Normocalcaemic,Vitamin D-Sufficient Hyperparathyroidism
At first assessment in 1995, 25 subjects had elevated S-PTH and normal S-Ca, of whom 12 of 608 were vitamin D sufficient thereby fulfilling the diagnostic criteria for nHPT, giving a prevalence of 2·0% in the age range 25–64 years ( Table 1 ). At the reassessment of nHPT, 13 years later, five individuals were either deceased or lost to follow-up. Three of the remaining subjects had normalized their S-PTH levels and were vitamin D sufficient. One subject had nHPT both in 1995 and in 2008. Two had vitamin D insufficiency with elevated S-PTH levels. One woman had developed breast cancer, mild hypercalcaemia (2·55 mmol/l), but normal S-PTH (36 ng/l) and high S-25(OH)D (133 nmol/l) with a daily supplementation of 1000 mg Ca and 800 IU Vitamin D3; a possible progression to pHPT (Fig. 1). Two of seven had fractured during follow-up.
(Enlarge Image)
Figure 1.
Flow chart for subjects with a serum parathyroid hormone level ≥60 ng/l in 1995 and at follow-up 13 years later. Left square shows subjects aged 25–64 years with normal S-calcium (S-Ca) and elevated serum parathyroid hormone (S-PTH) levels in 1995 and at the re-examination 13 years later. Left square, left column shows the flow chart for nHPT. Right square shows subjects with pHPT in 1995 and at follow-up 13 years later, the WHO MONICA study, Gothenburg, Sweden. Right square, left panel shows the flow chart for subjects with vitamin D-sufficient pHPT. nHPT, normocalcaemic and vitamin D-sufficient hyperparathyroidism; pHPT, primary hyperparathyroidism; sHPT, secondary hyperparathyroidism; Vit D insuff., vitamin D insufficiency defined as S-25(OH)D < 50 nmol/l; Suppl., daily use of calcium/vitamin D supplementation; y, years; Tx, treatment; DM, diabetes mellitus; hypert, hypertension; N = normal
Of those with normal S-Ca, high S-PTH and vitamin D insufficiency in 1995, n = 13, (Fig. 1) four individuals out of the remaining eight were still in the same state and three had normalized at follow-up. One developed sHPT.
pHPT was found in nine of the 608 subjects (1·5%) in 1995 (Fig. 1). Mean S-Ca was 2·69 ± 0·16 mmol/l, mean S-PTH 71·7 ± 9·1 ng/l (range 60–84). Two of the nine subjects in 1995 were lost to follow-up, one of whom passed away and one moved from town. Despite the fact that the subjects with pHPT in 1995 had received no treatment for HPT, all had normal S-Ca levels at follow-up (mean S-Ca 2·36 ± 0·07 mmol/l). Three had nHPT, one had vitamin D insufficiency and elevated S-PTH, and the remaining three had normal S-PTH (Fig. 1).
At the re-examination in 2008, at the age of 38–79, nHPT was prevalent in 45 of 410 subjects (11%) of this random population sample. They were compared with 232 subjects (57%) with S-25(OH)D ≥ 50 nmol/l and normal S-PTH ( Table 1 ). Of interest is that 133 of 410 (32%) had vitamin D insufficiency and were not included in the present analyses.
There was no gender or seasonal sampling difference between individuals with nHPT and vitamin D-sufficient individuals with normal S-PTH ( Table 1 ). S-PTH was positively correlated with age and BMI; therefore, all reported statistical comparisons were adjusted for age and BMI in Table 1 .
The prevalence of hypertension, determined by the use of antihypertensives, was higher, but S-25(OH)D was lower in nHPT than in subjects with normal S-PTH. There were no differences between groups regarding blood glucose, lipids, thyroid hormones, S-anti-TPO, vitamin B12, folic acid, phosphate, iron, creatinine, cystatin C, glucose, insulin, body height, weight, change in height or body weight or calcaneal QUS during 13 years ( Table 1 ).
The subjects with nHPT had higher weekly intake (adjusted for age and BMI) of fat cheese (P = 0·0028) and cream (P = 0·0114), but lower intake of fatty fish (P = 0·0358) and vitamin D fortified low fat milk (P = 0·0154) than subjects with normal S-PTH. The calcium intake/day was above the recommended daily intake of 1000 mg/day in both groups. There were no significant differences in calcium/vitamin D supplementation (mainly 1000 mg calcium and 800 IU cholecalciferol) or thiazides between the two groups ( Table 1 ). Physical activity at work or leisure time did not differ between groups.
Data from 1995 for the two groups compared in Table 1 showed a higher prevalence of hypertension and higher S-PTH and S-Osteocalcin levels in nHPT than in those with normal S-PTH in 2008. Notable is that the S-Ca and S-25(OH)D levels in 1995 did not differ between groups. The S-Ca levels in 2008 were evenly distributed within the normocalcaemic range in relation to S-PTH (Fig. 2).
(Enlarge Image)
Figure 2.
Distribution of subjects, n = 410, regarding S-Ca in relation to S-PTH with vitamin D insufficiency (S-25(OH)D < 50 nmol/l: open circles) and sufficiency (cross in circles). Subjects with normocalcaemic, vitamin D-sufficient hyperparathyroidism (nHPT) are evenly distributed in the upper middle section. The straight horizontal line indicates the reference level of S-PTH, 60 ng/l, and the two vertical lines show the reference levels of S-Ca between 2·15 and 2·49 mmol/l. The equation for the regression line estimate is given below the figure.
No increase in the incidence of kidney stones, fractures, myocardial infarction (OR = 1·99, 95%CI 0·65–11·18; P = 0·16) or stroke (OR = 1·41, 95%CI 0·45–4·47; P = 0·56) during life or in mortality rates after 2008 was found in subjects with nHPT compared with subjects with normal S-PTH.
In 2008, 14 subjects with sufficient vitamin D levels (S-25(OH)D range 56–133; median 85 nmol/l) had elevated S-Ca levels and normal S-PTH. None had thiazide treatment, and four had calcium/vitamin D supplementation. One woman underwent surgery for mammary cancer; otherwise no malignancies were known. One of these individuals had nHPT in 1995 (mentioned above with specification of analysis results), and the others had normal S-PTH and S-Ca levels at that time. Six subjects of the 14 (43%) with hypercalcaemia and normal S-PTH had sustained fractures (ns compared with nHPT). Two subjects with hypercalcaemia had S-PTH 56 and 58 ng/l and should probably be considered as pHPT. The remaining 12 subjects with hypercalcaemia had S-PTH levels between 21 and 43 ng/l. Three subjects, besides the 14, had pHPT (hypercalcaemia and elevated S-PTH). Should the definition of pHPT be hypercalcaemia with measurable S-PTH, then the prevalence would be 4·1% in the age span of 38–79 years. The linear correlation between S-Ca and S-PTH in subjects with and without vitamin D insufficiency is shown in Fig. 2.
If the upper serum intact PTH level was set at 60, 65 or 70 ng/l, the prevalence of nHPT in 1995 was 2·0%, 1·0% and 0·5%, respectively, and at the re-examination in 2008, the prevalence was 11·0%, 7·8% and 4·9%, respectively. Factors of significance in a stepwise logistic regression analysis were previous osteocalcin and S-PTH, S-25(OH)D and treated hypertension. The higher the cut-off level for S-PTH, the stronger independent significant association for hypertension was seen ( Table 2 ). Furthermore, a level of S-25(OH)D ≥ 90 nmol/l resulted in S-PTH below 60 ng/l in all subjects.
Results
Prevalence of HPT in 1995 and at Follow-up
At first assessment in 1995, 25 subjects had elevated S-PTH and normal S-Ca, of whom 12 of 608 were vitamin D sufficient thereby fulfilling the diagnostic criteria for nHPT, giving a prevalence of 2·0% in the age range 25–64 years ( Table 1 ). At the reassessment of nHPT, 13 years later, five individuals were either deceased or lost to follow-up. Three of the remaining subjects had normalized their S-PTH levels and were vitamin D sufficient. One subject had nHPT both in 1995 and in 2008. Two had vitamin D insufficiency with elevated S-PTH levels. One woman had developed breast cancer, mild hypercalcaemia (2·55 mmol/l), but normal S-PTH (36 ng/l) and high S-25(OH)D (133 nmol/l) with a daily supplementation of 1000 mg Ca and 800 IU Vitamin D3; a possible progression to pHPT (Fig. 1). Two of seven had fractured during follow-up.
(Enlarge Image)
Figure 1.
Flow chart for subjects with a serum parathyroid hormone level ≥60 ng/l in 1995 and at follow-up 13 years later. Left square shows subjects aged 25–64 years with normal S-calcium (S-Ca) and elevated serum parathyroid hormone (S-PTH) levels in 1995 and at the re-examination 13 years later. Left square, left column shows the flow chart for nHPT. Right square shows subjects with pHPT in 1995 and at follow-up 13 years later, the WHO MONICA study, Gothenburg, Sweden. Right square, left panel shows the flow chart for subjects with vitamin D-sufficient pHPT. nHPT, normocalcaemic and vitamin D-sufficient hyperparathyroidism; pHPT, primary hyperparathyroidism; sHPT, secondary hyperparathyroidism; Vit D insuff., vitamin D insufficiency defined as S-25(OH)D < 50 nmol/l; Suppl., daily use of calcium/vitamin D supplementation; y, years; Tx, treatment; DM, diabetes mellitus; hypert, hypertension; N = normal
Of those with normal S-Ca, high S-PTH and vitamin D insufficiency in 1995, n = 13, (Fig. 1) four individuals out of the remaining eight were still in the same state and three had normalized at follow-up. One developed sHPT.
pHPT was found in nine of the 608 subjects (1·5%) in 1995 (Fig. 1). Mean S-Ca was 2·69 ± 0·16 mmol/l, mean S-PTH 71·7 ± 9·1 ng/l (range 60–84). Two of the nine subjects in 1995 were lost to follow-up, one of whom passed away and one moved from town. Despite the fact that the subjects with pHPT in 1995 had received no treatment for HPT, all had normal S-Ca levels at follow-up (mean S-Ca 2·36 ± 0·07 mmol/l). Three had nHPT, one had vitamin D insufficiency and elevated S-PTH, and the remaining three had normal S-PTH (Fig. 1).
Cross-sectional Comparison of Subjects With nHPT and Subjects With Normal S-PTH in 2008
At the re-examination in 2008, at the age of 38–79, nHPT was prevalent in 45 of 410 subjects (11%) of this random population sample. They were compared with 232 subjects (57%) with S-25(OH)D ≥ 50 nmol/l and normal S-PTH ( Table 1 ). Of interest is that 133 of 410 (32%) had vitamin D insufficiency and were not included in the present analyses.
There was no gender or seasonal sampling difference between individuals with nHPT and vitamin D-sufficient individuals with normal S-PTH ( Table 1 ). S-PTH was positively correlated with age and BMI; therefore, all reported statistical comparisons were adjusted for age and BMI in Table 1 .
The prevalence of hypertension, determined by the use of antihypertensives, was higher, but S-25(OH)D was lower in nHPT than in subjects with normal S-PTH. There were no differences between groups regarding blood glucose, lipids, thyroid hormones, S-anti-TPO, vitamin B12, folic acid, phosphate, iron, creatinine, cystatin C, glucose, insulin, body height, weight, change in height or body weight or calcaneal QUS during 13 years ( Table 1 ).
The subjects with nHPT had higher weekly intake (adjusted for age and BMI) of fat cheese (P = 0·0028) and cream (P = 0·0114), but lower intake of fatty fish (P = 0·0358) and vitamin D fortified low fat milk (P = 0·0154) than subjects with normal S-PTH. The calcium intake/day was above the recommended daily intake of 1000 mg/day in both groups. There were no significant differences in calcium/vitamin D supplementation (mainly 1000 mg calcium and 800 IU cholecalciferol) or thiazides between the two groups ( Table 1 ). Physical activity at work or leisure time did not differ between groups.
Data from 1995 for the two groups compared in Table 1 showed a higher prevalence of hypertension and higher S-PTH and S-Osteocalcin levels in nHPT than in those with normal S-PTH in 2008. Notable is that the S-Ca and S-25(OH)D levels in 1995 did not differ between groups. The S-Ca levels in 2008 were evenly distributed within the normocalcaemic range in relation to S-PTH (Fig. 2).
(Enlarge Image)
Figure 2.
Distribution of subjects, n = 410, regarding S-Ca in relation to S-PTH with vitamin D insufficiency (S-25(OH)D < 50 nmol/l: open circles) and sufficiency (cross in circles). Subjects with normocalcaemic, vitamin D-sufficient hyperparathyroidism (nHPT) are evenly distributed in the upper middle section. The straight horizontal line indicates the reference level of S-PTH, 60 ng/l, and the two vertical lines show the reference levels of S-Ca between 2·15 and 2·49 mmol/l. The equation for the regression line estimate is given below the figure.
No increase in the incidence of kidney stones, fractures, myocardial infarction (OR = 1·99, 95%CI 0·65–11·18; P = 0·16) or stroke (OR = 1·41, 95%CI 0·45–4·47; P = 0·56) during life or in mortality rates after 2008 was found in subjects with nHPT compared with subjects with normal S-PTH.
Hypercalcaemia at the Cross-sectional Analyses in 2008
In 2008, 14 subjects with sufficient vitamin D levels (S-25(OH)D range 56–133; median 85 nmol/l) had elevated S-Ca levels and normal S-PTH. None had thiazide treatment, and four had calcium/vitamin D supplementation. One woman underwent surgery for mammary cancer; otherwise no malignancies were known. One of these individuals had nHPT in 1995 (mentioned above with specification of analysis results), and the others had normal S-PTH and S-Ca levels at that time. Six subjects of the 14 (43%) with hypercalcaemia and normal S-PTH had sustained fractures (ns compared with nHPT). Two subjects with hypercalcaemia had S-PTH 56 and 58 ng/l and should probably be considered as pHPT. The remaining 12 subjects with hypercalcaemia had S-PTH levels between 21 and 43 ng/l. Three subjects, besides the 14, had pHPT (hypercalcaemia and elevated S-PTH). Should the definition of pHPT be hypercalcaemia with measurable S-PTH, then the prevalence would be 4·1% in the age span of 38–79 years. The linear correlation between S-Ca and S-PTH in subjects with and without vitamin D insufficiency is shown in Fig. 2.
Different Cut-off Levels of S-PTH and Regression Analyses
If the upper serum intact PTH level was set at 60, 65 or 70 ng/l, the prevalence of nHPT in 1995 was 2·0%, 1·0% and 0·5%, respectively, and at the re-examination in 2008, the prevalence was 11·0%, 7·8% and 4·9%, respectively. Factors of significance in a stepwise logistic regression analysis were previous osteocalcin and S-PTH, S-25(OH)D and treated hypertension. The higher the cut-off level for S-PTH, the stronger independent significant association for hypertension was seen ( Table 2 ). Furthermore, a level of S-25(OH)D ≥ 90 nmol/l resulted in S-PTH below 60 ng/l in all subjects.
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