BILIARY OBSTRUCTION ASSOCIATED WITH ICTERUSGRAVIS NEONATORUM

BY

REGINALD LIGHTWOOD, M.D., F.R.C.P.Physician to Out-Patients, Hospital for Sick Children, Great Ormond Street, London;

and Physician to the Children's Department, St. Mary's Hospital, PaddingtonAND

MARTIN BODIAN, M.D., L.R.C.P. & S., D.C.P.Pathologist, Hospital for Sick Children, Great Ormond Street

For twenty years it has been known that obstruc-tive jaundice may occasionally be seen in icterusgravis neonatorum. Still (1927) quoted the viewthat the bile of excessive haemolysis becomes tooviscid to pass freely along the ducts, and he mentionsthe low pressure at which it is secreted. This viewdoes not altogether explain the facts, because amarked obstructive phase does not necessarily gowith the greatest haemolysis or the deepest preced-ing jaundice. MacClure (1931) suggested that thepresence of a foreign substance in the bile causedcoagulation in the bile capillaries. We favour athird possibility-namely, that biliary obstructionis due to swelling of damaged hepatic cells-becausehistological studies of icterus gravis show that suchan association exists. The association is seen also inconditions other than icterus gavis, for example,stagnation of bile may be seen just outside areas ofmaximal necrosis in infective hepatitis.

Skelton and Tovey (1945) postulate two forms ofbiliary obstrution in association with icterus gravis:(a) blockag of one of the larger bile ducts with in-spissated bile; and (b) conversion of the bile ductsinto a fibrous cord. First let us consider the latter,that is, atresia ofthe bile ducts associated with icterusgravi

Blary Arsia Associatedwith Icteru GravisNeonatorum

Pasachoff (1935) reported the case, fatal at theage of five days, of a coloured girl who some twelvehours after birth had deep jaundice, hepatospleno-mgaly, and erythroblastosis, yet no anaemia On

the fourth day haemorrhage appared and thestools were white. A moderate degree of anaemiadeveloped. Necropsy showed extensive extra-medullary haematopoiesis, kernlterus, completeatrsia of the bile ducts, and c ral aplasia. Thiscase was reported in the pre-Rh period, and, there-fore, the diagnosis of icterus gravis, though probablycorrect, could not be established beyond alldoubt.

H.TN. Sanford (1940) reported the case ofan infantwho at the age of two hours had marked anaemia(red blood cells 1,600,000 per cmmn) and eyythro-

blastosis (nucleated red blood cells 162,000 perc.mm.). The icteric index was 500 units (35 mg.per 100 c.cm.). Professor Sanford kindly sent thepathologist's report to one of us (R. L.) and wequote: 'The whole of the gall-bladder is slightlythickened and the lumen contains approximately1 c.cm. of thick stringy bile; practically completestenosis is seen, and this is traced to the ampufla ofVater. A probe can be inserted into the ampullafor a distance of three millimetres. The cystic ductis so small that a small probe cannot be passed.The same is true of the patent common duct. Thelumen of the common bile duct is a-few millisin diameter.' The mother was Rh-negative, thefather Rh-positive, and another child born two yearslater also Rh-positive; this one developed a typicalerythroblastois foetalis at birth. Sanford concludesthat the first baby was a case of ' atresia ' of the bileducts associated with erythroblastosis foetalis yet wecannot entirely concur with this view. It appearsfrom the pathologist's report that this was not a caseof atresia of the bile ducts but one with some degreeof stenosis, which is not very infirequent. Again,the diagnosis of erythrobLastosis foetalis, since itoccurred in the pre-Rh period, was not quite proven.The latter child of this family was tested for theRh factor and the mother found to be Rh-negative,but there is no report that she developed anti-Rhagglutinins.

Skelton and Tovey (1945) report two cases of ery-throblasosis foetalis associated with congenitalatresia of the bile ducts:FAmILY G. E. The patient, a second child (the

first was normal), developed jaundice on the first day,passed bile in the urine, and died aged two days;no blood count was reported. Necropsy disclosederythroblastosis, marked erythropoiesis in the liverand spleen, fibrous obliteration of the commonbile duct, and kemikterus. The father was Rh-positive; the child's Rh factor was not examined(this was in 1942). The first-born child was sub-sequently examined and found to be Rh-positive,the mother was Rh-negative, and no antibody wasdemonstrable three years after the birth of theaffected child.CoCEwrr. We tlhink that in this case no final

proof of the aiation of the two conditions has209

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ARCHIVES OF DISEASE IN CHILDHOODbeen given. The child was not tested for the Rhfactor, anaemia is not mentioned as a clinicalfeature, no Rh antibodies were found in the'mother'sserum three years after the-birth of the child, and themother's serum was apparently not tested at the timewhen antibodies could reasonably be expected.None of the necropsy findings (erythroblastosis,extra-medullary erythropoiesis, or kernikterus) areabsolutely pathognomic of icterus gravis, thoughthey are all highly suggestive.

FAmIY M. The patient, a second child (the firstbeing born normal and now alive and well) hadjaundice on the first day, with bile in the urine, andclay-coloure4 stools. Cholecysto-gastrostomy, per-formed for fibrous occlusion of the common duct,was followed by recovery. This child was Rh-positive, and its father Rh-positive. Its motherRh-negative. The mother's serum was not wasexamined for agglutinins at the time of the infant'sillness, but they were present in the mother's bloodat the third and -fourth pregnancies, which resultedin two babies with erythroblastosis foetalis; thesedied at the age of four and three days respectively,both with kernikterus.

COMMENT. No suggestion has ever been made thatthis second child in that family was a case of ery-throblastosis foetalis. It has been suggested, how-ever, that it was a case of atresia of the common bileduct. Though we do not know all the clinicaldetails, we venture to suggest that the diagnosis ofatresia of the bile duct at operation is often difficultto make. To illustrate this point we would like tomention a recent case in which an experiencedpaediatric surgeon was concerned. This was apatient, aged one month, with obstructive jaundicefrom the age of four days, and cholecysto-gastros-tomy was performed. At necropsy twenty-fourhours after operation the bile ducts were patent, andthe obstruction was found to be due to liver cirrhosisof obscure nature, Rh incompatibility having beenexcluded. - But assuming that atresia was presentin the second child in Family M, there is no reasonwhy congenital atresia of the bile ducts and icterusgravis should not occur in different children of thesame family. For these reasons we consider that adirect association was not established in Family M.The same authors go on to quote a third family of

six children, the fourth ofwhich died from congenitalobliteration of the bile duct. Its Rh factor was notexamined. The sixth child died from erythroblast-osis foetalis, Rh antibodies having been present inthe mother's blood at the sixth pregnancy. Thisagain appears to be a case of the two conditions,biliary atresia and erythroblastosis, occurring in-different children of one family.We have been unable to find any more reports in

the literature of the association of erythroblastosisand congenital atresia, but we now mention a patientwho has come under our observation through thecourtesy of Dr. Donald Paterson, yet again therewas no absolute proof of the association of the twoconditions.M. S., a male baby (two siblings are alive and

well and had no neonatal jaundice or anaemia),developed jaundice from the third day which lastedeight days. When six weeks old he had bruisingand became anaemic. The jaundice recurred atthe age of seven weeks and increased in depth. Ateight weeks the liver was found to be enlarged, thespleen was not palpable, and the blood count was1,500,000 erythrocytes per c.mm. Haemoglobin was4-8 g. per cent., and two normoblasts were found per100 white blood cells. The white blood count was20,600 per c.mm.; van den Bergh 6-7 mg. per 100c.cm. Urine contained bile pigment. The faeceswere very pale. Rh investigations carried outwhen the baby was nine weeks old showed the babyto be Rh-positive and the mother Rh-negative. Noanti-Rh agglutinins were present in the mother'sserum. The child was given a blood transfusion ofRh-negative group 0 blood, and the blood count roseto 5,900,000 erythrocytes per c.mm. When agedfour months and still deeply jaundiced, the child wasadmitted to the Hospital for Sick Children, GreatOrmond Street. His blood count was then5,700,000 per c.mm. (no normoblasts). Haemo-globin was 16-1 g. per cent. The Rh investigationswere repeated and confirmed. A laparotomy wasperformed; the gall-bladder was found to be solidand rubbery and the liver large and cirrhotic, andno bile ducts suitable for anastomosis were found.The child died seven days later at the age of fourand a half months. The liver was found to .becirrhotic. Bile plugs were found in the intercellularbile canaliculi. The epithelium of the intrahepaticbile ducts was normal. No extramedullary erythro-poiesis was noted. The gall-bladder was small andcontained very little white bile. The cystic ductand common bile duct were occluded. The hepaticducts appeared to be patent but were very narrow.The spleen was much enlarged and showed a markedincrease of fibrous tissue.

CoMMwNT. In this case there was early neonataljaundice; at two months there was recurrence of thejaundice, which was clinically obstructive in type;there was late onset of a severe anaemia, and laterstill cirrhosis of the liver and intercellular bilethrombi. Though the mother was Rh-negativeand the infant Rh-positive, no evidence of Rh im-munization was found in the mother's serum whenthe infant was nine weeks old; so that in this case ofbiliary atresia there is jgain no proof of erythroblast-osis foetalis due to Rh incompatibility.

DiscussionThe above survey of cases coming under Skelton

and Tovey's Type B of biliary obstruction associatedwith icterus gravis leads us to the conclusion that inno instance has a direct etiological association beenproved beyond doubt, though some cases have beenhighly suggestive of this association.We have also considered eight cases of atresia of

the bile ducts which have been tested in regard tothe Rh factor at the Hospital for Sick Children,Great Ormond Street. No evidence of Rh iso-immunization was obtained. The series is verysmall, but certainly lends no support to the idea thatRh incompatibility is an etiological factor in con-genital atresia of the bile ducts.

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BILIARY OBSTRUCTION IN ICTERUS GRAVIS NEONATORUMBiiary Obstrction in Icterus Gravis Neonatorm

witbout Atresia of the Bile DuctsIn this type of biliary obstruction in icterus gravis

we include both intrahepatic and extrahepaticobstruction other than atresia of the bile ducts.Skelton and Tovey's Type A, i.e. blockage of oneof the larger bile ducts with inspissated bile, isincluded in this group.The jaundice of icterus gravis is mainly haemolytic,

though an obstructive element is sometimes presentas well. When there is obstruction it usually occursas an evanescent phase, though there have beenoccasional cases reported in the literature with theperiod of obstruction lasting for several months.Serological testing has added so much to the ac-curacy of diagnosis that we propose to confine our-selves to cases which have been reasonably estab-lished by Rh investigations. They may show an earlyonset of an obstructive phase which may be con-tinuous for several weeks or months, or an evanes-cent phase of haemolytic jaundice with a recurrenceof the icterus after a few weeks. and then biliaryobstruction, usually partial, lasting for several moreweeks. This sequence is illustrated by the followingcase (Lightwood, 1943).

Case 1. A. C., a male, was a second child. Theonly sibling, aged four years, was jaundiced for thefirst three to four days of life, but is now healthy.

Jaundice appeared twenty-four hours after birthand lasted fourteen days; pallor was not noted; thestools were normal. Ten days later, at the age ofthree and a half weeks, the stools became pale andthe urine dark. During the next week the babybecame increasingly pale and jaundiced (greenishtinge). One week later still he was seen at hospitalwith jaundice, anaemia, abdominal distension,prominent veins of the abdominal wall, and ascites(making palpation of the liver and spleen imposs-ible). The stools were pale and the urine dark,and the diagnosis between icterus gravis and con-genital atresia of the bile ducts was not easily made.The blood piclure did not decide the diagnosis:haemoglobin was 85 per cent., and red blood cells3,480,000 per c.mm., the colour index 1-3, and whiteblood cells 22,600 per c.mm. Erythroblastaemia wasnot present and would not have been likely to persistso late. The icterus index was 50. The directvan den Bergh reaction was positive, and the indirectreaction 10 units. Wassermann reaction and Kahnreaction of mother and baby were negative. Rhtests, however, showed the baby to be Rh-positive;his mother was Rh-negative, and her blood containedRh antibody. Therefore the diagnosis of icterusgravis was established.The infant was- gravely ill, and the abdomen

needed paracentesis on two occasions, 10 oz. and 20oz. being withdrawn. The haemoglobin fell to 60per cent.. and an Rh-negative blood transfusion of150 c.cm. was given. Thereafter the haemoglobinlevel was well maintained. Owing to the prolongedjaundice and the presence of such considerableascites, the prognosis seemed bad, but after para-centesis and blood transfusion the child began toimprove. Subsequently he gained weight satis-factorily, and ascites and jaundice slowly dis-appeared during the next six weeks. This was afteran obstructive phase lasting eleven weeks. Even

after this there were sUight recurrences of obstructionof some two days' duration (two attacks).

Case 2. D. K., a male, aged eleven hours, wasadmitted to the Hospital for Sick Children, GreatOrmond Street. under Dr. W. G. Wyllie, with markedjaundice and hepatosplenomegaly. Birth weightwas 72 lb. The child had asphyxia (the cord waswound twice round the neck), but revived withlobelin.Two siblings, aged seventeen and fourteen years,

were alive and well. The third child of the familydied with jaundice at the age of eighteen days. Thefourth child miscarried, and the fifth was thepatient. On examination, orange-yellow jaundicewas noticed, and the liver was palpable three fingers'breadth below the costal margin; the spleen waspalpable. Red blood cells were 3.960.000 perc.mm., with 92 normoblasts per 100 white bloodcells. The baby was Rh-positive; the mother wasRh-negative, and one week after delivery her serumcontained Rh antibody of a titre 1 in 64. At twodays old, 205 normoblasts were found per 100 whiteblood cells. Subsequently the normoblast countdecreased gradually. The urine contained bile pig-ment, and the stools were pale. At one week of agethe serum bilirubin was 28-5 mg. per 100 c.cm. Atthree weeks of age the alkaline plasma phosphatasewas 18 4 units per 100 c,cm. (normal 10-20 units).This was taken as an indication against extrahepaticobstruction, and, therefore, no laparotomy was per-formed. The obstructive jaundice lasted aboutfour months. When seen, at five months, the infantwas feeding and gaining well. The jaundice hadcompletely disappeared, and the van den Berghreaction in the serum was negative.

The clinical histories just given do not explain themechanism of obstruction. In contrast, the follow-ing cases, coming to necropsy, throw light on thepathology underlying the obstructive phase oferythroblastosis foetalis for they show that at leasttwo states may be found at necropsy, (a) pigmentstones, and (b) cirrhosis.

A. Pignent Stones causing ExtraepaticObstruction

Case 3. A. H., a male, aged four and a halfmonths, came under the care of Dr. Donald Pater-son at the Hospital for Sick Children, London.His seven-year-old brother had had no jaundice, buta three-year-old brother had had jaundice from thethird to the fourteenth day after birth. The patienthad had a normal birth (weight 7 lb. 8 oz.), wasbreast-fed for three days, and had a 'septic' um-bilicus until two months old. There was no neo-natal jaundice, but jaundice from two and a halfmonths without constitutional disturbances; stoolswere pale with a yellow tinge, and the unne was darkand contained bile pigment; there was no vomiting,and he was taking his feeds well. When admitted tohospital he had marked jaundice. The liver could befelt one and a half fingers' breadth below the costalmargin. The spleen was not felt. Heart and lungswere normal. Red blood cells were 5,120,000 perc.mm. of blood, haemoglobin 110 per cent. (15-4g.per 100 c.cm.), reticulocytes 1-4 per cent., andthere were no nucdeated red cells. White- bloodcells were 14,000 per c.mm. with 69 per cent.lymphocytes. The baby was Rh-positive, the

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mother Rh-negtive, with anti-Rh a nins (titre1 in 32). The blood Wassermann reaction of themother was negativ. Liver function tests were asfollows; van den Bergh, immediate direct positive;quantitative, 8-6 mg. per 100 c.cm. (normal up to0-5 mg.). Alkaline serum phosphatase was 45-6units (normal 10 to 20). Takata-Ara reaction wasnegative.

In view of the obshtctive type ofjaundice, with ahigh serum phosphatase and no anaemia, atsia ofthe bile duct was suspected and reassessment of thecase in a further fortnight decided upon. Mean-while the baby was sent home. More than a weeklater he was readintted in extraem dehydrationfollowing five days' diarhoea and vomiting, anddied after a few hours. Necropsy showed a wasted,jaundiced infant with moderately enlarged liver anda gall-bladder of normal size. Bile could besqueezed through the common bile duct. Foursmall dark pigment stones were found in the commonbile duct and cystic duct, together with muchpigment-sand which was also present in the gall-bladder. There was some dilatation of the bilepassages, including the hepatic ducts behind the siteof partial obstruction (fig. 1). The portal systemswere enlarged, with a moderate increase of reticulinwhich was dense and stained with van Gieson'smixture (figs. 2 and 3). There was some albuminousdegeneration of liver cells. The sinusoids were con-gested; the bile duct epithelium was normal. Anoccasional bile thrombus was seen in the inter-cellular bile canaliculi.ComaNT. This is a case of erythroblastosis

foetalis due to Rh iso-immunization, coming tonecropsy during an obstructive phase of jaundice.The obstruction was extrahepatic in nature, due tothe presence of bile pigment stones within the largerbile ducts, the liver being comparatively normal. Weare not aware of any previous reports of such naturein proved cases of Rh incompatibility, and thetendency to formation of bile pigment stones in thisneonatal form of haemolytic jaundice has notreceived attention.Pigment stones were also found in another similar

case. An infant, aged six months, with a history ofjaundice lasting from the second day for five weeks.At six months of age there was no anaemia. Thebaby was Rb-positive, the mother Rh-negative, witha Rh antibody, titre 1 in 64. The liver was onefinger's breadth below the costal margin. Thespleen was not palpable. At necropsy the liver wasmacroscopically and microscopically normal. Thegall-bladder was small and contained pale bile andthree small pigment stones. The bile passages werepatent.

Still' 1927) reported three cases of biliary calculiin infants aged nine months, eight months, and fivemonths respectively, with no history of jaundice inany of them. At the same time he reviewed sometwenty cases reported in the literature, and some ofthese were infants with jaundice, and may have beenassociated with icterusgravis neonatorum.In the literature of icterus gravis there are reports

referrg to obstructive jaundice in newly-borninfants being due to inspissated bile within the largerbile ducts (Skelton and Tovey, 1945; Davidsohn,1945; Ladd, 1935). Moreover, in certain instansurgeons have claimed to have dislodged the

obstructing masses bymanipulation, but could hardlyhave been sure of their nature; therefore thetendency to formation of bile-pigment stones in thistype of haemolytic disease, as in acholuric jaundice,is of interest. Perhaps after a phase of intrahepaticobstruction with bile plugs within the finer branchesof the bile ducts, these plugs become dislodged andpass into the larger bile ducts and form concretionsthere. Such a mechanism may be responsible incertain cases of prolonged obstructive jaundice inassociation with erythroblastosis foetalis. There is,however, another mechanism.

B. Cbosis caangaepatic ObstrctionCase 4. G. B., a female, aged seven weeks, came

under the care ofDr. Donald Paterson at the Hospitalfor Sick Children, Great Ormond Street, London.This was a third child, one having had erythro-blastosis and being alive and well, and one havingdied from erythroblastosis and pneumonia. Thepatient had jaundice from birth, and was Rh-positive;the mother was Rh-negative, with Rh antibody,titre 1 in 8; the father was homozygous Rh1Rh,.An Rh-negative blood transfusion, 120 c.cm., wasgiven when the child was four days old. Haemo-globin was 98 per cent. before transfusion anddropped to 66 per cent. at 15 days. There wasincreasing abdominal swelling from the sixth week oflife. When admitted to hospitaL the child had aswollen abdomen and cyanosis. She was jaundiced,with faint heart sounds and fluid in the abdomen.Red blood cells were 3,540,000 per c.mm., no nor-moblasts. Yellowish fluid (150 c.cm.) was with-drawn, and subsequently an uneven liver palpated.Another Rh-negative blood transfusion of 70 c.cm.was given, but the infant died three days afteradmission.At necropsy there was a good deal of clear yellow

fiee fluid in the abdominal cavity. The liver waslarge, firm, and greenish-brown, the surface finelygranular. Cross section suggested fibrosis. Theliver showed marked fatty degeneration and disinte-gration of liver cells, with perilobular and multi-cellular cirrhosis. There were many bile thrombiwithin the intercellular canaiculi, normal bile ductepithelium, and no evidence of erythropoiesis (figs. 4to 7).CommENT. This was a case of Rh iso-imm a-

tion with obstructive jaundice of seven weeks'standing, showing cirrhosis of the liver at necropsywith evidence of intrahepatic bile duct obstruction.

Case 5. M. C., a male full-term baby, weighing7 lb. 14 oz. at birth, left the maternity department ofa London hospital on the twelfth day, weighing 7 lb.8 oz., with no abnormal phys signs. He wasreadmitted to the hospital at six weeks because hehad not gained weight since birth. We could notobtain any history of neonatal jaundice from themother, but the Rh serology was investigated.The baby was Rh-positive, the father homozygousRhbRhl, and the mother Rh-negative, with weakanti-Rh agglutinins in serum, titre i in 1-butnone were present in her milk. At eleven weeks thebaby was noticed to be very pale, and a blood countgave the following results: red blood cells 2,540,000per c-mm.; haemoglobin 46 per cent.; colour index0-92. The weight was 9 lb. 10 oz. He was given an

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FIG. I-Liver, case 3, showing four pigment stonesin dilated common bile duct and cystic duct.(Natural size.)

FIG. 2.-Microphotograph of liver, case 3, showingnorml liver pattern and a large portal systemwith increase in collagen. Stained by vanGieo. (x go.)

FIG. 3.-Microphotograph of liver, case 3, showingincrease in reticulin in portal systems. Silverimpregnation stain. (x 60.)

VIYWW0N

FIG. 3.

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FIG. 4.-Microphotograph of liver, case 4, showing earlyperilobular ciThois and many intercellular bilethrombi. Stained by van Gieson. (x 60.)

FIG. 6.-Microphotograph of liver, case 4, showing vacuo-lation (fatty degeneration) and necrosis of livercells. Many intercellular bile thrombi are present.Stained by haematoxylin and eosin. (x 175.)

FIG. 5.-Microphotograph of liver, case 4, showingincrease and condeasation of reticulin, particularlyin perilobular areas. Silver impregnation stain.(x 60.)

FIG. 7.-Microphotograph of liver, case 4, showing abile duct with normal epithelium in a portal system,surrounded by disintegrated liver columns.

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FIG. 8.-Microphotograph of liver, case 5, showing earlyportal and perilobular cirrhosis, marked vacuolationof liver cells (fatty degeneration), and a number ofintercellular bile thrombi. Stained by van Gieson.(x 112.)

FIG. 10.-Microphotograph of liver, sibling of case 5,showing fibrous bands with round cell infiltration,surrounding large and small groups of liver cells.Stained by van Gieson. (x 60.)

FIG. 9.-Microphotograph of liver, case 5, showingincrease and condensation of reticulin in partalsystems and perilobular areas. Silver impregnationstain. (x 60.)

FIG. 11.-Microphotograph of liver, sibling of case 5,showing increase and condensation of reticulinfibres breaking up liver columns into large and smallcell groups. Silver impregnation stain. (x 60.)

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ARCHIVES OF DISEASE IN CHILDHOODiron mixture and did not attend the hospital for aboutsix weeks. At five and a half months he was ad-mitted to the Hospital for Sick Children, GreatOrmond Street, under Dr. B. Schlesinger. He wasconsiderably under weight, the liver was firm andenlarged two fingers' breadth below the costal margin.The spleen was not palpable, and there was nojaundice or oedema. Rh investigations of theformer hospital were confirmed. Red blood cellswere 4,650,000 per c.mm., and the serum, van denBergh, and Takata-Ara reactions were negative.Alkaline serum phosphatase was 24-9 units (normal10 to 20 units). The blood Wassermann reactionwas negative.

Three weeks after admission the baby developed asevere middle-ear infection, with diarrhoea andvomiting, jaundice, teleangiectases, and smallhaematemeses. and he died. At necropsy the liverwas three fingers' breadth below the costal margin,firm, with finely granular surface. The gall-bladderwas normal. The bile passages were patentthroughout. Histology of the liver showed earlyfibrosis, penrlobular, and also round small cellgroups.There was marked vacuolation of liver cells. Thebile duct epithelium was normal. A fair number ofbile plugs were found in the intercellular bilecanaliculi, and small bile globules in liver cells(figs. 8, 9).CoMMENT. This case of Rh iso-immuniza-

tion is of interest because at a late stage considerableanaemia developed. Jaundice was not discovered inthe early stages. At necropsy, cirrhosis of the liverwas found. Another point of interest is the familyhistory, and this is the main reason why the case isincluded in our series. Siblings were as follows:(1) a miscarriage in 1934; (2) a male child died atthree months of ? marasmus in 1935 (? history ofdropsy, no further details available); (3) a baby,born in 1939, died at ten weeks of cirrhosis of theliver; (4) the fourth child was the baby whose caseis described above.

HISTORY OF THE THIRD CHILD

The third child of this family, a female, wasjaundiced from the third day for a short time. Atseven weeks an obstructive phase of jaundicedeveloped and lasted eight days. A third phase ofjaundice developed at nine weeks, with diarrhoeaand blood-stained stools, and the infant was ad-mitted to the Hospital for Sick Children, GreatOrmond Street, London. Red blood cells were2,960,000 per c.mm., haemoglobin 60 per cent.,blood Wassermann reaction negative. A laparot-omy was performed, and a large quantity of freefluid removed. The liver was small and greenish-yellow, and the gall-bladder dilated. The bile ductswere apparently normal. Two days later the opera-tion findings were confirmed at necropsy. Histologyof the liver showed intense multicellular fibrosiswith numerous intercellular bile thrombi. Theepithelium of the bile ducts was normal.

This baby must have been Rh-positive, since herfather was homozygous Rh-positive. No test wasmade for Rh agglutinins in the mother's serum(in 1939) but it is reasonable to assume that the thirdinfant was a case of Rh iso-immunization, aswas the fourth child (case 5 above), and that this ledto liver cirrhosis in both cases. The intermittentobstructive jaundice is another interesting feature inthis case.

DiscussionThe fundamental work on iso-immunization in

erythroblastosis has taken us far on the road to fullunderstanding of this disease, but understandingwill not be complete until a number of clinical andpathological facts have been correlated. For in-stance, why should the clinical symptoms occasion-ally make their first appearance as late as the third orfourth week after birth? Why should the jaundicesometimes persist for several weeks or even months?In erythroblastosis the haematology has beenintensively studied, but the pathology of the liver hasreceived insufficient attention; haemopoiesis hasbeen generally noted, but little attention has beengiven to the changes which can often be seen in theliver cells. In early cases of icterus gravis, Hawksleyand Lightwood (1934) showed the possibility ofconsiderable necrosis in the polygonal cells, and thathepatic cirrhosis may follow at a later stage. Theseobservations were confirmed by Henderson (1942),who found even greater changes in stillborn ery-throblastic foetuses, and by Gilmour (1944).The condition of the bile ducts in erythroblastosis

has also received too little attention. On clinicalgrounds the jaundice has been regarded as purelyhaemolytic. In icterus gravis the stools are usuallywell-coloured and bile pigment is often excessive.Hawksley and Lightwood (1934) accepted thehaemolytic mechanism, but showed that there couldbe an evanescent obstructive phase as well. Thus itbecame necessary to recognize two mechanisms,haemolytic and obstructive (Ross and Waugh, 1936),and haemolysis is the factor chiefly concerned.

Biliary obstruction may occur at the height of thehaemolytic jaundice or may only appear two to fourweeks afterwards. The icterus is never whollyobstructive unless a late stage is reached. It is whenthe phase of obstruction is prolonged that confusionwith congenital obliteration of the bile ducts is likely(Lightwood, 1943). Both conditions may showclinical remissions. Anaemia is often present incases of atresia of the bile ducts, and we have seencounts of 3,000,000 red cells per c.mm.; in one case(M. S., see p. 2) the red count was 1.500,000 perc.mm. The presence or absence of bile in urine andstools are certainly not distinguishing features: wehave seen cases of icterus gravis in which stercobilinwas absent from stools. The alkaline serum phos-phatase may be of critical value. A normal valueis evidence against extrahepatic obstruction. Thedegree of rise in phosphatase does not, however, helpin differentiating intrahepatic from extrahepaticobstruction: we have seen values of some 40 unitsin atresia of the bile ducts, and of some 80 units incirrhosis ofthe liver with patent main bile ducts. Onthe other hand, low values may be found in cirrhosisand higher figures in atresia.The data in the present paper suggest that biliary

obstruction may appear as early as the first week incases of erythroblastosis. or later, and that, onceestablished, this type of icterus may continue forseveral months, or pursue a recurrent course.

In our fatal cases we have observed varving

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BILIARY OBSTRUCTION IN ICTERUS GRAVIS NEONATORUM 217

degrees of albuminous degeneration, fatty degenera-tion, and focal or diffuse necrosis of liver cells.Increase of reticulin was noted in all the fatal cases.In some it was most marked in the portal systems,which were enlarged. In other cases reticulin wasparticularly increased in the periphery of the lobules,but also around small groups of cells. Wherereticulin fibrils were condensed, they could be stainedwith van Gieson's mixture. We have deliberatelylooked for histological evidence to indicate that thelining epithelium of the bile ducts can be damaged orstructurally altered in icterus gravis, for example byan antigen-antibody reaction in the neighbourhood,or by stagnation of bile in their lumina. No suchevidence has been seen. In a few cases we havefound that the obstruction is extrahepatic throughthe presence of pigment stones in the larger ducts.

In icterus gravis, where there is prolonged biliaryobstruction, the clinical picture closely resemblescongenital atresia, and it is natural that a causalrelation has been suggested by more than oneobserver, but we have been unable to obtain anywholly satisfactory evidence of any such cause andeffect. Although there are records of suggestivecases, we find that the evidence to date does notindicate a true association.

While an obstructive jaundice persists, the prog-nosis remains in doubt though it is by no meansnecessarily bad. In favourable cases the jaundiceeventually clears, but in others cirrhosis occurs.Our findings in case 5 and sibling suggest another

etiological factor for familial cirrhosis of the liver.

SummaryThe first part of the paper contains a review of the

literature of cases of biliary atresia thought to becausally associated with icterus gravis neonatorum.In the light of Rh serology, no such associationappears to have been proved beyond doubt, thoughsome cases are highly suggestive. At any rate, Rh

iso-immunization would not appear to be a majoretiological factor in the pathogenesis of atresia ofbile ducts.

In the second part of the paper, specimen casesare reported illustrating the intermittent and thecontinuous obstructive type of jaundice occurringin icterus, gravis. This is followed by case andnecropsy reports indicating the pathology under-lying obstructive jaundice in icterus gravis: intra-hepatic obstruction due to liver-cell damage whichmay lead to cirrhosis of liver, or extrahepaticobstruction due to pigment stones in the main bileducts. The diagnosis between these two conditionsand atresia of the bile ducts is discussed.

We wish to acknowledge the kindness of thoseat the Hospital for Sick Children, Great OrmondStreet, who have helped in the investigations of thematerial published in this paper, in particular ofMr. V. C. Conlay, A.I.M.L.T., who has beenresponsible for the histological preparations. Weare also indebted to Mr. E. V. Willmott, A.R.P.S.,for the microphotographs.

REFERENCES

Davidsohn, I. (1945). J. Amer. med. Ass., 127, 633.Gilmour, J. R. (1944). Arch. Dis. Childh., 19, 1.Hawksley, J. C., and Lightwood, R. (1934). Quart. J.

Med. N.S., 3, 155.Henderson, J. L. (1942). Arch. Dis. Childh., 17, 49.Ladd, W. E. (1935). Ann. Surg., 102, 742.Lightwood, R. (1943). Arch. Dis. Childh., 18, 156.MacClure, E. (1931). Z. Kinderheilk., 51, 86.Pasachoff, H.D. (1935). Amer. J. Dis. Child., 50, 1.084.Ross, S. G. and Waugh, T. R. (1936). Ibid., 51, 1,059.Sanford, H. N. (1940). The Neu International Clinics:

Vol. 2. New series three; p. 159, and privatecommunication.

Skelton, M. O., and Tovey, G. H. (1945). Brit. med. J.,2, 914.

Still, G. F. (1927). Common Disorders and Diseases ofChildhood. 5th ed. Oxford University Press,p. 375. London.

(1899). Trans. Path. Soc. Lcnd.. 50, 151.

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