Canad. M. A. J. July 1, 1957, vol. 77 REVIEW ARTICLE: CA AND P METABOLISM 45 REVIEW ARTICLE (d) Vitamin D and/or calcium de- ficiency: (i) In diets; (ii) In A REVIEW OF CALCIUM AND gastro-intestinal disorders of malabsorption; (iii) In preg- PHOSPHORUS METABOLISM nancy and lactation. PART II: HYPOCALCIEMIA (2) Pseudo Pseudo Hypoparathyroid- ism H. Z. HOLLINGER, M.D., C.M.A and C. J. PATTEE, M.D., C.L.,t Mlontreal III. TETANY-as a result of electrolyte disturb- ances THIS IS THE LAST in a series of review papers38"'; dealing with calcium and phosphorus metabol- I. SECONDARY HYPERPARATHYROIDISM ism. Since the discussion of the causes of hyper- was prob- calcaomia" was completed with a review of A. Secondary hyperparathyroidism primary hyperparathyroidism, for the sake of ably first noted by MacCallum in 1905 in a pa- continuity secondary hyperparathyroidism result- tient with nephritis, and Erdheim in 1906 de- ing from hypocalc,emia will be discussed. scribed similar findings in a case of rickets. The The outline below will be followed. most common cause of this condition is chronic long-standing renal disease due to congenital ano- malies of the genito-urinary tract, pyelonephritis, I. SECONDARY HYPERPARATHYROIDISMI pyonephrosis and glomerulonephritis. It has also A. (1) Congenital genito-urinary ano- been reported in the occasional case of pituLitary malies. basophilic and eosinophilic tuimours, and in (2) Occasionally in pituitary eosino- cases in which pituitaiy tumours were associ- philic and basophilic tumours. ated with islet cell enlargement of the pancreas, (3) From any cause producing a long- from any cause producing a long-standing tend- standliig tendency to hypocal- ency to hypocalcamia, in Paget's disease, mul- cGemia. tiple myeloma or in secondary malignant bone (4) In Paget's disease, multiple mye- metastases. In the latter, the cause is unknown. loma anid secondary malignant When hypocalcoemia occurs, or when hypocal- metastases in bone. cmic tendencies are present due to a poor cal- B. Retnal Rickets (Renal Osteitis Fibrosa cium intake, in pregnancy or lactation, para- Generalisata) thvroid hvperplasia develops in an attempt to (a) Pathogenesis raise the serum calcium level. (b) Treatment Pathologically, the glands are diffusely en- C. Renal Acidosis wvith Osteomiialacia larged and hyperplastic. Adenomata are rare. (a) Pathogenesis Castleman and 'Mallory1 in 1935 described a de- (b) Treatment crease or absence of the intercellular fat tissue, a D. Fanconi Sy ndromne rarety of mitoses, and the predominance of nor- (a) Pathogenesis mal-sized chief cells, more oxyphil cells than (b) Treatment one would expect for the age of the patient and an increase in the number of vasserhelle (water II. PRIMIARY AND IDIOPATHIC clear) cells (containing much glycogen). Occa- HYPOPARATHYROIDISMI sionally the glands may be smaller than normal It be that the A. Etiology and Pathogenesis and yet they are overactive. may B. Signs and Symptonms fat content is decreased and replacement occurs (1) Tetany-latent and acute forms with epithelial cells. (2) Skin, central nervous system, blood The two main causes of secondary hyperpara- and bone changes thyroidism are in chronic renal disease in which C. Differential Diag,nosis renal function impairment or insufficiency may (1) Other syndromes associated with be present. These twvo causes are: (a) "tubular tetany disease with associated glomeruLlar disease" in (a) Secondary hyperparathyroid- which there is retention of phosphate as well as ism other acid radicals, and (b) "tubular disease (b) Pseudohypoparathyroidism: without glomerular malfunction" and without (i) Etiology and pathogenesis; phosphate retention. (ii) Signs and symptoms; (iii) Treatment. B. RENAL RICKETS (c) Electrolyte disturbances (a) Pathiogenesis *Research Fellowr, Clinical Investigation Unit, Queen Mary In cases with tubular and glomerular diseases Veterans Hospital, Montreal. both present, one finds a retention of non pro- tDirector, Clinical Investigation Unit, Queen MIa.ry 'Vet- erans Hospital, Montreal. tein nitrogen, phosphate, sulphate, a normal to Canad. M. A. J. 46 REVIEW ARTICLE: CA AND P METABOLISM July 1, 1957, vol. 77 low serum calcium, severe acidosis with a low lithiasis may occur. Therapy consists in over- CO2 combining power and either a high chloride coming the acidosis and in decreasing the phos- or a low serum sodium level. There is a de- phate intake. Sodium citrate, 2-3 g. orally four creased ability to conserve base and hence a times a day, increases the CO2 combining power more alkaline urine with an increased excretion of the plasma Citric acid can be added to the of potassium, sodium and calcium. If much po- sodium citrate to increase intestinal acidity an(i tassium is lost, the signs and symptoms simulat- so increase the absorption of calcium. The rela- ing familial periodic paralysis with low voltage tive shift, however, towards alkalinity in the T waves in the electrocardiogram may develop. presence of a high serum phosphorus and low Phenolsulfonphthaleiii excretion is impaired; serum calcium levels may be sufficient to pre- anxmia and high serum phosphatase are present. cipitate tetany. According to Albright and Secondary calcifications in the lung, gastric mu- Reifenstein, this is more theoretical than real. In cosa, kidney tissues, an increased tendency to addition to a high calcium and low phosphorus develop M6nckeberg's medial sclerosis and occa- diet, a calcium sldt such as calcium gluconate sionally calcium deposits about the joints, may (about 5 g., three times a day) should be given also be observed. With the phosphate retention orally with at least 50,000 unlits of vitamin D. On and the supersaturation with respect to the cal- such a regimen the bone lesions improve and cium times phosphorus product, there cannot be one may see x-ray evidence of healing within much delay in caclisnn precipitatioin. Ultimately 2-3 months. Unfortunately, the renal disease and bone disease develops in adults indistinguishable the antemia remain. The nephrocalcinosis or from osteitis fibrosa generalisata. In 1936, Al- nephrolithiasis are corrected when the acidosis is bright prefixed "renal" to the osteitis fibrosa overcome by therapy and need never recur, pro- generalisata. vided future episodes of acidosis which increase In children, in addition to the usual bone the urinary calcium excretion are prevented. alterations, there are epiphvseal changes with slipping of the epiphyses which radiologically C. RENAL AcIDosis WITH OSTEOMALACIA look like rickets, and thus in children the condi- (a) Pathogenesis tion was called renal rickets or dwarfism (because In tubular dysfunction without glomerular dis- growth was affected). Albright, Drake and Sul- ease, the renal acidosis leads to an osteomalacia. kowitch2 showed that microscopically the epiphy- In this condition, because of a presumably defec- seal changes were not the same as in true tive ammonium ion formation, an excess of rickets. It was also noted that primary hyper- sodium, potassium and calcium cations is ex- parathyroidism in children does not result in creted, the urine titratable acidity falls, and the slipped epiphyses. plasma CO2 combining power decreases. As a The stages in this type of renal disease seem result of the decreased serum calcium concentra- to be an increased urinary calcium excretion be- tion, the parathyroid glands are stimulated and cause of the acidosis which leads to a lowered urinary phosphate excretion increases. The net serum calcium level; the increased phosphate re- result is a low serum calcium and phosphoris tention also leads to a lowered serum calcium, concentration. Because of these low concentra- which in tuni increases parathyroid activity re- tions, a calcification of bone occurs and osteo- sulting in an increased tendency to excrete phos- malacia primarily develops. Ultimately increased phorus. The latter cannot be accomplished be- stresses and strains will be placed upon the cause of glomerular disease. A direct effect on skeletal system, with the result that the alkaline bone reabsorption is exerted by the parathyroid phosphate level will rise. In this type of renal hormone, tending to elevate the serum calcium disease nephrolithiasis or nephrocalcinosis is and thereby increasing the plasma phosphate much rarer because the blood levels of these even more. Ingalls, Donaldson and Albright3 in electrolytes about the renal tubules are relatively 1943 confirmed the work of previous investiga- low. tors.4` In nephrectomized dogs, it was shown that parathyroid hormone does have a direct de- (b) Treatment calcifying action on bone aside from the seem- The treatment here is to make up for base lost. ingly direct action on the kidneys to excrete Thus one can provide the patient with sodium phosphate.-18 This has recently been confirmed citrate, sodium lactate and/or calcium gluconate, by Grollman.7 If one believes only in the renal and if the plasma potassium is low, potassium action of parathyroid hormone, then the secon- citrate may be given. Oral citric acid will, by dary hyperparathyroidism need not cause the tending to lower the pH of the intestinal tract, bone changes but may be explained purely on increase calcium absorption. Hence a combina- the basis of the acidosis which results in in- tion of 140 g. of citric acid and 90 g. of sodium creased bone reabsorption. citrate is dissolved in one litre of water and the patient is required to take 50-100 c.c. of this (b) Treatment mixture daily. As for the bone lesions, 50,000 Because of the deranged electrolyte levels with units of vitamin D should be given daily and phosphate retention, nephrocalcinosis or nephro- about 5 g. of calcium gluconate three times a Canad. MI. A. J. July 1, 1937, vol. 77 REVIEW ARTICLE: CA AND P METABOLISM 47 day. Once the osteomalacia has been corrected, be directly related to the glycosuria. There was one need only give alkali to overcome the no excess cystinuria. He differentiated therefore acidotic tendency and osteomalacia will not two types of amino-diabetes, those in which the recur.