Citric acid and calcium metabolism.

Recently there has been increasing realisation of tile important part played by citric acid in the body’s metabolism. Thus administration of pyruvic acid, the intermediate metabolite common to the utilisation of carbohydrate, protein and perhaps fat, causes increased urinary excretion of citrate. Many tissues can form citrate by condensation of pyruvate and oxalacetate followed by reduction, and Krebs (1937) postulated the existence of a tissue respiration cycle in which pyruvate and oxalacetate yielded a succession of six carbon acids, among which was citric acid, until by loss of hydrogen and carbon dioxide oxalacetate was regenerated ready to continue the cycle with another molecule of pyruvate (Fig. 1). Since Dickens (1941) showed that the skeleton contains 90 per cent or more of the body’s citric acid and Class and Smith (1943) demonstrated its presence in various body concretions, evidence has been accumulating that this substance plays an important part in the metabolism of bone. Schersten (1931) found that the citrate content of the whole blood of man varied from 1 .5 to 40 milligrams/100 millilitres ; whereas, according to Pucher, Sherman and Vickery (1936) , that of the dog is slightly lower, from 09 to 1 .9 milligrams/l00 millilitres. Several factors influence the blood citrate level. Boothby and Adams (1932) have shown that it decreases with advancing age and Agrell (1946) has demonstrated a rise after muscular work. The blood level was found by Smith and Orten (1938) to be dependent on the dietary citric acid and is increased by oral administration of citrate or citrate precursors such as lactate, malate, fumerate or succinate. According to Ostberg (1931) values for the normal daily citrate excretion of human adults vary from 02 to 1 0 grammes and lower results are found in dogs. The citric acid is evidently the product of endogenous metabolism since Sherman, Mendel and Smith (1936) have found that it continues to appear in the urine during starvation. During the menstrual cycle variations occur in urinary citrate, and decreases are observed after oestrogen administration according to Shorr, Bernheim and Taussky (1942). The metabolism of calcium has long been thought to be associated with that of citric acid. Thus citrate has been shown by Pincus, Peterson and Kramer (1926) to form a soluble complex with calcium and it has been assumed that such a soluble complex exists in blood and accounts for the non-ionisable part of the diffusible fraction of serum calcium. Gomori and Gulyas (1944) showed that citrate injections in dogs made serum calcium more ultrafilterable so that a rapid urinary excretion of calcium took place. The state of calcium in the blood stream appears thus to influence its urinary excretion, and if the diffusible fraction of serum calcium is increased then the gbomerular filtration rate may also be increased. Chang and Freeman (1950) injected neutralised citric acid into dogs and similarly found not only increased plasma and urine citrate but also marked urine calcium increases. On the other hand, calcium chloride injections produced no change in plasma citrate but reduced urine citrate. Alwall (1944) showed that parathormone produced not only a raised serum calcium but also a parallel rise in serum citrate. Increases in both urine calcium and citrate have been found by Shorr, Almy, Sloan, Taussky and Toscani (1942) after parathormone injections in a hypoparathyroid patient, and similar results were produced in a hyperparathyroid patient with calcium injections. In Gomori’s experiments above, in which dogs were injected with