situ, the thyroid beinlg removed, while on the other hand the removal of by the operation than are herbivora and omnivora, where the complete

Transcription

1 FURTHER OBSERVATIONS UPON THE FUNCTIONS OF THE THYROID AND PARATHYROID GLANDS. BY SWALE VINCENT, Professor of Physiology in the University of Manitoba, Winnipeg, Canada, AND W. A. JOLLY, Assistant to the Professor of Physiology in the University of Edintburgh. (From the Physiological Laboratories of the Universities of Edinburgh and Manitoba.) Introductory. In our previous paperl we recorded some observations upon the thyroid and parathyroid glands. The observations caused us to question the view recently put forward, that the function of the thyroid gland is, as regards the question of preservation of life, subsidiary to that of the parathyroids. Nor were we able to confirm the theory that removal of the parathyroids caused invariably acute nervous symptoms and speedy death, while removal of the thyroid was followed by " cachexia strumipriva," and in the case of monkeys true myxcederna. We found that removal of the parathyroids did not necessarily induce nervous symptoms, nor removal of the thyroid myxcedema. Nervous symptoms sometimes supervened, when parathyroid glands were left in situ, the thyroid beinlg removed, while on the other hand the removal of the parathyroids did not always lead to the development of such symptoms. We noted, however, that two cats in which the parathyroids were extirpated exhibited acute nervous symptoms, and died as a result of the operation. This operation is a difficult one, and as in these cases we found, post mortem, that the thyroid had itself suffered injury, we concluded that simple parathyroidectomy in the cat, where the thyroid gland is left uninjured, is not necessarily fatal, and we attributed symptoms when they occurred to the absence, or interference with the functional integrity, of both sets of glands. In some cases, even of carnivora, which are more seriously affected by the operation than are herbivora and omnivora, where the complete I This Journal, xxxii. No

2 296 S. VINCENT AND W. A. JOLLY. operation was performed, prolonged survival followed with little or no appreciable signs of departure from a state of health. In the majority of cases among the carnivora fatal results more or less rapidly supervened upon the operation. We observed that while the signs of ill-health in those animals which survived the complete operation for a considerable time were so slight as to be almost imperceptible, yet the animals were more prone to such affections as conjunctivitis, skin diseases, and catarrh of various kinds, indicating a lowering of the general health, due to the absence of the specific function of the thyroid and parathyroids. The experiments now recorded are on the whole confirmatory of those described in our previous paper. The experiments on dogs, prairie wolves, and badgers were performed in the University of Manitoba, and we beg to acknowledge the valuable assistance of Dr Torrance of Winnipeg. Experiments on Monkeys. In the following experiments on monkeys the thyroid glands were completely removed. thyroid and para- 1. Macacus rhesus J. A well-developed isthmus was removed along with both thyroid lobes and the parathyroids. Cornpletely recovered from operation and remained well for 20 days, when it had an epileptiforin fit, from which it completely recovered. It remained well for 9 days after the fit, when it was removed from the artificially heated room and placed in a cold room. It became quieter and tamer. Did not eat well. Shivered but did not show any special symptoms. Died 4 days after transference to cold room, 32 days after operation. 2. Macaous rhesus $. Remained well for 14 days, when some trembling of the limijbs was observed but the animal remained quite lively. Seven days later this monkey was transferred from the artificially heated room to the cold room along with monkey No. 1. Became quieter, some stiffness of limbs was observed but no tetany. After remaining for 4 days in the cold room it was put back into the warm room. The monkey thereafter remained well for two months, when it was killed-88 days after operation. 3. Macacus rhesus g. Showed no nervous or other symptoms and remained perfectly well till it was killed 81 days after operation.

3 THYROID AND PARA THYROID GLANDS Macacus rhesus ;. Isthmus with thyroid lobes and all 4 parathyroids removed. The monkey remained well until 3 days after operation when tremors were noticed in the hind limbs with symptoms of malaise and anorexia. It recovered completely from these symptoms, and remained well. It was killed 68 days after operation. 5. Callothrix e. No tremors nor other symptomns were observed, and the monkey remained well until it was killed on the 62nd day after operation. 6. Callothrix f. Difficult operation. The thyroid was diffuse. There was considerable ha3morrhage, and more extensive damage to the neck structures resulted than in other cases. The monkey died in convulsions on the day following the operation. Post mortem the recurrent laryngeal nerve on one side was found to have been included in a ligature. This series of experiments on monkeys confirms those which we previously recorded. The nervous symptoms when they ensued as in Exps. 1 and 4 were transient and the monkeys entirely recovered from them. Monkey No. 6, which died on the day following operation, was found post mortem to have one recurrent laryngeal nerve included in a ligature and probably sustained other injuries to the nerves. It will be seen later that in the experiments on cats now recorded the only one which succumbed to acute nervous symptoms was a very young animal in which the neck structtures were therefore delicate and would easily suffer injury. We are inclined to think that the acute nervous symptoms are frequently associated with damage to the nerves at the operation. In none of the monkeys were there any of the signs observed which are described as most characteristic of myxcedema in the human subject. Never have we seen any swellings of the subcutaneous tissue in any part of the body, nor were such swellings induced by the transfer of two monkeys from the artificially heated to a cold room, although one of them died as a result of the altered conditions. With the exception of the nervous symptoms, from which recovery was the rule, the monkeys exhibited no very definite ill-effects as the result of the operation. Our observations on this point were confirmed by the other workers in the laboratoryl. The absence of myxcedematous swellings in both of our series, that 1 We do not think that the monkeys were entirely unaffected by the operation, but neither we nor any of those who saw them could diagnose myxcedema.

4 29D8 S. VINCENT AND W. A. JOLLY. is to say after 13 complete extirpations in monkeys, is in accordance with Munk's resultsl. Kishi also failed to find myxcedema in his operated monkeys2. Experiments on Cats. 1. Cat g. Both thyroid lobes removed, anid 3 paratbyroids. One external parathyroid left in situ. For 20 days the cat remained well. Then it developed a nasal catarrh and conjulnctivitis. It grew progressively worse, exhibited retraction of the abdomen and tremors, and died 33 days after operation. Post mortem: the parathyroid left at the operation showed a few colloid containing vesicles at the margin. This parathyroid had not undergone the extensive alteration observed in other cases. 2. Cat?. Complete operation. Typical nervous symptoms with tetany and tremors developed. These passed off and the cat was free from nervous symptoms for a considerable time before its death, which occurred 38 days after operation. 3. Cat g. Thyroid lobes and inter nal parathyroids removed. External parathyroids left in situ. No nervous symptoms developed, but the cat suffered from nasal catarrh and conjunctivitis, which appeared 12 days after operation. Forty-four days after operation administration of thyroid extract was commenced. At first 0 2 grm. of the dried extract was given daily. This was increased 5 days later to 0 3 grrn. per dtem and thyroid feeding was kept up for 20 days. The cat became more lively. Its appetite improved and the nasal catarrh and conjunctivitis disappeared. Its weight also increased slightly. Thyroid feeding was stopped after 20 days. A month later the conjunctivitis was again present. The cat was lethargic, weak, and affected with nasal catarrh. After an interval in the thyroid administration of 43 days it was continued, 0 3 grm. being given daily for 3 months. The improvement in health was not so marked as previously, but there was no conjunctivitis nor catarrh and the weight was found to have increased. On stopping thyroid feeding the cat became rapidly worse, and was killed, unconscious and in extremis, 23 days later, 189 days after operation. Post mortem: the external parathyroids were found in a condition which we are inclined to interpret as one of degeneration. 1 Virchow's Archiv, CL. S Virchow's Archiv, CLXXVI. S

5 T1HYROID AND PARA THYROID GLANDS Cat C. Operation as in the preceding case. The external parathyroids being left. The cat remained fairly well for 11 months, the only symptoms observable being slight lethargy and a-tendency to mange. During the course of the experiment the cat was fed for 40 days exclusively upon raw meat and water. The effect of this was ntl, the animal neither gaining nor losing in weight. An unoperated cat was at the same time fed upon the same diet as a control. A slight diminution in its weight was observed by the end of 40 days. Later, thyroid feeding was adopted in the case of the thyroidectomised cat and continued for 62 days. A distinct improvement in its condition resulted. The cat appeared more natural and lively and the weight increased. The cat was killed 289 days after operation. Post mortem: the parathyroids which had been left behind showed distinct though not very extensive changes in the direction of thyroid tissue. 5. Cat C. Right external parathyroid left in situ. The remaining parathyroids removed with the thyroid. The cat remained fairly well, exhibiting merely drowsiness and some impairment of activity, for 2 months. Thyroid feeding (0 3 grm. of thyroid extract per diem) was commenced 56 days after operation and continued for 10 days. The cat became more lively and was indistinguishable from the normal. Killed 2 months after thyroid feeding was discontinued. 6. Cat e. All 4 parathyroids removed. Thyroid left in situ. The parathyroids were ligatured and cut away. No untoward symptoms were observed. Killed 90 days after operation. Post mortem: no parathyroids were found remaining. 7. Young cat C. All 4 parathyroids were removed, the bleeding being cbecked by the cautery. Thyroid gland left. Three days later typical nervous symptoms developed and the animal died the same day. Experiments on Dogs. The following experiments, although we cannot pretend that they are completely satisfactory, yet seem to IJs to deserve narration as indicating the extreme difficulty of the operation of parathyroidectomy, and as pointing to the relation which subsists between freedom from symptoms and freedom from injury to the whote thyroid apparatus. PH. XXXIV. 20

6 300 S. VINCENT AND W. A. JOLLY. 1. Young dog,. Two parathyroids on left side seen and removed, left thyroid lobe suffered to remain. Right lobe removed along with the 2 parathyroids from the right side. The extent of the operation was checked by microscopic examination of the tissues removed. The animal lived free from symptoms for 51 days, when it was killed. Post mortem: a parathyroid was found on the left side. 2. Dog $. The operation was the same as in the preceding experiment, with the same result. The post mortem finding was also the same, a parathyroid having been left behind on the left side. 3. Dog $. All 4 parathyroids seen and removed. Considerable damage done to thyroid by cautery. Typical nervous symptoms ensued and death on the 3rd day. Post mortemn: the thyroid was found extensively necrosed as a result of cauterisation. 4. Dog J. Four bodies, apparently the parathyroids, removed Bleeding checked with cautery. On microscopic examination only two of these bodies could be verified as parathyroids, the other two parathyroids presumably remaining. Typical nervous symptoms ensued, and the animal died in convulsions on the 6th day. Unfortunately serial sections were not cut post mortem through the whole of both thyroid lobes. 5. Dog c. Five bodies removed during the operation of parathyroidectomy: cautery used with great caution. On mnicroscopic examination one of these bodies was found not to be parathyroid. The other four were parathyroids. The animal was killed on the 19th day, having shown no symptoms. 6. Dog $. Four parathyroids seen and removed. This was verified by microscopic examination. Killed 20 days later without symptoms having developed. 7. Dog cf (10 months old). Four bodies, apparently parathyroids, removed. On microscopic examination one of these was found not to be parathyroid. Killed 22 days later, not having shown symptoms. Post mortem: no parathyroid could be found on naked eye examination. Microscopic examination was not made of the tissues left. 8. Dog $ (6 to 8 months old). Four parathyroids seen and removed, also a median nodule of thyroid. All very distinct. Right thyroid considerably cauterised. The four bodies were examined

7 TiHYROID AND PARA THYROID GLANDS. 301 microscopically and found to be parathyroids. Killed 8 days later, having remained perfectly well 9. Dog J (5 months old). Four bodies, apparently parathyroids, removed. On microscopic examination one of these was found to be thyroid. Killed 6 days later, having presented no symptoms1. In our previous paper we recorded a series of parathyroidectomies in cats and found that only 33 0/0 of the experiments proved fatal, and we concluded from this that simple parathyroidectomy in this animal when the thyroid gland is left uninjured is not fatal. Our fatal cases were those in which we had done most damage to the whole thyroid apparatuis. At that time we had not attempted simple parathyroidectomy in dogs for the reason that the difficulties which we emphasised in cats seemed to be even greater in dogs. During the last year, however, an attempt has been made to test the effect of removal of all the parathyroids in dogs, leaving the thyroid as little damaged as possible. We consider that the results support our view that in extirpation experiments synmptoms when they occur are to be attributed to interference with the functional integrity of both thyroids and parathyroids talken as a whole. If one removes the parathyroids and does little or no damage to the thyroid the animal appears to suffer no ill consequences, or if one removes a considerable portion of the thyroid and yet leaves the parathyroids, a similar negative result will follow. But if the parathyroids be removed and considerable damage be done to the thyroid, or if the thyroid lobes be removed and the parathyroids injured, we may frequently get acute symptoms and rapid death. But it must be remembered that this is not a constant rule, for in manly cases in various groups of mammals we can remove the whole apparatus with impunity. Especially is this the case in rats. During the course of our former experiments we attempted by the administration of thyroid and parathyroid extract to prevent the onset of symptoms after the complete operation and to diminish their severity when such symptoms had ensued, but without success. It will be seen from the preceding experiments that we have been successful in bringing about an improvement in the condition of three cats from which the thyroid lobes had been removed but in which parathyroids had been left in situ. 1 These dogs owing to lack of accommodation were killed sooner than was desirable, but symptoms when they occur, nearly always appear on or about the 3rd day. 20-2

8 302 S. VINCENT AND W. A. JOLL Y. In the course of our former series of experiments, in order to test whether feeding almost exclusively on a proteid diet would induce or aggravate symptoms after thyroidectomy we fed a monkey which had undergone this operation upon fibrin. The fibrin was pressed into tablets together with some sugar in order to render it palatable to the monkey. The animal, which had previously shown transient nervous symptoms, was fed exclusively on these tablets for 7 days without any alteration being noted in its condition. As will be seen from the preceding notes of experiments on cats, we fed a cat, from which the thyroid had been removed but in which 2 parathyroids were allowed to remain, upon meat and water exclusively for 40 days. No changes in its condition could be perceived. The weight was maintained and otherwise the cat remained well. An unoperated animal fed during the same period upon the same diet was found to have decreased somewhat in weight. We are not therefore able to affirm that the incidence or severity of symptoms after thyroidectomy are dependent upon the nature of the feeding. Experiments on Prairie Wolves (Canis latrans) and Badgers. The experiments upon these animals were prompted by our experience with foxes. It was thought possible that purely carnivorous animals would resent thyroidectomy to a more marked degree than herbivora or omnivora. But this has not turned out to be the case. The wolves behaved precisely as do dogs, and the badgers were totally unaffected by the operation. The difference in behaviour of different groups of animals does not then depend on diet. This matter we have also, as before mentioned, tested in another way. Prairie Wolves. 1. Complete operation. Sixteen hours later an attack of rapid breathing ensued, and 20 hours after operation a convulsive attack. Next day typical nervous symptoms set in and were observed at intervals during 2 days. Three days after operation the animal was well. It showed no further nervous symptoms but became weaker and died 38 days after operation. There was no swelling of the subcutaneous tissues. 2. Four parathyroids and the left thyroid lobe removed. Right

9 THIYROID AND PARA THYROID GLANDS. 303 lobe left in situ. The animal showed no appreciable symptoms and was killed 63 days after operation. Note. In this case it is possible that one parathyroid was left behind, although no parathyroid tissue was found post mortem. Badgers. 1. Thyroid and parathyroids removed. All 4 paratbyroids were found on cuitting serially the tissue removed. No apparent symptoms ensued. The animal was killed 57 days later. No thyroid nor parathyroid tissue found post mortem. 2. Thyroid and parathyroids removed. All 4 parathyroids were verified microscopically. Remained without symptoms for 37 days, when it was killed. No thyroid nor parathyroid tissue found post mortem. So far as can be judged from the two experiments performed the prairie wolf reacts to the operation in a similar way to the dog. The two experiments upon badgers were entirely satisfactory from the point of view of operation, all 4 parathyroids being microscopically demonstrated in each case, and we must therefore group ba'dgers with monkeys and rats in that they show little if any perceptible ill-effects from the operation. Experiments on Rats. 1. White rat. Parathyroids ligatured and cut away. Thyroid left in situ. Remained in apparently perfect health for 61 months, after which it was killed. No parathyroid tissue found post mortem, on microscopic examination. 2. Black and white rat. Parathyroids removed as in the previous case. The rat was apparently unaffected by the operation and remained well for 6j months, when it was killed. Post mortem as in No. 1. These experiments on rats are confirmatory of those which we recorded previously, and would indicate that the removal of parathyroids may be carried out with impunity in the case of rats. In view of the fact that 4 paratlhyroids are very constantly present in most other mammals we made careful anatomical studies in the rat with the object of determining whether in this animal there are in reality only 2 parathyroids or whether others exist and have been overlooked either on account of their lying at some distance from the

10 R. VINCENT AND W. A. JOLl Y. thyroid, as do the external parathyroids in rabbits, or for some other reason. We failed, however, to find more than one parathyroid in relation to each thyroid lobe in rats and also in mice. In the case of the cat also we have made an effort to ascertain whether the presence of accessory parathyroids in addition to the four normally found is of common occurrence. We carefully examined the neck and mediastinum of 7 cats, cutting all small bodies which appeared possibly to consist of parathyroid tissue. The majority of these bodies were found to be lymphoid in character or to be cysts lined by columnar, flattened, or ciliated epithelium. In one case a true accessory thyroid was found close to one of the thyroid lobes. In no case were accessory parathyroids present. These dissections confirmed what we had been led to believe in the course of our experiments, viz.-that accessory or additional parathyroids, if present at all, are very rare in cats'. The marked variability in position of the external parathyroid is apt to make it appear that accessory parathyroids are commoner than is found to be the case. In our former paper we described and depicted certain changes which occurred in parathyroids left behind after removal of the thyroid. We considered that these changes represented a more or less successful attempt on the part of the organism to reconstruct thyroid from parathyroid. These results seemed to point to the accuracy of the earlier view that parathyroids were embryonic thyroids2. There are moreover other reasons which lead one to conclude that thyroid and parathyroid are not separate and independent organs. In the human parathyroid it is not rare to find colloid vesicles in all respects resembling those of the thyroid. In fact it would seem that there is after all no fundamental distinction between the essential histological constituents of the two tissues. The intervesicular cells of the thyroid are almost identical with the parathyroid cells, and such differences in arrangement as exist may be the direct result of the formation of the colloid substance. Further, it is not rare to find structures in various animals about which it is difficult to say whether they are thyroids or parathyroids. In many thyroids there are solid masses of cells, not however so distinctly marked off as the parathyroids 1 In one cat there was found a small body at some distance from the thyroid, which proved to be parathyroid. There was some doubt, however, as to whether all the four parathyroids were also present, and it is difficult to say whether this was a true accessory gland or an aberrant externa4 parathyroid. 2 For literature on this point see our former paper.

11 THYROID AND PARATHYROID GLANDS. 305 proper, which are practically identical in structure with the latter bodies. The internal parathyroid is frequently in direct continuity with the thyroid at one part, and it is impossible to draw any strict line of demarcation between the two. CONCLUSIONS. We consider that the experiments recorded in the present communication support the views expressed in our first. These are in brief as follows: Neither thyroid nor parathyroids can be considered as organs absolutely essential for life. Rats and guinea-pigs do not seem to suffer at all as the result of extirpation. Monkeys only show transient nervous symptoms. Dogs, cats, foxes, and prairie wolves frequently suffer severely and die. On the other hand badgers do not appear to be affected by the operation'. When parathyroidectomy proves fatal this is probably due to the severe damage simultaneously done to the thyroid2. Thyroid and parathyroids are to be looked upon as a single physiological apparatus, the two kinds of tissue being intimately associated embryologically and working together physiologically. When the thyroid is removed the parathyroids appear capable of functionally replacing it to a certain extent and their histological structure changes accordingly. In our former paper will be found sketches showing the changes from parathyroid to thyroid. In no animals, not even in monkeys, have we been able to induce any swellings of the subcutaneous tissue, which is the most striking feature of myxoedema in the human subject. We think therefore that the pathology of myxcedema must be more complex than simple thyroid insufficiency. [The expenses of this investigation were defrayed by grants from the Brit. Assoc. for the Advancement of Science (Committee on Ductless Glands), Moray Fund (University of Edinburgh) and the Carnegie Trust for the Universities of Scotland.] I The American badger is a purely carnivorous animal. 2 It is possible that there may be a difference between the results of severe damage to the thyroid apparatus and its total removal.