Abstract
Objective: To analyse sick leave in women at risk of primary hyperparathyroidism before its diagnosis.
Design: Case-control study nested within a screened cohort of postmenopausal women. Cases were women with hyperparathyroidism without prior knowledge of their disease and no traditional symptoms or complications. Controls were women from the screened population without hyperparathyroidism.
Setting: Population based screening within a Swedish community.
Subject: 48 case-control pairs of women aged 55-70 years.
Main outcome measure: Sick leave during the 5 years before diagnosis.
Results: Total duration of sickness benefits was longer in the cases than controls, and this discrepancy included sick leave on full time or half time and for periods of longer than a week. Cases had an increased risk of sick leave more than half of the investigated time compared with controls (odds ratio 12). Doctors’ certificates showed that the overrepresented sick leave in the cases related mainly to cardiovascular diseases.
Conclusion: Asymptomatic mild primary hyperparathyroidism in postmenopausal women is accompanied by a previously unrecognised morbidity, which has consequences for clinical management of the disorder and its impact on the health economy.
Key messages
Primary hyperparathyroidism mainly affects postmenopausal women, many of whom lack classic symptoms and complications of the disorder and are currently considered suitable for conservative follow up
Postmenopausal women with asymptomatic primary hyperparathyroidism drew more sickness benefit than matched controls during the 5 years before the diagnosis
Cardiovascular diseases were the main cause of sick leave
The duration of sick leave was not correlated with age or serum calcium concentration
Mild undiagnosed hyperparathyroidism in postmenopausal women is linked with previously unrecognised ill health of importance to the clinical and economic impact of the disorder
Introduction
Postmenopausal women are at risk of primary hyperparathyroidism, and many seem to have only mild or no symptoms of the disorder.1–3 On the basis of assumptions of a generally benign disease course, surveillance has been advocated in asymptomatic women with uncomplicated hypercalcaemia of a mild to moderate extent.4 Detailed evaluation of such patients has shown that they have uncharacteristic symptoms of tiredness and other psychological symptoms, which can improve after parathyroid surgery.5,6 Analyses of the outcome of conservative follow up and surgery may be distorted by patients’ knowledge of the existence of a treatable disorder. We carried out a nested case-control study to examine sick leave before diagnosis and knowledge of mild primary hyperparathyroidism in postmenopausal women recruited by population based screening.
Subjects and methods
Primary hyperparathyroidism was diagnosed in 109 (2.1%) of 5202 women aged 55-75 years attending population based mammography screening.2 Diagnosis of primary hyperparathyroidism was based on repeated fasting serum calcium and intact serum parathyroid hormone concentrations and included women with normal serum calcium values.2 The disorder was verified histologically in 60 women who underwent parathyroidectomy. For each woman with primary hyperparathyroidism we randomly selected a control matched for age and season of biochemical investigation from the screened population (table 1). Eligibility criteria for cases and controls included a serum creatinine concentration below 160 μmol/l to exclude the existence of severe renal diseases. All women gave informed consent for participation in the study, which was approved by the ethics committee.
Table 1.
Clinical characteristics of all women with hyperparathyroidism recruited by screening and of sample of women who had not retired from work 5 years before date of screening. Figures are means (SD)
| Variable | All patients (n=109) | Current sample
|
|
|---|---|---|---|
| Cases (n=48) | Controls (n=48) | ||
| Age (years) | 66.6 (5.8) | 62.9 (4.1)* | 62.7 (4.2) |
| Serum calcium (mmol/l)† | 2.59 (0.14) | 2.59 (0.16)‡ | 2.34 (0.08) |
| Serum parathyroid hormone (ng/l)§ | 66.5 (36.3) | 68.9 (41.5)‡ | 29.3 (8.9) |
| Serum creatinine (μmol/l)¶ | 84 (16.9) | 82 (14.5) | 82 (10.5) |
| Parathyroid weight (mg)** | 591 (892)‡‡ | 631 (899)†† | Not done |
P<0.0002 v all other patients (Wilcoxon rank sum test).
Ortocrescolophthalein dye binding, corrected for serum albumin, normal range 2.20-2.60 mmol/l.
P<0.0001 v controls (Wilcoxon signed rank test).
Allegro IRMA (Nichols Institute, San Juan Capistrano, California), normal range 12-55 ng/l, intra-assay and interassay variation at 27 ng/l of 3.4% and 6.1%, respectively.
Reference range 64-106 μmol/l.
Total weight of abnormal parathyroid tissue at operation.
N=61.
N=33.
All data on sick leave were provided by the regional social insurance office, which recorded sick leave and retirement within the screened population. In 48 (44%) case-control pairs neither the case nor the control had retired, because of age (mandatory retirement age 65 years) or illness, 5 years before the date of screening for primary hyperparathyroidism. The duration, cause, and type of sick leave for these case-control pairs was investigated in the 5 years before the day of screening. This period of time was the length of follow up within the study. Interview at biochemical diagnosis supported the absence of traditional symptoms of primary hyperparathyroidism,6 although three cases admitted to constantly feeling tired on direct questioning. Before screening the diagnosis was unknown to all affected women, although two of them had had hypercalcaemia.
Three cases and the same number of controls were housewives at the time of screening. The case or control of 27 pairs had retired because of disease (9 cases, 5 controls) or age (3 cases, 10 controls) during the 5 year period. Both the case and control were excluded from analysis from the date of any full time retirement in the pair to ensure equal years at risk for sick leave. Partial retirement (6 cases, 2 controls) was disregarded. Women with hyperparathyroidism who retired during the study had similar serum calcium and parathyroid hormone concentrations to those who completed the 5 year analysis. The total duration of follow up comprised 348 person years with an individual mean of 3.6 (SD 1.6) years.
For each woman total duration of sick leave was divided by the length of follow up within the study to standardise for variability among the case-control pairs. Benefits on full (100%) or half (50%) time and short (⩽1 week) or long (>1 week) time were available during the analysed time period. As these subtypes are partially exclusive recorded days for a particular sickness benefit were divided by the number of days at risk for this particular benefit type. A physician’s certificate for sick leave was required only for periods exceeding a week. The diagnoses on the certificates were grouped according to ICD-9 (international classification of diseases, ninth revision) and could be retrieved for 93% of the periods of long term sickness benefit.
Analysis
We used the Wilcoxon non-parametric tests (Wilcoxon rank sum test and Wilcoxon signed rank test). The relation between the proportion of sick days and case or control status was also analysed on the basis of the logistic regression model estimated by the conditional maximum likelihood method. The variable sick day proportion was calculated as days of sick leave divided by the number of available days. It was considered both in continuous and categorised forms. The exact categorisation was found to be important. P<0.05 was considered significant. Descriptive results are presented as means (SD).
Results
The duration of sick leave differed significantly between the cases and controls (table 2). It was longer in the cases for all benefit types except for those for short term sick leave. Long term sick leave in the cases was greatest for musculoskeletal and cardiovascular diseases and differed from the controls only for the cardiovascular diseases (table 3). The periods of sick leave on full time sickness benefit (mean 164 (SD 348) days v 26 (66) days) and long term benefit (220 (387) days v 71 (112) days) were longer in the cases than in the controls (P=0.010 and 0.046), but the frequency of periods of sick leave did not differ. The total duration of sickness benefit for cases was not correlated with age or serum calcium and parathyroid hormone concentrations (r=0.0006, 0.002, and 0.049, respectively).
Table 2.
Mean (SD) proportion of days of sick leave (days of sick leave divided by available days) and mean (SD) number of days of sick leave taken by women with hyperparathyroidism and by controls
| Sick leave | Cases (n=48)
|
Controls (n=48)
|
P value*
|
|||||
|---|---|---|---|---|---|---|---|---|
| Proportion of sick leave | Days of sick leave | Proportion of sick leave | Days of sick leave | Proportion of sick leave | Days of sick leave | |||
| Full time (100%) | 0.23 (0.33) | 255 (385) | 0.08 (0.16) | 113 (187) | 0.023 | 0.037 | ||
| Half time (50%) | 0.08 (0.20) | 62 (183) | 0.1 (0.035) | 11 (52) | 0.030 | 0.028 | ||
| Long term (>7 days) | 0.24 (0.35) | 309 (477) | 0.08 (0.16) | 111 (197) | 0.008 | 0.005 | ||
| Short term (⩽7 days) | 0.006 (0.007) | 8 (10) | 0.011 (0.013) | 13 (16) | 0.021 | 0.052 | ||
| Total | 0.25 (0.35) | 317 (475) | 0.09 (0.16) | 124 (202) | 0.010 | 0.010 | ||
Wilcoxon signed rank test comparing cases and controls.
Table 3.
Mean (SD) days of long term sick leave according to diagnosis in women with hyperparathyroidism and in controls
| Disease group (ICD-9)* | Cases (n=48) | Controls (n=48) | P value† |
|---|---|---|---|
| Infectious | 3.2 (6.8) | 4.4 (10) | 0.931 |
| Mental | 14 (86) | 31 (122) | 0.441 |
| Circulatory | 111 (345) | 1.0 (5.4) | 0.017 |
| Respiratory | 1.2 (4.3) | 13 (54) | 0.136 |
| Gastrointestinal | 3.4 (11) | 2.1 (6.1) | 0.398 |
| Musculoskeletal | 169 (387) | 51 (148) | 0.162 |
Tumours or endocrine, neurological, and urogenital diseases were rarely or never given as reasons for sick leave.
Wilcoxon signed rank test.
The proportion of women who had taken no long term sick leave was similar in cases and controls (27% v 25%), but such sickness benefit during half or more of the available days was substantially more common in the cases (27% v 2%; table 4). Estimation with the conditional maximum likelihood method of the relation between the proportion of sick days and case or control status confirmed these results. The odds ratio for having a sick day proportion of at least 0.50 was 11.9 (95% confidence interval 1.4 to 105.0) for cases compared with the controls.
Table 4.
Relation between proportion of sick leave and case-control status with conditional logistic regression. Odds ratios (95% confidence interval) based on 48 women with hyperparathyroidism and 48 controls
| Proportion of sick days* | No of cases | No of controls | Odds ratio (95% CI) |
|---|---|---|---|
| 0 | 13 | 12 | 1.0 |
| 0.01-0.02 | 7 | 12 | 0.5 (0.2 to 1.8) |
| 0.03-0.49 | 15 | 23 | 0.6 (0.2 to 1.7) |
| 0.50-1.00 | 13 | 1 | 11.9 (1.4 to 105) |
Recorded days of sick leave divided by available days.
Discussion
Screening for hyperparathyroidism
Screening for primary hyperparathyroidism was performed mainly to analyse prevalence and symptoms of the disorder in a group of women at risk.2 It was attached to population based mammography screening, which is offered every second year to women in Uppsala aged 55-75 years.7 The mammography screening was attended by 71% of those invited, which is consistent with findings in other Swedish urban areas.8 Since 90% of the women underwent determination of serum calcium concentrations during the investigated 17 month period, 45% of the underlying population was included in the examination for hyperparathyroidism. The recruitment was similar in all age groups.2 Only 56% of the women with hyperparathyroidism underwent parathyroid surgery; the remaining women did not have the operation because of personal preferences, severe comorbidity, and mild hypercalcaemia. The patients who underwent the operation had a similar mean age and serum calcium concentrations to those who did not have the operation, which supports the diagnosis in all those recruited by the screening.2
The currently examined cases were representative of all the recruited patients with respect to the serum calcium and serum parathyroid hormone concentrations. Their younger age was expected as women who had retired from work 5 years before the screening were excluded. As the cases and controls were drawn from the same population based screening any selection bias should be minimised. Moreover, recall bias seems unlikely as insurance data were used and the cases were unaware of their hyperparathyroidism before screening. Almost twice the number of cases than of controls retired because of ill health during the investigation, and there was no association between these retirements and serum calcium concentration. The annual duration of sick leave in women with hyperparathyroidism was fairly constant during the 5 year period (not shown), which supports a limited association between the need of sick leave and subsequent retirement. The recorded type and duration of sick leave and the differences in these respects between the cases and controls consequently could reflect true and hitherto unrecognised effects of primary hyperparathyroidism.
Sick leave in undiagnosed hyperparathyroidism
On average the cases were on sick leave for 17% of the investigated time, while the corresponding 7% in the controls approached the value of all postmenopausal Swedish women.9 The distribution of sick leave in the cases and controls was skewed. The proportion of cases with at least half of the study period on sick leave was substantially higher than in the controls (27% v 2%), and a 12 times higher odds for such sick leave was found. The increased need for sick leave among the women with hyperparathyroidism encompassed all benefit types except for short term leave lasting up to a week. Consistent with the present data, short term sick leave relates mainly to intercurrent infections.10
Diagnoses on doctors’ certificates of long term sick leave are reliable when they are gathered into major disease groups.11 In women with hyperparathyroidism in this study, cardiovascular disorders were overrepresented and musculoskeletal diseases were the main cause of such sick leave. Moreover, no such woman had any period of sick leave due to the specified diagnosis of hyperparathyroidism. Cardiovascular risk factors such as hypertension, hyperlipidaemia, and glucose intolerance, as well as musculoskeletal complications, are recognised phenomena in primary hyperparathyroidism, although the response of some of these disorders to parathyroid surgery is controversial.12–14 In some studies of primary hyperparathyroidism, cardiovascular disorders have been proposed as causes of premature death, particularly in older age groups, with complete normalisation after parathyroid surgery.15–18
Clinical perspective on sick leave in hyperparathyroidism
Primary hyperparathyroidism characteristically is a slowly progressive disease.1,5 In our subjects with this condition it was probably present during the entire observation period. Repeated biochemical testing in the 2 years after diagnosis substantiated stable serum calcium and parathyroid hormone concentrations.2 Moreover, over a quarter of the women consistently had normal calcium concentrations, and all of them would have remained undetected without the strict criteria for identification of the disorder that we used.2 Parathyroid surgery involved an attempt to explore influences of active treatment under novel circumstances. Currently prevailing criteria with regards to age, serum calcium concentration, and the lack of classic symptoms and complications of hyperparathyroidism would favour conservative follow up in the present cases.4,6 The hitherto unrecognised influences of hyperparathyroidism on sick leave give a new understanding to the morbidity and economic impact of this common endocrine disorder of postmenopausal women. Any influences on the clinical management of this risk group, however, await studies on reversibility of the increased need for sick leave after parathyroid surgery.
Acknowledgments
We thank the staff at the Uppsala Social Insurance Office.
Footnotes
Funding: Swedish Medical Research Council, Swedish Cancer Society.
Conflict of interest: None.
References
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