Concentration of serum calcium is not correlated with symptoms or severity of primary hyperparathyroidism: An examination of 20,081 consecutive adults.

BACKGROUND: Guidelines for operative treatment of primary hyperparathyroidism include calcium levels >1 mg/dL above normal. We sought to determine whether greater calcium concentrations were associated with increased symptoms or disease severity. METHODS: A retrospective review of a prospectively maintained database of adults undergoing parathyroidectomy for primary hyperparathyroidism, grouped according to greatest preoperative calcium level: those patients with calcium concentrations between 10.0 and 11.0 mg/dL and those with >11.0 mg/dL. We compared subjective symptoms and objective measures of disease severity. RESULTS: The review included 20,081 adults who were split nearly evenly between calcium concentrations between 10.0 and 11.0 (10,430, 51.9%) and those with >11.0 mg/dL (9,651, 48.1%). In both groups, an absence of symptoms related to primary hyperparathyroidism was uncommon (<5%). All subjective and objective measures of disease severity were nearly identical with no significant differences (percentages for calcium concentrations between 10.0 and 11.0 and those with >11.0 mg/dL, respectively), including fatigue (72% for both groups), heartburn (37% vs 34%), bone pain (50% vs 48%), sleep disturbances (68% vs 65%), osteoporosis (40% in both groups), kidney stones (21% vs 22%), chronic kidney disease with glomerular filtration rate <60 (29% vs 32%), and hypertension (50% vs 53%). CONCLUSION: Serum calcium concentrations of greater than or less than 11 mg/dL are unrelated to symptoms and disease severity in primary hyperparathyroidism. There is no evidence to support a serum calcium threshold in parathyroidectomy guidelines.

Surgical cure of primary hyperparathyroidism ameliorates gastroesophageal reflux symptoms.

OBJECTIVE: Gastroesophageal reflux disease (GERD) symptoms are commonly reported in primary hyperparathyroidism (pHPT). Although a calcium-mediated cause-and-effect relationship has been suggested, it remains unknown if parathyroidectomy improves GERD symptoms. METHODS: Over a 22-month period, 1,175 (39%) of 3,000 consecutive adult patients with pHPT and symptomatic GERD (on prescription reflux medications daily for ≥2 years) undergoing parathyroidectomy were entered into a prospective study. Standardized Frequency Scale for Symptoms of GERD (FSSG) questionnaire was used to assess symptoms before, 1 and 2 years after parathyroidectomy. RESULTS: Daily prescription medication was used by 81%, while 19% used daily non-prescription drugs, both for a mean of 2.9 ± 0.7 years. GERD symptoms improved (26%) or resolved completely (36%) in 62% of patients (p < 0.0001 vs. preoperative baseline) 1 year after parathyroidectomy. Prescription medications for GERD decreased from 81% of enrolled patients to 26% (p < 0.0001) 12 months postoperatively, with 39% having complete symptom relief and taking no medications (p < 0.0001). Daily use of prescription GERD medications decreased to occasional over-the-counter drug use in 35% after parathyroidectomy (p < 0.0001). Mean FSSG scores decreased significantly postoperatively (pre-op: 18.0 ± 8.0 vs. post-op: 10.0 ± 5.0; p < 0.0001), with significant improvements in all 12 FSSG categories, including motility (pre-op: 7.3 ± 3.0 vs. post-op: 4.4 ± 3.0; p < 0.0001) and acid reflux symptoms (pre-op: 10.8 ± 5.0 vs. post-op: 5.9 ± 4.0; p < 0.0001). Symptomatic improvements were durable 2 years after parathyroidectomy. CONCLUSION: Symptomatic GERD is common in pHPT. Parathyroidectomy provides significant, durable relief of both motility and acid reflux symptoms allowing discontinuation of prescription drug use for GERD in most (74%) patients providing yet another indication for parathyroidectomy in pHPT.

Abandoning unilateral parathyroidectomy: why we reversed our position after 15,000 parathyroid operations.

BACKGROUND: Our group championed the techniques and benefits of unilateral parathyroidectomy. As our experience has matured, it seems this limited operation might be appropriate only occasionally. METHODS: A single surgical group's experience with 15,000 parathyroidectomies examined the ongoing differences between unilateral and bilateral techniques for 10-year failure/recurrence, multigland removal, operative times, and length of stay. RESULTS: With limited experience, 100% of operations were bilateral, decreasing to 32% by the 500(th) operation (p < 0.001), and long-term failure rates increased to 6%. Failures were 11 times more likely for unilateral explorations (p < 0.001 vs bilateral), causing gradual increases in bilateral explorations to 97% at the 14,000(th) operation (p < 0.001). Ten-year cure rates are unchanged for bilateral operations, and unilateral operations show continued slow recurrence rates of 5% (p < 0.001). Removal of more than one gland occurred 16 times more frequently when 4 glands were analyzed (p < 0.001), increasing cure rates to the current 99.4% (p < 0.001). Of 1,060 reoperations performed for failure at another institution, intraoperative parathyroid hormone levels fell >50% in 22% of patients, yet a second adenoma was subsequently found. Operative times decreased with experience; bilateral operations taking only 5.9 minutes longer on average (22.3 vs 16.4 minutes; p < 0.001), which is 25 minutes less than unilateral at the 500(th) operation (p < 0.001). By the 1,000(th) operation, incision size (2.5 ± 0.2 cm), anesthesia, and hospital stay (1.6 hours) were identical for unilateral and bilateral procedures. CONCLUSIONS: Regardless of surgical adjuncts (scanning, intraoperative parathyroid hormone), unilateral parathyroidectomy will carry a 1-year failure rate of 3% to 5% and a 10-year recurrence rate of 4% to 6%. Allowing rapid analysis of all 4 glands through the same 1-inch incision has caused us to all but abandon unilateral parathyroidectomy.

The effect of vitamin D levels on postoperative calcium requirements, symptomatic hypocalcemia, and parathormone levels following parathyroidectomy for primary hyperparathyroidism.

BACKGROUND: Low vitamin D-25 is common in primary hyperparathyroidism but the effect of this deficiency on postparathyroidectomy calcium requirements is unclear. METHODS: A prospective study was conducted on 4 groups based on preoperative vitamin D-25 levels: very low (<20 ng/mL, n = 500); low (21 to 30 ng/mL, n = 500); normal (>30 ng/mL, n = 500); and supplemented (<25 ng/mL supplemented to >40 ng/mL, n = 285). Patients were placed on identical postoperative oral calcium regimens, and hypocalcemia symptoms were recorded. Total calcium requirements for 2 weeks postoperation were calculated and parathormone (PTH) levels were measured for 2-6 months. RESULTS: Mean vitamin D levels (ng/mL) for each group were: very low (14.2); low (24.4); normal (38.3); and supplemented (16.5 supplemented to 54.3). Postoperative oral calcium requirements (in grams) were identical for all groups (18.7, 18.2, and 18.6, and 19.0, respectively, all P = NS); the incidence and timing of hypocalcemia symptoms were nearly identical for all groups: 8.1%, 7.9%, and 7.8% (P = .8). Elevated postsurgical PTH was identical (below 8%) and was not influenced by vitamin D levels. CONCLUSION: The incidence of hypocalcemic symptoms and the postoperative calcium requirements are identical for patients with very low, low, normal, or supplemented (high) vitamin D. The incidence of persistently elevated PTH postoperatively is also unrelated to preoperative vitamin D levels. Vitamin D supplementation from very low to high levels has no clinical benefit.

Calcium, parathyroid hormone, and vitamin D in patients with primary hyperparathyroidism: normograms developed from 10,000 cases.

OBJECTIVE: To better define the typical and atypical biochemical profiles of patients with surgically proven primary hyperparathyroidism. METHODS: In this single-center, prospectively conducted study of consecutive patients with surgically proven primary hyperparathyroidism over a 7-year period, we analyzed serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations. RESULTS: A total of 10 000 patients were included, and more than 210 000 calcium, parathyroid hormone, and 25-hydroxyvitamin D values were evaluated. Both calcium and parathyroid hormone levels demonstrated a Gaussian distribution with the average calcium concentration being 10.9 ± 0.6 mg/dL and the average parathyroid hormone concentration being 105.8 ± 48 pg/mL. The average highest calcium and parathyroid hormone concentrations were 11.4 ± 0.7 mg/dL and 115.3 ± 50 pg/mL, respectively. At least 1 calcium value of 11.0 mg/dL was seen in 87% of patients, but only 21% had 1 or more calcium value above 11.5 mg/dL. Only 7% had a single serum calcium level reaching 12.0 mg/dL. Normocalcemic hyperparathyroidism was seen in just under 3% of patients who had identical findings at surgery. An average parathyroid hormone concentration less than 65 pg/mL was seen in 16%, with 10% of patients who had no high parathyroid hormone values. The average 25-hydroxyvitamin D concentration was 22.4 ± 9 ng/mL, with levels decreasing as calcium levels increased (P<.001); 36% had 25-hydroxyvitamin D levels below 20 ng/mL. CONCLUSIONS: Patients with PHPT present with a number of distinct biochemical profiles, but as a group, they present with a near-normal Gaussian distribution of both calcium and parathyroid hormone levels. Either serum calcium or parathyroid hormone remained normal in 13% of patients, yet the findings at surgery are similar to those of patients with elevated calcium or parathyroid hormone. Low 25-hydroxyvitamin D is an expected finding in patients with PHPT, decreasing as serum calcium levels increase.

Prospective study in 3,000 consecutive parathyroid operations demonstrates 18 objective factors that influence the decision for unilateral versus bilateral surgical approach.

BACKGROUND: Although localizing studies are well-known predictors of which patients are candidates for unilateral versus bilateral parathyroid exploration, there are a number of other factors that have positive or negative influence preoperatively and intraoperatively. STUDY DESIGN: A prospective study was conducted during 20 months on 3,000 consecutive patients undergoing surgery for primary hyperparathyroidism to determine which factors caused the surgeons to explore bilaterally or, in contrast, influenced a unilateral approach. Seventeen preoperative and 5 intraoperative objective points were documented on all patients to see how decisions were made. RESULTS: Parathyroidectomy was unilateral in 32% and bilateral in 68%. Preoperative factors that had a positive predictive value in dictating a unilateral approach were (in decreasing frequency): positive sestamibi, previous parathyroid/thyroid surgery, age older than 80 years, anticoagulation medications, morbid obesity, and presence of large goiter (all p < 0.001). Preoperative parameters dictating a bilateral approach included negative sestamibi, more than one focus on sestamibi, contralateral thyroid disease, family history, lithium use, history of radiation, MEN, age younger than 20 years, and pregnancy (all p < 0.001). Intraoperative parameters influencing conversion of unilateral to bilateral were false-positive sestamibi, hormone measures not meeting sufficient levels, abnormal ipsilateral gland, and contralateral thyroid pathology identified (all p < 0.001). Factors that had no effect were gender, degree of calcium, and/or parathyroid hormone elevation, and age between 20 and 80 years. Cure rates were 99.9% for bilateral and 99.0% for unilateral (p = 0.057). CONCLUSIONS: High-volume surgeons use a number of identifiable objective factors to determine the best candidates for unilateral versus bilateral parathyroid exploration. Localizing studies such as sestamibi scans ultimately play a minor role in determining how many parathyroid glands are evaluated.

Postoperative calcium requirements in 6,000 patients undergoing outpatient parathyroidectomy: easily avoiding symptomatic hypocalcemia.

BACKGROUND: To determine the amount and duration of supplemental oral calcium for patients with varying clinical presentations discharged immediately after surgery for primary hyperparathyroidism. STUDY DESIGN: A 4-year, prospective, single-institution study of 6,000 patients undergoing parathyroidectomy for primary hyperparathyroidism and discharged within 2.5 hours. Based on our previous studies, patients are started on a sliding scale of oral calcium determined by a number of preoperative measures (ie, serum calcium, body weight, osteoporosis) beginning 3 hours postoperation and decreasing to a maintenance dose by week 3. Patients reported all hypocalcemia symptoms daily for 2 weeks. RESULTS: Seven parameters were found to have a substantial impact on the amount of calcium required to prevent symptomatic hypocalcemia: preoperative serum calcium >12 mg/dL, >13 mg/dL, and >13.5 mg/dL, bone density T score less than -3, morbid obesity, removal of >1 parathyroid, and manipulation/biopsy of all remaining glands (all p < 0.05). Each independent variable increased the daily calcium required by 315 mg/day. Using our scaled protocol, <8% of patients showed symptoms of hypocalcemia, nearly all of whom were successfully self-treated with additional oral calcium. Only 6 patients (0.1%) required a visit to the emergency room for IV calcium, all occurring on postoperative day 3 or later. CONCLUSION: After outpatient parathyroidectomy, a specific calcium protocol has been verified that eliminates development of symptomatic hypocalcemia in >92% of patients, identifies patients at high risk for hypocalcemia, and allows self-medication with confidence in a predictable fashion for those patients in whom symptoms develop.

Hyperparathyroidism during pregnancy and the effect of rising calcium on pregnancy loss: a call for earlier intervention.

INTRODUCTION: Hyperparathyroidism (HPT) during pregnancy is rare but poses a significant danger to mother and baby yet the incidence of pregnancy loss and its relationship to the degree of calcium elevation is not known. DESIGN: A retrospective patient series from a single practice examined the past and current obstetrical histories of pregnant patients with primary HPT. RESULTS: Over a period of 6-years, 32 women age ranging from 19 to 40 years had a total of 77 pregnancies while having elevated serum calcium levels because of primary HPT (incidence 0.7% of all women with primary HPT). Fifteen patients underwent parathyroidectomy during the second trimester resulting in an uneventful delivery of a healthy infant between 36 and 40 weeks gestation. There were no maternal or infant complications at surgery or during the subsequent delivery. Thirty of the remaining 62 pregnancies (48%) were lost, a rate that is 3.5-fold higher than expected (P < 0.05). In those who did not have the HPT addressed after the first miscarriage, one-third lost one or more additional pregnancies. Pregnancy loss occurred typically in the late first or early second trimester, with second trimester losses (30%) being sixfold higher than expected (P < 0.01) and over 4 weeks later than typical (P < 0.05). Foetal loss was seen at all levels of elevated maternal calcium but most were above 11.4 mg/dl (2.85 mmol/l). The rate of foetal loss increased directly with increasing maternal serum calcium levels (R = 0.972). CONCLUSIONS: HPT during pregnancy is under recognized and is associated with a 3.5-fold increase in miscarriage rates. Pregnancy loss often occurs in the second trimester and is associated with multiple miscarriages when not addressed. Pregnancy loss is more common as calcium levels exceed 11.4 mg/dl (2.85 mmol/l), but can be seen at all elevated calcium levels. Emphasis is placed on earlier recognition and surgical cure before becoming pregnant, however, once pregnant, surgery should be offered early in the second trimester for those with calcium levels above 11.4 mg/dl.

5,000 parathyroid operations without frozen section or PTH assays: measuring individual parathyroid gland hormone production in real time.

BACKGROUND: Determining the physiologic activity (hormone production) of individual parathyroid glands can provide tremendous guidance during parathyroidectomy. METHODS: A 6.5-year prospective study of 5,000 patients with sporadic, non-multiple endocrime neoplasia (MEN) primary hyperparathyroidism who underwent surgery without frozen section or parathyroid hormone (PTH) assays was conducted. Patients who had a frozen section were not included; the removal of parathyroid glands was determined solely by the physiologic activity of each gland as determined by contained radioactivity. All operations were within 2.25 hours of sestamibi scanning. Ex vivo measurements of parathyroid glands, thyroid nodules, lymph nodes, thymus, and fat were obtained from all patients, constituting >32,000 specimens. All patients had at least two parathyroid glands evaluated; 59% had four glands evaluated. Ratios were compared with histology and preoperative/postoperative labs. RESULTS: Parathyroid glands occur in three distinct groups according to their hormone production, indicating the type of pathology present. Adenomas (n=5,120) contained 57+/-38% of background radioactivity; hyperplastic glands (n=640) contained 16+/-4%; and normal glands (n=9,400) contained 4+/-0.1% (all p<0.00001). Fat and lymph nodes were always less than normal glands (p<0.005). There was no overlap between different tissue types in any individual (p<0.001). Contained radioactivity was a better predictor of cure than histology (p<0.0001). The average operative time was 19.4 minutes with (99.9%) discharged within 5 hours. The initial cure rate was 99.23% with missed contralateral second adenomas causing all failures (subsequently cured). CONCLUSIONS: Measures of sequestered radioactivity is an extremely accurate estimate of individual parathyroid gland hormone production allowing near 100% distinction between normal, hyperplasic, and adenomatous glands as well as distinguishing parathyroids from other neck tissues (fat, lymph nodes, thyroid). This instantaneous measurement is sufficient to determine which glands should be removed and which should remain in situ, while eliminating frozen sections and PTH assays in nearly all patients undergoing parathyroid surgery. This insight allows the operation to progress very rapidly.

Shingles (varicella zoster) outbreaks in patients with hyperparathyroidism and their relationship to hypercalcemia.

Shingles (varicella zoster) can be a presenting symptom of hyperparathyroidism and occurs twice as often (rate, 3.7%) among patients with hypercalcemia than in age-matched cohorts of patients >40 years of age who have normal calcium levels. The incidence of shingles increased in a linear fashion, from an annual rate of 1.5% among patients with serum calcium levels <10.5 mg/dL to 11% among patients whose calcium levels reached 13 mg/dL (P<.05), a rate that is 6 times greater than that among age-matched historical control individuals (P<.05).

Diagnostic aspiration of parathyroid adenomas causes severe fibrosis complicating surgery and final histologic diagnosis.

OBJECTIVE: To determine whether fine-needle aspiration (FNA) of parathyroid adenomas may cause a severe fibrotic reaction of the gland and surrounding structures, making surgery more difficult and histology more confusing. DESIGN: A study was conducted over a 33-month period to compare the operative findings of 30 patients who underwent FNA of a parathyroid adenoma to those of 3000 patients who had not had their parathyroid tumor aspirated. Each patient's normal parathyroid glands also served as internal controls. All aspirations were performed by referring physicians under direct ultrasound guidance within 3 months of surgery, and all adenomas were located in routine positions. Patients who had previous thyroid or parathyroid surgery were not included. Patients with secondary or tertiary hyperparathyroidism were not included. MAIN OUTCOME: The control group (non-FNA) showed a fibrotic reaction in 127 (4.3%) tumors appreciated by the surgeon and recognized on histology. In contrast, tumors undergoing FNA had a dense and often severely fibrotic reaction seen at surgery in 19 of 30 (63%) (p < 0.0001) and on histology in 23 of 30 (77%) (p < 0.0001). The fibrotic reaction appeared to mimic malignancy on histology and increased in occurrence with increased numbers of aspiration passes and larger needle bore (p < 0.05). No normal glands (n > 7500) or hyperplastic glands (n = 488) demonstrated fibrosis in any patient. Tumors that were aspirated required an eightfold increase in time to remove (p < 0.005) and more than doubled the total operative time (p < 0.05). CONCLUSIONS: FNA of parathyroid adenomas can cause a severe fibrotic process that typically involves adjacent tissues. This reaction dramatically increases the difficulty of surgical resection, often requiring microdissection techniques to preserve nerves and assure complete removal. The fibrosis can cause confusing histology mimicking malignancy. FNA of parathyroid adenomas should be avoided unless absolutely necessary.

Hyperparathyroidism in patients over 80: clinical characteristics and their ability to undergo outpatient parathyroidectomy.

OBJECTIVE: Parathyroid surgery in elderly patients is commonly delayed due to perceived high operative risk. We evaluated the presentation of patients over 80 with primary hyperparathyroidism (PHPT) and their ability to tolerate outpatient, minimally invasive parathyroidectomy. METHODS: We conducted a prospective cohort study of 150 consecutive patients over the age of 80 for the treatment of sporadic, nonfamilial PHPT. Presenting symptoms were compiled by questionnaire and compared between male and female (32 males, 118 females) and to 2600 patients under the age of 80. All patients underwent minimally invasive parathyroidectomy and were discharged from the recovery room. Operative findings and outcomes were assessed. RESULTS: 97% reported at least one symptom--the majority had five or more. The most common symptoms were fatigue, hypertension, and memory problems (occurring in 62%, 62%, and 57% of patients, respectively). Symptoms were similar between men and women, with the exception of bone pain being twice as common in women and kidney stones being twice as common in men (both p < 0.05). Preoperative calcium and parathyroid hormone (PTH) levels as well as the frequency of each symptom closely paralleled those of patients less than 80 years old with no significant differences. Average operative time was 18 +/- 5 minutes with discharge averaging 1.9 +/- 0.2 hours later. The incidence of single adenoma, double adenoma, or hyperplasia was identical to patients less than 80 (p = NS). Two patients required rehospitalization within 30 days of the procedure (congestive heart failure and pulmonary embolism), neither one for hypocalcemia. There were no deaths, and the cure rate was 99.3%. CONCLUSION: PHPT is similar symptomatically, biochemically, and histopathologically between patients > 80 years old and younger patients. Modern techniques allow for small incisions, quick operative times, outpatient discharge, and uneventful recovery. Patients over 80 years old tolerate outpatient parathyroidectomy without event.

Safety of immediate discharge after parathyroidectomy: a prospective study of 3,000 consecutive patients.

OBJECTIVE: To evaluate the safety of immediate discharge after parathyroidectomy and to establish a protocol for the amount and duration of supplemental orally administered calcium for patients with varied clinical presentations of primary hyperparathyroidism. METHODS: A 40-months, prospective, single institution, cohort study of 3,000 consecutive patients undergoing parathyroidectomy and discharged within 2.5 hours after the operation is reviewed. The amount of oral calcium supplementation prescribed postoperatively varied according to a protocol that considered the degree of serum calcium elevation preoperatively as well as the intraoperative findings (hyperplasia versus adenoma). Symptoms of hypocalcemia were tracked, and all surgical outcomes were monitored. RESULTS: With use of the reported protocol, less than 7% of patients had postoperative symptoms of hypocalcemia, most of whom were successfully self-treated with additional orally administered calcium. Only 6 patients (0.2%) required a visit to the emergency department for intravenous calcium infusion, all occurring on postoperative day 3 or later, and none of these patients required rehospitalization. Postoperative calcium requirements varied on the basis of the degree of serum calcium elevation preoperatively, number of parathyroid glands removed or subjected to biopsy, presence of morbid obesity, and presence of severe osteoporosis. CONCLUSION: Patients with primary hyperparathyroidism can be sent home immediately after successful parathyroidectomy, provided specific measures are taken regarding postoperative oral calcium supplementation. Use of a specific calcium dosing protocol that considers several patient variables will prevent the postoperative development of symptomatic hypocalcemia in 93% of patients, identify patients at high risk of hypocalcemia, and allow most patients who develop symptoms of hypocalcemia to self-medicate in a simple and predictable fashion. Routine monitoring of postoperative serum calcium levels in the hospital can be safely eliminated if the details of this protocol are followed.

Minimally invasive radio-guided parathyroidectomy in 152 consecutive patients with primary hyperparathyroidism.

OBJECTIVE: To examine the results of minimally invasive radio-guided parathyroidectomy (MIRP) in the treatment of patients with primary hyperparathyroidism, including factors associated with negative technetium-labeled sestamibi scanning. METHODS: We retrospectively analyzed the findings in a group of 152 consecutive patients encountered during the period 2001 through 2004. The overall accuracy of preoperative sestamibi scanning was assessed, and the success of MIRP was determined on the basis of operative time, duration of hospital stay, and rate of complications. RESULTS: All 152 patients underwent preoperative sestamibi scanning; 118 (78%) had positive scans and were treated with MIRP, whereas 34 (22%) had negative scans and underwent traditional neck explorations. Patients with negative sestamibi scans had 5 times the incidence of concomitant thyroid disease in comparison with those who had positive sestamibi scans (P<0.01), and they had higher rates of parathyroid hyperplasia (26% versus 0%; P<0.01). In comparison with traditional neck dissection, MIRP-treated patients had shorter operative times (38 minutes versus 86 minutes; P<0.01) and shorter hospital stays (0.67 day versus 1.09 days; P<0.01). Among the MIRP-treated patients, 67% were discharged the same day as performance of the outpatient surgical procedure. Correction of hypercalcemia was accomplished in 116 of 118 patients (98%) who underwent MIRP. Complications in the MIRP group were low, including 1 postoperative hemorrhage. No cases of recurrent laryngeal nerve injury occurred. There were 2 false-positive sestamibi scans (1.3%). CONCLUSION: Parathyroid hyperplasia and concomitant thyroid pathologic conditions are associated with negative preoperative sestamibi scans. MIRP is applicable in 78% of patients with primary hyperparathyroidism and is a safe, effective operation that results in shorter surgical time, reduced hospital stay, and minimal complications.