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Ann Surg. Apr 2004; 239(4): 528–535.
PMCID: PMC1356258

The NIH Criteria for Parathyroidectomy in Asymptomatic Primary Hyperparathyroidism

Are They Too Limited?

Abstract

Objective:

To determine whether preoperative and postoperative symptoms and outcome differ in patients who meet or fail to meet the NIH criteria for parathyroidectomy.

Summary Background Data:

The NIH Consensus Conference on primary hyperparathyroidism in 1990 defined criteria for surgical intervention suggesting that some patients can be safely managed without surgery.

Methods:

Over a 3-year period, 202 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidism at a tertiary referral center were prospectively given a questionnaire regarding their symptoms and associated conditions during their initial and follow-up office visits as were 63 thyroid control patients. The 178 patients who completed the follow-up questionnaire were assigned to 2 groups according to the NIH criteria for parathyroidectomy. The frequency of preoperative symptoms and conditions associated with primary hyperparathyroidism as well as postoperative improvement in symptoms and surgical outcome were compared.

Results:

Of the 178 parathyroid patients, 103 met the NIH criteria for parathyroidectomy whereas75 did not. Patient profiles were similar in each group except mean ages, 55 versus 65, and preoperative serum calcium levels, 11.5 mg/dL versus 11.0 mg/dL (NIH and non-NIH groups, respectively; P < 0.001). The incidence of preoperative nonspecific somatic and neuropsychiatric symptoms and associated conditions was equivalent in both groups and more common than in the 63 thyroid control patients. After parathyroidectomy, symptomatic improvement was dramatic and equal between the 2 parathyroid groups. Postoperative mean serum calcium levels were similar (8.78 mg/dL, NIH group, versus 8.75 mg/dL, non-NIH group).

Conclusion:

Symptoms were more common in patients with primary hyperparathyroidism versus thyroid controls, but were not different between those patients who met the NIH criteria for parathyroidectomy and those who did not. Patients in both parathyroid groups benefited symptomatically after successful parathyroidectomy.

Primary hyperparathyroidism (HPT) occurs in 0.2% to 0.5% of the population, with approximately 100,000 new cases appearing in the United States each year.1,2 Primary HPT is the most common cause of hypercalcemia in outpatients and second to cancer in the inpatient population. This disease has evolved from one presenting with the classic triad “painful bones, kidney stones, and abdominal groans” to one where the symptoms are subtle and detection commonly occurs because of documented hypercalcemia on routine biochemical testing.3,4 The classic manifestations of primary HPT are best divided into symptoms (what one feels) and associated conditions (what can be measured, such as kidney stones, osteopenia) of the disease (Table 1). Today patients with primary HPT encompass a broad spectrum ranging from “asymptomatic,” with no apparent associated conditions, mild-to-moderate symptoms with no associated conditions, associated conditions but no symptoms, and finally a few with profound symptoms or parathyrotoxicosis.5

Table thumbnail
TABLE 1. Symptoms and Associated Conditions in Patients With Primary Hyperparathyroidism

Surgical excision of abnormal parathyroid tissue is the only definitive cure for primary HPT. Few would disagree that the best management for the patient with obvious symptoms or associated conditions of the disease or profound hypercalcemia (>12 mg/dL) is parathyroidectomy. The debate surrounds the issue of the best management of the “asymptomatic” patients or those with mild symptoms and no associated conditions of primary HPT. To address this issue, in 1990 the National Institutes of Health together with the National Institute of Diabetes and Digestive Kidney Diseases convened a consensus conference on the Diagnosis and Management of Asymptomatic Primary HPT. They concluded that there may be a subset of “asymptomatic” primary HPT patients who can be safely managed without operative intervention, and they defined a set of guidelines for operative intervention in these patients (Table 2). 2 The difficulties with these criteria are 2-fold: first, the definition of “asymptomatic” HPT is not clear, and second, the criteria for surgical intervention are not well-defined. Primarily, the criteria exclude many nonspecific physical and neuropsychological symptoms that appear to be more common in primary HPT and often improve after surgery.6–8 Furthermore, Burney et al9 as well as others,10,11 recently demonstrated in a prospective study that patients with primary HPT have significant functional health status impairment with dramatic improvement postoperatively that is independent of preoperative serum calcium levels.

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TABLE 2. NIH Criteria for Parathyroidectomy

The purpose of this investigation was to describe the frequency of symptoms and associated conditions in patients with primary HPT versus patients with nontoxic surgical thyroid disease and to compare the frequency of preoperative symptoms and conditions related to primary HPT between patients who meet or fail to meet the NIH criteria for parathyroidectomy. In addition, we examined the differences in postoperative symptomatic improvement among patients who meet or fail to meet the NIH criteria.

METHODS

Patient Selection

We studied 202 consecutive patients with primary HPT with no coexistent appreciable thyroid disease who underwent first-time parathyroidectomy between September 1996 and December 1999. All operations were performed by 1 surgeon at the University of California San Francisco/Mount Zion Medical Center. All patients were asked to prospectively complete a questionnaire regarding their symptoms and associated conditions pertaining to parathyroid disease at their initial office visit and again at their initial and subsequent postoperative visits.5 Permission to review patient charts and questionnaires was approved by the UCSF institutional review board (IRB# H5241-08605-10). This questionnaire has been described in greater detail by Chan et al6 The questionnaire was provided to the patient by a receptionist and completed prior to the patient's visit with the surgeon. Eighty-eight percent (178 of the 202) of the patients responded to both the preoperative and postoperative questionnaire. Average follow-up time was 1 month, but as long as 3 years in some cases. These 178 patients were then subdivided into 2 groups, the NIH group and the non-NIH group. To qualify for the NIH group, the patients had to meet one of the NIH criteria for parathyroidectomy as defined by the consensus conference in 1990 (Table 2).2 Of these 178 patients, 103 met the criteria and formed the NIH group whereas 75 comprised the non-NIH group. Comparisons were then made between the 2 groups concerning frequency of preoperative and postoperative symptoms and conditions as well as surgical outcome.

With regard to those parathyroid patients who were excluded (n = 24) based on incomplete follow-up data, there was no difference between this group and those with complete follow-up data (n = 178) with respect to gender, group assignment, age, number of preoperative symptoms, or number of associated conditions. There appears to be no selection bias based on the degree of sickness preoperatively as determined by the frequency of symptoms or conditions between those who were included and those who were excluded from the study.

To compare the frequency of symptoms and associated conditions of HPT with those of other endocrine conditions, 63 thyroid cases were selected as control patients. These patients were selected on the basis of having first-time thyroid or neck surgery, excluding those with Graves’ disease, Hashimoto's thyroiditis, or coexisting parathyroid disease, during the same time period as the parathyroid patients. These patients completed the same questionnaire as the parathyroid patients both preoperatively and postoperatively.

Outcomes Measured

Data that were collected for the HPT patients and thyroid controls from the preoperative and postoperative questionnaires was categorized into symptoms or clinical conditions possibly associated with primary HPT. There were 9 associated conditions and 14 symptoms that were investigated (Table 1). In addition, serum calcium and parathyroid hormone levels were collected when available as well as pathology results.

Patient Clinical Profile

The patients’ clinical profiles are shown in Table 3. The average age of the HPT sample as a whole was 58.93 ± 12.32, which is not significantly different from the thyroid control group (57.41 ± 13.87). As expected based on the NIH criteria of age <50 as an indication for parathyroidectomy, the NIH HPT group was significantly younger (55 years) than the non-NIH HPT group (65 years; t = 5.57, P < 0.0001). There was no significant difference in the distribution of gender between any of the groups. In addition, there was no significant difference in the pathologic diagnoses between the parathyroid groups.

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TABLE 3. Patient Profiles

Statistical Methods

Chi-square tests were used to determine whether there were between group differences in the presence or absence of preoperative symptoms or conditions. To examine differences in frequency of postoperative improvement in the NIH versus the non-NIH parathyroid groups, only those patients who reported the presence of each preoperative symptom were included in the postoperative improvement results, yielding smaller and more variable numbers in each analysis. Fisher exact test was used for analyses in which there were 5 or fewer observations per cell. A probability of P < 0.05 was the criterion for significance. Statview 4.51 was used in all analyses with the exception of the data in Figure 4, where the 2-sample test for binomial proportions was used to determine significance.

figure 13FF4
FIGURE 4. Frequency of preoperative symptoms in the NIH HPT group versus the non-NIH HPT group. Preoperatively the nonspecific somatic and neuropsychiatric symptoms are common in both groups with equal frequency.

RESULTS

One hundred seventy-eight patients with primary HPT completed both the preoperative and postoperative questionnaire. Of those patients, 103 fulfilled at least 1 of the NIH criteria for parathyroidectomy and were placed into the NIH group. Table 4 lists the frequency of each one of the criteria within the NIH group. Although not included in Table 4, it is interesting to note that 16 (16%) patients were included in the NIH group by meeting only the criteria of “age less than 50.” There was no significant difference between the 2 groups in gender distribution, preoperative PTH, or pathologic diagnoses (Table 3). As anticipated by the inclusion criteria for the NIH group, this group was significantly younger than the non-NIH group. In addition, the preoperative serum calcium values differed significantly (11.5 mg/dL in the NIH group versus 11.0 mg/dL in the non-NIH group; P < 0.001), which was not unexpected based on the NIH criteria of serum Ca > 12.0 mg/dL.

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TABLE 4. Characteristics of NIH Group

A third group of patients, composed of 63 patients who underwent thyroid operations as previously described, was chosen as a control group to compare the incidence of nonspecific somatic symptoms preoperatively and postoperatively. When compared with the hyperparathyroid patients as a whole, there was no significant difference between the age and gender distribution between the 2 groups. Overall, the HPT group was more symptomatic preoperatively than the thyroid group with an average of 5.59 ± 3.05 symptoms in the HPT group versus 3.13 ± 2.77 in the thyroid group (P < 0.0001). Figure 1 compares the incidence of preoperative symptoms between the thyroid control group and the primary HPT group. The hyperparathyroid group had higher frequencies of all 14 symptoms associated with primary HPT. Nine of the 14 symptoms were not only more common, but had a statistically significant association with the hyperparathyroid group. Prior to operation, only 5 (2.8%) patients with primary HPT had no symptoms, while 9 (14%) thyroid patients denied symptoms preoperatively (P < 0.005). Figure 2 demonstrates the incidence of associated conditions in the parathyroid versus the thyroid group. Most of the conditions were more frequent in the hyperparathyroid group, and there was a statistically significant association between HPT and 3 conditions: nephrolithiasis, osteoporosis, and osteopenia. Figure 3, which represents the change in symptom frequency after surgery, demonstrates that the HPT group had a significant decrease in eleven of fourteen symptoms after parathyroidectomy versus the thyroid group after thyroidectomy.

figure 13FF1
FIGURE 1. Frequency of preoperative symptoms in the combined primary hyperparathyroid group versus the thyroid group. The figure displays the preoperative incidence of 14 somatic symptoms that are possibly associated with primary HPT. Nine of the 14 symptoms ...
figure 13FF2
FIGURE 2. Incidence of preoperative associated conditions in the combined primary hyperparathyroid group versus the thyroid group. Seven of the conditions displayed are more common in the primary hyperparathyroid group than the thyroid controls.
figure 13FF3
FIGURE 3. Changes in the frequency of symptoms after surgery in the combined hyperparathyroid group versus the thyroid group. Overall, the hyperparathyroid group experiences a greater decrease in most of the associated symptoms.

We next compared the frequency of preoperative symptoms and conditions between the NIH HPT group and the non-NIH HPT group (Figs. 4 and 5). Figure 4 demonstrates that 13 of the 14 possibly related symptoms occurred with nearly equal frequency preoperatively in the 2 groups. The symptoms including fatigue, musculoskeletal aches and pains, weakness, and back pain were the most frequently noted symptoms and occurred in at least 50% of patients in both groups with primary HPT. Pruritus was the only symptom that differed significantly between the 2 groups occurring in 35% of the non-NIH group versus 18% of the NIH group (P < 0.05). The frequency of preoperative conditions in Figure 5 was also very similar between the 2 groups with the exception of nephrolithiasis and hypertension. Nephrolithiasis is one of the NIH criteria, accounting for the higher incidence in that group. Hypertension was significantly more prevalent in the non-NIH group over the NIH group (47% versus 32%). This is perhaps a reflection of the age of the 2 populations, with the non-NIH group on average 10 years older than the NIH group.

figure 13FF5
FIGURE 5. Incidence of preoperative conditions. The associated conditions of primary HPT occur equally preoperatively between the NIH and non-NIH groups with the exception of nephrolithiasis and hypertension.

The postoperative symptomatic improvement was also compared between the NIH group and the non-NIH group. The average follow-up time was 1 month. Figure 6 demonstrates the percentage of patients who experienced the symptom prior to operation that then reported improvement or absence of the symptom postoperatively. Both groups experienced significant improvement in most of the symptoms, with over 50% improvement in 10 of the 14 symptoms, including fatigue, low back pain, polydypsia, polyuria, nocturia, depression, memory loss, anorexia, nausea, and pruritus. The frequency of improvement was not significantly different between the NIH and non-NIH HPT groups for any of the symptoms noted.

figure 13FF6
FIGURE 6. Postoperative symptomatic improvement in the NIH HPT group versus the non-NIH HPT group. The improvement in somatic symptoms is significant and equal in both groups.

Postoperative outcome as measured by serum calcium, serum PTH, and number of persistent or recurrent cases was also examined between the 2 groups. Postoperatively, serum calcium levels were similar: 8.78 mg/dL in the NIH group and 8.75 mg/dL in the non-NIH group (P = 0.79). Serum PTH levels were not significantly different (45 ± 51 pg/mL in the NIH group versus 32 ± 27 pg/mL in the non-NIH group) (P = 0.10). There were 6 (5.8%) persistent/recurrent cases in the NIH group and 2 (3%) in the non-NIH group. The 5 cases in the NIH group included one double adenoma, one case of double adenoma where a third parathyroid tumor was found at the second operation, one missed retroesophageal single adenoma, and 3 cases of hyperplasia. The 2 cases in the non-NIH group included one double adenoma and one case of hyperplasia. There were no recurrent laryngeal nerve injuries, no cases of hypoparathyroidism, or other serious complications in either group.

DISCUSSION

The benefits of surgery are indisputable for patients with symptomatic hypercalcemia. There is little disagreement that surgery is indicated in all patients with symptomatic hypercalcemia or those patients with serum calcium levels above 12 mg/dL.10,12 However, some advocate that there is a subset of “asymptomatic” patients who can be safely medically managed without any increased morbidity or mortality.13–15 The NIH consensus conference in 1990 on primary HPT defined criteria for surgical intervention in this group of “asymptomatic” patients.2 The criteria, however, were established for an entity that was not well-defined. In fact, the conference does not address some of the more nonspecific symptoms such as fatigue, weakness, back pain, polyuria, and other symptoms that are very common in this group of patients and often interfere with their quality of life. We believe true “asymptomatic” HPT is uncommon. In our previous study,6 we document that fewer than 5% of patients with primary HPT had no symptoms, and more importantly, only 5.3% of these patients failed to have any improvement in symptoms or associated conditions after successful parathyroidectomy.

The purpose of this study was to determine if the frequency of preoperative symptoms and conditions associated with primary HPT differed in patients who meet the NIH criteria versus those who do not, and to determine if the postoperative outcomes differed between these 2 groups. First to reconfirm the association of these nonspecific symptoms and primary HPT, we compared the 178 patients in the HPT group to a control group of 63 patients with nontoxic thyroid conditions who underwent thyroid surgery during the same time period. Patients with thyroid operations were chosen because they had a similar operation with the same recovery period as the HPT patients. Similar to the results of our previous study,6 our results again demonstrate that there is a set of nonspecific somatic symptoms that appears to be more common in HPT patients, and the symptoms do not correlate to the degree of hypercalcemia except when it is severe. While the reason for the association of primary HPT with these nonspecific symptoms is not fully understood, this and other studies,6–9,16,17 demonstrate that many of these symptoms do improve after successful parathyroidectomy with the improvement in symptoms occurring as early as a week after surgery and remaining in most patients at follow-up periods as long as 2 years. In addition, improvement of some associated conditions is well documented after successful parathyroidectomy including resolution of hypercalcemia, increased bone mineral density, reversal of psychiatric symptoms, decreased incidence of nephrolithiasis, and decreased left ventricular hypertrophy which lessens the risk of death from cardiovascular disease.10,18

Our results demonstrate that the nonspecific somatic symptoms associated with primary HPT occur with equal frequency in the NIH group compared with the non-NIH group, with the exception of pruritus. In addition, there is relatively equal frequency of improvement in these symptoms after parathyroidectomy with over 50% of the patients in each group reporting improvement in at least 10 of the 14 symptoms. The frequency of associated conditions was also similar preoperatively with the exception of nephrolithiasis and hypertension. Nephrolithiasis is one of the NIH criteria, thereby accounting for this discrepancy. Hypertension was more common in the non-NIH group; this is probably due to the older mean age of this sample.19 Finally, when comparing postoperative outcomes between the 2 groups, there was no significant difference between mean serum calcium levels, mean serum PTH levels, and number of recurrent cases or failed operations. It is noteworthy that there were no recurrent laryngeal nerve injuries or patients with hypoparathyroidism in either group and the median duration of hospitalization was 1 day.

The NIH criteria for parathyroidectomy were established as guidelines to be used to determine what subset of “asymptomatic” primary HPT patients might be safely medically managed versus operative intervention. As previously discussed, 1 problem is that the definition of “asymptomatic” primary HPT is not clear. A more important unanswered question concerns the long-term complications in these patients when treated medically or not treated. The first 10-year prospective study to answer this question was undertaken in 1968 at the Mayo Clinic.20 They followed 147 patients with the provisional diagnosis of “biochemical” HPT over a 10-year period during which 38 (26%) were eventually treated surgically. Thirty-two patients died during the follow-up period and 1 developed hypercalcemic crisis. The indications for surgery varied and their conclusion was that it is not possible to define criteria that will predict which patients will ultimately develop complications or progressive disease. More recently, Silverberg et al performed a 10-year prospective study where they found that of 52 “asymptomatic” patients who did not initially undergo surgery, 27% required surgery over the 10-year period despite no change in serum calcium levels, urinary calcium excretion, or bone mineral density.10 Once again, they found no reliable predictors to determine who would eventually require surgery prior to the development of complications. Yet the NIH consensus conference suggested that serum calcium levels be measured biannually, and serum creatinine and bone density annually as a means of adequate medical surveillance. Another important question is whether untreated “asymptomatic” primary HPT adversely affects patient survival? Studies demonstrate that untreated primary HPT is associated with an increased mortality due to cardiovascular disease.11,21,22 It is noteworthy that in the study by Palmer et al,21 the patients had minimal hypercalcemia (mean calcium level 10.4 mg/dL). Hedbeck et al21 demonstrated that successful parathyroidectomy decreased the risk of premature death. In this study, younger patients and those with less severe disease returned to normal life expectancy sooner than older patients or those with more severe disease. On the other hand, a recent study of a relatively small cohort of patients in the United States failed to document an increased mortality rate in patients with primary HPT, but there was a positive correlation of death rate and serum calcium level.23 These conflicting results indicate the necessity for further research regarding the possible adverse effect of minimal hypercalcemia due to HPT on survival.

At the NIH workshop in 2002 regarding the 1990 consensus on “asymptomatic primary HPT,” certain previously recommended criteria remained the same including age less than 50 years and timing of surveillance.24 However, the serum calcium level to recommend parathyroidectomy decreased to greater than 1 mg above the upper limits of normal (or >11.5 mg/dL). The bone density recommendation was changed to a bone density at any site that is more than 2.5 SD below peak bone mass (ie, versus a young adult) rather than a z-score as an indication for parathyroidectomy. Using these new recommendations, we reexamined our data and found that among our non-NIH group, 11 patients based on serum calcium and 4 patients based on t score would now fulfill the NIH criteria for parathyroidectomy. Preliminary review of the outcomes for this subset of patients did not reveal any major differences in outcome versus the NIH or non-NIH groups. Thus the amended recommendations would not change the overall results of our study. Since our poster presentation of this data at the Endocrine Society meeting in June 2000, Sywak et al25 reported similar results in smaller patient cohorts but with longer follow-up.

Although primary HPT may or may not have an adverse effect on long-term mortality, we, as well as others,26 believe parathyroidectomy results in both subjective and objective benefits for patients with mild primary HPT. Furthermore, long-term prospective studies supporting the nonoperative approach demonstrate that at least 25% of patients will eventually require surgery, but none have been able to define criteria that will predict which patients will require surgery prior to the development of complications.10,20 While the NIH attempted to do this in the consensus conference in 1990, our study demonstrates no difference in preoperative symptoms or conditions, and equal improvement after surgery between 2 groups of patients, 1 that meets the NIH criteria, and 1 that does not. Based on this, we question whether such criteria should be used when determining which patients should undergo parathyroidectomy. We believe that virtually all patients with primary HPT benefit symptomatically, metabolically, and from a survival point of view after successful parathyroidectomy so that most patients with primary HPT should be treated surgically by an experienced surgeon.

Footnotes

Presented in part as a poster at the Endocrine Society meeting, June 2000, Toronto, Canada.

Supported in part by Mount Zion Health Systems and the Friends of Endocrine Surgical Oncology, the Gerald Heller Family Foundation, the Albert Clark Family Foundation, and the Sanford & Helen Diller Foundation. Monica S. Eigelberger, MD, was supported by a National Institute of Health, National Research Service Award #T32Ca09696 from the National Cancer Institute, Cancer Training Branch.

Reprints: Orlo H. Clark, MD, 1600 Divisadero Street, C342, San Francisco, CA 94143–1674. Email: ude.fscu.yregrus@okralc.

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