In some chemical reactions phosphorus is a negative or anticatalyzer. According to Bredig, phosphorus slows the decomposition of H2O2 even in the dilution of 1 mol in 20,000 liters of water in contrast to colloidal, platinum.
Phosphorus is an indispensable constituent of all living substances. The compounds in which phosphorus appears in the organism are derived from the highest step of oxidation of phosphorus, phosphoric acid. The powerful chemical property of reaction of elementary yellow phosphorus is not employed by the organism, moreover it exceeds physiologic bounds. Phosphorus itself and hydrogen phosphide are very poisonous. The insoluble phosphates of the bones stand at the lowest step of ability to react. In case of necessity the skeleton of the animal is a depot for calcium as well as phosphates, because in one-sided experimental calcium and phosphate deficiencies, only the skeleton suffers. A second step is formed to some extent by the alkali phosphates of the blood and fluids in general. Apart from their physico-chemical importance as salts of a weak acid for the maintenance of constant reaction in the body fluids (so-called buffer action), we must perceive in them the first available building material for the cell constituents containing phosphorus. Furthermore, the phosphatides (that is, the phosphoric acid derivatives of various fatty acids) participate as constituents of many lipoids essential to the structure of cell protoplasm (and indeed exactly in the especially active colloidal part). These labile substances obviously have a great significance in cell life and one may well presume some connection between their diversity in the cells of different organs, also between the specific lipoids and the specificity of organ functions.
According to A. Mayer and G. Schaeffer the phosphorus content of the lipoids is characteristic for each animal species. The phosphatides are markedly avid for oxygen and very easily oxidized. The capacity of the lipoids for metabolism, and lecithin (mono-amino-monophosphatide) is regarded as particularly important for the respiration of the nervous system.
Finally to be mentioned are the most complicated phosphorus compounds of the organism, the phosphoproteins (formerly nucleo albumins or phosphoglobulins). Apart from casein of milk and vitellin from the egg yolk, the nucleo-proteins come chiefly into consideration for the cell nuclei. The nucleic acid fraction of the nucleo-proteins is phosphorus containing. According to A.B. Macallum and J.B. Collip, the nucleus seems to be free from phosphate ions. Phosphorus is recognizable in the chromatin of the cell nucleus as well as in centrosomes. Youthful nuclei are phosphorus rich; later, with lessening of capacity for division, the phosphorus content markedly decreases. One also would not
go astray with the idea that the nuclear phosphorus content has a connection with growth and that this connection is also significant for the inheritable constitution.
No tissue is free from phosphorus. The heart is apparently the richest in phosphorus in the form of phosphatides in respect to the muscles. In the entire nervous system the P compounds are abundantly present. The liver is the richest of the parenchymatous organs.
An abundant use of phosphorus occurs in normal metabolism. The organic phosphorus compounds are excreted as inorganic phosphates, but inorganic phosphates have an important task in metabolic and energy changes.
While phosphorus is very easily oxidized in free air, the conditions for oxidation seem less favorable during and after resorption. This is because, in intoxication with large amounts, one finds phosphorus in the arterial blood and in the organs, especially in the liver, in an unbound form for several days. However, it may occur in the lowest step of oxidation in the expired air in that this shows luminescence. With intoxication with small amounts and fine division, the oxidation apparently proceeds rapidly so that no free phosphorus is found in the blood and the exhaled air does not show luminescence.
Phosphorus poisoning must be described here as the threatening background to the phosphorus picture. Phosphorus vapors release severe phenomena of irritation in the bronchial mucosa which leads rapidly to a pulmonary edema.
In one-half to twenty-four hours after the introduction of the poison the gastric symptoms usually appear. The patient vomits and has a burning pain in the epigastrium and the ejected material smells like phosphorus though later the material is more or less bilious.
Then follows, even after stronger doses, a two-to three day interval of comparative well being; indeed, one even speaks of euphoria. But still there appears a definite weakness with a nervous excitation and, three to four days after the ingestion, with the transient mental disturbances, the characteristic icterus appears. The epigastrium again becomes painful, the pains draw toward the right hypochondrium. One finds the liver enlarged and sensitive. Pains occur in all extremities; the patient becomes dejected, the pulse small, and the heart yields accessory sounds.
In the next few days the icterus increases, the liver definitely enlarges, though in some cases becomes smaller.
Then skin and mucous membrane bleeding begins. The vomiting reappears and bloody masses are evacuated; the gums, intestines and uterus bleed; the skin shows small petechia or extensive echymosis.
The blood pressure falls with increasing cardiac weakness. Slowing of the pulse is noted with the icterus and this may be maintained well into convalescence. In unfavorable cases the pulse rate is increased throughout the entire time. A high- grade tachycardia often appears antemortem. Fever up to 40O C is frequent.
In many cases the consciousness is clear up to shortly before death. In other cases, somnolence, delirium or convulsive attacks occur in the final twenty-four to forty-eight hours. In a case which survived, a paralysis was noted.
The urine decreases with the progression of the poisoning, and finally an almost complete anuria may exist. Bile pigments and bile acids are found in the urine. Urobilinogen is increased; in severe cases it may be diminished, the result of complete failure of the liver. Protein in moderate amounts is nearly always present. Casts, fatty casts, cellular detritus appear, and the urine usually contains moderate amounts of blood. Among 141 cases spontaneous glycosuria appeared in six, but an alimentary glycosuria could be provoked in 60 per cent of the cases.
The finding of a milk-like urine is perhaps traceable to free fat. Amino acids and peptone-like bodies and significant amounts of lactic acid are found and the excretion of ammonia can be considerably increased.
Pain in the throat, dryness in the mouth, redness of the pharynx, catarrhal phenomena of the mucous membranes are observations which may be overlooked by virtue of the more severe symptoms.
In severe poisonings death usually occurs on the seventh to eighth day. In very rare cases improvement may occur after the icterus has appeared, and during convalescence a marked diuresis is noted.
In chronic poisoning one observes, outside of the still to be discussed necrosis of the jaw, pustular eruptions, eczema of the skin, falling out of hair. Individuals may complain of dryness of the throat and of cough. The tongue is coated; the appetite is poor; and the patient complains of gastric pains, tenesmus, hiccough, and meteorism. Vomiting occurs and the stools may be bile-containing and particularly bile-poor.
Pathologico-anatomically, in the lungs are observed traces of catarrhal inflammation, more rarely pneumonic foci; exudates, in the pleura; in the stomach, infarcts, bleeding into the lumen,
in the funds and the pars pylorica, pinhead to pea-sized ulcers; the mucous membrane is often swollen, hyperemic and hemorrhagic, the mucousa doubled or tripled in size, indurated with marked pigment deposit and flat ulcers. The interstitial tissue is overgrown and many times develops in thick, broad plaques. In the duodenum the solitary follicles and the glands of Brunner are swollen and in the lower intestinal segments inflammatory phenomena are found. The gastric and intestinal contents are usually bloody.
The severe alterations in the liver are observed early. The liver is usually enlarged, only rarely lessened in size. The liver cells for the most part remain but are filled with fat globules. The interlobar connective tissue is often diminished, but many times and particularly in chronic poisoning it is so markedly developed that one may speak of definite interstitial hepatitis. With time it may come to a smooth induration or form a luetic-like hepar lobatum with numerous, deeply penetrating tongues of scars and finally the classic cirrhosis of the liver with its resultant manifestations; venous hyperemia of the gastric and intestinal mucosa, indurative enlargement of the spleen, ascites, hydrothorax.
The spleen is frequently enlarged in acute poisoning as well.
The kidneys are swollen for the most part, the epithelium of the urinary tubules filled with numerous fat globules. Connective tissue overgrowth is observed here in many cases.
The heart is fatty to a marked degree, the muscle fibres are thickly filled with droplets. The walls of small blood vessels and capillaries are likewise involved and together with the reduced capacity for coagulation of the blood the already mentioned marked bleeding is explained. In poisoning before the menstrual period, the menstrual flow becomes profuse and large hematoma may form in the ovaries. Likewise, brain hemorrhages are frequent in poisonings before the period.
Repeatedly in animal investigations as well as in human poisonings, fat emboli have been observed particularly in the lungs and the kidneys.
The entire musculature, particularly that of the abdominal and thigh muscles, can show fatty changes.
Of the blood effects of subacute phosphorus poisoning, the long known and often confirmed lessened or absent coagulability is of special significance to us for the bleeding tendency of phosphorus. The depression of coagulation or the absence of it is associated with defects in the fibrinogen and the coagulation- promoting ferment.
The alkalescence of the blood in phosphorus poisoning is considerably reduced. This can be demonstrated titrimetrically as well as the through estimation of the CO2 content of the arterial blood. The diminution of alkalescence is the result of altered metabolism which is accompanied by an increased production of acids. Probably a decrease in the complement is associated with it as Ehrlich and Morgenroth found in the blood of poisoned animals.
The formed elements of the blood likewise undergo considerable alteration, in particular the erythrocytes. It is striking that the different species of animals react differently. Rabbits do not show definite influence; in pigeons there is a high-grade hemolysis; in men appears, partly a decrease, partly a sudden increase of erythrocytes and as high as eight million have been found. This increase was only transient for the most part and this has lent support to the otherwise not certainly determined concept that besides the increase of erythrocytes there is also an increased destruction. The leukocytes seem at first diminished, then slightly increased.
ACTIONS ON THE BONY SYSTEM
Animal investigations and correspondingly the standard therapeutic use of phosphorus in the last decades have been directed primarily to the skeletal system. The most striking manifestation of chronic phosphorus poisoning, jaw necrosis, is the point of departure of experimental investigation. Wegner obtained in rabbits after a five to ten weeks residence in phosphorus containing air in imitation of this condition, a periostitis of the jaw with bony deposits on the alveolar border which went on to necrosis. From these investigations it was further yielded that continuous small doses of phosphorus could act as a formative stimulus on the bones and that the spongiosa was widely replaced by compacta. Kassowitz thereon tested phosphorus clinically in rickets and his recommendation still has value today. This has not been shaken by the fact that today irradiated ergosterin and no longer the great carrier of light (phosphorus) is the method of choice. From the findings of Kassowitz it may be stressed that with continuous and increasing doses of phosphorus a rarifying osteitis in the compacta, a marked growth of vascular rich cartilage and finally a melting down of bony inflammatory processes in the periosteum were found which he designated as like rickets.
In more recent times the role of phosphorus in the process of bone building has been more exactly studied in animals by Otsuki. In artificial fractures the resorption and new formation processes require more time than usual under small doses of phosphorus. But thereby was the resorption of old bone still more strongly delayed than the new formation so that a thickened bulwark of bone was the result of this rebuilding. Likewise in growing bones the depression of normal resorption predominated over the depression of new formation so that a broader and thicker layer of bone was the end effect. In spite of the damaging influence in the process of bone formation, the result was an excess of new bony tissue. This is also compatible with the findings of Wegner and Kassowitz.
In chronic poisoning of animals with phosphorus, the calcium and the phosphorus content of the bones increase considerably. Bernhardt and Rabe demonstrate a distinct influence of phosphorus on mineral metabolism and the formation of bone. Trisdall found the phosphorus content of the serum remaining at the same height during growth; with the conclusion of growth it rapidly fell and stayed at this level until death, but in a demand upon calcium metabolism, as in bone fracture, the growth level was again reached or even surpassed. The investigations of F. Sauerbruch and G. Hotz in patients with osteomalacia reveled that by the administration of phosphorus the organism gained the capacity to utilize calcium and also to retain and deposit it.
According to all this one may ascribe to phosphorus an influence on calcium metabolism in the sense of an activation and increased retention. It is worthy of note that even Wenger demonstrated a favorable influence on bone formation with phosphites as well as through unoxidized phosphorus itself. The close connection of phosphates to calcium economy has been mentioned in speaking of calcium. If one reviews the bone effects of phosphorus, the phosphites and phosphated together than the distance between the pure phosphorus and its various stages of oxidation diminishes in pharmacologic respects though at first it seemed to exist. Certainly it is not immaterial whether phosphorus, phosphites or phosphates are administered, but if we view the matter from various angles, it is seen that the difference lies not in the nature but in the intensity. Actually before the vigantol era, on account of the apparent danger of phosphorus, one had come to recommend phosphates in rickets and osteomalacia. That this phosphorus and phosphate therapy follows definitely the simile rule need not be stressed after the above discussion. In homoeopathy it has constantly been calcium phosphate which has been the most frequently used preparation in rickets and in bone therapy in general.
OTHER ORGAN ACTIONS
A certain similarity with the action on the bony tissue can be perceived in the action on other tissues. The end state of phosphorus poisoning in the form of the so-called fatty degeneration of the liver, the kidneys, the cells of the gastro- intestinal tract, the heart, the diaphragm, the skeletal muscle, and especially the vessel endothelium is well known. But if one follows the process more exactly, then from the prolonged action of small doses always an excitation of function occurs or an increased formation of tissue proceeds simultaneously. Even Harnack has perceived the new cell formation as minor grade action of the same poison whose stronger action effects death of the cells.
The cell action of phosphorus is best studied on the liver. At first the glycogen diminishes as do the cell proteids; the liver cells contract and show fatty degeneration. But according to the investigations of Opel, at the same time a new formation of young cells occurs. With stronger influence of phosphorus, the substitution by growing connective tissue or the epithelium of the biliary passages seems to gain preponderance. The situation of the kidney elements seems to be entirely the same.
It is worth of remark that also in the liver and heart, the calcium and phosphorus content increases in acute and still more in chronic phosphorus poisoning, while a marked decrease of calcium content and increase in total phosphorus has been found in skeletal muscle.
The well-known appearance of icterus in phosphorus poisoning has been traced to the finest biliary passage by the investigations of Stadelmann and Eppinger. Here also goes a state of increased secretion with increased amounts of biliary pigments, then apparently a stasis and destruction in the smallest biliary capillaries, a rupture of the capillaries with entrance of the bile into the lymphatic passages.
Here it may be remarked that phosphorus can be indicated in weakness of the heart muscle, nephritides and inflammatory liver affections. But in what form? That is the question in which the similarity of the structural end-results leaves us in the lurch. Here we must still consider the influence on the vascular endothelium and the reduction of the capacity for coagulation by phosphorus. Hemorrhages of all types can be further indications for the choice of phosphorus; also for, example, hemorrhagic nephritis. Similarly, an icterus increase the indications for phosphorus in pneumonia. Such supplementary structural indications, however, usually do not satisfy us but first the functional and subjective symptoms as they have been obtained from provings on the healthy give us exact differential characteristics.
The actions of phosphorus on metabolism, particularly on carbohydrate and fat, have been studied primarily on the liver, obviously, because the liver is the favored site of attack for phosphorus. In investigation of the fat metabolism one proceeds from the fatty degeneration of the liver and other organs. The view that in phosphorus poisoning an increased formation of fat occurs from protein destruction can easily be shown to be erroneous. To the contrary, animal investigation shows rather an increase in fat substitution, naturally not in the hunger stage, but to an increased degree when sufficient amounts of carbohydrates are introduced.
Through abundant administration of carbohydrates the appearance of fatty liver can be prevented in phosphorus poisoning in spite of the presence of fat depots. This signifies that fats burn only in the flame of carbohydrates, as it has been strikingly expressed.
The fatty infiltration of the liver is indeed a substitution of used carbohydrates and proteins and one may perceive with Rosenfeld that it is the last attempt at a defense against an impending damage to the protoplasm, naturally a defective substitution for the cell material being destroyed. The enrichment in ether soluble constituents (as phosphatides, cholestrein, etc.) particularly in the liver, less strongly in the heart and kidneys, in phosphorus poisoning is recognized as fatty infiltration through a series of investigations. In any case the wandering of fat in these organs from the fat depots of the body (in case such are present) has been demonstrated (through proof of the infiltration of a foreign type of fat). For the development of a fatty degenerative infiltration of the organ through transport from the depot also speaks the fact that the fat that the fat content of the blood is increased in phosphorus poisoning.
But the fatty degeneration of organ cells rests not exclusively upon fatty infiltration because in actuality the fat content is often not found increased. Much more it is concerned only with a visibility (perhaps coagulation?) of fat in the decomposition of cells, so-called fat phanerosis.
An increase of protein destruction through phosphorus is frequently demonstrated in animal experiments as well as in man through increased nitrogen excretion in the urine. But it seems that this increased protein destruction appears only with a fat and carbohydrate deficiency, also after utilization of this burning material. In general, the results of animal investigation refer to the starved animal. Moreover, Retting succeeded in avoiding the destruction of protein entirely or approximately through administration of larger amounts of carbohydrate.
Besides the quantitative increase of protein destruction there is also a qualitative alteration. The ammonia excretion in the urine is increased, from which an increased production of the acid in the body may be deduced. Sulphuric and phosphoric acid are increased in consequence to the increased destruction of cell proteins, and lecithin (lipoids), moreover lactic acid and other organic acids, appear in the blood and urine. But above all comes the excretions of imperfectly decomposed protein split products, amino acids (as glycocol, leucin, tyrosin), albuminoses, oxyprotein acid. Now one knows that in phosphorus poisoning the postmortem fermentative protein splitting in the liver, the so-called autolysis, is increased, and it is possible that the qualitative alteration of protein metabolism is associated with this influence of phosphorus on the fermentative decomposing process in the liver.
In general one can remark that a material which effects an increased and abnormal protein destruction belongs to the febrile agents, as it happens with phosphorus (and arsenic). Naturally, the already mentioned actions on the fat and protein metabolism are only crude toxic manifestations in the direction of consumption. More than crude directions cannot be presented at the present time for fatty degeneration, fever, and consumption.
Phosphorus attacks the carbohydrate metabolism earlier than the fat and protein metabolism. Through investigations it has been demonstrated that in phosphorus poisoning the glycogen markedly decreases, especially in the liver (less in the muscle). But in spite of rapid destruction of glycogen, no increase of blood sugar content appears and only rarely does man show a glycosuria. Accordingly, the burning of sugar seems increased. On the other side, in certain stages of phosphorus poisoning there seems to be a reduction of the limits of assimilation for sugar by man and therefore the early appearance of an alimentary glycosuria. How far the glycogen formation is disturbed or prevented is still not determined. In general it seems in the first phase of phosphorus action that the dissimilatory activity in carbohydrate metabolism is increased; in the second phase, the assimilatory activity is increased. If now one considers the production of acidosis and the appearance of organic acids in the blood and urine, then the similarity to diabetes in broad trends is not to be rejected.