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CHRONIC HYPOXAEMIA AND DECOMPENSATED ERYTHROCYTOSIS IN CYANOTIC CONGENITAL HEART DISEASE
313
CHRONIC HYPOXAEMIA AND DECOMPENSATED ERYTHROCYTOSIS IN CYANOTIC CONGENITAL HEART DISEASE MICHAEL H. ROSOVE WILLIAM G. HOCKING MARY M. CANOBBIO
JOSEPH K. PERLOFF JOHN S. CHILD DAVID J. SKORTON
Divisions of Cardiology and Hematology-Oncology, Departments of Medicine and Pediatrics, and the Adult Congenital Heart Disease
Program, UCLA Center for the Health Sciences, Los Angeles,
California,
USA
Among forty adults with cyanotic congenital heart disease there was a subset of eleven patients with especially pronounced erythrocytosis, repeatedly rising haematocrit, recurring symptoms of hyperviscosity, and little or no shift of the haemoglobin/ oxygen-dissociation curve. These patients were iron deficient as a result of many therapeutic phlebotomies; nevertheless their red-cell mass was comparable to that in iron-replete patients with similar, but stable, haematocrits. Iron repletion in the deficient patients resulted in rapidly increasing haematocrit and hyperviscosity. In one extreme case, erythropoiesis remained persistently iron deficient despite normal serum iron and ferritin levels. "Decompensated erythrocytosis" is an apt term for the excessive erythrocytic response and the associated phenomena. Summary
Introduction CHRONIC hypoxaemia in cyanotic congenital heart disease results from the mixing of venous and arterial blood. Serum erythropoietin levels rise,1,2 with the result that the erythroid marrow becomes hyperplastic and red-cell mass and total blood volume increase.3-6 Up to a point, oxygen transport and delivery are moderately enhanced/-13 but erythrocytosis raises whole-blood Viscosity, 4 15 and eventually may cause symptoms requiring phlebotomy for relief. 16 We have identified a subset of patients with cyanotic congenital heart disease whose excessive erythroid response represents adaptive failure. Patients and Methods
Forty consecutive patients (eighteen male, twenty-two female) drawn from the UCLA adult congenital heart disease programme. All but two, whose whereabouts are unknown, are still being followed up. The median period of observation was 5-1 years-from first UCLA evaluation to the most recent reevaluation, corrective surgery (seven patients), or death (five). The median age at the start of the study was 29 years (15-53 years). No patient used supplemental oxygen. Venoarterial mixing was associated with pulmonary hypertensive vascular disease in twentywere
34 Andrianakos AA, Sharp JT, Person DA, Lidsky MD, Duffy J. Cell-mediated immunity m rheumatoid arthritis. Ann Rheum Dis 1977; 36: 13-20. 35. Young RA, Bloom BR, Grosskinsky CM, Ivanyi J, Thomas D, Davis RW. Dissection of Mycobacterium tuberculosis antigens using recombinant DNA. Proc Natl Acad Sci USA 1985; 82: 2583-87. 36. Cohen IR, Holoshitz J, Van Eden W, Frenkel A. T-lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum 1985; 28: 841-45. 37. Steinman L, Rosenbaum JT, Sriram S, McDevitt HO. In vivo effects of antibodies to immuneresponse gene products: prevention of experimental allergic encephalitis. Proc Natl Acad Sci USA 1981; 78: 7111-14. 38. Waldor MK, Sriram S, Hardy R, et al. Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker Science
1985; 227: 415-17. 39. Adelman NE, Watling DL, McDevitt HO. Treatment of (NZBxNZW) F1 disease with anti-I-A monoclonal antibodies. J Exp Med 1983; 158: 1350-55. 40 Wofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med 1985; 161: 378-91.
low pulmonary arterial pressure and Symptoms of hyperviscosity included fatigue, dyspnoea, myalgia, arthralgia, headache, paraesthesiae, faintness, dizziness, visual disturbances, abdominal pain, chest pain, and reduced mental activity. Blood counts and red-cell indices were measured by automatic methods (Coulter Electronics). Mean values for each patient were used to calculate group means. All data are expressed as mean ± SD. six patients and normal resistance in fourteen.
or
Results The
patients were segregated into two groups. Group I (decompensated) consisted of eleven patients with unstable haematocrits that rose repeatedly over time with development of symptoms of hyperviscosity. Phlebotomy for relief of symptoms was required regularly from twice a year to twice a month. All these patients were iron deficient (serum iron-binding capacity increased and < 15% saturated). Group II (compensated) consisted of twentynine patients with more stable haematocrits. Six of these patients required phlebotomy, but only rarely (three of them only once). None was iron deficient. The highest sustained . haematocrit level without symptoms of hyperviscosity was 70%. Haematological data for both groups are shown in table i. Pulmonary vascular disease was slightly but not .significantly more common in group I than group II-8/11 (73%) v 13/29 (45%). Red-cell mass measured by means of chromium-51 and plasma volume measured by means of iodine-131-labelled albumin were determined in thirteen patients with haematocrit levels 60%(table II). Red-cell mass and total blood volume (red-cell mass plus plasma volume) were similar in the two groups. There were no significant correlations between mean corpuscular volume and either red-cell mass or total blood volume (r, == — 0-05 and - 0-22, respectively). Haemoglobin P50 values (in vivo pH) in eleven patients with haematocrits > 60% (28-1 ±1-2 mm Hg) were similar to those in normal subjects (26 7 ±0 6 mm Hg). The mean values for groups I and II were similar (27-9 ±1-1mm Hg, n=5,28’4±l-3mmHg,n=6). Iron repletion with oral ferrous sulphate or intravenous iron-dextran was attempted in five group I patients (table III). The haematocrit rose promptly in each patient with the development of hyperviscosity symptoms that necessitated phlebotomy. Iron was continued for 47+9 days after development of hyperviscosity symptoms in three patients, who required a total of 8 additional phlebotomies TABLE I-HAEMATOLOGICAL DATA
TABLE II-RED-CELL MASS AND BLOOD VOLUME STUDIES
314 TABLE III-RESPONSES OF FIVE GROUP I PATIENTS TO IRON TREATMENT
*Of treatment until symptoms of hyperviscosity appeared. tAt time of hyperviscosity symptoms.
(9-0 ±1-7 ml/kg). The haematocrit could not be stabilised in any
patient.
separate study, one patient received oral ferrous sulphate and intravenous iron-dextran for 6 months. He In
a
required phlebotomy (12-8+3-2 ml/kg) frequently (every 12 6 ±70 days); the mean daily iron removed was 0-75 mg/kg. The haematocrit was 73-8 ±3-1%, the erythrocyte count 9-3 ±0-4 x 1012/1, the reticulocyte count 6-3 ±0-8%, and blood volume 124 ml/kg. Thus, the mean number of circulating reticulocytes was 72-7 x 109/kg, compared with 3-5 x 109/kg in a normal individual with haematocrit 45%, erythrocyte count 5-0 x 1012/1, reticulocyte count 1-0%, and blood volume 70 ml/kg. The patient’s bone-marrow aspirate was hypercellular, with virtually no fat and a myeloid to erythroid ratio of 1/3. Despite normal serum levels of iron (95 ± 30 ug/dl, 29-3 ± 6-7% saturation of binding capacity) and ferritin (78-448 ng/ml) at equilibrium, microcytosis (80-3 ±2-2 fl), hypochromia (29 8 ±0-5 g haemoglobin per dl erythrocytes), and raised erythrocyte protoporphyrin (95 we 14 ug/dl erythrocytes, normal < 50) persisted. Normal haemoglobin electrophoresis, reticulocyte ot/ 0-globinchain-synthesis ratio, and serum lead levels excluded thalassaemia and lead poisoning as causes of the high protoporphyrin levels. Thus, it appears that normal incorporation of iron into newly developing erythrocytes achieved. No patient in either group had a cerebrovascular accident during observation or before UCLA presentation. Two groupI and three group II patients died. Four deaths were sudden, and one was due to pneumonia. Necropsy was carried out in three patients; the brain showed scattered microinfarcts in one. Discussion
was
not
Erythrocytosis is an adaptation that occurs in response to hypoxaemia at high altitudes or intracardiac and pulmonary vascular right-to-left shunts and intrinsic lung disease. It also results from tissue hypoxia caused by abnormal haemoglobins with defective oxygen binding or release. Raising red-cell mass increases oxygen transport and delivery7-13 but excessive erythrocytosis has the associated problem of hyperviscosity. In excessive erythrocytosis, red-cell production is not controlled, and negative feedback inhibition does not seem to occur. "Decompensated erythrocytosis" is an appropriate term for this state. Erythrocytosis decompensates in some patients with cyanotic congenital heart disease, as in some individuals with chronic mountain sickness at high altitude.17 The position of the haemoglobin-oxygen dissociation curve
is
a
determinant of oxygen transport and delivery. In
with cyanotic congenital heart disease the curve is normal or slightly right-shifted. It is not clear why. The mechanism of arterial hypoxaemia in cyanotic congenital heart disease is not the same as that at high altitude (alveolar oxygen tension is near normal, and hypoxaemia results from venoarterial mixing), so the optimum curve position for cyanotic congenital heart disease may not be the same as that for high altitude. Nevertheless, fmdings at high altitude are at least contextually interesting, and possibly relevant. In a low-oxygen atmosphere, a left-shifted curve increases oxygen loading and thus transport. Animals that have evolved at high altitude, such as the llama and vicuna, have left-shifted curves and do not rely on erythrocytosis as an adaptation to hypoxia.18 Human beings with mutant
patients
high-oxygen-affmity haemoglobins perform exceptionally well at high altitudes.19 The implication is that a left-shifted curve improves tissue oxygen delivery under such conditions. The usual response of human beings to moderate altitude (a rightward shift caused by a rise in erythrocyte 2,3-diphosphoglycerate content) may thus be maladaptive. 19 At very high altitude,zo at least 4500 M, 21 a net leftward shift results from hyperventilation (Bohr effect) and might be physiologically desirable. Phlebotomy is often carried out in older children and adults with cyanotic congenital heart disease to relieve hyperviscosity symptoms or to reduce the perceived risk of cerebral infarction. Iron depletion inevitably follows phlebotomy with the result that erythrocyte haemoglobin concentration falls, microcytosis aggravates hyperviscosity,22,23 and exercise performance is impaired 2’ The drive to red-cell production remains intense, and irondepleted patients maintain very high blood volumes by producing enormous numbers of very small hypochromic cells. Iron repletion alone is seldom successful, because the haematocrit rises rapidly in response to iron, resulting in hyperviscosity. One of our patients represented the extreme of decompensation-refractory iron-deficient erythropoiesis. Serum iron is rate-limiting on haemoglobin production in experimentally induced anaemia when it is below 70 Ilgl dl in man2s or 150 pg/dl in rabbits.26 A "normal" serum iron level may not satisfy the requirements of the hyperplastic erythroid marrow associated with haemolysis27 or thalassaemia intermedia.28 This patient’s serum iron, although "normal" (95::!:: 30 ug/dl), similarly appeared insufficient to supply the greatly expanded pool of erythroid precursors, representing failure of the iron procurement and delivery system in an extreme case of erythroid hyperplasia induced by hypoxaemia. This work was supported by the Streisand/American Professorship and the Rosalind W. Alcott Endowment.
Heart Association
Correspondence should be addressed to M. H. R., Department of Medicine, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90024, USA. REFERENCES 1. Koeffler HP, Goldwasser E. Erythropoietin radioimmunoassay in
evaluating patients
with polycythemia. Ann Intern Med 1981; 94: 44-47. 2. Erslev AS, Caro J. Pure erythrocytosis classified according to erythropoietin titers. Am J Med 1984; 76: 57-61. 3. Lawrence JH, Berliner NI, Huff RL. The nature and treatment of polycythemia. Studies on 263 patients. Medicine 1953; 32: 323-88. 4. Verel D Blood volume changes in cyanotic congenital heart disease and polycythemia
rubra
Circulation 1961; 23: 749-53. A, Button LN, Nathan DG, Miettinen OS, Nadas AS. Blood volume changes m cyanotic congenital heart disease. Am J Cardiol 1971; 27: 162-67. Scott WS, Elliot SR, Clay RC. Blood volume in congenital cyanotic heart disease. simultaneous measurements with Evans blue and radioactive phosphorus. Bull Johns Hopkins Hosp 1951; 89: 121-32. vera.
5. Rosenthal 6.
315
Reviews of Books Human Growth: A
Comprehensive Treatise
Second Edztion. Edited by F. Falkner and J. M. Tanner. New York: Plenum Press. 1986. Vol 1, pp 496,$69.50; Vol 2, pp 555,$75; Vol 3, pp
552,$75. IT would be difficult to think of two more appropriate editors for a treatise on human growth. Their first edition of these three volumes appeared in 1978 and it is a tribute to them that a second edition should have been called for and produced so rapidly. There are eighteen new chapters and thirteen of these deal with subjects not covered at all in the first edition. The remaining chapters have been updated and the three volumes provide an authoritative and comprehensive review of human growth. The first volume is divided between developmental biology and prenatal growth. The chapters on organ and tissue growth and differentiation and embryonic growth and fetal size confirm the importance of paracrine events and reveal how scanty our knowledge is of the molecular basis of these control mechanisms. There are provocative reviews of comparative growth and development, the evolution of the human growth curve, and growth as a target-seeking function, the last including the new concept of catch-down growth. The chapters on prenatal growth range from the anatomy and physiology of the placenta to the anthropometric and ultrasound measurement of fetal growth. They also cover metabolism, endocrinology, and immunity in the fetus and newborn infant. There are two chapters on the low-birthweight infant. The second volume comprehensively reviews postnatal growth and the neurobiology of the fetus and newborn infant. It explores the development, adaptability, and maturation of the central nervous system and applies these in chapters on patterns of early neurological development and the development of newborn
behaviour. The third volume opens with five chapters that are essential reading for anyone contemplating research on human growth. They cover methods of auxological measurement, the statistics of growth standards, population sampling for growth studies, and the use and abuse of growth standards. The last part of this edition includes a series of fascinating chapters that review the genetics of human fetal and postnatal growth and maturation and these are nicely followed by a discussion on the growth and development of human twins. There is then entertaining reading for anyone inquisitive about human growth with chapters on population differences in growth, on growth in the 18th and 19th centuries, and on secular growth changes. These are followed by an examination of growth in early
7 Rosenthal
A, Nathan DG, Marty AT, Button LN, Miettinen OS, Nadas AS. Acute hemodynamic effects of red cell volume reduction in polycythemia of cyanotic congenital heart disease. Circulation 1970; 42: 297-307. 8. Gregg DE, Wiggers CJ. The circulatory effect of acute experimental hypervolemia. AmJ Phytol 1933; 104: 423-32. 9. Murray JF, Gold P, Johnson BL Jr. Systemic oxygen transport in induced normovolemic anemia and polycythemia. Am JPhysiol 1962; 203: 720-24. 10. Richardson TQ, Guyton AC. Effects of polycythemia and anemia on cardiac output and other circulatory factors. Am J Physiol 1959; 197: 1167-70. 11. Castle WB, Jandl JH. Blood viscosity and blood volume: opposing influences upon oxygen transport in polycythemia. Semin Hematol 1966; 3: 193-98. 12. Cobb LA, Kramer RJ, Finch CA. Circulatory effects of chronic hypervolemia in polycythemia.J Clin Invest 1960; 39: 1722-28. 13. Beekman RH, Tuun DT. Acute hemodynamic effects of increasing hemoglobin concentration in children with a right to left ventricular shunt and relative anemia. J Am Coll Cardiol 1985; 5: 357-62. 14. Wells RE, Merrill EW. Influence of flow properties of blood upon viscosityhematocrit relationship. J Clin Invest 1962; 41: 1591-98. 15. Kontras SB, Bodenbender JG, Craenen J, Hosier DM. Hyperviscosity in congenital heart disease J Pediatr 1970; 76: 214-20. 16 Rudolph AM, Nadas AS, Borges WH. Hematologic adjustment to cyanotic congenital heart disease. Pediatrics 1953; 11: 454-64. 17 Monge CC, Whittembury J. Chronic mountain sickness and the physiopathology of hypoxemic polycythemia. In Sutton JR, Jones NC, Houston CS, eds. Hypoxia: man at altitude. New York: Thieme-Stratton, 1982: 51-56.
childhood in developing countries and its standing as a measure of the economic wellbeing of populations. These final chapters cover the relation of nutrition to fetal growth and in particular brain development and leaming. They should be read by anyone concerned with child health whether their interest is biological or
political. Though at first daunted by the arrival of three large volumes for review, I was soon enjoying the task: the wealth of information and its presentation is sufficient to whet the appetite of anyone interested in human growth. The authoritative manner in which the chapters are written and the excellence of the line drawings and photographs are enhanced by the enthusiasm and scholarship of the authors. Bristol Royal Hospital for Sick Children, Bristol BS2 8BJ
D. C. L. SAVAGE
Economics, Medicine and Health Care Gavin Mooney. Brighton: Wheatsheaf Books. 1986. Pp 171. 18.95.
AN American physician writing about health economics in the New England Journal of Medicine in 1980 felt that it was "dangerous to introduce extraneous factors into medical decisions, since consideration of such factors may eventually lead to considerations of age, social usefulness, and other matters irrelevant to medical practice. The example of medicine in Nazi Germany is too close to need further elucidation?" Whilst such an extreme view may be uncommon, the underlying rejection of the value of economics to the practice of medicine and provision of health care is a view that is widely held by doctors and other health professionals. Some economists have lately turned their attention away from their own disciplinary concerns and concentrated their efforts first on understanding medical views of such issues as scarcity, rationing, and valuation and subsequently on developing a dialogue with doctors about these issues. Pre-eminent amongst them has been Gavin Mooney who in this, his latest book, attempts to identify why economists and clinicians might not always see eye to eye. Starting with a description of how economists view the world in general, he identifies the ways in which classic economic considerations of the market run into difficulties when they encounter health care. Even doctors who are sympathetic towards the application of economics to medicine may become despondent on discovering that economics, the so-called dismal science, tends to raise more questions than it answers. Admittedly those it raises are ones that medicine has traditionally ignored: what is health? how can health be measured? what is the value of health? whose values should be adopted? what is need? and what form of equity should we pursue? In considering these questions the author demonstrates the
18. Hall
FG, Dill DB, Barron ESG. Comparative physiology in high altitudes. J Cell Comp Physiol 1936; 8: 301-13. 19. Herbel RP, Eaton JW, Kronenberg RS, Zanjani ED, Moore LG, Berger EM. Human llamas. J Clin Invest 1978; 62: 593-600. 20. West J, Boyer SJ, Graber DJ, et al. Maximal exercise at externe altitudes on Mount verest. J Appl Physiol 1983; 55: 688-98. 21. Winslow RM. Red cell function at extreme altitude. In: West JB, Lahiri S, eds. High altitude and man. Bethesda: American Physiological Society, 1984: 59-72. 22. Linderkamp O, Klose HJ, Betke K, et al. Increased blood viscosity in patients with cyanotic congenital heart disease and iron deficiency. J Pediatr 1979; 95: 567-69. 23. Hutton RD. The effect of iron deficiency on whole blood viscosity in polycythaemic patients. BrJ Haematol 1979; 43: 191-99. 24. Finch CA, Miller LR, Inamdar AR, Person R, Geiler K, Mackler B. Iron deficiency in the rat: physiologic and biochemical studies of muscle dysfunction. J Clin Invest 1976; 58: 447-53. 25. Hillman RS. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest 1969, 48: 443-53. 26. Jacobs P, Finch CA. Iron for erythropoiesis. Blood 1971; 37: 220-30. 27. Langer EE, Haining RG, Labbe RF, Jacobs P, Crosby EF, Finch CA. Erythrocyte protoporphyrin. Blood 1972; 40: 112-28. 28. Pootrakul P, Wattanaseree J, Anuwattanakulchai M, Wasi P. Increased red cell protoporphyrin in thalassemia: a result of relative iron deficiency. In: Urushikazi I, et al, eds. Structure and function of iron storage and transport proteins. Amsterdam: Elsevier Science Publishers, 1983: 535-40.
CHRONIC HYPOXAEMIA AND DECOMPENSATED ERYTHROCYTOSIS IN CYANOTIC CONGENITAL HEART DISEASE MICHAEL H. ROSOVE WILLIAM G. HOCKING MARY M. CANOBBIO
JOSEPH K. PERLOFF JOHN S. CHILD DAVID J. SKORTON
Divisions of Cardiology and Hematology-Oncology, Departments of Medicine and Pediatrics, and the Adult Congenital Heart Disease
Program, UCLA Center for the Health Sciences, Los Angeles,
California,
USA
Among forty adults with cyanotic congenital heart disease there was a subset of eleven patients with especially pronounced erythrocytosis, repeatedly rising haematocrit, recurring symptoms of hyperviscosity, and little or no shift of the haemoglobin/ oxygen-dissociation curve. These patients were iron deficient as a result of many therapeutic phlebotomies; nevertheless their red-cell mass was comparable to that in iron-replete patients with similar, but stable, haematocrits. Iron repletion in the deficient patients resulted in rapidly increasing haematocrit and hyperviscosity. In one extreme case, erythropoiesis remained persistently iron deficient despite normal serum iron and ferritin levels. "Decompensated erythrocytosis" is an apt term for the excessive erythrocytic response and the associated phenomena. Summary
Introduction CHRONIC hypoxaemia in cyanotic congenital heart disease results from the mixing of venous and arterial blood. Serum erythropoietin levels rise,1,2 with the result that the erythroid marrow becomes hyperplastic and red-cell mass and total blood volume increase.3-6 Up to a point, oxygen transport and delivery are moderately enhanced/-13 but erythrocytosis raises whole-blood Viscosity, 4 15 and eventually may cause symptoms requiring phlebotomy for relief. 16 We have identified a subset of patients with cyanotic congenital heart disease whose excessive erythroid response represents adaptive failure. Patients and Methods
Forty consecutive patients (eighteen male, twenty-two female) drawn from the UCLA adult congenital heart disease programme. All but two, whose whereabouts are unknown, are still being followed up. The median period of observation was 5-1 years-from first UCLA evaluation to the most recent reevaluation, corrective surgery (seven patients), or death (five). The median age at the start of the study was 29 years (15-53 years). No patient used supplemental oxygen. Venoarterial mixing was associated with pulmonary hypertensive vascular disease in twentywere
34 Andrianakos AA, Sharp JT, Person DA, Lidsky MD, Duffy J. Cell-mediated immunity m rheumatoid arthritis. Ann Rheum Dis 1977; 36: 13-20. 35. Young RA, Bloom BR, Grosskinsky CM, Ivanyi J, Thomas D, Davis RW. Dissection of Mycobacterium tuberculosis antigens using recombinant DNA. Proc Natl Acad Sci USA 1985; 82: 2583-87. 36. Cohen IR, Holoshitz J, Van Eden W, Frenkel A. T-lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum 1985; 28: 841-45. 37. Steinman L, Rosenbaum JT, Sriram S, McDevitt HO. In vivo effects of antibodies to immuneresponse gene products: prevention of experimental allergic encephalitis. Proc Natl Acad Sci USA 1981; 78: 7111-14. 38. Waldor MK, Sriram S, Hardy R, et al. Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker Science
1985; 227: 415-17. 39. Adelman NE, Watling DL, McDevitt HO. Treatment of (NZBxNZW) F1 disease with anti-I-A monoclonal antibodies. J Exp Med 1983; 158: 1350-55. 40 Wofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med 1985; 161: 378-91.
low pulmonary arterial pressure and Symptoms of hyperviscosity included fatigue, dyspnoea, myalgia, arthralgia, headache, paraesthesiae, faintness, dizziness, visual disturbances, abdominal pain, chest pain, and reduced mental activity. Blood counts and red-cell indices were measured by automatic methods (Coulter Electronics). Mean values for each patient were used to calculate group means. All data are expressed as mean ± SD. six patients and normal resistance in fourteen.
or
Results The
patients were segregated into two groups. Group I (decompensated) consisted of eleven patients with unstable haematocrits that rose repeatedly over time with development of symptoms of hyperviscosity. Phlebotomy for relief of symptoms was required regularly from twice a year to twice a month. All these patients were iron deficient (serum iron-binding capacity increased and < 15% saturated). Group II (compensated) consisted of twentynine patients with more stable haematocrits. Six of these patients required phlebotomy, but only rarely (three of them only once). None was iron deficient. The highest sustained . haematocrit level without symptoms of hyperviscosity was 70%. Haematological data for both groups are shown in table i. Pulmonary vascular disease was slightly but not .significantly more common in group I than group II-8/11 (73%) v 13/29 (45%). Red-cell mass measured by means of chromium-51 and plasma volume measured by means of iodine-131-labelled albumin were determined in thirteen patients with haematocrit levels 60%(table II). Red-cell mass and total blood volume (red-cell mass plus plasma volume) were similar in the two groups. There were no significant correlations between mean corpuscular volume and either red-cell mass or total blood volume (r, == — 0-05 and - 0-22, respectively). Haemoglobin P50 values (in vivo pH) in eleven patients with haematocrits > 60% (28-1 ±1-2 mm Hg) were similar to those in normal subjects (26 7 ±0 6 mm Hg). The mean values for groups I and II were similar (27-9 ±1-1mm Hg, n=5,28’4±l-3mmHg,n=6). Iron repletion with oral ferrous sulphate or intravenous iron-dextran was attempted in five group I patients (table III). The haematocrit rose promptly in each patient with the development of hyperviscosity symptoms that necessitated phlebotomy. Iron was continued for 47+9 days after development of hyperviscosity symptoms in three patients, who required a total of 8 additional phlebotomies TABLE I-HAEMATOLOGICAL DATA
TABLE II-RED-CELL MASS AND BLOOD VOLUME STUDIES
314 TABLE III-RESPONSES OF FIVE GROUP I PATIENTS TO IRON TREATMENT
*Of treatment until symptoms of hyperviscosity appeared. tAt time of hyperviscosity symptoms.
(9-0 ±1-7 ml/kg). The haematocrit could not be stabilised in any
patient.
separate study, one patient received oral ferrous sulphate and intravenous iron-dextran for 6 months. He In
a
required phlebotomy (12-8+3-2 ml/kg) frequently (every 12 6 ±70 days); the mean daily iron removed was 0-75 mg/kg. The haematocrit was 73-8 ±3-1%, the erythrocyte count 9-3 ±0-4 x 1012/1, the reticulocyte count 6-3 ±0-8%, and blood volume 124 ml/kg. Thus, the mean number of circulating reticulocytes was 72-7 x 109/kg, compared with 3-5 x 109/kg in a normal individual with haematocrit 45%, erythrocyte count 5-0 x 1012/1, reticulocyte count 1-0%, and blood volume 70 ml/kg. The patient’s bone-marrow aspirate was hypercellular, with virtually no fat and a myeloid to erythroid ratio of 1/3. Despite normal serum levels of iron (95 ± 30 ug/dl, 29-3 ± 6-7% saturation of binding capacity) and ferritin (78-448 ng/ml) at equilibrium, microcytosis (80-3 ±2-2 fl), hypochromia (29 8 ±0-5 g haemoglobin per dl erythrocytes), and raised erythrocyte protoporphyrin (95 we 14 ug/dl erythrocytes, normal < 50) persisted. Normal haemoglobin electrophoresis, reticulocyte ot/ 0-globinchain-synthesis ratio, and serum lead levels excluded thalassaemia and lead poisoning as causes of the high protoporphyrin levels. Thus, it appears that normal incorporation of iron into newly developing erythrocytes achieved. No patient in either group had a cerebrovascular accident during observation or before UCLA presentation. Two groupI and three group II patients died. Four deaths were sudden, and one was due to pneumonia. Necropsy was carried out in three patients; the brain showed scattered microinfarcts in one. Discussion
was
not
Erythrocytosis is an adaptation that occurs in response to hypoxaemia at high altitudes or intracardiac and pulmonary vascular right-to-left shunts and intrinsic lung disease. It also results from tissue hypoxia caused by abnormal haemoglobins with defective oxygen binding or release. Raising red-cell mass increases oxygen transport and delivery7-13 but excessive erythrocytosis has the associated problem of hyperviscosity. In excessive erythrocytosis, red-cell production is not controlled, and negative feedback inhibition does not seem to occur. "Decompensated erythrocytosis" is an appropriate term for this state. Erythrocytosis decompensates in some patients with cyanotic congenital heart disease, as in some individuals with chronic mountain sickness at high altitude.17 The position of the haemoglobin-oxygen dissociation curve
is
a
determinant of oxygen transport and delivery. In
with cyanotic congenital heart disease the curve is normal or slightly right-shifted. It is not clear why. The mechanism of arterial hypoxaemia in cyanotic congenital heart disease is not the same as that at high altitude (alveolar oxygen tension is near normal, and hypoxaemia results from venoarterial mixing), so the optimum curve position for cyanotic congenital heart disease may not be the same as that for high altitude. Nevertheless, fmdings at high altitude are at least contextually interesting, and possibly relevant. In a low-oxygen atmosphere, a left-shifted curve increases oxygen loading and thus transport. Animals that have evolved at high altitude, such as the llama and vicuna, have left-shifted curves and do not rely on erythrocytosis as an adaptation to hypoxia.18 Human beings with mutant
patients
high-oxygen-affmity haemoglobins perform exceptionally well at high altitudes.19 The implication is that a left-shifted curve improves tissue oxygen delivery under such conditions. The usual response of human beings to moderate altitude (a rightward shift caused by a rise in erythrocyte 2,3-diphosphoglycerate content) may thus be maladaptive. 19 At very high altitude,zo at least 4500 M, 21 a net leftward shift results from hyperventilation (Bohr effect) and might be physiologically desirable. Phlebotomy is often carried out in older children and adults with cyanotic congenital heart disease to relieve hyperviscosity symptoms or to reduce the perceived risk of cerebral infarction. Iron depletion inevitably follows phlebotomy with the result that erythrocyte haemoglobin concentration falls, microcytosis aggravates hyperviscosity,22,23 and exercise performance is impaired 2’ The drive to red-cell production remains intense, and irondepleted patients maintain very high blood volumes by producing enormous numbers of very small hypochromic cells. Iron repletion alone is seldom successful, because the haematocrit rises rapidly in response to iron, resulting in hyperviscosity. One of our patients represented the extreme of decompensation-refractory iron-deficient erythropoiesis. Serum iron is rate-limiting on haemoglobin production in experimentally induced anaemia when it is below 70 Ilgl dl in man2s or 150 pg/dl in rabbits.26 A "normal" serum iron level may not satisfy the requirements of the hyperplastic erythroid marrow associated with haemolysis27 or thalassaemia intermedia.28 This patient’s serum iron, although "normal" (95::!:: 30 ug/dl), similarly appeared insufficient to supply the greatly expanded pool of erythroid precursors, representing failure of the iron procurement and delivery system in an extreme case of erythroid hyperplasia induced by hypoxaemia. This work was supported by the Streisand/American Professorship and the Rosalind W. Alcott Endowment.
Heart Association
Correspondence should be addressed to M. H. R., Department of Medicine, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90024, USA. REFERENCES 1. Koeffler HP, Goldwasser E. Erythropoietin radioimmunoassay in
evaluating patients
with polycythemia. Ann Intern Med 1981; 94: 44-47. 2. Erslev AS, Caro J. Pure erythrocytosis classified according to erythropoietin titers. Am J Med 1984; 76: 57-61. 3. Lawrence JH, Berliner NI, Huff RL. The nature and treatment of polycythemia. Studies on 263 patients. Medicine 1953; 32: 323-88. 4. Verel D Blood volume changes in cyanotic congenital heart disease and polycythemia
rubra
Circulation 1961; 23: 749-53. A, Button LN, Nathan DG, Miettinen OS, Nadas AS. Blood volume changes m cyanotic congenital heart disease. Am J Cardiol 1971; 27: 162-67. Scott WS, Elliot SR, Clay RC. Blood volume in congenital cyanotic heart disease. simultaneous measurements with Evans blue and radioactive phosphorus. Bull Johns Hopkins Hosp 1951; 89: 121-32. vera.
5. Rosenthal 6.
315
Reviews of Books Human Growth: A
Comprehensive Treatise
Second Edztion. Edited by F. Falkner and J. M. Tanner. New York: Plenum Press. 1986. Vol 1, pp 496,$69.50; Vol 2, pp 555,$75; Vol 3, pp
552,$75. IT would be difficult to think of two more appropriate editors for a treatise on human growth. Their first edition of these three volumes appeared in 1978 and it is a tribute to them that a second edition should have been called for and produced so rapidly. There are eighteen new chapters and thirteen of these deal with subjects not covered at all in the first edition. The remaining chapters have been updated and the three volumes provide an authoritative and comprehensive review of human growth. The first volume is divided between developmental biology and prenatal growth. The chapters on organ and tissue growth and differentiation and embryonic growth and fetal size confirm the importance of paracrine events and reveal how scanty our knowledge is of the molecular basis of these control mechanisms. There are provocative reviews of comparative growth and development, the evolution of the human growth curve, and growth as a target-seeking function, the last including the new concept of catch-down growth. The chapters on prenatal growth range from the anatomy and physiology of the placenta to the anthropometric and ultrasound measurement of fetal growth. They also cover metabolism, endocrinology, and immunity in the fetus and newborn infant. There are two chapters on the low-birthweight infant. The second volume comprehensively reviews postnatal growth and the neurobiology of the fetus and newborn infant. It explores the development, adaptability, and maturation of the central nervous system and applies these in chapters on patterns of early neurological development and the development of newborn
behaviour. The third volume opens with five chapters that are essential reading for anyone contemplating research on human growth. They cover methods of auxological measurement, the statistics of growth standards, population sampling for growth studies, and the use and abuse of growth standards. The last part of this edition includes a series of fascinating chapters that review the genetics of human fetal and postnatal growth and maturation and these are nicely followed by a discussion on the growth and development of human twins. There is then entertaining reading for anyone inquisitive about human growth with chapters on population differences in growth, on growth in the 18th and 19th centuries, and on secular growth changes. These are followed by an examination of growth in early
7 Rosenthal
A, Nathan DG, Marty AT, Button LN, Miettinen OS, Nadas AS. Acute hemodynamic effects of red cell volume reduction in polycythemia of cyanotic congenital heart disease. Circulation 1970; 42: 297-307. 8. Gregg DE, Wiggers CJ. The circulatory effect of acute experimental hypervolemia. AmJ Phytol 1933; 104: 423-32. 9. Murray JF, Gold P, Johnson BL Jr. Systemic oxygen transport in induced normovolemic anemia and polycythemia. Am JPhysiol 1962; 203: 720-24. 10. Richardson TQ, Guyton AC. Effects of polycythemia and anemia on cardiac output and other circulatory factors. Am J Physiol 1959; 197: 1167-70. 11. Castle WB, Jandl JH. Blood viscosity and blood volume: opposing influences upon oxygen transport in polycythemia. Semin Hematol 1966; 3: 193-98. 12. Cobb LA, Kramer RJ, Finch CA. Circulatory effects of chronic hypervolemia in polycythemia.J Clin Invest 1960; 39: 1722-28. 13. Beekman RH, Tuun DT. Acute hemodynamic effects of increasing hemoglobin concentration in children with a right to left ventricular shunt and relative anemia. J Am Coll Cardiol 1985; 5: 357-62. 14. Wells RE, Merrill EW. Influence of flow properties of blood upon viscosityhematocrit relationship. J Clin Invest 1962; 41: 1591-98. 15. Kontras SB, Bodenbender JG, Craenen J, Hosier DM. Hyperviscosity in congenital heart disease J Pediatr 1970; 76: 214-20. 16 Rudolph AM, Nadas AS, Borges WH. Hematologic adjustment to cyanotic congenital heart disease. Pediatrics 1953; 11: 454-64. 17 Monge CC, Whittembury J. Chronic mountain sickness and the physiopathology of hypoxemic polycythemia. In Sutton JR, Jones NC, Houston CS, eds. Hypoxia: man at altitude. New York: Thieme-Stratton, 1982: 51-56.
childhood in developing countries and its standing as a measure of the economic wellbeing of populations. These final chapters cover the relation of nutrition to fetal growth and in particular brain development and leaming. They should be read by anyone concerned with child health whether their interest is biological or
political. Though at first daunted by the arrival of three large volumes for review, I was soon enjoying the task: the wealth of information and its presentation is sufficient to whet the appetite of anyone interested in human growth. The authoritative manner in which the chapters are written and the excellence of the line drawings and photographs are enhanced by the enthusiasm and scholarship of the authors. Bristol Royal Hospital for Sick Children, Bristol BS2 8BJ
D. C. L. SAVAGE
Economics, Medicine and Health Care Gavin Mooney. Brighton: Wheatsheaf Books. 1986. Pp 171. 18.95.
AN American physician writing about health economics in the New England Journal of Medicine in 1980 felt that it was "dangerous to introduce extraneous factors into medical decisions, since consideration of such factors may eventually lead to considerations of age, social usefulness, and other matters irrelevant to medical practice. The example of medicine in Nazi Germany is too close to need further elucidation?" Whilst such an extreme view may be uncommon, the underlying rejection of the value of economics to the practice of medicine and provision of health care is a view that is widely held by doctors and other health professionals. Some economists have lately turned their attention away from their own disciplinary concerns and concentrated their efforts first on understanding medical views of such issues as scarcity, rationing, and valuation and subsequently on developing a dialogue with doctors about these issues. Pre-eminent amongst them has been Gavin Mooney who in this, his latest book, attempts to identify why economists and clinicians might not always see eye to eye. Starting with a description of how economists view the world in general, he identifies the ways in which classic economic considerations of the market run into difficulties when they encounter health care. Even doctors who are sympathetic towards the application of economics to medicine may become despondent on discovering that economics, the so-called dismal science, tends to raise more questions than it answers. Admittedly those it raises are ones that medicine has traditionally ignored: what is health? how can health be measured? what is the value of health? whose values should be adopted? what is need? and what form of equity should we pursue? In considering these questions the author demonstrates the
18. Hall
FG, Dill DB, Barron ESG. Comparative physiology in high altitudes. J Cell Comp Physiol 1936; 8: 301-13. 19. Herbel RP, Eaton JW, Kronenberg RS, Zanjani ED, Moore LG, Berger EM. Human llamas. J Clin Invest 1978; 62: 593-600. 20. West J, Boyer SJ, Graber DJ, et al. Maximal exercise at externe altitudes on Mount verest. J Appl Physiol 1983; 55: 688-98. 21. Winslow RM. Red cell function at extreme altitude. In: West JB, Lahiri S, eds. High altitude and man. Bethesda: American Physiological Society, 1984: 59-72. 22. Linderkamp O, Klose HJ, Betke K, et al. Increased blood viscosity in patients with cyanotic congenital heart disease and iron deficiency. J Pediatr 1979; 95: 567-69. 23. Hutton RD. The effect of iron deficiency on whole blood viscosity in polycythaemic patients. BrJ Haematol 1979; 43: 191-99. 24. Finch CA, Miller LR, Inamdar AR, Person R, Geiler K, Mackler B. Iron deficiency in the rat: physiologic and biochemical studies of muscle dysfunction. J Clin Invest 1976; 58: 447-53. 25. Hillman RS. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest 1969, 48: 443-53. 26. Jacobs P, Finch CA. Iron for erythropoiesis. Blood 1971; 37: 220-30. 27. Langer EE, Haining RG, Labbe RF, Jacobs P, Crosby EF, Finch CA. Erythrocyte protoporphyrin. Blood 1972; 40: 112-28. 28. Pootrakul P, Wattanaseree J, Anuwattanakulchai M, Wasi P. Increased red cell protoporphyrin in thalassemia: a result of relative iron deficiency. In: Urushikazi I, et al, eds. Structure and function of iron storage and transport proteins. Amsterdam: Elsevier Science Publishers, 1983: 535-40.