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Hemolytic anemia associated with Wilson's disease
COMMENTS CURRENT
ON LITERATURE
Hemolytic anemia associated ;tb Wilson's disease I x 1 9 1 2 A neurologist in London, S. A. Kinnier Wilson, 1 first reported the disease which bears his name. He described the condition as a "progressive lenticular degeneration . . . a familial nervous disease associated with cirrhosis of the liver. ''1 Subsequently, the disease was shown to be related to an abnormality in copper metabolism, and in recent literature has been classified as an inborn error of metabolism, probably a deficiency in an enzyme-apoenzyme system. The hepatolenticular degeneration of Wilson's disease is thought to result from an inherent inability to synthesize the copperbinding serum protein, ceruloplasmin, with consequent accumulation of copper in the body, especially in the liver and in the brain. 2 Urinary excretion of copper is increased, and the level of copper in the plasma is decreased. Ceruloplasmin is described as an alpha2 globulin having oxidase activity, whose blue color is due to a copper content of 8 atoms per molecule. Normally this protein comprises approximately 0.5 per cent of the total serum proteins, about 30 my. of ceruloplasmin per 100 ml. of serum. In Wilson's disease there may be a marked reduction in the concentration of this copperbinding serum protein. As much as 60 to 80 per cent of the serum copper is no.t bound to ceruloplasmin, as compared with the situation in normal persons in whom only about 10 per cent of the copper is not protein bound. Although the exact mechanism is not entirely understood, it is thought that Vol. 71, No. 2, pp. 284-287
the increased concentration of loosely bound, nonceruloplasmin copper in the serum permits the accumulation of copper in the tissues, and results in the increased excretion of copper in the urine. Recent studies indicate that there is also an excessive absorption of copper from the gut. a In time the copper content increases in the cirrhotic liver and in the degenerating lenticular nucleus of the brain. Characteristically the degenerative process involves the basal ganglia. This deficiency in ceruloplasmin follows a familial pattern, and is thought to be inherited as a single gene autosomal recessive, with boys and girls affected equally. In many of the recorded instances there has been consanguinity among the parents, and a high incidence of the disease in collateral relatives. The heterozygous carrier of the gene can be detected by a special test which measures the rate of incorporation of Cu 64 into ceruloplasmin, when labeled cupric acetate or sulfate is given by mouth. Border-line deficiency in ceruloplasmin is revealed by such quantitative studies, a Three basic features comprise the clinical syndrome originally described by Wilson: extrapyramidal neurological symptoms, cirrhosis of the liver, and a Kayser-Fleischer ring in the cornea. The corneal defect, a brownish green ring at the periphery in the region of Descemet's membrane is seen in about three fourths of the patients. In one reported instance, 3 the patient sought medical advice because of difficulty in dark adaptation, and in this case the corneal ring was
Volume 71 Number 2
the only significant physical finding. Neither liver nor central nervous system damage was observed. In most instances the disease becomes apparent clinically in the latter part of childhood, marked by a rigidity of the skeletal musculature and by involuntary movements. There may be severe emotional instability and convulsive laughter without provocation. The facial expression is one of constant smiling; the speech becomes jerky and irregular. Although the involuntary movements may be of any type, tremors involving the upper extremities to a greater degree than the lower ones are characteristic. As a rule, the tremor is present at rest, but it is marked in associaton with voluntary movements. In infants and children the presenting symptoms may be those of hepatic disease, and in this age range the diagnosis of hepatolenticular degeneration is a possibility in unexplained cirrhosis. Subsequently the neurological changes appear. In older children, tremor may be the initial sign, and is often diagnostic in type. Since the symptom complex in this condition seems to result from copper accumulation in the body, therapy has been directed toward removal of the excess copper in an effort to arrest the progressive degeneration before irreversible damage occurs in the cerebral cortex and the basal ganglia. Several chelating agents 2, ~ have been used, notably British Anti-Lewisite (BAL) and Versene. ~ In some instances these agents have been combined with high protein intake and potassium sulfide, or a form of CarboResin after meals in an attempt to reduce the absorption of copper from the gut. In some patients the usefulness of BAL is limited by toxic manifestations and growing resistance. More recently the sulfhydryl amino acid, penicillamine (dimethyl cysteine, Cuprimine),t has been shown to be of value in the removal of copper. Penicillamine hydrochloride can be synthesized from penicillin, is stable in the reduced form, can be *Versene, Versenate, Dow Chemical Company. tMerck, Sharp, and Dohme.
C o m m e n t s on current literature
2 85
administered parenterally, is extremely soluble, and is excreted rapidly by the kidney. In some patients with Wilson's disease, remarkable improvement has followed its use. Since diet may be a contributing factor, it has been recommended that foods high in copper content should be avoided wherever possible. An informative study of Wilson's disease was published recently by a group of investigators in London? This study by McIntyre and his co-workers 4 deals with the occurrence of hemolytic anemia, particularly as the initial episode in children who later develop the characteristic neurological, psychiatric or hepatic forms of the disorder. Three cases are described, two in children and one in a young adult. The first case was that of a 12-year-old boy who had lassitude and recurrent abdominal pain for a period of four months. During the fourth month the pain increased in severity, jaundice developed, with dark urine but normal-colored stools. Physical examination at this time showed deep jaundice, bruised shins, mild generalized lymphadenopathy, and hepatosplenomegaly. The hemoglobin was 5.6 Gm. per 100 ml., and the reticulocyte count 45 per cent. Total serum bilirubin was 37.5 mg. per 100 ml. (conjugated, 20 mg. per 100 ml.); alkaline phosphatase was 2 King-Armstrong (K.A.) units, glutamic-pyruvic transaminase, 36 S.F. units, serum albumin, 26 Gm., and globulin, 2.6 Gm. per 100 ml. The possibility of hemolytic anemia was considered. However, there was no excess of fecal stercobilinogen, and careful investigation failed to reveal a cause for the hemolysis. Aseites developed which cleared rapidly with diuretic therapy; the jaundice cleared and the hemoglobin level improved. Three months later jaundice and ascites recurred, and the child was admitted to the Royal Free Hospital, London, for evaluation. On admission the jaundice and ascites were apparent but not marked. Kayser-Fleischer rings were confirmed by slit-lamp examination. A diagnosis of Wilson's disease was made, and copper studies were initiated.
286
Comments on current literature
Penicillamine therapy, 0.9 Gm. per day, was instituted and was continued. The hemoglobin and alkaline phosphatase rose, and the bilirubin level fell, but the general condition of the child declined. Hemolytic episodes recurred, and the hospital course was complicated by electrolyte problems, and fever associated with bacteremia. The child died 11 months following the initial episode. Postmortem examination showed the liver shrunken, macronodular, cirrhotic, with evidence of fibrotic changes in the pancreas. Analysis of liver tissue showed the copper content high. The second child, a boy 9 years of age, experienced a similar course, with recurrent abdominal pain, hepatomegaly, and ascites. Periods of epistaxis were frequent, and spider nevi were numerous, especially on the hands and face. There were no abnormal neurological signs. The hemoglobin was 9.2 Gm. per 100 ml., and the red cells were hypochromic. The total serum bilirubin was 3.0 mg. per 100 ml. (conjugated 1.3 mg.). No bilirubin was present in the urine. Gradual deterioration occurred, and the child was transferred to the Royal Free Hospital. On this admission the findings were essentially the same. Kayser-Fleischer rings were noted and confirmed. The hemoglobin had fallen to 6.6 Gm. per 100 ml., and the platelet count was 117,000. The total serum bilirubin was 5.0 mg. per 100 mt. (conjugated 3.5 rag.), and the alkaline phosphatase, 9 K.A. units per milliliter. The serum protein was 5.7 Gin. per 100 ml. (albumin 1.8 Gin., globulin, 3.9 Gm.). A diagnosis of Wilson's disease was made, but specific therapy was withheld because of the poor condition of the child. Diuretic therapy was introduced for increasing ascites, and the child received 500 ml. of packed ceils by transfusion. He died on the ninth hospital day; the chief findings at necropsy were micronodular cirrhosis, splenomegaly, and ascites. Copper content of the liver was 162 mg. per 100 Gm. of dry tissue. The third case described is that of a 21year-old woman who experienced episodes of jaundice with hepatosplenomegaly for a period of 4 years. There was persistent mild
The ]ournal o[ Pediatrics August 1967
hyperbilirubinemia, but no bilirubin in the urine. The hemoglobin fluctuated between 10 and 13 Gm. per 100 ml. Eventually severe ascites developed, and there were episodes of abnormal behavior. The speech became slurred. On admission to the hospital a diagnosis of Wilson's disease was made on the basis of corneal rings and blood serum levels of copper and ceruloplasmin. This patient made excellent progress on penicillamine therapy (0.9 Gm. daily); speech and behavior improved; liver and spleen decreased in size. After a period of therapy with good response, the dose of penicillamine was reduced to 0.9 Gm. once a week. However, this patient still experiences recurrent episodes at irregular intervals. At the time of the authors' report she was doing fairly well with no evidence of hemolysis. All three of the patients suffered from hepatolenticular degeneration with clinical and laboratory evidence of liver disease, with cirrhosis. All three showed corneal rings; in two of these patients the serum ceruloplasmin was low, and in all three the urinary copper output was high. Postmortem analysis showed high copper content of the liver in two of the patients. The association with hemolysis and anemia of sudden onset was definite in all three cases. Detailed copper analysis and hematological studies were carried out by the authors 4 in all three patients, and in two of them for a considerable period of time. The results suggest that "a flux of copper occurred during the period o.f hemolysis." During the acute hemolytic episodes large amounts of copper were excreted in the urine, in contrast with the normal excretion observed in three control patients, who had hemolytic crises but no evidence of Wilson's disease. 4 The authors 4 discuss the possible mechanism by which the hemolysis might occur; "... a mechanism analogous to that of enzootic jaundice in sheep" is considered by them to be the most likely explanation. Hemolytic anemia with recurrent acute episodes has been observed in sheep allowed to graze in pastures where the soil is rich in copper. The findings in sheep, particularly
Volume 71 Number 2
Comments on current literature
in the younger animals, are very similar to the authors' observations, who emphasize that especially in childhood and early adolescence the diagnosis of Wilson's disease should be considered a possibility in unexplained episodes of acute hemolysis. RUSSELL J. BLATTNER, M.D.
REFERENCES
1. Wilson, S. A. K.: Progressive lenticular degeneration: A familial nervous disease associ-
287
ated with cirrhosis of the liver, Brain 34: 295, 1912. 2. Blattner, R. J.: Chelating agents in the treatment of hepatolenticular degeneration (Wilson's disease), J. PEDIAT. 52: 758, 1958. See references. 3. Blattner, R. J.: Heterozygous carriers in Wilson's disease, J. PeDIAT. 59: 460, 1961. See references. 4. McIntyre, N., Clink, H. M., Levi, A. J., Cumings, J. N., and Sherlock, S.: Hemolytic anemia in Wilson's disease, New England J. Med. 276: 439, 1967.
ON LITERATURE
Hemolytic anemia associated ;tb Wilson's disease I x 1 9 1 2 A neurologist in London, S. A. Kinnier Wilson, 1 first reported the disease which bears his name. He described the condition as a "progressive lenticular degeneration . . . a familial nervous disease associated with cirrhosis of the liver. ''1 Subsequently, the disease was shown to be related to an abnormality in copper metabolism, and in recent literature has been classified as an inborn error of metabolism, probably a deficiency in an enzyme-apoenzyme system. The hepatolenticular degeneration of Wilson's disease is thought to result from an inherent inability to synthesize the copperbinding serum protein, ceruloplasmin, with consequent accumulation of copper in the body, especially in the liver and in the brain. 2 Urinary excretion of copper is increased, and the level of copper in the plasma is decreased. Ceruloplasmin is described as an alpha2 globulin having oxidase activity, whose blue color is due to a copper content of 8 atoms per molecule. Normally this protein comprises approximately 0.5 per cent of the total serum proteins, about 30 my. of ceruloplasmin per 100 ml. of serum. In Wilson's disease there may be a marked reduction in the concentration of this copperbinding serum protein. As much as 60 to 80 per cent of the serum copper is no.t bound to ceruloplasmin, as compared with the situation in normal persons in whom only about 10 per cent of the copper is not protein bound. Although the exact mechanism is not entirely understood, it is thought that Vol. 71, No. 2, pp. 284-287
the increased concentration of loosely bound, nonceruloplasmin copper in the serum permits the accumulation of copper in the tissues, and results in the increased excretion of copper in the urine. Recent studies indicate that there is also an excessive absorption of copper from the gut. a In time the copper content increases in the cirrhotic liver and in the degenerating lenticular nucleus of the brain. Characteristically the degenerative process involves the basal ganglia. This deficiency in ceruloplasmin follows a familial pattern, and is thought to be inherited as a single gene autosomal recessive, with boys and girls affected equally. In many of the recorded instances there has been consanguinity among the parents, and a high incidence of the disease in collateral relatives. The heterozygous carrier of the gene can be detected by a special test which measures the rate of incorporation of Cu 64 into ceruloplasmin, when labeled cupric acetate or sulfate is given by mouth. Border-line deficiency in ceruloplasmin is revealed by such quantitative studies, a Three basic features comprise the clinical syndrome originally described by Wilson: extrapyramidal neurological symptoms, cirrhosis of the liver, and a Kayser-Fleischer ring in the cornea. The corneal defect, a brownish green ring at the periphery in the region of Descemet's membrane is seen in about three fourths of the patients. In one reported instance, 3 the patient sought medical advice because of difficulty in dark adaptation, and in this case the corneal ring was
Volume 71 Number 2
the only significant physical finding. Neither liver nor central nervous system damage was observed. In most instances the disease becomes apparent clinically in the latter part of childhood, marked by a rigidity of the skeletal musculature and by involuntary movements. There may be severe emotional instability and convulsive laughter without provocation. The facial expression is one of constant smiling; the speech becomes jerky and irregular. Although the involuntary movements may be of any type, tremors involving the upper extremities to a greater degree than the lower ones are characteristic. As a rule, the tremor is present at rest, but it is marked in associaton with voluntary movements. In infants and children the presenting symptoms may be those of hepatic disease, and in this age range the diagnosis of hepatolenticular degeneration is a possibility in unexplained cirrhosis. Subsequently the neurological changes appear. In older children, tremor may be the initial sign, and is often diagnostic in type. Since the symptom complex in this condition seems to result from copper accumulation in the body, therapy has been directed toward removal of the excess copper in an effort to arrest the progressive degeneration before irreversible damage occurs in the cerebral cortex and the basal ganglia. Several chelating agents 2, ~ have been used, notably British Anti-Lewisite (BAL) and Versene. ~ In some instances these agents have been combined with high protein intake and potassium sulfide, or a form of CarboResin after meals in an attempt to reduce the absorption of copper from the gut. In some patients the usefulness of BAL is limited by toxic manifestations and growing resistance. More recently the sulfhydryl amino acid, penicillamine (dimethyl cysteine, Cuprimine),t has been shown to be of value in the removal of copper. Penicillamine hydrochloride can be synthesized from penicillin, is stable in the reduced form, can be *Versene, Versenate, Dow Chemical Company. tMerck, Sharp, and Dohme.
C o m m e n t s on current literature
2 85
administered parenterally, is extremely soluble, and is excreted rapidly by the kidney. In some patients with Wilson's disease, remarkable improvement has followed its use. Since diet may be a contributing factor, it has been recommended that foods high in copper content should be avoided wherever possible. An informative study of Wilson's disease was published recently by a group of investigators in London? This study by McIntyre and his co-workers 4 deals with the occurrence of hemolytic anemia, particularly as the initial episode in children who later develop the characteristic neurological, psychiatric or hepatic forms of the disorder. Three cases are described, two in children and one in a young adult. The first case was that of a 12-year-old boy who had lassitude and recurrent abdominal pain for a period of four months. During the fourth month the pain increased in severity, jaundice developed, with dark urine but normal-colored stools. Physical examination at this time showed deep jaundice, bruised shins, mild generalized lymphadenopathy, and hepatosplenomegaly. The hemoglobin was 5.6 Gm. per 100 ml., and the reticulocyte count 45 per cent. Total serum bilirubin was 37.5 mg. per 100 ml. (conjugated, 20 mg. per 100 ml.); alkaline phosphatase was 2 King-Armstrong (K.A.) units, glutamic-pyruvic transaminase, 36 S.F. units, serum albumin, 26 Gm., and globulin, 2.6 Gm. per 100 ml. The possibility of hemolytic anemia was considered. However, there was no excess of fecal stercobilinogen, and careful investigation failed to reveal a cause for the hemolysis. Aseites developed which cleared rapidly with diuretic therapy; the jaundice cleared and the hemoglobin level improved. Three months later jaundice and ascites recurred, and the child was admitted to the Royal Free Hospital, London, for evaluation. On admission the jaundice and ascites were apparent but not marked. Kayser-Fleischer rings were confirmed by slit-lamp examination. A diagnosis of Wilson's disease was made, and copper studies were initiated.
286
Comments on current literature
Penicillamine therapy, 0.9 Gm. per day, was instituted and was continued. The hemoglobin and alkaline phosphatase rose, and the bilirubin level fell, but the general condition of the child declined. Hemolytic episodes recurred, and the hospital course was complicated by electrolyte problems, and fever associated with bacteremia. The child died 11 months following the initial episode. Postmortem examination showed the liver shrunken, macronodular, cirrhotic, with evidence of fibrotic changes in the pancreas. Analysis of liver tissue showed the copper content high. The second child, a boy 9 years of age, experienced a similar course, with recurrent abdominal pain, hepatomegaly, and ascites. Periods of epistaxis were frequent, and spider nevi were numerous, especially on the hands and face. There were no abnormal neurological signs. The hemoglobin was 9.2 Gm. per 100 ml., and the red cells were hypochromic. The total serum bilirubin was 3.0 mg. per 100 ml. (conjugated 1.3 mg.). No bilirubin was present in the urine. Gradual deterioration occurred, and the child was transferred to the Royal Free Hospital. On this admission the findings were essentially the same. Kayser-Fleischer rings were noted and confirmed. The hemoglobin had fallen to 6.6 Gm. per 100 ml., and the platelet count was 117,000. The total serum bilirubin was 5.0 mg. per 100 mt. (conjugated 3.5 rag.), and the alkaline phosphatase, 9 K.A. units per milliliter. The serum protein was 5.7 Gin. per 100 ml. (albumin 1.8 Gin., globulin, 3.9 Gm.). A diagnosis of Wilson's disease was made, but specific therapy was withheld because of the poor condition of the child. Diuretic therapy was introduced for increasing ascites, and the child received 500 ml. of packed ceils by transfusion. He died on the ninth hospital day; the chief findings at necropsy were micronodular cirrhosis, splenomegaly, and ascites. Copper content of the liver was 162 mg. per 100 Gm. of dry tissue. The third case described is that of a 21year-old woman who experienced episodes of jaundice with hepatosplenomegaly for a period of 4 years. There was persistent mild
The ]ournal o[ Pediatrics August 1967
hyperbilirubinemia, but no bilirubin in the urine. The hemoglobin fluctuated between 10 and 13 Gm. per 100 ml. Eventually severe ascites developed, and there were episodes of abnormal behavior. The speech became slurred. On admission to the hospital a diagnosis of Wilson's disease was made on the basis of corneal rings and blood serum levels of copper and ceruloplasmin. This patient made excellent progress on penicillamine therapy (0.9 Gm. daily); speech and behavior improved; liver and spleen decreased in size. After a period of therapy with good response, the dose of penicillamine was reduced to 0.9 Gm. once a week. However, this patient still experiences recurrent episodes at irregular intervals. At the time of the authors' report she was doing fairly well with no evidence of hemolysis. All three of the patients suffered from hepatolenticular degeneration with clinical and laboratory evidence of liver disease, with cirrhosis. All three showed corneal rings; in two of these patients the serum ceruloplasmin was low, and in all three the urinary copper output was high. Postmortem analysis showed high copper content of the liver in two of the patients. The association with hemolysis and anemia of sudden onset was definite in all three cases. Detailed copper analysis and hematological studies were carried out by the authors 4 in all three patients, and in two of them for a considerable period of time. The results suggest that "a flux of copper occurred during the period o.f hemolysis." During the acute hemolytic episodes large amounts of copper were excreted in the urine, in contrast with the normal excretion observed in three control patients, who had hemolytic crises but no evidence of Wilson's disease. 4 The authors 4 discuss the possible mechanism by which the hemolysis might occur; "... a mechanism analogous to that of enzootic jaundice in sheep" is considered by them to be the most likely explanation. Hemolytic anemia with recurrent acute episodes has been observed in sheep allowed to graze in pastures where the soil is rich in copper. The findings in sheep, particularly
Volume 71 Number 2
Comments on current literature
in the younger animals, are very similar to the authors' observations, who emphasize that especially in childhood and early adolescence the diagnosis of Wilson's disease should be considered a possibility in unexplained episodes of acute hemolysis. RUSSELL J. BLATTNER, M.D.
REFERENCES
1. Wilson, S. A. K.: Progressive lenticular degeneration: A familial nervous disease associ-
287
ated with cirrhosis of the liver, Brain 34: 295, 1912. 2. Blattner, R. J.: Chelating agents in the treatment of hepatolenticular degeneration (Wilson's disease), J. PEDIAT. 52: 758, 1958. See references. 3. Blattner, R. J.: Heterozygous carriers in Wilson's disease, J. PeDIAT. 59: 460, 1961. See references. 4. McIntyre, N., Clink, H. M., Levi, A. J., Cumings, J. N., and Sherlock, S.: Hemolytic anemia in Wilson's disease, New England J. Med. 276: 439, 1967.