å¡ CASE REPORT å¡ A Patient with Severe Iron-Deficiency Anemia and Memory Disturbance Toshiharu Anezaki, Katsuhiko Yanagisawa*, Katsuhiko Ibayashi** and Tadashi Miyatake* A 56-year-old woman presented with severe iron-deficiency anemia and memory distur bance. She had been in a state of severe iron deficiency for many years due to an unbalanced diet. Aerobic exercise test revealed an abnormal elevation of lactate and pyruvate reflecting mitochondrial dysfunction. After iron replacement therapy, WAIS verbal IQ score improved from 63 to 83, and levels of lactate and pyruvate on aerobic exercise test were normalized. We raise the possibility that severe and long-term iron deficiency anemia may cause memory disturbance due to mitochondrial dysfunction. (Internal Medicine 31: 1306-1309, 1992) Key words: mitochondrial dysfunction, aerobic exercise test
Intr o duction Iron is a heavy metal of biological importance not only as a component of hemoglobin but also as a constituent of enzymes of the electron transport system within mitochondria, in the form of heme in the cytochromes, and in the form of non-heme iron (1-3). It has become apparent that iron deficiency causes various systemic diseases with decreased concentration of mitochondrial cytochromes in tissues, as well as iron-deficiency anemia (IDA) (1-6). Recently it was reported that inhibition of cytochrome oxidase causes impairment of learning and We report a case of severe hippocampal plasticity (7).iron deficiency anemia in a patient who suffered from memory disturbance. She had been in the state of severe iron deficiency for many years due to an unbalanced diet. Aerobic exercise test revealed an abnormal elevation of lactate and pyruvate characteristic of mitochondrial dysfunction. The findings in the present case suggest that severe iron deficiency may cause memory disturbance due to hippocampal dysfunction arising from mitochondrial disorder. Case Report A 56-year-old right-handed woman with approximately a 40-year history of unbalanced diet was admitted to our
hospital for memory disturbance. She did not take any regular meals or drink milk, because of avoidance. After in the management of completion of junior high school, she helped her sister's grocery store. At 54 years of age, she was noted to make mistakes in the making of change and sometimes she could not remember whether she had received the money from the customer or not. These memory disturbances worsened slowly, and at 56 years of age, she was no longer able to work at the store. Her family noted personality change, she became stubborn and unconcerned with her appearance. She had not complained of general fatigue, dizziness or palpitation for the past 40 years. She was admitted to our hospital on September 14, 1990, because revealed her memory General physical examination thatdisturbance her height had progressed. was 153cm and weight 47.6kg. Her blood pressure was 114/70mmHg and pulse 72 per minute. Her skin was pale, and palpebral conjunctiva was markedly anemic. Furthermore, she had severe spoon nail. There was grade-2 systolic murmur at the apex, but there was no lymphadenopathy or hepatosplenomegaly. Neurological examination revealed that she was alert and cooperative. She had no cranial nerve palsy, pyramidal, extrapyramidal signs, cerebellar ataxia or muscle weakness. Neuropsychological status was evaluated using the Wechsler Adult Intelligence Score (WAIS),
From the Department of Neurology, Brain Research Institute, Niigata University, Niigata, *the Department of Neurology, Tokyo Medica Dental University, Tokyo, and **the Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata Received for publication March 24, 1992; Accepted for publication September ll, 1992 Reprint requests should be addressed to Dr. Toshiharu Anezaki, the Department of Neurology, Brain Research Institute, Niigata Univers 757, Ichiban-cho, Asahimachidohri, Niigata 951, Japan 1306
Internal
Medicine
Vol. 31, No. ll (November
1992)
IDA and Memory Disturbance Mini Mental State Examination (MMSE), Miyake's Memory Test (MMT), Raven's Coloured Progressive Matrices (RCPM) and other tests. These examinations revealed low intelligence; WAIS verbal IQ score was 63 (Fig. 1), and MMSE score was 15. She showed particularly severe impairment in memory function, but she had only slight disorientation as to time and place, and no other focal signs such as right-left disorientation, finger agnosia, color agnosia, visuo-spatial agnosia, or conFig. 1. WAIS verbal IQ scores before and after iron replacement. Her WAIS verbal IQ score increased from 63 to 83 after iron replacment. closed circles: before iron replacement, open circles: 80 days after iron replacement.
Fig. 2. Computed tomography of the brain showing cortical atrophy of the parieto-occipital lobes and mild dilatation of the temporal horn of the lateral ventricles suggesting atrophy of the hippocampus. Internal
Medicine
Vol. 31, No. ll (November
1992)
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Anezaki et al structional apraxia were noted. Hematological study revealed hypochromic microcytic anemia with a hemoglobin value of 4.3 g/dl, hematocrit of 19%, and red blood cell count of 3.31 x 106/ml. The white blood cell count was 2,900/ml with a normal differ ential count. Serum iron concentration was 6 /ig/dl, and ferritin was 1 ng/ml. Examination of bone marrow smears revealed granulocyte/erythrocyte ratio of 1.0; there was Blood chemistry findings were all within normal limits. erythroid hyperplasia, but no blasticwere cells as were observed. Serum vitamin (Vit.) concentrations follows: Vit.Bl, 4.7 /ig/dl (normal range; 1.5-6.0 jug/dl); Vit.B6, 2.5ng/ml (4.5-20.0ng/ml); Vit.B12, 290pg/ml (230 830pg/ml); and folic acid, 3.2ng/ml (2.3-6.5 ng/ml). Investigation of the etiology of IDA revealed no focus of chronic bleeding in the gastrointestinal tract or genitourinary tract. Intestinal malabsorption was ruled out, since the hemoglobin value was normalized after iron replacement therapy was begun (ferrous citrate sodium: lOOmg/day orally). Therefore, the IDA was apparentrytomography caused by the diet. maked Computed of iron-deficient the brain revealed cortical atrophy of the parieto-occipital lobe, and mild dilatation of the temporal horn of the lateral ventricle suggesting atrophy of the hippocampus (Fig. 2). Electro encephalographic findings were almost normal except for the few slow waves (6-7 Hz) at bilateral parietal lobes.
To evaluate the mitochondrial function, we measured serum lactate and pyruvate levels before and after exercise on a bicycle ergometer (15 watts, 15 minutes) (8). Her serum lactate and pyruvate levels were abnormally elevated after exercise, as occures in mitochondrial After encephalomyopathy 80 days of oral (Fig. iron therapy, 3). the hemoglobin concentration was normalized to 14.3 mg/dl and the red blood cell count increased to 5.26 x 106/ml. Furthermore, the levels of lactate and pyruvate during aerobic exercise test normalized (Fig. 3). At the same time, her WAIS verbal IQ score increased to 83, but the MMSE score remained unchanged. Discussion Although the present patient was diagnosed as having IDA and memory disturbance, the possibility of Alzheimer's disease was not completely ruled out. Her neurological deficit was mainly memory disturbance without other cognitive dysfunction. Furthermore, her neuropsychological disturbance was improved by replacement of iron. Therefore, her memory disturbance was thought to be caused by iron deficiency rather than by Alzheimer's Recently Bennettdisease. et al reported that the inhibition of cytochrome oxidase causes impairment of learning and
Fig. 3. Aerobic exercise test. Lactate and pyruvate concentrations in serum during minimal exercise on bicycle ergometer (at 15 watts for 15 minutes); before (closed circles) and 80 days after iron replacement therapy (open circles). 1308
Internal
Medicine
Vol. 31, No. ll (November
1992)
IDA and Memory Disturbance hippocampal plasticity in azide-treated rats (7). In the present case, the aerobic exercise test revealed abnormal elevations of lactate and pyruvate levels which were normalized by iron replacement therapy, suggesting that the patient had mitochondrial dysfunction (8, 9). From this evidence, one could speculate that the patient's memory disturbance was caused by dysfunction of mito It has become in recent years that iron de chondria in theevident hippocampus. ficiency causes impairment in psychomotor development of infants and children (10). Memory disturbance is not generally encountered in patients with IDA. However, in the present case, the degree of iron deficiency was severe and the duration of anemia was thought to be longer than 40 years. The findings in the present case indicate that severe and long-term IDA may cause memory disturbance due to mitochondrial dysfunction.
2) Beutler E. Iron enzyme in iron deficiency IV. Cytochrome oxidase in rat kindney and heart. Acta haematol 21: 371, 1959. 3) Beutler E, Blaisdell RK. Iron enzymes in iron deficiency III. Catalase in rat red cells and liver with some further observations on cytochrome C. J Lab Clin Med 52: 694, 1958. 4) Beutler E, Blaisdell RK. Iron enzyme in iron deficiency II. Catalase in human erythrocytes. J Clin Invest 37: 833, 1958. 5) Beulter E, Blaisdell RK. Iron enzymes in iron deficiency V. Succinic dehydrogenase in rat liver, kidney and heart. Blood 15: 30, 1960. 6) Dallman PR, Schwartz HC. Distribution of cytochrome C and myoglobin in rats with dietary iron deficiency. Pediatrics 35: 677, 1965. 7) Bennett MC, Diamond DM, Stryker SL, et al. Cytochrome oxidase inhibition impairs learning and hippocampal plasticity: implications for Alzheimer's disease. Neuroscience 16: 1346, 1990 (Abstract). 8) Ogasahara S, Nishikawa Y, Yorifuji S, et al. Treatment of Kearns-Sayre syndrome with coenzymes Q10. Neurology 36: 45,1986. 9) Kreisberg RA. Lactate homeostasis and lactic acidemia. Ann Intern Med 92: 227, 1980. 10) Walter T, Andraca I, Chadud P, Perales CG. Iron deficiency Referen ces anemia: adverse effects on infant psychomotor development. 1) Beutler E. Iron enzyme in iron deficiency I. Cytochrome C. Am Pediatrics J 84: 7, 1989. Med Sci 234: 517, 1957.
Internal
Medicine
Vol. 31, No. ll (November
1992)
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Intr o duction Iron is a heavy metal of biological importance not only as a component of hemoglobin but also as a constituent of enzymes of the electron transport system within mitochondria, in the form of heme in the cytochromes, and in the form of non-heme iron (1-3). It has become apparent that iron deficiency causes various systemic diseases with decreased concentration of mitochondrial cytochromes in tissues, as well as iron-deficiency anemia (IDA) (1-6). Recently it was reported that inhibition of cytochrome oxidase causes impairment of learning and We report a case of severe hippocampal plasticity (7).iron deficiency anemia in a patient who suffered from memory disturbance. She had been in the state of severe iron deficiency for many years due to an unbalanced diet. Aerobic exercise test revealed an abnormal elevation of lactate and pyruvate characteristic of mitochondrial dysfunction. The findings in the present case suggest that severe iron deficiency may cause memory disturbance due to hippocampal dysfunction arising from mitochondrial disorder. Case Report A 56-year-old right-handed woman with approximately a 40-year history of unbalanced diet was admitted to our
hospital for memory disturbance. She did not take any regular meals or drink milk, because of avoidance. After in the management of completion of junior high school, she helped her sister's grocery store. At 54 years of age, she was noted to make mistakes in the making of change and sometimes she could not remember whether she had received the money from the customer or not. These memory disturbances worsened slowly, and at 56 years of age, she was no longer able to work at the store. Her family noted personality change, she became stubborn and unconcerned with her appearance. She had not complained of general fatigue, dizziness or palpitation for the past 40 years. She was admitted to our hospital on September 14, 1990, because revealed her memory General physical examination thatdisturbance her height had progressed. was 153cm and weight 47.6kg. Her blood pressure was 114/70mmHg and pulse 72 per minute. Her skin was pale, and palpebral conjunctiva was markedly anemic. Furthermore, she had severe spoon nail. There was grade-2 systolic murmur at the apex, but there was no lymphadenopathy or hepatosplenomegaly. Neurological examination revealed that she was alert and cooperative. She had no cranial nerve palsy, pyramidal, extrapyramidal signs, cerebellar ataxia or muscle weakness. Neuropsychological status was evaluated using the Wechsler Adult Intelligence Score (WAIS),
From the Department of Neurology, Brain Research Institute, Niigata University, Niigata, *the Department of Neurology, Tokyo Medica Dental University, Tokyo, and **the Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata Received for publication March 24, 1992; Accepted for publication September ll, 1992 Reprint requests should be addressed to Dr. Toshiharu Anezaki, the Department of Neurology, Brain Research Institute, Niigata Univers 757, Ichiban-cho, Asahimachidohri, Niigata 951, Japan 1306
Internal
Medicine
Vol. 31, No. ll (November
1992)
IDA and Memory Disturbance Mini Mental State Examination (MMSE), Miyake's Memory Test (MMT), Raven's Coloured Progressive Matrices (RCPM) and other tests. These examinations revealed low intelligence; WAIS verbal IQ score was 63 (Fig. 1), and MMSE score was 15. She showed particularly severe impairment in memory function, but she had only slight disorientation as to time and place, and no other focal signs such as right-left disorientation, finger agnosia, color agnosia, visuo-spatial agnosia, or conFig. 1. WAIS verbal IQ scores before and after iron replacement. Her WAIS verbal IQ score increased from 63 to 83 after iron replacment. closed circles: before iron replacement, open circles: 80 days after iron replacement.
Fig. 2. Computed tomography of the brain showing cortical atrophy of the parieto-occipital lobes and mild dilatation of the temporal horn of the lateral ventricles suggesting atrophy of the hippocampus. Internal
Medicine
Vol. 31, No. ll (November
1992)
1307
Anezaki et al structional apraxia were noted. Hematological study revealed hypochromic microcytic anemia with a hemoglobin value of 4.3 g/dl, hematocrit of 19%, and red blood cell count of 3.31 x 106/ml. The white blood cell count was 2,900/ml with a normal differ ential count. Serum iron concentration was 6 /ig/dl, and ferritin was 1 ng/ml. Examination of bone marrow smears revealed granulocyte/erythrocyte ratio of 1.0; there was Blood chemistry findings were all within normal limits. erythroid hyperplasia, but no blasticwere cells as were observed. Serum vitamin (Vit.) concentrations follows: Vit.Bl, 4.7 /ig/dl (normal range; 1.5-6.0 jug/dl); Vit.B6, 2.5ng/ml (4.5-20.0ng/ml); Vit.B12, 290pg/ml (230 830pg/ml); and folic acid, 3.2ng/ml (2.3-6.5 ng/ml). Investigation of the etiology of IDA revealed no focus of chronic bleeding in the gastrointestinal tract or genitourinary tract. Intestinal malabsorption was ruled out, since the hemoglobin value was normalized after iron replacement therapy was begun (ferrous citrate sodium: lOOmg/day orally). Therefore, the IDA was apparentrytomography caused by the diet. maked Computed of iron-deficient the brain revealed cortical atrophy of the parieto-occipital lobe, and mild dilatation of the temporal horn of the lateral ventricle suggesting atrophy of the hippocampus (Fig. 2). Electro encephalographic findings were almost normal except for the few slow waves (6-7 Hz) at bilateral parietal lobes.
To evaluate the mitochondrial function, we measured serum lactate and pyruvate levels before and after exercise on a bicycle ergometer (15 watts, 15 minutes) (8). Her serum lactate and pyruvate levels were abnormally elevated after exercise, as occures in mitochondrial After encephalomyopathy 80 days of oral (Fig. iron therapy, 3). the hemoglobin concentration was normalized to 14.3 mg/dl and the red blood cell count increased to 5.26 x 106/ml. Furthermore, the levels of lactate and pyruvate during aerobic exercise test normalized (Fig. 3). At the same time, her WAIS verbal IQ score increased to 83, but the MMSE score remained unchanged. Discussion Although the present patient was diagnosed as having IDA and memory disturbance, the possibility of Alzheimer's disease was not completely ruled out. Her neurological deficit was mainly memory disturbance without other cognitive dysfunction. Furthermore, her neuropsychological disturbance was improved by replacement of iron. Therefore, her memory disturbance was thought to be caused by iron deficiency rather than by Alzheimer's Recently Bennettdisease. et al reported that the inhibition of cytochrome oxidase causes impairment of learning and
Fig. 3. Aerobic exercise test. Lactate and pyruvate concentrations in serum during minimal exercise on bicycle ergometer (at 15 watts for 15 minutes); before (closed circles) and 80 days after iron replacement therapy (open circles). 1308
Internal
Medicine
Vol. 31, No. ll (November
1992)
IDA and Memory Disturbance hippocampal plasticity in azide-treated rats (7). In the present case, the aerobic exercise test revealed abnormal elevations of lactate and pyruvate levels which were normalized by iron replacement therapy, suggesting that the patient had mitochondrial dysfunction (8, 9). From this evidence, one could speculate that the patient's memory disturbance was caused by dysfunction of mito It has become in recent years that iron de chondria in theevident hippocampus. ficiency causes impairment in psychomotor development of infants and children (10). Memory disturbance is not generally encountered in patients with IDA. However, in the present case, the degree of iron deficiency was severe and the duration of anemia was thought to be longer than 40 years. The findings in the present case indicate that severe and long-term IDA may cause memory disturbance due to mitochondrial dysfunction.
2) Beutler E. Iron enzyme in iron deficiency IV. Cytochrome oxidase in rat kindney and heart. Acta haematol 21: 371, 1959. 3) Beutler E, Blaisdell RK. Iron enzymes in iron deficiency III. Catalase in rat red cells and liver with some further observations on cytochrome C. J Lab Clin Med 52: 694, 1958. 4) Beutler E, Blaisdell RK. Iron enzyme in iron deficiency II. Catalase in human erythrocytes. J Clin Invest 37: 833, 1958. 5) Beulter E, Blaisdell RK. Iron enzymes in iron deficiency V. Succinic dehydrogenase in rat liver, kidney and heart. Blood 15: 30, 1960. 6) Dallman PR, Schwartz HC. Distribution of cytochrome C and myoglobin in rats with dietary iron deficiency. Pediatrics 35: 677, 1965. 7) Bennett MC, Diamond DM, Stryker SL, et al. Cytochrome oxidase inhibition impairs learning and hippocampal plasticity: implications for Alzheimer's disease. Neuroscience 16: 1346, 1990 (Abstract). 8) Ogasahara S, Nishikawa Y, Yorifuji S, et al. Treatment of Kearns-Sayre syndrome with coenzymes Q10. Neurology 36: 45,1986. 9) Kreisberg RA. Lactate homeostasis and lactic acidemia. Ann Intern Med 92: 227, 1980. 10) Walter T, Andraca I, Chadud P, Perales CG. Iron deficiency Referen ces anemia: adverse effects on infant psychomotor development. 1) Beutler E. Iron enzyme in iron deficiency I. Cytochrome C. Am Pediatrics J 84: 7, 1989. Med Sci 234: 517, 1957.
Internal
Medicine
Vol. 31, No. ll (November
1992)
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