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Parathyroidectomy for hypercalcemiccrisis: 40 years’ experience andlong-term outcomesJennifer Cannon, MD,a John I. Lew, MD,a and Carmen C. Solorzano, MD,a,b Miami, FL,and Nashville,TN

Background. Hypercalcemic crisis is a serious and potentially life-threatening complication of markedlyincreased serum calcium concentrations most commonly due to severe primary sporadic hyperparathy-roidism (HPT).Methods. A review of 1,310 consecutive patients with severe sporadic HPT who underwentparathyroidectomy at a single institution from April 1970 through July 2009 was performed. Of thisseries, 88 patients were treated operatively for hypercalcemic crisis associated with signs and symptoms ofacute calcium intoxication and/or serum calcium concentrations $14 mg/dL (3.5 mmol/L). Clinicalpresentation, laboratory values, operative success, operative failure, and disease recurrence werecompared to noncrisis patients.Results. Preoperative calcium and parathyroid hormone (PTH) concentrations were significantly greateramong patients with hypercalcemic crisis. Crisis patients had a greater incidence of mental statuschanges, fatigue, ectopic glands, and pancreatitis. Postoperatively, calcium and PTH levels were similar.Overall, crisis patients had a lesser rate of operative success compared to noncrisis patients (92% vs97%). With the advent of intraoperative PTH monitoring--guided focused parathyroidectomy in 1993,success rates equalized (95% vs 97%). There was no difference in disease recurrence. Overall follow-upwas 59 months.Conclusion. Hypercalcemic crisis patients are appropriately treated by expeditious parathyroidectomy, butoverall have slightly lesser rates of initial operative success than noncrisis patients. Long-term resultsreveal similar serum calcium, PTH concentrations, and recurrence rates at a mean follow-up of nearly5 years. (Surgery 2010;148:807-13.)

From the Division of Endocrine Surgery,a University of Miami Miller School of Medicine, Miami, FL; and theDivision of Endocrine Surgery,b Vanderbilt University, Nashville, TN

HYPERCALCEMIC CRISIS is a rare and potentially life-threatening complication of severe calcium intoxica-tion that is most commonly due to sporadic primaryhyperparathyroidism (HPT). This condition is asso-ciated with profound disturbances in mental status,cardiac, renal, and gastrointestinal function in thepresence of markedly increased serum calcium andparathyroid hormone (PTH) concentrations.

Hanes1 described the clinical syndrome of ‘‘hy-perparathyroid crisis’’ and reported the first knownhuman death attributable to this phenomenon in1939. In ensuing years, numerous studies have

d at the 67th Annual Meeting of the Central Surgicalion, Chicago, Illinois, March 10–13, 2010.

requests: Carmen C. Solorzano, MD, Vanderbilt Univer-ical Center, 597 Preston Research Building, 2220 PierceNashville, TN 37232-6860. E-mail: carmen.solorzano@

ilt.edu.

60/$ - see front matter

Mosby, Inc. All rights reserved.

016/j.surg.2010.07.041

reported that early diagnosis, prompt preoperativemedical management, and expeditious parathy-roidectomy provide the best therapy for hypercalce-mic crisis. Many of these studies, however, havelimited patient numbers and focus on the immedi-ate success of treatment; few reports describe thelong-term outcomes in a large population.2-12

With expeditious parathyroidectomy as the cor-nerstone treatment of patients with hypercalcemiccrisis, long-term outcomes should be equivalent tothose patients undergoing parathyroidectomy whodo not present in crisis. This study describes thesurgical outcome and long-term results of hyper-calcemic crisis patients after parathyroidectomycompared to noncrisis patients over a 40-yearperiod at a single institution.

METHODS

The records of 1,310 patients who underwentparathyroidectomy at the University of MiamiHealth System from April 1970 to July 2009were reviewed retrospectively from a prospectively

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collected database approved by the InstitutionalReview Board. All patients treated for secondary,tertiary, or familial hyperparathyroidism were ex-cluded from this study.

A total of 88 patients from this group wereidentified as having hypercalcemic crisis, definedas having signs and symptoms of acute calciumintoxication and/or serum calcium concentrations$14 mg/dL (3.5 mmol/L) with the biochemicalprofile being the primary criterion for inclusion.In all patients for whom these data were available,PTH levels were increased. C-terminal parathyroidassays, which were first used in 1972, were replacedby 2-site immunoradiometric intact PTH assaysfrom 1990 to 1993. Thereafter, immunochemolu-minescent assays were used.

Some patients in this study were initially treatedmedically at outside hospitals for severe hypercal-cemia before admission to this institution. Onarrival to this medical center, all patients wereresuscitated promptly with intravenous isotonicsodium chloride and given loop diuretics to de-crease serum calcium concentrations. Hypocalce-mic drugs, such as bisphosphonates, were also usedas adjuncts to decrease serum calcium concentra-tions. Once optimized medically, all patients under-went expeditious parathyroidectomy as describedpreviously.13

Before 1993, bilateral neck exploration wasperformed in an attempt to visualize all the para-thyroid glands, with the resection of enlargedglands based on surgeon judgment and histopa-thology. If more than 1 enlarged gland wasresected, leading to normal or low calcium con-centrations postoperatively, or if hypercalcemiapersisted postoperatively after the excision of asingle enlarged gland, the patient was judged tohave multigland disease.

After 1993, the initial standard bilateral neckexploration was replaced by focused parathyroidec-tomy that involved preoperative parathyroid glandlocalization and intraoperative parathyroid hor-mone (IPM)--guided excision based solely on para-thyroid function as described previously.14 Patientswith more than 1 hypersecreting gland removedduring focused parathyroidectomy or patients whoexperienced persistent hyperparathyroidism afterremoval of 1 enlarged gland with IPM-guided fo-cused parathyroidectomy were determined to havemultigland disease.

Demographic, biochemical, and operative datawere collected and compared between crisis andnoncrisis patients. Main outcome measurementswere operative success, operative failure, and re-currence. Operative success was defined as normal

calcium for 6 months or longer after parathyroid-ectomy. Operative failure was defined as increasedserum calcium and PTH levels within 6 monthsafter parathyroidectomy. Recurrence was definedas increased serum calcium and PTH levels after 6months of eucalcemia.

Postoperatively, calcium and vitamin D supple-mentation were administered frequently in antic-ipation of clinically important hypocalcemia in thisgroup of patients with severe bone mineral lossdue to long-standing disease. When possible, se-rum calcium concentrations were monitored inthe immediate postoperative period at 2 and 6months and yearly thereafter.

Statistical analyses were performed using SPSSstatistical software (version 17.0; SPSS Inc., Chicago,IL). Continuous variables were compared using theStudent t test, and the Chi-square statistic was usedto compare categorical and nonparametric data. AP value of #.05 was considered statisticallysignificant.

RESULTS

There were a significantly greater percentage ofmen in the crisis group compared to the noncrisisgroup (Table I). The mean preoperative serum cal-cium, PTH, and creatinine concentrations weresignificantly greater among crisis than noncrisispatients. The greatest PTH level (4,479 pg/mL)was seen in a noncrisis patient. Notably, this wasa C-terminal assay performed in a patient with re-nal insufficiency. An intact N-terminal assay waslater performed in this same patient before opera-tion and was also increased, but not to this markeddegree (35 pg/mL; normal range, 8--24 pg/mL).

The majority of patients had at least 1 symptomsuggestive of HPT (Table II). Pancreatitis, fatigue,and alterations in mental status were all signifi-cantly more prevalent in crisis compared to noncri-sis patients. Kidney stones (or a history thereof),bone pain, and/or other manifestations of bonemineral disease were seen with equal frequency.

More noncrisis than crisis patients underwentIPM (71% vs 47%, respectively; P < .0001) and pre-operative sestamibi scans (67% vs 47%, respectively).Among patients with sestamibi scans, correct localiza-tion rates were equal (78% for each group). Morecrisis patients, however, underwent bilateral neck ex-ploration (Table III). There was no difference in therate of multigland disease between the crisis and non-crisis groups. Mediastinal ectopic glands were foundmore frequently in crisis than noncrisis patients. Thy-mic ectopic glands were seen with essentially equalfrequency between the groups. Larger abnormalglands were more commonly found in crisis patients,

Table I. Demographic, biochemical, and operative history in crisis and noncrisis patients

Crisis N = 88 Noncrisis N = 1,222 P value

Age, y 57 ± 17 59 ± 13 .255Sex, n (%)

Male 31 (35) 318 (26) .045Female 56 (64) 904 (74)

Previous parathyroidectomy, n (%) 9 (10) 76 (6.2) .173Previous thyroidectomy, n (%) 3 (3.4) 49 (4.0) 1.000Calcium* (mg/dL) ± SD 15.6 ± 2.0 11.8 ± 0.8 <.0001PTH (pg/mL)y ± SD 782 ± 878 231 ± 302 <.0001Creatininez (mg/dL) ± SD 1.6 ± 0.9 0.98 ± 0.4 <.0001

*To convert calcium to SI units (mmol/L), multiply by 0.25.yThe PTH SI equivalent of ng/L requires no conversion factor.zTo convert creatinine (mmol/L), multiply by 88.4.

PTH, Parathyroid hormone; SD, standard deviation.

Table II. Presenting symptoms in crisis andnoncrisis patients

PresentationCrisis

N = 88Noncrisis

N = 1,222 P value

Bone, n (%) 26 (30) 404 (33) .558Mental status

changes, n (%)16 (18) 34 (2.8) <.0001

Kidney stones, n (%) 23 (26) 368 (30) .471Fatigue, n (%) 29 (33) 279 (23) .037Pancreatitis, n (%) 3 (3.4) 2 (0.2) .003

Table III. Operative data in crisis and noncrisispatients

CrisisN = 88

NoncrisisN = 1,222 P value

BNE, n (%) 34 (39) 296 (24) .005MGD, n (%) 7 (8.0) 89 (7.3) .831IPM, n (%) 41 (47) 862 (71) <.001Mediastinal, n (%) 9 (10) 29 (2.4) .001Thymic, n (%) 3 (3.4) 31 (2.5) .494Cancer, n (%) 4 (4.5) 7 (0.6) .004Gland size*

(cm) ± SD2.42 ± 1.17 1.80 ± 0.93 .001

*Gland size = longest linear dimension.

BNE, Bilateral neck exploration; MGD, multigland disease; IPM, intrao-perative parathyroid hormone monitoring; SD, standard deviation.

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and final pathology revealed parathyroid carcinomamore frequently in patients with hypercalcemiccrisis.

There was a lesser rate of operative success seenin the crisis patients (81/88; 92%) compared tononcrisis patients (1,185/1,222; 97%; P = .02). Withthe implementation of focused IPM guided exci-sion as our standard operative approach in 1993,however, success rates between the 2 groups equal-ized, with 39/41 (95%) successful crisis operationsand 840/862 (97%) successful noncrisis operationswhen IPM was used (P = .298). Postoperativecalcium and PTH levels were similar between the2 groups (Table IV). A total of 69% of the hypercal-cemic crisis patients had $6 months follow-up(range, 6--400), whereas 76% of noncrisis patientshad $6 months follow-up (range, 6--447). Therewas no difference in recurrence rates betweengroups. The overall 30-day mortality was 1 perioper-ative death (1%) occurring in the crisis group.

Of the 7 crisis group operative failures, 2 weredue to missed glands in multigland disease; of the 37noncrisis failures, 12 were due to missed glands.A total of 2 crisis and 3 noncrisis failures were aresult of misdiagnoses or presumed misdiagnoses

due to various etiologies, including sarcoidosis, fa-milial hypercalcemic hypocalciuria, and causes neverelucidated. Parathyroid carcinoma contributed tooperative failure in 2 crisis patients. Although therewere no failures due to malignancy in the noncrisispopulation, there were late disease recurrences.For example, the last failure patient in the crisisgroup underwent multiple explorations and imag-ing without identification of an abnormal parathy-roid gland. However, 5 years later, she presented inhypercalcemic crisis at an outside hospital where4-dimensional imaging by computed tomographyrevealed an ectopic parathyroid adenoma abovethe carotid bifurcation.

DISCUSSION

Since the 1930s, PTH excess leading to severehypercalcemia has been recognized as a cause ofsignificant morbidity and mortality.1,15 The needfor urgent medical therapy and surgical interven-tion in these patients with hypercalcemic crisishas been well-established. Although early case

Table IV. Outcome data in crisis and noncrisis patients with sporadic primary hyperparathyroidism

Crisis N = 88 Noncrisis N = 1,222 P value

Overall failure, n (%) 7 (8.0) 37 (3.0) .024Failure with IPM,* n (%) 2 (4.9) 22 (2.6) .298Overall recurrence, n (%) 2 (2.3) 26 (2.1) .712Recurrence with IPM,* n (%) 2 (4.9) 13 (1.5) .145Calciumy (mg/dL) ± SD 9.4 ± 0.9 9.4 ± 0.6 .269PTHy (pg/mL) ± SD 69 ± 66 55 ± 57 .127Creatinine (mg/dL) ± SD 1.3 ± 0.6 1.1 ± 0.9 .164Follow-upz (m) ± SD 69 ± 89 59 ± 69 .002

*N = 41 crisis; N = 862 noncrisis.yOperative failures not included in analysis.zIncludes all patients in study population, including patients lost to follow-up at 0 months.

IPM, Intraoperative parathyroid hormone monitoring; PTH, parathyroid hormone; SD, standard deviation.

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studies describe patients with palpable neck masses,florid symptoms, and fatal outcomes, more recentreports demonstrate the high index of suspicionrequired to identify these patients and initiatemedical therapy while awaiting the results of con-firmatory laboratory testing.2-7,11-13,16-19

Symptoms of severe sporadic HPT can be subtleor vague and may be attributable to a myriad ofother causes. Patients may not present with thetypical symptoms of this condition, such as bonedisease or nephrolithiasis; instead, they may show anonspecific constellation of symptoms includingfatigue, weakness, nausea/vomiting, and altera-tions in mental status. Once a secure diagnosis ismade and the patient is stabilized, expeditiousparathyroidectomy has led to excellent operativeoutcomes and significantly lesser rates of periop-erative mortality.3-7,11,16,19

The definition of hypercalcemic crisis, itself, isnot uniform across the literature. The most fre-quently used concentration of serum calcium asthe lower limit of defining ‘‘crisis’’ is 14 mg/dL or15 mg/dL.4-6,13,18-23 Patients, however, may have se-vere symptoms of calcium intoxication, includingobtundation, necrotizing pancreatitis, and renalfailure at concentrations below this limit. Con-versely, other individuals may demonstrate nosymptoms at all, even at such markedly increasedcalcium concentrations. In previous reports of hy-percalcemic crisis, these apparently asymptomaticpatients have been excluded.19,20

Symptoms may not always be immediately at-tributed to the high calcium concentrations, andthe association is realized only in retrospect whenthe symptoms resolve with parathyroidectomy. Ad-ditionally, severe bone mineral disease may exist inpatients with severe hypercalcemia, but is not nec-essarily appreciated and/or documented at thetime of surgical evaluation. With consideration ofthe aforementioned, all patients with a serum

calcium $14 mg/dL (3.5 mmol/L) were includedin the crisis group of this study. The majority ofthese patients did indeed have overt symptoms,with only 1 patient describing no clearly attribut-able hypercalcemic signs or symptoms.

This current study found that 7% of patientspresenting with severe sporadic HPT over a 40-yearperiod presented with hypercalcemic crisis. Thesecrisis patients were more likely to be male, havemental status changes, fatigue, pancreatitis, andparathyroid cancer compared to patients with lessercalcium concentrations. Consistent with otherseries,2,4,5,16,17,22 there was a greater percentage ofmen in the crisis group compared to the noncrisisgroup, although not approaching the female tomale ratio of 1:1 seen in some reports. Furthermore,crisis patients had significantly larger glands andwere more likely to present with ectopicallylocated mediastinal parathyroid glands.

Operative treatment was successful initially in 92%of patients in the crisis group, with parathyroidcancer and presumed misdiagnoses accounting forthe main causes of operative failure. Despite a slightlylesser initial success rate, long-term outcomes incrisis patients were similar to those achieved innoncrisis patients. Of the 88 patients with hypercal-cemic crisis, 45 (51%) individuals underwent oper-ations before 1993, when focused parathyroidectomywas thereafter performed routinely at this institution.In contrast, only 25% of noncrisis patients hadparathyroidectomy performed before 1993. Thisdiscrepancy between operative approaches mayexplain the greater rate of bilateral neck explorationobserved in crisis patients, as well as the lower rate ofIPM and preoperative localization.

Although hypercalcemic crisis patients presenttoday with many severe manifestations, the intro-duction of multichannel autoanalyzers in the late1970s has led to the earlier detection of severesporadic HPT, before disease progression to a

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more advanced state. As a result, hypercalcemiccrisis has become a relatively more unusual man-ifestation of severe sporadic HPT.

Mental status changes were found to be signif-icantly more prevalent in patients presenting withhypercalcemic crisis. This observation has beenalso reported by previous authors who observedcentral nervous system dysfunction as the predom-inant clinical feature of crisis patients.16,18,19,24

Some of the more subtle symptoms of calcium ex-cess are manifest as fatigue, depression, or ‘‘mentalfogginess,’’ and are often overlooked until they arealleviated by parathyroidectomy. With a more pro-foundly increased serum calcium concentration, itseems reasonable that the symptoms of alteredmental status may be more dramatic and easilyobserved.

Pancreatitis was also more commonly seen inthe crisis population. Although the absolute num-bers in both groups were small, the percentage ofcases of pancreatitis seen in patients with hyper-calcemic crisis was significantly greater. This find-ing has also been described in other reports.A 25% rate of pancreatitis was reported in a seriesof 8 patients,23 whereas a slightly lesser rate of 17%was reported in another series.17 In yet another se-ries of 59 hypercalcemic crisis cases, only a 4% rateof pancreatitis was described, similar to thatobserved in the current report.19

To our knowledge, this study identified moremediastinal ectopic glands in the crisis populationthan other published reports. Comparisons of sitesand frequency of ectopic glands were hindered,however, because intrathyroidal, submandibular,retropharyngeal, and other common cervical ec-topic sites were not actively recorded for research,as was done for mediastinal and thymic glands.Additionally, the definition of what constitutes anectopic gland is not uniform among reports; glandsfound in the tracheoesophageal groove may be con-sidered orthotopic by some yet ectopic by others.

Similarly, different investigators use differentmethods to determine the size of abnormal para-thyroid glands. At our institution, size is determinedsolely by measurements taken in 3 dimensions, withthe largest measurement in any 1 direction used forcomparison. Other groups may use weight alone orin combination with dimension. Regardless, moststudies that compared gland size between crisis andnoncrisis patients concluded, as did the currentstudy, that crisis patients have larger glands thannoncrisis patients.2,3,22,23

Parathyroid carcinoma is a rare cause of severesporadic HPT, comprising less than 1% of cases. Inhypercalcemic crisis, however, parathyroid carcinoma

was seen in 4.5% of patients in the current study,which is consistent with the 5.0% rate reported in arecent review of the literature23 that included selectedseries and case reports reflecting a 29-year period. Inthis review, the greatest percentage of crisis patientswith parathyroid carcinoma came from a report of36 cases of acute hyperparathyroidism22 in which an8.5% rate of parathyroid carcinoma among the crisispopulation studied versus a 1.8% rate in noncrisispatients was observed.

The sheer expanse of time covered by the datacollection period is a strength of this study and yetmay represent a potential limitation because olderdata may not be easily verified. Changes in operativetechnique after 1993 altered outcomes and im-proved success rates among crisis patients. However,about half of the crisis patients (51%) were treatedbefore the implementation of focused parathyroid-ectomy with IPM guidance as our standard opera-tion, perhaps limiting the impact of this change onour data and cohort. Other limitations of this studyinclude the advent of new technologies, variablelaboratory assays, and broadened indications forparathyroidectomy over the past 4 decades.

In conclusion, this study---which spans a 40-yearperiod---is, to our knowledge, the largest single-institution series of hypercalcemic crisis patientsreported in the literature to date.13,19-22 Despitevariations in the management and surgical treat-ment of both crisis and noncrisis patients overthis period, this study demonstrates that long-term outcomes among crisis and noncrisis patientsare similarly excellent. As this study with a medianfollow-up of nearly 5 years demonstrates, the long-term surgical outcome of patients treated for hy-percalcemic crisis is durable and equivalent totheir noncrisis counterparts.

REFERENCES

1. Hanes FM. Hyperparathyroidism due to parathyroid ade-noma, with death from parathormone intoxication. AmerJ Med Sci 1939;197:85-9.

2. Lemann J Jr, Donatelli AA. Calcium intoxication due to pri-mary hyperparathyroidism: a medical and surgical emer-gency. Ann Intern Med 1964;60:447-61.

3. Coffey RJ, Potter JF, Canary JJ. Diagnosis and surgical con-trol of hyperparathyroidism. Ann Surg 1965;161:732-6.

4. Payne RL, Fitchett CW. Hyperparathyroid crisis: a survey ofthe literature and a report of two additional cases. Ann Surg1965;161:737-45.

5. MacLeod WAJ, Holloway CK. Hyperparathyroid crisis: acollective review. Ann Surg 1967;166:1012-5.

6. Clunie GJA, Gunn A, Robson JS. Hyperparathyroid crisis. BrJ Surg 1967;54:538-41.

7. Bartlett WC. Acute hyperparathyroid crisis. Am J Surg 1967;114:796-9.

8. Gardner RJ, Koppel DM. Hyperparathyroid crisis. Arch Surg1969;98:674-6.

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9. Bayat-Mokhtari F, Palmieri GMA, Moinuddin M, PourmandR. Parathyroid storm. Arch Intern Med 1980;140:1092-5.

10. Chow S, Williams C, Cole E. Parathyroid storm: rare mani-festation of primary hyperparathyroidism. Can Med AssocJ 1986;134:503-4.

11. Keeling CA, Abrahamson MJ, Harloe DGJ. Fatal hyperpara-thyroid crisis. Postgrad Med J 1987;63:111-2.

12. Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol 2001;12:S3-9.

13. Lew JI, Solorzano CC, Irvin GL III. Long-term results of par-athyroidectomy for hypercalcemic crisis. Arch Surg 2006;141:696-9.

14. Irvin GL III, Solorzano CC, Carneiro DM. Quick intraoper-ative parathyroid hormone assay: surgical adjunct to allowlimited parathyroidectomy, improve success rate, and pre-dict outcome. World J Surg 2004;28:1287-92.

15. Lowenburg H, Ginsburg TM. Acute hypercalcemia: reportof a case. JAMA 1932;99:1166.

16. Wang C, Guyton SW. Hyperparathyroid crisis: clinical andpathologic studies of 14 patients. Ann Surg 1979;190:782-90.

17. Kelly TR, Zarconi J. Primary hyperparathyroidism: hyper-parathyroid crisis. Am J Surg 1981;142:539-42.

18. Fitzpatrick LA, Bilezikian JP. Acute primary hyperparathy-roidism. Am J Med 1987;82:275-82.

19. Sarfati E, Desportes L, Gossot D, Dubost C. Acute primaryhyperparathyroidism: experience of 59 cases. Br J Surg1989;76:979-81.

20. Schweitzer VG, Thompson NW, Harness JK, Nishiyama RH.Management of severe hypercalcemia caused by primary hy-perparathyroidism. Arch Surg 1978;113:373-81.

21. Bondeson AG, Bondeson L, Thompson NW. Clinicopatho-logical peculiarities in parathyroid disease with hypercalcae-mic crisis. Eur J Surg 1993;159:613-7.

22. Gasparri G, Camandona M, Mullineris B, Raggio E, Vigna S,Dei Poli M. Acute hyperparathyroidism: our experiencewith 36 cases. Ann Ital Chir 2004;75:321-4.

23. Phitayakorn R, McHenry CR. Hyperparathyroid crisis: useof bisphosphonates as a bridge to parathyroidectomy.J Am Coll Surg 2008;206:1106-15.

24. Coffey RJ, Lee TC, Canary JJ. The surgical treatment of pri-mary hyperparathyroidism: a 20 year experience. Ann Surg1977;185:518-21.

DISCUSSION

Dr Tina Yen (Milwaukee, WI): The study nicely showsthat patients with primary hyperparathyroidism (HPT)who present in hypercalcemic crisis have excellentlong-term operative outcomes similar to patients whoundergo surgery in a noncrisis situation. I have 3 generalquestions.

My first question is, over time, has the proportion ofsporadic primary HPT patients presenting in crisischanged? I would expect that, with earlier and betterdiagnosis of HPT in the more contemporary timeperiods, there would be a smaller proportion of patientspresenting in crisis. What percent of patients wereknown to have the diagnosis of primary HPT at thetime of presentation and crisis? And did this percentagechange over time?

Second, compared to the noncrisis group, moreoperative failures in the crisis group were due to carci-noma or misdiagnosis. What were the causes of hyper-calcemia in these 2 misdiagnosed cases and the other 3

misdiagnosed cases in the noncrisis group? Your resultshighlight that, when a patient presents in hypercalcemiccrisis, we should perform an appropriate workup to ruleout other causes of hypercalcemia besides primary HPTprimary to operating. If we do operate, we should have arelatively strong suspicion for cancer and be preparedfor a cancer operation if intraoperative findings areconsistent with carcinoma.

Lastly, do you have information on time from admis-sion to surgery in these crisis patients? So, in this morecontemporary era, are these patients being optimizedquicker and undergoing surgery sooner?

Dr Jennifer Cannon (Miami, FL): We actually lookedat this specifically. Over time, the proportion of hyper-parathyroid patients has changed. Overall, I don’t be-lieve the absolute numbers of patients withhyperparathyroid crisis have changed. However, in theearlier years, the proportions were significantly higher.

And I do, as you brought up, think that, with theadvent and increased use of multichannel chemistryserum analysis, we are picking up more patients earlierwho are less symptomatic with less florid presentations ofhyperparathyroidism. We do see, over the whole 40-yearperiod, about a 6.7% rate of hypercalcemic crisis for theentire period; again, absolute numbers probably haven’tchanged a whole lot, but the percentage has.

In regard to whether or not the patients presentingin crisis were known to have a diagnosis of hyperpar-athyroidism prior to their presentation, we didn’tspecifically capture that data in this study; however, in1 of our prior papers, we did look at this, and approx-imately 20% of the crisis patients did carry a medicalhistory of hyperparathyroidism. In this study, specifi-cally, 9 of the 88 patients had undergone a priorparathyroidectomy.

In regard to the question regarding the misdiagnosesin our group, in the crisis group there were 2 misdiag-noses. One was a presumed diagnosis of sarcoidosis. Thisdiagnosis was made based on a lymph node that was sentat the time of operation as a possible parathyroid gland.The final pathology returned as a granulomatous lymphnode, and the final pathology report was read as consis-tent with sarcoidosis.

So, I agree that a very thorough evaluation of thesepatients prior to operation is important. This case wasfrom very early in our experience prior to some of thebetter parathyroid hormone (PTH) assays. The secondcase is probably better qualified as a presumed misdiag-nosis. This patient had very extensive bilateral neckoperation and had several glands removed. She did notimprove after her operation. She subsequently died, andon postmortem examination was found to have 7 basi-cally normal-appearing parathyroid glands, if youinclude the ones that were removed at her operation.

Among the noncrisis failures, these were primarily,again, better classified as presumed misdiagnoses. Intrying to review their charts and looking through thebiochemical evaluation, it’s a little bit difficult to deter-mine exactly what the source of the misdiagnosis was.These may have been renal disease or they had some

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degree of renal insufficiency not recognized at the timeof the evaluation. At least 1 on retrospective reviewappeared to actually be benign familial hypercalcemichypercalciuria. So, again, I agree that a very thoroughevaluation of the patient prior to operation is critical.

Then finally, your third question, looking at the timefrom admission to operation in these patients, again, thiswasn’t something that we specifically evaluated in thispaper. However, in another fairly recent paper looking athypercalcemic crisis at our institution, we did look at thetime from admission to surgery, and the average wasfound to be about 5 days.

Dr Steven DeJong (Maywood, IL): I recommend themanuscript to the membership when it is published. Itreally goes through a nicely studied and very meticu-lously studied group of patients over a nearly 40-year pe-riod of time with an impressive follow-up of 5 years. Itteaches us a lot about these unique patients with hyper-calcemic crisis. I would like to ask a couple of questions.

Number 1, did you run into any different localizationpatterns preoperatively with patients that presented withhypercalcemic crisis versus those that were in the non-crisis group? For example, was ultrasound particularlyhelpful? Was parathyroid scanning particularly helpful?Were there any patterns that emerged that were differ-ent from what we see in our elective patients withparathyroid disease?

Second, does your data or does your difference incure rate suggest that there is an optimal surgicalapproach for these patients? Simply put, should we bedoing bilateral explorations on all patients with a crisis?Or, coming from an institution that has pioneeredunilateral parathyroid surgery, is a unilateral approachappropriate for most of these patients?

Third, in your manuscript, you described a phenom-enon of increased PTH postoperatively in a number ofpatients that were higher than in patients in yournoncrisis group. I’d be interested in your thoughts onwhy that was. Did you propose that these patientspresented with a higher degree of bone disease, orwere there other factors involved?

Dr Jennifer Cannon (Miami, FL): Your first questionis in terms of the different preoperative localization pat-terns, specifically in relationship to sestamibi scans. Welooked at this, and, in all honesty, there was no differ-ence. In those patients in the crisis group who had sesta-mibi scans and those patients in the noncrisis group, ifthey had a localization study, they had no difference inlocalization. I did not specifically look at the differencein ultrasound. More patients had sestamibi scans justlooking through our data, but the concordance wasequal in each of those groups. There was no specific dif-ference in that patient population.

In terms of the difference in cure rate versusperforming a bilateral neck exploration versus a focusedparathyroidectomy, part of the issue with the bilateralneck exploration and the reason that a majority or ahigher percentage of our patients in crisis had a bilateralneck exploration simply has to do with the extensivetime period covered by our study.

Nearly 50% of the crisis patients were operated onprior to 1993, which is when we changed our standardpractice pattern of performing a focused versus a bilat-eral neck exploration. And I think, to some extent, thatchange may sort of skew our results a little bit. I thinkthat, when you include the use of intraoperative PTHmonitoring, include the use of preoperative localization,the cure rates are actually the same.

Your third question, the increased PTH postopera-tively, yes, this is included in our manuscript, but wesubsequently removed the failures from our evaluationand reanalyzed our data. And, when the failures areremoved from the analysis, there is no difference inpostoperative PTH in the group---in both groups. Theyare statistically equal.

Dr Chris McHenry (Cleveland, OH): Jennifer, verynice presentation. I just have 2 short questions for you.

First, did the ratio of single-gland disease and multig-land disease differ between patients that had thehypercalcemic crisis and patients with primary hyperpar-athyroidism without crisis?

And then, my second question is, 1 of the concerns inpatients with hypercalcemic crisis is the risk of arrhyth-mias that occurs as a result of the calcium effect on theQT interval. And I want to know, can you comment onwhat calcium level is safe to operate on these patients?And when do you decide that it’s okay to operate onthese patients?

Dr Jennifer Cannon (Miami, FL): Thank you somuch, Dr McHenry. We actually found no differencein the rate of single versus multigland disease betweenour crisis and noncrisis patients. Again, one could say,how are you defining multigland disease? At the Univer-sity of Miami, we do define multigland disease based pri-marily on function. However, in the cases prior to 1993,the definition was based on a bilateral neck explorationwith surgeon judgment and histopathology playing amore prominent role, while, after 1993, it was basedmore on function, with a gland being removed andthen checking our intraoperative PTH level. But, regard-less of which time period you look at, our rates of multig-land disease were equal between the 2 groups.

As far as the arrhythmias associated with hypercalce-mia, it certainly is something that needs to be taken intoaccount when medically stabilizing these patients priorto operation. I think one would want your calcium to bearound 12, 12.5 maybe, at the highest before you want totake these patients to the operating room. That’scertainly a critical consideration in operating on thepatient.

Dr Peter Angelos (Chicago, IL): I was intrigued by, if Iunderstand your data correctly, that there are more menthan women that presented in hypercalcemic crisis. Did Icatch that correctly?

Dr Jennifer Cannon (Miami, FL): Not in specificnumbers. Percentagewise, 35% of the men---or 35% ofthe hypercalcemic crisis patients---were male and 64%were female. So, while not absolute numbers, it was ahigher percentage than seen in nonemsis patients(26% vs 74%).