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'Krebs Cycle' and Steroid Metabolism Arch Dis Child: first published as 10.1136/adc.34.177.371 on 1 October 1959. Downloaded from THE RELATIONSHIP BETWEEN CALCIUM-PHOSPHORUS METABOLISM, THE 'KREBS CYCLE' AND STEROID METABOLISM BY ETTORE DE TONI, Jr. and SERGIO NORDIO From the Department ofPaediatrics, Gaslini Children's Hospital, Genoa University School of Medicine, Italy (REcEIvED FOR PUBLICATION MARCH 6, 1959) It has been shown in the course of the last few We have become conversant in recent years with years that the number of factors playing a part in the importance of the relationship between ossifica- calcium-phosphorus (Ca-P) metabolism is far greater tion, parathyroid hormone, vitamin D and the than had been known. It was found that the 'Krebs cycle' (Glanzmann, Meier and Walthard, calcification of bones depends in the first place on 1946; Heinz, Miller and Rominger, 1947; Harrison the 'citric acid cycle' and on adenosine triphosphate and Harrison, 1952a; Nordio, Semach and Grego, (ATP) (oxidative phosphorylation) (Dickens, 1941; 1956; de Toni, 1957). In rickets the citric acid Albaum, Hirshfeld and Sobel, 1952; Dixon and level in the blood and urine is diminished (Harrison, Perkins, 1952; Marks, Hiatt and Shorr, 1953). 1954; Nordio et al., 1956). The same phenomenon Alkaline phosphatase intervenes chiefly in the is observed in idiopathic hypercalcaemia (Forfar, processes concerned with the formation of the Balf, Maxwell and Tompsett, 1956; Nordio et al., by copyright. organic substance of the skeleton. 1956). Administration of vitamin D and, although Some factors as yet unknown (citrates ?) similarly less regularly, of parathormone leads to a rise in the regulate the action of the parathyroid hormone, an citric acid level in blood and urine (Harrison and action which has not yet been accurately defined Harrison, 1952a; Steenbock and Bellin, 1953; (Zweymiller, 1958). The role played by the para- Nordio et al., 1956). Considerable importance is thyroid in classical and in vitamin D resistant rickets attributed to the 'citric acid cycle' in the renal is still uncertain (Lamy, Royer, Frezal and Lestradet, tubules in connexion with the regulation of the 1958). Similarly, the action of vitamin D seems to acid-base balance and the reabsorption of phos- be dependent on factors which regulate the sensi- phorus, amino acids and glucose (Harrison and http://adc.bmj.com/ tivity of the organism to its effect (Fanconi and Harrison, 1941; Durand, Manzini, Bruni and Spahr, 1956). The suprarenals have acquired some Semach, 1956; Nordio et al., 1956). As is known, degree of importance, as was shown in studies on the synthesis of steroids has the 'Krebs cycle' as its idiopathic hypercalcaemia, on tetany occurring in starting point, and it may be possible to interpret the newborn infants of diabetic mothers and on hyper- various disturbances of calcium-phosphorus meta- calcaemia with osteosclerosis found in a number of bolism also in terms of the Krebs cycle. cases of myxoedema (Gittleman, Pincus, Schmerzler on September 27, 2021 by guest. Protected and Saito, 1956; Winberg and Zetterstrom, 1956; Classical Rickets Treated with ATP Anderson, Brewis and Taylor, 1957; Royer, Lestradet and Habib, 1958; Zetterstrom and We have studied the following four cases of Arnhold, 1958). Cortisone acts as an antagonist of classical rickets in the florid stage, no treatment with vitamin D by impairing the absorption of calcium vitamin D ever having been given. from the intestines; another action of cortisone is Case 1 was a boy aged 2 years 4 months; Case 2 was to reduce the rate of tubular reabsorption of phos- a girl aged 4 years 1 month (sister of Case 1); Case 3 phorus (Roberts and Pitts, 1953). It is possible that was a boy aged 19 months, and Case 4 was a girl aged there is a relationship between the suprarenals and 13 months. the parathyroid glands, as suggested by cases of Treatmeat. All four cases received ATP intra- hypoparathyroidism associated with Addison's muascuarly, the dosage being, in Cases I and 2, 5 mg. disease (Leonard, 1946; Papadatos and Klein, 1954; daily for a period of 50 days and 10 mg. daily for a Whitaker, Landing, Esselborn and Williams, 1956). further period of 25 days; in Case 3, 5 mg. daily for a 371 Arch Dis Child: first published as 10.1136/adc.34.177.371 on 1 October 1959. Downloaded from 372 ARCHIVES OF DISEASE IN CHILDHOOD period of 20 days and 10 mg. daily for a further period sister had suffered from rickets and still showed signs of 10 days; and in Case 4, 5 mg. daily for a period of of the disease. The radiological and biochemical findings 40 days. in both twins were more or less identical. These were cases of classical rickets with hyperamino- The biochemical findings showed: a moderately low aciduria and slight changes in the acidification of the blood phosphorus level with slightly increased phos- urine. Results of treatment are shown in Table 1. The phaturia; a marked increase in phosphatase, increased citrate content of the blood was markedly lowered in amino-aciduria, considerable lowering of the blood citric two cases only, in contrast to the other cases studied by acid level and marked hypercitruria (Table 2). Table 3 Harrison (1954) and Nordio, Segni and Massaccesi, 1957. gives the blood and urine citric acid levels compared with The citric acid content of the urine was not markedly normals. lowered and in Case 2 it was even raised, whilst the figures In contrast to findings in normal subjects, intravenous for blood citric acid were low. Administration ofATP led loading with citric acid did not lead to any marked rise to a definite improvement in the radiological picture of in the citric acid content of the blood (Fig. 5). The citric the bones (Figs. 1-4), to a rise in blood phosphorus, and acid content of the urine before citric acid administra- in three instances to a lowering of the phosphatase tion was 6-75 mg. per hour; after loading it was figures. The changes in phosphaturia and in the citric 32-4 mg. per hour. acid levels in the urine and blood did not conform to any By simultaneous determination of the endogenous regular pattern, and the changes in urinary amino acids creatinine clearance, we were able to show that the were only slight. glomerular filtration rate of citrate was less than the final urinary excretion rate (Table 4). In a number of normal Rickets and Seitivity to Vitam D subjects of different ages and in other cases of rickets Case 5. This boy, aged 18 months, had radiological of the classical type we have always found the urinary and clinical signs of severe rickets. The main biochemical excretion per minute of citric acid to be smaller than the features were as follows: the blood citric acid level was glomerular filtration per minute. Our findings suggest a markedly lowered with a comparative increase of urinary lowering of the renal threshold for citric acid in the twins. output of citric acid; there was a moderate lowering of It appears that in these cases the renal tubules excrete the blood phosphorus level with normal urinary output rather than reabsorb citric acid. These studies show the existence in certain forms of rickets of a 'citric renal of phosphorus, and a moderate rise in phosphatase by copyright. (Table 2). diabetes'. TREATmET. After daily administration of 10,000 i.u. The mother of the twins showed a very low blood of vitamin D2 over a period of 40 days the following citric acid level and a very high urinary citric acid output. findings were noted. There was an increase in calcifica- Similarly, the sister of the twins, who was affected by tion of the bones but severe deformities of the metaphyses rickets, showed a very low blood citric acid level (Table 5). were still present. There was a return to normal of the The father and brothers, who were free from rickets, had blood phosphorus but no change in phosphatase or normal blood citric acid kvels. It seems that the citrate. After two months' treatment with ATP (10 mg. marked familial predisposition to rickets was associated daily) the radiological picture became normal and there with a change in citrate metabolism. was some improvement in the phosphatase level. This case shows partial resistance to vitamin D but complete TREATMENT. Case 6, following a single injection of http://adc.bmj.com/ clinical and radiological cure with ATP. 15 mg. (600,000 i.u.) of vitamin Db, was given 5,000 i.u. daily by mouth over a period of two months. We noted Cases 6 and 7. These twins, aged 17 months, had only a slight improvement in the radiological picture but severe clinical and radiological signs of rickets. One the phosphorus content of the blood became normal on September 27, 2021 by guest. Protected FIGS. I and 2.ca 3. Before ATP treatment. FKaS. 3 and 4.-Case 3. After ATP treatment. Arch Dis Child: first published as 10.1136/adc.34.177.371 on 1 October 1959. Downloaded from CALCIUM-PHOSPHORUS METABOLISM AND OSSIFICATION 373 I e4- (i -4 + -09 . _ + -o (.' 0 ! + t+.L (O + U (.4V (.4 ~ ~ ~ ~ ~ C |< % W1--%c O -WI_ an~ en en r4 WI"0 is+V r -_ I. by copyright. U3 IU %l_N jX .<W u, en < r tnE C4o cU, -JJ U U6 ... En http://adc.bmj.com/ .J 0 C) fA. U. <<s:eAo>nsn*|t - + en1el0 --- a s s_T on September 27, 2021 by guest. Protected , esl >otoxuaa- 0 * wt ~ + + ~+++ 01 . ._ .. .... 00a5 C :. : oco~.~. It , glll'=~ E~~0onC Arch Dis Child: first published as 10.1136/adc.34.177.371 on 1 October 1959.
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