460

JAUNDICEBy SHEILA SHERLOCK, M.D., F.R.C.P.

Department of Medicine, Postgraduate Medical School of London

Jaundice or icterus, is the yellow colouration ofthe skin by bile pigment. It is only clinicallyvisible when the serum bilirubin concentrationexceeds about 2 mg. per Ioo ml. and artificial lightadds considerably to the difficulty in detectingmild degrees. Since bile pigment has an affinityfor elastic tissue, skin, ocular sclera and bloodvessels which contain many elastic fibres becomeparticularly yellow.

Bilirubin is almost all derived from destructionof the haemoglobin of erythrocytes in the reticulo-endothelial cells of bone marrow, spleen andliver. Recent isotopic studies, however, haveshown that I0-15 per cent. is derived from somesource other than the haemoglobin of matureerythrocytes, and that this is possibly haematinor protoporphyrin (London et al., I950). Thebilirubin is transported to the liver attached tothe serum albumin (Klatskin and Bungards, 1956).Bile Pigments in SerumThe van den Bergh reaction has traditionally

been used to distinguish two types of bilirubin inserum, indirect (which has not passed through theliver cells) and direct (which has passed throughthe liver cells). Controversy has existed whetherthe different speeds of diazotization in the van denBergh reaction are due to two different pigments,to different attachments to serum proteins or tothe presence of a catalyst in the serum. Thedifferences do not depend on protein binding inthe serum for electrophoretic studies show thatdirect and indirect reacting pigments are bothattached mainly to albumin (Martin, 1948; Grayand Kekwick, 1948); neither can a catalyst bedemonstrated in the serum. The situation hasbeen clarified by the work of Cole, Lathe andBilling (I954) who used the technique of reversephase partition chromatography to demonstratethree pigments in jaundiced serum which areindependent of protein. One, bilirubin, corre-sponds to the pigment reacting indirectly in thevan den Bergh reaction; the other two, pigment Iand pigment 2, give a direct reaction. Furtherobservations by Bollman (1956) show that both

bilirubin and pigment i are present in the serumof the hepatectomized dog and hence are ofextra-hepatic origin. Billing (1955) has shownthat in obstructive jaundice and hepatitis theproportion of pigment i in the serum is greaterthan that of pigment 2 or bilirubin. She suggeststhat, in liver disease, in addition to obstructionpreventing excretion of pigment into the bilethere is also an impairment in conversion ofbilirubin to pigment i and of pigment i to pigment2. The practical significance of these observationshas yet to be clarified although in the future thebetter diagnosis of jaundice may follow themeasurement of the various bilirubin fractions.The bilirubin then passes through the paren-

chymal cells of the liver into the biliary passagesand so into the intestines. Andrews (I955) hasput forward an interesting new hypothesis of thesecretion of bile pigment by the liver. He suggeststhat pigment is first metabolized by the liver cellsbut that the enormous canalicular system in theliver not only transports bile pigment but alsoexcretes direct reacting bilirubin and alkalinephosphatase through its walls. This is by nomeans proved but, if it were so, some of theobscure instances of obstructive-type jaundiceoccurring with patent extrahepatic ducts mightbe explained. They could be functional distur-bances of the bile canaliculi analogous to func-tional disturbances of the renal tubules.

In the intestine the bilirubin undergoes bac-terial reduction by the intestinal flora to ster-cobilinogen which is colourless and then tostercobilin which is orange-yellow in colour(Watson et al., 1954). Some stercobilinogen isabsorbed from the intestines and re-excreted intothe bile. The very small quantity of absorbedstercobilinogen not re-excreted passes into thegeneral blood stream and is removed in the urineas urobilinogen and further reduced to urobilin(Fig. i).The van den Bergh reaction has little practical

diagnostic value. Although usually indirect inhaemolytic jaundice, a direct component is foundwhen the serum bilirubin level exceeds about

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October I956 SHERLOCK: Jaundice 461

RETICULOENDOTHELIAL VASCULAR COMPARTMENT LIVERSYSTEM _____

HAEMOGLOBINTO - BILIRUBIN- PROTEIN

BILIRUBIN 7 /_' BILIRUBIN

IN BILE

ENTERO-/HEPATIC ( 8TERCOBILINOGEN IN

KIDNEY /\ CIRCULATION INTESTINESOF'

NO BILIRUBIN STERCOBILI NOGEENUROBILINOGEN0-4 MG/DAY

STERCOBILINOGEN300 MG/DAY

'NORMAL BILE PIGMENT METABOLISMUROBILINOGEN AND STERCOBILINOGEN ARE CHEMICALLY IDENTICAL

FIG. I. By courtesy of Blackwell Scientific Publications Ltd., Oxford.

3 mgm./Ioo ml. and biphasic reactions also occurin both hepatocellular and obstructive jaundice.Types of Jaundice

Theoretically jaundice could arise in threeways, by increased breakdown of haemoglobin-haemolytic jaundice, by obstruction of the bilepassages-obstructive jaundice, and by failure ofthe liver cells to excrete bile-hepato-cellularjaundice. In practice, however, jaundice isusually of mixed type. In predominantly hae-molytic jaundice, for instance, there is a secondaryhepato-cellular component related to the anaemia.The jaundice of portal cirrhosis although mainlyhepato-cellular is contributed to by diminishedsurvival of erythrocytes. The jaundice of acutevirus hepatitis, although mainly hepato-cellular,is also due to intra-hepatic distortion and obstruc-tion of minute bile channels. Even jaundicefollowing total obstruction to the common bileduct soon acquires a lesser hepato-cellular com-ponent due to the secondary changes in the livercells when the bile ducts are obstructed. Theseconsiderations explain the frequent apparentfallibility of liver function tests and the clinicalanomalies which may add to the diagnosticconfusion.

TABLE I.CLASSIFICATION OF JAUNDICE

Hepato-cellularrserumAcute-virus hepatitis infectr e

Chronic-cirrhosis (portal or post-necrotic)ObstructiveWith extrahepatic carcinoma of the ampulla

obstruction choledocholithiasis, etc.rP.A.S.chlorpromazine

acute drugs. organic arsenicalsWithout extra- [ methyl testosterone

hepatic L~ butazolidineobstruction chronic ('primary biliary

cirrhosis ')malignant deposits in liver

Haemolytic congenitalacquiredN.B. Reticulosis

UraemiaCirrhosisBlood transfusion

Congenital hyperbilirubinaemia ± unidentified pigmentin liver cells.

Clinical Management of the JaundicedPatient

HistoryAntecedent dyspepsia or a previous attack of

biliary colic suggests choledocholithiasis. Pro-

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462 POSTGRADUATE MEDICAL JOURNAL October 1956

gressive failure of general health and weight lossfavours a carcinomatous aetiology. If the patienthas had any injection in the preceding six months,the diagnosis is serum hepatitis until disproved;injections include Mantoux testing, BCG vaccina-tion, tattooing, as well as blood or plasma trans-fusions. Absolute anorexia with aversion tosmoking suggests virus hepatitis. The rate of onsetof jaundice is important; in virus hepatitis thepatient becomes jaundiced rapidly, often in amatter of hours, and the colour quickly deepens.Obstructive jaundice is slower in its beginnings.Persistent mild fluctuant jaundice suggests portalcirrhosis or haemolytic jaundice and in thesepatients the stools are well coloured. Biliary colicshould be noted and the back or epigastric pain ofpancreatic carcinoma.

Examination (Table 2, Fig. 2)Anaemia and weight loss are noted, also the

depth of jaundice. A hunched-up position in bedsuggests pancreatic carcinoma. The skin should

PHYSICAL SIGNS IN JAUNDICE

Depth Jcm . .'Nut'iti'Xantheldsma o Anamia

^ .a Sig Primary TUouFetor Hepaticus- Lymphadenopathy

Uasculbr Spider 4'Purpuro d Hir

Scratch Mrk SpleenGall Bddr, ir Veinsliver : . Alcz/W itm

Xantlhomal

J. Noil wrhiteClubbed

Pigmentation - Oei·t'bd

FIG. 2.--Physical signs in the jaundiced patient.

be observed carefully. Bruising may indicate pro-thrombin deficiency, purpura, often axillary or onthe forearms, is not uncommon with the thrombo-cytopenia of portal cirrhosis. Other signs ofchronic hepato-cellular disease include vascularspiders, palmar erythema, white nails (Terry, I954),disappearance of secondary sexual hair and gyne-comastia. Parotid swellings and Dupuytrens con-tractures are often found in cirrhotic patients whoare alcoholic (Summerskill and Davidson, 1956).Scratch marks on the skin suggest obstructivejaundice and in chronic obstruction the patientmay show melanin pigmentation, clubbing of thefingers, xanthomata on eyelids, extensor surfacesand palmar creases with hyperkeratosis related tovitamin A lack. Pigmentation and ulcers on theshins are found in congenital haemolytic jaundice.Malignant deposits in the skin should be noted. Asearch is made for any primary growth.

TABLE 2

SIGNIFICANCE OF PHYSICAL SIGNS IN JAUNDICEExamination Significance

NutritionPoor 'Cirrhosis. Cancer.Obesity Gall-stones.

Anaemia Haemolysis. Cancer. Cirrhosis.Search Primary Tumour Lung, Breast, Stomach, Colon,

Thyroid, etc.Lymphadenopathy Cancer. Reticulosis.SkinDepth Jaundice Mild-Haemolytic. Green-

Prolonged obstruction.Vascular spiders Hepato-cellular jaundice.Melanosis Prolonged biliary obstruction.Xanthomata ,, ,, ,,Scratch marks Biliary obstruction.Bruises Prothrombin deficiency.Purpura ? Cirrhosis.Sexual hair Absent cirrhosis.Pigmented shins Congenital spherocytosis.Ankle oedema Cirrhosis. Inferior vena caval

obstruction.Tumour deposits Cancer.

HandsPalmar erythema Cirrhosis.Clubbing nails Biliary cirrhosis, portal

cirrhosis.White nails Cirrhosis.

Periumbilical veins Cirrhosis.Ascites Cirrhosis, cancer.LiverVery large Cancer. Obstructive jaundice.

Cirrhosis.Impalpable Cirrhosis. Fulminant hepatitis.Tender Hepatitis.

Splenomegaly Cirrhosis, Hepatitis, Haemo-lytic.

Gall-BladderPalpable Extra-hepatic biliary obstruc-

tion.Tender Cholecystitis.

Fetor Hepaticus Portal-systemic encephalo-fusin Tremor pathy (hepato-cellularExaggerated Reflexes jaundce).Exaggerated Reflexes

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October 1956 SHERLOCK: Jaundice 463

Abdominal examination includes noting thepresence of dilated abdominal wall veins sug-gesting a portal collateral circulation, ascites, liversize, tenderness and palpability of the gall bladderand splenomegaly.. Peripheral oedema is recorded.

Essential InvestigationsUrine. The most satisfactory sensitive tests for

bilirubin are the tablet test (Tallack and Sherlock,I954) or Fouchet's method. These are indicatedfor the early diagnosis of virus hepatitis and ofdrug jaundice, for instance, that complicatingchlorpromazine therapy. They may also be usedto screen liver function in workers exposed tohepatotoxins. Persistent absence of urobilinogensuggests total obstruction of the common bile duct.Persistent excess of urobilinogen with a negativebilirubin test supports a haemolytic jaundice.

Faeces. Persistent acholic stools confirm extra-hepatic biliary obstruction. The presence of apositive test for occult blood favours ampullarypancreatic carcinoma or may occur in the cirrhoticpatient with portal hypertension.

If a careful daily chart is kept of faecal colourand the presence of excess urinary urobilinogenmore elaborate investigations may prove un-necessary and many unnecessary laparotomieswould be avoided.

Serum Biochemical Tests. The essential mini-mum is the serum bilirubin and phosphatase levelsand one seroflocculation test. The serum bilirubinlevel confirms jaundice, assesses severity and isused to follow progress. Serum alkaline phos-phatase values over 30 King Armstrong units(greater than Io Bodansky units) strongly suggestbiliary obstruction if bone disease is not present.It must, however, be remembered that high valuessometimes occur in patients with portal cirrhosiswith but slight icterus. Among the numbers avail-able, the choice of seroflocculation tests is anindividual one. The zinc sulphate turbidity andthe thymol turbidity are a satisfactory combination.These tests, however, do not measure liver func-tion, but reflect mainly changes in the serumglobulins, and these correlate with activity of thereticulo-endothelial system. The seroflocculationtests are therefore liable to be positive in diseasessuch as malaria, infectious mononucleosis or rheu-matoid arthritis without indicating disease of theliver cells.

If possible, serum albumin and globulin levelsshould be measured quantitatively, although inacute jaundice, whatever the aetiology, they maybe little changed. In more chronic hepato-cellularaundice the depression in albumin and rise inglobulin is diagnostically useful. Electrophoreticanalysis of the serum is performed routinely inthe Chemical Pathology Department of the Post-

graduate Medical School and has proved of sur-prising value. The virtually normal serum albuminwith elevated aC globulins in obstructive jaundicecontrasts with the albumin depression and yglobulin elevation of hepato-cellular jaundice.

Haematology. A low total leukocyte count witha lymphocytosis suggests hepato-cellular jaundice,although in very severe virus hepatitis there maybe a leukocytosis with increased polymorpho-nuclears.

Radiology. A chest film is routinely taken toshow primary or secondary tumour. A plain filmof the abdomen may reveal hepatomegaly orsplenomegaly and o per cent. of gall stones areradio-opaque. A barium meal may show oeso-phageal varices and in patients with hepatomegalydue to cirrhosis or secondary cancer the lessercurve of the stomach may be displaced and evenrigid. Distortion and altered mobility of the duo-denum is seen in carcinoma of the pancreas.Cholecystography is contraindicated, for, evenwith theO newer contrast media, such as biligrafin,there is insufficient excretion of the dye into thebiliary track to give informative films.

Needle Liver Biopsy. This technique has sur-prisingly little place in the diagnosis of jaundice,being indicated in only 15 per cent. of patientswith this symptom. The technique has its greatestmorbidity in the icteric subject, especially if thejaundice is of hepato-cellular type. Prothrombintime must be normal before the puncture andblood must be ready for transfusion if there is com-plicating intraperitoneal haemorrhage. The hepatichistological pattern is characteristic in the threemain types of jaundice, but cannot be relied uponto distinguish obstructive jaundice due to extra-hepatic bile duct obstruction from that occurringwithout blocked main bile passages.Haemolytic Jaundice

Investigations should include careful familyhistory with haematological investigation of sib-lings if possible, haemoglobin level and absolutevalues, reticulocyte count, blood film for sphero-cytosis and immature cells, erythrocyte fragility,Coombs' test and bone marrow examination.Occasionally other investigations may be necessary,such as the measurement of the survival of trans-fused red cells and a quantitative estimation offaecal and urinary urobilinogen. Pigment gallstones may be associated, adding an obstructiveelement to the jaundice.The Place of Surgery

It should rarely, if ever, be necessary to resortto operation to diagnose the type of jaundice,although it may be necessary to elucidate the cause.If there is any doubt concerning the diagnosis, it

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464 POSTGRADUATE MEDICAL JOURNAL October 1956

is better to wait three weeks rather than explorethe bile passages of a patient with hepato-cellularjaundice and so run the very real risk of precipi-tating acute liver failure. The intervening periodis occupied by careful clinical observation, dailyexamination of urine and stools and weekly routinebiochemical tests. If there is still doubt, needlebiopsy is a usual preliminary to surgery. Thepatient rarely suffers from the delay. If the diag-nosis is virus hepatitis, he will probably be re-covering spontaneously; if cirrhosis, the diagnosisshould be obvious; and if obstructive, the changesoccurring in the liver are essentially reversible.Biliary cirrhosis will not develop in a matter ofweeks. If the diagnosis is carcinoma of the pan-creas or biliary ducts or metastatic carcinoma,chances of a radical removal are so remote thatthey are unlikely to be affected by the few weeks'delay. Jaundice is rarely a surgical emergency.When operation is indicated the exploration shouldbe thorough and, if any diagnostic doubt remains,should include operative liver biopsy and operativeor post-operative cholangiography.Medical TreatmentWhile the stools are acholic dietary fat should

be restricted. High protein intake is encouragedprovided the patient does not show the features ofimpending hepatic coma.

Itching is treated by phenol and calamine lotionsand by anti-histaminic drugs. If pruritus becomesintolerable, methyl testosterone, 25 mg. dailysublingually, may be given, although this has thedisadvantage of increasing the jaundice and causingmasculinizing features in women (Lloyd-Thomasand Sherlock, 1952). Prednisolone is also some-times effective. Hormone therapy should neverbe given for the transient pruritus associated withacute hepatitis.When infective cholangitis complicates obstruc-

tive jaundice it may be temporarily controlled bytetracycline therapy, although operative relief ofthe obstruction is essential for permanent cure.

Special Types ofJaundiceIt is clearly impossible to describe all the

various types of jaundice and examples have beenchosen where new developments are being made.

Jaundice in PregnancyThere is no specific pregnancy jaundice and

even in pre-eclampsia or eclampsia jaundice ismild and terminal. The common causes of jaun-dice in pregnancy are gall stones and virus hepa-titis. Choledocholithiasis is common, for the serumand biliary cholesterol levels rise in pregnancy andcyesis is associated with delayed gall bladderemptying. Virus hepatitis is contracted either

through needle punctures in the ante-natal clinicor by close contact with excreta of the patient'sother children. In spite of the traditional badprognosis of virus hepatitis in pregnancy, in mostinstances the attack does not differ from thatoccurring in the non-pregnant and the fulminantform (' acute yellow atrophy') is very rare. Thepatient should be supervised in hospital; termina-tion is usually contraindicated. Miscarriages oftenoccur (four out of 11 in one series) and the foetalmortality is considerable. Foetal abnormalitiesare unusual and neonatal hepatitis or cirrhosisdo not occur (Martini, 1953).Jaundice in Infancy

So-called 'physiological jaundice' is deepestand most prolonged in premature infants. It isfor the most part due to hepatic immaturity andis, therefore, hepato-cellular.

Haemolytic disease of the new-born is theTesult of Rhesus or A-B-O iso-immunization inthe mother. It is characterized by patechiae,hepato-splenomegaly and many primitive red cellsin the circulating blood.

In both the above conditions the pigment cir-culating is bilirubin (reacting indirectly in thevan den Bergh reaction), which is increased evento 40 mg./Ioo ml. These are the only types ofjaundice where this pigment achieves such levelsand this is presumably due to failure of the liverto convert to pigment 2. Bilirubin has an affinityfor nervous tissue, especially the basal ganglia, andis believed responsible for kernicterus, the mostdreaded complication of neonatal jaundice (Clair-eaux, Cole and Lathe, 1953). The height of theserum bilirubin is an important indication forexchange transfusion (Mollison and Cutbush,1949). The teeth become green, probably due totoxic action of bilirubin on the enameloblasts(Claireaux, Gerrard and Marsland, I955).

Congenital anomalies of the bile duct are rarecauses of neonatal jaundice. The extra-hepaticor intra-hepatic ducts may be affected. Jaundicedevelops within io days of birth and continuesunrelentlessly until death at age one to four years.Pruritus is troublesome and xanthomas maydevelop later. Few of these patients are relievedby surgery, although all should be explored.

Hepatitis is frequent in the new-born, and Gellis(i955) has collected 75 instances, including sevenfamilies in whom more than one child was affected.Jaundice may appear at birth or develop soon after-wards. The infant is unwell, does not take itsfeeds, may die rapidly with fulminant hepatitis orrecover after a mild illness. After a relapsingcourse the baby may make an apparent recoveryonly to appear in childhood with hepatic cirrhosisHepatic histology shows an acute hepatitis with

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October 1956 SHERLOCK: Jaundice 465

multinucleated liver cells, indicating rapid re-generation, foci of erythropoietic activity andhaemosiderosis (Dible et al., 954). It is thought,although not proved, that this condition is virushepatitis of serum type transmitted from themother. It is probably an important cause ofcirrhosis, not only in childhood, but also inadolescence and early adult life.The circulating bile pigment associated with

congenital lesions of the bile duct or neonatalhepatitis is mostly of the direct type, has no affinityfor nervous tissue, and kernicterus is a very rarecomplication.

Other rarer causes of neonatal jaundice includegalactosaemia and viraemia due to the herpes sim-plex virus. With the emergence of antibiotic-resistant staphylococci umbilical sepsis with mildjaundice is being encountered again.Drug JaundiceThere are four possible types of iatrogenic

jaundice. Serum hepatitis may be transmitted bythe syringe or needle with which the drug is given.Jaundice due to direct toxic action on liver cellsis extremely rare and the maximal damage pro-duced by drugs such as gold is usually on thekidney. Similarly, haemolytic jaundice due to suchdrugs as sulphonamides, phenylhydrazine or tobenzine derivatives is very uncommon. An ob-structive type of drug jaundice, however, is ex-tremely frequent (Johnson and Doenges, 1956).Drugs causing it include methyltestosterone,organic arsenicals (Hanger and Gutman, 1940),butazolidine, paramino-salicylate, thiouracil, di-nitrophenol and the most common is chlorpro-mazine and this will be described as the prototype.Chlorpromazine Jaundice

Jaundice occurred in I.4 per cent. of 7,599patients treated with the drug (Doughty, 1955).The jaundice appears in the second or third weekof therapy or may even start as long as two weeksafter stopping the drug. It is preceded by mildmalaise, fever, chills and nausea. Anorexia is not soconspicuous as with virus hepatitis. The tempera-ture may rise to iI0°. Hepatomegaly is inconstant.The jaundice is of obstructive type, with palestools, bilirubinuria, raised serum alkaline phos-phatase levels, negative seroflocculation tests andoften conspicuous itching. Needle biopsy of theliver shows only centrizonal bile retention with aminimal cellular increase in the portal zones witheosinophils conspicuous. The peripheral bloodsometimes shows an eosinophilia. The jaundice isusually mild and clears within two weeks of stop-ping the drug. Occasionally, however, it maypersist as long as six months, but with eventualrecovery. The only fatalities have been reported

Livercell -0

Canaliculus0 0

0holaniole Site of Lesion

I Bile

0 0

FIG. 3.-Diagram of the biliary system showing theprobable site of the lesion in chlorpromazinejaundice.

in patients with underlying chronic liver damage orwith a serious concomitant condition, such as car-cinoma or congestive heart failure.An allergic aetiology is supported by the eosino-

philia, but the drug has been exhibited again afterrecovery with no recurrence ofjaundice (Garmany,May and Folkson, I954).The site of the lesion seems to be in the cholan-

gioles (Fig. 3), but its nature is unknown. Strangu-lation by the slight exudate in the portal sinusseems unlikely, as does primary cholangitis. Ametabolic anomaly of the cholangiole similar toprimary tubular defects in the kidney is possiblebut not proved. Werner and co-workers (I950)suggested that methyl testosterone jaundice mightbe due to altered hydration of bile, excessive waterbeing reabsorbed in the canaliculi so that the bilebecomes very viscid and blocks the cholangiole.This again seems unlikely, for the number ofcanaliculi is so great that occlusion of a few bybile thrombi would not be sufficient to producejaundice.No special treatment is needed for this type of

jaundice. Every jaundiced patient, however, mustbe questioned about previous medication and, ifnecessary, confronted with chlorpromazine tabletsfor recognition. There is a real risk of thesepatients undergoing surgical operations. A similarpicture may sometimes be seen in some patientswith virus hepatitis or with Hodgkin's disease andalso lead to confusion with extra-hepatic biliaryobstruction.

Chronic Intra-hepatic Obstructive Jaundice(Primary Biliary Cirrhosis)This condition resembles chlorpromazine drug

jaundice in being of obstructive type without anextra-hepatic biliary obstruction being demon-

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466 POSTGRADUATE MEDICAL JOURNAL October I956strated. The site of obstruction is presumably inthe cholangioles. This is, however, a chronic,incurable disease and drugs have not so far beenincriminated in the aetiology. The condition ismore frequent in women (io to i). It is of gradualonset with mild jaundice and itching; hepato-splenomegaly is constant. Hepatic histology showsbile retention with a florid exudative lesion in theportal zones, which eventually develops to biliarycirrhosis. Serum cholesterol levels may rise veryhigh with the production of xanthomata (xantho-matous biliary cirrhosis). An important distinctionfrom extra-hepatic biliary obstruction is the absenceof bouts of cholangitis (rigors, fever, exacerbationsofjaundice and itching) and the condition is alwayspainless. Laparotomy with cholangiography isusually needed to prove patency of the extra-hepatic bile ducts. The-course is three to io yearsand complications include bleeding duodenalulcer, oesophageal varices, thinning of the bones(Atkinson et al., I956) and finally inter-currentinfection or liver cell failure with ascites andhepatic coma.

Treatment includes control of anaemia, calciumSandoz, 6 g. daily, and regular intramuscularvitamins A, D and K. Pruritus may needtreatment.

Symptomless JaundiceThe problem may arise of the patient who feels

well but is intermittently mildly jaundiced. Slightjaundice may continue for some months after virushepatitis without fibrosis in the liver (Hqlt, I950).Alternatively, the patient may have a true post-hepatitic cirrhosis. Choledocholithiasis is unlikelywithout symptoms. Congenital spherocytosis(acholuric jaundice) exists in all grades of severity,including the patient who notices only icterus fromtime to time and is never clinically anaemic. Thediagnosis in this latter group is made by familyhistory, splenomegaly, spherocytes in blood smear,reticulocytosis and diminished erythrocyte fragility.When the above conditions have been excluded,

there remains the congenital hyperbilirubinaemias(constitutional hepatic dysfunction). Jaundice,often with mild nausea and languor, occurs inter-mittently throughout life. This is the only physicalsign. Two types are recognized, depending on thepresence of excess pigment in the liver. Congenitalhyperbilirubinaemia with unidentified pigment inthe liver was described by Dubin and Johnson

(I954). The liver biopsy, naked eye, appears blackand, microscopically, the liver cells contain a non-iron, non-bile pigment allied to the lipochromes,but whose exact nature is unknown. This groupalso show a slightly raised serum alkaline phos-phatase level and the gall-bladder fails to fill oncholangiography. In addition, serum from thistype with pigment in the liver, in contrast to thatwithout, shows a high percentage of ' direct bili-rubin ' and bile appears in the urine. Investigationusually shows that serum bilirubin values areraised in relatives.

Patients with symptomless jaundice demand themost complete investigation and aspiration needlebiopsy is usually needed for accurate diagnosis.

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med. J., 2, 439.GELLIS, S. (1955), Personal communication.GRAY, C. H., and KEKWICK, R. A. (1948), Nature, I6I, 274.HANGER, F. M., and GUTMAN, A. B. (1940), J. Amer. med.

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44, 589.KLATSKIN, G., and BUNGARDS, L. (1956), J. clin. Invest.

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med. Y., 2, 1289.LONDON, I. M., WEST, R., SHEMIN, D., and RITTENBERG,D. (I95o), J. Biol. Chem., 184, 351.MARTIN, N. H. (1948), Biochem. J., 42, xv.MARTINI, G. A. (1953), Schweiz. Ztschr. f. Path. u Bakt., 16, 475.MOLLISON, P. L., and CUTBUSH, M. (1949), Brit. med. J.,

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