Wilson's disease: a common liver disorder? W. GRANT THOMPSON,* MD, FACP, FRCP[CI; P. ST. GEORGE HYSLOP, MD; R. BARR, MB, CH B, FRCP[C]; A. SASS-KORTSAK, MD, FRCP[C] In two sibships 7 of '24 sIblings were homozygous for Wilson's disease. in family A, the largest kindred of this recessively inherited disease thus far reported, the proband presented with chronic active hepatitis, one sibling died of cirrhosis, a second had clinical evidence of chronic liver disease and two others had biochemical and histologic changes in liver biopsy specimens. In family B the proband had cirrhosis and portal hypertension and one sibling had biochemical and histologic evidence of liver disease. All six living patients had low serum concentrations of cerulopiasmin and copper and a high 24-hour urinary excretion of copper, which was greatly increased by administration of D -panicillamine. Nona showed neurologic abnormalities and only one had Kayser-Fleischer rings (detectable only by slit-lamp examination). Each patient had an erythrocyte sedimentation rate (ESR) of 8 mm/h or less. After 3 and 2 years, respectively, of o-peniciiiamlne therapy the conditions of the two probands had Improved. Liver function became normal in three siblings, and no abnormalities developed in the remaining one. Thus, since Wilson's disease may present with chronic active hepatitis or cirrhosis with a normal ESR and without ocular or neurologic signs, It may be a more common cause of liver disease in young people than has been appreciated. Dans deux fratries 7 membres sur 24 ont 6te trouves homozygotes pour Ia maladie de Wilson. Chez Ia familie A, Ia plus nombreuse signai. A ce jour & porter cette maladie r6cessive h6r6ditaire, le propositus a pr6sente une h6patite chronique active, une soeur est morte de cirrhose, un autre membre a manifest6 des signes cliniques de maladie h.patique chronique et chez deux autres Ia biopsie du foie a montre des changements biochimiques et histologiques. Dans Ia famille B le From the gastroenterology unit, department of medicine, and department of laboratory medicine, Ottawa Civic Hospital and University of Ottawa; and department of pediatrics, Hospital for Sick Children, Toronto, and University of Toronto 6Address until Aug. 1, 1978: Department of medicine, Bristol Royal Infirmary, Bristol, England Reprint requests to: Dr. W.G. Thompson, Gastroenterology unit, 1st link, Ottawa Civic Hospital, 1053 Caning Ave., Ottawa, Ont. KlL 4E9
propositus souffrait de cirrhose et d'hypertension porte, et un autre membre montrait des signes biochimiques et histologiques daffection hepatique. Les patients vivants avaient tous des taux seriques falbies de ceruloplasmine et de cuivre et une excr6tion urinaire de 24 heures du cuivre elevee, laquelle a 6t6 fortement augmentee par l'administration de D -penicillamine. Aucun sujet n'a pr6sente de deficit neurologique et un seul etait porteur d'anneaux de Kayser.-. Fieischer (decelables seulement a i'examen a Ia lampe a fente). Tous les patients avalent une vitesse de s6dimentation des erythrocytes (VSE) de 8 mm/h ou moms. AprAs respectivement 3 et 21/2 ans de traitement a Ia D -peniciliamine i'6tat des deux propositus s'etalt am6iior6. Chez trois sujets Ia fonction h6patlque s'est normalisee et le dernier n'a pas d6velopp6 d'anomalie. Donc, puisque Ia maladle de Wilson peut se pr6senter sous Ia forme d'une hepatite chronique active ou d'une cirrhose, en pr6sence d'une VSE normale et sans manifestation oculaire ou neurologique, elle peut Atre une cause plus fr6quente qu'escompte d'h6patite chez les jeunes gens.
For estimations of serum copper and ceruloplasmin concentrations blood was taken with copper-free equipment and centrifuged, and the supernatant was frozen. For measurement of urine copper concentration urine was collected in copper-free equipment and an aliquot was frozen. The methods of estimation of ceruloplasmin and serum and urine copper concentrations have been described previously.4'5 The D-penicillamine-loading test was performed as follows:6 All the patient's urine was collected in copper-free equipment for 8 days. A single dose of approximately 0.58 g/m2 of r-penicillamine was administered by mouth at the beginning of day 4 and regular doses of 500 mg ql2h were begun on day 6. If the daily excretion of copper in the urine exceeded 1000 p.g after the single dose and after the regular treatment was begun, the test was considered positive. Liver specimens were obtained at autopsy or laparotomy, or by biopsy.
Wilson's disease, a disorder of copper metabolism characterized by copper overload and autosomal recessive inheritance, was originally described by Wilson,1 a neurologist, in 1912. Neurologic disturbances and Kayser-Fleischer rings have been emphasized as presenting features, but patients have also presented with chronic active hepatitis2 or cirrhosis.3 We have studied two large families in which seven persons had this disease. The lack of neurologic and ocular manifestations in these patients has led us to suspect that this affliction is not a rare cause of liver disease.
Family A Proband, patient 4: A 17-year-old girl was healthy until August 1973, when, after an adjustment of her birth control medication, she noticed her ankles were swollen; the medication was discontinued. Subsequently diarrhea, lethargy and distaste for cigarettes developed but her appetite remained normal. In October 1973 she consulted her physician because of amenorrhea, and jaundice was noted. She was admitted to Ottawa Civic Hospital Oct. 28, 1973, where scieral icterus was detected but not spider nevi or palmar erythema. The liver was not palpable and percussion showed it to be small. There was no ascites, but 2+ pitting edema was noted in the ankles. Neurologic examination yielded negative results. Hemoglobin value was 10.6 g/dL; reticulocyte count, 7.2%; and ESR, 2 mm/h. Serum values were as follows: SGOT, 115 lU/L; total bilirubin, 2.3 mg/dL (direct value, 0.8 mg/dL); alkaline phosphatase, 90 lU/L: and albumin, 1.8 g/dL. Prothrombin time was 20.2 s and lupus erythematosus cell preparation was negative. Serum protein electrophoresis demonstrated normal globulins, and testing for hepatitis B antigen yielded negative results. A clinical diagnosis of chronic active hepatitis was made. A liver biopsy was not done because of the prolonged pro-
Methods Metabolic studies were conducted at the Ottawa Civic Hospital or the Hospital for Sick Children in Toronto. Hemoglobin concentration and leukocyte count were determined with the Coulter Counter and the erythrocyte sedimentation rate (ESR) was measured by the method of Wintrobe. Serum concentrations of glutamic oxaloacetic transaminase (SGOT), bilirubin, alkaline phosphatase and albumin were measured by an autoanalyser.
Results Pertinent laboratory findings are summarized in Table I.
Case reports
CMA JOURNAL/JULY 9, 1977/VOL. 117 45
Table I.Data* for seven patients with Wilson's disease
Patient no. Family A
Serum Serum 24-h urine copper (.&g) Age at SGOT. copper ceruloplasmin presentation Reticulocytes ESRt (lU/I) (.g/dL) (mg/dL) Basal After penicillamine (yr) (%) (mm/h) (
propositus souffrait de cirrhose et d'hypertension porte, et un autre membre montrait des signes biochimiques et histologiques daffection hepatique. Les patients vivants avaient tous des taux seriques falbies de ceruloplasmine et de cuivre et une excr6tion urinaire de 24 heures du cuivre elevee, laquelle a 6t6 fortement augmentee par l'administration de D -penicillamine. Aucun sujet n'a pr6sente de deficit neurologique et un seul etait porteur d'anneaux de Kayser.-. Fieischer (decelables seulement a i'examen a Ia lampe a fente). Tous les patients avalent une vitesse de s6dimentation des erythrocytes (VSE) de 8 mm/h ou moms. AprAs respectivement 3 et 21/2 ans de traitement a Ia D -peniciliamine i'6tat des deux propositus s'etalt am6iior6. Chez trois sujets Ia fonction h6patlque s'est normalisee et le dernier n'a pas d6velopp6 d'anomalie. Donc, puisque Ia maladle de Wilson peut se pr6senter sous Ia forme d'une hepatite chronique active ou d'une cirrhose, en pr6sence d'une VSE normale et sans manifestation oculaire ou neurologique, elle peut Atre une cause plus fr6quente qu'escompte d'h6patite chez les jeunes gens.
For estimations of serum copper and ceruloplasmin concentrations blood was taken with copper-free equipment and centrifuged, and the supernatant was frozen. For measurement of urine copper concentration urine was collected in copper-free equipment and an aliquot was frozen. The methods of estimation of ceruloplasmin and serum and urine copper concentrations have been described previously.4'5 The D-penicillamine-loading test was performed as follows:6 All the patient's urine was collected in copper-free equipment for 8 days. A single dose of approximately 0.58 g/m2 of r-penicillamine was administered by mouth at the beginning of day 4 and regular doses of 500 mg ql2h were begun on day 6. If the daily excretion of copper in the urine exceeded 1000 p.g after the single dose and after the regular treatment was begun, the test was considered positive. Liver specimens were obtained at autopsy or laparotomy, or by biopsy.
Wilson's disease, a disorder of copper metabolism characterized by copper overload and autosomal recessive inheritance, was originally described by Wilson,1 a neurologist, in 1912. Neurologic disturbances and Kayser-Fleischer rings have been emphasized as presenting features, but patients have also presented with chronic active hepatitis2 or cirrhosis.3 We have studied two large families in which seven persons had this disease. The lack of neurologic and ocular manifestations in these patients has led us to suspect that this affliction is not a rare cause of liver disease.
Family A Proband, patient 4: A 17-year-old girl was healthy until August 1973, when, after an adjustment of her birth control medication, she noticed her ankles were swollen; the medication was discontinued. Subsequently diarrhea, lethargy and distaste for cigarettes developed but her appetite remained normal. In October 1973 she consulted her physician because of amenorrhea, and jaundice was noted. She was admitted to Ottawa Civic Hospital Oct. 28, 1973, where scieral icterus was detected but not spider nevi or palmar erythema. The liver was not palpable and percussion showed it to be small. There was no ascites, but 2+ pitting edema was noted in the ankles. Neurologic examination yielded negative results. Hemoglobin value was 10.6 g/dL; reticulocyte count, 7.2%; and ESR, 2 mm/h. Serum values were as follows: SGOT, 115 lU/L; total bilirubin, 2.3 mg/dL (direct value, 0.8 mg/dL); alkaline phosphatase, 90 lU/L: and albumin, 1.8 g/dL. Prothrombin time was 20.2 s and lupus erythematosus cell preparation was negative. Serum protein electrophoresis demonstrated normal globulins, and testing for hepatitis B antigen yielded negative results. A clinical diagnosis of chronic active hepatitis was made. A liver biopsy was not done because of the prolonged pro-
Methods Metabolic studies were conducted at the Ottawa Civic Hospital or the Hospital for Sick Children in Toronto. Hemoglobin concentration and leukocyte count were determined with the Coulter Counter and the erythrocyte sedimentation rate (ESR) was measured by the method of Wintrobe. Serum concentrations of glutamic oxaloacetic transaminase (SGOT), bilirubin, alkaline phosphatase and albumin were measured by an autoanalyser.
Results Pertinent laboratory findings are summarized in Table I.
Case reports
CMA JOURNAL/JULY 9, 1977/VOL. 117 45
Table I.Data* for seven patients with Wilson's disease
Patient no. Family A
Serum Serum 24-h urine copper (.&g) Age at SGOT. copper ceruloplasmin presentation Reticulocytes ESRt (lU/I) (.g/dL) (mg/dL) Basal After penicillamine (yr) (%) (mm/h) (
