COLUMBIA LIBRARIES OFFSITE HEALTH SCIENCES STANDARD HX641 44992 RC655 .R39 The thyroid and para RECAP ColumSta®niber§tt? intfjeCitpofJIetogork g>cf)ool of Bental anb 0m\ burger? Reference Htbrarp THE THYROID AND PARATHYROID GLANDS RICHARDSON Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/thyroidparathyroOOrich The Thyroid AND Parathyroid Glands HUBERT RICHARDSON, M.D. LATE PATHOLOGIST TO MOUNT HOPE RETREAT; PATHOLOGIST TO MARYLAND ASYLUM AND TRAINING SCHOOL FOR FEEBLE-MINDED CHILDREN; DEMONSTRATOR OF PHYSIOLOGIC CHEMISTRY, UNIVERSITY OF MARYLAND WITH SEVENTY-SEVEN HALF-TONE ILLUSTRATIONS MADE FROM SPECIAL DRAWINGS BYE. P. WIG HTM AN PHILADELPHIA P. BLAKISTON'S SON & CO IOI2 WALNUT STREET '905 Copyright 1905, By P. Blakiston's Son & Co Press of The new Era Printing company Lancaster, Pa. PREFACE. The work that lias been done on the thyroid and para- thyroid glands within the past ten or fifteen years has contributed to medical literature one of its most bril- liant chapters. The careful elucidation of their physi- ological functions, the discovery of the active principle of the thyroid and its therapeutic application, has -filled us with wonder and surprise. But a few years ago the most advanced text-books gave them but a passing ref- erence and dismissed the whole subject with the vague suggestion that the gland was constructed and placed in its position by the Divine Architect of the human body as an ornament to the neck, like a bit of molding in a house or a Doric finish to a column. Later it was sup- posed to have some relation to the voice, or to regulate in some compensatory manner the intracranial blood sup- ply, but nothing was known of its true function and im- portance. Since Brown-Sequard and Bernard emphasized the theory of an internal secretion, which brought upon the former an avalanche of ridicule, and Sir William Gull and Murray followed in rapid succession with their start- ling revelations concerning the function of this "terra incognita, ' ' it has been my great pleasure to follow, with enthusiastic interest, the contributions throwing new light on this subject, and apply to practical therapeutics the facts made clear by these investigations and observations. Following in rapid succession after the discovery of the function of the thyroid gland came the announcement that certain conditions of a grave and persistent character were due to the congenital or acquired absence or abridg- VI PEEFACE. inent of the gland, and that these were relieved by en- grafting a gland from a healthy animal into the peri- toneum or other parts of the body, or by injecting hypo- dermically a glycerin solution of the gland of the sheep, and finally that the same purpose could be accomplished by the use of the fresh gland per orem. Then came the discovery that the gland could be desiccated and used as any other drug with equal efficacy and with greater accuracy. Further research soon developed the fact that still other conditions, chiefly associated with arrested, retarded or perverted development, either of a physical or psychical character, but generally both constituting what the French have called "type Loraine" have been found to be asso- ciated with an arrested development of the organ and could be relieved by the administration of the dried gland. It has been also demonstrated that certain functions, chiefly menstruation and gestation, demand an extra ex- penditure of thyroid secretion, which, if not supplied, leads to distinct symptoms, which are also relieved by the administration of the dried gland. Not resting here, earnest investigations have shown that it is a most potent oxidizer, with all the far-reaching effects of such an agent on the animal economy, and that it is a blood pressure reducer of seemingly a more exact and reliable character than any remedy heretofore found in our materia medica. Developments are also being rapidly made concerning other ductless glands and those having an internal secre- tion that affect the normal relation and balance of the human economy. The suprarenal gland has become a standard therapeutic agent to a less degree, but sufficient to give promise of further development in the future. That the therapeutic applications of the pharmaceutical preparations of these glands are not more extensively PEEFACE. Vll availed of in medical practice is due, no doubt, to the fact that these useful developments have not yet been crystallized into the text-books, and, being scattered through the medical literature of many languages, have not been made available to the rank and file of the profes- sion. Appreciating the therapeutic possibilities of the animal glands, I often have occasion to regret that the brilliant results of the work that is being done along these lines has never, as far as I know, been collected into one comprehensive volume, so that it can be availed of with- out an amount of research with the necessary access to libraries that are not within reach of the average physi- cian. It was on this account that I urged Dr. Richardson to give to the profession a compilation of the whole sub- ject, adding his personal observations and the scientific researches he has made in following up the practical ap- plication, with analyses of the human gland under various conditions of mental and physical impairment, and also by his urinalyses and blood examinations, as well as the blood-pressure tests of those to whom it was being ad- ministered, especially among the insane and degenerates, while pathologist at Mount Hope Retreat. His capacity for research, his familiarity with the sev- eral languages in which the best literature on the subject has been written, and his general versatility render him, in my opinion, most capable of doing this work, and I feel assured that his book will supply a need as much felt by the other members of the profession as by myself. I am convinced that it will be well and thoroughly done, and I am sure I can vouchsafe it a kind and generous reception. CHAS. G. HILL, A.M., M.D., Professor of Nervous and Mental Diseases, Baltimore Medical College; Physician-in-Cliief to Mount Hope Retreat. CONTENTS. Chapter I. Historical 1 Chapter II. Embryology — Anatomy — Histology — The Parathyroids .... 8 Chapter III. Physiology 20 Chapter IV. Chemistry of the Thyroid Gland 56 Chapter V. Goitre 73 Chapter VI. Surgery of the Thyroid Gland 100 Chapter VII. The Thyroid in Infections Diseases 121 Chapter VIII. Acute Thyroiditis 129 Chapter IX. Syphilis of the Thyroid 139 Chapter X. Cretinism 144 Chapter XL Myxedematous Infantilism 161 Chapter XII. Myxedema 188 Chapter XIII. Basedow's Disease 199 Chapter XIV. Thyroid Feeding in General Therapeutics 233 Bibliography 255 Index 259 ix LIST OF ILLUSTRATIONS. 1. The position of the thyroid after removal of the muscles (v. Eiselsberg) 9 2. Absence of isthmus (Marshall) 10 3. Isthmus with large pyramid (Marshall) 10 4. Double pyramid (Marshall) 11 5. Absence of isthmus with pyramid on left side (Mar- shall) 11 6. The thyroid arteries (v. Eiselsberg) 13 7. Normal thyroid gland 14 8. The position of the parathyroid glands (Zuckerkandl) 16 9. Normal parathyroid gland 18 10. Monkey in tetanic attack after extirpation of thyroid (v. Eiselsberg) 35 11. A four months old kid whose thyroid was removed at 21 days old (v. Eiselsberg) 39 12. Control animal from the same birth (v. Eiselsberg) ... 39 13. Lamb, 6 months old, the thyroid being removed on the tenth day (v. Eiselsberg) 41 14. Control animal (v. Eiselsberg) 43 15. Aorta of thyroidectomized sheep showing atheroma (v. Eiselsberg) 44 16. Circular stricture of the trachea from goitre (Demme) 80 17. Bayonet-shaped trachea from bilateral goitre (Demme) 81 18. Showing the enlarged veins in goitre (Wolfler) 82 19. Bending and narrowing of the trachea by goitre (Demme) 83 20. Goitre of accessory thyroids (Adjutolo) 84 21. Retrosternal goitre in a deep-seated thyroid lobe (Wuhr- man) 85 22. Intrathoracic goitre (Dittrich) 85 23. Follicular, goitre (v. Eiselsberg) 86 24. Goitre marked by diffuse follicular hypertrophy (v. Mikulicz) 87 25. Colloid goitre (v. Bruns) 88 26. Follicular goitre with ectasia of the veins of the skin (v. Eiselsberg) 89 xi Xll LIST OF ILLUSTRATIONS. 27. Cystic goitre (v. Billroth) 90 28. Cystic goitre (v. Brims) 91 29. Struma vasculosa 110 30. Adenoma of thyroid 110 31. Cachexia strumipriva in a girl 26 years old (v. Bruns) 116 32. Congestion of the thyroid 122 33. Tuberculosis of thyroid 135 34. Columnar celled carcinoma of thyroid gland 141 35. Adeno-carcinoma of thyroid gland 141 36. Cretin with goitre (v. Bruns) 145 37. Cretin with goitre (v. Mikulicz) 146 38. Cretin, 22 years old (v. Wagner) 147 39. Cretin (v. Wagner) 148 40. Acute thyroiditis 150 41. Suppurative struma of thyroid gland 150 42. Atrophic gland from a case of myxedema 152 43. Myxedematous gland 153 44. 45. A case of sporadic cretinism before and after thy- roid feeding (v. Bruns) 156 46, 47. A case of sporadic cretinism, aged 6 years, before and after 6 months' thyroid feeding 158 48. Cretin, aged 12 years (Dr. Rogers) 160 49. Skull of cretin calf 162 50. Infantilism, aged 17 years (Hertoghe), before treatment 166 51. Infantilism, aged 17 years (Hertoghe), after 6 months' treatment 166 52. Infantilism, aged 17 years (Hertoghe), after 1 year's treatment 166 53. Infantilism, aged 17 years (Hertoghe), after 2 years' treatment 166 54. Skiagram of the hand of a type Loraine 17 years old. . 168 55. Skiagram of the hand of normal child 6 years old 169 56. Skiagram of the hand of a case of myxedema 19 years old 169 57. Skiagram of the hand of a type Loraine, 16 years old . . 170 58. Skiagram of a normal hand 20 years old 171 59. A case of infantilism, 19 years of age (author's case), before treatment, height 4 ft. 6^ in., weight 76 lbs. 172 60. A case of infantilism, 19 years of age (author's case), after treatment, height 4 ft. 11 in., weight 92 lbs. 172 61. Infantilism simulating type Loraine, aged 21 years (Hertoghe), before treatment 174 LIST OF ILLUSTRATIONS. xiii 62. Infantilism simulating type Loraine, aged 21 years (Hertoghe), after 4 months' treatment 174 63. Infantilism simulating type Loraine, aged 21 years ( Hertoghe ) , after 7 months ' treatment 174 64. Normal boy 17 years 177 65. Type Loraine, 27 years 177 66. Myxedematous infantilism, 18 years 177 67. 68. Achondroplasia (Comby) 181 69. Myxedema 184 70. Incomplete myxedema (Hertoghe), before treatment. . 192 71. Incomplete myxedema (Hertoghe), after 6 months' treatment 192 72. Incomplete myxedema (Hertoghe), before treatment. . 193 73. Incomplete myxedema (Hertoghe), after treatment... 193 74. Basedow's disease 200 75. Thyroid gland in Basedow's disease 225 76,77. Masked Basedow's disease with slight exophthalmos 227 THE THYROID AND PARATHYROID GLANDS. CHAPTEE I. HISTORICAL. The use of animal organs in medicine dates from very early times. Plinius states that the Greeks and Romans used the testicles of asses and even the semen for impo- tence ; in Albania these organs are used for the same pur- pose today, and also for amenorrhea. Paracelsus, in the sixteenth century, recommended the spleen for the latter condition. Among barbarous and semi-civilized peoples, as well as among the peasantry in all countries, these cus- toms exist. The Chinese physician prescribes dried mouse and lizard ; the native African uses the liver of snakes both internally and externally as an antidote for snake bite; the warrior eats the heart of the lion to give him courage. In Southern France snails are used for indigestion as well as a luxury; in Cornwall and Devonshire earthworms are given for the same purpose. In the materia medica, pepsin, pancreatin, ingluvin, codliver oil and ox gall are official, all of which are animal extracts connected with the digestive functions, so that the use of other organs or their extracts is but a short step in organotherapy. In recent times Brown-Sequard reawakened interest in the subject by his scientific experiments of removing the glands from animals and observing the result. He argued that every gland of the body, whether it l l 2 THE THYEOID AND PAEATHYKOID GLANDS. possessed an excretory duct or not, produced a secretion which was necessary for the well being of the organism, and that it should be possible when an organ ceased to functionate to substitute the secretion of healthy glands either by transplantation, hypodermic injection of the extract or feeding by the mouth. His first attempt was the use of orchitic extract, christened " Brown-Sequard Elixir," for sterility or impaired virility. The remedy was a failure and brought much undeserved ridicule upon its advocate, but his reputation as a scientist caused others to investigate the subject, resulting in the discovery of the use of the thyroid gland in myxedema, which is one of the greatest triumphs of medicine in the nineteenth century. Brown-Sequard 's statements were investigated by the Biological Society of Paris, and they reported that by the injection of semen and orchitic extract there was produced a marked increase in both mental and physical force. These experiments and the report excited the pub- lic into a belief that the elixir of life had been discovered, and that old age could be rejuvenated, with the natural consequence that pharmaceutical preparations appeared on the market with the most extraordinary advertise- ments. Notwithstanding all this, the foundation was laid, and many workers have been steadily perfecting organ- otherapy, so that two glands at least, the thyroid and the adrenals, have taken a definite place in medicine. There can be no doubt that the testicles and ovaries have a further function than to secrete the substances necessary for procreation. The effect of castration on the mental and physical condition is well known. In those castrated before puberty, as the "castratos" of Italy, there is an arrest of development, both mental and, to a certain extent, physical ; the voice remains childish, while their physical appearance and mannerisms are those of an overgrown child, with a tendency to effeminacy. Those HISTOKICAL. 6 castrated after puberty are heavy, sullen, suspicious-look- ing men, without energy or ambition, while as a rule their mentality is below the average. "Whatever may be the active agent in the testicles, the absence of which produces these results, it has so far been impossible to supply its place by the use of Brown- Sequard 's extract. The experiments of Fiirbringer and Pulawski in Germany and Fere, Baudin, BourTee in France gave only negative results. The Russian chemist, Poehl, after much careful an- alysis, extracted spermin from the testicle. He found that the ovaries, salivary glands, thyroid, liver, spleen, and probably the brain substance, also contained spermin in small quantities, and argued that this substance circu- lated in the organism and was of physiological importance. A vast amount of experimental work was carried out by Tarchanow and others. They found that the resistance of the nerve centers was increased, so that the convulsions of strychnin and tetanus were controlled, and also that young dogs injected with spermin developed more quickly and better than the control animals. They summarized their results by saying that spermin was an energetic stimulant of the nervous system and probably also of other organs, and that it increased the muscle force by raising the blood pressure. Ovarian extract has several advocates. Muret gives four reasons for its use: (1) without ovaries there is no uterine development or menstruation; (2) ablation of ovaries in young children causes them to grow up without feminine attributes; (3) after puberty loss of ovaries entails cessation of menstruation and atrophy of genital organs; (4) osteomalacia is sometimes cured by oopho- rectomy. The extract has not come into general use, but there seems to be considerable evidence of its value dur- ing the menopause, in some cases of chlorosis and in 4 THE THYROID AND PARATHYROID GLANDS. dysmenorrhea. At Mount Hope Retreat it was tried in some nervous and mental cases said to be the result of laparotomy and in a few other cases where it was thought genital trouble existed without any apparent beneficial results. In a paper read before the American Medico- Psychological Society in 1898, Dr. E. S. Dewey stated that operations on the genitourinary organs stood first on the list of surgical operations producing mental dis- turbance. Considering that the most important periods of life are coincident with changes in the genital organs, and that the effect of even such a small defect as lacera- tion of the cervix will produce very considerable nervous symptoms, it does not appear unreasonable to suppose that the normal functionation of the organs of generation is necessary for the health of the organism, and that the ovaries and testicles being secretory in their nature should supply to the system something necessary for its well being. The thymus gland has been used in many different dis- eases without any very definite results. It was first given to a patient suffering from Basedow's disease in mistake for thyroid by Dr. Owens. As it produced an apparent beneficial effect, it was tried in other cases with varying results. Svehla attempted to determine its physiological effect, coming to the following conclusions : Injection into the femoral vein produced a fall in blood pressure, due to weakening or paralysis of the vasoconstrictors, with in- crease in the pulse rate, due to direct influence on the heart; large doses produced an excitement, dyspnea and collapse, ending in death with postmortem evidence of asphyxia. Baumann found that the thymus contained iodin in organic combination, but in much smaller quantity than the thyroid. As the thymus atrophies at puberty and its persistence after that age is pathological, being associated HISTORICAL. 5 with certain forms of epilepsy, and with Basedow's dis- ease it seems improbable that its administration to the adult will produce beneficial results. Splenic extract has not received much attention. H. C. Wood reports three cases of Basedow's disease as being benefited by it. It has also been given with benefit in cases of melancholia attonita. In leukemia it gave nega- tive results. It is on the market as "eurythrol," but pro- duces gastric pain and therefore does not permit of con- tinuous use. Bone marrow from the ribs of young animals has been extensively used in anemia without producing satisfactory results. Fraser reports its administration as having in- creased the hemocytes from 1,869,000 to 3,900,000 and the hemoglobin from 38 per cent to 78 per cent in 27 days. The pituitary body is an organ which from its ana- tomical position would appear to belong to the central nervous system. Situated in the sella turcica, it is pro- tected from injury, and from its glandular structure and large blood supply it should be of importance to the well being of the organism. Physiological experiments by its extirpation have so far given negative results, and, with the possible exception of akromegaly, in which it is usu- ally found enlarged, it has not been associated with any disease. In animals after thyroidectomy it has been found enlarged by Steida, Hofmeister and Grley, but whether it is a compensatory hypertrophy has not been determined. The administration of its extract has so far produced only negative results. Anatomically, according to Andriesen, its function would appear to be to take up oxygen from the blood stream and to destroy or render innocuous the metabolic waste products of the central nervous system. Chemically it contains iodin, but in very small quantities. The last mentioned writer gives the following as the predictable results of its ablation: 6 THE THYKOID AND PAEATHYEOID GLANDS. Malassimilation of oxygen by the nerve tissues with accu- mulation of waste products, thus bringing about a nutri- tional failure and death of the central nervous system, when the following symptoms would be produced, depres- sion and apathy, muscular weakness, loss of coordination and equilibration, development of twitchings and irreg- ular contractions of the muscles, a want of sufficient heat production and consequent subnormal temperature with wasting of the body tissues. Desiccated brain and spinal cord have been used with a few reported successes on the principle that in certain dis- eases the chemical processes for the formation of the specialized substances necessary for the nutrition and functionation of the nervous system may be interfered with, the administration of the brain and cord containing the specialized substances ready formed might supply the place of the lost function. Constantine Paul, Babes, Gibier, Dana and others report cases of neurasthenia, epi- lepsy, bulbar paralysis and chorea as benefited by its use. In Mount Hope a very obstinate case of melancholia, which had resisted the usual treatment, showed marked improvement through its use, but in several other cases no improvement was observed. The parotid gland has been used in dysmenorrhea with reports of success, but the connection is not apparent. Grlycocholate of soda has been used with success in treat- ing diseases of the liver, especially in hepatic colic. None of the so-called cholagogues of the Pharmacopeia increase the flow of bile, while experiment has shown conclusively that the bile salts are the only cholagogue at our com- mand. As the bile is an excretion of the liver as well as being a necessity for the proper absorption of fats, it is of the utmost importance that the quantity should be kept at normal. The solvent action of the sodium glycocholate on cholesterin and the bile pigments render it of great HISTOBICAL. 7 service in hepatic colic, both as preventing the formation of gall stones and also as a solvent for stone already present. It seems from various reports to be of great nse in torpid liver, acting as a purge for that organ ; also, in some cases of chronic constipation, in malarial and post- febrile hepatic insufficiency. The extract of the suprarenal capsule has obtained a permanent place in medicine, the active principle adre- nalin is used extensively in minor surgical operations as a hemostatic ; internally it raises the blood pressure and stimulates the heart. Extracts of the prostate gland, the liver, the kidney and the lymphatic glands have all been tried with nega- tive results. The thyroid gland has proved to be of the greatest im- portance as a regulator of the general metabolism, inter- ference with its function producing cretinism, infantilism, myxedema and Basedow's disease, while from its. power- ful physiological action upon the blood-vessels the extract or the dried gland is a most valuable addition to the Pharmacopeia. CHAPTER II. EMBRYOLOGY— ANATOMY— HISTOLOGY— THE PARATHYROIDS. Embryology.— The thyroid gland is developed from the anlages, one median and two lateral, which unite to form a common differentiation. The median anlage is an in- vagination vi the floor of the pharynx between the bases of the second and first bronchial arches lying between the two parts of the tongne and consisting of a small pouch, which commences to expand laterally at a very early age to form the median duct, the opening of which upon the tongue corresponds to the foramen cecum. The duct itself is known as the ductus thyroglossus, which persists up to the eighth week, gradually elongating as the thyroid and tongue separate. The ductus thyroglossus is obliterated, but occasionally exists throughout life as the ductus lin- gualis.* The lateral anlages are derived from the ento- derm of the fourth gill clefts ; the fourth entodermal pouch develops a ventral prolongation, becoming a closed vesicle entirely separated from the pharynx; the vesicle curves forward to form round hollow buds. The union of the three anlages takes place about the seventh week. His records that in a human embryo of the eighth week the formation of the hollow acini had begun, and that they were lined with epithelial cells, the gland consisting of two globes connected by a narrow isthmus. Anatomy.— The thyroid body is a highly vascular gland, consisting of two lobes, an isthmus and pyramid, situated between the second and sixth tracheal ring, covered an- teriorly by the sternohyoid, omohyoid and sternothyroid muscles, while the sternocleidomastoid also overlaps it. 8 ANATOMY. The posterior surface is concave and rests on the trachea and larynx, covering the recurrent laryngeal nerves. The Fig. 1. — The position of the thyroid after removal of the muscles. (v. Eiselsberg.) lateral lobes cover the carotid arteries; are conical in shape, extending from the fifth or sixth tracheal ring to 10 THE THYROID AND PARATHYROID GLANDS. the side of the thyroid cartilage covering the inferior corners and adjacent portions of the alse. The isthmus usually lies across the second and third rings of the trachea, but is inconstant in shape and position, often being entirely absent. From the isthmus or from the adjacent portions of one of the lobes a slender conical Fig. 2. — Absence of the isthmus. (Marshall.) Fig. 3. — Isthmus with large pyramid. (Marshall.) process ascends upward to the hyoid bone called the pyra- mid or middle lobe. Occasionally it is attached to the hyoid bone by fibrous or muscular tissue, so that it follows the movements of the vocal organs. In front the pre- tracheal fascia extends from the isthmus and adjacent portions of the lateral lobes to the front of the cricoid cartilage, the lower border of the thyroid cartilage form- ing a distinct anterior ligament. Each lobe is further AX ATOMY, 11 attached by a firm band of fibrous tissue, the lateral liga- ment, to the side of the cricoid cartilage and to the first two or three rings of the trachea. Each lateral lobe meas- ures about 50 mm. in length by 30 mm. in width by 18 mm. in thickness at its largest part. The isthmus measures nearly 12 mm. and from 6 mm. to 18 mm. in thickness. The weight of the gland varies very much with age and Fig. 4. — Double pyramid. (Marshall.) Fig. 5. — Absence of isthmus with pyramid on left side. (Marshall.) in different countries. Virchow places it at from 30 to 60 grms. ; Schaefer in England from 30 to 40 grms. Wells, of Chicago, gives the average weight of 60 glands removed in that city as 22 grms. ; the gland decreases in weight as age advances. The average weight in persons over 45 years of age in "Wells' series was only 16 grms., while in persons from 20 to 45 the average was 25 grms. The gland appears to be smaller in females than in males, increasing in size during pregnancy and menstruation. 12 THE THYEOID AND PARATHYROID GLANDS. Usually the lateral lobes are not perfectly symmetrical, the left being most often the larger of the two, while the isthmus and pyramid vary in size, may be entirely absent or fused into one or other of the lateral lobes. The pyra- mid occurs, according to Streekiesen, in 104 out of 153 cases or about 68 per cent. Marshall only found it in 24 out of 60 cases or 40 per cent. Out of the 104 of Stree- kiesen 's cases it was glandular up to the hyoid bone in 55, in 12 it was connected to the bone by fibrous tissue, in 2 by muscle. These muscular fasciculi, which occasionally descend from the hyoid bone to the gland or to its pyra- mid, are known as the levator glandulse thyroidae. The fibers are mostly derived from the hyoid muscle, but occa- sionally are independent. The arteries of the gland are the superior thyroid from the external carotid, the inferior thyroid from the thyroid axis of the subclavian and sometimes the thyroidea ima from the arch of the aorta. They are remarkable for their anastomoses and large size. They terminate in a capillary network upon the outside of the acini. The veins which are also large form a plexus from which the superior middle and inferior thyroid veins are formed on each side. The superior and middle thyroid veins open into the internal jugular, the inferior veins form a plexus in front of the trachea and empty into the innominate veins. The lymphatics of the thyroid body form numerous large anastomosing trunks, both at the surface and throughout the substances of the organ. They originate, according to Frey, in the connective tissue which unites the gland vesicles, with the cavity of which they appear not to be in communication. Hiirthle has, by using in- termittent pressure, caused injection fluid to pass into the vesicles by the lymphatics. Colloid substance is at times found in the lymphatics similar to that found in the ves- ANATOMY. 13 icles, which appears to pass between the epithelial cells into the interstitial connective tissue and thence into the lymphatics. The nerves are derived from the middle and inferior cervical ganglia of the sympathetic and accompany the blood vessels. Accord- ing to Andriesen there are no ganglionic cells in their course, their branch- es extending close to the base of the epithelium cells. Accessory thyroids are ' common, being formed by detachments of small por- tions of the gland in the embryonic stage, and by division of the pyramidal process. They may be found anywhere between the arch of the aorta and the hyoid bone, some- times' even within the bone itself. Anomalies are common, either the pyramid or the isthmus may be absent or both, the isthmus occa- sionally passes behind the trachea, one lobe or both may be absent. These deviations from normal are permitted by the fact that, unlike most parenchyma- tous glands, the location of its secreting structure bears no relation to any fixed outlet or duct. Fig. 6. — The thyroid arteries, (v. Eiselsberg.) 14 THE THYROID AND PARATHYROID GLANDS. Histology. — The texture of the thyroid gland is firm, appearing granular to the naked eye; it is invested by a thin transparent layer of dense areolar tissue which con- nects it with the adjacent parts, imperfectly separating its substance into small lobules of irregular form and size. When the organ is cut into a yellow glossy fluid, colloid, escapes from the cut surface. Imbedded in its substance are multitudes of closed ves- icles, which are held together in groups or imperfect lobules of areolar tissue. The wall of each vesicle consists of a simple layer of cubical or col- umnar epithelial cells, which, according to Langandorff, are of two kinds, viz : those which are actually secreting the ma- terial contained in the vesicles, colloid cells, and other re- serve cells which may take the place of the colloid cells or which may become detached and mingle with the secretion. Both Langandorff and Hiirthle agree in sta- ting that the secretion is formed partly by exudation from the cells and partly by their complete transformation into colloid substance. Bozzi describes three classes of cells, chief cells, colloid cells and cells undergoing retrograde metamorphosis. The chief cells are the most numerous and contain highly refractive bodies which he considers to be colloid substance ; they also contain finer bodies, which are probably incompletely formed colloid, but Babes and others state them to be the pigment from the destroyed red corpuscles; fat globules and protoplasm granules are also present. The cells appear not to have a distinct membrane, but to blend with one another, the outer ends resting on the basement membrane. The colloid cells are Fig. 7.— Normal thyroid gland. THE PAKATHYKOIDS. 15 smaller than the chief cells and lie in irregular groups between the chief cells from which they are probably derived; they possess a nearly homogeneous protoplasm more deeply colored, not unlike the colloid substance in appearance ; they vary in shape, some appearing round or oval, with the protoplasm almost destroyed, its remains collected around a central mass which appears to be colloid containing characteristic vacuoles, the nucleus being at one side ; they also group together so as to resemble folli- cles; sometimes free colloid is found between the cells. The cells showing retrograde metamorphosis have no col- loid mass, the nucleus loses its staining properties and gradually becomes indistinct, the granules are smaller and the protoplasm contains colloid in droplets not running together to form a mass ; these cells are formed when the follicles fuse together and seem to be due to nutrition degeneration. Embryonal rests are also found mostly near the capsule, but also scattered around in the connective tissue having large nuclei with a small amount of protoplasm, they do not appear to develop when the gland is partially removed. The method of colloid formation has not yet been set- tled. Virchow was of the opinion that it was first formed indirectly by the cells in so far that the secreted mucoid fluid was changed into colloid. Hiirthle claimed to have seen droplets of colloid in the cells, and that the cells in- creased in size on the formation of the drops, concluding that the colloid arose from the protoplasm of the cells. Langhans, Langandorfr, Gutkneckt and others are of the opinion that the cells themselves are transformed into colloid. THE PAKATHYKOIDS. The parathyroids consist of two pairs of small glandular masses,' first described by Sandstrom in 1880, constant in man and other mammals, always lying in close proximity 16 THE THYKOID AND PAEATHYEOID GLANDS. to the lateral lobes of the thyroid body. They vary in size from 3 mm. to 15 mm. in diameter with an average of about 6 mm. ; are flattened and of a reddish color, some- what like the thyroid itself. In structure, however, they differ from the thyroid proper, being composed of solid masses of epithelial-like cells, which often appear to be in sections, arranged in an- astomosing columns with numerous convoluted blood vessels between them. Con- nected with the cell masses there are frequently lymph follicles, differing complete- ly from the thyroid and not to be confounded with the accessory thyroids. Ac- cording to Grley they repre- sent embryonic portions of the true gland, and if left after the removal of the lat- ter they are able to develop further and take on the functions of the main organ. It is thus he accounts for the failure to obtain in some animals the usual results of thyroidectomy. This is, however, denied by Edmunds, although they appear to increase in size after the operation and to act vicari- ously to some extent. Kohn states that there is one parathyroid (outer epithelial body) constantly present in mammals on the lateral surface of each lateral lobe and another on each mesial surface (the inner epithelial body). Associated with these are small bodies of adenoid tissue which have the characteristics of thymus gland including Fig. 8. — The position of the para- thyroid, glands. (Zuckerkandl.) THE PARATHYROIDS. 17 the epithelial rests or corpuscles of Hassel and which tend to blend insensibly with the neighboring interstitial tissue of the thyroid. According to Pienant the tissue of the parathyroids is similar in appearance and structure to that of the carotid glands and is not embryonic thyroid tissue. He states that they take their origin from the fourth inner bronchial cleft of the embryo from which also part of the thymus and the lateral rudiments of the thyroid are de- rived, whereas the main portion of the thymus and the carotid glands are derived from the third cleft. The theory that the parathyroids are embryonic tissue is hardly tenable, from the fact that they develop in chro- nological advance of the thyroid. It must also be con- sidered that they resemble the suprarenal, the anterior pituitary and the carotid glands, which must be looked upon as adult tissue. In structure they seem to be made up of entodermal epithelial cells, separated by capillaries, suggestive of the suprarenal. This is most noticeable in compensatory hypertrophy, but, as Edmunds points out, there are no acini and no secretion of colloid substance. Gley has recently taken up the position, supporting it by physiological experiment, that the parathyroids are glands sni generis and have a specific function related to that of the thyroid. Welch describes the parathyroids as being completely invested by a fibrous capsule and either con- nected with the thyroid gland by a pedicle of fibrous tissue or situated within the body of the gland, but always com- pletely separated from it by connective tissue. From the deep surface of its fibrous capsule irregular septa are given off, dividing the gland into irregular lobules. Clusters of fat cells are generally present along the course of the vessels and of the connective tissue septa within the gland to which the yellow tint is probably due. The parathyroids are of epithelial structure and are composed of two distinct kinds of cells. The principal 2 18 THE THYROID AND PARATHYROID GLANDS. cells have a relatively small homogeneous protoplasmic body, which takes on basic anilin dyes in varying degrees of intensity, and a relatively large pale nucleus with an open chromatin network. They constitute the greater part of the gland tissue. In their arrangement they show at least four different types: (1) a continuous uniform cell mass; (2) a continued cell mass, interrupted at fre- quent intervals by strands of connective tissue, so that on section the strands appear to be surmounted by epithelial cells; (3) a series of anasto- mosing columns of cells in a vascular fibrous reticulum, so that on section the epithelial cells appear as discrete mass- es completely surrounded by vascular connective tissue ; (4) groups of small acini, each containing a small mass of colloidal material in its lumen and lined by a single layer of epithelial cells. It seldom happens that a parathyroid is composed of cells ex- clusively arranged in one type. The second kind of cell is oxyphilic, having relatively to the principal cells a large granular protoplasmic body, the granules of which are highly oxyphilic, with a small darkly staining nucleus and densely arranged chromatin. These cells are not always present. There are three types of disposition: (1) a uniform cell mass, sharply defined from the principal cells and situated either deep in the substance of the gland or immediately beneath its capsule; (2) a few columns of cells which gradually mix with the principal cells; (3) a single acini lined with oxyphilic cells containing a colloid lobule in the lumen. "Welch considers that the para- Fig. 9. -Xormal Parathyroid eland. THE PAEATHYKOIDS. 19 thyroids resemble the anterior lobe of the pituitary body more than the suprarenal and that it is unlike thyroid tissue ; that the colloid material does not represent a higher stage of glandular development, but is rather retrograding or degenerative in its nature. CHAPTER III. PHYSIOLOGY. The early physiologists looked upon the thyroid gland as having no essential function, probably from its having no duct by which its secretion could be conveyed to the general system, and from its variable size, position and shape, it was stated to be for the purpose of rounding out the neck, as having some connection with sleep, as influencing the voice, that it acted as a reservoir for the blood regulating the brain supply. The connection of the gland with the organs of generation had very early at- tracted the attention of the laity. In Southern Italy it has long been the custom for the parent to measure the circumference of the daughter's neck before and after marriage, an increase in size being considered as an evi- dence of conception. It was not till 1859 that systematic investigations as to the function of the gland were commenced. Schiff per- formed thyroidectomy on dogs and found that they in- variably died, and therefore the gland was necessary to life. A. and J. Biverdin described the symptoms pro- duced by thyroidectomy, Ord followed in 1878, and then Kocher on the same lines, stimulating Schiff to further experiments. Schiff reported in 1884 that the extirpa- tion of the gland was not only followed by death to the animal, but that it also produced spasms and convulsions, which were prevented by the implantation of the gland under the skin or in the peritoneal cavity. These experi- ments were the commencement of an enormous amount of work by a large number of scientists in every country, 20 PHYSIOLOGY. 21 resulting in a number of different theories as to the physi- ology of the organ, many of which have been proved to be erroneous and are now of little interest except to the historian. The function of the thyroid gland is said to commence "in utero, " or soon after birth (Wolfler). Horsley con- siders that it commences before birth, but is greatest dur- ing the period of growth, lessening as the vital processes decline. He bases his opinion on the decrease of the secretory power of the gland in phthisis, in which the col- loid substance gradually disappears and the epithelial cells pass into the embryonic state, from the fact that removal of the gland is more fatal in young than in older animals, and that it decreases both in size and activity in old age. Nielsen is of opinion that the gland is concerned in the change of mucoid into connective tissue during the fetal months. The writer has analyzed the thyroid glands of several children who died immediately after birth, and also a few prematurely born, and has never been able to find a trace of iodin or of the blood pressure reducing substance. In children of two and three weeks old who had died of cachexia, no iodin was found. The earliest age at which he found iodin was three months. There is a remarkable difference between the calf and the human fetus. In the former the thyroid gland contains iodin in utero. As it has been shown that thyroglobulin is excreted by the mammary gland, with the milk in the human, the child receiving in this manner the necessary amount for its metabolism, it seems possible that one of the reasons why the human infant is so difficult to raise on artificial food is the absence of the necessary amount of thyroid secretion in the artificial food. As the calf is born with a function- ating thyroid, cow's milk probably does not contain the amount of thyroid secretion necessary for the development of the infant. 22 THE THYROID AND PARATHYROID GLANDS. The function of the gland has been studied chiefly by the indirect method of observing the symptoms after re- moval of the gland from animals, and some cases in man, where the operation was performed for disease. In the early experiments the importance of the parathyroids was not recognized, and consequently the symptoms were the result of the removal of both thyroid and parathyroids, which has caused much confusion, being further compli- cated by the different results obtained with different ani- mals— -in some instances as in the rabbit— due to the para- thyroids being some distance from the thyroid and not be- ing removed in the operation with the thyroid. Ewald came to the conclusion that birds survived the operation ; that rodents and herbivora generally survived with no marked effects, and that in aged dogs the symptoms were usually light. Reptiles, young carnivora, monkeys and man invariably die after the operation if it is completely carried out. Horsley, in 1891, divided animals into four classes: (1) birds and rodents, in whom no cachexia was produced; (2) ruminants and ungulates, in whom the symptoms developed slowly; (3) man and monkeys, in whom the cachexia was certain but the symptoms mod- erate; (4) carnivorous animals, in whom the cachexia was most severe and rapid. These results seemed to show that the food habits of the animals had some bearing on the importance of the gland to the system, viz: that car- nivora were the most affected, graminivorous and corn eating animals the least affected, while the omnivora occu- pied a middle position. The later experiments of Hof- meister, de Quervain, Grley and Edmunds have shown that there is little or no difference, provided that the whole of the thyroid, accessory thyroids and parathyroids are removed. The symptoms produced by the extirpation of the gland are of particular interest from their resemblance to vari- PHYSIOLOGY. 23 ous observed pathological conditions in man, and have been the means of recognizing many obscure diseases as being the resnlt of cessation or perversion of function of the glands. In dogs, after the removal of the gland, the first most noticeable symptom is a derangement of the functions of the medulla oblongata, consisting in vomiting and dys- phagia. The efforts of vomiting are accompanied by salivation, often preceding an attack of convulsions lasting till the animal dies. The vomited matter consists of bile and mucus; anorexia is often present, and when the re- fusal to take food is absolute it is a sure sign of a rapidly fatal result. Sometimes the animal preserves the appetite but finds great difficulty in taking nourishment, owing to the continuous spasmodic contractions of the masseter and the fibrillar contractions of the muscles of the tongue. Moreover, the dysphagia usually present renders it as difficult to swallow fluids as solids, and if by chance any food does enter the stomach it is immediately rejected, with an increase of convulsive movements, the animal finally ceasing to make any attempt to take food. Vomit- ing occurs even when the food is carefully introduced with the tube. In a few instances the animal continues to eat, but the food accumulates in the stomach, the abdomen becomes distended and the large intestine fails to dis- charge its contents. Trophic disturbances may appear in the form of excoriations, especially affecting the region of the articulations in the fore and hind limbs, which may suppurate, never showing any inclination to heal. Mus- cular paresis and partial paralysis occur usually among the earlier symptoms, the extensors in particular being affected, causing the staggering gait which is usually very marked. Spasms are of frequent occurrence, which, in the first instance, affect the masseter and temporal mus- cles, but soon spread to the muscles of the body, and seem 24 THE THYROID AND PARATHYROID GLAXDS. to be the result of discharges which take place at regular intervals. This condition lasts for two or three days, when a violent general convulsion may occur, with a tend- ency to tetanus. At this period the respiration is greatly increased, in some cases being as high as 220 per minute, death often supervening in one of these convulsions. Co- incident with increase of respiration comes increase of temperature, 42.0 degrees C. and even 43.6 degrees C. having been observed. In the intervals between the at- tacks the temperature has been observed to fall 4 degrees below normal. In 1887 Munk made the statement that dogs survived operations which deprived them of the functions of the thyroid gland, provided the wound healed well, but if swelling of an inflammatory or edematous nature, or a swelling dependent on hemorrhage or upon accumulations of the secretions of the wound occurred, the animals died with characteristic symptoms. Munk performed the op- eration of isolation of the gland by doubly ligating and dividing the veins of the gland. He then lifted the lobes out of their capsules and completely severed them from their connections with the body of the animal by ligation of the vessels and nerves of the hilus, returning the lobes to their original position. Xine dogs survived his experi- ments which were repeated and confirmed by Boginski. Halstead suspecting that Munk had overlooked the acces- sory glands and also small portions of the main gland, went over the same ground in the most complete manner, finding that his suspicions were correct. He found that when the gland was perfectly isolated death ensued with the usual symptoms, which varied somewhat in different animals, the most regular being conjunctivitis, trismus, persistent erection of the penis, fibrillary tremors of the tongue and of the muscles generally. He then experi- mented with partial isolation, which he brought about by PHYSIOLOGY. 25 ligating all the vessels except the thyroid artery, which supplies the upper lobe and the vein from the lower lobe. The symptoms thus produced were not identical with those occurring in complete isolation. The most constant were tongue tremors, licking movements, anemia, con- junctivitis, general tonic and clonic spasms, inflammation of gums, with occasionally a falling out of the hair, accom- panied with an itching of the skin, producing an edema- tous appearance not unlike myxedema. This latter symp- tom only occurred when the wound did not heal by first intention. He next experimented with piecemeal removal of the gland and observed that the same symptoms were produced, the amount of gland removed in order to pro- duce them varying in different dogs, probably on account of the size and number of the accessory glands and to individual peculiarities, one dog doing well and remaining in good health with only one-eighteenth of the gland re- maining. During the experiment a female who had had the left and the lower third of the right lobe removed was impregnated by a healthy unoperated dog. She gave birth to eight puppies, whose thyroid glands were at least twelve times larger than normal. It is remarkable that in this case and also in a similar one that a few hours before whelping the symptoms of complete thyroid de- privation manifested themselves although each animal possessed much more thyroid than was actually required for her wants. It had previously been observed that tetany had appeared previous to labor in cases with con- genital thyroid insufficiency. These experiments have been repeated recently with the same result by Edmunds and are suggestive. It would be interesting to observe if an excessive secretion or administration of thyroid during pregnancy would not produce a reduced thyroid in the produce, which, if it took place, might account for some cases of sporadic cretinism. 26 THE THYKOID AND PAEATHYEOID GLANDS. Horsley divides the symptoms of thyroidectomy into those of over action and of want of action. The first symptom of over action is fibrillar muscular tremor, re- sembling tetany. The individual contractions of the mnscles follow one another in monkeys at the customary rate of clonus, viz : eight to ten per second. Summation next occurs, tetanoid spasms follow and finally rigidity and contraction. Symptoms of want of action are motor paralysis and anesthesia, the toxemic condition producing functional neurosis, epilepsy, hemiplegia, etc. Tissue changes are also marked, emaciation of an acute form, with mucin in the connective tissue. If, however, the cretinoid condition supervenes there is no increase of mucin, but fibroid changes occur, coupled with emaciation. Virchow suggests that the edema characteristic of myxe- dema is a metaplasia of the subcutaneous fat into mucus, with an increase of volume ; the skin becomes coarse and dry from the absence of secretion ; the subcutaneous tissue thickened and inelastic; the hair falls out, becoming thin and gray. Disorders of temperature also occur. The intrinsic changes, viz : the modifications which are intro- duced into the normal heat balance ofT the subject after elimination of the traumatic factor, consist of a rise of from 4 degrees to 5 degrees during the acme of the mus- cular twitching. The coincidence of this rise in tempera- ture with the nerve disturbances suggests that it may be dependent on a derangement of the heat controlling cen- ters. Before death the temperature is subnormal. Ex- ternal heat has a great effect on the operated animal, ex- ternal cold precipitating the symptoms. Animals which were apparently in good health while kept in a high tem- perature developed the characteristic symptoms at once on being exposed to cold. The blood changes show a connection between the gland and the blood metabolism. Normal! v the leucocvtes are PHYSIOLOGY. 27 present in a greater proportion in the veins than in the arteries of the gland, and this proportion is greater than that fonnd in the veins of the limbs. After thyroid- ectomy there is an increased venosity of the blood, with a great diminntion of the amonnt of oxygen. This decrease of oxygen in the arterial blood may be so great as to be less than the oxygen in normal venous blood, a condition which wonld account for many of the symptoms. If a portion of the thyroid gland be removed there is a compensating hypertrophy of the remaining part which undergoes histological changes, the cubical cells become columnar, the vesicles become oblong or branched and the colloid substance becomes more watery, changes which are almost identical with those found in the gland in Base- dow's disease. These changes are not affected by division of the sympathetic. SchifT found, after destroying the sympathetic nerve fibres acconrpanying the blood vessels to one lobe, that the lobe remained identical in minute structure. Horsley tried similar experiments with re- spect to the recurrent laryngeal nerve with the same re- sult. Katzenstein could find no difference in the two lobes after stimulating one and not the other. Edmunds excised the superior laryngeal nerve and a considerable length of the vasosympathetic lower down on the same side, thus any secreting fibres passing by the recurrent laryngeal nerve would be cut off. On this side the thyroid lobe was not touched or even seen. On the other side the lobe, together with the parathyroids, was excised. Of the ten dogs experimented upon three died in one, two and three days. No symptoms occurred, but death appeared to be due to the operation, as the thyroid lobe was found to be almost free from colloid and the secreting cells mul- tiplying into the vesicles. Seven of the dogs lived longer, six showing symptoms ; one, howerer, was operated on again after twenty-eight days without having shown any 28 THE THYEOID AND PARATHYROID GLANDS. symptoms. One was allowed to live 242 days, dying with a thyroidal symptoms. Another was killed at the end of 271 days suffering from severe symptoms. The other four were operated on a second time. The pathological findings in these cases varied somewhat. In one, in which the lobe was removed by a second operation, the gland was devoid of colloid, the cells multiplying into the cavities of the vesicles. In another, which had well marked tremors but recovered, the gland was found to be much enlarged, weighing 3.5 grins., or about three or four times larger than normal. The colloid had disappeared, the increase in size being due to growth of young tissue between the vesicles, the secreting cells were not multiplying into the vesicles. The animal which lived 242 days, dying with severe symptoms, had a normal gland and a normal para- thyroid. In the animal killed after 272 days there were some normal vesicles, but there were also vesicles filled with multiplying cells from which the colloid had wholly disappeared. Hiirthle has experimented on the effect of the stimula- tion of various nerves by the f aradic current on the secre- tion of the gland, and has had negative results from both the laryngeal nerves and the vasosympathetic. On the contrary, Gr. A. Schaefer found that the cells of the thy- roid show the same changes as those of other glands after the injection of pilocarpine. As pilocarpine only pro- duces its effects by nerve stimulation it follows that the secretion of the thyroid must be influenced by the stimula- tion of some nerve or nerves. Hiirthle suggests that the stimulation of the gland is due to the presence of certain unknown substances in the blood, and states that tying the gall duct in dogs produced homogeneous globules in the epithelial cells and lymph spaces of the gland, which showed the same inclination to solidify and gave the same staining reactions as the follicular colloid substance, prov- PHYSIOLOGY. 29 ing that the passing of certain constituents of the bile into the blood produced increased secretion of the gland, and that any nervous influence that may exist is not cen- tral, but is due to the ganglia either in or in the imme- diate neighborhood of the gland, and further, that the enlarged gland of Basedow's disease is not primarily of central origin. Sandstrom discovered the parathyroids in 1880, and in 1881 Cresswell Baker independently also observed the glands but did not recognize them in animals, describing them as undeveloped portions of the thyroid gland. In 1884 Horsley identified and described the parathyroids, but they were not thoroughly studied till 1892, when Gley published a set of papers recording his experiments. Under the name of "glandules thyroidiennes " he de- scribed in the rabbit two glands, one on each side of the trachea, situated at some distance below the thyroid, so that in previous operations for thyroidectomy in that ani- mal these glands had probably not been removed. In the dog, on the contrary, the corresponding structures were so closely incorporated with the outer surface of the lat- eral thyroid lobes that they must have been almost, in- variably removed with the thyroid. On account of these different anatomical arrangements he suggested the causes for the relative insusceptibility of the rabbit to thyroid- ectomy; he removed both the thyroids and the parathy- roids from a series of rabbits with the result that in the majority of cases acute symptoms and speedy death en- sued. Further, he found that the removal of the thyroid alone, leaving the parathyroids in situ, produced in the dog and the rabbit little or no result. At the time of these experiments (1892) the existence of the internal para- thyroids was not known, and Gley's work only applies to the external parathyroids. No really accurate knowl- edge of the position of these glands was published till 30 THE THYROID AND PARATHYROID GLANDS. 1895, when Kohn's elaborate monograph on the thyroid gland of the cat demonstrated the fallacies underlying all previous operations. He found that in the cat, dog, rab- bit, and probably in other mammalia, there were four parathyroids, and he further showed conclusively that these bodies were not thyroids but were independent spe- cific structures, naming them "the external and internal epithelial corpuscles of the thyroid." In 1896 Vassali and Generali published the result of their experiments. They removed all the four parathy- roids, leaving the thyroid in situ in ten cats and in nine dogs. Of the cats nine died by the tenth day, while one was living at the end of a month. All the dogs died within eight days, the symptoms in both cats and dogs being the same as those previously recorded as the result of thyroidectomy. As a rule, however, conclusive attacks were absent or only very slight, but on the other hand, the phenomena of diminished nervous excitability pre- dominated in the form of paralysis, which rapidly killed the animal. Rouxeau performed on the rabbit what Vas- sali and Generali had done on the dog and cat, viz: he removed the four parathyroids, leaving the thyroid intact. The results were not uniform, but he concludes that re- moval of the parathyroids is much more serious than re- moval of the thyroid alone in the rabbit. Moussu comes to the conclusion that the functions of the thyroid and parathyroids are different ; that suppression of the thyroid produces only chronic symptoms, while the suppression of the parathyroids induces acute symptoms. He also in- duced experimental cretinism in the dog, cat, and birds by the removal of the thyroid, the parathyroids being left intact. Welsh, after a number of very careful experi- ments, comes to the following conclusions: (1) Removal of all four parathyroids in the cat leads to acute and severe symptoms, with a rapidly fatal issue, even though the thy- PHYSIOLOGY. 31 roid be retained practically uninjured. (2) Eemoval of three parathyroids does not lead to death, but may cause transient symptoms similar to those which result from removal of all the glandules; loss of two parathyroids does not produce any appreciable result. (3) Eemoval of the thyroid and some of the parathyroids may lead to death with acute symptoms, if only one parathyroid is left, but may not induce any obvious derangement if two parathyroids are retained, at least not for several months. (4) Administration of fresh parathyroid by the mouth has no effect, either in mitigating the symptoms or in averting death after removal of the thyroid and parathyroids in the cat, even though relatively enormous doses are given. In 1898 Edmunds published the results of his very elab- orate experiments as to the functions of the parathyroids, of which the following are the most important. In two dogs about one quarter of one lobe and the external para- thyroids were left, the rest being removed. Neither of these dogs showed any symptoms during the nine and twenty-six days they were allowed to live. In two other dogs the upper part of the thyroid was left on each side, with the addition that in each a length of the vasosym- pathetic was removed on one side. One of the dogs suf- fered from tetany, rigidity of the limbs, tremors, emacia- tion, and a trophic lesion of the skin, in the second dog the only symptom was emaciation ; twenty-nine days later the remaining portion of the gland was removed, the dog dying with the usual symptoms. In eight dogs one ex- ternal parathyroid was left and only just sufficient thyroid to avoid interference with the blood supply. The dogs had no symptoms, except that one of them became thin. Three of these dogs were subsequently killed and the parathyroids identified by microscopical examination. In the other five it was attempted to remove the parathyroids during life. In two this was successfully accomplished, 32 THE THYROID AND PARATHYROID GLANDS. with the result that the animals had the usual symptoms. In the other three dogs the part removed proved not to be parathyroids and no symptoms resulted, the parathyroids being found on postmortem examination. In seven other dogs it was intended to leave the external parathyroids, but microscopical examination proved that the tissue left was not parathyroid, all three dogs dying with the usual symptoms. As dogs live when the parathyroids are left and die when it is subsequently removed, or when only a small piece of thyroid proper is left instead, it seems evi- dent that the excision of the parathyroids is the cause of the acute symptoms, tremors, rigidity, convulsions, dysp- nea and death, which follow the total excision of the thyroid and parathyroids, and further it suggests that the excision of the thyroid proper only causes the symp- toms of myxedema. In four rabbits, from which the thyroid was removed, leaving the parathyroids, the health failed, the hair fell out, edema occurred in the lower part of the face, followed by death. Vassali and General! have found that if all the four parathyroids in the dog are excised and the whole of the thyroid left the dog will die with the usual symptoms in a few days, while if one of the parathyroids is left and the whole of the thyroid re- moved the animal will live. Grley found that if the whole of the thyroid proper and one parathyroid were removed in rabbits the animal would live, but if the remaining parathyroids were excised the rabbit would die with the usual symptoms. In dogs in which a single parathyroid was left and a minute piece of the thyroid no symptoms of any kind appeared, even after five months. The ani- mals were kept so long in order to see if the parathyroids developed into thyroid tissue. They did not, but the cells became more definitely arranged in rows, small collections of secretion were seen and the trabecule of connective tissue were much thickened. PHYSIOLOGY. 33 In order to obtain an obvious case of myxedema, the whole of the thyroid gland was removed from four mon- keys. In the first there was muscular weakness, the hair fell out extensively from the front of the chest and there was some swelling about the face, but only temporarily. Four and a half months after the operation a well-marked edema occurred in the face but quickly passed away, and in six and a half months the monkey was well. The other three monkeys died with the usual symptoms. The fail- ure to obtain true myxedema in these cases was appa- rently caused by the animals dying from the nerve symp- toms before the myxedema had time to develop. Four other monkeys were operated upon as before and treated with thyrocolloid, prepared according to Hutchinson's method. The first monkey died in six days in spite of treatment, and the second had slight symptoms on the first day which passed off. On the twenty-seventh day the treatment was stopped, three days later symptoms ap- peared but passed off, when treatment was renewed, the animal, however, dying on the forty-first day. The third monkey had no symptoms from the first; the treatment was stopped on the sixteenth day ; on the twenty-first day symptoms appeared, treatment was resumed, the symp- toms disappeared, and five months after the operation the monkey was well. In the fourth monkey symptoms ap- peared on the third day and the monkey died on the seventh day in spite of treatment. Though three out of four of the monkeys died yet treatment had some effect. Edmunds summarizes the results of his experiments, com- ing to the following conclusions : ( 1 ) the parathyroids of dogs have as much or more to do with saving them from acute myxedema as the thyroid proper; (2) although the extract from the thyroids of sheep may keep off and re- lieve the symptoms in thyroidless monkeys it will not, as a rule, save their lives; (3) a parathyroid will not by 34 THE THYEOID AXD PARATHYROID GLANDS. process of compensatory hypertrophy develop into thyroid tissue; (4) the mortality was 44 per cent after total ex- cision of the parathyroids, and after excision of both thy- roid and parathyroids the mortality was 80 per cent, even with thyroid feeding; (5) the symptoms produced by the excision of the parathyroids are the same as by the com- plete operation (thyroid and parathyroids), viz: tremors, a slow and unstable gait, passing into paralysis of the hind limbs, emaciation and muscular weakness. The microscopic changes found in the thyroid lobes in cases of excision of the parathyroids are marked in these cases which survive the operation a few days. There is a diminution in the amount of colloid in the vesicles, the vesicles themselves becoming oblong and branched, the secreting cells columnar or multiply so as to fill the cavity of the vesicle and there is an excessive amount of young thyroid tissue between the vesicle. Edmunds considers these changes to be identical with those described as com- pensating hypertrophy of the thyroid and with the changes found in Basedow's disease; there is, however, an apparent decrease in the size of the gland. In two of the dogs, after partial parathyroidectomy, there were marked eye symptoms. Auld and others have noted eye symptoms after thyroid feeding, Beclere re- porting a case where a patient, partly by mistake, took 60 grins, of sheep's thyroid in a week, which was followed by thyroidismus and a certain amount of exophthalmos. Edmunds performed a number of experiments to investi- gate the point, the subject being of great importance from the possibility of its offering an explanation of the pathol- ogy of Basedow's disease. Total thyroidectomy was performed on ten monkeys, five of whom had had thyroid feeding before the opera- tion. Of the five which had no thyroid feeding two showed narrowing of palpebral fissure, one at first widen- PHYSIOLOGY. 35 ing, followed by narrowing, and in two no change. Of the five which had thyroid feeding, in two there was exophthalmos with widening of the fissures; in one nar- rowing, and in two no change. In another monkey no operation was performed, but it was fed with large doses of an extract equal to about half a sheep's thyroid per diem. A considerable widening of the palpebral fissures resulted, with perhaps some protrusion of the eyeballs. Edmunds, in further experiments on six monkeys fed with from a half to three whole sheeps ' thyroids per day, produced prop- tosis, dilatation of the pupils, widening of the palpebral fissure, erec- tion of the hairs of the head, falling out of the hair in patches, paral- ysis of one or more limbs, emaciation and muscular weakness, followed by death from asthma. The average life of the monkeys after the commence- Fig. 10. — Monkey in tetanic attack after extirpation of thyroid, (v. Eiselsberg. ) ment of the treatment was seventy-six days. Microscopic examination of the thyroids and of pituitary glands were made, but no pathological condition could be detected. Shortly before death the animal showed an objection to light and to being looked at. As the effect of thyroid feeding on the eye might be produced by action on the central nervous system, com- municating with the cervical sympathetic or by local action 36 THE THYROID AND PARATHYROID GLANDS. on the ganglia in and about the eye, the cervical sympa- thetic was divided on one side in two monkeys and the animals fed in doses corresponding to about three sheeps' thyroids per day. In twelve days the eyes on the unop- erated side were seen to be more prominent and the palpe- bral fissure wider than before treatment; the eyes on the operated side also became very wide and prominent. A considerable length of the nerve was removed to prevent the probability of repair. This experiment is borne out by a case reported by Boissou. The patient, a girl of twenty years old, was submitted to resection of the cer- vical sympathetics, first on one side and then on the other, for Basedow's disease. Notwithstanding the operation the exophthalmos continued and became so severe that the eyes could not be closed, the cornea sloughed, sight was lost, the patient dying in a short time. This case and Edmunds' experiments show that the cervical sympathetic is not the main factor in producing the protrusion of the eyeballs, and it also seems probable that thyroid extract acts partly through the cervical sym- pathetic and partly locally. Experiments were also made on rabbits, with the thyroid with the two smaller parathy- roids removed. In one rabbit the eyes became more promi- nent and remained so ; in one no change was observed for nine months, when the eyes began to get narrow, becoming very narrow before death. The cervical sympathetic was excised on both sides to see if it produced further narrow- ing; in two the eyes became very narrow before the ani- mals died, which occurred in two or three days ; in three the eyes narrowed and the animals lived, and in one there was no change. The thyroids of the four surviving rab- bits were excised, the two larger parathyroids being left intact. In one there was a marked increase in the nar- rowing, in the other two no immediate effect, but the ani- mals died ten months later with very narrow eyes. In the PHYSIOLOGY. 37 rabbit in which division of the sympathetic had produced no symptom, the excision of the thyroid was followed by death in three days with narrow eyes. In further experiments to observe the effect of the ex- cision of the parathyroid on the eye, Edmunds excised both cervical sympathetica in a rabbit, which caused nar- rowing of the palpebral fissures ; later he excised the thy- roid together with the two smaller parathyroids, leaving the two large parathyroids. This operation produced no further narrowing. In five rabbits he excised the two larger parathyroids, leaving the thyroid intact, together with the two smaller parathyroids. In four animals the eyes became somewhat wider for a time, reverting to nor- mal : in one there was no change. In six rabbits the op- posite operation was performed, namely, the two larger parathyroids were left intact and the thyroid lobes with the two smaller parathyroids were excised. The results varied, in three of the rabbits it was noticed that the eyes for a time were wider than normal, four of the rabbits died and, at the time of death, their eyes were much narrowed ; two were killed at a time when the eyes were normal. Edmunds summarizes his results as follows : (1) That after complete excision of the thyroid and parathyroids the great majority of dogs die within a few days and cannot be saved by thyroid feeding, but a small minority survive even after the complete operation. (2) In operations in which one or more parathyroids are left the dogs as a rule survive. (3) That when only the thyroid is left they die as a rule. (4) That with respect to operations that paralyze the secretory nerves of the thyroid the dogs often die, al- though possessed of the whole of one thyroid lobe, to- gether with the parathyroids of 'the same side, or even as in Halstead's experiments when possessed of the whole thyroid. 38 THE THYROID AND PAEATHYEOID GLANDS. (5) With respect to the microscopical appearances of the parts left in the experiments, the parathyroids seem merely to hypertrophy, and they do not change into thy- roid tissue proper. The thyroid tissne may remain un- altered even though the dog may die of athyroidic symp- toms, or it may materially alter and this in one or two days ; either the colloid diminishes or entirely disappears, vesicles enlarge and the lining membrane becomes con- voluted. This may occur to such a degree as to present appearances closely resembling, if not identical with, those in a papilloma, or the colloid may disappear, the vesicles may retain their shape and the round cells may multiply into and fill the cavity of the vesicles, thus pro- ducing an appearance somewhat similar to that seen in carcinoma, but though much hypertrophy sometimes oc- curs nothing of the nature of invasion has been seen. (6) In the central nervous system changes have been found corresponding to paralytic symptoms, the lesions that occur are observed mainly in the large cells, varying from chromatolysis of the Nissl granules to a complete destruction of the cells. (7) In the eyes of monkeys, dogs and rabbits he finds that when an animal is dying of athyroidic symptoms, whether after a complete or only partial extirpation, there is, as a rule, narrowing of the palpebral fissures. After the removal of the parathyroids a condition of widening of the eyes occurs, which coincides with the view that Basedow's disease is connected with the parathyroids. Moussu has experimented with the parathyroids and comes to the conclusion that the acute convulsive attacks in thyroidectomized animals are due to the parathyroids having been removed, and that if operated dogs are given the watery extract of from twelve to twenty horses ' para- thyroids the convulsions are arrested. He further states that myxedema is not helped by the administration of PHYSIOLOGY. 39 parathyroid (confirmed by Ckarrin), but that he has seen improvement in a case of Basedow's disease by the injec- tion of the extract of eight horses ' parathyroids per diem. He sums up that the removal of the thyroid, leaving the parathyroids produces myxedema in man and perhaps Fig. 11.— A 4 months old kid whose thyroid was removed at 21 days old. (v. Eiselsberg.) Fig. 12.— Control animal from the same birth, (v. Eiselsberg.) also in swine and dogs; in other species progressive ca- chexia. In the young of man, swine, goats, dogs, cats and birds it produces cretinism, which is improved by the administration of thyroid. That the removal of the para- thyroids in carnivora produces death, which was formerly attributed to the absence of the thyroid, and that the par- 40 THE THYROID AND PARATHYROID GLANDS. tial removal of the parathyroids produces symptoms sim- ilar to Basedow's disease, it has not been shown as yet that the parathyroids are diseased in Basedow's disease, nor that feeding with parathyroids will benefit the patient. A few cases are recorded, but as yet the benefit of the treatment must be regarded as "not proven." There seems to be no doubt that the two sets of glands are not wholly independent, for the removal of the thy- roids causes changes in the parathyroids, and the excision of the parathyroids changes in the thyroid. One very attractive theory suggests itself, that the symptoms of myxedema are due to the failure or removal of the thyroid, while removal or failure of the parathyroids produces the tremors and other nervous symptoms, with the general symptoms of Basedow's disease. If the failure of the parathyroids causes hypertrophic changes in the thyroid, as shown by Edmunds, it may be supposed that the in- creased secretion of the altered thyroid would cause ex- ophthalmos, and thus we should have, as in Basedow's disease, tremors, exophthalmos, etc. Edmunds states that excision of the parathyroids produces sometimes exoph- thalmos, sometimes enophthalmos, and exophthalmos can be converted into enophthalmos by the removal of the thyroid lobes. Total thyroidectomy in the monkey is usually followed by enophthalmos, exceptionally exoph- thalmos, while thyroid feeding produces exophthalmos in monkeys, as a rule. Prof. Freiherr v. Eiselsberg experimented with the re- moval of the thyroid in young animals. He removed the thyroid from two lambs at ten days old, keeping another as control. In a month the control animal was much larger than the operated lambs, and at six months the control animal was as heavy as both the other operated lambs together. It weighed 35 kg., compared with 10 kg. and 14 kg. Not only was the physical growth arrested, PHYSIOLOGY. 41 but the mental condition was very evidently defective, and there was also a want of coordination. At the autopsy there was calcification of the aorta, which had the appear- ance of being due to senile changes and not to inflamma- tion. He operated on young goats, pigs, rabbits and asses and found the same results, namely, arrest of physical and mental development, comparable to cretinism. Fig. 13.— Lamb, 6 months old, the thyroid being removed on the tenth day. (v. Eiselsberg.) The influence of the thyroid secretion on the morphol- ogy of the organs of generation in both sexes has been demonstrated by many observers. It is an ancient tradi- tion that the thyroid enlarges at the first menstruation, in certain women, each period producing an appreciable en- largement of the gland. There seems also to be a bal- ancing as it were between the flow of blood and the gland. A suppression of menstruation often produces a swelling of the gland, which disappears on the reestablishment of the flow. There is also a very remarkable connection pointed out by Gautier that the menstrual blood contains 42 THE THYROID AND PAEATHYEOID GLANDS. iodin and arsenic, both of which substances are a part of the normal secretion of the thyroid. In girls it has often been stated that the first sexual act produces an enlarge- ment of the gland. There seems to be no connection be- tween the thyroid and the sexual act in the male, it having never been observed to swell after the first coitus but en- larges about the time of puberty and occasionally a pal- pable goitre may form. The enlargement of the gland during the rut has been observed in the dog, cat, rat, sheep and deer, and was described by Wagner in 1858. The effect of the thyroid, development on puberty is of great importance. Broca (" Goitre and Cretinism, ' ' 1891) states that in the complete cretin puberty is never estab- lished. The reproductive functions are nil and sterility is absolute, while arrested development of the sexual organs is almost a constant symptom of infantilism. Occasion- ally there are cases of hyperthyroidea occurring at pu- berty, which Brissaud explains as a result of a difficult sexual metamorphosis, or, in other words, that an arrested development of the sexual organs may produce thyroid derangements. In cretinism, and especially in infantil- ism, the increase in the development of the sexual organs under thyroid treatment is very marked. It is of im- portance, from a therapeutic standpoint, to note that the increase in size of the thyroid gland is anterior to the development of the sexual organs, the secretion of the gland being increased, the surplus is utilized to stimulate growth, and, therefore, if the gland does not increase, puberty does not occur and the growth is retarded, pro- ducing infantilism. During pregnancy there is a marked modification of the gland. Freund observed augmentation of volume in forty-five out of fifty women. Lange established that the enlargement commenced about the fourth month in pri- miparas and the fifth month in multiparas. The gland PHYSIOLOGY. 43 commences to diminish seven or eight days after confine- ment and quickly recedes to normal ; sometimes the hyper- trophy continues through lactation. Lange found that out of 133 cases 25 did not show any hypertrophy ; examina- tion showed that 20 of these presented albuminuria, and he argued that the relative insufficiency of the thyroid has an influence on the kidney. Experimentation confirmed his theory. Lange removed four-fifths of the thyroids in a Fig. 14. — Control animal, (v. Eiselsberg.) number of cats, producing no symptoms except in those with young, the latter dying and the autopsy showing fatty degeneration of the kidney. Several of the operated cats were impregnated, developing albuminuria and the kidney degeneration. This experiment shows a possibility of eclampsia being connected with hypothyroidea. The thyroid has also some effect upon the production of milk. M. Wauters experimented upon a cow who, for fifteen days, had averaged 11.5 litres of milk per day. He gave 6 grms. of fresh thyroid for ten days, during 44 THE THYROID AND PARATHYROID GLANDS. which time the average amount of milk rose to 12.55 litres. On the following eight days he gave 8 grms. thyroid and the milk rose to 13.8 litres per diem. The average quan- tity of milk during the twenty days the animal was under treatment was 13.17 litres, being an increase of 1.67 litres per day. Lange took nine hens eighteen months old and gave one of them from 10 to 30 grms. of thyroid daily. During the following twenty-eight days the eight hens laid forty- two eggs, or an average of 5.25 eggs, while the hen receiv- ing thyroid laid during the same period sixteen eggs ; the Fig. 15. — Aorta of thyroidectomized sheep showing atheroma. (v. Eiselsberg. ) weight of the eggs also increased 10 grms. Lange had previously observed that a thyroidectomized hen laid an egg with a very thin shell weighing only 5 grms. Metabolism experiments have been made during the administration of fresh thyroid gland, thyroid sicca and thyroidin on healthy subjects, in myxedema, in Basedow's disease, in obesity and in thyroidectomized animals, which give practically the same results. In thyroidectomized animals without thyroid feeding there is a greatly in- creased elimination of nitrogen and a decreased elimina- tion of phosphorus, the latter rising on the administration of thyroid. Boos kept a dog under observation for two months, estimating the elimination of nitrogen, sodium chlorid and phosphoric acid. He then administered 3.0 PHYSIOLOGY. 45 grins, and later 6.0 grins, thyroid sicca daily. There was an increased elimination if nitrogen, sodium chlorid and phosphoric acid. He then removed the thyroids and con- tinued the administration of the thyroid sicca, the nitrogen and sodium chlorid elimination was further increased, but the phosphoric acid was diminished. The nitrogen elim- ination in the unoperated animal rose from 3.04 to 3.8 and from 3.4 to 4.15 and in the operated animal from 3.61 to 5.35. Magnus Levy found that the amount of oxygen utilized by a subject at rest was 3.1 to 5.36 ccm., while in the obese it was only 2.82 (v. Noorden found 2.64). By the administration of thyroid he could raise the used from 2.26 to 2.36 on the fifteenth day and to 2.55 on the nineteenth day, the loss of weight in the nineteen days being 4 kg. Theile and Nehrung raised the from 2.87 to 3.43, or 20 per cent; v. Noorden raised the used 21 per cent, which lasted fourteen days after the thyroid feeding was suspended. Magnus Levy treated a myx- edematous patient with thyroid tablets, thyroantitoxin and iodothyrin. With the tablets the patient lost weight from 42 to 39.2 kg., the pulse rose from 60 to 120, temperature from 36.2 to 37.5, the O used from 1.22 to 2.15, the respira- tion quotient sank from 0.85 to 0.71. With Fraenkel's antitoxin the amount of O used was not increased nor did the pulse rate increase, the body weight did not fall but increased 1 kg. The iodothyrin produced about the same effect as the tablets, the O rose from 1.3 to 1.98, the respi- ration quotient fell from 0.83 to 0.74, the pulse rate rose from 60 to 100, the body weight fell from 44.2 to 41.9 kg. Strive found the O used increased in a healthy subject by the administration of thyroid tablets 20 to 23 per cent, while the increase of C0 2 eliminated was somewhat less. Voit arrived at the same conclusions. Venehren experimented with three normal young men, giving 0.1 to 0.3 iodothyrin per diem and found no change 4(3 THE THYROID AND PARATHYROID GLANDS. in the nitrogen elimination, but in two older subjects there was a marked increase. Dennig found that the nitrogen elimination was increased on the administration of thyroid sicca. Blubtreu and "Wendelstaat, in a metabolism experi- ment on the latter, found that by taking three to four tablets, equal to about 2 grains thyroid sicca each, he lost 3 kg. in weight and 15.97 nitrogen, equal to 500 grins, muscle substance, therefore 16 per cent of the loss of weight was due to loss of muscle substance. Scholz found that by taking three tablets daily his case lost no weight. Before taking the tablets the elimination showed a nitro- gen retention -4- 3.7567, while taking the tablets the nitro- gen retention was reduced to + 2.6399. Eichter found in the period before administration of the thyroid an N re- tention + 4.95, during the experimental period -(-3.22, and during the after period +4.0. Gluzinski and Lem- berger obtained about the same results by the administra- tion of tablets, but on giving the fresh gland the retention N of +2.1 was reduced to — 1.48, showing that while the subject lost 1 kg. weight he lost 6.24 grms. N, equal to 200 grms. muscle substance, or 20 per cent of the total loss was, therefore, muscle substance. Eichter, in order to see if it were possible to reduce the weight without loss of nitrogen, put a subject on a diet containing 20.07 N and equal to 2988 calories, or 40 calories per kg. of body weight. He gave ten, fifteen and twenty thyroid tablets two days each. The subject lost 2 kg. in five days with a nitrogen retention of + 12.89, showing that under suffi- ciently nitrogenous diet it is possible to reduce weight without loss of muscle substance. In this case the only change noted in the urine was an increase of xanthin elimination. Schorndorff, in a most elaborate and carefully con- ducted metabolism experiment on a dog 25 kg. weight in nitrogen equilibrium, found that on the administration of PHYSIOLOGY. 47 thyroid the elimination of nitrogen was increased during the first eight days by 1.59 grms. per diem. The elimina- tion then sank to equilibrium, then rose to slight minus and then again fell to equilibrium. The total nitrogen taken was 729.13, eliminated 731.96 equal to a loss of 0.1 grin, per diem. He next increased the amount of thyroid in order to see if after the elimination of the fat the in- creased oxidation would cause increased loss of nitrogen. During twenty-two days the animal received 729.93 N and lost 760.51 N equal to 927.0 grms, muscle substance; the dog had lost in all 2200 grms. weight, and had, therefore, lost 1273.0 grms. fat; this loss was equal to 40.0 grms. muscle substance and 55.0 grms. fat daily. Contrary to other observers he found that as soon as the thyroid feed- ing ceased the excessive nitrogen elimination ceased, the animal gaining weight rapidly. He concluded that the increased elimination of nitrogen in the first few days of thyroid feeding is due to the elimination of extractive sub- stances, while the fat metabolism really spares the proteid nitrogen. When the body fat has been reduced to a cer- tain point the nitrogen elimination is increased by the oxidation of proteid. The effect of thyroid feeding upon the metabolism is the result of increased oxidation and consequent loss of weight. The intake of oxygen is increased, the carbon dioxid given off is increased, the nitrogen elimination is increased. In the first few days, probably by the elimina- tion of extractives, it is possible, by proper diet, to prevent any loss of nitrogen, the loss of weight being then due to the oxidation of the fat and loss of water. The chlorid and phosphoric acid elimination are also increased, uric acid elimination is not affected, but a slight increase in the xanthin bodies has been observed, the total quantity of urine is usually increased. There is also quite a percep- tible increase of perspiration which, if very marked, may cause the urine to decrease in quantity. 48 THE THYEOID AND PAEATHYEOID GLANDS. The administration of thyroid in large doses produces a condition known as thyroidismus, resembling in many points the symptoms of Basedow's disease. Exophthal- mos has been observed by Notthaft in the case of a patient who took very large doses for obesity. The resemblance to Basedow's disease was so marked that the diagnosis of Basedow's disease was made before the real cause was discovered. The tremors, mental depression, rapid pulse, diagnostic of Basedow's disease, are almost invariably produced by overdoses of thyroid. Ewald gives a de- tailed account of the symptoms observed in various cases. The pulse rate is increased to 100-120 or higher, palpita- tion of the heart, stenocardiac attacks, rise in temperature, a feeling of weakness with constriction of the chest, tremors, insomnia, increased diuresis but, if the sweating is very profuse, the twenty-four hours' urine may be re- duced to 300 ccm. or less, with increased elimination of nitrogen, chlorids and phosphoric acid, and may con- tain albumin ; the respiration is accelerated, headache and rheumatoid pains occur, eructations, loss of weight and complete anorexia, thirst, dizziness, loss of consciousness, increased flow of saliva, pruritis, urticaria, erythema, ec- zema; the heart may become so weak and the vessels so dilated that the patient will keep his head below the level of the heart. Sugar has been observed in the urine by Dale, Jones, Ewald, Bennig and others. It occurred in one case at Mount Hope. Levulose and inosite have both been recorded as occurring. The mental symptoms are usually those of depression. The writer took 24 grs. per diem for three days for experimental purposes, and the depression was so great that the experiment could not be continued. In other cases there is a precordial anxiety with an ill-defined but very real fear of impending danger. Maniacal symptoms occur, usually of a melancholic type, and suicidal tendencies may appear. PHYSIOLOGY. 49 The action of thyroid feeding on the heart and circula- tion has been studied by Oliver, Schaef er, Gley, Langlois, Gurnard and Martin. They find that the pulse becomes weak and rapid. Oliver, by means of his hemodynamo- meter and arteriometer, showed that the blood pressure is very markedly reduced, while the arteries and arterioles are dilated, especially the peripheral vessels, producing the perspiration. Gurnard and Martin showed that, after the vessels had been dilated and the heart weakened by the injection of thyroid extract, they could be rapidly restored to normal by the injection of suprarenal extract. The blood changes after thyroidectomy are more constant than any other pathological findings and offer an explana- tion to most of the symptoms produced by the operation. Horsley, Herzen and Eojwitsh found that the blood be- came more venous, the former showing that the arterial blood might contain less oxygen than was normal in venous blood. Alberti and Tizzoni found that the in the ar- terial blood was reduced from 7 to 8 vol. to 8 to 11 vol. ; Vassali propounded the theory that the red corpuscles lost their power to combine with oxygen, and found that when he injected the expressed fluid from a gland into the veins of an operated dog, whose venous blood was almost black, after a few hours the blood became normal in color. As was previously mentioned it has been observed that operated animals react to external temperatures very readily ; the formation of C0 2 is immediately increased on their being brought into the cold, which only takes place after some time in normal animals. This points to a vaso- motor disturbance. Schaefer has shown that the intra- venous injection of thyroid extract reduces blood pressure, and Oliver that the calibre of the radial artery is increased at the same time. Lewy made a careful examination of the blood in operated animals and found that the specific gravity was always reduced, but that no other very con- 4 50 THE THYEOID AND PAEATHYEOID GLANDS. stant changes existed; further, that no relation appeared to exist between the severity of the symptoms and the anemic changes ; normally the leucocytes are present in greater proportion in the veins than in the arteries of the gland, and the proportion is greater than that found in the limbs. Formanck and Haskovic found the number of red corpuscles invariably reduced and the leucocytes in- creased, the total solids and iron were diminished. Duc- ceschi found that in operated dogs before the commence- ment of the convulsion the serum albumin increases and the serum globulin decreases, the total proteids vary from the commencement of the convulsions to the death of the animal, the globulin continues to increase, and the serum albumin and total albuminoids decrease as in starvation. Bottazzi finds the same changes as Ducceschi; also that the red corpuscles part with their hemoglobin very readily, lose in specific gravity and that there is an increase in fibrin. Masoin claims to have found a toxin in the blood of operated animals as well as in the urine; Zuntz and Geppert found acid substances in the blood; (Hey found that the blood serum of operated animals produced typical symptoms when injected into the blood of normal animals ; Edmunds and Baldi on the contrary could obtain no symp- toms under the same conditions. Excess of mucin has been found in the blood of myxe- dematous patients and in that of operated animals. Halle- burton analyzed the blood tissues and organs of a case of myxedema; the tissues were finely minced, weighed and usually kept a day in methyl alcohol, decanted and the tissues treated with lime water or dilute barium hydrate solution, allowed to macerate for a few days, strained, and the mucin precipitated from the filtrate by the addition of weak acetic acid, filtered through a weighed filter, washed with alcohol and ether, dried at 100 degrees C. to a constant weight and weighed. PHYSIOLOGY. 51 By this method a number of analyses have been made with varying results. The skin of the thigh of a still-born child contained 0.96 per cent mucin ; the abdominal skin of children from seven weeks to nine years of age 0.39 to 1.02 per cent, with an average 0.766 per cent; skin from the same part in grown people contained 0.11 to 0.64 per cent, with an average of 0.385 per cent; in connective tissue 0.5 per cent; in Achilles tendons 0.298 to 0.77 per cent; in the parotid gland only a trace. In a patient who had suffered for ten years from myxedema Cranston Charles found fifty times more mucin than normal in the skin of the foot. Halleburton found 0.81 to 0.72 per cent, and once 0.012 per cent, average 0.374 per cent; the quantity in the tendons was increased, 1.42 per cent in the heart, 1.65 per cent in the spleen, 2.21 per cent in the lungs, 0.7 per cent in the parotid. In the blood which clotted imper- fectly there was no mucin found, neither in the peri- cordial, peritoneal or cerebro-spinal fluids. Horsley and Halliburton (Brit. Med. Jour., 1885) found that in monkeys, after the extirpation of the gland, mucin was increased in the tissue as shown by the following table : Sub- Skin. Tendons. Muscle. Parotid, maxillary. Blood. Normal 0.089 7th day after operation . . 0.045 29th " " .. 0.108 49th " " . . 0.23 55th " " .. 0.312 It was also noted that the blood coagulated very slowly, but that the proportions of serum globulin to serum albu- min were normal. It was further observed that pigs did not become myxedematous on thyroidectomy and that there is a quantity of mucin in normal pigs' tissue, the skin contained 0.209 per cent, tendons 0.403 per cent, muscle none, parotid trace, submaxillary gland 0.416 per 0.009 0.09 trace 0.016 trace 0.15 0.208 1.036 trace 0.24 trace 0.17 0.33 0.08 0.255 trace 0.072 0.6 0.35 52 THE THYROID AND PARATHYROID GLAXD3. cent, blood none, pancreas 0.009. In sheep, on whom the operation had no apparent effect until they were turned out in the cold, the "urine became thick with mucus when the symptoms appeared. Byrom Bramwell has observed this symptom in patients suffering from myxedema. Halliburton concludes from the above analyses that the percentage of mucin in the tendons of myxedematous patients slightly exceeds normal, but that excess of mucin in the tissues is not pathognomic of the disease. He re- ports one case in which the mucin was very excessive. Wagner claimed that by the injection of mucin into the vessels of cats he produced tremors and tetanoid spasms resembling those of thyroidectomy. The pathological findings in thyroidectomized animals are not marked nor constant, and seem to be the result of starvation rather than toxemia. In the nervous system various writers have found a number of lesions but none occur with sufficient regularity or uniformity to permit them to be considered as pathognomic of the condition. In the central nervous system anemia and edema of the brain and hyperemia with extravasations in the spinal cord have been frequently observed. Pisenti found cavi- ties in the lumbar and costal portions of the cord contain- ing only traces of nerve substance, but such cavities are often found in hyperemic conditions of the brain and cord. In the brain substance a condition of encephalitis paren- chymatosis, accompanied by swelling of the nerve cells and axis-cylinder; also a small round cell in filtration of the meninges of the upper portion of the cord have been noted by Horsley and Arthoud. Mayon found a neur- itis vagi. Langhans and Kopp, examining the peripheral nerves in the acute cachexia of dogs and in the more chronic cases of monkeys, men and cretins, found changes of an inflammatory nature. Although no definite constant change has been observed in the nervous system there can PHYSIOLOGY. 53 be no doubt that the symptoms are of central origin. Setoff has shown that the tetanic convulsions ceased on section of the nerve trunks ; Lang cut the sciatic nerve in an operated dog and saw the twitching cease in the muscles supplied by the nerve ; Horsley and Lang cut the cord at the eighth vertebra and saw the twitching almost cease in the extremities. The motor area of one hemisphere was removed by Horsley in five operated dogs, the twitchings were more marked on the side which was intact. The re- sults of these experiments prove that the disturbances are of central and not peripheral origin. Zesas and Crede and also Lemke found that the spleen became enlarged after removal of the thyroid, and Lohlein that after the removal of the spleen the thyroid en- larged. Zanda claimed that if the spleen was removed four weeks the thyroid could be removed without causing any symptoms, and argued that the spleen produced toxic substances which it was the function of the thyroid to neutralize. Fano on repeating Zanda 's experiments did not confirm his results. Hofmeister, Albertoni, Tizzoni, Gley and de Quervain failed to confirm Zesas and Crede 's observations, and found in five cases of men dying of cachexia strumipriva that the spleen was unusually small in four cases and of normal size in one. Lang in over forty experiments failed to show any connection between the spleen and the thyroid. Gley found that by extirpating portions of the thyroid at different times in rabbits he could produce hypertrophy of the hypophysis cerebri, the weight of the latter being increased from 0.02, the average normal weight, to 0.101 grms. There has been much speculation as to the possi- bility of the vicarious action of the hypophysis for the thyroid, which was rendered probable by the former oc- casionally containing iodin, but there has been very little evidence forthcoming in support of the theory. 54 THE THYROID AND PARATHYROID GLANDS. In operated animals the temperature is usually normal except during the tetanic spasms, when it may rise 2 to 5 degrees C, Herzen on one occasion observing a tempera- ture of 43.4 degrees C, later the temperature falling be- low normal ; it may go as low as 33 degrees C. There is marked susceptibility to cold in operated animals, which is also very evident in myxedematous patients. Munk, Lang and Kocher observed that the patients suffering from cachexia strurnipriva were more comfortable in warm rooms, complaining of cold at ordinary temperature. By increasing the external temperature operated animals can be kept alive much longer and the cachexia and tetany reduced to a minimum. Whether the feeling of cold is central in origin or the result of trophic changes of the skin has not been decided. During the convulsions the respiration is increased, between the attacks it is normal or reduced; the type is normal. The heart's action is increased in volume. The urine shows no very marked change, it is usually decreased in quantity, of an increased specific gravity and may contain albumin during the convulsions. The tox- icity has been found to be increased by Gley and Laulanie, who claim that on the injection of the urine of an oper- ated animal into the veins of an unoperated animal typical symptoms were produced. Alonzo and others have failed to corroborate their results and could find no appreciable difference. The nitrogen and chlorid elimination is in- creased, while the phosphoric acid is decreased, the pro- portion of neutral sulphur to total sulphur is also in- creased. The increased elimination of nitrogen and chlorids is no doubt due to the progressive anemia and consequent starvation, while the decreased phosphoric acid and increased neutral sulphur may be due to decreased oxidation. There is probably some connection between the phosphorous metabolism and the thyroid secretion, as; PHYSIOLOGY. 55 the effect of congenital absence or early removal of the gland produces an arrest of development, especially of the skeleton, the long bones and vertebras suffering the most. Hofmeister made exact comparative measurements in animals and found that the growth of the long bones was decreased one-third. The influence of food on the symptoms of thyroidectomy is marked. Briesacher found that dogs suffered less and could be kept alive longer if fed on well-cooked meat and milk, while if given raw meat or meat extract they suc- cumbed much earlier. On milk diet the animals lived longer or survived in apparently perfect health with only one-third to one-fifth of the gland remaining. Herbivora seem also to suffer less than the carnivora, due presumably to their vegetable diet. CHAPTER IV. CHEMISTRY OF THE THYROID GLAND. Since the thyroid has been proved to be a secreting organ and of vital importance to the system, the chemical nature of its secretion has been the subject of most careful research by numbers of physiological chemists, both in Germany and England, their efforts having been directed to the isolation of the active principle. That the gland contained considerable quantities of extractives, viz : xan- thin, kypoxanthin, kreatin, kreatinin, paralactic acid, ino- site (?), indicating high metabolic activity was early proved, but none of these could be looked upon as the active principle. White and Davis, working on the hy- pothesis that the active principle was a ferment, obtained a body which had some activity. Gourlay failed to find a ferment which would dissolve mucin, which was consid- ered at that time to be the function of the gland, but he isolated a nucleo albumin which produced intravascular clotting, and which he claimed existed in the colloid sub- stance. Bubnow extracted three different forms of pro- teid, one apparently a globulin; Notkin following on the same lines isolated a substance which he believed was the toxic product of metabolism, which underwent decompo- sition in the gland through the action of an hypothetical enzyme. In 1895 Sigmund Fraenkel isolated a crystal- line alkaloid-like body resembling guanidin to which he gave the empirical formula C 6 H n N30 5 . Drechsel later described a body identical with that of Fraenkel and another similar to it. Fraenkel 's thyroantitoxin was a hygroscopic crystalline substance, soluble in water and alcohol, neutral to slight alkalinity and gave the alkaloid 56 CHEMISTRY OF THYROID GLAND. 57 reactions. Injected into animals it failed to produce a fall in blood pressure but increased the pulse rate; admin- istered to thyroidectomized animals it caused some im- provement in their condition. Fraenkel's observations have not, however, been confirmed ; the epoch-making dis- covery of Professor Baumann of Freiburg, in 1896, of a body containing iodin in organic combination in the thy- roid of man and of many animals, possessing the physio- logical characteristics of the gland, prevented any further experiments in that line. Baumann describes the sub- stance he isolated, which he named ' ' thyroidin, ' ' as a brownish amorphous compound which decomposed on heating, giving off the odor of pyridin, it is insoluble in water, sparingly soluble in alcohol but dissolves readily in dilute alkalis, being precipitated by acids, it gave no proteid reactions, and constantly contained phosphorus; he obtained 9.3 per cent iodin in crystalline form from this substance. Baumann was unable to complete his work, owing to his lamented death in 1897, when physi- ological chemistry lost one of its ablest disciples. His method for the isolation of the thyroidin consisted in digesting the gland for several hours with a 10 per cent mineral acid on a sandbath with a return condenser and extracting the residue with 90 per cent alcohol. He proved that the substance was iodin in proteid combina- tion, and he named it thyroid albumin. Drechsel and Baumann found that the iodin-containing proteid could be dissolved in normal salt solution, which solution he diluted with fifteen volumes of distilled water, passed carbon dioxid througli it, obtaining a precipitate of a globulin containing iodin, he added acetic acid to the filtrate and boiled, securing a precipitate of albumin which also contained iodin, and therefore concluded that there were two iodin-containing proteids in the gland, a globulin and an albumin. 58 THE THYROID AXD PARATHYROID GLAXDS. Oswald extracted 99.5 grms. of liurnan thyroid which contained 21.92 nig. iodin ten times with normal salt solu- tion, and obtained 17.26 mg. I in solution, being 78.7 per cent of the total I; Lambach obtained 97.8 per cent in solution ; in neither case was there any iodin in inorganic combination. Oswald then proceeded by Pick's method to separate the albumins and found that the precipitation commenced at 0.26 and continued up to 0.44 saturation, so that at 0.5 saturation one proteid was completely precipitated, in the nitrate precipitation begun at 0.64 and continued up to 0.82 saturation when the nitrate contained no proteid. He found that the first precipitate contained iodin but no phosphorus, while the second precipitate contained no iodin but contained phosphorus, proving that the sepa- ration of the proteids was complete. The first precipitate was dissolved in water, filtered and again half saturated with ammonium sulphate. This precipitate was dialyzed till free from ammonium sulphate, redissolved in alcohol (95 per cent), filtered and the precipitate dried. An easier method which dispenses with the tedious dialyzing is to dissolve the precipitate from the half-saturated am- monium sulphate solution in water and precipitate with dilute acetic acid, filter, dissolve the precipitate in 0.1 per cent sodium hydrate, precipitate with acetic acid, washing the precipitate with water acidulated with acetic acid. The precipitate is only very slightly soluble in water, but is more easily dissolved by the addition of neutral salts, is very soluble in dilute alkalis, is precipitated by slight acidulation with acetic or hydrochloric acids. Sat- uration with sodium chlorid produces only a slight cloudi- ness, saturation with magnesium sulphate and half satura- tion with ammonium sulphate give complete precipitation. These reactions are those of the globulins and Oswald designates the iodin-containing globulin as thyroglobulin. CHEMISTKY OF THYEOID GLAND. 59 Myosin is precipitated from its solution in neutral salts by acids and gives the other globulin reactions, egg and serum globulin are not thus precipitated. This substance is not pseudoniucin, as is often stated, as pseudomucin is not precipitated by acids. Thyroglobulin is precipitated by sulphuric acid but is not soluble in excess. It is also precipitated by phos- photungstic acid, phosphomolybdic acid, ferrocyanid of potassium, acetic acid, iodomercuric potash, trichloracetic acid and by copper sulphate. It gives the color reactions for proteids, the biuret reaction, Millon 's reaction, Adam- kiewicz's reaction, Mollisch reaction and the xanthopro- teic reaction. The salt free solution becomes cloudy on heating but does not coagulate, on the addition of 10 per cent magne- sium sulphate it coagulates at 65 degrees C; it contains sulphur which combines with lead. From the strong result of Mollisch's reaction it may be assumed that it contains a large carbohydrate group in the molecule; after boiling for two hours with 5 per cent solution of hydrochloric acid the solution gives the red reaction with a-naphthol and sulphuric acid, and also reduces Fehling's solution and ammonia silver oxid, while it fails to give the typical phloroglucin and hydrochloric acid reaction, it gives a brown color with this test, showing that pentose is not present ; it forms osazone with a melting point of 100 degrees C. with phenylhydrazin (Hutchinson failed to obtain a reducing substance from sheeps' thyroid and Eeinbach from the colloid of calves ' thyroids) . In making the elementary analysis of his thyroglobulin Oswald used the Fresenius method for estimating the iodin, having found that the estimation as silver iodid gave too high results, owing to the precipitation of silver chlorid. As the estimation of the iodin in the preparations on the market is of value as an indication of their activitv the 60 THE THYEOID AXD PAEATHYROID GLANDS. method is here given: A weighed quantity of the sub- stance to be tested is placed in a nickel or porcelain crucible with a little water and pure sodium hydrate, evaporated to dryness, a little potassium nitrate added, then incinerated, the residue dissolved in hot water, fil- tered, and the filtrate placed in a well-stoppered bottle with about 10 ccm. of carbon disulphid, acidulated with sulphuric acid and nitrous acid, the solution is extracted several times with carbon disulphid, the iodin is dissolved in the carbon disulphid which is washed two or three times with water. The titration is then carried out with a solu- tion of hyposulphite .of soda standardized against a solu- tion of potassium iodid of known strength. T\ Tien thyrogiobulin is submitted to pepsin digestion for four weeks a gray brown flocculent precipitate remains, which contains iodin, gives the xanthoproteic reaction but neither the biuret, Millon's nor Mollisch's reactions, and is precipitated from its solution with phosphotungstic acid. Hutchinson, by digesting thyrogiobulin prepared by his method, obtained a substance which gave no biuret reaction but contained 0.8 per cent phosphorus, showing that the residue contained nucleoalbumin as well as thyro- iodin. Oswald separated the albumoses and peptones in the solution from the pepsin digestion by the Pick method and found that the protalbumose and deuteroalbumose contained iodin in quantity and that the peptone B con- tained a small quantity, while the heteroalbumose and peptone A contained only faint traces, which were prob- ably due to impurities. The digestion of thyrogiobulin with trypsin for four weeks resulted in a clear solution, which only gave faint cloudiness with ammonium sulphate, acetic acid produced no precipitate, showing that the iodin thyrogiobulin was completely broken up, though the solution contained iodin in organic combination. On concentration of the solution CHEMISTRY OF THYEOID GLAND. 61 tyrosin crystals were found and on further concentration leucin. This decomposition by trypsin digestion and the iodin remaining in organic combination shows that the iodin is not combined in the tyrosin group of the thyro- globulin molecule. Thyroglobulin treated with 10 per cent sulphuric acid on the sandbath with a return condenser is split up, leaving a brown flocculent residue and a brown colored solution, on filtering and washing till the wash water is free from sulphuric acid, extracting with boiling alcohol till the latter is no longer discolored, the alcohol solution evaporated to dryness and dried to a constant weight leaves a brownish powder, which is insoluble in water or acids but is easily soluble in alkali. It gives neither the biuret, Millon's or Mollisch's reactions but gives the xan- thoproteic reaction, contains much iodin and corresponds with Baumann's thyroidin. Thyroglobulin is split up with concentrated acids and with barium hydrate. Oswald proved the physiological effect of the thyro- globulin on the metabolism of animals, finding that it in- creased the elimination of nitrogen. The second proteid separated from the normal salt solu- tion of the gland, and which contained no iodin, contained 0.16 per cent phosphorus, coagulated in a 10 per cent solution of magnesium sulphate at 73 degrees C. with Sis'* From Colloid Goitres g f rom Kl '5-2 I . S'S.lo *'* M *-! *J 6 U§ e w "j bo S "S ~ e - -2 .~ ■? ■eg "§ S is S gg sS sp § s e^ .«<=. s^ s^ p-M-S i; N © a