Gut, 1986, 27, 1377-1381

Wilson's disease: clinical presentation and use ofprognostic indexHISHAM NAZER, R J EDE, A P MOWAT, AND ROGER WILLIAMS

From the Department of Child Health and the Liver Unit, King's College Hospital and School of Medicineand Dentistry, Denmark Hill, London

SUMMARY As the results of treatment in Wilson's disease are so dependent on the stage at whichpenicillamine therapy is started, the antecedant history in 34 patients with Wilson's disease was

analysed with particular respect to the earliest manifestations of the disease. Lethargy andanorexia (70%) jaundice (56%) and abdominal pain (48%) were the commonest symptoms andless common were intellectual deterioration (22%) and recurrent epistaxes (22%). The durationof symptoms before diagnosis ranged from five days to three years (mean 10O5 months) and inonly five of the patients was the diagnosis established before referral. Analysis of the physicalsigns at presentation showed hepatomegaly (81%) and splenomegaly (70%) to be common andthe only signs which were significantly more common in the 13 fatal cases were jaundice andascites. In three of these and in one other patient who survived the clinical course was

exceptionally severe and was indistinguishable from fulminant hepatic failure. Based on theseverity of abnormality of serum aspartate aminotransferase, bilirubin, and prothrombin time on

admission a prognostic index was derived which enabled complete separation of fatal and non-

fatal cases and when subsequently used in a further nine index cases correctly predicted theoutcome. Two further cases found to have indices in the fatal category did well after livertransplantation, which needs to be considered as soon as the diagnosis is established in cases withsuch severe liver damage.

Initial symptoms in Wilson's disease are frequentlynon-specific and delay in diagnosis and institution ofpenicillamine therapy is all too common. This isparticularly important because once signs of hepaticfailure occur the response to chelation therapy isoften disappointing.' Indeed, episodes of jaundiceearlier in childhood are usually attributed to infec-tious hepatitis2 and the possibility of underlyingchronic liver disease is often overlooked. Whenpresentation is with the classical neurological fea-tures of tremor, dysarthria and dystonia there islittle difficulty in diagnosis but occasionally the onlyabnormality is a history of progressive intellectualdeterioration which may not be brought to medicalattention until a late stage. Similar delay in diagnosismay occur when presentation is with less commonmanifestations of the disease such as haemolyticanaemia,3 haematuria,4 amenorrhoea or musculo-skeletal involvement.5 Moreover, it is rare for thediagnosis to be made, except in siblings of probands,

Address for corrcspondence: Dr Roger Williams. Liver Unit. King's CollegeSchool of Medicine and Dentistry, Denmark Hill, London SE5 8RX. UK.

Received for publication 28 February 1986.

before significant liver or neurological damage hasoccurred.

In the present study we have retrospectivelyanalysed the clinical and biochemical features pre-sent at diagnosis in 27 index cases and in sevenasymptomatic siblings to determine which of thesymptoms and signs are present early and likely tobe overlooked. In addition we have attempted todefine laboratory features which might allow theidentification of patients with a poor prognosis atthe time of presentation who might be suitable forhepatic transplantation. A prognostic index basedon the abnormalities in liver function tests in theseindex cases has been applied prospectively in afurther 11 index cases and in two of these hepatictransplantation was subsequently performed.

Methods

PATIENTS

DIAGNOSIS OF WILSON'S DISEASE AND DERIVATIONOF PROGNOSTIC INDEXThirty four patients with Wilson's disease were seen

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in the Paediatric Department and Liver Unit of thishospital over the period January 1971 to August1982. Diagnosis was based on the following criteria:serum caeruloplasmin <0 2 g/l (normal range 0-2 to0-6 g/l) and/or urinary copper excretion >1.25,umol/24 h with an increased hepatic copper (>300,ug/g dry liver). Other causes of liver disease such aschronic active hepatitis, hepatitis B virus infection,and a1-antitrypsin deficiency were excluded byappropriate investigations.The severity of hepatic dysfunction on admission,

as evidenced by the prolongation in prothrombintime, aspartate transferase activity and serum bili-rubin was graded from 0-4 as shown in the Table. Aprognostic index based on the sum of these indi-vidual scores was calculated in all but one of theindex cases for whom the biochemical data onadmission was incomplete. Thus a maximum scoreof 12 was possible in those patients with the mostsevere derangement of liver function. This prognos-tic index was applied prospectively to a further 11

index cases admitted between August 1982 andApril 1985.

Results

The mean age at presentation was 15 years (range6-33 years) in the 27 symptomatic index cases (18male and nine female patients) and 10-5 years(range 6 months-21 years) in the seven asympto-matic siblings (five male and two female) of theprobands diagnosed by family screening. Thirteen(48%) of the index cases died between one and 53days of admission to this hospital, (five dying withinthe first five days of admission).The duration of symptoms before referral of the

27 index cases ranged from five days to three years(mean 10.5 months). Lethargy and anorexia (70%),jaundice (56%) and abdominal pain (48%) were themost common symptoms. A history of progressiveintellectual deterioration was obtained in six (22%)cases and the same number had a history ofrecurrent epistaxes. In three of the adult cases the

presenting symptoms were predominantly neurolo-gical with tremor of one or both hands. One of thesepatients had been transiently jaundiced two yearspreviously while another had had pain in the rightknee for six months due to chondromalacia patellae.The diagnosis of Wilson's disease had already

been made in two children before referral. One hadpresented with haemolytic anaemia while the otherwas found to have asymptomatic hepatosplenome-galy when examined during a respiratory tractinfection. The remaining 14 children (defined as ageless than 15 years) were referred when liver diseasewas suspected because of the appearance of jaun-dice in the previous one to six weeks (11 children) ora raised aspartate transaminase detected in theprevious two months (three children). In the lattergroup the initial features were a haemolytic anaemiastarting six months earlier in one, haematuria andmassive albuminuria of five months duration in thesecond, while the third patient had had malaise forfive years, growth failure for three years andepisodes of giddiness for one year. Of the 11

children referred with unexplained jaundice, fivehad been unwell for up to 18 months with lethargyand malaise but with the additional features ofdeteriorating school performance, abdominal pain,pallor, epistaxis, and fever each being present in onechild. Non-specific abodminal pain of up to sevenmonths duration was a dominant symptom inanother three children with pallor, fever, andvomiting each being an additional feature in onechild.

Non-specific malaise, nausea, vomiting, andabdominal pain were also presenting symptoms infive of the adult cases with unexplained jaundice andin three of these there was also a history of frequentepistaxes. In two adults and two of the 11 childrenwho presented with jaundice the clinical picture wasthat of fulminant hepatic failure, with rapid onset ofencephalopathy and death in three cases. The fourthcase, a 16 year old boy, had a previous history ofjaundice at the age of six years but had remainedwell until six weeks previously when he developed a

Table Derivation of prognostic index

Score (in points) 0 1 2 3 4

Serum bilirubin* ([LmolI1)(NR 3-20 [tmolI1) <M10 100-150 151-200 201-3(H) >300

Serum aspartate* transferase (IU/I)(NR 7-40 lU/I) <100 100-150 151-200 201-3()0 >3(X)

Prolongation int prothrombin time (s) <4 4-8 9-12 13-2) >30

*Determined by Technicon SMAC 11 system.tDetermined by one stage Quick test standardised to international normalised ratio.

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Wilson's disease: clinical presentation and use of prognostic index

frontal headache, diarrhoea, and lethargy but by thetime of admission he had deteriorated to grade IIencephalopathy.Of the physical signs recorded at the time of

diagnosis the most common were hepatomegaly(81%), splenomegaly (70%), Kayser-Fleischer ringsby slit-lamp examination (74%), jaundice (63%)and pallor (56%). Nearly half the patients haddetectable ascites (48%) while spider naevi werepresent in 30%. Jaundice and ascites were signifi-cantly more common in the fatal cases, occurring in92% and 85% respectively as compared with 29%and 14% of the survivors (p<0-001).

HAEMATOLOGICAL AND BIOCHEMICAI FINDINGSTen patients were anaemic (haemoglobin <10 gIdl)on admission while a further seven became anaemicduring admission. In four cases this was caused bygastrointestinal haemorrhage while in six cases itwas because of haemolysis with reticulocyte countsof up to 30%.

Biochemical evidence of liver disease was foundin all 27 cases. The serum bilirubin, aspartatetransaminase and prothrombin time (normal range12-13 seconds) at presentation were significantlymore abnormal in those cases that subsequentlydied, the mean±SD being respectively 506±456smol/l, 710±635 IU/I and 49±35 seconds prolonged

as compared with 50±62 ,tmol/l, 93+78 IU/I and4-6±3-2 seconds in the survivors (p<0-005, Wil-coxon's rank test). Use of the prognostic score in the26 index cases for whom complete data were

5- -

No of I.21

0

0 1 2 3 4 5 6 7 8 9 10 11 12Total score

Survivors Fatal cases

Fig. 1 Dotted lines represent the nine additionalprospective cases, five ofwhom died (cross-hatchedcolumns).

available and in the nine additional cases revealedthat all 17 cases with a score of six or less survivedwhereas the 18 patients with a score of seven ormore on admission died (Fig. 1). A further two caseswith scores of seven and eight received liver graftsand were therefore excluded from the analysis.Serum immunoglobulins were estimated in 19

patients and in every case one or more of the classeswas increased. Serum IgG was increased in 10patients (mean 24-2 g/l, range 15*6-36 g/l), IgA innine patients (mean 6-4 g/l, range 4-7-8.6 g/l) andIgM in 12 patients (mean 6-6 gil, range 2-4-9-3 g/l).Non-organ specific auto-antibodies (anti-nuclear,mitochondrial and smooth muscle), determined in17 cases, were found in only one patient with a titreof 1:40 to smooth muscle antibodies.Serum caeruloplasmin determined in 25 of the

index cases, was low in 21 (84%) cases, but normalin 4 (16%) (median 0-11 g/l, range 0-046 g/l).Urinary copper excretion was increased in 21 (81%)of the 26 patients in whom it was determined(median 12*2 ,umol/l, range 1-3-145 ,umol/l). Innone of the cases were both the serum caeruloplas-min and urinary copper excretion in the normalrange. Serum copper, determined in 25 patients wasnormal in 11, increased in three and decreased in 11.The hepatic copper concentration was increased inall 14 cases in which it was determined with amedian value of 681 [tg/g dry liver (range 333-1780[tg/g, normal value 15-55 ,ug/g). There was nosignificant difference in serum copper, serum caeru-loplasmin, urinary copper excretion, or hepaticcopper content between the fatal cases and thosewho survived.

Liver histology, obtained in 20 of the index cases,showed micronodular cirrhosis in 17, chronic activehepatitis with moderate piecemeal necrosis, portalinflammatory infiltrate and bridging fibrosis in one,and diffuse fatty infiltration with nuclear vacuola-tion in another. In seven patients liver biopsy wasnot carried out because of excessive prolongation ofprothrombin time.

ASYMPTOMATIC SIBLINGSSeven siblings (three from the same family) werefound to have Wilson's disease and their ages atdiagnosis ranged from 6 months-20 years (mean10-5 years). Hepatomegaly and Kayser-Fleischerrings were each detected in three patients whilesplenomegaly was detected in two. Biochemical testsof liver function were normal in all but one of theaffected siblings in whom the serum aspartateaminotransferase was 155 IU/l. In all seven patientshaemoglobin, while cell counts, and platelet countswere within the normal range. Serum caeruloplas-min was low in four and urinary copper increased in

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Nazer, Ede, Mowat, and Williams

six of the seven siblings. Percutaneous liver biopsy,done in four cases, showed minimal fatty changeswith portal fibrosis in two cases and normal liverarchitecture in the remaining two. The liver coppercontent was increased in all four cases, (median1180 ,ug/g, range 800-1550 [tg/g).

Six of the siblings have remained asymptomaticsince starting penicillamine therapy while theseventh developed Parkinsonian features and painin the left elbow and both hips three months afterstarting this treatment. Radiological investigation ofthe hips revealed new bone formation arising fromthe lesser trochanters (Fig. 2a). Trientine dihy-drochloride (TETA) was substituted for penicilla-mine and over the ensuing six months his symptomsslowly abated. A repeat radiograph eight monthslater showed considerable improvement with re-sorption and remodelling of the new bone (Fig. 2b).

Discussion

Although all 27 symptomatic cases showed some

features of hepatic involvement at diagnosis thesewere rarely the first symptoms of the disease.Careful clinical evaluation, which showed abnorma-lities in five of the seven asymptomatic siblings, andstandard biochemical testing of liver function mighthave led to earlier consideration of a liver disease.We had believed that the clinical and diagnosticfeatures of Wilson's disease were already wellknown but with only five cases having had thecorrect diagnosis made before referral and fourhaving documented haemolytic anaemia it is evidentthat the diagnosis is frequently overlooked. Particu-lar difficulty in diagnosis occurs in patients present-ing with fulminant hepatic failure in whom liverbiopsy is precluded and the serum caeruloplasmindoes not help in distinguishing Wilson's disease fromother causes of fulminant hepatic failure.6 Urinarycopper estimation may be helpful in such patientsprovided there is no renal failure. When caerulo-plasmin and urinary copper excretion are equivocaldetermination of tissue copper concentration willusually be diagnostic although final histological

Fig. 2 (a) New bone formation over the lesser trochanter ofthefemur during treatment with D-penicillamine. (b) Thesame bone eight months later (following substitution of TETA) showing resorption and remodelling ofthe new bone.

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Wilson's disease: clinical presentation and use of prognostic index 1381

confirmation may only be possible, once recoveryhas occurred or at necropsy (as in one case in thepresent series). Using this approach it was possibleto establish the correct diagnosis in every case in thisseries without recourse to expensive radioisotopeuptake studies.7 It is significant that Kayser-Fleischer rings, which are considered to be diagnos-tic in patients with a neurological presentation8 arefrequently absent in those presenting with hepatolo-gical features of the disease9 and in the presentseries were absent on slit-lamp examination in 26%of cases.The importance of screening the families of the

index cases is shown by the diagnosis of Wilson'sdisease in seven asymptomatic siblings who remainwell on long term chelation therapy. The case of the17 year old boy who developed pain and stiffness inboth hips within a few weeks of starting penicilla-mine is of particular interest. New bone formation isone of several skeletal abnormalities recognised inpatients with Wilson's disease. In one series'0 33 of38 cases showed some evidence of bony abnormalitywhich ranged from mild demineralisation in themajority to chondromalacia and osteoarthritis in 15patients. The cause of these skeletal abnormalities isunknown but does not appear to be related tocopper toxicity alone because copper loading inexperimental animals does not produce skeletalchanges. Golding and Walshe5 have suggested thatthese changes could be related to penicillaminetherapy and the subsequent resorption and remod-elling of the new bone during treatment with TETAappears to support this view. This chelating agentappears to be as effective as penicillamine inproducing cupuresis1 but it is expensive, experiencein its use is restricted, and supplies are limited. Asthe vast majority of patients are effectively treatedwith penicillamine, TETA should be used only inpatients who develop severe side effects of penicilla-mine. The use of oral zinc sulphate which has beenadvocated'2 13 as an alternative treatment warrantsfurther appraisal in our view.With regard to the prognosis in Wilson's disease

the presence of jaundice and ascites were the onlyclinical signs of prognostic value, being associatedwith a significantly higher mortality. Our prognosticindex based on the scoring of liver function tests onadmission, permitted complete separation betweenfatal cases and survivors and should thereforeenable the likely outcome to be predicted in newlydiagnosed cases, thus permitting earlier considera-tion of hepatic transplantation in those with a poorprognosis. Indeed, hepatic transplantation was suc-cessfully carried out in two such cases admitted to

the Liver Unit in whom the prognostic index wasseven and eight respectively (within the fatal range).Both these patients are alive and well havingsurvived for three and a half years and one yearrespectively from the time of liver grafting. A thirdcase with a prognostic index of seven died whileawaiting a suitable donor organ. As liver graftingcures the underlying biochemical defect, chelationtherapy is no longer necessary although lifelongimmunosuppression will be required. In contrast all17 patients with scores of six or less are nowasymptomatic with normal liver function tests afterthe institution of chelation therapy. Early considera-tion of the diagnosis of Wilson's disease in patientswith unexplained liver disease followed by promptand appropriate treatment should enable the highmortality from this condition to be reduced signifi-cantly.

References1 Nazer H, Ede RJ, Mowat AP, Williams R. Wilson's

disease in childhood: variability of clinical presenta-tion. Clin Paediatr 1983; 22: 755-7.

2 Silverberg M, Gellis SS. The liver in juvenile Wilson'sdisease. Paediatrics 1962; 30: 402-13.

3 McIntyre N, Clink HM, Levi AJ, Cumings JN,Sherlock S. Haemolytic anaemia in Wilson's disease. NEngi J Med 1967; 276: 439.

4 Pellett H, Gallard L, Monier D, Ruitton-Ugliengo.Maladie de Wilson's a debut trompeur. Hematurie puissyndrome d'hypertension portale. Pediatrie 1965; 20:472-3.

5 Golding DN, Walshe JM. Arthropathy of Wilson'sdisease. Study of clinical and radiological features in 32patients. Ann Rheum Dis 1977; 36: 99-111.

6 McCullough AJ, Fleming CR, Thistle JL et al. Diagno-sis of Wilson's disease presenting as fulminant hepaticfailure. Gastroenterology 1983; 84: 161-7.

7 Sternlieb I, Scheinberg IH. The role of radiocopper inthe diagnosis of Wilson's disease. Gastroenterology1979; 77: 138-42.

8 Scheinberg I, Sternlieb I. Wilson's disease. Phila-delphia. Saunders, 1984: 95.

9 Slovis TL, Dubois RS, Rodgerson DO et al. The variedmanifestations of Wilson's disease. J Pediatr 1971; 78:578-84.

10 Mindelzun R, Ekin M, Scheinberg IH, Sternleib I.Skeletal changes in Wilson's disease. A radiologicalstudy. Radiology 1970; 94: 127-32.

11 Walshe JM. Treatment of Wilson's disease with trien-tine (triethylene tetramine) dihydrochloride. Lancet1982; 1: 643-7.

12 Brewer GJ, Gretchen MH, Prasad AS et al. Oral zinctherapy for Wilson's disease. Ann Intern Med 1983; 99:314-20.

13 Deiss A. Treatment of Wilson's disease. Ann InternMed 1983; 99: 398-400.

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