- Email: [email protected]
Improvement in patient-reported physical and mental health after parathyroidectomy for primary hyperparathyroidism
Endocrine Improvement in patient-reported physical and mental health after parathyroidectomy for primary hyperparathyroidism Kyle Zanocco, MD,a,b Zeeshan Butt, PhD,a,b,c David Kaltman, BS,a Dina Elaraj, MD,a David Cella, PhD,b,c Jane L. Holl, MD, MPH,b and Cord Sturgeon, MD,a Chicago, IL
Background. The majority of patients with primary hyperparathyroidism (PHPT) are diagnosed without the classic signs of renal or osseous complications. Vague and subjective symptoms have been attributed to PHPT but have been difficult to measure during the medical encounter. The Patient-Reported Outcomes Measurement Information System (PROMIS) of the National Institutes of Health contains validated measures of physical and mental health that can be administered by the use of computer-adaptive testing (CAT). The objective of this study was to evaluate the feasibility of PROMIS assessment in the clinical setting to measure changes in patient-reported health before and after parathyroidectomy. We hypothesized that patients undergoing parathyroidectomy for PHPT would report greater improvement in mental and physical health compared with control patients. Methods. Adult PHPT patients scheduled for parathyroidectomy and control patients requiring diagnostic thyroid operation were enrolled prospectively during a 6-month period. Patients were administered clinically relevant PROMIS health domains via CAT at a preoperative visit and 3 weeks after operation. A change in score of 5 or greater for each PROMIS instrument was defined as clinically important. Statistical significance of pre/post-surgery changes in scores was determined using paired t tests. Results. A total of 35 patients with PHPT and 9 control patients completed the study. The mean number of PROMIS items answered during an assessment was 67 (range 51–121, SD 15.4). Median completion time was 8.2 minutes (range 3.4–38.4, SD 4.7). Clinically important improvement after parathyroidectomy in the PHPT group was greater than in the control group in 5 PROMIS domains. The score improvement experienced by PHPT patients was 8.8 in Fatigue, 6.7 in Sleep-Related Impairment, 5.0 in Anxiety, 7.0 in Applied Cognition, and 6.2 in Depression (all P < .05). Conclusion. PROMIS is an efficient clinical assessment platform for measuring patient-reported outcomes in PHPT via CAT. Several domains of physical and mental health in patients with PHPT show statistically and clinically important improvement after parathyroidectomy. (Surgery 2015;158:837-45.) From the Department of Surgery,a Center for Healthcare Studies,b and Department of Medical Social Sciences,c Northwestern University Feinberg School of Medicine, Chicago, IL
PRIMARY HYPERPARATHYROIDISM (PHPT) causes hypercalcemia through excessive secretion of parathyroid hormone. When untreated, this condition has resulted traditionally in osteoporosis and nephrolithiasis as
the result of long-term disruption in calcium homoeostasis; however, the disease presentation has changed dramatically during the past several decades.1 Approximately 75% of new PHPT patients
Kyle Zanocco’s participation in this study was supported in part by the Northwestern University Feinberg School of Medicine Center for Healthcare Studies under an institutional award from the Agency for Healthcare Research and Quality, T-32 HS 000078 (PI: Jane L. Holl, MD, MPH).
Reprint requests: Cord Sturgeon, MD, Department of Surgery, Northwestern University Feinberg School of Medicine, 676 N St. Clair St. Ste 650, Chicago, IL 60611. E-mail: csturgeo@ nmh.org.
Presented at the 10th Annual Academic Surgical Congress in Las Vegas, NV, February 3–5, 2015.
Ó 2015 Elsevier Inc. All rights reserved.
Accepted for publication March 18, 2015.
0039-6060/$ - see front matter http://dx.doi.org/10.1016/j.surg.2015.03.054
SURGERY 837
838 Zanocco et al
are now diagnosed incidentally via multiphasic blood screening, and many are now discovered without the traditional physical manifestations of this disease.1 Although parathyroidectomy is indicated for all patients with symptomatic PHPT, the management of patients with so-called ‘‘asymptomatic’’ or ‘‘mild’’ PHPT is controversial. The current guidelines of the international consensus conference for the management of asymptomatic PHPT recommend parathyroidectomy for PHPT with any of the following clinical parameters: younger than 50 years of age, serum calcium greater than 1.0 mg/dL greater than the upper laboratory limit of normal, 24-hour urine calcium concentration greater than 400 mg/dL, creatinine clearance of less than 60 ml/min, bone mineral density T-score of less than 2.5 at any site, or the presence of nephrolithiasis, nephrocalcinosis, or vertebral fracture on imaging examinations.2 Observation is recognized by the guidelines as an acceptable alternative to parathyroidectomy for patients who do not meet these operative criteria. Despite these recommendations, many believe that parathyroidectomy is the optimal treatment for the majority of ‘‘asymptomatic’’ or ‘‘mild’’ PHPT patients who do not meet the guidelines.3-6 Although progression of disease during observation was once thought to be rare, it is now known that PHPT patients who do not meet the criteria for parathyroidectomy have an approximately 25% risk of progression, including the development of osteoporosis or nephrolithiasis if they are observed during a 10-year period.7 In addition, parathyroidectomy has been found to be more cost-effective than observation or pharmacologic therapy for patients with asymptomatic PHPT.4 Vague neurocognitive symptoms including fatigue and cognitive impairment have been attributed to PHPT but have been difficult for physicians to measure during the medical encounter.8-10 A growing body of evidence suggests that even those with mild biochemical disease experience improvement in these symptoms after curative parathyroidectomy, questioning whether any patient with PHPT can be truly asymptomatic.11 The debate concerning the optimal treatment of patients with PHPT who do not meet the consensus criteria for parathyroidectomy exists because of differing interpretations of the risk/benefit balance of parathyroidectomy for this disease. Those who support observation believe that the risks of parathyroidectomy outweigh the expected benefits of biochemical cure. Those who favor parathyroidectomy for these patients believe that the benefits of cure, including potential improvements in quality of life, outweigh the operative risks of parathyroidectomy. More data about the impact
Surgery September 2015
of parathyroidectomy on quality of life are needed to inform the debate regarding the optimal management strategy for this group of patients. The Patient-Reported Outcomes Measurement Information System (PROMIS) of the National Institutes of Health has the capability to acquire these data. PROMIS contains standardized measures of physical, mental, and social health that can be administered efficiently to patients via computeradaptive testing (CAT).12 This system calculates individual T-scores for various domains of health based on patient responses to multiple choice items. The objective of this study was to investigate the effects of parathyroidectomy on patient-reported mental and physical health in patients with PHPT and to assess the feasibility of acquiring this information in the clinic setting using PROMIS. We hypothesized that: 1. Patients with PHPT would report improved mental and physical health after undergoing successful parathyroidectomy compared with control patients undergoing thyroid operation for benign disease. 2. Both patients with PHPT who meet and do not meet the current consensus guideline recommendations for parathyroidectomy would have improved mental and physical health after parathyroidectomy.
METHODS Study population. Approval from the Northwestern University Institutional Review Board was obtained for this prospective study. Participant enrollment occurred during a 6-month period from September 1, 2012 to February 28, 2013. Patients older than the age of 18 who were evaluated in the Northwestern Memorial Faculty Foundation Endocrine Surgery Clinic and had a biochemical diagnosis of PHPT (serum calcium exceeding 10.5 mg/dL with a serum parathyroid hormone [PTH] level at or exceeding 50 pg/mL) were eligible for inclusion. A PTH level of 50 was selected, because this level is in the middle of the laboratory’s normal PTH range (12–88). Patients with thyroid nodules requiring diagnostic hemithyroidectomy or total thyroidectomy also were enrolled as controls. Exclusion criteria included the presence of persistent or recurrent PHPT after previous parathyroidectomy, an inherited form of hyperparathyroidism, parathyroid cancer, current use of antipsychotic medications, or use of a mobility aid. Control patients with thyroid nodules that were determined to be malignant also were excluded from the study. Assessment of patient-reported outcomes. Study patients who agreed to participate were registered
Surgery Volume 158, Number 3
in Assessment Center (www.assessmentcenter.net), the Web-based platform used for the administration of PROMIS instruments. Participants were then provided access to a desktop or tablet computer to complete a patient-reported outcomes assessment. Twelve PROMIS v1.0 banks representing domains of physical and mental health were determined to be most relevant to the identification of the symptomatic disease burden in PHPT based on literature review and the opinion of 2 practicing endocrine surgeons.8-10,13-15 The selected physical health domains included Fatigue, Interest in Sexual Activity, Pain Intensity, Physical Function, Global Satisfaction with Sex Life, Sleep Disturbance, and SleepRelated Impairment. The selected mental health domains included Anger, Anxiety, Applied Cognition---Abilities, Applied Cognition---General Concerns, and Depression. Patients were administered computerized assessments of these domains during their preoperative and 3-week postoperative clinical encounters. In nine domains, CAT was employed to achieve an accurate score using the fewest possible number of items. These items were selected using a computer algorithm based on a patient’s response to a previously administered item. The CAT algorithm was programmed so that patients continued to complete items in a domain until a T-score estimate with a standard error of 0.3 or smaller was achieved, or the patient completed a maximum of 12 items. A computer-delivered short form was employed for three domains that were not supported by CAT (Pain Intensity, Interest in Sexual Activity, and Satisfaction with Sex Life). Medical record review. Review of the medical record was performed to subclassify patients with PHPT according to the presence or absence of an indication for parathyroidectomy as recommended by the current guidelines of the international consensus conference for the management of asymptomatic primary hyperparathyroidism.2 Available demographic and baseline laboratory data also were abstracted from the medical records. PHPT cure was defined as normalization of serum calcium level after parathyroidectomy. Data analysis. Descriptive statistical analysis and hypothesis testing was performed on the study data with Stata 12.1 (StataCorp LP, College Station, TX). A change in instrument score of 5 or greater was defined as clinically important based on previously published data.16 Statistical significance of differences in age and baseline laboratory values between PHPT and control patients was determined using an unpaired t-test (a = .05). Pearson’s v2 testing was used to determine significance of differences in sex, race, and ethnicity categories (a = .05).
Zanocco et al 839
Fig 1. Study flow of the PHPT group. Of the 53 patients with PHPT approached, 40 (75%) had a curative parathyroidectomy and 35 (66%) completed both pre- and postoperative assessments. Patients who did not complete the testing are shown in the periphery with explanations for their exclusion or absence from the group that completed both assessments.
Statistical significance of pre/postoperative changes in PROMIS scores and laboratory values was determined using paired t tests (a = .05). RESULTS Study flow and participant data. Figures 1 and 2 show the complete study flow of the patients in the PHPT and control groups, respectively. Fifty-three patients with PHPT and 13 control patients were approached for participation. After nonenrollment and exclusions, 85% of patients with PHPT and 77% of control patients completed a preoperative PROMIS assessment. All patients were able to complete the assessments without assistance after a brief tutorial. Table I displays the demographic characteristics and preoperative laboratory values for these remaining participants. Demographics were comparable between the PHPT and control groups. The mean total serum calcium concentrations in the PHPT group were 10.9 mg/dL compared with 9.3 mg/dL in the control group (P < .0001). Serum TSH was normal in both groups. 35 patients with PHPT who had a successful parathyroidectomy and 9 control patients completed a postoperative PROMIS assessment. Five other PHPT patients underwent successful parathyroidectomy, but did not complete a postoperative assessment, because they did not attend a postoperative clinic appointment before the end of the study using the office-based PROMIS assessment on May 15, 2013. In the PHPT group, total serum calcium decreased from a mean of 10.9 to 9.8 (P < .0001) and PTH decreased from 125 to
840 Zanocco et al
Fig 2. Study flow of thyroid surgery control patients. Of the 13 thyroid nodule control patients approached, 9 (69%) completed both pre- and postoperative assessments. Patients that did not complete the testing are shown in the periphery with explanations for their exclusion or absence from the group that completed both assessments.
58 (P < .0001). In the control group TSH increased from 1.38 to 2.42 (P = .22), but remained within the normal range. The mean number of PROMIS items answered during an assessment was 67 (range 51–121, SD 15.4). Median completion time of the PROMIS assessment was 8.2 minutes (range 3.4–38.4, SD 4.7). The average time between preoperative PROMIS assessment and operation was 40 days (range 2–139, SD 28) in the PHPT group and 38 days (range 23–54, SD 13) in the control group (P = .75). The average time between operation and postoperative PROMIS assessment was 22 days (range 20–24, SD 8) in the PHPT group and 23 days (range 18–27, SD 6) in the control group (P = .73). Patient reported outcomes pre/postoperation. Preoperative patient-reported health tended to be worse for all measured PROMIS domains in the PHPT group compared with control patients, but statistically significant differences were only observed in the Pain Intensity and Physical Function domains (Table II). Patients with PHPT who underwent curative parathyroidectomy had statistically and clinically important improvement in the PROMIS Physical Health domains of Fatigue, Sleep Disturbance, and Sleep-Related Impairment and in the PROMIS Mental Health domains of Anger, Anxiety, Applied Cognition---Abilities, Applied Cognition---General Concerns, and Depression (Table III). In the control group, Pain Intensity and Physical Function were
Surgery September 2015
statistically and clinically worse during postoperative assessment (Table IV). When the improvement in each domain for PHPT patients after curative parathyroidectomy was compared to the postoperative improvement in the control patients, greater improvement was observed in the PHPT group in the Fatigue, Pain Intensity, Physical Function, Sleep-Related Impairment, Anxiety, Applied Cognition---Abilities, and Depression domains (Table V). Similar improvement in PROMIS scores was observed in PHPT patients who met and did not meet criteria guidelines of the current international consensus conference for parathyroidectomy (Tables VI and VII). The only significant observed difference between these 2 groups was improved interest in sexual activity in patients who did not meet consensus criteria for parathyroidectomy (Table VII). DISCUSSION This study demonstrates that several domains of physical and mental health in patients with PHPT are improved after parathyroidectomy. The findings also suggest that these domains improve in ‘‘asymptomatic’’ PHPT patients who do not meet consensus criteria for parathyroidectomy to the same extent as PHPT patients who do meet the criteria. Furthermore, given a median completion time of less than 10 minutes for the assessment of 12 domains, computer-delivered PROMIS instruments have the practical value of time-efficient administration in an outpatient clinic setting. The wide range of PROMIS items required by different patients to complete the assessment is notable and demonstrates the ability of CAT to create efficiency compared with standard questionnaires by eliminating unnecessary questions. Several previous studies have investigated the effects of treated and untreated PHPT on patientreported overall health and well-being. Three, randomized, prospective trials of parathyroidectomy versus observation for mild PHPT have used the SF-36 assessment tool to measure quality of life in their subjects.17-19 The SF-36 is a 36-item instrument that assesses limitations in physical and social activities, pain, general mental health, energy, and general health perceptions.20,21 The nonparticipation rate was high in all of these studies, and no information about underlying characteristics of the nonparticipants was provided. A benefit of parathyroidectomy ranging from a 5–25% improvement in SF-36 scores compared with observation was evident in some of the quality of life measures, including bodily pain, general health, social and
Zanocco et al 841
Surgery Volume 158, Number 3
Table I. Patient demographics and preoperative laboratory values Primary hyperparathyroidism (n = 45) Mean age, y (SD) Sex Female Male Race Asian Black/African American White Unknown Ethnicity Hispanic/Latino Not Hispanic/Latino Unknown Laboratory values (SD) Total serum calcium, mg/dL Serum PTH, pg/mL TSH, mIU/L
Control group: benign thyroid nodule (n = 10)
55 (12.0)
51 (10.1)
36 (80%) 9 (20%)
7 (70%) 3 (30%)
1 4 38 2
(2%) (9%) (84%) (4%)
0 3 (30%) 6 (60%) 1 (10%)
3 (7%) 31 (69%) 11 (24%)
0 8 (80%) 2 (20%)
P value .28 .49
.25
.65
10.9 (0.6), n = 45 117 (54), n = 45 1.70 (0.74), n = 31
9.4 (0.5), n = 8 Not measured 1.38 (0.87), n = 9
<.0001 n/a .36
PTH, Parathyroid hormone; TSH, thyroid-stimulating hormone. Bold text denotes statistical significance.
Table II. Comparison of preoperative PROMIS scores in patients with primary hyperparathyroidism and control patients with benign thyroid nodules Domain Physical Health Fatigue Interest in Sexual Activity Pain Intensity Physical Function Satisfaction with Sex Life Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Operation for hyperparathyroidism (95% CI) (n = 45)
Controls: operation for benign thyroid nodule (95% CI) (n = 10)
P value
52.3 51.6 38.4 49.1 53.7 51.6 50.0
(48.4–56.1) (48.4–54.9)* (35.8–41.0) (46.6–51.6) (49.6–57.7)y (48.4–54.7) (46.1–53.8)
49.3 53.4 31.9 56.1 53.9 49.4 49.0
(47.0–51.8) (48.3–58.5) (29.2–34.6) (52.4–59.8) (47.0–60.7)z (44.9–53.9) (45.9–52.0)
.20 .54 .0007 .003 .96 .40 .66
51.9 53.0 46.5 37.3 50.3
(48.7–55.1) (50.1–55.7) (43.9–49.1) (33.0–41.6) (47.7–53.0)
50.3 51.8 50.4 34.7 46.0
(46.0–54.6) (48.2–55.3) (46.3–54.5) (28.3–41.2) (41.1–50.8)
.53 .57 .09 .48 .10
*n = 41. yn = 33. zn = 8. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
emotional role function, vitality, and mental health, but the observed benefits were not consistent across the 3 studies. The broad scales used in the SF-36 may have lacked the necessary precision to detect subtle differences in symptom severity that affect the quality of life in PHPT. In an attempt to address the lack of precision when applying generic quality of life measures to patients with PHPT, a disease-specific outcome assessment tool was developed to identify those
symptoms most likely to respond to parathyroidectomy.22,23 This tool documented severity of 13 symptoms related to PHPT using a visual analog scale to produce a symptom score. Using this tool, 203 patients with PHPT were given this assessment before and after parathyroidectomy. A significant improvement in symptom score was shown in postoperative PHPT patients compared to a control group of nontoxic thyroidectomy patients. The improvement in symptom scores in PHPT
842 Zanocco et al
Surgery September 2015
Table III. Comparison of preoperative and postoperative PROMIS scores in patients who had curative parathyroidectomy (n = 35) Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Preoperative score (95% CI)
Postoperative score (95% CI)
P value
53.7 50.8 38.4 49.1 52.6 53.1 51.1
(49.1–58.3) (47.1–54.5) (35.1–41.6) (46.3–52.0) (47.8–57.4) (49.5–56.6) (46.6–55.5)
44.9 52.6 38.1 51.7 55.0 48.0 44.4
(41.9–47.9) (49.4–55.9) (35.7–40.6) (49.4–54.0) (51.0–59.0) (44.7–51.2) (40.8–48.0)
<.0001 .12 .87 .02 .06 .003 .0003
52.4 53.4 45.9 38.1 50.9
(48.7–56.1) (50.2–56.6) (43.1–48.8) (33.2–43.1) (47.9–53.9)
44.5 48.4 52.9 29.8 44.6
(42.0–46.9) (45.7–51.2) (50.6–55.3) (26.4–33.1) (41.8–47.4)
<.0001 .0002 <.0001 <.0001 <.0001
*n = 30. yn = 26. PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
Table IV. Comparison of preoperative and postoperative PROMIS scores in control patients who had operation for thyroid nodules (n = 9) Domain Physical Health Fatigue Interest in Sexual Activity Pain Intensity Physical Function Satisfaction with Sex Life Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Preoperative score (95% CI)
Postoperative score (95% CI)
P value
49.5 52.5 32.0 56.4 52.1 49.7 49.5
(46.8–52.2) (47.1–57.9) (29.0–35.1) (52.3–60.5) (44.2–59.9) (44.7–54.8) (46.2–52.7)
49.7 52.4 39.0 51.4 52.3 48.2 48.6
(45.5–53.9) (46.5–58.4) (33.5–44.4) (48.8–54.0) (46.0–58.5) (42.7–53.6) (45.0–52.2)
.90 .90 .02 .02 .91 .27 .43
51.1 52.1 49.5 36.8 46.4
(47.6–55.4) (48.1–56.0) (45.5–53.6) (31.8–41.8) (40.9–51.8)
47.2 51.4 48.2 30.3 46.9
(42.0–52.4) (48.1–54.8) (44.1–52.3) (21.0–39.7) (41.7–52.2)
.06 .70 .42 .06 .79
CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
patients compared with controls has been shown recently to be durable at 10 years.24 Although these studies included both symptomatic and asymptomatic patients, there was no analysis of the subgroup of asymptomatic patients. Therefore, it is not known if the asymptomatic group showed improvement in symptom scores comparable to symptomatic patients. Mood and neuropsychologic symptoms have been studied in cases limited to asymptomatic PHPT. A study of 24 asymptomatic PHPT patients undergoing parathyroidectomy and 23 control patients undergo hemithyroidectomy measured mood symptoms with the Hospital Anxiety,
Hospital Depression, and Mood Rating Scale.25 Statistically significant improvement in all 3 scales was observed postoperatively in the PHPT group but not in the control group. Another study of 25 asymptomatic patients in Japan showed no improvement with parathyroidectomy based on an 8-item questionnaire that asked about neuropsychologic symptoms before and after parathyroidectomy; however, this study was inadequately powered to conclude that no improvement occurred.26 Many of these studies were limited by nonspecific (in the case of the SF-36) or overly narrow symptom assessments that lacked a robust connection to
Zanocco et al 843
Surgery Volume 158, Number 3
Table V. Postoperative improvement in PROMIS scores compared with controls Operation for hyperparathyroidism (95% CI) (n = 35)
Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
8.8 1.8 0.3 2.6 2.4 5.1 6.7
(5.0–12.5) (0.5 to 4.1) (2.8 to 3.3) (0.5–4.6) (0.1 to 4.8) (1.9–8.4) (3.3–10.1)
7.9 5.0 7.0 8.3 6.2
(4.5–11.3) (2.6–7.3) (4.4–9.6) (4.7–11.9) (3.4–9.1)
Controls: operation for benign thyroid nodule (95% CI) (n = 9) 0.19 0.1 6.9 5.1 0.2 1.6 0.9 4.3 0.6 1.4 6.5 0.6
P value
(3.4 to 3.0) (1.5 to 1.1) (12.7 to 1.2) (9.2 to 0.9) (4.2 to 4.6) (1.5 to 4.7) (1.6 to 3.3)
.0004 .14 .03 .003 .33 .10 .005
(0.2 (3.0 (5.0 (0.2 (5.4
.17 .04 .0005 .60 .02
to to to to to
8.8) 4.2) 2.3) 13.2) 4.2)
*n = 30 in the hyperparathyroidism group and n = 9 in the benign thyroid nodule group. yn = 26 in the hyperparathyroidism group and n = 6 in the benign thyroid nodule group. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
Table VI. PROMIS scores stratified by presence of consensus criteria for parathyroidectomy Met consensus guideline criteria for parathyroidectomy (n = 25) Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Preoperative score (95% CI) 54.8 52.9 36.9 49.6 53.7 53.0 51.7
(50.0–59.7) (48.6–57.3) (33.3–40.6) (46.2–53.0) (48.0–59.3) (48.8–57.1) (47.2–56.2)
Postoperative score (95% CI) 45.7 52.7 37.3 52.3 54.5 48.8 46.0
Did not meet consensus guideline criteria for parathyroidectomy (n = 10) P value
Preoperative score (95% CI) (38.4–63.3) (38.7–52.9) (34.5–49.5) (41.6–54.3) (39.2–48.8) (45.1–61.7) (36.9–62.0)
Postoperative score (95% CI) 42.9 52.3 40.1 50.1 55.9 45.8 40.4
(37.3–48.4) (48.6–55.9) (34.0–46.2) (44.6–55.6) (48.8–63.1) (38.2–53.4) (31.8–49.1)
P value
(42.0–49.5) (48.2–57.3) (34.6–40.1) (49.8–54.9) (49.2–59.8) (45.1–52.5) (42.0–49.9)
.0005 .85 .82 .05 .39 .02 .004
50.8 45.8 42.0 47.9 50.2 53.4 49.5
52.8 (48.7–56.9) 44.7 (41.8–47.5) 54.3 (50.9–57.6) 49.6 (46.4–52.7) 45.4 (42.5–48.3) 50.7 (48.7–52.8)
.0009 .002 .0001
51.3 (41.6–60.9) 44.0 (38.2–49.7) 51.2 (42.4–60.0) 45.5 (39.5–51.6) 47.2 (39.3–55.1) 58.4 (52.6–64.2)
.01 .04 .006
38.0 (32.2–43.8) 30.7 (26.7–34.7)
.003
38.4 (26.9–49.9) 27.4 (20.3–34.6)
.007
51.2 (48.3–54.2) 46.1 (42.9–49.2)
.002
50.0 (41.3–58.7) 41.1 (34.8–47.4)
.02
.03 .03 .53 .07 .11 .07 .04
*n = 21 in ‘‘Met Criteria’’ group and n = 9 in ‘‘Did Not Meet’’ group. yn = 18 in ‘‘Met Criteria’’ group and n = 8 in ‘‘Did Not Meet’’ group. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
health-related quality of life. Compared to these other assessments, the mental and physical domains of PROMIS investigated in this study are both more comprehensive and related closely to the aspects of health that have been proposed to be affected in PHPT patients without overt physical manifestations of the disease.11 Our study has several limitations. While significant differences in PROMIS scores pre- and post-
parathyroidectomy were demonstrated in several domains, the study was underpowered to detect differences in improvement of PHPT patients compared with control patients with thyroid surgery. The 35 PHPT patients and 9 control patients who completed both pre- and postoperative assessments had 27% power to detect a clinically significant difference, whereas 63 patients would have been necessary in each group to achieve a power of
844 Zanocco et al
Surgery September 2015
Table VII. Postoperative improvement in PROMIS scores stratified by presence of consensus criteria for parathyroidectomy Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Meet criteria (95% CI) (n = 25) 9.1 0.2 0.4 2.8 0.9 4.1 5.8 8.2 4.7 5.3 7.2 5.2
(4.4–13.8) (2.2 to 1.8) (4.0 to 3.2) (0.0–5.6) (1.2 to 2.9) (0.6–7.7) (2.0–9.5) (3.7–12.6) (1.9–7.5) (2.9–7.7) (2.8–11.7) (2.0–8.3)
Do not meet criteria (95% CI) (n = 10) 8.0 6.4 1.9 2.1 5.7 7.6 9.0 7.3 5.7 11.2 3.1 8.9
P value
(0.8–15.2) (0.6–12) (4.7 to 8.5) (0.3 to 4.5) (1.6 to 13.0) (0.7 to 15.8) (0.6–17.4)
.79 .03 .51 .71 .17 .41 .44
(2.0–12.5) (0.4–11.0) (4.2–18.3) (3.9–18.1) (1.8–16.1)
.78 .71 .10 .34 .30
*n = 21 in ‘‘Met Criteria’’ group and n = 9 in ‘‘Did Not Meet’’ group. yn = 18 in ‘‘Met Criteria’’ group and n = 8 in ‘‘Did Not Meet’’ group. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
80% given an alpha of 0.05. While the demographic characteristics of the PHPT and control groups were relatively similar, the control patients experienced significant worsening of pain intensity after operation compared with unchanged pain intensity in the patients with PHPT. This increased level of postoperative pain may be related to the extent of the operation, given that 56% of control patients underwent a total thyroidectomy, a more extensive operation than a routine parathyroidectomy. Patients with benign thyroid disease undergoing exclusively hemithyroidectomy would make a better control group, because the extent of operation better approximates that of an uncomplicated parathyroidectomy. Unfortunately, many of the hemithyroidectomy patients in our Endocrine Surgery Clinic were not scheduled for this procedure until biopsy results from their initial clinical encounter were reviewed and were not available for study enrollment or assessment in the clinic. A substantially greater duration for enrollment would have been necessary to obtain more participants in this group. It is also possible that patients with PHPT have different expectations than patients undergoing thyroid operation with respect to postoperative pain and many of other subjective health domains based on preoperative counseling and literature suggesting improvement in these domains. Longer-term data to assess durability of improvement beyond a 3-week postoperative visit would address this potential bias and should be a priority for further investigation.
In conclusion, multiple domains of patient reported physical and mental health improve after parathyroidectomy for both symptomatic and ‘‘asymptomatic’’ PHPT patients who do not meet the current consensus criteria for parathyroidectomy. In light of the new ability afforded by PROMIS to efficiently and precisely measure these domains in a clinical setting, many patients with PHPT designated incorrectly as ‘‘asymptomatic’’ can now be designated as ‘‘symptomatic’’ and likely to benefit from parathyroidectomy. REFERENCES 1. Sosa JA, Udelsman R. The parathyroid glands. In: Townsend CM, editor. Sabiston textbook of surgery: the biological basis of modern surgical practice. 19th ed. Philadelphia, PA: Elsevier Saunders; 2012. 2. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014;99:3561-9. 3. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608-14. 4. Zanocco K, Angelos P, Sturgeon C. Cost-effectiveness analysis of parathyroidectomy for asymptomatic primary hyperparathyroidism. Surgery 2006;140:874-81; discussion 881–882. 5. Zanocco K, Sturgeon C. How should age at diagnosis impact treatment strategy in asymptomatic primary hyperparathyroidism? A cost-effectiveness analysis. Surgery 2008; 144:290-8. 6. Eigelberger MS, Cheah WK, Ituarte PH, Streja L, Duh QY, Clark OH. The NIH criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism: are they too limited? Ann Surg 2004;239:528-35.
Surgery Volume 158, Number 3
7. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341: 1249-55. 8. Bilezikian JP, Khan AA, Potts JT Jr. Third International Workshop on the Management of Asymptomatic Primary H. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009;94:335-9. 9. Macfarlane DP, Yu N, Donnan PT, Leese GP. Should ’mild primary hyperparathyroidism’ be reclassified as ’insidious’: is it time to reconsider? Clin Endocrinol 2011;75:730-7. 10. Roman SA, Sosa JA, Mayes L, et al. Parathyroidectomy improves neurocognitive deficits in patients with primary hyperparathyroidism. Surgery 2005;138:1121-8; discussion 1128–9. 11. Udelsman R, Pasieka JL, Sturgeon C, Young JE, Clark OH. Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:366-72. 12. Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol 2010;63: 1179-94. 13. Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:351-65. 14. Weber T, Keller M, Hense I, et al. Effect of parathyroidectomy on quality of life and neuropsychological symptoms in primary hyperparathyroidism. World J Surg 2007;31: 1202-9. 15. Coker LH, Rorie K, Cantley L, et al. Primary hyperparathyroidism, cognition, and health-related quality of life. Ann Surg 2005;242:642-50. 16. Yost KJ, Eton DT, Garcia SF, Cella D. Minimally important differences were estimated for six Patient-Reported Outcomes Measurement Information System-Cancer scales in advanced-stage cancer patients. J Clin Epidemiol 2011;64: 507-16.
Zanocco et al 845
17. Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2004;89:5415-22. 18. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 2007;92:1687-92. 19. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007;92:3114-21. 20. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31:247-63. 21. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care 1992;30:473-83. 22. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513-8; discussion 518–519. 23. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942-9. 24. Pasieka JL, Parsons L, Jones J. The long-term benefit of parathyroidectomy in primary hyperparathyroidism: a 10year prospective surgical outcome study. Surgery 2009;146: 1006-13. 25. Kahal H, Aye M, Rigby AS, Sathyapalan T, England RJ, Atkin SL. The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism. Clin Endocrinol 2012;76:196-200. 26. Tsukahara K, Sugitani I, Fujimoto Y, Kawabata K. Surgery did not improve the subjective neuropsychological symptoms of patients with incidentally detected mild primary hyperparathyroidism. Eur Arch Otorhinolaryngol 2008;265: 565-9.
Background. The majority of patients with primary hyperparathyroidism (PHPT) are diagnosed without the classic signs of renal or osseous complications. Vague and subjective symptoms have been attributed to PHPT but have been difficult to measure during the medical encounter. The Patient-Reported Outcomes Measurement Information System (PROMIS) of the National Institutes of Health contains validated measures of physical and mental health that can be administered by the use of computer-adaptive testing (CAT). The objective of this study was to evaluate the feasibility of PROMIS assessment in the clinical setting to measure changes in patient-reported health before and after parathyroidectomy. We hypothesized that patients undergoing parathyroidectomy for PHPT would report greater improvement in mental and physical health compared with control patients. Methods. Adult PHPT patients scheduled for parathyroidectomy and control patients requiring diagnostic thyroid operation were enrolled prospectively during a 6-month period. Patients were administered clinically relevant PROMIS health domains via CAT at a preoperative visit and 3 weeks after operation. A change in score of 5 or greater for each PROMIS instrument was defined as clinically important. Statistical significance of pre/post-surgery changes in scores was determined using paired t tests. Results. A total of 35 patients with PHPT and 9 control patients completed the study. The mean number of PROMIS items answered during an assessment was 67 (range 51–121, SD 15.4). Median completion time was 8.2 minutes (range 3.4–38.4, SD 4.7). Clinically important improvement after parathyroidectomy in the PHPT group was greater than in the control group in 5 PROMIS domains. The score improvement experienced by PHPT patients was 8.8 in Fatigue, 6.7 in Sleep-Related Impairment, 5.0 in Anxiety, 7.0 in Applied Cognition, and 6.2 in Depression (all P < .05). Conclusion. PROMIS is an efficient clinical assessment platform for measuring patient-reported outcomes in PHPT via CAT. Several domains of physical and mental health in patients with PHPT show statistically and clinically important improvement after parathyroidectomy. (Surgery 2015;158:837-45.) From the Department of Surgery,a Center for Healthcare Studies,b and Department of Medical Social Sciences,c Northwestern University Feinberg School of Medicine, Chicago, IL
PRIMARY HYPERPARATHYROIDISM (PHPT) causes hypercalcemia through excessive secretion of parathyroid hormone. When untreated, this condition has resulted traditionally in osteoporosis and nephrolithiasis as
the result of long-term disruption in calcium homoeostasis; however, the disease presentation has changed dramatically during the past several decades.1 Approximately 75% of new PHPT patients
Kyle Zanocco’s participation in this study was supported in part by the Northwestern University Feinberg School of Medicine Center for Healthcare Studies under an institutional award from the Agency for Healthcare Research and Quality, T-32 HS 000078 (PI: Jane L. Holl, MD, MPH).
Reprint requests: Cord Sturgeon, MD, Department of Surgery, Northwestern University Feinberg School of Medicine, 676 N St. Clair St. Ste 650, Chicago, IL 60611. E-mail: csturgeo@ nmh.org.
Presented at the 10th Annual Academic Surgical Congress in Las Vegas, NV, February 3–5, 2015.
Ó 2015 Elsevier Inc. All rights reserved.
Accepted for publication March 18, 2015.
0039-6060/$ - see front matter http://dx.doi.org/10.1016/j.surg.2015.03.054
SURGERY 837
838 Zanocco et al
are now diagnosed incidentally via multiphasic blood screening, and many are now discovered without the traditional physical manifestations of this disease.1 Although parathyroidectomy is indicated for all patients with symptomatic PHPT, the management of patients with so-called ‘‘asymptomatic’’ or ‘‘mild’’ PHPT is controversial. The current guidelines of the international consensus conference for the management of asymptomatic PHPT recommend parathyroidectomy for PHPT with any of the following clinical parameters: younger than 50 years of age, serum calcium greater than 1.0 mg/dL greater than the upper laboratory limit of normal, 24-hour urine calcium concentration greater than 400 mg/dL, creatinine clearance of less than 60 ml/min, bone mineral density T-score of less than 2.5 at any site, or the presence of nephrolithiasis, nephrocalcinosis, or vertebral fracture on imaging examinations.2 Observation is recognized by the guidelines as an acceptable alternative to parathyroidectomy for patients who do not meet these operative criteria. Despite these recommendations, many believe that parathyroidectomy is the optimal treatment for the majority of ‘‘asymptomatic’’ or ‘‘mild’’ PHPT patients who do not meet the guidelines.3-6 Although progression of disease during observation was once thought to be rare, it is now known that PHPT patients who do not meet the criteria for parathyroidectomy have an approximately 25% risk of progression, including the development of osteoporosis or nephrolithiasis if they are observed during a 10-year period.7 In addition, parathyroidectomy has been found to be more cost-effective than observation or pharmacologic therapy for patients with asymptomatic PHPT.4 Vague neurocognitive symptoms including fatigue and cognitive impairment have been attributed to PHPT but have been difficult for physicians to measure during the medical encounter.8-10 A growing body of evidence suggests that even those with mild biochemical disease experience improvement in these symptoms after curative parathyroidectomy, questioning whether any patient with PHPT can be truly asymptomatic.11 The debate concerning the optimal treatment of patients with PHPT who do not meet the consensus criteria for parathyroidectomy exists because of differing interpretations of the risk/benefit balance of parathyroidectomy for this disease. Those who support observation believe that the risks of parathyroidectomy outweigh the expected benefits of biochemical cure. Those who favor parathyroidectomy for these patients believe that the benefits of cure, including potential improvements in quality of life, outweigh the operative risks of parathyroidectomy. More data about the impact
Surgery September 2015
of parathyroidectomy on quality of life are needed to inform the debate regarding the optimal management strategy for this group of patients. The Patient-Reported Outcomes Measurement Information System (PROMIS) of the National Institutes of Health has the capability to acquire these data. PROMIS contains standardized measures of physical, mental, and social health that can be administered efficiently to patients via computeradaptive testing (CAT).12 This system calculates individual T-scores for various domains of health based on patient responses to multiple choice items. The objective of this study was to investigate the effects of parathyroidectomy on patient-reported mental and physical health in patients with PHPT and to assess the feasibility of acquiring this information in the clinic setting using PROMIS. We hypothesized that: 1. Patients with PHPT would report improved mental and physical health after undergoing successful parathyroidectomy compared with control patients undergoing thyroid operation for benign disease. 2. Both patients with PHPT who meet and do not meet the current consensus guideline recommendations for parathyroidectomy would have improved mental and physical health after parathyroidectomy.
METHODS Study population. Approval from the Northwestern University Institutional Review Board was obtained for this prospective study. Participant enrollment occurred during a 6-month period from September 1, 2012 to February 28, 2013. Patients older than the age of 18 who were evaluated in the Northwestern Memorial Faculty Foundation Endocrine Surgery Clinic and had a biochemical diagnosis of PHPT (serum calcium exceeding 10.5 mg/dL with a serum parathyroid hormone [PTH] level at or exceeding 50 pg/mL) were eligible for inclusion. A PTH level of 50 was selected, because this level is in the middle of the laboratory’s normal PTH range (12–88). Patients with thyroid nodules requiring diagnostic hemithyroidectomy or total thyroidectomy also were enrolled as controls. Exclusion criteria included the presence of persistent or recurrent PHPT after previous parathyroidectomy, an inherited form of hyperparathyroidism, parathyroid cancer, current use of antipsychotic medications, or use of a mobility aid. Control patients with thyroid nodules that were determined to be malignant also were excluded from the study. Assessment of patient-reported outcomes. Study patients who agreed to participate were registered
Surgery Volume 158, Number 3
in Assessment Center (www.assessmentcenter.net), the Web-based platform used for the administration of PROMIS instruments. Participants were then provided access to a desktop or tablet computer to complete a patient-reported outcomes assessment. Twelve PROMIS v1.0 banks representing domains of physical and mental health were determined to be most relevant to the identification of the symptomatic disease burden in PHPT based on literature review and the opinion of 2 practicing endocrine surgeons.8-10,13-15 The selected physical health domains included Fatigue, Interest in Sexual Activity, Pain Intensity, Physical Function, Global Satisfaction with Sex Life, Sleep Disturbance, and SleepRelated Impairment. The selected mental health domains included Anger, Anxiety, Applied Cognition---Abilities, Applied Cognition---General Concerns, and Depression. Patients were administered computerized assessments of these domains during their preoperative and 3-week postoperative clinical encounters. In nine domains, CAT was employed to achieve an accurate score using the fewest possible number of items. These items were selected using a computer algorithm based on a patient’s response to a previously administered item. The CAT algorithm was programmed so that patients continued to complete items in a domain until a T-score estimate with a standard error of 0.3 or smaller was achieved, or the patient completed a maximum of 12 items. A computer-delivered short form was employed for three domains that were not supported by CAT (Pain Intensity, Interest in Sexual Activity, and Satisfaction with Sex Life). Medical record review. Review of the medical record was performed to subclassify patients with PHPT according to the presence or absence of an indication for parathyroidectomy as recommended by the current guidelines of the international consensus conference for the management of asymptomatic primary hyperparathyroidism.2 Available demographic and baseline laboratory data also were abstracted from the medical records. PHPT cure was defined as normalization of serum calcium level after parathyroidectomy. Data analysis. Descriptive statistical analysis and hypothesis testing was performed on the study data with Stata 12.1 (StataCorp LP, College Station, TX). A change in instrument score of 5 or greater was defined as clinically important based on previously published data.16 Statistical significance of differences in age and baseline laboratory values between PHPT and control patients was determined using an unpaired t-test (a = .05). Pearson’s v2 testing was used to determine significance of differences in sex, race, and ethnicity categories (a = .05).
Zanocco et al 839
Fig 1. Study flow of the PHPT group. Of the 53 patients with PHPT approached, 40 (75%) had a curative parathyroidectomy and 35 (66%) completed both pre- and postoperative assessments. Patients who did not complete the testing are shown in the periphery with explanations for their exclusion or absence from the group that completed both assessments.
Statistical significance of pre/postoperative changes in PROMIS scores and laboratory values was determined using paired t tests (a = .05). RESULTS Study flow and participant data. Figures 1 and 2 show the complete study flow of the patients in the PHPT and control groups, respectively. Fifty-three patients with PHPT and 13 control patients were approached for participation. After nonenrollment and exclusions, 85% of patients with PHPT and 77% of control patients completed a preoperative PROMIS assessment. All patients were able to complete the assessments without assistance after a brief tutorial. Table I displays the demographic characteristics and preoperative laboratory values for these remaining participants. Demographics were comparable between the PHPT and control groups. The mean total serum calcium concentrations in the PHPT group were 10.9 mg/dL compared with 9.3 mg/dL in the control group (P < .0001). Serum TSH was normal in both groups. 35 patients with PHPT who had a successful parathyroidectomy and 9 control patients completed a postoperative PROMIS assessment. Five other PHPT patients underwent successful parathyroidectomy, but did not complete a postoperative assessment, because they did not attend a postoperative clinic appointment before the end of the study using the office-based PROMIS assessment on May 15, 2013. In the PHPT group, total serum calcium decreased from a mean of 10.9 to 9.8 (P < .0001) and PTH decreased from 125 to
840 Zanocco et al
Fig 2. Study flow of thyroid surgery control patients. Of the 13 thyroid nodule control patients approached, 9 (69%) completed both pre- and postoperative assessments. Patients that did not complete the testing are shown in the periphery with explanations for their exclusion or absence from the group that completed both assessments.
58 (P < .0001). In the control group TSH increased from 1.38 to 2.42 (P = .22), but remained within the normal range. The mean number of PROMIS items answered during an assessment was 67 (range 51–121, SD 15.4). Median completion time of the PROMIS assessment was 8.2 minutes (range 3.4–38.4, SD 4.7). The average time between preoperative PROMIS assessment and operation was 40 days (range 2–139, SD 28) in the PHPT group and 38 days (range 23–54, SD 13) in the control group (P = .75). The average time between operation and postoperative PROMIS assessment was 22 days (range 20–24, SD 8) in the PHPT group and 23 days (range 18–27, SD 6) in the control group (P = .73). Patient reported outcomes pre/postoperation. Preoperative patient-reported health tended to be worse for all measured PROMIS domains in the PHPT group compared with control patients, but statistically significant differences were only observed in the Pain Intensity and Physical Function domains (Table II). Patients with PHPT who underwent curative parathyroidectomy had statistically and clinically important improvement in the PROMIS Physical Health domains of Fatigue, Sleep Disturbance, and Sleep-Related Impairment and in the PROMIS Mental Health domains of Anger, Anxiety, Applied Cognition---Abilities, Applied Cognition---General Concerns, and Depression (Table III). In the control group, Pain Intensity and Physical Function were
Surgery September 2015
statistically and clinically worse during postoperative assessment (Table IV). When the improvement in each domain for PHPT patients after curative parathyroidectomy was compared to the postoperative improvement in the control patients, greater improvement was observed in the PHPT group in the Fatigue, Pain Intensity, Physical Function, Sleep-Related Impairment, Anxiety, Applied Cognition---Abilities, and Depression domains (Table V). Similar improvement in PROMIS scores was observed in PHPT patients who met and did not meet criteria guidelines of the current international consensus conference for parathyroidectomy (Tables VI and VII). The only significant observed difference between these 2 groups was improved interest in sexual activity in patients who did not meet consensus criteria for parathyroidectomy (Table VII). DISCUSSION This study demonstrates that several domains of physical and mental health in patients with PHPT are improved after parathyroidectomy. The findings also suggest that these domains improve in ‘‘asymptomatic’’ PHPT patients who do not meet consensus criteria for parathyroidectomy to the same extent as PHPT patients who do meet the criteria. Furthermore, given a median completion time of less than 10 minutes for the assessment of 12 domains, computer-delivered PROMIS instruments have the practical value of time-efficient administration in an outpatient clinic setting. The wide range of PROMIS items required by different patients to complete the assessment is notable and demonstrates the ability of CAT to create efficiency compared with standard questionnaires by eliminating unnecessary questions. Several previous studies have investigated the effects of treated and untreated PHPT on patientreported overall health and well-being. Three, randomized, prospective trials of parathyroidectomy versus observation for mild PHPT have used the SF-36 assessment tool to measure quality of life in their subjects.17-19 The SF-36 is a 36-item instrument that assesses limitations in physical and social activities, pain, general mental health, energy, and general health perceptions.20,21 The nonparticipation rate was high in all of these studies, and no information about underlying characteristics of the nonparticipants was provided. A benefit of parathyroidectomy ranging from a 5–25% improvement in SF-36 scores compared with observation was evident in some of the quality of life measures, including bodily pain, general health, social and
Zanocco et al 841
Surgery Volume 158, Number 3
Table I. Patient demographics and preoperative laboratory values Primary hyperparathyroidism (n = 45) Mean age, y (SD) Sex Female Male Race Asian Black/African American White Unknown Ethnicity Hispanic/Latino Not Hispanic/Latino Unknown Laboratory values (SD) Total serum calcium, mg/dL Serum PTH, pg/mL TSH, mIU/L
Control group: benign thyroid nodule (n = 10)
55 (12.0)
51 (10.1)
36 (80%) 9 (20%)
7 (70%) 3 (30%)
1 4 38 2
(2%) (9%) (84%) (4%)
0 3 (30%) 6 (60%) 1 (10%)
3 (7%) 31 (69%) 11 (24%)
0 8 (80%) 2 (20%)
P value .28 .49
.25
.65
10.9 (0.6), n = 45 117 (54), n = 45 1.70 (0.74), n = 31
9.4 (0.5), n = 8 Not measured 1.38 (0.87), n = 9
<.0001 n/a .36
PTH, Parathyroid hormone; TSH, thyroid-stimulating hormone. Bold text denotes statistical significance.
Table II. Comparison of preoperative PROMIS scores in patients with primary hyperparathyroidism and control patients with benign thyroid nodules Domain Physical Health Fatigue Interest in Sexual Activity Pain Intensity Physical Function Satisfaction with Sex Life Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Operation for hyperparathyroidism (95% CI) (n = 45)
Controls: operation for benign thyroid nodule (95% CI) (n = 10)
P value
52.3 51.6 38.4 49.1 53.7 51.6 50.0
(48.4–56.1) (48.4–54.9)* (35.8–41.0) (46.6–51.6) (49.6–57.7)y (48.4–54.7) (46.1–53.8)
49.3 53.4 31.9 56.1 53.9 49.4 49.0
(47.0–51.8) (48.3–58.5) (29.2–34.6) (52.4–59.8) (47.0–60.7)z (44.9–53.9) (45.9–52.0)
.20 .54 .0007 .003 .96 .40 .66
51.9 53.0 46.5 37.3 50.3
(48.7–55.1) (50.1–55.7) (43.9–49.1) (33.0–41.6) (47.7–53.0)
50.3 51.8 50.4 34.7 46.0
(46.0–54.6) (48.2–55.3) (46.3–54.5) (28.3–41.2) (41.1–50.8)
.53 .57 .09 .48 .10
*n = 41. yn = 33. zn = 8. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
emotional role function, vitality, and mental health, but the observed benefits were not consistent across the 3 studies. The broad scales used in the SF-36 may have lacked the necessary precision to detect subtle differences in symptom severity that affect the quality of life in PHPT. In an attempt to address the lack of precision when applying generic quality of life measures to patients with PHPT, a disease-specific outcome assessment tool was developed to identify those
symptoms most likely to respond to parathyroidectomy.22,23 This tool documented severity of 13 symptoms related to PHPT using a visual analog scale to produce a symptom score. Using this tool, 203 patients with PHPT were given this assessment before and after parathyroidectomy. A significant improvement in symptom score was shown in postoperative PHPT patients compared to a control group of nontoxic thyroidectomy patients. The improvement in symptom scores in PHPT
842 Zanocco et al
Surgery September 2015
Table III. Comparison of preoperative and postoperative PROMIS scores in patients who had curative parathyroidectomy (n = 35) Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Preoperative score (95% CI)
Postoperative score (95% CI)
P value
53.7 50.8 38.4 49.1 52.6 53.1 51.1
(49.1–58.3) (47.1–54.5) (35.1–41.6) (46.3–52.0) (47.8–57.4) (49.5–56.6) (46.6–55.5)
44.9 52.6 38.1 51.7 55.0 48.0 44.4
(41.9–47.9) (49.4–55.9) (35.7–40.6) (49.4–54.0) (51.0–59.0) (44.7–51.2) (40.8–48.0)
<.0001 .12 .87 .02 .06 .003 .0003
52.4 53.4 45.9 38.1 50.9
(48.7–56.1) (50.2–56.6) (43.1–48.8) (33.2–43.1) (47.9–53.9)
44.5 48.4 52.9 29.8 44.6
(42.0–46.9) (45.7–51.2) (50.6–55.3) (26.4–33.1) (41.8–47.4)
<.0001 .0002 <.0001 <.0001 <.0001
*n = 30. yn = 26. PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
Table IV. Comparison of preoperative and postoperative PROMIS scores in control patients who had operation for thyroid nodules (n = 9) Domain Physical Health Fatigue Interest in Sexual Activity Pain Intensity Physical Function Satisfaction with Sex Life Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Preoperative score (95% CI)
Postoperative score (95% CI)
P value
49.5 52.5 32.0 56.4 52.1 49.7 49.5
(46.8–52.2) (47.1–57.9) (29.0–35.1) (52.3–60.5) (44.2–59.9) (44.7–54.8) (46.2–52.7)
49.7 52.4 39.0 51.4 52.3 48.2 48.6
(45.5–53.9) (46.5–58.4) (33.5–44.4) (48.8–54.0) (46.0–58.5) (42.7–53.6) (45.0–52.2)
.90 .90 .02 .02 .91 .27 .43
51.1 52.1 49.5 36.8 46.4
(47.6–55.4) (48.1–56.0) (45.5–53.6) (31.8–41.8) (40.9–51.8)
47.2 51.4 48.2 30.3 46.9
(42.0–52.4) (48.1–54.8) (44.1–52.3) (21.0–39.7) (41.7–52.2)
.06 .70 .42 .06 .79
CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
patients compared with controls has been shown recently to be durable at 10 years.24 Although these studies included both symptomatic and asymptomatic patients, there was no analysis of the subgroup of asymptomatic patients. Therefore, it is not known if the asymptomatic group showed improvement in symptom scores comparable to symptomatic patients. Mood and neuropsychologic symptoms have been studied in cases limited to asymptomatic PHPT. A study of 24 asymptomatic PHPT patients undergoing parathyroidectomy and 23 control patients undergo hemithyroidectomy measured mood symptoms with the Hospital Anxiety,
Hospital Depression, and Mood Rating Scale.25 Statistically significant improvement in all 3 scales was observed postoperatively in the PHPT group but not in the control group. Another study of 25 asymptomatic patients in Japan showed no improvement with parathyroidectomy based on an 8-item questionnaire that asked about neuropsychologic symptoms before and after parathyroidectomy; however, this study was inadequately powered to conclude that no improvement occurred.26 Many of these studies were limited by nonspecific (in the case of the SF-36) or overly narrow symptom assessments that lacked a robust connection to
Zanocco et al 843
Surgery Volume 158, Number 3
Table V. Postoperative improvement in PROMIS scores compared with controls Operation for hyperparathyroidism (95% CI) (n = 35)
Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
8.8 1.8 0.3 2.6 2.4 5.1 6.7
(5.0–12.5) (0.5 to 4.1) (2.8 to 3.3) (0.5–4.6) (0.1 to 4.8) (1.9–8.4) (3.3–10.1)
7.9 5.0 7.0 8.3 6.2
(4.5–11.3) (2.6–7.3) (4.4–9.6) (4.7–11.9) (3.4–9.1)
Controls: operation for benign thyroid nodule (95% CI) (n = 9) 0.19 0.1 6.9 5.1 0.2 1.6 0.9 4.3 0.6 1.4 6.5 0.6
P value
(3.4 to 3.0) (1.5 to 1.1) (12.7 to 1.2) (9.2 to 0.9) (4.2 to 4.6) (1.5 to 4.7) (1.6 to 3.3)
.0004 .14 .03 .003 .33 .10 .005
(0.2 (3.0 (5.0 (0.2 (5.4
.17 .04 .0005 .60 .02
to to to to to
8.8) 4.2) 2.3) 13.2) 4.2)
*n = 30 in the hyperparathyroidism group and n = 9 in the benign thyroid nodule group. yn = 26 in the hyperparathyroidism group and n = 6 in the benign thyroid nodule group. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
Table VI. PROMIS scores stratified by presence of consensus criteria for parathyroidectomy Met consensus guideline criteria for parathyroidectomy (n = 25) Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Preoperative score (95% CI) 54.8 52.9 36.9 49.6 53.7 53.0 51.7
(50.0–59.7) (48.6–57.3) (33.3–40.6) (46.2–53.0) (48.0–59.3) (48.8–57.1) (47.2–56.2)
Postoperative score (95% CI) 45.7 52.7 37.3 52.3 54.5 48.8 46.0
Did not meet consensus guideline criteria for parathyroidectomy (n = 10) P value
Preoperative score (95% CI) (38.4–63.3) (38.7–52.9) (34.5–49.5) (41.6–54.3) (39.2–48.8) (45.1–61.7) (36.9–62.0)
Postoperative score (95% CI) 42.9 52.3 40.1 50.1 55.9 45.8 40.4
(37.3–48.4) (48.6–55.9) (34.0–46.2) (44.6–55.6) (48.8–63.1) (38.2–53.4) (31.8–49.1)
P value
(42.0–49.5) (48.2–57.3) (34.6–40.1) (49.8–54.9) (49.2–59.8) (45.1–52.5) (42.0–49.9)
.0005 .85 .82 .05 .39 .02 .004
50.8 45.8 42.0 47.9 50.2 53.4 49.5
52.8 (48.7–56.9) 44.7 (41.8–47.5) 54.3 (50.9–57.6) 49.6 (46.4–52.7) 45.4 (42.5–48.3) 50.7 (48.7–52.8)
.0009 .002 .0001
51.3 (41.6–60.9) 44.0 (38.2–49.7) 51.2 (42.4–60.0) 45.5 (39.5–51.6) 47.2 (39.3–55.1) 58.4 (52.6–64.2)
.01 .04 .006
38.0 (32.2–43.8) 30.7 (26.7–34.7)
.003
38.4 (26.9–49.9) 27.4 (20.3–34.6)
.007
51.2 (48.3–54.2) 46.1 (42.9–49.2)
.002
50.0 (41.3–58.7) 41.1 (34.8–47.4)
.02
.03 .03 .53 .07 .11 .07 .04
*n = 21 in ‘‘Met Criteria’’ group and n = 9 in ‘‘Did Not Meet’’ group. yn = 18 in ‘‘Met Criteria’’ group and n = 8 in ‘‘Did Not Meet’’ group. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
health-related quality of life. Compared to these other assessments, the mental and physical domains of PROMIS investigated in this study are both more comprehensive and related closely to the aspects of health that have been proposed to be affected in PHPT patients without overt physical manifestations of the disease.11 Our study has several limitations. While significant differences in PROMIS scores pre- and post-
parathyroidectomy were demonstrated in several domains, the study was underpowered to detect differences in improvement of PHPT patients compared with control patients with thyroid surgery. The 35 PHPT patients and 9 control patients who completed both pre- and postoperative assessments had 27% power to detect a clinically significant difference, whereas 63 patients would have been necessary in each group to achieve a power of
844 Zanocco et al
Surgery September 2015
Table VII. Postoperative improvement in PROMIS scores stratified by presence of consensus criteria for parathyroidectomy Domain Physical Health Fatigue Interest in Sexual Activity* Pain Intensity Physical Function Satisfaction with Sex Lifey Sleep Disturbance Sleep-Related Impairment Mental Health Anger Anxiety Applied Cognition – Abilities Applied Cognition – General Concerns Depression
Meet criteria (95% CI) (n = 25) 9.1 0.2 0.4 2.8 0.9 4.1 5.8 8.2 4.7 5.3 7.2 5.2
(4.4–13.8) (2.2 to 1.8) (4.0 to 3.2) (0.0–5.6) (1.2 to 2.9) (0.6–7.7) (2.0–9.5) (3.7–12.6) (1.9–7.5) (2.9–7.7) (2.8–11.7) (2.0–8.3)
Do not meet criteria (95% CI) (n = 10) 8.0 6.4 1.9 2.1 5.7 7.6 9.0 7.3 5.7 11.2 3.1 8.9
P value
(0.8–15.2) (0.6–12) (4.7 to 8.5) (0.3 to 4.5) (1.6 to 13.0) (0.7 to 15.8) (0.6–17.4)
.79 .03 .51 .71 .17 .41 .44
(2.0–12.5) (0.4–11.0) (4.2–18.3) (3.9–18.1) (1.8–16.1)
.78 .71 .10 .34 .30
*n = 21 in ‘‘Met Criteria’’ group and n = 9 in ‘‘Did Not Meet’’ group. yn = 18 in ‘‘Met Criteria’’ group and n = 8 in ‘‘Did Not Meet’’ group. CI, Confidence interval; PROMIS, Patient-Reported Outcomes Measurement Information System. Bold text denotes statistical significance.
80% given an alpha of 0.05. While the demographic characteristics of the PHPT and control groups were relatively similar, the control patients experienced significant worsening of pain intensity after operation compared with unchanged pain intensity in the patients with PHPT. This increased level of postoperative pain may be related to the extent of the operation, given that 56% of control patients underwent a total thyroidectomy, a more extensive operation than a routine parathyroidectomy. Patients with benign thyroid disease undergoing exclusively hemithyroidectomy would make a better control group, because the extent of operation better approximates that of an uncomplicated parathyroidectomy. Unfortunately, many of the hemithyroidectomy patients in our Endocrine Surgery Clinic were not scheduled for this procedure until biopsy results from their initial clinical encounter were reviewed and were not available for study enrollment or assessment in the clinic. A substantially greater duration for enrollment would have been necessary to obtain more participants in this group. It is also possible that patients with PHPT have different expectations than patients undergoing thyroid operation with respect to postoperative pain and many of other subjective health domains based on preoperative counseling and literature suggesting improvement in these domains. Longer-term data to assess durability of improvement beyond a 3-week postoperative visit would address this potential bias and should be a priority for further investigation.
In conclusion, multiple domains of patient reported physical and mental health improve after parathyroidectomy for both symptomatic and ‘‘asymptomatic’’ PHPT patients who do not meet the current consensus criteria for parathyroidectomy. In light of the new ability afforded by PROMIS to efficiently and precisely measure these domains in a clinical setting, many patients with PHPT designated incorrectly as ‘‘asymptomatic’’ can now be designated as ‘‘symptomatic’’ and likely to benefit from parathyroidectomy. REFERENCES 1. Sosa JA, Udelsman R. The parathyroid glands. In: Townsend CM, editor. Sabiston textbook of surgery: the biological basis of modern surgical practice. 19th ed. Philadelphia, PA: Elsevier Saunders; 2012. 2. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014;99:3561-9. 3. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608-14. 4. Zanocco K, Angelos P, Sturgeon C. Cost-effectiveness analysis of parathyroidectomy for asymptomatic primary hyperparathyroidism. Surgery 2006;140:874-81; discussion 881–882. 5. Zanocco K, Sturgeon C. How should age at diagnosis impact treatment strategy in asymptomatic primary hyperparathyroidism? A cost-effectiveness analysis. Surgery 2008; 144:290-8. 6. Eigelberger MS, Cheah WK, Ituarte PH, Streja L, Duh QY, Clark OH. The NIH criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism: are they too limited? Ann Surg 2004;239:528-35.
Surgery Volume 158, Number 3
7. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341: 1249-55. 8. Bilezikian JP, Khan AA, Potts JT Jr. Third International Workshop on the Management of Asymptomatic Primary H. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009;94:335-9. 9. Macfarlane DP, Yu N, Donnan PT, Leese GP. Should ’mild primary hyperparathyroidism’ be reclassified as ’insidious’: is it time to reconsider? Clin Endocrinol 2011;75:730-7. 10. Roman SA, Sosa JA, Mayes L, et al. Parathyroidectomy improves neurocognitive deficits in patients with primary hyperparathyroidism. Surgery 2005;138:1121-8; discussion 1128–9. 11. Udelsman R, Pasieka JL, Sturgeon C, Young JE, Clark OH. Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:366-72. 12. Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol 2010;63: 1179-94. 13. Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:351-65. 14. Weber T, Keller M, Hense I, et al. Effect of parathyroidectomy on quality of life and neuropsychological symptoms in primary hyperparathyroidism. World J Surg 2007;31: 1202-9. 15. Coker LH, Rorie K, Cantley L, et al. Primary hyperparathyroidism, cognition, and health-related quality of life. Ann Surg 2005;242:642-50. 16. Yost KJ, Eton DT, Garcia SF, Cella D. Minimally important differences were estimated for six Patient-Reported Outcomes Measurement Information System-Cancer scales in advanced-stage cancer patients. J Clin Epidemiol 2011;64: 507-16.
Zanocco et al 845
17. Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2004;89:5415-22. 18. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 2007;92:1687-92. 19. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007;92:3114-21. 20. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31:247-63. 21. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care 1992;30:473-83. 22. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513-8; discussion 518–519. 23. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942-9. 24. Pasieka JL, Parsons L, Jones J. The long-term benefit of parathyroidectomy in primary hyperparathyroidism: a 10year prospective surgical outcome study. Surgery 2009;146: 1006-13. 25. Kahal H, Aye M, Rigby AS, Sathyapalan T, England RJ, Atkin SL. The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism. Clin Endocrinol 2012;76:196-200. 26. Tsukahara K, Sugitani I, Fujimoto Y, Kawabata K. Surgery did not improve the subjective neuropsychological symptoms of patients with incidentally detected mild primary hyperparathyroidism. Eur Arch Otorhinolaryngol 2008;265: 565-9.