© Springer International Publishing Switzerland 2017Brendan C. Stack, Jr. and Donald L. Bodenner (eds.)Medical and Surgical Treatment of Parathyroid Diseases10.1007/978-3-319-26794-4_27
27. A History of Hyperparathyroidism
Former Professor of Surgery, Division of Endocrime Surgery, University of California, San Francisco, San Francisco, CA, USA
Orlo H. Clark
Endocrine disorders are primarily caused by increased or decreased secretion of a hormone (from the Greek word first proposed in 1905 by Starling, meaning to excite, arouse, or set in motion) . The first mentioned endocrine operation in antiquity was castration . The last endocrine gland to be discovered was the parathyroid gland . These tiny millet-sized structures are situated near the thyroid gland in the neck and were often inadvertently removed during thyroid operations that caused hypocalcemia and tetany . Parathyroid glands could also become neoplasms and secrete too much parathyroid hormone thus resulting in hypercalcemia with kidney and/or bone disorders. In this chapter I will clarify the progress leading to the discovery of primary hyperparathyroidism and how it should most effectively be treated.
In the eighteenth century John Hunter (1728–1793), the English anatomist and surgical scientist, noted that “only one testicle was necessary to maintain normal sexual function and that castration prevented the growth of antlers in a stag” . He also reported the effects of the transplantation of a cock’s testis to the abdomen of a hen and the subsequent change of secondary sex characteristics as well as the importance “of the testes for maintaining the seminal vesicles, prostate and Cooper’s gland” . Arnold A. Berthold (1803–1861), however, was the first to suggest that the testes maintained secondary sex characteristics by acting directly in the blood.
At about the same time as Hunter, the Swiss scientist Albrecht von Heller (1708–1777) from Berne, Switzerland identified the thyroid, thymus, and spleen as organs without ducts that secreted substances directly into the blood . The concept of internal secretion with organs secreting substances directly into the blood stream was not generally accepted until the French physiologist Claude Bernard (1833–1878) reported that the liver secretes sugar directly into the portal vein (internal secretion) and bile into the common bile duct (external secretion). Bernard suggested that the spleen, adrenals, thyroid, and lymph glands functioned by internal secretion . In 1855 Thomas Addison (1793–1860), a physician at Guy’s Hospital in London, reported that absence or destruction of the supra renal or adrenal glands in man causes disease and death . Following Addison’s report, Charles J.E. Brown-Sequard (1817–1894) removed adrenal glands from rats. Although his results were not entirely convincing because of inconclusive findings, and death from the operation itself, he observed that the animals had symptoms similar to those occurring in patients dying from Addison’s disease. He suggested that the adrenal glands are essential for life .
By the end of the nineteenth century thyroidectomy was an accepted operation. Unfortunately some patients developed postoperative myxedema , caused by thyroid hormone deficiency, and some tetany , because of inadvertent parathyroidectomy causing parathyroid hormone deficiency and hypocalcemia. In 1891 George Murray, a pathologist and physician from Newcastle-upon-Tyne, successfully treated a woman with an endocrine deficiency, myxedema . When he injected sheep thyroid tissue into this patient with severe hypothyroidism, she experienced a dramatic clinical improvement . One year later Edward Fox of Plymouth, England reported that “half a sheep’s thyroid, lightly fried and taken with currant jelly once a week was also effective.” in treating myxedema . This was the first successful demonstration of organotherapy , the treatment of an endocrine deficiency with preparations derived from endocrine glands.
Anatomy and Microscopy of the Parathyroid Glands
Sir Richard Owen (1804–1892) the Conservator of the Hunterian Museum, Royal College of Surgeons, London and Natural History Department, British Museum, identified a parathyroid gland in the Indian one horned rhinoceros from the London zoo. This Rhino died from a fractured rib and injured lung after an attack by an elephant . Owen presented his autopsy findings of “a small, compact yellow structure in the expected location in the neck of the rhinoceros” at the Zoological Society on February 12, 1852. He preserved the trachea. This structure can be seen today at the Hunterian Museum of the Royal College of Surgeons. The related article was not published, however, until 1862. Owen’s successor A.J.C. Cave, the Professor of Anatomy at the Royal College of Surgery, discovered that Owen’s article was originally published in 1852, not 1862, thus making Owen the first person to identify a parathyroid gland in animals .
In 1852, the same year as Owen’s original presentation on the parathyroid gland Ivar Viktor Sandstrom (1852–1889) was born in Sweden. While working as a medical student in the Anatomy Department at the University of Uppsala in 1877 as a research assistant for Professor Edward Clasen, he identified parathyroid glands first in dogs and subsequently in the cat, rabbit, ox, horse, and man [13, 14]. He was surprised that other anatomists had not observed these glands. His extensive studies included dissections of 50 human cadavers. He suggested the name of “glandulae parathyroideae” . First publishing on this subject in 1880, he writes “Almost 3 years ago I found on the thyroid of a little dog a tiny growth, barely the size of a hemp seed which lay enclosed within the same capsule of tissues as that gland, though it was dissimilar in its lighter color” [16–18]. When Sandstrom submitted his 31 page article on the discovery of the parathyroid gland to the prestigious German press, it was rejected . He was invited, however, to present his findings at the meeting of the Scandinavian Society of Natural Science in Stockholm in 1880. Even though there was little interest in his discoveries, the same year he received the Hwasser Award from the Uppsala Medical Association for his work in this field . During his presentation Sandstrom described the size, shape, color, blood supply, and histology of the normal parathyroid glands which he noted were not lymph nodes. “He postulated that the glands were an embryonic extension of the thyroid arrested in various stages of development and he astutely recognized that their location varied in animals and man” . He also acknowledged that in 1855 Robert Remak (1815–1865), an embryologist at the University of Berlin, had described “a parathyroid gland as being associated with the thymus and distinct from the thyroid” . In 1863 Rudolf Virchow (1821–1902), the famous pathologist from the University of Berlin, also identified a parathyroid gland that he believed was a distinct structure and was not ectopic thyroid tissue or a lymph node. There was no follow up by Remak or Virchow, but subsequent anatomical and histological studies by A Kohn in 1895 confirmed Sandstrom’s findings that the parathyroid glands were not thyroid tissue . Sandstrom suffered from severe depression and committed suicide on June 2, 1889. He is credited with “the last discovery of an organ in humans, an honor he surely would have cherished” .
Parathyroid Gland Function
Eugene Gley (1857–1930), Professor of Physiology and the Brown-Sequard Chair at the College de France in Paris studied the parathyroid glands because of his interest in the function of the thyroid gland. Gley was aware of Sandstrom’s discovery of the parathyroid glands from his reading in the atlas of rabbit anatomy “Die Anatomie des Kaninchens” by W. Kraus published in 1884 . The text made reference to Sandstrom’s previous publication. Gley’s experiments in dogs documented that removal of four parathyroid glands usually resulted in tetany (a term from the Greek word tetanus “to stretch” first used in 1852 by Lucien Covisart, the personal physician of Napoleon III). The term was popularized by the French clinician Armand Trousseau (1801–1867) in his lectures [20, 22]. Gley’s findings, as published in 15 articles from1881 to 1897, proved that removal of the parathyroid glands and not the thyroid gland was responsible for postoperative tetany . Soon after Gley’s findings, Julio Vassale (1862–1912) and Francesco Generali (1896) and others also reported that parathyroidectomy, and not thyroidectomy, resulted in tetany .
Of interest was that parathyroidectomy is more harmful regarding blood calcium levels than simultaneous excision of both the thyroid and parathyroid glands . It wasn’t until 1962 that Douglas Copp and colleagues in Vancouver documented that a calcium lowering hormone (calcitonin) is present in the thyroid gland . In 1901 Jacob Loeb (1859–1924), a professor of biology at the University of California, Berkeley, reported that he could effectively treat neuromuscular irritability caused by hypocalcemia, by giving calcium . James B. Collip and Clark developed a method for measuring the concentration of calcium in the blood that became the standard method for determining blood calcium for many years in most laboratories .
Vassale and Generali and many others including Gley believed that the parathyroid glands have an antitoxic function. Support for this theory was provided by Arthur Biedl in 1907, who reported that blood-letting and transfusion of normal blood relieved the symptoms of tetany in parathyroidectomized animals . In 1909, MacCallum (1874–1944) and Voegtlin (1879–1960) at Johns Hopkins in Baltimore and others confirmed the results of these experiments, and reported that blood-letting either relieved the tetany or made it less severe. They subsequently stated that post-parathyroidectomy tetany was associated with hypocalcemia . In 1924 Noel Paton reported “that complete removal of the parathyroid tissue leads to a fatal toxemia; he further suggests that the parathyroids through their internal secretion control the tone of muscles by regulating metabolism, i.e., the production and destruction of guanidine in the body” .
In 1924 A Hanson (1888–1959) from Minnesota first prepared and patented an effective parathyroid extract . One year later J. Collip (1892–1965) from Edmonton, Alberta prepared a purer parathyroid extract . Collip addressed the question regarding the cause of post-parathyroidectomy tetany . He stated “that a very strong case has been made out for the guanidine intoxication theory of post-parathyroidectomy tetany . The evidence, however, consists so largely of the circumstantial type that it fails to carry with it the weight of final conviction” . In 1924 Collip documented that the injection of his parathyroid extract effectively treated post-parathyroidectomy tetany , thus disproving the toxin theory.
In 1923 the Norwegian physician—scientist Harold Salveson also addressed the etiology of post-parathyroidectomy tetany . He documented “that complete parathyroid ablation invariably lowered the blood calcium, that the blood sugar level was not altered and that guanidine accumulation occurred only terminally during agonal convulsions” . These observations as well as the presentation of tetany after parathyroidectomy in humans documented both the etiology of the tetany and the importance of preserving the parathyroid glands during thyroid operations.
Parathyroid autotransplantation was done in the early nineteenth century and helped confirm the function of the parathyroid glands. In 1909 William Halsted reported that parathyroid transplantation was “successful in 61 % of the cases in which a deficiency greater than one half has been created” . Excision of the auto transplanted parathyroid gland in animals that had previously had all parathyroid glands removed resulted in tetany .
Hyperfunction of the Parathyroid Glands and Bone Disease
In 1891 during a festschrift lecture for Rudolf Virchow (1821–1902) Friedrich von Recklinghausen (1833–1910), a professor of pathology from Strasbourg, presented three patients with osteitis fibrosa cystica and bone tumors. One of these patients had a “reddish brown lymph node” below the thyroid . The lymph node was probably a parathyroid tumor. In 1904 Max Askanazy (1865–1940), a pathologist from Tubingen, documented that multiple abnormal parathyroid glands were present in patients with osteomalacia as well as in rats with rickets . He also identified a probable parathyroid tumor in a patient with osteitis deformans but did not confirm it histologically until 1930 . C.E. Benjamins and J.P.L. Hulst each identified a probable parathyroid tumor by gross and histological examination as did other surgeons prior to 1910 .
In 1906 Jacob Erdheim (1874–1937) from Vienna made the important observation that when he cauterized and destroyed the parathyroid glands in rats, they not only developed tetany , as reported by Gley, but also developed abnormal calcification of the teeth. He thought that both conditions were the result of hypoparathyroidism . These observations encouraged him to examine the parathyroid glands in patients who died with bone disease. In 1907 he reported the presence of hyperplasia of the parathyroid glands in patients with osteomalacia , and in 1911 he observed parathyroid hyperplasia in rachitic rats . At this time most experts who were interested in bone disorders thought that the parathyroid glands became enlarged to compensate for the bone disease. The finding of one abnormal parathyroid gland with other normal parathyroid glands rather than all parathyroid glands being abnormal conflicted with this hypothesis. In 1915 Freidrich Schlagenhaufer (1866–1930) from Vienna suggested that a parathyroid tumor is responsible for the bone disease rather than the reverse . He described two patients with severe bone disorders who had solitary parathyroid tumors and recommended parathyroidectomy . In 1925 his observations were supported by the studies of Hoffheinz, who reported that 85 % of 44 patients with von Recklinghausen’s bone disease had only one abnormal parathyroid gland. He concluded that primary hyperparathyroidism is more likely to be the cause of the bone disease rather than a consequence of the bone disease .
Parathyroid Surgery and Remarkable Patients
In 1910 Albert J. Ochsner and Ralph L. Thompson, in their textbook titled Thyroid and Parathyroid Glands reported that a number of solitary parathyroid tumors was observed by surgeons and pathologists . “Most of these growths have been of small size” . Weichselbaum from Stuttgart and others suggested that these be called adenomas “although a distinct boundary line between adenoma and hyperplasia cannot be sharply drawn” . Erdheim, MacCallum, Weichselbaum, Verebely, Goris, and others found parathyroid tumors in patients with osteitis fibrosa cystica, and most were solitary tumors .