.

646
646
THE
TH
CANADIAN MEDICALASSOCIATION JOURNAL
CAAINMDCLASCATO ORAMy13[May 1931

ejieoturaginig sigin of the effects of treatmeint. ated and rapidly growing, and hence plastic,
Wlheni this is accompanied by a retardation or imiobile, and possibly phagoeytic, though not in
cessation of bone destruction by the tumour the strict sense of the word as used by Champy.
cells the result is a very striking one. In all of Some observations made during the treatment
the eases of this short series increased calcifica- of carcinoma with the colloidal solution also led
tion and ossification were noted in the radio- to the conielusion that the young, un-differen-
grams, together with apparent retardation and tiated and plastic cancer cells were similarly
cessationl of bone destruction by the tumour destroyed.
cells. It is usually assumed that the erosive To Dr. G. E. Richards, Director of the Department
action uponi the involved bone is affected by the of Radiology, the Toronto General Hospital, we owe
much for lis great assistance in making car eful com-
tuiimour cells only while they are un-differenti- parative reports on the stereoscopic films in the cases.

THE PHYSIOLOGY OF THE PARATHYROID GLANDS*

By J. B. COLLIP, PH.D., AI.D., D.SC.,
Departm ent of Biochemistry, McGill University,
Mont}real
SINCE comprehensive reviews of the physi- Calcium is one of the essential inorganic ele-
ology of the parathyroid glands and of ments coneerned in vital processes. While the
calciumi nmetabolisnm- h-ave been published,1"' 21, 31 amount of this substance which naturally oceurs
it will be our purpose to discuss in detail only in. living tissue is very minute as compared,
the more recent developments in this field. for example, with sodium and potassium, it is
The function of the parathyroid apparatus, in nevertheless of equal significance. The calciun
so far as we understand it at present, is that of a contelit of human blood serum of the normal
regulator of caleium metabolism. This function subjec t is between 9 and 11 mgm. per cent, while
is apparently directed toward the maintenance that of the plasma, according to Stewart and
of a definite level of total calcium in the eireu- Percival,31 may be 10 to 15 per cent higher.
lating plasma and is subserved by the action of It is of interest that the caleium content of red
the internal secretion elaborated by the glanids. cells is very low. Some workers claim that the
The exact mechanismii by whiich this result is red eil is calcium-fiee, but others have found
attained is still unknown. The receent work of appreciable amounts therein.22' 2' The calcium
Hunter2' points to a specific effect of the para- which is present in the eirculating plasma exists
thyroid hormone on the activity of the osteo- in different forms, but until more exact methods
clasts of bone. Also it has been abundantly have been developed for the estimation of these
proved that the increase in the blood serium special fractions it is useless to dogmatise on the
calcium which is observed following the injec- significance of any one of them. On a priori
tion of the parathyroid hormone is due to the grounds one might expect the ionized calcium
mobilization of this element from the bone to be most significant. The amount of ionized
reservoirs. calcium is probably never more than 2 mgm. per
As the physiology of the parathyroid gland is cent; the remainder exists in non-ionized form,
so very closely associated with the biochemistry both in organic and in inorganic combination.
of calcium, it will be of interest to review brief- The organically bound calcium is non-diffusible
ly some of the outstanding facts in regard to and represents approximately 4.5 mgm. per cent
calcium metabolism. of the serum calcium. The total calcium content
of spinal fluid is from 5 to 6 mgm. per cent.
A paper read in the Section of Bacteriology.
* According to Cameron and Moorhouse,9 this re-
Pathology, Physiology, and Biochemistiry, ninety-eighth presents the diffusible calcium of the plasma.
annual meeting of the British Medical Association,
Winnipeg, August 28, 1930. The calcium colntent of muscle and the
May 1931] COLLnP: PHYSIOLOGY OF PARATHYROID GLANDS 647

parenchymatous tissues is lower than that of assimilable than the phosphate or carbonate.
blood plasma, values from 4 to 7 mgm. per cent Lactose administered with calcium appears to
having been obtained. To what extent the influence its absorption favourably. Bergeim8
calcium of tissue is intracellular can only be has attributed this result to an increased pro-
conjectured, but if the distribution parallels duction of lactic acid in the intestine. Also,
that obtaining in the blood, the calcium content the normal acidity of the stomach contents
of the tissue cells must be very low indeed. must influence the ionization of calcium com-
The level of blood calcium in the normal sub- pounds present in the food and hence facilitate
ject remains constant, but nevertheless calcium their absorption. The presence of phosphate
is continuously being added to it as a result of and carbonate will inhibit the assimilation of
the absorptive processes in the upper intestinal c!1ium due to the formation of relatively in-
tract, and removed therefrom through the ex- sohuble compounds. A slight acidity of the in-
cretory channels of kidney and bowel as well as testinal contents probably affords the most
by deposition in bone. favourable circumstance for the absorption of
The chief use of calcium is in relation to the calcium.
building up of the structural elements of bone Recent work with vitamin D has shown that
and tooth, and it plays -a very important role this substance influences directly the absorptive
in a number of physiological processes, such as process for calcium, and it is probably true
in the clotting of blood and coagulation of the that the main factor in the assimilation of
caseinogen of milk. More important still, it in- calcium is the normal functioning of the
fluences in a very specific manner neuro- mucous membrane of the small intestine, and
muscular tone and irritability. This latter effect in this vitamin D appears to play a very
is probably due to ionized calcium, and since definite regulatory action.
changes in blood pH can influence the degree of
ionization of the calcium there may be no es- EXCRETION
sential difference between true parathyroid Walsh and Ivy,35 by the use of dogs with
tetany due to a lowered calcium content of the Thiry-Vella fistule, have shown that calcium
blood and the tetany of over-ventilation, or of is actively excreted by the lower ileum and
alkalosis, associated with a normal blood calcium colon. The faecal calcium represents, there-
but a diminution in ionization due to an in- fore, both the unabsorbed calcium of the food
creased pH. and re-excreted calcium. Calcium is excreted
by the kidney in the normal subject in amounts
ABSORPTION varying from 0.1 grm per day on a low cal-
There are many factors uwhich influence the cium diet -to 0.5 grm. on a normal diet. Acid-
absorption of calcium from the alimentary forming diets tend to increase the urinary
canal, such as the nature of the calcium com- calcium. This fact has been made use of by
pounds themselves, the pH of the intestinal Aub and his associates in the treatment of lead
contents, and the type of foodstuffs, as well as poisoning.4 The production of a condition of
other inorganic substances present. Since cal- acidosis by the ingestion of ammonium chloride
cium is excreted into the lower bowel it is in amounts of 12 grm. per day increased the
impossible to -estimate from an analysis of the daily output of calcium in the urine from 0.1
feces obtained over a known calcium dietary to 1.1 grm. in three days without affecting the
regime how much calcium has been absorbed faecal calcium.
or how much excreted. It has been very diffi- On a diet very low in calcium the excretion
cult, therefore, to obtain reliable information of the element is markedly reduced, but not
as to the degree of assimilation of orally ad- completely so. The calcium reserves of the
ministered calcium compounds. Irrespective of skeletal tissues are drawn upon under such
the type of compound which.is administered circumstances in the endeavour to maintain the
orally it is probably absorbed in the ionized normal level of blood calcium. This protective
form. mechanism tends soon to fail and the blood cal-
Therefore, any soluble salt, such as the cium level falls; with low blood calcium tetany,
chloride, lactate, or gluconate, will be more or latent tetany, may appear.
 648
648 THE CANADIAN MEDicAL
THE CANADIAN ASSOCIATION JOURNAL
MEDICAL Assoc~~~~~~~~~TIoN JOURNAL [May 1931~~~~~
[May 1931

The daily requirement of calcium in the the result that most severe and usually fatal
adult has been given by Sherman as from 0.4 tetany occurs within a much shorter interval
to 1 grm. per day.30 During the growth period of time. The blood serum calcium may, for
the daily requirement is, however, very much instance, be 8 mgm. per cent, with an in-
more. Also during pregnancy and lactation organic phosphate of 11 mgm. per cent at the
there is a much greater demand for calcium, time of death from tetany within 14 hours of
and unless the supply be adequate the calcium parathyroidectomy.
reserves of bone are drawn upon to supply the Hess'7 in contrasting infantile tetany and
needs respectively of the growing fetus and inifantile rickets has pointed out that the
milk production. former may supervene suddenly in the course
of the latter disease, and its appearance is
RELATION OF INORGANIC PHOSPHORUS 4 associated with a change in the calcium-
TO CALCIUM
phosphorus ratio of the infant's blood. This
Calcium metabolism is closely linked with change in ratio results both from a fall in the
the metabolism of phosphorus and changes in blood serum calcium and a rise in the inorganic
the inorganic phosphate content of either food phosphate.
or blood may profoundly affect calcium meta-
bolism. Thus a disproportion between calcium THE INTERNAL SECRETION OF THE PARATHYROID
and phosphate in the food (excess phosphate) GLANDS
may result in the assimilation of comparatively It is a remarkable fact that the maximum
little calcium. The raising of the inorganic physiological activity of the parathyroid glands
phosphate of the blood, as by the injection of has only been obtained after the fresh or
sodium phosphate solution, leads at once to a acetone-preserved tissue has been treated as a
marked fall in the level of blood calcium. The preliminary step with 3 per cent hydrochloric
ratio between calcium and inorganic phosphate acid in a boiling water bath for forty minutes.
in the blood is of equal significance to the Prolonged acid hydrolysis results in destruc-
actual value of either, and in all cases of frank- tion of the active principle, but a definite de-
ly disordered calcium metabolism the inorganic gree of hydrolysis appears to be essential to
phosphate of blood serum, as well as the cal- -free the hormone from the linkage in which it
cium content, should always be determined. is bound in the intact normal gland.'0 2 It
We have had many examples of the importance must be assumed that the intact glands in the
of this ratio in our studies of experimental course of their normal functioning are able to
tetany. Thus a low blood calcium may be well liberate the active principle in small amounts
tolerated in the presence of a low serum in- as required, a process which in vitro requires
organic phosphate. Fatal tetany has been ob- a strong acid reaction.
served in the presence of a comparatively mild The purification of the active principle has
hypocalcemia but associated with a marked not yet been carried beyond a proteose-like
increase in serum inorganic phosphate. This fraction obtained by submitting the original
is perhaps best illustrated by a comparison of hydrolysate to repeated salting-out processecs
the effects of parathyroidectomy in the dog and isoelectric precipitations. Either the
and rabbit. Removal of the parathyroid glands hormone itself is of protein nature, or else it
in the dog is followed by a gradual and pro- is intimately associated with such a substance.
gressive fall in the blood serum calcium. The It has been repeatedly shown that all demon-
inorganic phosphate of the blood tends to re- strable physiological activity of active extracts
main stationary during the first period (some is completely lost by treatment with either of
hours to two days) and then it may slowly the proteolytic enzymes pepsin or trypsin.
rise. Tetany appears and, if untreated, results Also all our attempts to devise some effective
in death in a variable period of time, depend- method of oral administration of the hormone
ing largely on the pre-operative treatment of have met with complete failure.
the animal. In the case of parathyroidectomy The physiological effect of the hormone is
in the rabbit, one observes a much more rapid that of a mobilizer of blood plasma calcium,
increase in inorganic phosphate of serum, with and there is ample proof that the source of
May 1931 ] COLLIP: PHYSIOLOGY OF PARATHYROID GLANDS 649
May
1931]
COLI:
PHYSIOLGYOFPRAH
-

the additional calcium which appears in the liver occurs until the peak of the curve of
blood stream under the influence of the ex- serum calcium has been passed and the terminal
tract is bone. There is a great difference in phenomena of parathyroid hormone over-
the effect of the hormone in different species. dosage have appeared. The kidney tissue at
The dog is the only laboratory animal which the terminal stage of acute parathyroid
is satisfactory for standardization of the ex- hormone overdosage may contain more than
tract. The normal dog responds as a rule to 250 mgm. per cent of calcium, while heart
injections of the parathyroid hormone by a muscle has been found at times to contain more
rise in blood serum calcium, which -is related than 50 mgm. per cent. The liver may contain
to the size of the dose administered. If suffi- a greatly increased amount, or it may show
cient extract is given marked hypercalcemia only a moderate increase. Muscle does not
develops and with it a train of symptoms are take up any great amount, as values over 12
ushered in which invariably result in death of mgm. per cent have not been observed. The
the animal. The symptoms in the order of excessive deposit of calcium salts in the kidney
their appearance are anorexia, vomiting, diar- is due to the final failure of this organ to com-
rhiea, muscular weakness, lassitude, respira- bat the high blood calcium by excretion. It
tory distress, passing of blood by the bowel, becomes clogged with the substance it is
bloody vomit and finally complete collapse. endeavouring to eliminate. The excessive and
A study of the progressive changes in blood selective absorption of calcium by the heart
chemistry during parathyroid hormone over- muscle is of great interest and no doubt ac-
dosage has been very instructive. The blood counts in part at least for the peculiar irregu-
serum calcium curve may be represented as a larities of the heart in parathyroid hyper-
gradual ascent to a level of 20 mgm. per cent. calcaemia which have been studied by Edwards
It remains at this level for, some hours, then in and Page."'
the terminal stages it usually falls a few milli- Experimental chronic parathyroid hyper-
grams per cent. The inorganic phosphorus of calcewmia results in serious depletion of the
the serum is practically unaffected until the calcium stores and a condition of metastatic
blood serum calcium has reached a level of 15 -calcification of certain soft tissues associated
mgm. per cent. It then rises rapidly and con- with nephrolithiasis.20
tinuously till death ensues. Coincident with Probably there is no better example of
the rise in inorganic phosphorus there is chronic hypercalcaemia due to hyperfunction-
evidence of rapid failure of kidney function ing of the parathyroid glands than the clinical
and in addition to suppression of urinary secre- entity of generalized osteitis fibrosa recently
tion the non-protein nitrogen and urea of, the reviewed so excellently by Hunter.2' The
blood increase at a uniform rate until at death study of these clinical cases of true hyper-
values of well over 100 mgm. per cent of urea parathyroidism has done much to further
nitrogen are reached; also there is evidence of elucidate the physiology of these glands, par-
a marked acidosis in the latter period. ticularly as relating to the human subject.
No untoward symptoms are manifested by Before discussing these recent contributions
the dog as a rule until the blood serum calcium from the clinical side more in detail, I should
has reached 15 mgm. per cent. Dogs may be like to refer to the extraordinary differences
mnaintained in a condition of mild hyper- which exist as between species in the response
calcaemia over a period of weeks by small daily to administered parathyroid hormone. The
doses of the hormone without any marked ill dog is, as we have seen, specially sensitive to
effects, although such treatment undoubtedly this hormone, and excessive, dosage causes
causes a great loss of skeletal calcium due to death. The cat is less sensitive, and some
excessive excretion in the urine of calcium workers have found difficulty in producing
salts. hypercalcemia by the use of the extract, while
Tissue analyses for calcium made at different others have had varying success. The normal
levels of hypercalcemia indicate that apart rat and rabbit are practically imimune to the
from the kidney no marked increase in the cal- hormone in so far as changes in blood chemistry
cium content of such tissues as muscle and are concerned. An amount of extract which is
.-650650 THE CAN"UN MEDim AssociATioN JOURNAL [May 1931
THE~ ~ ~ ~ ~ ~ ~ ~ ~ -.- .CAAIAN--
MEDCA
--
ASOIATONJURA
-1
[a13

sufficient to kill 10 dogs may be administered calcium reserves, as the administration of am-
to a rabbit without ill effects. On the other monium chloride to such a case was followed by
hand, relatively small amounts of the extract. an increased excretion of calcium. Considerable
have prevented the fall in blood calciu-m in variation in the blood response of the human
the parathyroidectomized rabbit and have off- subject has also been reported. One individual
set the development of tetany. It is possible may respond well to the extract, while another
that there is some fundamental difference in may show little or no change in the blood serum
the manner in which the calcium reserves are calcium content following a course of injections.
laid down and given up in different animals. Somewhat similar conditions are found in dogs,
There is also the possibility that the excretory though non-reactors are not so frequently met
channels are more effective and responsive to with, but because there are such, it is necessary
slight changes in the blood calcium in some to use at least 10 or more animals in standardiz-
animals than in others. This possibility must ing -the preparation. This is in order to take
be further tested by appropriate experiments. care of individual variations in response to the
We have been unable to demonstrate any injection of the hormone.
effect of injections of the hormone in non- While it is definitely established that para-
laying hens, yet it has been shown by Riddle thyroid activity influences calcium metabolism
and Reinhart28 that the calcium content of the in a very profound manner, it must, also be re-
blood serum of the dove is directly related to membered that calcium metabolism is affected by
the phases of the sex cycle. During ovulation a number of other factors, such as diet, acidosis,
there is an increase of 100 per cent in the alkalosis, exophthalmic goitre, and more partic-
blood serum calcium. Sun and MeOwan32 have ularly vitamin D. A low calcium diet has been
recently reported a study of the calcium con- found to produce a depletion of the calcium salts
tent of the blood serum and the histological in trabecule of bone.6 A lowering of blood
structure of the parathyroid glands of the serum calcium has also been produced by low
mature Leghorn hen as affected by ovulation. calcium diets.
They found, in brief, during the period when Acidosis causes an increased calcium excretion
the egg weighed 0.1 grm. or less an average and an increase in the degree of ionization of
value of 13.7 mgm. for blood serum calcium. blood calcium. Alkalosis has somewhat the re-
Egg weights between 9 and 18 gra-ms were verse effect. Osteoporosis of marked degree has
associated with an average of 25.6 mgm. per cent been observed in certain cases of exophthalmic
of serum calcium, and egg weights of from 30 goitre in which there has been no evidence of
to 57 grm. gave an average of 19.25 mgm. for parathyroid gland disease.21
serum calcium. Also definite histological Vitamin D has an effect on calcium meta-
changes in the parathyroid glands were asso- bolism almost equal- to that of the- parathyroid
ciated with the high blood calcium, values. glands, and it is as yet an unsolved problem as
These changes consisted in a distortion of the to what is the exact interrelationship of func-
columns of cells associated with an apparent tion between vitamin D and the parathyroid
increase in the connective tissue of the trabe- hormone. Vitamin D administered to dogs in
cula and were more closely linked with the excessive amounts has produced fatal hyper-
period of falling blood serum calcium. calctmmia with associated symptoms very similar
The active extract has been shown to be to those manivfest during parathyroid hormone
specific for the treatment of parathyroid tetany, over-dosage.38 Also vitamin D has been shown
and completely parathyroidectomized dogs have to relieve parathyroid tetany and to raise the
been kept in a normal condition with normal blood serum calcium in the parathyroidectomized
blood calcium and phosphorus levels when ade- animal. Taylor has recently found that the
quate doses have been administered. Aub" 6 beneficial effects of vitamin D in the form of
however, has reported that in the human sub- irradiated ergosterol gradually fail in totally
jects treated over a prolonged period with the parathyroidectomized dogs, and that the treated
hormone a condition of immunity to the specific animals ultimately die of tetany, although the
-alciuimnobilizg effect may develop. He has treatment prolongs their lives- for a matter of
shown-that this is not due to a depletion of days.88 Watchorn8m and Ashford3 have recently
May 1931]
May 1931]
COLLIP: PHYSIOLOGY
COLLW: PHYSIOLOGY
O-P
OF
PARATHYROID GLANDS
PARATHYROID GLANDS 65.I
651

shown that in hypervitaminosis D in rats and paratus and trauma of the remainder. Trauma
rabbits respectively a great increase in the exere- of the parathyroid glands leads to a marked
tion of calcium occurs. The work of Massen- suppression of function which, however, is not
gale and Nussmeier25 on chicks suggests that the permanent. Fatal tetany may occur in a rabbit
production and maintenance of hypercalcmia following traumatization of the glands. Treat-
by excessive administration or irradiated ergos- ment should consist of large doses of calcium
terol is largely dependent on the presence in the salts by mouth, or of subcutaneous injections
food of adequate amounts of calcium. Hyper- of parathyroid hormone or intravenoug calcium
calcification of bone has been reported by Hess chloride if the condition of the patient is acute.
and his associates16 as a result of vitamin D Vitamin D therapy should also be of value.
overdosage in a young human subject. Free- Complete parathyroidectomy in the human sub-
man and Farmer'3 fotund a decrease in the per- ject is a matter of grave concern, since it may
centage of diffusible calcium of the serum in require long-continued treatment, and if such
vitamin D overdosage in the rabbit. This was a case develops an immunity to the hormone
associated with an increase in the total serum adequate control of the calcium metabolism
calcium. may become- impossible and death result.4
That vitamin D hypercalevemia is definitely Since the introduction of irradiated ergosterol
linked with increased calcium absorption ap- it is possible that such a fatality may be
pears to be established. Whether it can cause avoided in the future.
mobilization of calcium from the bone reserves In the tetany of spontaneous hypo-parathy-
is not so clear; if it causes thij latter effect, roidism there is as a rule a lowered blood serum
is the action a direct one, or do the parathyroid calcium and an increased inorganic phosphate.
glands act as an intermediary? No final It is of interest to' note that lesions of the
answer is to be had to this question with our ectodermal tissues, such as 'cataract, brittleness
present knowledge of the subject. There is and ridging of the nails, and enamel defects of
other definite evidence that parathyroid gland the teeth, have been described in association
function and vitamin D are closely linked. Re- with hypo-parathyroidism in the human sub-
cently Morgan an'd Garrison27 have found that ject. Cataract has been observed in rats six
young dogs reared on artificial diets with a months after parathyroidectomy.12 It is also a
Ca: P ratio of 1.18 to 1.64 without vitamin D common occurrence in parathyroidectomized
respond but little to parathyroid hormone in- dogs.
jections, whereas similar dogs given vitamin Infantile tetany does not differ materially
D show abnormally large increases' in serum from tetany of spontaneous hypoparathyroid-
calcium and inorganic phosphate when injected ism in the adult in so far as the blood
with the parathyroid extract. chemistry picture is concerned. Since infan-
Also Higgins and Sheardl8 19 have noted tile tetany is so frequently associated with
hyperplasia of the parathyroid glands of chicks infantile rickets it is evident that its etiology
reared under blue or amber glass. Two per is not entirely a matter of hypoparathyroid-
cent of cod liver oil in the diet of control birds function. Hess,'7 in discussing this question,
prevented this reaction of the parathyroid says "the simple theory of a deficiency of
tissue. These authors express the opinion that calcium due to a lack of function of the para-
the visible as well as the ultra-violet rays of thyroid glands is not absolutely satisfactory.
sunlight are essential for normal parathyroid Some other factor seems to be involved. We
development. do not find the parallelism we should expect
between tetany in infants and in animals, and
CLINICAL CONDITIONS IN WHICH CALCIUM the decrease of calcium in the blood. In other
ME:TABOLISM OR PARATHYROID FUNCTION words, although calcium and the function of
IS DISTURBED the parathyroid glands play the dominant role,
Tetany.- 'Post-operative tetany represents the there seem to be other factors which qualify
nearest clinical parallel to parathyroidectomy their effect in relation to th-e development of
in the dog. As a rule it is due in part to re- tetany."
moval of a portion of the parathyroid ap- Hyperventilation, or "alkalosis tetany," is
652
652 THE CANADuN, MmicALAssocIATION JOURNAL
Tm. CANADIAN M.UUCAL ASSOCIATION JOURNAL [May 1931
[May1931

met with clinically in the form of spontaneous served an increase of 0.59 mgm. in the cerebro-
tetany due to over-ventilation. It may also spinal fluid calcium.
occur in the presence of alkalosis due to ex- Generalized osteitis fibrosa of von Reckling-
cessive alkalinization, or as a result of loss of hausen. - Hunter21 has recently reviewed the
HCI through vomiting. There is no change literature relating to this type of case, and
in the blood serum calcium in such cases, but has been able to add some of his own cases in
a decrease in the degree of ionization due to which most detailed studies of calcium meta-
the increased pH of the blood. bolism and bone pathology have been carried
Osteomalacia.-Although the bone changes out. Fourteen cases have been published to
observed in osteomalacia are not of the same type date and there is every evidence that in this
as those seen in typical rickets the general disease the underlying cause is a condition of
view at present is that osteomalacia is the hyperparathyroidism, associated as a rule with
counterpart in adult life of low calcium rickets a parathyroid tumour. Among some of the
in children. A low blood serum calcium is noteworthy cases of this disease recently re-
uniformly found in osteomalacia with or with- ported are those of Mandl,24 Hannon,'4 Barr5
out an increased inorganic phosphorus. Tetany and associates, and Hunter.21 The main find-
is also a common occurrence in this disease. ings as regards blood chemistry and meta-
The most constant metabolic phenomenon is a bolism in this disease are hypercalcemia and
net loss in calcium.26 an excessive excretion of calcium salts, especi-
ally by the kidneys. There is usually a
Hunger osteopathy.-Various forms of hnger lowered inorganic serum phosphate and the
osteopathy occurred in Austria, Germany and plasma phosphatase is greatly increased. Ac-
Poland during the war.21 Detailed blood cording to Hunter, radiograms show a greatly
chemistry studies in such cases are lacking, but diminished density of all bones examined' as
the causative factors were undoubtedly lack of compared with controls of normal subjects of
vitamins, chiefly D, and of calcium and phos- like age, size and sex. Cyst-like areas, some
phorus in the diet. Rickets, late rickets, osteo- of them trabeculated, may be present. Exten-
malacia and Paget's disease all increased sive areas of decalcification may occur and
greatly both in incidence and severity during spontaneous fracture is a frequent occurrence.
this period. Marked hypertrophy of the para- A local condition of giant-cell tumour has been
thyroid glands was observed by Schmorl29 in a mistaken for sarcoma.7 Microscopic examina-
man of 73 who had suffered from hunger tion of the bone reveals no evidence of true
osteomalacia. osteomalacia. There is a great decrease in the
Renal rickets and ccliac rickets.-In both of calcium salts of the bone, which have been re-
these conditions a lowered blood serum calcium moved by a process of lacunar resorption by
has been found. The blood inorganic phos- osteoclasts. The resorption is widespread, but
phorus in renal rickets is usually greatly in- is accompanied by focal formation of new
creased, values as high as 14 mg. having been bone.21 Bilateral renal calculi were found in
reported. Inorganic phosphorus in the blood Barr's case.
serum of cases of coeliac rickets has not been In the 14 cases which have been reported of
very thoroughly investigated. Vollmer and the blood serum, calcium varied from 13.1 to
Serebrijski'4 have reported a case- in which the 23.6 mgm. per cent, and the plasma phosphorus
blood serum phosphorus was 2.9 mgm. and the between 1.0 and 2.7 mgm. The calcium output
calcium 5.4. It is stated that the osteoporotic in the urine varied from a slight increase to an
bones of eceliac rickets tend to fracture, where- eightfold increase. These observations are of
as in renal rickets the bones are more elastic the greatest interest for they afford for the first
and tend to bend. time a means of contrasting spontaneous hyper-
Chorea.-Suggestive evidence that a slightly parathyroidism inm man with parathyroid hor-
lowered calcium content of both blood serum mone overdosage in the dog. The' essential dif-
and cerebro-spinal fluid exists in chorea has ference appears to be in regard to the inorganic
recently been obtained by Warner.86 Co- phosphorus response. This factor remains nor-
incident with recovery this investigator ob- mal or sub-normal in man in hyperparathyroid-
May 1931] COLLIP: PHYSIOLOGY OF PARATHYROID GLANDS 653

ism, whereas it rises to high levels in the dog DISCUSSION

in parathyroid hormone overdosage. It is for PROF. V. H. K. MOORHOUSE (Winnipeg) discussed
the mechanism of secretion by the parathyroids. To
this reason that death occurs in the dog, whereas what stimuli is this secretion a responset There are
the human subject can apparently withstand for nerve fibres along the course of the blood vessels, ap-
a long period a high level of blood calcium pro-
parently autonomic, and probably arising from the
cervical sympathetic. It still remains to be ascertained
duced by hyperfunction of the parathyroid tis- whether excitation of these will induce the secretion.
sue. The changes which are brought about in The chemical excitors, if there be such, are unknown.
Perhaps the level of blood calcium is the determinant
the skeletal structures in this disease are, how- factor.
ever, parallel with the results obtained in normal The actual manifestation of tetany is characteristic
of a nerve protoplasm disturbance. Excitation of nerve-
animals treated with parathyroid extract over a muscle becomes increased about ten times over normal.
prolonged period. It can be observed after section of the nerve and up to
The diagnosis of hyperparathyroidism can the time of its degeneration. The peripheral nerves are
not the only sites of disturbance following parathyroid-
now be made on the basis of radiograms and ectomy. Chronaxie is lengthened, suggesting lowering of
blood chemistry. Treatment has been surgical, excitation, and this observation cannot at present be
easily correlated.
and either a parathyroid tumour has been found There are sensory and afferent as well as motor
and removed or else normal glands have been disturbances. In dogs and cats intense irritation about
mouth and nose is observable. The loss of appetite and
removed. After the removal of a parathyroid vomiting seen in such animals following removal of the
tumour the blood calcium has been observed to parathyroids probably are due to effects on the nerve
centres in the mid-brain and medulla. There is a
fall rather rapidly, and subnormal values have general involvement of the nervous system but different
resulted in some cases to such an extent as to parts are unequally affected.
precipitate attacks of tetany. This post-opera- PROF. J. C. MEAKINS (Montreal) considered that
tive condition has been controlled where it has the criterion of disturbance of parathyroid function is
to be found in study of blood calcium and calcium
appeared by calcium and parathyroid therapy. balance, although the latter is open to many fallacies.
There are six diseases associated with disturbance of
REFERENCES calcium metabolism, parathyroid deficieney (spasmodic
1. ALBRIGHT AND ELLSWORTH, J. Chem. Invest., 1929, 7: 183, tetany), nephrosis, steatorrhcea with megalocolon, in-
2. ALLARDYcE, unpublished work. fantile rickets, osteomalacia, and generalized osteitis
3. ASHroRD, Biochem. J., 1930, 24: 661. fibrosa (Von Recklinghausen's disease). Of these only
4. Aus, Harvey Lecture8, 1928-29, p. 151; Boston Med. d two are associated with lesions of the parathyroid-
Surg. J., 1926, 194: 844. parathyroid tetany, and its antithesis, generalized
5. BARR, BULGER AND DIxoN, T. Am. M. A8s., 1929, 92: 951. osteitis fibrosa. There has been considerable confusion
6. BAUER, AUB AND ALBRIGHT, J. Exper. Med., 1929, 49: 145. in the study of the latter and of osteomalacia, and this
7. BECK, Arch. f. klcn. Mhtr., 1928, 152: 123. must be borne in mind in utilizing the earlier literature.
8. BERGEIM, J. Biol. Ohem., 1926, 70: 51. In nephrosis with a lowered calcium deficiency there is
9. CAMERON AND MiooHousE, J. Biol. Chem., 1925, 63: 687. usually a good response to parathyroid therapy, al-
10. COLLIP, Harvey Lectures, 1925-26, p. 113. though the cause and effect are not yet known.
11. EDWARDS AND PAGE, Am. T. Phy8iol., 1926, 78: 235.
12. ERDHEIM, Mitt. a. d. Gkenzgeb d. Med. ui. Chir., 1906, 16: DR. D. Roy MCCULLAGH (Cleveland) reported the
632. results of a series of cases studied by himself and Dr.
13. FREEMAN. AND FARMER, Proc. Soc. Exper. Med. & Biol.,
1930, 27: 970. E. P. McCullagh exhibiting parathyroid deficiency follow-
14. HANNON, SHORK, MCCLELLAN AND DuBois, T. Clin. Invest., ing operation. They have endeavoured to find a means of
1930, 8: 215. controlling phosphate metabolism in this condition.
15. HEss, LEWIS AND RaVXIN, T. Am. M. A88., 1928, 90: 783.
16. HESS, W'EINSTOCK AND ROOKER, Proc. Soc. Exper. Biol. d They have observed that while many such cases exhibit
Med., 1930, 27: 298. a constant low level of serum calcium the patient's
17. HEss, Rickets and Osteomalacia, Lea & Febiger, Philadelphia, tetany symptoms vary -from day to day, parallel with
1929.
18. HIGGINS AND SHEARD, Am. J. Physiol., 1928, 85: 299. the inorganic phosphate in the serum. In normal sugar
19. HIGGINS, FOSTER AND SHEARD, Am. T. Physiol., 1930, 94: tolerance curves it is well recognized that as the blood
91. Eugar rises the phosphates show a fall (slightly delayed).
20. HUEPER, Arch. Path. & Lab. Med., 1927, 3: 14.
21. HUNTrR, The Lancet, 1930, 1: 897; Proc. Roy. Soc. Med., In post-operative parathyroid tetany the relationship is
1929, 23: 27. somewhat emphasized. As the phosphate falls the neuro-
22. JONES, J.. Biol. Chem., 1921, 49: 187. muscular excitability lessens. An attempt has been made
23. LEIBOFF, .J. Biol. Chem., 1930, 85: 759.
24. MANDL, Zentralbl. f. Chir., 1926, 53: 260; Zentralbl. f. to apply this finding to treatment. After a carbo-
Chir., 1929, 56: 1739. hydrate- meal the symptoms are greatly, but only
25. MASSENGAE AND NUssmzIR, J. Bo. Chem., 1930, 87: 415. temporarily, relieved; calcium gluconate is ineffective,
26. MILES AND FENG, T. Exper. Med., 1925, 22: 433.
27. MORGAN AND GARRISON, J. Biol. Oh-elm, 1930, 85: 687. but administration of lactose has been found to give
28. RIDDLE AND REINHART, Am. J. Physiol., 1926, 76: 660. very beneficial results, these being accompanied by a
29. SCHMORL, MiinCh. med. Wchnschr., 1919, 66: 1057. slow steady fall of blood phosphates.
30. SHERMAN, J. Biol. Chem. 1920, 44: 21.
31. STEWART AND PERCIVAL, Physiol. Reviews, 1928, 8: 283;
Biochem. J., 1928, 22: 548. PROF. A. T. CAMERON (Winnipeg) referred to re-
82. SUN AND MCOWAN, Proc. Physiol. Soc., June 7, 1930. sults he had obtained showing that the blood calcium
33. TAYL.OR, BRANION AND KAY, Proc. Physiol. Soc., May 16, of normal young rats is below normal, and at a level
1930.
34. VOLLMER AND SEREBRIJSKI, Zeit. f. Kinderheilk., 1925, 39: associated with tetany, for a large part of the year,
655. although open tetany is never manifested. The explana-
35. WALSH AND IVY, Proc. Soc. Exper. Biol. & Med., 1927-28, tion obviously seemed to be a dietary deficiency in
25: 839.
36. WARNER, The Lancet, 1930, 1: 339. vitamin D, and he reported results recently obtained by
37. WATCHORN, Biochem. J., 1930, 24: 631. one of his students, Mr. C. F. Code, supporting this
654654 ~ ~~
TH
CANADIAN MEDICAL
THE Cx,Am. MEIA
ASSOCIATION JOTJRNAL
AS,ITO JORA [Ma
1931 2i
[May 1931

view. In these animals the blood calcium can be main- reasonable that the main control over the height of
tained during winter at maximum or normal levels by blood calcium is exercised by the vitamin, perhaps
feeding food irradiated from a carbon-are lamp, or by through the parathyroids. The available evidence bear-
adding irradiated ergosterol to the diet. Numerous ing on the effect of vitamin dosage and over-dosage
observations by various workers have shown beyond following parathyroidectomy is quite conflicting, while
doubt that marked over-dosage of the vitamin will little if any work seems to have been done to ascertain
markedly increase the plasma calcium. Since, however, the result of continuous parathyroid injection in experi-
over a considerable range of vitamine dosage the blood mental rickets, and the speaker suggested that study of
calcium remains constant, whereas any injection of the these problems might well throw much greater light on
parathyroid secretion has its effect, the inference is the whole problem of calcium metabolism.

THE CLINICAL ASPECT OF DISTURBANCES OF THE

PARATHYROID GLAND*
BY J. C. MEAKINS, M.D., LL.D. (EDIN.), F.R.C.P. (EDIN.),
Director, Department of Medicine, McGiU University,
Montreal
may be stated briefly that the function of the
IT parathyroid function, and then determine if such an associa-
glands is the maintenance of' the tion is tenable on known facts.
calcium content of the blood plasma at a defite On what basis or criterion may it be tentatively
level and the control of the ca l-iiff a A1~Wvf assumed that a disturbance of parathyroid func-
the body. It would also appear that these tion might exist? The function of the para-
glands have an important function in regulating thyroid has already been defined. There could
the calcium metabolism of the fixed tissues, therefore be no better tentative criterion than
particularly the osseous system. one which would indicate a disturbance of this
For some twenty-five years the absence or normal function of calcium regulation. In the
deficiency of the parathyroid function has been table are given the various disease conditions
identified with a lowering of the blood plasma which are associated with a disturbance of the
calcium and the associated occurrence of increased calcium metabolism. There has been included
electrical excitability of the neuro-muscular a record of the phosphorus content of the blood,
system, producing the well-known clinical picture as the calcium and phosphorus metabolism is so
of spasmodic tetany. But it has been only in intimately associated that frequently it is im-
comparatively recent years that clinical bio- possible to interpret the significance of the first
chemical 'and pathological studies have enlarged without a knowledge of the second. Of these
our horizon and associated other abnormal six conditions there is definite knowledge that
conditions with disturbances of the parathyroid 1 and 6 ("parathyroid tetany" and osteitis
function. I think it may be taken that, theoretic- fibrosa) are intimately connected with abnormal
ally, this function might be disturbed in one of function of the parathyroid glands.
three ways, as follows. There might be either: "Parathyroid tetany" is a condition which
(1) a decrease in the normal function; (2) an occurs subsequent to removal of the parathyroid
increase in the normal function, or (3) a perversion glands or to their injury or degeneration from
of the normal function. So far as is known at the some other abnormal cause. It is characterized
present time no such condition as would occur by increased mechanical or electrical excitability
under the third category has been recognized as of the neuro-muscular system, with muscular
such. There are therefore left for consideration hypertonicity leading to painful spasmodic con-
such conditions as might be identified under the tractions of the muscles of the limbs, trunk, and
first two sections. It might serve a useful certain internal muscles such as those of the
purpose to consider at this time what conditions larynx, diaphragm, bladder, and bowel. There
might be caused bya derangement of parathyroid is also a pronounced decrease of the calcium
content of the blood, which is usually in pro-
*A paper read in the Section of Bacteriology, Patho- portion to the degree of muscular irritability.
logy, Physiology, and Biochemist at the combined There is little or no change in the pH 'of the
meeting of the British and Canadian Medical Associations
Winnipeg, August 28th, 1930. plasma. This syndrome may be either per-