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Anemia and heart disease
13x
Annotations
and hyperglobulinemia have no detectable effect on the relationship Protein = 383 (S.G. - 1.007) where S.G. is the specitic gravity found by the technique of Phillips and associates.1~2Furthermore, there is evidence that the amino-acid N content of a globulin molecule (measured by Kjeldahl procedures) can be influenced by diet, but not that such influence is reflected in the specific volume of the protein. In the clinical consideration of a patient’s plasma protein level the existence of an appreciable diurnal variation in the albumin concentration is frequently overlooked. The extent of this is from 2 to 8 Gm. per liter (mean: 5 Gm. per liter), increasing during the day. Also relevant here are the errors inherent in the particular method used. Individual albumin determinations by either a standard biuret method3 or by electrophoresis and dye-binding have a precision of about + 7 per cent. The precision of the total protein determination by the biuret reaction is about +_5 per cent, and by the specific gravity method +_3 per cent. When there is the unavoidable error of a total protein and an albumin assay of a particular plasma being of opposite sign, an inordinately large effect on the magnitude of the albumin-globulin ratio occurs, because of the fact that the normal plasma A/G ratio is close to unity. This alone appears to be sufficient reason for discontinuing the custom of correlating the A/G ratio (rather than the albumin or the globulin level) with the patient’s clinical state. The large number of published articles in reference to paper electrophoresis of plasma proteins in no way reflects the value of the technique in assisting the clinical assessment of individual patients. In research on specialized proteins and on substances bound to proteins, electrophoresis is of immense v.alue, but when applied to plasma protein estimation it is of disappointingly limited clinical v-alue. \Vith the great majority of patients it gives information which merely confirms what can be deduced from the results of simpler tests. Moreover, the albumin and globulin concentrations obtained by paper electrophoresis are no more accurate, and are frequently less accurate, than those obtained by other fractionation procedures because
Anemia
and
heart
the dye-binding capacities of the individual proteins (used in their calorimetric estimation) alter in disease. In hospitals (not served by chemical laboratories with mass automation), selective blood screening investigations for deranged protein metabolistn may most usefully, and economically, be undertaken in the following order: (1) total protein by specific gravity, (2) quantitative gamma globulin and fibrinogen by turbidity tests, (3) qualitative test for plasma proteins by thymol reaction. The rapid and accurate measurement of total protein in a patient’s plasma-such as is given by the specific gravity-remains of particular value, because it can give immediate information about the development and response to therapy of decreased estracellular fluid volume, dehydration, hemoconcentration, and shock. Alternatively, the iinding of a low protein level will almost always be due to albumin deficiency which occurs in many conditions affecting the liver or the kidneys. D. Watson, D.Sc., F.R.I.C. Division of Biochemistry The Royal Women’s Hospital dlelbor~rne N3, Victoria, Australia REFERENCES 1. Phillips, R. A., Van Slyke, D. D., Hamilton, 1’. B., Dole, V. P. and Archibald, R. M.: Copper sulphate method for measuring specific gravities of whole blood and plasma, Bull. Ii. S. Army Med. Dept. 71:66, 1943. 2. Phillips, R. A., Van Slyke, D. D., Dole, V. P., Emerson, K., Hamilton, P. B., and Archibald, R. M.: Copper sulphate method for measuring specific gravities of whole blood and plasma, New York, 1945, Josiah Macy, Jr., Foundation. 3. Reinhold, J. G.: In Reiner, M., editor: Staudard methods of clinical chemistry, Vol. I, New York, 1953, Academic Press, p. 88. 4. Rogers, J. A., and Watson, D.: Evaluation of the specitic gravity drop method for serum protein estimation, M. J. Australia 2:690, 1963. 5. Salt, H. B.: Micro-analytical methods for proteins in blood plasma. A critical review, Analyst 78:4, 1953.
disease
In the assessment of a patient with heart disease it is important to consider anemia, because anemia itself may bring about considerable disturbance in the circulation and may also aggravate or bring to light underlying cardiac disease. Whether the anemia is of the iron-deficient or the megaloblastic type, and irrespective of its cause, the resultant circulatory effects are the same. Where anemia is acute, after hemorrhage or sudden rapid hemolysis, the situation is usually obvious. The effects are
those of a sudden decrease in the blood volume or of anoxia by reason of the rapid reduction in the circulating red cell mass. Chronic anemia, on the other hand, may be more difficult to recognize. It is important, however, that it should be recognized, because severe chronic anemia may affect the heart in three ways. It may produce a hyperkinetic state, it may cause or precipitate angina or acute coronary insufficiency, or it may result in nutritional degenerative changes
A nnotntions
which affect the cardiac reserve. All these conditions arise from the deficiency of oxygen in the blood. The effects produced depend on the severity and chronicity of the anemia, the integrity of the myocardium, and the age of the patient. The hemodynamic disturbances are all compensating ones in chronic anemia; the increased cardiac output is maintained by tachycardia, by a raised venous filling pressure, or both. In general, the velocity of the circulation rate of the blood flow is increased in proportion to the severity of the anemia, and there is evidence that the percentage utilization of oxygen is enhanced. Only if the anemia is very long standing does the heart undergo dilatation and hypertrophy, and treatment of the anemia before this stage is reached will completely reverse the other disturbances. Electrocardiographic changes, such as low-voltage complexes and T-wave changes, can also be abolished by treatment. The reversal of the hemodynamic effects of chronic anemia has recently been well demonstrated by Roy and associates1 in 51 patients with anemia due mainly to ancylostomiasis who were studied before and after treatment. Even a slight degree of anemia may lead to myocardial insufficiency when there is severe ischemic heart disease. However, anemia may cause angina when there is little or no underlying coronary disease, although probably only if the hemoglobin is under 4 or 5 Gm. per cent. Cardiac pain in anemic patients without any underlying disease of the coronary arteries has been recorded: Coombs2 reported 8 cases out of 36, and \h’illius and Giffin,a 43 (2.7 per cent) out of 1,560 patients with pernicious anemia. Nevertheless, there is a certain amount of doubt about the degree of anemia necessary to produce cardiac symptoms. Many workers*B5 consider that the hemoglobin usually has to fall to less than 7 Gm. per cent before any symptoms or signs are noted, but there are exceptions. As Hunter6 has pointed out, many anemic patients have cardiovascular symptoms (dyspnea on exertion, palpitations, syncopal attacks, edema, etc.) similar to those complained of by patients with organic heart disease. Porter and \%:atson James5 rightly emphasized that the potential ill effect of anemia on the diseased heart, on the senile heart, or on the heart laboring under the stress of hypertension, hyperthyroidism, valvular heart disease, pregnancy, or arteriovenous fistula, is a clinical problem of major importance. Relief of the anemia may be a deciding factor between recovery or continued cardiac failure. Anemia, whatever its underlying cause, is now relatively easy to treat, provided that the cause is discovered. Anemia in cardiac patients should first be fully investigated and then efficiently treated, and, when this is done, re-examination will frequently reveal that the condition of the heart is better than was previously thought possible. In cases of iron-deficiency anemia, after sources of loss of blood have been sought and treated, the dietary history considered, and, if necessary, the absorption of iron studied, treatment will normally be given in the form of iron by mouth or by injection. In pernicious anemia, when the diagnosis has been established by the typical blood picture,
139
megaloblastic bone marrow, histamine-fast achlorhydria, and a low serum vitamin B,z concentration, replacement therapy by injection of vitamin BI? is a well-established form of treatment. Recent work,7,8 however, has shown that vitamin RI? may be given by mouth, provided that it is given in sufficient doses. That adequate replacement is necessary from a cardiac point of view is suggested by the work of Jasinski and associates,g who have shown that vitamin B12 is important in the metabolism of the myocardium. Oral therapy gives a maximum reticulocyte response, effective and permanent elevation of hemoglobin and red cell count, and also maintains the serum vitamin Bls at a normal level. The neurological manifestations of a lack of vitamin Blz can also be alleviated.“’ Any dosage lower than 300 pg daily may maintain a normal blood picture, bllt it does not keep the serum vitamin B12 within the normal range. Treatment that does not do so should not be considered to be adequate. Blood transfusion is, of course, a necessity in acute cases of anemia, whether due to hemorrhage or hemolysis, but in chronic anemia, great care must be taken because of the risk that acute pulmonary edema may be induced by an ill-judged or ill-timed blood transfusion. G. S. Kilprrtvick, M.D., M.R.C.P.E. J. L. Withey, M.B., B.S. i2fcedical Vnit and Institute of Pathology U’elsh National School of fifeda’cine, Cavdiff, Wales REFERENCES 1. Roy, S. B., Bhatia, M. L., Mathur, V. S., and Virmani, S. : Haemodynamic effects of chronic severe anaemia, Circulation 28:346, 1963. 2. Coombs, C. F.: Cardiac symptoms of pernicious anaemia, with particular reference to cardiac pain, Brit. M. J. 2:185, 1926. 3. Willius, F. A., and Giffin, H. 2.: Angina1 syndrome in pernicious anaemia, Am. J. Clin. Sc. 30:174, 1927. 4. Brannon, E. S., Merrill, A. J., Warren, J. V., and Stead, E. A.: The cardiac output in patients with chronic anaemias measured by the technique of right atria1 catheterisation, J. Clin. Invest. 24:332, 1945. 5. Porter, W. B., and Watson, James, G.: The heart in anaemia, Circulation 8:111, 1953. 6. Hunter, A.: The heart in anaemia, Quart. J, med. 15:107, 1946. 7. Waife, S. O., Jansen, C. J., Crabtree, R. E., Grinnan, E. I.., and Fouts, P. J.: Oral vitamin B~z without intrinsic factor in the treatment of pernicious anaemia, Ann. Int. med. 58:810,1963. 8. Withey, J. L., Jones, J. H., and Kilpatrick, G. S.: Long-term trial of oral treatment of pernicious anaemia with vitamin B1? peptide, Brit. M. J. 1:1583, 1963. 9. Jasinski, B., Stiefel, G. E., Frei, H., and Wuhrmann, F.: Untersuchungen iiber das Schicksal und die Verteilung im Organismus des peroral oder parenteral verabreichten Vitamin RI?, Clin. Chim. Acta 1:189, 19.56. 10. Mooney, F. S., and Heathcote, J. G.: Oral treatment of subacute combined degeneration of the cord, Brit. M. J. 1:1585, 1963.
Annotations
and hyperglobulinemia have no detectable effect on the relationship Protein = 383 (S.G. - 1.007) where S.G. is the specitic gravity found by the technique of Phillips and associates.1~2Furthermore, there is evidence that the amino-acid N content of a globulin molecule (measured by Kjeldahl procedures) can be influenced by diet, but not that such influence is reflected in the specific volume of the protein. In the clinical consideration of a patient’s plasma protein level the existence of an appreciable diurnal variation in the albumin concentration is frequently overlooked. The extent of this is from 2 to 8 Gm. per liter (mean: 5 Gm. per liter), increasing during the day. Also relevant here are the errors inherent in the particular method used. Individual albumin determinations by either a standard biuret method3 or by electrophoresis and dye-binding have a precision of about + 7 per cent. The precision of the total protein determination by the biuret reaction is about +_5 per cent, and by the specific gravity method +_3 per cent. When there is the unavoidable error of a total protein and an albumin assay of a particular plasma being of opposite sign, an inordinately large effect on the magnitude of the albumin-globulin ratio occurs, because of the fact that the normal plasma A/G ratio is close to unity. This alone appears to be sufficient reason for discontinuing the custom of correlating the A/G ratio (rather than the albumin or the globulin level) with the patient’s clinical state. The large number of published articles in reference to paper electrophoresis of plasma proteins in no way reflects the value of the technique in assisting the clinical assessment of individual patients. In research on specialized proteins and on substances bound to proteins, electrophoresis is of immense v.alue, but when applied to plasma protein estimation it is of disappointingly limited clinical v-alue. \Vith the great majority of patients it gives information which merely confirms what can be deduced from the results of simpler tests. Moreover, the albumin and globulin concentrations obtained by paper electrophoresis are no more accurate, and are frequently less accurate, than those obtained by other fractionation procedures because
Anemia
and
heart
the dye-binding capacities of the individual proteins (used in their calorimetric estimation) alter in disease. In hospitals (not served by chemical laboratories with mass automation), selective blood screening investigations for deranged protein metabolistn may most usefully, and economically, be undertaken in the following order: (1) total protein by specific gravity, (2) quantitative gamma globulin and fibrinogen by turbidity tests, (3) qualitative test for plasma proteins by thymol reaction. The rapid and accurate measurement of total protein in a patient’s plasma-such as is given by the specific gravity-remains of particular value, because it can give immediate information about the development and response to therapy of decreased estracellular fluid volume, dehydration, hemoconcentration, and shock. Alternatively, the iinding of a low protein level will almost always be due to albumin deficiency which occurs in many conditions affecting the liver or the kidneys. D. Watson, D.Sc., F.R.I.C. Division of Biochemistry The Royal Women’s Hospital dlelbor~rne N3, Victoria, Australia REFERENCES 1. Phillips, R. A., Van Slyke, D. D., Hamilton, 1’. B., Dole, V. P. and Archibald, R. M.: Copper sulphate method for measuring specific gravities of whole blood and plasma, Bull. Ii. S. Army Med. Dept. 71:66, 1943. 2. Phillips, R. A., Van Slyke, D. D., Dole, V. P., Emerson, K., Hamilton, P. B., and Archibald, R. M.: Copper sulphate method for measuring specific gravities of whole blood and plasma, New York, 1945, Josiah Macy, Jr., Foundation. 3. Reinhold, J. G.: In Reiner, M., editor: Staudard methods of clinical chemistry, Vol. I, New York, 1953, Academic Press, p. 88. 4. Rogers, J. A., and Watson, D.: Evaluation of the specitic gravity drop method for serum protein estimation, M. J. Australia 2:690, 1963. 5. Salt, H. B.: Micro-analytical methods for proteins in blood plasma. A critical review, Analyst 78:4, 1953.
disease
In the assessment of a patient with heart disease it is important to consider anemia, because anemia itself may bring about considerable disturbance in the circulation and may also aggravate or bring to light underlying cardiac disease. Whether the anemia is of the iron-deficient or the megaloblastic type, and irrespective of its cause, the resultant circulatory effects are the same. Where anemia is acute, after hemorrhage or sudden rapid hemolysis, the situation is usually obvious. The effects are
those of a sudden decrease in the blood volume or of anoxia by reason of the rapid reduction in the circulating red cell mass. Chronic anemia, on the other hand, may be more difficult to recognize. It is important, however, that it should be recognized, because severe chronic anemia may affect the heart in three ways. It may produce a hyperkinetic state, it may cause or precipitate angina or acute coronary insufficiency, or it may result in nutritional degenerative changes
A nnotntions
which affect the cardiac reserve. All these conditions arise from the deficiency of oxygen in the blood. The effects produced depend on the severity and chronicity of the anemia, the integrity of the myocardium, and the age of the patient. The hemodynamic disturbances are all compensating ones in chronic anemia; the increased cardiac output is maintained by tachycardia, by a raised venous filling pressure, or both. In general, the velocity of the circulation rate of the blood flow is increased in proportion to the severity of the anemia, and there is evidence that the percentage utilization of oxygen is enhanced. Only if the anemia is very long standing does the heart undergo dilatation and hypertrophy, and treatment of the anemia before this stage is reached will completely reverse the other disturbances. Electrocardiographic changes, such as low-voltage complexes and T-wave changes, can also be abolished by treatment. The reversal of the hemodynamic effects of chronic anemia has recently been well demonstrated by Roy and associates1 in 51 patients with anemia due mainly to ancylostomiasis who were studied before and after treatment. Even a slight degree of anemia may lead to myocardial insufficiency when there is severe ischemic heart disease. However, anemia may cause angina when there is little or no underlying coronary disease, although probably only if the hemoglobin is under 4 or 5 Gm. per cent. Cardiac pain in anemic patients without any underlying disease of the coronary arteries has been recorded: Coombs2 reported 8 cases out of 36, and \h’illius and Giffin,a 43 (2.7 per cent) out of 1,560 patients with pernicious anemia. Nevertheless, there is a certain amount of doubt about the degree of anemia necessary to produce cardiac symptoms. Many workers*B5 consider that the hemoglobin usually has to fall to less than 7 Gm. per cent before any symptoms or signs are noted, but there are exceptions. As Hunter6 has pointed out, many anemic patients have cardiovascular symptoms (dyspnea on exertion, palpitations, syncopal attacks, edema, etc.) similar to those complained of by patients with organic heart disease. Porter and \%:atson James5 rightly emphasized that the potential ill effect of anemia on the diseased heart, on the senile heart, or on the heart laboring under the stress of hypertension, hyperthyroidism, valvular heart disease, pregnancy, or arteriovenous fistula, is a clinical problem of major importance. Relief of the anemia may be a deciding factor between recovery or continued cardiac failure. Anemia, whatever its underlying cause, is now relatively easy to treat, provided that the cause is discovered. Anemia in cardiac patients should first be fully investigated and then efficiently treated, and, when this is done, re-examination will frequently reveal that the condition of the heart is better than was previously thought possible. In cases of iron-deficiency anemia, after sources of loss of blood have been sought and treated, the dietary history considered, and, if necessary, the absorption of iron studied, treatment will normally be given in the form of iron by mouth or by injection. In pernicious anemia, when the diagnosis has been established by the typical blood picture,
139
megaloblastic bone marrow, histamine-fast achlorhydria, and a low serum vitamin B,z concentration, replacement therapy by injection of vitamin BI? is a well-established form of treatment. Recent work,7,8 however, has shown that vitamin RI? may be given by mouth, provided that it is given in sufficient doses. That adequate replacement is necessary from a cardiac point of view is suggested by the work of Jasinski and associates,g who have shown that vitamin B12 is important in the metabolism of the myocardium. Oral therapy gives a maximum reticulocyte response, effective and permanent elevation of hemoglobin and red cell count, and also maintains the serum vitamin Bls at a normal level. The neurological manifestations of a lack of vitamin Blz can also be alleviated.“’ Any dosage lower than 300 pg daily may maintain a normal blood picture, bllt it does not keep the serum vitamin B12 within the normal range. Treatment that does not do so should not be considered to be adequate. Blood transfusion is, of course, a necessity in acute cases of anemia, whether due to hemorrhage or hemolysis, but in chronic anemia, great care must be taken because of the risk that acute pulmonary edema may be induced by an ill-judged or ill-timed blood transfusion. G. S. Kilprrtvick, M.D., M.R.C.P.E. J. L. Withey, M.B., B.S. i2fcedical Vnit and Institute of Pathology U’elsh National School of fifeda’cine, Cavdiff, Wales REFERENCES 1. Roy, S. B., Bhatia, M. L., Mathur, V. S., and Virmani, S. : Haemodynamic effects of chronic severe anaemia, Circulation 28:346, 1963. 2. Coombs, C. F.: Cardiac symptoms of pernicious anaemia, with particular reference to cardiac pain, Brit. M. J. 2:185, 1926. 3. Willius, F. A., and Giffin, H. 2.: Angina1 syndrome in pernicious anaemia, Am. J. Clin. Sc. 30:174, 1927. 4. Brannon, E. S., Merrill, A. J., Warren, J. V., and Stead, E. A.: The cardiac output in patients with chronic anaemias measured by the technique of right atria1 catheterisation, J. Clin. Invest. 24:332, 1945. 5. Porter, W. B., and Watson, James, G.: The heart in anaemia, Circulation 8:111, 1953. 6. Hunter, A.: The heart in anaemia, Quart. J, med. 15:107, 1946. 7. Waife, S. O., Jansen, C. J., Crabtree, R. E., Grinnan, E. I.., and Fouts, P. J.: Oral vitamin B~z without intrinsic factor in the treatment of pernicious anaemia, Ann. Int. med. 58:810,1963. 8. Withey, J. L., Jones, J. H., and Kilpatrick, G. S.: Long-term trial of oral treatment of pernicious anaemia with vitamin B1? peptide, Brit. M. J. 1:1583, 1963. 9. Jasinski, B., Stiefel, G. E., Frei, H., and Wuhrmann, F.: Untersuchungen iiber das Schicksal und die Verteilung im Organismus des peroral oder parenteral verabreichten Vitamin RI?, Clin. Chim. Acta 1:189, 19.56. 10. Mooney, F. S., and Heathcote, J. G.: Oral treatment of subacute combined degeneration of the cord, Brit. M. J. 1:1585, 1963.