Acute hemolytic anemia as a presenting manifestation of Wilson disease

Volume 86 Number 2

B r i e f clinical and laboratory observations

Acute hemolytic anemia as a presenting manifestation of Wilson disease George R. Buchanan, M.D., Boston, Mass.

I T HAS R E C E N T L Y BEEN D E M O N S T R A T E D t h a t a s e v e r e a c u t e h e m o l y t i c a n e m i a c a n o n rare o c c a s i o n b e a n early m a n i f e s t a t i o n o f W i l s o n disease ( h e p a t o l e n ticular degeneration).1-3 D e s c r i b e d in this r e p o r t are two p a t i e n t s , s e e n w i t h i n a 2 - m o n t h p e r i o d at t h e C h i l d r e n ' s H o s p i t a l M e d i c a l C e n t e r , w h o illustrate t h a t W i l s o n disease m u s t b e c o n s i d e r e d in t h e differential diagnosis o f a c u t e C o o m b s - n e g a t i v e h e m o l y t i c a n e m i a in p r e v i o u s l y well c h i l d r e n , e v e n in t h e a b s e n c e o f clinically o b v i o u s liver disease. CASE REPORTS Case 1. S. J. is a 10-year-old white girl who was well until one week after a measles immunization when she suddenly developed pallor, icterus, and dark urine. Two days later physical examination revealed pallor, mild jaundice, and a barely palpable liver and spleen (both 1 to 2 cm below the costal margins). The neurologic examination was normal and no Kayser-Fleischer rings were visible. Hematocrit values and reticulocyte counts during admission are outlined in Fig. 1. The red blood cell indices were normal except for a slight macrocytosis consistent with an elevated reticulocyte count, and red blood cell morphology was normal except for polychromasia and prominent basophilic stippling. White blood cell and platelet counts were normal. Results for the following tests were negative or normal: osmotic fragility, Heinz body preparation, heat denaturation for unstable hemoglobin, glucose-6-phosphate screen, hemoglobin electrophoresis, fetal hemoglobin determination, gamma and nongamma Coombs, cold agglutinins, and sucrosewater test. The plasma haptoglobin concentration was slightly reduced (26 mg/dl). Serum bilirubin concentration was initially 3.4 mg/dl total and 1.0 mg/dl direct, but within several days it reverted to normal. SGOT was 86 Karmen IU/ml, SGPT 54 IU/ ml, and LDH 143 IU/ml. Total concentration of serum proteins and serum alkaline phosphatase were normal. The compensated hemolytic episode lasted approximately a week (Fig. 1); no transfusions were required. After discharge with a diagnosis of hemolytic anemia of unknown etiology the laboratory value for ceruloplasmin returned markedly low (18% of normal, with From the Division o f Hematology-Oncology of the Department of Medicine, Children's Hospital Medical Center, and the Department of Pediatrics, Harvard Medical School Reprint address:Division of Hematology-Oncology, Children's HospitalMedical Center, 300 LongwoodA re, Boston, Mass. 02115.

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the normal range 56 to 164%). Slit-lamp examination of the cornea at this time revealed obvious Kayser-Fleischer rings; chelation therapy with penicillamine was promptly initiated. Urina~'y copper excretion patterns and liver biopsy confirmed t h e diagnosis of W i l s o n disease. T h e p a t i e n t r e m a i n s hematologically normal 6 m o n t h s later. Evaluation of the family revealed an asymptomatic 6-year-old sibling with Wilson disease. Case 2. E. M. is a previously well 13-year-old white boy who was admitted to a hospital with a 3-week history of malaise, anorexia, and pallor, and a 2-day history of icterus and dark urine. Physical examination revealed lethargy, jaundice, and mild hepatosplenomegaly. Kayser-Fleischer rings were not clearly evident on routine examination. Hematologic data, other than the hematocrit values and reticulocyte counts outlined in Fig. 1, included an initial leukocytosis with a normal differential and a normal platelet count. The prothrombin time and activated partial thromboplastin time were prolonged and failed to normalize after parenteral vitamin K. Red blood cell morphology was normal except for polychromasia, occasional target cells, and basophilic stippling. Serum haptoglobin concentration was a borderline low value (33 mg/dl). Serum Abbreviations used SGOT: serum glutamic oxaloacetic transaminase SGPT: serum glutamic pyruvic transaminase LDH: lactic dehYdrogenase bilirubin concentration was 12.3 mg/dl total with 6.8 mg/dl direct, SGOT 106 IU/ml, SGPT 31 IU/ml, LDH 152 IU/ml, and total concentration of serum proteins 6.6 gm/dl with reversal of the albumin to globulin ratio. The urine contained bile and glucose (despite a normal blood glucose level). In view of the experience gained from Case 1, Wilson disease was immediately suspected and the day after admission slit-lamp examination confirmed this diagnosis. The serum ceruloplasmin was 15% of normal and urinary copper excretion was markedly increased. Several transfusions of packed red blood cells were required and penicillamine therapy was begun. Over the course of the next 3 weeks signs of hemolysis abated. Four months after diagnosis and initiation of therapy he is hematologically normal. DISCUSSION W i l s o n disease, w h i c h ususally m a n i f e s t s itself with liver involvement or progressive neurologic dysf u n c t i o n , 4 c a n occasionally p r e s e n t as acute h e m o l y t i c a n e m i a , as t h e s e two p a t i e n t s d e m o n s t r a t e . It is hyp o t h e s i z e d t h a t in i n d i v i d u a l s with W i l s o n disease large q u a n t i t i e s o f hepatic c o p p e r are i n t e r m i t t e n t l y r e l e a s e d into t h e b l o o d s t r e a m , r e s u l t i n g in a t r a n s i e n t e l e v a t i o n o f e r y t h r o c y t i c a n d u r i n a r y c o p p e r a n d in a n a c u t e e p i s o d e o f h e m o l y s i s . 1, 2 W h e n t h e c o p p e r r e l e a s e c e a s e s , as it u s u a l l y d o e s w i t h i n a f e w d a y s , t h e h e m o l y s i s a b a t e s a n d w i t h i n s e v e r a l weeks t h e p a t i e n t

2 46

Brief clinical and laboratory observations

The Journal of Pediatrics February 1975

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Fig. 1. Course of the hematocrit values and reticulocyte counts of Case 1 and Case 2. becomes hematologically normal again. Such episodes may antedate clinical signs of significant liver disease (as in Case 1), sometimes by months o r even years. The hemolytic anemia of Wilson disease resembles t h a t o f a c u t e c o p p e r p o i s o n i n g in h u m a n s 6 a n d "enzootic disease" of sheep, a condition characterized by chronic copper poisoning and periodic hemolysis.7 A variety of pathophysiologic mechanisms have been proposed to explain effects of copper on the red blood cell,6 including inhibition of various red blood cell enzymes, 8 d i r e c t e r y t h r o c y t e m e m b r a n e d a m a g e r e s u l t i n g in reduced adenosine triphosphate utilization,9 and oxidative denaturation of hemoglobin with Heinz body formation. Many of the studies of effects of copper on red

blood cells, however, have been done with copper concentrations far in excess of those ever likely to occur in vivo. In these children the morphologic changes of red blood cells are nonspecific and standard diagnostic studies are nonrevealing. Since early diagnosis and prompt initiation of chelation therapy may prevent irreversible liver damage, s it is imperative that all children over 6 or 7 years of age who develop acute hemolytic anemia of obscure etiology be investigated for Wilson disease. Such investigations would include slit-lamp e x a m i n a t i o n of the c o r n e a for K a y s e r Fleischer rings, a complete set of liver function tests, and a serum ceruloplasmin determination. Other pro-

Volume 86 Number 2

B r i e f clinical and laboratory observations

c e d u r e s ( s e r u m , red b l o o d cell, a n d u r i n a r y c o p p e r levels, family studies, liver biopsy, a n d h e p a t i c c o p p e r m e a s u r e m e n t , etc.) w o u l d b e i n d i c a t e d in s e l e c t e d cases to c o n f i r m t h e diagnosis.

REFERENCES 1. Deiss A, Lee GR, and Cartwright GE: Hemolytic anemia in Wilson's disease, A n n Intern Med 73:413, 1970. 2. Melntyre N, Clink HM, Levi AJ, Cumings JN, and Sherlock S: Hemolytic anemia in Wilson's disease, N Engl J Med 276:439, 1967. 3. Slovis TL, Dubois RS, Rodgerson DO, and Silverman A: The varied manifestations of Wilson's disease, J PEDIATR 78:578, 1971. 4. Walshe JM: Wilson's disease. The presenting sYmptoms, Arch Dis Child 37:253, 1962.

Acute infantile hemiplegia with cerebrosp&al fluid eosinophilic pleocytos&: An unusual case of visceral larva migrans Donald C. Anderson, M.D.,* Robert Greenwood, M.D., Marvin Fishman, M.D., and Irving G.

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Deiss A, Lynch RE, Lee GR, and Cartwright GE: Longterm therapy of Wilson's disease, Ann Intern Med 75:57, 1971. 6. Oski F: Chickee, the copper, Ann Intern Med 73:485, 1970. 7, Cartwright GE, Hodges RE, Gubler CJ, Mahoney JP, Daum K, Wintrobe MM, and Bean WB: Studies on copper metabolism. XIII. Hepatolenticular degeneration, J Clin Invest 33:1487, 1954. 8. Boulard M, Blume L-G, and Beutler E: The effect of copper on red cell enzyme activities, J Clin Invest 51:459, 1972. 9. Feig SA, Segal GB, Shohet SB, and Nathan DG: Energy metabolism in human erythrocytes. II. Effects of glucose depletion, J Clin Invest 51:1547, 1972.

a c u t e h e m i p l e g i a in i n f a n c y a s s o c i a t e d w i t h C S F e o s i n o p h i l i c pleocytosis, p r e s u m a b l y d u e to a n ascarid infection.

CASE R E P O R T S. H. (SLCH No. 73-9294), an !8-month-old female, was admitted to St. Louis Children's Hospital because of a 3-day history of progressive weakness of her right arm and leg. There were no concomitant illnesses or symptoms. T h e patient's family lived on a farm with dogs, horses, chickens, swine, and rabbits and she had been noted to ingest soil on many occasions.

Kagan, Ph.D., St. Louis, Mo., and Atlanta, Ga.

VISCERAL LARVA M I G R A N S results f r o m i n v a s i o n o f human viscera by the larvae of nematodes which usually are parasitic in a n i m a l hosts a n d o c c u r s m o s t c o m m o n l y in c h i l d r e n following i n g e s t i o n o f soil c o n t a m i n a t e d with o v a o f t h e dog ascarid, Toxocara canis. 1,2 A n etiologic association b e t w e e n a n i m a l ascarid species o t h e r t h a n T. canis a n d V L M has b e e n s u g g e s t e d b u t n o t well d o c u m e n t e d . 2, 3 T h i s case r e p o r t w o u l d a p p e a r to s u p p o r t s u c h a n a s s o c i a t i o n a n d t h e o c c u r r e n c e o f a n From the Edward Mallinckrodt Department o f Pediatrics, Washington University School o f Medicine, the Divisions o f lnfectious Diseases and Neurology at St. Louis Children's Hospital and the Parasitology Division, Center for Disease Control Supported in part by the A llen P. and Josephine B. Green Foundation, Mexico, Missouri; and United States Public Health Service Grant No. 5TOINS05633-04. *Reprintaddress:Department of PediatricsDavid Grant Medical Center TravisAFB, Calif 94535.

Abbreviations used VLM: visceral larva migrans CSF: cerebrospinal fluid IHA: indirect hemagglutination BF: bentonite flocculation CNS: central nervous system

The child was a large obese female with weight, height, and head circumference measurements greater than the ninetieth percentile. Vital signs and general physical examination were normal except for signs of left otitis media. The child was irritable and spoke using single words. Her neurologic examination disclosed moderate weakness of her right arm and leg associated with increased deep tendon reflexes and an extensor plantar response. On admission her hemoglobin was 12.8 gm/dl, white blood cell count 17,400/mm 3 with 30% eosinophils, 15% neutrophils, and 53% lymphocytes. The total eosinophil count was 5,139/ m m J. No basophilic stippling was present. Results of serum electrolytes, blood urea nitrogen, glucose, and liver function tests were within normal limits. A chest radiograph demon-