Ha~F'i-' Apdo 69

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Volume 708 Number 6

Ha'-'~ f'I-'" Al D~. '" t: C ~)! 'C' E <:-

"-\,,1 ..., 8/BL!OTECA Colin G. Thomas,jr, MD, Chapel Híll, N.C 48 Apdo . 69 ¡ "_080 -BILBAO F h D .I S U "" .I N h C l " S h 1 V,zc;a Es ~ rom t e epartment o) urgery, nzverslty o) ort aro zna c 00 o pana University 01 North Carolina Hospitals, Chapel Hill, N.C.

IT IS A DISTINCT AND CHERISHEDHONOR to be the ~pularity, much to the detriment of OUTmedical her- president of the American Association of Endocrine itage. Surgeons and to address you in this capacity. Previous Hyperfunction of the glands of Owen can be epito- addresses have covered a myriad of subjects and have mized by the presentation of some early patients who been witness to the erudition and catholicity of interests provide a perspective on diagnosis, natural history, and of our membership. management. Emphasis on patients seemsappropriate This presentation will relate to the glands of Owen, since the patients rarely receive credit for their Tole in their discovery, their physiologic significance, and the OUTundérstanding of normal and abnormal physiology. consequences of their hyperfunction. Parathyroid has Although this mar not be new information, 1 would re- always seemed an unimaginative and vapid term Cofa mind you of a quote from George Santayana 1, "That gland the function of which is so critical to our well-be- which is not too well understood is not too oft rt:peated." ing. Most endocrine glands were named for their con- DISCOVERY OF THE PARATHYROm figuration (pineal, thymus, thyroid), function (ovary, GLANDS pituitary, testes), or composition (pancreas). Only the adrenal, distinguished by its relation to the kidney, was The glands of Owen can be traced to a few courageous named because of its fortuitous location. For these amphibians that, some 100 million years ago, had suf- glands to be named after their discoverer has a more ro- ficient hubris to crawl ashore. At that time endocrine mantic implication and is as explicit as to function as the control of their calcium and .phosphate metabolism, term parathyroid. Unfortunately, eponyms have lost requisite for their bony skeletons, was maintained through steroids, vitamin D metabolites, and the peptide Presented at the Eleventh Annual Meeting of the American hormone calcitonin. A more terrestrial environment Association of Endocrine Surgeons, Cleveland, Ohio, April constituted a stimulus for the production of a hormone 22-24, 1990. adequate for maintenance of calcium and phosphate ion Reprint requests: Colin G. Thomas, Jr, MD, Department homeostasis.These glands were essentially the last to of Surgery, Universit) of North Carolina, 136 Burnetl- appear in the evolution of the vertebrate endocrine Womack Building, Campus Box 7210, Chapel Hill, NC 27514. system.la Despite their essentiality in mili ion s of speciesfor the 11/6/23350

SURGERY 939

.--:;7~ 940 Thomas Surgery December 1990

Fig. 2. Ivar Sandstrom(1852-1889). (From SeipelCM. Bull Fig. 1. Sir Richard Owen, KCB, FRS (1804-1892).(From Inst Hist Med 1938;6:179-222.) Cave AJE. Richard Owen and the discoveryof the parathy- raid glands.London: Oxford University Press,1953:217-22.) oats,rice, carrots artd bread in Brobdignagianquantities daily ever since,and might havegane on digesting,had he not by someclumsy fall or otherwiseinexplicable process,cracked a maintenance of the bony skeleton, the responsible endo- rib; said fracture injuring the adjacentlung and causingbis crine glands were not discovered until 140 years ago. demise.His anatomywill furnish forth an irnmortal Mono- "On the 24th of May, 1834, fue Zoological Society of graph,and so comfortcomes to me in a shapein which it can- London acquired it's first specimen of the Great Indian not be had by any of my brother Fellows."3 Rhinoceros (Rhinoceros unicornis)." This animal, a male, arrived at fue Society's menagerie on September The deteriorating clinical course of fue rhinoceros 20, 1834; it reached an age of about 20 years on was succinctly recorded in fue Head-keepers Minute November 19, 1849. It was "anatomized" by Sir Rich- Book4: ard Owen, Hunterian Professor and Conservator of fue "1849, November12th Rhinocerosvomited slimy mucus. Museum in fue Royal College of Surgeons of England 14th ditto ditto with blood (1827-1856) (Fig. 1). Owen welcomed fue opportunity 15th ditto ditto ditto to dissect fue anatomy of this rare species, wbich is ev- 16th ditto ditto ditto, & from the nostril ident in fue following excerpt from a letter to one of bis 17th ditto ditto ditto ditto sisters2: 18th ditto ditto ditto ditto 19th ditto ditto ditto ditto" " Amongst other matters time-devouring, and putting out of Today, this would not be an acceptable record of a memory mundane relatives, sisters included, has been the de- ceaseof my ponderous and respectable old friend and client the patient's illness or attending involvement. rhinoceros. 1 call him 'client' because fifteen years ago 1 pa- The protracted and laborious dissection was carried tronized him, and took it upon my skill, in discerning through out at the Conservator's resident quarters of the Royal a pretty thick birle the infernal constitution, to ayer that the College of Surgeons. Owen's wife recorded in her diary beast would live to be a credit to the Zoological Gardens, and that "as a natural consequence" of this animal's death that he was worth the 1,000 guineas demanded for him. The there is a quantity of fue rhinoceros-approximately 2 Council had faith and bought him, and he has eaten their hay, tons-on fue premises. Owen performed fue dissection Volume 108 Presidential address 941 Number 6

during the winter months of 1849 to 1850 and indicated He emphasized the difference in these glands from that the rhinoceros had passed into an "offensive state accessory thyroid glands and suggested fue name glan- of decomposition." On Feb. 12, 1850, Owen presented dulae parathyroideae, which expressed the characteris- the resulting monograph to a meeting of the Zoological tic of being bye-glands to the thyroid. Sandstrom Society.4 emphasized that although "an accessory thyroid gland Owen's astutenessas an anatomist was evident from is found in only one of ten cases, every individual has his discovery of "a small compact yellow glandular body several glands of this kind."s Sandstrom's excitement attached to the thyroid at the point where the vein and reward must have been comparable to that of the emerged." He had no prior knowledge of the presence surgeon who, after much searching, identifies an elusive of this small organ, which was in diameter and circum- parathyroid adenoma. ference no greater than a sixpenny piece. Owen's pub~ Sandstrom did not postulate any particular function lication in March 1852, "On the Anatomy of the Indian but did speculate on clinical relevance. Rhinoceros,"4 is recognized as the classic paper on the "For the purpose of diagnosing a tumor of the parathyroid subject. gland, 1 want to point out the proximity of the glands to the Ivar Sandstrom celebrated his first birthday in March esophagus and the recurrent nerve, whereby in cases of a 1853. He matriculated at the University of Upsala in pathological growth process there mar easily occur a com- 1871, received his preclinical degree in 1878, and was pression of the former and a paralysis of the latter."6 appointed as "prosektor" in anatomy during 1879 to 1880 (Fig. 2). He obtained rus diploma as a physician Sandstrom's cornments in a letter to his family on the in 1887. Hispublication, "OnaNew GlandinManand presentation of his findings to a meeting of the presti- Several Marnmals-Glandulae Parathyroideae,"S was gious natural scientists at Stockholm are prescient today. published in the Upsala Liikarefórenings Fórhand- "Everyone seemedto be there with the intention of showing linger, 1880. This discovery was made in 1877 while what 'discoveries' he had made, and at the same time give the Sandstrom was sti" a medical student. astonished world the opportunity to have a look at the fortu- "About threeyears ago (1877),1 found onthe thyroid gland nate discoverer. 1 cannot help the sad and discouraging of a dog a small organ, hardly as big as a hemp seed,which impression that most of OUTscientists are more apt to work for was enclosedin the sameconnective tissue capsule as a thy- their own reputation than for the sake of science itself, and that roid, but could bedistinguished therefrom by a lighter color. the latter is regarded as a kind of modero album, wherein a A superficial examinationrevealed an organ of totally differ- lot of gentlemen compete to get their llames written. But for ent structure from that of the thyroid, and with a very rich the discovery itself, for the revealed truth the interesl was lit- vascularity evenin the cal and the rabbit similar glands tle or none."6 were found. However,time and material did not allow me to In searching the literature at that time, Sandstrom continue the investigationsand it was not until this winter also cites two authors, namely, Remak (1855) and Ru- (1880) that 1 have been able to take the problem up again. ...Although the probability of finding something dolph Virchow (1863), who mar had identified these hitherto unrecognizedseemed so small that it was exclusively glands earlier.6 Unfortunately, Sandstrom's academic with the purposeof completingthe investigations,rather than career was terminated by his suicide in 1889! with the hopeof finding somethingnew, that 1 begana care- The glandulae parathyroideae at this time were ba- fui examinationof this region. So much the greaterwas my sically structures in search of a function. A clue to their astonishment;therefore when, in the first individual exam- function was the development of tetany after thyroidec- ined,1 found on both sidesat the inferior border of the thy- tomy. Tetany was looked on as an acute form of roid gland an organ of the sizeof a small pea,which, judging "cachexia struma priva" or hypothyroidism.8 Gley9 from its exterior, did not appearto bea lymph gland, nor an demonstrated that removal of the parathyroid glands accessorythyroid gland, and upon histologic exarnination rather than the thyroid was the cause of death in the showeda rather peculiar structure."6 experimental animal after thyroidectomy. However, he Sandstrom's description was so complete that little still thought of the par~thyroid glands as residual em- was to be added for several decades.He emphasized the bryonic thyroid. Vassale and Generalil0 were first to frequency with which the gland was embedded in fat clearly document that thyroidectomy leads to myxedema and might be overlooked unless the transparency of the and parathyroidectomy to tetany. They also confirmed fat lobule was examined against a strong light-analo- that parathyroid tissue left in situ in the rabbit did not gous to ultrasound evaluation of today. He thought the mature into normal thyroid. glands should be looked on as embryonic thyroid glands A major advance was the establishment of the concept that had been arrested at an early stage of development. that tetany was caused by hypocalcemia and was not due 942 Thomas Surgery December 1990

girl described by Davies-Colley in 1884 with typical changes in her mandible and long bones in association with multiple renal calculi. Osteitis fib:-osa cystica. The predominant manifes- tation of primary hyperparathyroidism was described by Friederick Daniel van RecklinghausenlS (1833- 1910). In 1891 he described the case ofHerr Bleich, the seventh of 16 casesin a festschrift (volume of writings by different authors presented as a tribute) in honor of the seventy-first birthday of Rudolph Virchow. Herr Bleich illustrated all the findings now included in the term osteitisfibrosa cystica oi von Recklinghausen. Von Recklinghausen, in describing this patient, used the termfibrosa osteitis,multiple osteosarkome.The clinical picture was described by AIbright.16 "Herr Bleich wasa 40 yearold married maganwho had un- dergonea mercurycure for syphilis. In April, 1888,he fell from a three meter high ladder and eight days later he was hospitalizedbecause of severepain in his hipo It was clear whethera fracture of the neck of the femur or a coxitis was presentoHe was treated with extensionuntil August when improvementwas so far advancedthat he beganto walk with a stick. In Octoberthe patientslipped, fell againsta bench,and fracturedhis clavicle.He wasreadmitted to the SurgicalClinic where he underwenta transversefracture of the diaphysisof the right femur while lying in [;Iedbecause the bedpanwas clumsily maneuvered.Continued pain and unsatisfactory Fig. 3. Felix Mandl (1892-1975).(From OrganCH. Surgi- union mde it necessaryto transfer him to a non-clinical divi- cal Rounds 1985;3:69-70.) sionof the City Hospital. In the courseof the summerof 1889, he not only showedthe rpostextensive bending of severallong bones,but complainedof excruciatingpain in many bonesand to a toxin that accumulated after parathyroidectomyo t t Hanson t2 developed extracts of the parathyroid, which appeared very emaciated.Although the fracture seemedto heal, the patient was unable to raise the leg, marasmus he believed enhaI)ced the action of insulino Collipt3 increasedand he died on October 4, 1889. Van Reckling- demonstrated that such extracts consistently or uni- hausenmade a detaileddescription of Herr Bleich's skeleton, forrnly prevented or relieved tetany in the experimental and emphasizedthree of the chief pathologicalcharacteristics animal and that the probable manner of action of the of the bone diseasewhich so often accompanieshyperpar- horrnone was through a direct effect on calcium metab- athyroidism:widespread fibrosis, cysts, and brown (or giant- olismo cell) tumors."

EARL y CLINICAL OBSERVATIONS jung,17 in 1933, reviewed the original autopsy repon at the Pathological Institute of Strassburg and noted the The association between bone disease and parathy- following statement: "Above the left thyroid gland, a raid enlargement was again one of observation and lymph gland, red-brown in color is present." Even to- speculation, and this association was finally determined dar some of our most astute surgeons have difficulty in by studies in the patient. The earliest clinical reports on differentiating a lymph gland from a parathyroid gland. hyperparathyroidism have been culled from the litera- It was evident that van Recklinghausen had failed to ture by Selwyn Taylor14 who cited (1) "the boney make a relation betweenthe small tumor in the neck and changes of osteitis fibrosa" in a prehistoric North fue advanced boDe disease of bis patient. American lndian; (2) a 42-year-old man who had halles In 1904 Askanazy18described a patient with osteitis that softened like leather and who was a patient of the fibrosa cystica and commented on the presence of a par- French surgeon Courtial (1705); (3) Bevan's report in athyroid tumor. He was fue first to make the association 1743 of a 40-year-old woman with severe hypotonia, between the two entities. However, because of the stat- polyuria, and pliable soft halles who at autopsy had soft ure and the highly respected opinions of Professor ja- halles consisting of a fibrous shell; and (4) a 13-year-old cob Erdheim,19 an eminent Viennese pathologist (1906), V(úumc 108 Presidential address 943 Number 6

~ Fig. 4. ElvaDawkins. (From Barr DP, Bulger HA. Aro J Med Sci 1930;179:449-76.)

the enlarged parathyroid gland found in this type of bone disease was generally regarded as a secondary Fig. 5. IsaacY. Olch (1897-1987). phenomenon. The relation between calcium metabolism, bone disease, and the parathyroid glands was a career interest of Erdheim. From bis studies on rats and 25 X 15 X 12 mrn was removed from the left inferior observations in man, he concluded that the enlargement area behind the thyroid gland. Within a few days the of the parathyroid glands in bone disease was a patient's condition improved, the calciurn content of the compensatory phenomenon. urine and blood was considerably lower, and he felt A few skeptics, however, including Schlagenhaufer2° better. At 4 months the boneswere seenby roentgenog- (1915), pointed out that in von Recklinghausen's disease raphy to be more dense;the bone pain had subsided,and of boDe the parathyroid enlargement involved only one for the first time in years he was able to sit up in bed and gland,which would be difficult to explain if the hyper- walk with the aid of crutches. trophy were secondary or compensatory. However, an- Mandl's observations was presented to the Medical other decadepassed before Schlagenhaufer's recornmen- Society in Vienna, Dec. 4, 1925. Present were Profes- dation that the parathyroid "tumor" be removed was sor Eiselsberg, a student of endocrine glands, and a implemented. number of well-known Viennese surgeons and physi- Felix Mandl!1 a Viennese surgeon, established the cians. Apparently they expressed little reaction to this etiologic relationship between a parathyroid tumor and remarkable achievement.22 von Recklinghausen's osteitis fibrosa cystica {Fig. 3). At After 6 years of improvement, Jahne's condition 34 years of age, Albert J ahne, a streetcar conductor, ex- worsened. By September 1932, he once more had a re- perienced initial symptoms of pain and a senseof tired- nal calculus, hypercalcemia, hypophosphaternia, and ness in bis legs. Within 4 years the diagnosis of von bis bones became decalcified. The patient was incapac- Recklinghausen's disease was established, culminating itated and underwent surgery again on Oct. 18, 1933; in pathologic fractures of bis lego Jahne had received no tumor was found in the entire neck region or in the parathyroid extract from animal s without benefit and mediastinum. A large portion of the thyroid gland was failed to improve after transplantation of four parathy- removed, which by microscopy included two parathyroid glands from a moribund patient. On July 30, 1925, roid glands. The patient showed no improvement and under local anesthesia,a parathyroid tumor measuring died in February 1936. Autopsy did not reveal parathy- 944 Thomas S'urge/}' Decembcr 7990

Table l. Patients with primary hyperparathyroidismtreated by parathyroidectomy,1925 to 1930

Beck24 Beck 1927 41jfemale 2 "adenoma," sÍze of Tetany almond, coffee bean Gold25 Gold 1927 56jfemale 13.1 -- Barr et al.26 Olch 8/1/28 56jfemale Adenoma, 3 cm, "walnut Severe tetany sÍzed"

Wilder28 Rankin 12/17/28 35/female 12.8 Carcinoma, 5 X 3.5 X 3 Paresthesias cm

Snapper29.30 Lanz 2/28/29 56/male 19-23 Adenoma, 2.4 X 1.4 cm Disoriented,impending tetany

Boyd et al.3! Peterson 4/12/29 19jmale 17.6 3.5 X 2.5 cm Paresthesias,mild 1etany (serum calcium, 5 mgjdl)

Barr and BuIger27 Btown 6/18/29 38/male 13.3-16.7 2.5 cm palpable mass Paresthesias

Compere32 Phemister 6/24/29 59jfemale 1 x 1.5cm Paresthesias

Hunter33 WaltOfi 11/29/29 44/female 12-16.7 3 x 3 x 3.7 cm Paresthesias

roid tissue or a parathyroid tumor anywhere in the ural history of hyperparathyroidism as inftuenced by body.23 surgical treatment. Although the immediate results of Mandl's observations were significant since they parathyroidectomy were drama tic, serious problems of clearly demonstrated that, in bis patient, the boDe dis- tetany, renal failure, and recurrent disease remained. ease, von Recklinghausen's osteitis fibrosa cystica, was Including Mandl's patients, 10 well-documented re- secondaryto a small tumor of the parathyroid. The pa- ports are cited chronologicaIly (Table 1). tient had a remarkable recovery, but after 6 years bis In 1927 Beck24removed two parathyroid tumors (one disease recurred. was the size of an almond, and the other was the size of a coffee bean) from a 41-year-old woman. Three years INITIAL RESUL1'8 OF SURGICAL TREA TMENT earlier she had undergone amputation of her right leg for a sarcoma. Her elevated serum caIcium level re- A review of the initial patients who were successfully turned to normal by postoperative dar 3. Tetany operated on between 1925 and 1930 for von Reckling- followed on postoperative dar 5; the patient died of tet- hausen's diseaseprovides a striking picture of the nat- any on postoperative dar 21. In the Sameyear, Gold25

I VO/lIme 108 Presidential address 945 ,"Jum be/" 6

t readmitted 1 year later because of a fracture of the left humerus, a tumor of the mandible, and a benign giant cell sarcoma of the left ulna (Fig. 4). Elva Dawkins' Medication Follo~-up course is summarized in a letter from her surgeon, Dr. l. Y. Olch (Fig. 5) to Dr. Walter Ballinger (1972). improvement, recurrente at 8 yr, 2 normal .."1 remember her vividly because of the way the diagnosis was parathyroids removed at 9 yr without improvement; death made and the postoperative course, which was very stormy. at 11 years-no tumor at ...we were struck by the marked hypotonia of most of the voluntary muscle and the formation of the tumors and autopsyDied -fractures in tetany 21 days that followed rather minor trauma. On her second admission the hypotonia and the calcium depletion of her postoperativelyMarked -bones improvement at 6 mo had increased greatly and these along with kidney stones Calcium lactate, had made her a good subject for ward rounds, conferences and Improved, died of renal parathormone, clinics. This was where Henry Dixon first saw her. He was insufficiency 14 mo intravenous calcium a senior student who was doing some extra work with Ran- postoperatively chloride som, Professor of Neurology at Northwestern. They had been -Relief of bone pain, increased working with frog muscle nerve preparations studying the bone density, disappearance cha~ges in tonicity as affected by the relative concentration of I of maxillary tumor at 18 mo; ~clum ve~us phosphorus in suspending solutions. With no recurrence at f2 yr hl~her calclum concentration, the muscle tone decreased. Calcium lactate, At 10 years, "walks, with one Dlxon wondered whether this had any relation to Mrs. At 10 years, "walks, with one . parathyroid extract, stick, able to lead a nonnalnormal Dawkins and so the next moming he drew blood and found . intravenous calcium life" her serum calcium was nearly 17 mg%. He called this to liCe" compound Bulger's attenúon and we had the patient transferred to his -Improved; progressive bone ~etabolism war~. Detai!ed calcium studies indicated she was repair at 3 mo, recurrence at In mar.ked negatlve calclum balance. The association of par- 3 yr, reoperation at 14 yr athyrold tumors and calcium dysfunction had been known for with improvement; death many years, but the previous cases had been found at post from renal failure at 17 yr mortero an~ the first ~eck that was expl.ored for a parathyroid Tumor transplanted Well at 7 yr; transplanted tumor was In 1926 (SIC)by Mandl. 1 dld not know about this to rectus abdominis tumor not palpable case at the time 1 did Elva Dawkins. We were able to make Calcium lactate Calcium 12.6 mg/dl and OUTdiagnosis preoperatively on the basis of the laboratory phosphorus 5.7 mg 9 mo work. That pointed up the difference in European and Amer- postoperatively ican medicine of that time. They prided themselves on their -Good recovery with clinical observaúons and intuition and derided OUTreliance on improvement in all laboratory procedures. Elva Dawkins was notable in the way symptoms, 10 days diagnosis was made and she enabled Bulger and Dixon to carry out extensive metabolic studies both before and after surgery. She went to surgery on August 1, 1928 and a tumor about 3 cm. in diameter was found behind the lower pole of ~ : the right thyroid lobe. Her hypercalcemia immediately began to drop and the next moming she began to show signs of se- "~ I vere tetany. It was necessaryto give her large doses of calcium .t chloride intravenously to control the tetany (Fig. 6). She had .to be maintained on calcium lactate as long as she lived and eventually died of renal insufficiency.".

Barr, Bulger, and Dixon26 published a report of Elva Dawkins in the Joumal of the American Medical Asso- ciation on March 23, 1929, "Hyperparathyroidism," after having presented fue paper before the Central 80-

.She died 14 rnonths after surgery [written cornrnunication,P. M Weeks,MD, 1990].

I~Immediate 946 Thomas Surgery December7990

8va Dawkins, August 1 -23,1928 Fig. 6. Courseof Elva Dawkins. (From Barr DP, Bulger HA. Am J Med Sci 1930;179:449-76.)

ciety for Clinical Research,Nov. 23, 1928. The follow- Providence, R.I., in 1897. After attending Brown Uni- ing year they cited fue current thinking regarding the versity and Johns Hopkins School of Medicine, he re- association of osteomalacia,parathyroid tumors or par- ceived bis MD in 1921 and interned on the surgical athyroid hyperplasia, high serum calcium level, and the service at Johns Hopkins School of Medicine, spending physiologic changes that occurred when an excess of considerable time with Joseph Bloodgood in surgical parathyroid secretion was presentoThe concept of hy- pathology. He moved to Washington University School perparathyroidism was introduced and is an excellent of Medicine and worked with Dr. E.L. Opie in pathol- example of inductive reasoning. The clinical features of ogy before starting bis residency with Dr. Evarts Gra- this new entity were defined as follows: (1) rarefaction hamoHejoined the facuhy as an assistant professor and of bone; (2) fue occurrence of multiple cystic bone was very active in surgical pathology. tumors, several of which, on pathologic exarnination, Wilder's28 patient was a 35-year-old woman with have been found to be giant cell sarcoma; (3) muscular generalized osteitis fibrosa and giant cell tumors of the weakness and hypotonia; (4) abnormal excretion of caI- maxilla and femur. She underwent excision of a tumor cium in the urine and fue formation of calcium stones; measuring 5 X 3.5 X 3 cm; subsequent diagnosis was and (5) abnormally high serurn calcium. parathyroid carcinoma (Dec. 1, 1928). Four months af- "AlI of these changesare secondary to, or associated ter surgery she had improved greatly and gave up use with, a parathyroid hyperplasia or parathyroid of crutches. Her serum calcium level was 8.3 mgjdl, and tumor.,,27 They algo cited a personal cornmunication roentgenography showed increased density of bones. with Dr. E.F. DuBois and Dr. j.C. Aub who had Mter 12 years no diseasehad recurred, which makes the studied a similar case(Captain Charles Martell) 2 years diagnosis of carcinoma "suspect" (written communica- earlier and who had removed from the patient two nor- tion, J. van Heerden, MD, 1990). mal parathyroid glands,which resulted in considerable Snapper29reported a 56-year-old man with a 7 -year clinical improvement. history of legpain, pathologic fractures, and a diagnosis The resolution of Elva Dawkins' problem is an ex- of osteomalacia. His serum calcium level ranged from 19 ample of the contribution of a thoughtful medical stu- to 22 mgjdl. ProfeSsor Lanz removed this patient's dent. Fortuitously, a patient with such severehypotonia 24 X 14mm adenoma, on Feb. 28, 1929. The serum was seenby a medical studentwho was studying the ef- calcium level fell to 8.5 mgjdl on dar 5 and to 7.2 mgj fect of calcium concentrationson muscle tone. He asked dI on dar 12. The patient was confused and disoriented fue right question: Could fue calcium level be a factor and was treated with calcium lactate (4 gm daily), par- in Mrs. Dawkins' hypotonia? athyroid extract (Collip), and an intravenous calcium Isaac Y. Olch (1897-1987), fue first surgeon in this compound. After 4 weeks the serum calcium level was country to remove a parathyroid adenoma, was born in 9.4 mgjdl. Snapper's description articulates dramatic J'o/ume 708 Presidential address 947 Number 6

~.:~ .: Fig. 8. Patient of Dr. E.L Compere. (From CompereEL. Surg GynecolObstet 1.930;50:783-94.)

Fig. 7. Marvin Freshla. (From Boyd JD, Milgram JE, StearnsG. JAMA 1929;93:684-8.) Barr and Bulger27 also :reported a 38-year-old man with a serum calcium level of 13 to 16 mg/ di and with improvement after parathyroidectomy. "The patient a giant cell tumor of the mandible who underwent re- remained a small bent man with crooked legs, but the moval by Dr. J. Barrett Brown Uune 12,1929) ora 2.5 unfortunate man chained to bis bed in agony had been cm palpable adenoma. At Olch's suggestion, 1 cc of tu- changed into a cheerful man who had no more pain mor was transplanted into the rectus abdominis muscle. and who recorded with delight bis daily improvement The patient was well at 7 years. The transplanted tu- in walking."29 Roentgenography show that he also had mor was not palpable (written cornmunication, P.M. an extraordinary degree of arterial sclerosis. Ten years Weeks, MD, 1990). later he walked with one stick and lead a normal Dr. D.B. PhemisterUune 24,1929) exciseda 1 X 1.5 life.30 cm tumor from a 59-year-old woman who had severe Boyd et al.31 cited a 19-year-old man with progres- skeletal deformity (Fig. 8). The postoperative serum sive bowing of bis extremities (Fig. 7) and a serum cal- calcium level of 6.9 mg/dl was accompanied by pares- ciuro level of 17.6 mgjdlA parathyroid tumor measur- thesias,and fue patient was treated with calcium lactate, ing 35 X 25 rnm was removed by Frank Peterson of the 2 gm three times daily.32 Nine months later the serum University of Iowa (ApriI12, 1929). The postoperative calcium level was 12.5 mg/dl and the phosphorus level, serum calcium level was 5.0 mgjdl, and there was "mild 5.7 mg/dl. tetany." Recurrent hypercalcemia was present at 3 The last of these 10 patients was reported by years; reoperation was performed at 14 years (serum Hunter .33 Dr. A.J. Walton removed a 30 X 30 X 37 calcium level of 15.9 mgjdl and serum phosphorus level rnm tumor in a 44-year-old woman in November 1929. of 3.8 mgjdl) and additional parathyroid tissue was re- The preoperative serum calcium level ranged between moved. Seventeenyears later the patient was dying of 12 to 16 mg/dl. Paresthesias were noted after surgery. renal failure causedby bilateral nephrocalcinosis (writ- The patient was much improved at postoperative day ten cornmunication, E.E. Mason, MD, 1990). 10, and the bone pains were gane.

~ 948 Thomas Surgery December7990

teoporosis (osteopenia), giant cell tumors (osteoclasto- mas), bony deformity, pathologic fractures, nonunion, and loss of height. The muscle weakness,extreme flex- ibility of joints, severebone pain, and deformity resulted in complete disability. Renal calculi, which was com- monly an associated finding, was not a common initial complaint. However, complications of renal insufficiency and urinary tract infection were probably the cause of late deaths in these initial patients. Follow-up in general was strikingly brief; hypercalcemia recurred in three of these 10 patients. Postoperatively, tetany was also a greater problem than today,causing the death of Beck's patient and of the most celebrated patient of the time, namely Captain Charles Martell (Fig. 9). Although the story of Charles Martell (1889-1932) has been told on numerous occasions,16,35. 36 a few highlights are worth reiterating. Symptoms of pain in the groin, leg, and hip began at the age of 22 years. During the next 3 years, in addition in pain in bis heels, leg, and back, he had fractures of the left clavicle, right humerus, and several vertebrae. He had also lost stat- ure and had become pigeon-breasted. At fue end of uri- nation, he passedfine white gravel. He was completely disabled at the age of 27 years, and at the age of 30 years Uanuary 1926) was hospitalized at Bellvue Hospital, New York, N. Y., under fue caTeof Dr. Eugene DuBois. Fig. 9. Charles Manell. (From Bauer W, FedermanDD. Roentgenograms showed severe osteopenia,compressed Metabolism 1962;11:21-9.) vertebrae, cystic changes in fue femur, and numerous pathologic fractures. Tbe serum calcium level was 14.8 mgjdl and fue phosphorus level was 3.3 mgjdl. He had Mandl23 writes of two patients who were operatedon shrunk a total of 7 inches, exhibiting marked kyphosis before 1930. Both had generalized osteitis fibrosa, and and extreme muscular hypotonia with unusual flexi- the condition improved after excision of a parathyroid bility of many joints. With the provisional diagnosis of tumor. hyperparathyroidism, fue patient was transferred to the The clinical picture of hyperparathyroidism as man- Massachusetts General Hospital and, after metabolic ifest in fuese initialpatients is essentially unknown to- studies, underwent removal of a normal parathyroid day. In most patients the diagnosis is established by gland in May and again in June 1926 (one of five nod- I¡ routine screening of serum electrolytes, and many have ules excised at the first operation and one of six at the t. \ ; relatively few symptoms.34In a sense,the most common second operation proved to be parathyroid). Both pro- 't method of diagnosis is by serendipity. This too has a cedures were performed by Dr. E. P. Richardson. AI- precedent. though no change occurred in the Captain's calcium Dr. J. Morelle, from Louvain, in 1932 had on bis metabolism, bis physicians convinced themselves that he service a patient with primary hyperparathyroidism. had improved clinically and published their observa- He instructed a medical student to draw blood to mea- tions in 1929 (2 years after parathyroidectomy).37 The SUTeserum calcium level. The student carefully fol- casewas published under fue title "Parathyroidectomy lowed Morelle's directions, but he went to fue wrong in Osteomalacia"37 and lead to confusion about the bed. The patient's serum calcium level was elevated! cause of osteitis fibrosa cystica since clinical improve- Here was the first diagnosis of hyperparathyroidism by ment seemedto be obtained by the removal of two nor- serendipity. mal parathyroid glands. No real change occurred in the The long-term but subtle effects of excessive par- patient's condition, and by 1931 he was dependent on athormone secretion is reflected in fue skeletal changes crutches. Mter four additional cervical exploratory op- described by von Recklinghausen-bony cysts, os- erations (three by Dr. Oliver Cope), 90% of a 3 cm tu- ~ i:t Volume 108 Presidential address 949 ; Number 6 i ,.' mor was removedfrom the mediastinumby Dr. E. D. inadequacy of histopathologic criteria for differ- .Churchill. The remainderof the tumor was suturedon entiation.45 its pedicle and placed in a superficial position in the Since hyperparathyroidism was described in Herr sternalnotch. Death from tetanyoccurred 6 weeksafter Bleich almost 100 years ago, more precise methods of surgery.38 diagnosis and of localization of the lesion and excellent Dr. Oliver Cope,38who has mademonumental con- results from surgical correction have evolved. As we im- tributions to the surgeryof hyperparathyroidism,com- proved our understanding of this disease,our manage- mented at another time, ment should be less empiric and more rational, based on "Leaving a good portion of an adenoma does not seemto be etiologic mechanisms, pathophysiology, and natural too good an idea. ...some of OUTother patients treated in this history . way have turned out to have further hyperparathyroidism and In conclusion, we seethe end result of the effort made a remnant had to be removed eventually. For a time we had by those hubristic fish that 100 million years ago had the an idea that it would be good to leave a portion of the adenoma courage to crawl ashore. Had these fish been more dif- to minimize the post-operative tetany. This has not proved to fident, no glands of Owen would have been discovered be 39 necessary.... and perhaps we would not havethe problems of hyper- RECENTDEVELOPMENTS parathyroidism today. Our present concept of parathyroid gland hyperfunction is the antithesis of fue concept that prevailed at fue time Mandl transplanted parathyroid glands into Al- bert Jahne because of a presumed parathyroid defi- ciency. Although the pathogenic mechanisrns are still unclear, a number of exciting developments have occurred that should further OUTunderstanding of this disease. The intact immunoparathormone assayhas provided a more precise means of differentiating hyperparathy- i roidism from other causes of hypercalcemia. This I ! method has advanced to fue point that intraoperative monitoring of fue immunoreactive parathyroid hormone level is possible.40Studies on dispersed cells from ade-

i nomas, hyperplastic glands, and carcinomas have dis-closed altered "set points" at which calcium regulatesthe secretion of parathyroid hormone. Increased par-athyroid cell proliferation in combination with derangedcalcium-regulated parathyroid hormone release,resultsin primary hyperparathyroidism.41 Localization proce-dures have been of help primarily in patients undergo-ing reoperation, in reducing morbidity, and in increas-ing the successof fue operative procedure.42 Radiola-beled monoclonal antibodies hold fue promise of aspecific and sensitive method of identifying parathyroidtissue.43 Amino acid sequencing has led to an appreci- ation of those segments of fue hormone that are respon-sible for active binding to its receptor and biologic activ-ity. This permitsthe design of a molecule that binds toreceptors but has no biologic activity, resulting in a veryeffective hormone antagonist.44 DNA probes suggest that parathyroid adenomas are more likely clonal than multicellular in origino This has obvious implications I1I with reference to OUTability to discriminate betweenadenoma and hyperplasia and should help resolve the

.I1I11 950 Thomas Surgery December1990

genseitigenBeziehungen. Festchr Rudolf Virchow (Berlin), 34. Healh H, HodgsonSF, KennedyMA. Primary hyperparalhy- 1891:1-89. roidism; incidence,morbidilY and polenlial economicimpact in 16. Albright F. A pageout of the history of hyperparathyroidisrn. a communilY. N Engl J Med 1980;302:189-93. J Clin Endocrinol 1948;8:637-57. 35. RolandCG. Hyperparalhyroidism in someearly palienls. Arch 17. Jung E. Etude clitique de I'hyperparathyroidisrne.Cong Fr Inlem Med 1970;126:558-9;565-6. Chir 1933;42:200-68. 36. Bauer W, Federman DD. Hyperparalhyroidism epilomized: 18. AskanazyM. Uber Ostitis deformansohne ostoidesGewebe. thecase ofCaplain CharlesE. Manell. Metabolism1962;11:21- Arb Geb Path Anat lnst Tubingen 1904;4:398-422. 9. 19. ErdheirnJ. Uber epithelkorperbefundebei Osteornalacie.Sit- 37. RichardsonEP, Aub JC, Bauer W. Paralhyroidectomyin os- zungsbAcad WissenschWien Math Naturw 1907;116:311-70. teomalacia.Ann Surg 1929;90:730-41. 20. SchlagenhauferF. Zwei falle van Parathyreoideaturnoren. 38. CopeO. The story of hyperparathyroidismat the Massachusetts Wien Klin Wochenschr1915;28:1362. GeneralHospital. N Engl J Med 1966;21:1174-82. 21. Mandl F. TherapeutischerVersuch bei Ostitis fibrosageneral- 39. FaheyTJ, MeyersWPL. Documentedhyperparalhyroidism of isatarnittels Extirpation einesEpithelkorperchemurnors. Wien 36 yearsduration. Cancer 1957;35:803-7. Klin Wochenschr1925;50:1343-4. 40. FischerS, Flentje D, CattelhackC, Blind E, Buhr H, Schmidt- 22. Organ CH. Felix Mandl. Surgical Round 1985;3:69-70. Gayr H. Intraoperativeand postoperalivekinelics of intact par- 23. Mandl F. Hyperparathyroidisrn. SURGERY1947;21:394-440. athyroid hormonesecretion in hyperparathyroidism.Presented 24. BeckA. Aussprache.Arch F Klin Chir 1928:152:123-4. at the 33rd World Congressof Surgery,International Associa- 25. Gold H. Entfernung eines Epithelkoerperchemurnorswegen tion of EndocrineSurgeons, Toronto, Ontario, Canada,1989. Ostitis fibrosa. Wien Med Wochenschr1927;77:1734. 41. Brown EM, LeBoff MS. Physiologyof hyperparathyroidism. 26. Barr DP, Bulger HA, Dixon HH. Hyperparathyroidisrn. In: Fanhman EH, ed. Progressin surgery:parathyroid surgery. JAMA 1929;92:951-2. vol 18. New York: S Karger; 1986:13-22. 27. Barr DP, Bulger HA. The clinical syndrorneof hyperparathy- 42. Doppman JL. Reoperativeparathyroid surgery; localization roidism. Am J Med Sci 1930;179:449-76. procedures.In: Fanhman EH, ed. Progressin surgery: par- 28. Wilder RM. Hyperparathyroidisrn;turnorof parathyroidglands athyroid surgery. vol 18. New York: S Karger; 1986:117-32. associatedwith ostitis fibrosa. Endocrinology1929;13:232-44. 43. CanceWG, Otsuka FL, Dilley WG, et al. A potential new ra- 29. Snapperl. Parathyroid turnor and changesof the bones.Arch diopharmaceuticalfor parathyroid imaging: radiolabeledpar- lnter Med 1930;46:506-23. athyroid-specificmonoclonal antibodies. Pan 1. Evaluation of 30. Snapperl. Different featuresof the syndromeof hyperparathy- (I-125)-labeled antibodiesin anude mousemodel system. Inl J roidisrn. Acta Med Stand 1940;103:321-40. Rad Appl Instrum [B] 1988;15:299-304. 31. Boyd JD, Milgrarn JE, StearnsG. Clinical hyperparathy- 44. RosenblattM. Peptidehormone antagonisls that are effectivein roidisrn. JAMA 1929;93:684-8. vivo. N Engl J Med 1986;315:1004-13. 32. CornpereEL. Bonechanges in hyperparathyroidisrn.Surg Gy- 45. Arnold A, StauntonCE, Kim HG, Gaz RD, KronenbergHM. necolObstet 1930;50:783-94. Monoclonality and abnonnal parathyroid hormone genesin 33. Hunter D. Hyperparathyroidisrn(hyperfunction of a parathy- parathyroidadenomas: N Engl J Med 1988;318:658-62. raid turnor in a caseof generalizedostitis fibrosa). ProcR Soc Med 1929;23:227-34.

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