6Disorders of carbohydrate metabolism in the red blood corpuscle

Abstract

Summary An important outcome of the study of abnormalities of glucose metabolism in the red cells has been a greater understanding of the modulating effect of 2,3-DPG on the oxygen affinity of blood as well as the relationship of oxygen affinity to erythropoiesis via the erythropoietin mechanism. In those conditions in which the oxygen affinity of the red cell is abnormal either due to an enzyme defect with altered 2,3-DPG level or an abnormal haemoglobin, the haemoglobin level will be adjusted accordingly (Bellingham and Huehns, 1968). With an increased oxygen affinity the proportion of oxygen released from the red cells will be decreased. Consequently the erythropoietin drive to the marrow will increase and the haemoglobin will rise. Conversely with a decreased oxygen affinity the haemoglobin will fall. Using these new ideas one can attempt to predict what the effect of altering the oxygen affinity would be in various clinical conditions to see if these would be beneficial. The inherited red cell defects with a low oxygen affinity such as PK deficiency and some abnormal haemoglobins, e.g. Hb-Hammersmith, would benefit by an increase in O 2 affinity. In these the return to a normal oxygen affinity would increase the erythropoietin drive to marrow and thus increase the red cell mass. This group also contains sickle cell disease. As the polymerisation of Hb-S leading to sickling is dependent on the production of a sufficient concentration of deoxy Hb-S in the cell, a shift of the oxygen dissociation curve to the left (increase in oxygen affinity) will reduce sickling by decreasing the deoxygenation of the red cells at tissue Pot. However, the increase in packed cell volume which is known to occur would increase the viscosity problems if sickling did occur (May and Huehns, 1976). In angina or intermittent claudication a lowering of the oxygen affinity might be beneficial in that the proportion of oxygen released from the blood would be increased, thus improving the amount of exercise possible before the onset of symptoms. Unfortunately lowering of the oxygen affinity will reduce erythropoietin production and lower the haematocrit. The end result after two or three weeks would be that oxygen delivery returns to the pretreatment value. The only long-term advantage might be that the lower haematocrit would minimize any viscosity problems which were contributing to the clinical symptoms. In a patient with an Hb of for example 16 grams/100 ml a lowering of Hb to 12 grams/100 ml with the same oxygen release in the tissues may be of some benefit. The situation in cyanotic chest disease, chronic renal disease and inneonatal problems of oxygen delivery is not clear. In respiratory disease a case could be made out for raising the oxygen affinity to increase oxygen loading in the lungs. However, careful analyses, taking into account the arterial and venous oxygen tension in relation to the position of the in vivo oxygen dissociation curve are necessary. The shape of the curve may also be important as it has been shown (Bellingham, 1972) that in vivo a high affinity is physiologically only possible in association with loss of co-operativity (i.e. reduced `n' value). In chronic renal disease a further lowering of oxygen affinity may be of benefit, providing that this does not lead to further anaemia due to suppression of the erythropoietin drive to the marrow. From the foregoing discussion it seems likely that there will be a place for therapeutic adjustment of the oxygen affinity and several approaches to this problem are presently under investigation. o 1. Reaction of haemoglobin in vivo with some chemical agent may increase the oxygen affinity. This is the mode of action of cyanate, which increases the oxygen affinity by carbamylating the terminal amino groups of the globin chains, thus cyanate has a small beneficial effect on sickle disease. It has unfortunately proved too toxic (Harkness, 1975) for oral clinical use, presumably due to reaction with other proteins in the body (see Peterson and Cerami, 1974; May and Huehns, 1976). 2. Another approach is to design compounds to fit the 2,3-DPG (or another) binding site on the haemoglobin molecule which would then stabilise either the deoxy (or oxy) form of haemoglobin. Several such compounds are already under investigation (Bedell et al, 1976). 3. Compounds designed to fit the 2,3-DPG binding site may of course also fit the 2,3-DPG binding site of enzymes concerned in the synthesis or breakdown of 2,3-DPG and alter the 2,3-DPG level in the cell. As 2,3-DPG is only of importance in the red cell this may be a non-toxic approach to the in vivo adjustment of oxygen affinity.