). More recently erythroblastosis(Craig, 1950) and fibrosis in children with acuteleukaemia following folic acid antagonists (Colsky,Greenspan and Warren, 1955) have been reported.These do not at present warrant further discussionwith regard to the cases reported here.

DISCUSSIONA condition in the liver, with obliteration of

hepatic veins as a predominant feature, has beenestablished beyond doubt as occurring in infantsand children. The reports from Jamaica, Egypt,India, South Africa and Europe, submitted bydifferent authors, substantiate this. In Jamaica,Egypt, South Africa, Europe and some cases fromIndia-such as those of Rhadakrishna Rao andRamchandra Rao, some of Bhende's and Deoras'cases, as well as the Indian children reported in thepresent paper-this obliteration is prominent andhas been of sufficient importance to be consideredby the various investigators to be responsible for thedevelopment of fibrosis and cirrhosis subsequent tothe obstruction, or, at least, to have played animportant role in the development of fibrosis andcirrhosis. On the other hand, there are severalwriters from India who have expressly denied thepresence of hepatic venous lesions and it is obviousthat more study is needed to clarify this point.Unlike the picture in Jamaica, I.C.C. does not appear

to have the characteristic acute episode with thedevelopment of massive ascites, which separates thisentity quite clearly from any other. Much of thestudy in I.C.C. has therefore necessarily been per-formed on well-established cases of cirrhosis andevery histopathologist knows that in such an eventa recapitulation of the morphogenesis is frequentlyimpossible. On the basis of studies in cirrhotics inJamaica, it is suspected that at least some of thevessels called by Indian workers patent hepatic veinbranches are in fact examples of collateral circula-tion. Injection studies of the hepatic veins withradio-opaque material (Stuart and Bras, 1957) mayassist considerably here. In addition, it is by nomeans certain that all the authors describing I.C.C.have indeed reported on one disease entity only,instead of on a variety of diseases which have liverdamage and subsequently fibrosis in common.

It seems, however, improbable that the liver celldegeneration and necrosis so uniformly observed byall the students could in all cases be secondaryto veno-occlusion. This mechanism was acceptedin Jamaica for veno-occlusive disease since all caseshad sufficient changes in the hepatic veins to explainthe centrilobular necrosis observed, even though theJamaican workers have always stressed the fact thathepato-cellular damage, either primary or con-current, but independent, of the hepatic venousocclusion, cannot be excluded. It appears necessarythat post-mortem vascular injection studies of theliver should be done in I.C.C.Analogous controversial statements exist in the

veterinary literature. Experimental work on poison-ing with certain toxic plants (Crotalaria sp. andSenecio sp.) has demonstrated liver cell damagewhich has been extensively commented upon bysome authors (Bras et al., 1957). Other authorsworking with the same plant species noticed changesof the hepatic veins; whilst, in South Africa, Seneciopoisoning in man has been observed to producehepato-venous occlusion (Selzer and Parker, 1951).Our own experiments on rats with Senecio andCrotalaria have produced extensive liver celldegeneration and necrosis in many animals withoutchanges in the hepato-venous tree, while in someother animals a disease indistinguishable fromhumanveno-occlusive disease has been produced. Lastly,Crotalaria fed to cattle in Jamaica has also resultedin veno-occlusive disease and fibrosis.

It would, therefore, appear acceptable to postulatethat toxic liver damage in children may produceeither liver cell degeneration and necrosis con-current with changes in the cholangioles as describedin cholangiolitic cirrhosis (Rossle, 1930; Watsonand Hoffbauer, 1946), or hepato-venous changes,

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INDIAN CHILDHOOD CIRRHOSIS 385or both. This certainly appears to be the case insuch experimental animals as rats, cattle, horses.Experiments are at present being conducted with theobject in view of trying to separate the parenchymaltoxic component from the vascular toxic component.

SUMMARYCirrhosis of the liver is common in children in

parts of India, especially in West Bengal and Madras,and in the West Indian island of Jamaica, where itusually occurs as a late result of 'veno-occlusivedisease of the liver'. The literature concerning veno-occlusive disease is reviewed, with especial referenceto its possible relation to the ingestion of planttoxins of certain 'bush teas', particularly species ofCrotalaria and Senecio.The clinical and pathological features of 15 cases

of Indian childhood cirrhosis (I.C.C.) seen inCalcutta, West Bengal, are presented, analysed andcompared with accounts in the literature. A two-stage clinical classification is suggested: (1) stage ofhepatomegaly, (2) stage of clinical cirrhosis. Thesocio-economic background of the present cases iscompared with reports by previous workers.The clinical picture and morbid anatomy of

veno-occlusive disease and I.C.C., as judged by theliterature and the present cases, are compared andcontrasted. While some cases are clinically similar,the absence in I.C.C. of the acute episode that occursin some children with veno-occlusive disease isstressed. Hepatic venous occlusion was found inall six of the 15 children who were liver biopsied orwho came to necropsy. This histological featurehas been noted by some other investigators, althoughmore workers have stressed the presence of paren-chymal damage.

It is noted that, in both experimental animals andin veterinary medicine, it has been shown thatcertain plant toxins may sometimes act on liver cellsand sometimes on the hepatic veins. The possibilityof a similarly varied response in children issuggested.

Our thanks are due to Dr. R. N. Chaudhuri Director,School of Tropical Medicine, Calcutta, and to Dr.K. V. Krishnan, Director, All-India Institute of Hygieneand Public Health, Calcutta, for their advice andcooperation; and to Dr. Y. M. Bhende for permittingus to examine liver slides from Dr. Deoras' and hiscollection of autopsy material.

REFERENCESAchar, S. T. and Chacko, R. (1954). Indian J. med. Sci., 8, 442Asprey, G. F. and Thornton, P. (1953). W. Indian med. J., 2, 233.

Beaver, P. C., Snyder, C. H., Carrera, G. M., Dent, J. H. and Lafferty,J. W. (1952). Pediatrics, 9, 7.

Bhende, Y. M. and Deoras, S. M. (1954). Indian J. med. Sci., 8, 21.Blankhart, D. M. (1953). Docum. Med. georg. trop. (Amst.), 5, 7.Brahmachari, U. and Brahmachari, P. (1938). In The British Encyclo-

paedia oj Medical Practice, Vol. 8, p. 132. London. Quotedby Indian Council of Medical Research Report (1955).

Bras, G. R. (1955). In Protein Malnutrition. Proceedings of aConference in Jamaica (1953), ed. Waterlow, J. C. Cam-bridge.

and Berry, D. M. (1956). W. Indian med. J., 5, 37.and Gyorgy, P. (1957). In press.

and Hill, K. R. (1956). Lancet, 2, 161.Jelliffe, D. B. and Stuart, K. L. (1954). A.M.A. Arch. Path.,57, 285.

and Watler, D. C. (1955). W. Indian med. J., 4, 201.Burkhardt, L. (1938). Frankfurt Z. Path., 52, 567.Chatterjee, D. (1940). Indian med. J., 34, 266.Chaudhuri, K. C. (1944). Indian J. Pediat., 11, 61.Colsky, J., Greenspan, E. M. and Warren, T. N. (1955). A.M.A.

Arch. Path., 59, 198.Craig, J. M. (1950). Ibid., 49, 665.Davidson, J. (1935). J. Path. Bact., 40, 285.Fernando, P. B. (1954). J. Child. Hosp. Colombo, 3, 3.Gibbons, J. B. (1888). Indian med. Gaz., 23, 52.Hashem, M. (1939). J. roy. Egypt. med. Ass., 22, 319.-(1948). Ibid., 31, 541.Hill, K. R., Rhodes, K., Stafford, J. L. and Aub, R. (1953). Brit.

med. J., 1, 117.Higginson, J. (1956). Proc. Kampala Conf. on Cancer of the Liver.Indian Council of Medical Research (1955). Indian J. med. Res.,

43, 723.Jelliffe. D. B., Bras, G. and Stuart, K. L. (1954a). Ann. trop. Med.

Parasit., 48, 386.(1954b). Pediatrics, 14, 334.

Karunaratne, W. A. E. (1951). In Liver Disease: Ciba FoundationSvmposium, p. 106. London.

K6nig, J. (1943). Virchows Arch. path. Anat., 311, 527.Krishna Rao, P. (1950). Indian med. Gaz., 85, 150.Lahiri, S. C. (1936). Ibid., 71, 313.Lie, K. J. and Tjokronegoro, S. (1954). Docum. Med. geogr. trop.

(Amst.), 6, 193.McFarlane, A. L. and Branday, W. J. (1945). Brit. med. J., 1, 838.Prabhu, M. B. (1940). Indian J. Pediat., 7, 121.Radhakrishna Rao, M. V. (1934). Indian J. Pediat., 1, 166.

(1935). Indian J. med. Res., 23, 69.- (1954). Malnutrition in African Mothers, Infants and Young

Children. Report of 2nd Inter-African Conference onNutrition, Gambia, 1952, pp. 101, 147, 358. London.

Ramachandra Rao, P. 1935). Cirrhosis of the Liver. Ph.D. Thesis.London. Cited by Brahmachari, U. and Brahmachari, P.(1938).

Rhodes, K. (1952). Brit. J. Nutr., 6, 198.Rossle, R. (1930). In Handbuch der speziellen pathologischen.

Anatomie und Histologie, ed. Henke, F. and Lubarsch, O.,band 5, teil 1, p. 449. Berlin.

Selzer, G. and Parker, R. G. F. (1951). Amer. J. Path., 27, 885.Sen, B. C. (1887). Indian med. Gaz., 22, 338.Sherlock, S., Summerskill, W. H. J., White, L. P. and Phear, E. A.

(1954). Lancet, 2, 453.Srivastava, J. B. and Aikat, B. K. (1954). Trans. Sympos. on Liver

Injury, Gwalior, Ind. Ass. Path., Bombay, p. 30. and in IndianJ. med. Sci., 8, 446.

Stein, H. (1957). Brit. med. J., 1, 1946.Stuart, K. L. and Bras, G. (1955). Brit. med. J., 2, 348.

-, (1956). W. Indian med. J., 5, 33.(1957). Quart. J. Med.

Suckling, P. V. and Campbell, J. A. H. (1957). J. trop. Pediat.,2, 173.

Walters, J. H. and Waterlow, J. C. (1954). Spec. Rep. Ser. med.Res. Coun. (Lond.), No. 285.

Waterlow, J. C. (1948). Ibid., No. 263.Watson, C. J. and Hoffbauer, F. W. (1946). Ann. intern. Med.,

25, 195.Wurm, H. (1939). Klin. Wschr., 18, 1527.

AddendumA recent paper from South Africa has reported

three typical cases of veno-occlusive disease inAfrican children under the age of 18 months. Allwere verified at necropsy (Stein, 1957).

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CirrhosisLiver and Indian Childhood Veno-occlusive Disease of the

Derrick B. Jelliffe, Gerrit Bras and Kanai L. Mukherjee

doi: 10.1136/adc.32.165.3691957 32: 369-385 Arch Dis Child

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