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What Causes Tetany After Removal of the Parathyroid Glands? MacCallum, Voegtlin, and Calcium

Sawin, Clark T. MD

Feature: Historical Note

From the Office of the Medical Inspector, Veterans Health Administration, Washington, DC.

Address correspondence to: Clark T. Sawin, M.D., Office of the Medical Inspector (10MI), Veterans Health Administration, 810 Vermont Avenue NW, Washington, DC 20420.

In March 1908, a short paper, barely one page long (see this issue’s Classic) appeared in the monthly bulletin of the Johns Hopkins Hospital. In it, William G. MacCallum (1874–1944), then an associate Professor of Pathology at the Hopkins Medical School, and his chemical colleague, Carl Voegtlin (1879–1960), briefly described some of their findings in dogs that had had their parathyroid glands removed [1]. It had been known for more than a decade that this procedure would cause tetany, but no one knew exactly why. The MacCallum-Voegtlin team showed that the operated dogs not only got better, at least temporarily, if they were given injections of calcium salts, but that the dogs had a low level of calcium in the blood. This information is now so second nature to us 95 years later that it seems distinctly unremarkable. Although we tend to think of tetany and hypocalcemia following parathyroidectomy as obvious and that the issue must have been settled by this single set of experiments, at the time the conclusion was far from apparent to others, and the issue itself was controversial for the better part of the next two decades.

Who were these two investigators and why were they studying the parathyroid glands? MacCallum was Canadian and came to Hopkins from the University of Toronto where he was clearly a bright student. He was enamored of the classics and essentially majored in Greek, intending to make its study his life’s work when he graduated in 1894. His father, a general practitioner from Ontario, thought not and insisted that William take sufficient science courses to qualify for medical school [2]. So, William did. Then, when he heard that there was a new medical school in Baltimore that had just opened in 1893 and not only required a college degree but also a reading knowledge of French and German and the ability to translate Latin, he thought that would be just the place for him. And, because he had taken all those science courses, he thought he deserved advance standing. So he not only applied for admission to the Johns Hopkins Medical School but asked that he be admitted as a second-year student. A physician friend of his family who knew the famous professor of medicine at Hopkins, William Osler (1849– 1919), suggested that MacCallum write Osler to ask for the advanced placement. Osler turned him down. Undaunted, MacCallum then wrote to the dean, William H. Welch (1850–1934), who was also the professor of pathology, and asked the same question. MacCallum came to Hopkins as a second-year student that fall.

MacCallum graduated from medical school having just turned 23 years old at the top of his class of 15; all but one did a rotating internship at the Hopkins hospital (the other joined the faculty directly). It is said that MacCallum wanted to then go on to Osler’s service to do a residency in medicine. Once again, Osler turned him down (though a few years later after MacCallum had made a name for himself and become a professor, the two became close friends despite the age difference of 25 years). So MacCallum turned again to Welch who took him on as the only Assistant Resident in Pathology for the next 2 years (1898–1900). MacCallum’s career in pathology was set for life. After the 2 years were over, Welch appointed MacCallum Resident Pathologist, and MacCallum essentially ran the service. Technically, MacCallum’s hospital appointment remained Resident for the next 9 years; apparently, there were no other hospital appointments available. However, he progressed rapidly in the school’s academic hierarchy and became Associate Professor of Pathology in 1902. In large part because he developed an innovative course in pathological physiology, he was appointed to a newly founded professorship in that field in 1908. By this time the 34-year-old had become quite well known; the next year, 1909, he moved to New York to become professor in Columbia’s Department of Pathology and pathologist to the Presbyterian Hospital where he stayed for most of the next decade. His last academic move came in 1917 when he returned to Baltimore to replace his former chief, Welch, as Hopkins’ Professor of Pathology.

Voegtlin was not a physician like MacCallum but rather came to Hopkins as a Ph.D. in 1906. He was originally recruited to the Department of Medicine by Lewellys Barker who had replaced Osler as Professor of Medicine in 1905. Barker thought that a Department of Medicine ought to be actively involved in research so he set up three, albeit modest, laboratories within the department. One was physiological, one was biological (which turned out to be largely infectious disease and immunology), and the third was chemical. Voegtlin, who was Swiss and came to Hopkins via Freiburg; Manchester, England; and Madison, Wisconsin, was appointed as director of the chemical laboratory. He stayed only 2 years in that position as he moved to the Department of Pharmacology in 1908; 5 years later he left academia to join the U.S. Government’s Hygienic Laboratory, the precursor of the NIH, as pharmacologist. Eventually, he was appointed to head the National Cancer Institute in 1938.

MacCallum’s interest in the parathyroid glands probably began about 1902 as he worked with William S. Halsted (1852–1922), Hopkins’ Professor of Surgery, on the pathology of the thyroid and parathyroid glands. Halsted was continuing to perfect his surgical approach to the thyroid and wanted to better his approach to saving the parathyroids, so easily damaged during that surgery. His goal was the avoidance of postoperative tetany, which was known to be related to damage to, or removal of, the parathyroids. Halsted knew about the fragile blood supply to these tiny glands; he and Herbert McLean Evans (1882– 1971), then a medical student and later to become one of America’s best-known endocrinologists, a few years later in 1907 carefully defined the parathyroids’ vascular anatomy [3]. Careful surgery preserved these vessels and averted most parathyroid damage. But what was not known was why, if the parathyroids were damaged, tetany occurred.

What was known then was that thyroid hormone stimulated certain tissues of the body as did the only other defined hormone at the time, epinephrine. Perhaps, then, the parathyroids secreted something that directly suppressed certain tissues and prevented muscle twitching and tetany. Another prevalent theory about hormones then was that they had an antitoxin effect, ie, they destroyed various toxins (otherwise unspecified) or prevented them from acting. So some thought that tetany was caused by a hypothetical tetany toxin; the thinking was that the parathyroids either metabolized the toxin or prevented it from acting and so their absence allowed tetany to occur. MacCallum, and many others, had, by the first decade of the 20th century, tried parathyroid extracts to treat postoperative tetany; sometimes with apparent success and sometimes not. In 1906, for example, Halsted had a patient who developed tetany; he desperately needed help and so called on MacCallum. MacCallum gave Halsted his entire supply of bovine parathyroids to give (by mouth) to this patient; she seemed to do well. They gave other patients parathyroid emulsions subcutaneously, also with apparent benefit. MacCallum had no evidence, however, as to whether the parathyroids made a hormone or detoxified a toxin although he was unable to confirm Russian work that suggested there was a toxin against both the thyroid and parathyroid glands.

It is really not at all clear why MacCallum then turned to investigate the role of calcium in the tetanic phenomenon. There was no precedent for an intermediary between a hormone and responding tissues. The best estimate is that there were several influences. Jacques Loeb (1859–1924), the polymath and founder of general biology, had shown various effects of different salt solutions on muscle twitching and the suppression of the twitching by calcium or analogous ions such as magnesium. MacCallum’s own younger brother, also a Hopkins medical graduate (1900) who died of tuberculosis in 1906, had also gotten similar findings. Further, animals without parathyroids sometimes did not get tetany if the diet contained a good deal of milk, an obvious source of calcium. Perhaps these thoughts played in MacCallum’s mind and he decided to act because, if it worked, calcium would be a simpler therapy than parathyroid emulsions.

In any case, whatever the precise reason, MacCallum, the pathophysiologist, and Voegtlin, the laboratory chemist, got together and gave several salt solutions to parathyroidectomized dogs to see what happened. Their own words tell the story: “all violent symptoms produced by parathyroidectomy, muscle twitching, and rigidity...etc., may be almost instantly cured by the injection of a solution of a calcium salt” [1]. They went on in their complete paper, published the next year, to show that this result was consistent and that parathyroidectomy caused a clear-cut fall in the serum calcium [4]. One would have thought that these data would have settled the issue and that they were immediately received as a major advance in endocrinology. They were not.

MacCallum himself advocated the idea that the parathyroid glands prevented tetany by mobilizing calcium, as we do now, but he was still willing to consider the idea of a toxin. Further, he himself had shown that the effect was not specific to calcium; magnesium also worked but had more side effects. Others, unable to confirm MacCallum’s work, chose to regard the calcium effect on blunting tetany as a simple pharmacologic effect, a sedative of sorts. Others also had trouble showing that there was a low level of serum calcium after parathyroidectomy; the measurement of serum calcium was not simple. For example, Voegtlin’s method seems to have required about 50 ml of blood for each assay (methods that needed only about 2 ml were not available until the 1920s). And MacCallum did not find a rise in serum calcium in dogs given his crude parathyroid extract. Still, for a few years after 1908, the idea that tetany was caused by a low serum calcium was seen by many as reasonable.

During the 1910s, however, the toxin idea took hold again, in large part because a definite substance, guanidine or methylguanidine, was thought to be the specific tetany toxin [5]. Chemists claimed that one or the other of these substances were raised in dogs without parathyroids, at least in the urine, and that parathyroid deficiency was the cause of both the rise in guanidine and tetany. The toxin theory held sway for most of the 1910s. MacCallum was at Columbia for most of this time and seems to have stopped most of his experimental work. There was no consensus on the cause of tetany.

During the 1920s, the pendulum swung back to the idea that hypocalcemia caused the tetany after removal of the parathyroids. There was no clear and clean refutation of the guanidine-toxin theory although by 1924 measurements of guanidine had improved and none was found in animals without parathyroids. By the mid-1920s, an effective parathyroid extract had been developed; this focussed attention back to the gland rather than to a toxin. The idea of toxins was itself fading as a viable explanation for any endocrine change. And endocrinology itself was changing; hormones rather than toxins were the things of interest. MacCallum and Voegtlin’s original papers in 1908– 1909 were not, as some said, the “proof that the parathyroids control calcium metabolism”—that took another 15 years or so—but they did direct the still nascent field of internal secretions toward an alternative and indirect explanation of a hormonal effect. That it took so long again points to the fact that ideas rarely capture the minds of all in a moment but rather have to compete with older ideas and win acceptance over time.

After going to New York in 1909, MacCallum turned his efforts to teaching and the writing of a new textbook of pathology. First published in 1916, the book rapidly became the standard student text in pathology [6]. It established new ground by focussing on disease processes rather than on organ systems and, although it became somewhat dated after 2 decades or so, remained a standard text until MacCallum’s death in 1944. No doubt the book reflected his qualities as an excellent teacher in that he left much for his students to find out for themselves; he was also an enthusiast in responding to good questions. Nevertheless, MacCallum gave an aloof, even brusque, appearance, likely because of an innately shy nature (“I was never a good mixer...I scarcely got to know my classmates at Toronto”), and was not known for his administrative ability or for developing the junior persons in his department. Despite the fact that the Hopkins Medical School opened only because of the generosity of several wealthy women, MacCallum “had no great use for women in medicine” or perhaps in other areas of life (he never did marry).

While MacCallum did little in endocrinology after his parathyroid work, that work of almost 100 years ago was a signal contribution to hormonal understanding and, once accepted and understood, broadened the view at the time of how hormones acted. MacCallum’s overall work in pathology was also highly regarded; he was one of relatively few physicians elected to the National Academy of Sciences (1921). He lived a full life at Hopkins though his last years were difficult. After suffering a debilitating stroke that paralyzed his right side and left him unable to speak, he died, bedridden in February, 1944 at 69 years of age.

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REFERENCES

1. MacCallum WG, Voegtlin C. On the relation of the parathyroid to calcium metabolism and the nature of tetany. Bull Johns Hopkins Hosp 1908; 19: 91.
2. Longcope WT. William George MacCallum (1874–1944).
3. Halsted WS, Evans HM. The parathyroid glandules. Their blood supply, and their preservation in operation upon the thyroid gland. Ann Surg 1907; 46:489.
4. MacCallum WG, Voegtlin C. On the relation of tetany to the parathyroid glands and to calcium metabolism. J Exper Med 1909; 11:118.
5. Dolev E. A gland in search of a function: The parathyroid glands and the explanations of tetany 1903–1926. J Hist Med Allied Sci 1987; 42:186.
6. MacCallum WG. A Text-book of Pathology. Philadelphia, PA: W. B. Saunders; 1916.
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OTHER SOURCES

Harvey AM. Adventures in Medical Research. A Century of Discovery at Johns Hopkins. Baltimore, Johns Hopkins University Press, 1976.
Harvey AM, Brieger GH, Abrams SL, et al. A Model of Its Kind. Vol. I. A Centennial History of Medicine at Johns Hopkins. Baltimore, John Hopkins University Press, 1989.
Munson PL. Parathyroid hormone and calcitonin. In: McCann, SM, ed. Endocrinology. People and Ideas. Bethesda, American Physiological Society, 1988, p. 239.
Simpson S. Physiology, physiological chemistry and experimental pathology and the parathyroid glands. In: Barker LF, et al. Endocrinology and Metabolism. New York, D. Appleton and Co., 1922. Vol. 1, p. 509.
© 2003 Lippincott Williams & Wilkins, Inc.