A Discussion of the Forms of Blood Calcium

Calcium has numerous functions in human metabolism. It comprises (as tri-calcium phosphate and calcium carbonate) about 98% of the mineral component of bone and tooth structure.¹ It forms an important blood buffer (as ionized calcium bicarbonate). It is a necessary constituent of tissue fluids in maintaining proper electrical potential balance in muscle and nerve.

The accompanying chart attempts to illustrate the various phases and controlling factors of calcium metabolism as far as it has been followed in medical literature to date.

The calcium and phosphorus forms in the bloodstream are represented by the paragraphs within the circle in the center of the chart. The bloodstream functions principally to carry these forms to the various parts of the body where they are needed. We are primarily interested in how the calcium is put into this bloodstream, how it is kept there, and how it is deposited in various tissues where and when it is needed. Inasmuch as phosphorus is intimately connected with calcium in its deposition as bone, we have included phosphorus in this treatment.

Dietary Absorption of Calcium and Phosphorus

First, calcium and phosphorus are absorbed into the blood from the food in the small intestine. In order for the blood to pick up calcium from the small intestine the calcium must be in the form of simple, soluble and diffusible salts.² More complex calcium salts are utilized only if there is enough hydrochloric acid present in the stomach to break them down into simpler salts.³ The parathyroid hormone aids this absorption,² and large doses of vitamin D likewise,⁴ probably by increasing the osmotic demand through the conversion of diffusible to non-diffusible calcium.

Phosphorus is obtained from foods in the form of inorganic phosphates, lecithins, phosphatides, etc.,⁵ and unsaturated fatty acids aid in its absorption,⁶ probably activated by vitamin F.⁷ This phosphorus goes into a blood reserve consisting of lecithins, and inorganic phosphates, some of which are diffusible,^6,5 this reserve comprising about 30% of the serum phosphorus.² (The other 70% is combined with Ca as seen later.)

Calcium Forms in Serum

Various investigators have stressed the important fact that study of the blood concentration of the inorganic salts gives no indication of the rate of direction of their flow into the excretory channels or into the tissues.³

The assimilated calcium salts become diffusible ionic calcium mainly as bicarbonate, (Ca(HCO3)2) on reaching the bloodstream⁸ comprising roughly about 20% of the serum calcium.²(Most biochemists consider the ionized calcium to be mainly bicarbonate, however when tissue fluid calcium is precipitated as dental calculi or eliminated by perspiration the major percentage is in the form of phosphate.^37,81,16)

This ionized calcium depends for its concentration upon physio-chemical relationships with free floating proteins, tissue fluids, and an amount of blood alkaline salts of higher periodic activity, such as potassium or magnesium, which tend to replace it.⁶ It thus acts in part as a blood buffer.⁸

The concentration of diffusible ionized calcium in the blood serum increases to an extent with a lowered pH of the blood serum.^8,2 This may be due to the fact that lowered pH results in the fixation of more potassium and magnesium buffer salts. When these salts are lowered they are replaced by calcium ions and the total calcium in blood will increase, resulting in more elimination.³

Depending upon the amount of free floating serum proteins, this type of ionic calcium will combine with these proteins into a non-diffusible calcium proteinate, which is a blood calcium reserve.² This calcium proteinate will split and give back ionic calcium if the serum protein concentration is reduced. This calcium proteinate reserve comprises about 38% of serum calcium.²

Vitamin C is a catalyst for protein synthesis and thus it would follow that it is necessary to the retention of this reserve.⁹ The integrity of this reserve thus is probably dependent upon vitamin C and is lowered in scurvy.

The ionic calcium bicarbonate is also in physio-chemical relationship with a non-ionized form of calcium bicarbonate comprising about 5% of total serum calcium, but having no known physiological significance.¹⁰

Calcium in Tissue Fluids–Tetany

The ionic calcium, being diffusible, is an important constituent of tissue fluids, serving to maintain muscle tone, and being essential to normal action of the sympathetic nervous system.¹¹ Both parathyroid hormone,^2,12 and vitamin F¹³ are necessary to maintain a proper concentration of ionic calcium in tissue fluids.

One of the ways in which parathyroid hormone insures this calcium concentration is by its promotion of the excretion of the higher periodic alkaline salts (K and Mg) having a calcium sparing action.¹⁴ Other means will be mentioned further in this discussion. If (as a result of parathyroidectomy) the calcium ions in tissue fluids drop below a necessary concentration there is an electrical potential disturbance resulting in hyperexcitability and spontaneous contractions of muscle, called tetany.² Since ionic calcium is the only diffusible blood serum form of calcium, and this is low in tetany, the total blood calcium will also be lowered in this condition. As we shall see, this does not happen in rickets.

Excretion of Calcium

If more ionic calcium than is necessary is present, and there is not free floating serum protein to take it up as a blood reserve, it will be excreted. Normal muscular activity causes an increase in sweat gland excretion with a temporary sharp drop in ionic calcium.¹⁵ This may explain why tremors may be associated with hard exercise. When calcium is lowered no more is excreted after the urinary threshold of 8.5 mg. per 100 cc. is reached.¹⁶

In order for calcium bicarbonate to remain in solution its media must be acid or contain an excess of CO2.⁸ Urinary excreted calcium will therefore only be soluble in acid urine because of the absence of CO2. An alkaline urine will result if basic salts (Na, K, Mg, etc.) are excreted. Normally these basic elements are replaced with ammonia (synthesized in the kidney)¹⁷ and retained in the blood. In hyperparathyroidism^14,18 and vitamin A deficiency,¹⁹ basic salts are excreted. The resulting alkaline urine precipitates the ionic calcium with the pathological deposition of renal calculi.

Some calcium bicarbonate is in the saliva. The same holds true here. It has been shown clinically that a high phosphorus intake will result in dental calculi.⁶

Rickets and Tetany

Bones and cement of teeth¹ are composed about 88% of calcium phosphate and 12% calcium carbonate hydroxide and fluoride in varying proportions.¹⁰ The calcium and phosphate are deposited together by the enzyme phosphatase.²⁰

The only calcium and phosphorus in the bloodstream that forms bone structure is a special form of ultra-filtrable, non-diffusible calcium phosphorus.² This calcium-phosphorus complex is colloidal and answers best to the description of calcium-phosphorus bone precursor. Apparently, it is a loosely held combination of phosphorus esters and calcium. The specific action of apy anti-rachitic substance or vitamin D is the formation of this calcium-phosphorus compound in the blood from ionic calcium and inorganic phosphates. In rickets this colloidal complex is always lowered, although total serum calcium is usually normal.² The breakdown of this calcium-phosphorus complex gives rise to corresponding amounts of ionic calcium and diffusible phosphorus resulting in phosphorus excretion.²

That is the essential difference between rickets and tetany. In tetany the diffusible ionic calcium is low. But in rickets, it is the special ultra-filtrable, non-diffusible calcium-phosphorus complex that is low with a correspondingly high diffusible calcium and consequently normal total serum calcium.²

It has been demonstrated that parathyroid hormone promotes the excretion of serum phosphorus.²¹ By lowering the phosphorus the chances of formation of calcium-phosphorus compound is lessened, and ionic calcium will remain as it is. Thus parathyroid accelerates rachitic lesions.^3,2 Vitamin F raises blood phosphorus,¹³ promotes the diffusion of ionic calcium into the tissue fluids,¹³ probably by breaking up the calcium-phosphorus colloidal complex, to form ionic calcium. Thyroid has a similar effect in raising ionic calcium and has been called a calcium eliminator for this reason. In presence of vitamin D, vitamin F cooperates in mobilizing phosphorus for vitamin D to form into calcium-phosphorus complex.

In accounting for all known forms of serum calcium it is of interest to note that the ultra-filtrable calcium phosphorus bone precursor has a non-colloidal counterpart with which it is in physio-chemical balance.2 The ultra-filtrable calcium-phosphorus complex accounts for about 30% of total serum calcium and about 70% of the total serum phosphorus,2 while its physio-chemical partner comprises about 10% of total serum calcium and about 5% total serum phosphorus.²

Bone and Tooth Formation

The osteoblasts or bone forming cells secrete a local enzyme, phosphatase, which hydrolyzes the phosphorus ester component of ultra-filtrable calcium-phosphorus bone precursor, giving rise to phosphate ions³³ and apparently calcium ions which are precipitated as calcium-phosphate bone salt.^22,20,33

Normal physiological amounts of parathyroid hormone tend to stimulate osteoblastic formation²¹ and thus the formation of phosphatase; however, as mentioned later, hyperparathyroidism reverses to some extent the activity of this enzyme.²² Normal amounts of vitamin D tend to keep this enzyme locally concentrated and out of the bloodstream.²⁰ Adrenal cortex acts similarly.²³ In vitamin C deficiency the osteoblasts degenerate, preventing phosphatase formation and thus prevent calcification of bone.¹⁰ Vitamin C also catalytically activates the action of this enzyme phosphatase.²⁴ This accounts for the deficient bone and tooth development in scurvy or pyorrhea.

The bones form a vast storehouse of calcium reserves which are drawn upon to supply calcium in dietary lack or in pregnancy. In early pregnancy it is interesting to note that estrogen increases the density and thickness of the mother’s bones thus augmenting the calcium reserve.²² In these conditions, it is probable that phosphatase reverses its activity and redissolves bone so that the calcium is resorbed into the blood as ionic calcium bicarbonate and phosphate. (Most enzymes are known to be reversible depending upon hormonic and substrate controls or conditions.³³) Hypervitaminosis D,^25,26 hyperparathyroidism,^12,25,22 and thyroid²⁸ supply ionic calcium by bone resorption in emergency, apparently through this enzyme reversibility.

Resorption of bone, resulting from reversing of phosphatase enzyme as described above, is called osteitis fibrosa generalisata. If there are not enough calcium salts precipitated into the organic matrix due to deficiency of calcium-phosphorus bone precursor, as in rickets, the condition is called osteomalacia. If there is an underactivity or degeneration of the osteoblasts, (phosphatase formers) with resulting phosphatase deficiency and consequent incomplete calcification, the condition is called osteoporosis.²⁹

The underactivity or degeneration of osteoblasts may be caused by atrophy from disuse29 or from vitamin C deficiency.10 In osteoporosis there may arise an increase in serum ionic calcium since bone resorption is taking place faster than calcification, with resultant overloading of kidney calcium excretion capacity and consequent kidney damage.²⁹ An erroneous diagnosis of hyperparathyroidism (bone resorption from phosphatase activity) may be made in this condition which may be due to inanition of skeleton²⁹ or from vitamin C deficiency.¹⁰

Silberberg and Silberberg divide the formation of mammalian bone into three distinct periods, the extent of metabolism being predetermined. Various hormones accelerate or retard the rate of metabolism in each period but do not change the total extent of metabolic activity which is predetermined by heredity. The physiological effect of various hormones in accelerating or retarding the rate of activity in each period is shown in the following chart.²²

Ordinarily the enzyme phosphatase is only found locally near the osteoblasts.²¹ In some pathological conditions it “leaks” into the blood stream which could explain pathological calcium deposition in the blood vessels (arteriosclerosis), in tissues, and in joints (arthritis). Rickets,²⁷ hyperparathyroidism,²⁷ and tremendous dosages of vitamin D²¹ cause a rise of phosphatase in the blood stream. Adrenal cortex prevents this rise.²³ Vitamin D normally keeps phosphatase localized.²⁰

Pathological Calcium Metabolism

Much clinical experience has demonstrated the toxic calcification of tissue, especially in pregnancy, resulting from high dosages of synthetic vitamin D.²¹ Tremendous dosages of vitamin D are used in the treatment of arthritis with some success. This dosage would create considerable demand for ionic calcium, and pathological joint deposits can give this calcium to the blood. It is possible that this may account for the success of vitamin D in these conditions, although there is insufficient experimental evidence to warrant a positive conclusion. Single high dosages or tremendous dosages of vitamin D would seem to be contra-indicated by reason of its promotion of phosphatase in the bloodstream, which can cause pathological calcium deposits in blood vessels as arteriosclerosis. Arteriosclerosis from hypervitaminosis D is a common clinical picture.³⁰

In view of the presence of arteriosclerosis resulting from hypervitaminosis D in the absence of its synergist vitamin F, we might assume that vitamin F would tend to prevent arteriosclerosis in this respect. The fact that arteriosclerosis is a rare disease in China,³⁶ where the diet contains foods high in F, such as soybean products, deserves careful investigation.

Arthritis is also apparently not a common disease in China, there being no reference to it in Dr. Snappers’ review of cases he encountered in the Peiping’ Union Medical College Hospital.³⁶

It has been noticed that cod liver oil does not have the pathological calcifying effects of viosterol or synthetic vitamin D. Recent work has shown that cod liver oil contains vitamin F.³¹ It might be remembered that vitamin F increases ionized calcium at the expense of calcium-phosphorus complex.

A lack of phosphorus will cause a poor production of colloidal calcium-phosphorus bone precursor. Phosphorus deficiency has been claimed to be a primary cause of rickets.^2,32 The action of vitamin F in promoting phosphorus absorption⁶ should not be overlooked in this sense.

In such a phosphorus deficiency the serum content of ionic calcium may become super-saturated and deposit pathological calcium carbonate in the joints and tissues.³⁵

The etiological factors in disorders of calcium metabolism, other than endocrine abnormalities, may be dietary deficiencies of vitamin D, vitamin F, vitamin C, calcium, or phosphorus, or more likely a combination of these.

In children, this absence of calcium deposition means that bone and tooth structure will fail to keep pace with the growing body, and rickets, deformities, and dental malformations are a result. In adults, the resorption of bony structure may mean a tendency to fracture easily, dental caries, pyorrhea, and resorption of the alveolar ridge with loose teeth. These deficiencies may also cause a disturbed balance of serum ionic calcium bicarbonate and serum phosphorus that will precipitate insoluble calcium forms aggravating arteriosclerosis or arthritis.

Calcium metabolism is a field of biochemistry which probably has more extensive ramifications than the study of any other nutritional element. In view of the importance of this subject, it is surprising how incomplete our knowledge is and what few attempts have been made to put what knowledge we have on a systematic basis. A proper review of the subject would touch upon almost every phase of biochemistry.

 

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