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Anne Kristine Amstrup, Lars Rejnmark and Leif Mosekilde

Objective

Primary hyperparathyroidism (PHPT) is associated with feelings of fatigue and depression, as well as limitation to physical and mental functioning. These quality of life (QoL) characteristics improve after parathyroidectomy. However, whether former patients fully regain QoL compared with healthy controls is largely unknown.

Design and patients

Cross-sectional study. Fifty-one former PHPT patients, successfully treated by surgery (mean time since parathyroidectomy 7.4 (range 5–15) years), and 51 sex- and age-matched healthy controls.

Methods

The 36-item Short-Form Health Survey version 2 and the WHO-Five Well-being Index. The surveys included questions on overall physical and mental health, functioning, and limitation in daily life activities.

Results

Former patients scored significantly lower compared with controls in physical functioning (P=0.01), role limitation caused by emotional problems (P=0.01), vitality (P<0.001), and general health (P=0.01). Compared with the controls, cases had a lower median (interquartile range) score of physical component summary (PCS; 54.9 (47.9–58.7) vs 49.6 (45.2–55.9), P=0.03) and mental component summary (MCS; 55.4 (49.7–58.1) vs 52.5 (44.7–55.5), P=0.04). There was no association between time since operation and PCS or MCS. Compared with controls, cases had higher body mass index (BMI; 26.0±4.7 vs 28.8±6.0 kg/m2, P<0.001) and a higher frequency of cardiovascular diseases (CVD; 41.2 vs 62.7%, P=0.03). After adjustment for differences in BMI and CVD, PCS did no longer differ between groups. However, adjustments did not change the finding of a lower MCS in cases compared with controls.

Conclusion

Even though QoL may improve substantially after surgery, former PHPT patients still have reduced QoL compared with healthy controls.

Free access

Silje Hovden, Lars Rejnmark, Søren A Ladefoged and Peter H Nissen

Objective

Familial hypocalciuric hypercalcemia (FHH) type 1 is caused by mutations in the gene encoding the calcium-sensing receptor (CASR). Recently, mutations affecting codon 15 in the gene AP2S1 have been shown to cause FHH type 3 in up to 26% of CASR-negative FHH patients. Similarly, mutations in the gene GNA11 have been shown to cause FHH type 2. We hypothesized that mutations in AP2S1 and GNA11 are causative in Danish patients with suspected FHH and that these mutations are not found in patients with primary hyperparathyroidism (PHPT), which is the main differential diagnostic disorder.

Design

Cross-sectional study.

Methods

We identified patients with unexplained hyperparathyroid hypercalcemia and a control group of verified PHPT patients through review of 421 patients tested for CASR mutations in the period 2006–2014. DNA sequencing of all amino acid coding exons including intron–exon boundaries in AP2S1 and GNA11 was performed.

Results

In 33 CASR-negative patients with suspected FHH, we found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype–phenotype correlations. We did not identify any pathogenic mutations in GNA11. No pathogenic mutations were found in the PHPT control group.

Conclusions

We suggest that the best diagnostic approach to hyperparathyroid hypercalcemic patients suspected to have FHH is to screen the CASR and AP2S1 codon 15 for mutations. If the results are negative and there is still suspicion of an inherited condition (i.e. family history), then GNA11 should be examined.

Free access

Lars Rejnmark, Peter Vestergaard, Lene Heickendorff and Leif Mosekilde

Objective

Although calcitriol (1,25(OH)2D) is considered the biologically active vitamin D metabolite, several studies have shown that calcidiol (25OHD) is the vitamin D metabolite that is most closely linked to parathyroid function and indices of calcium homeostasis. Moreover, low levels of 25OHD have been associated with increased risk of different diseases including cancer, diabetes, and myopathy.

Design

Cross-sectional study.

Methods

We studied relations between plasma concentrations of 25OHD, 1,25(OH)2D, and parathyroid hormone (PTH) in fasting plasma samples from 315 healthy postmenopausal women randomly selected from the local background population.

Results

P-1,25(OH)2D levels varied in a concentration-dependent manner with P-25OHD levels (P<0.001). Thus, P-1,25(OH)2D levels were the lowest in women with vitamin D insufficiency, i.e., P-1,25(OH)2D levels were reduced by approximately one-third in subjects with P-25OHD levels below 25 nmol/l compared with levels above 80 nmol/l (P<0.01). The association was most pronounced at P-25OHD concentrations below 80 nmol/l, whereas no major increase in P-1,25(OH)2D was observed at P-25OHD concentrations above 80 nmol/l. In multiple regression analysis, PTH was a minor although significant predictor of P-1,25(OH)2D levels.

Conclusions

In normal postmenopausal women, the conversion of 25OHD to active vitamin D depends on the substrate concentration. Our data support that vitamin D insufficiency should be considered at P-25OHD levels below 80 nmol/l.

Free access

Aliya A Khan, Bart Clarke, Lars Rejnmark and Maria Luisa Brandi

Purpose

Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy.

Methods

We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review.

Conclusions

During pregnancy, calcitriol levels increase by two- to—three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies.

Free access

Niels Frederik Breum Jakobsen, Lars Rolighed, Peter H Nissen, Leif Mosekilde and Lars Rejnmark

Background

Familial hypocalciuric hypercalcemia (FHH) is often due to inactivating variants in the calcium-sensing receptor (CASR) gene causing chronically elevated plasma calcium levels with inappropriately normal or elevated parathyroid hormone levels. In patients with primary hyperparathyroidism, the state of hyperparathyroid hypercalcemia is associated with reduced muscle strength and impaired quality of life (QoL).

Objective

To study whether FHH affects muscle function, postural stability, and QoL.

Design

In a cross-sectional study, we investigated muscle strength (handgrip, elbow flexion/extension, and knee flexion/extension), balance function, physical activity, and QoL in 50 patients with FHH and in a similar number of age- and gender-matched population-based healthy controls. All but one of the FHH cases had genetically verified inactivating variants in the CASR gene.

Results

Studied subjects (n=100, 68% females) had a mean age of 56.0 years. Muscle strength as assessed by measuring maximum force and maximum force production did not differ between the groups. Neither did groups differ in terms of QoL, physical activity, or postural stability, as assessed during normal standing with eyes open, normal standing with eyes closed, semi-tandem standing, or tandem standing. Adjustment for vitamin D status (plasma 25-hydroxyvitamin D levels) and BMI did not change results.

Conclusion

Despite a state of chronic hypercalcemia, muscle strength, balance function, and QoL are not impaired in patients with FHH. Our findings are reassuring for patients with FHH as they should not be considered as having a severe disease.

Free access

Lars Rolighed, Lars Rejnmark, Tanja Sikjaer, Lene Heickendorff, Peter Vestergaard, Leif Mosekilde and Peer Christiansen

Context

Impairments of muscle function and strength in patients with primary hyperparathyroidism (PHPT) are rarely addressed, although decreased muscle function may contribute to increased fracture risk.

Objective

We aimed to assess the changes in muscle strength, muscle function, postural stability, quality of life (QoL), and well-being during treatment with vitamin D or placebo before and after parathyroidectomy (PTX) in PHPT patients.

Design

A randomized placebo-controlled trial.

Patients

We included 46 PHPT patients, mean age 58 (range 29–77) years and 35 (76%) were women.

Interventions

Daily treatment with 70 μg (2800 IU) cholecalciferol or placebo for 52 weeks. Treatment was administered 26 weeks before PTX and continued for 26 weeks after PTX.

Main outcome measures

Changes in QoL and measures of muscle strength and function.

Results

Preoperatively, 25-hydroxyvitamin D (25OHD) increased significantly (50–94 nmol/l) compared with placebo (57–52 nmol/l). We did not measure any beneficial effects of supplementation with vitamin D compared with placebo regarding well-being, QoL, postural stability, muscle strength, or function. In all patients, we measured marked improvements in QoL, well-being (P<0.01), muscle strength in the knee flexion and extension (P<0.001), and muscle function tests (P<0.01) after surgical cure. Postural stability improved during standing with eyes closed (P<0.05), but decreased with eyes open (P<0.05).

Conclusions

Patients with PHPT and 25OHD levels around 50 nmol/l did not benefit from vitamin D supplementation concerning muscle strength, muscle function, postural stability, well-being, or QoL. Independent of preoperative 25OHD levels, PTX improved these parameters.

Free access

Louise Lind Schierbeck, Lars Rejnmark, Charlotte Landbo Tofteng, Lis Stilgren, Pia Eiken, Leif Mosekilde, Lars Køber and Jens-Erik Beck Jensen

Objective

To investigate the relationship between vitamin D status in healthy women and cardiovascular outcome.

Design and methods

Between 1990 and 1993, 2016 healthy, recently postmenopausal women were enrolled in the Danish Osteoporosis Prevention Study. Serum levels of 25-hydroxyvitamin D (25(OH)D, nmol/l) were measured at baseline. Participants were followed for 16 years. The primary end point was a combination of death, heart failure, myocardial infarction (MI) and stroke. Vitamin D deficiency was defined as serum 25(OH)D<50 nmol/l. The primary end point was adjusted for other risk factors of adverse cardiovascular events (age, smoking, blood pressure, hip–waist ratio, education and family history of MI).

Results

At baseline, mean age was 50 years and BMI 25. Women with vitamin D deficiency (n=788) had more cardiovascular risk factors than vitamin D-replete women (n=1225). Compared with vitamin D-replete women, women with low 25(OH)D levels had significantly higher BMI and triglycerides, lower HDL and hip–waist ratio and less education. More were smokers among the vitamin D deficient (47 vs 38%). A primary end point was experienced by 118 (15%) with vitamin D deficiency and by 125 (10%) of the vitamin D replete. Hazard ratio (HR) was 1.49 (95% confidence interval: 1.16–1.92; P=0.002) in the vitamin D deficient. Adjusted HR was 1.32 (1.02–1.71; P=0.03). In total, 135 women died; of these, 65 (8%) were of the vitamin D deficient and 70 (6%) in the vitamin D-replete group; unadjusted HR was 1.44 (1.02–2.01; P=0.04) for vitamin D deficiency.

Conclusion

Healthy women with vitamin D deficiency have increased risk of adverse cardiovascular outcome.

Free access

Signe Engkjær Christensen, Peter H Nissen, Peter Vestergaard, Lene Heickendorff, Lars Rejnmark, Kim Brixen and Leif Mosekilde

Introduction

Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign, inherited condition caused by inactivating mutations in the calcium-sensing receptor (CASR) gene. Both FHH and primary hyperparathyroidism (PHPT) are characterized by elevated P-calcium, normal or elevated plasma-parathyroid hormone (P-PTH), and typically normal renal function. In PHPT, vitamin D metabolism is typically characterized by low plasma levels of 25-hydroxyvitamin D (25OHD), and high plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)2D). In FHH, the vitamin D metabolism is not very well known.

Objective

To compare and evaluate plasma 25OHD, 1,25(OH)2D, and PTH in FHH and PHPT.

Design

Cross-sectional study.

Materials

About 66 FHH patients with mutations in the CASR gene, 147 patients with surgically verified PHPT, and 46 controls matched to FHH patients according to age (±5 years), sex, and season. All patients had a P-creatinine <140 μmol/l.

Methods

We measured P-calcium, P-Ca2 +, P-albumin, P-creatinine, P-phosphate, P-magnesium, and P-PTH by standard laboratory methods. P-25OHD and P-1,25(OH)2D were measured by RIA or enzyme immunoassay. In FHH, all protein-coding exons in the CASR gene were sequenced and aligned to GenBank reference sequence .

Results

PHPT patients had higher body mass index (2p<0.01), together with higher P-PTH (2p<0.01) and P-1,25(OH)2D (2p<0.01) compared with FHH patients. The groups had similar levels of P-Ca2 + and of P-25OHD. The phenotypic expression of the CASR mutations (as determined by the degree of hypercalcemia) did not influence the levels of P-1,25(OH)2D.

Conclusion

Even though P-calcium and P-25OHD were comparable, P-1,25(OH)2D and P-PTH differed between FHH and PHPT.

Free access

Jens Bollerslev, Lars Rejnmark, Claudio Marcocci, Dolores M Shoback, Antonio Sitges-Serra, Wim van Biesen and Olaf M Dekkers

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.

Free access

Niels Frederik Breum Jakobsen, Esben Laugesen, Lars Rolighed, Peter H Nissen, Per Løgstrup Poulsen, Erling Bjerregaard Pedersen, Leif Mosekilde and Lars Rejnmark

Objective

Loss-of-function variants in the gene encoding the calcium-sensing receptor (CASR) result in familial hypocalciuric hypercalcemia (FHH), causing hypercalcemia with high normal or elevated parathyroid hormone levels. The CASR may also influence electrolyte and water homeostasis. It is unknown whether FHH affects cardiovascular health. We, therefore investigated whether FHH is associated with changes in the regulation of the cardiovascular system by measuring 24-h blood pressure (BP), arterial stiffness and vasoactive hormones.

Design

Cross-sectional study comparing 50 patients with FHH to age- and gender-matched controls.

Results

Studied subjects (69% women) had a mean age of 56years. A similar number of patients and controls (33%) were on treatment with antihypertensive drugs. Overall, no differences were found between groups in 24-h ambulatory BP or pulse wave velocity. However, compared with controls, diastolic BP during nighttime was lower in FHH females (60±5 vs 66±9mmHg, P<0.01) and higher in FHH males (69±6 vs 64±5mmHg, P=0.02). FHH was associated with a significantly higher plasma osmolality (P<0.01), higher plasma levels of vasopressin (P<0.01) and a higher renal excretion of epithelial sodium channels (ENaCs) (P=0.03), whereas urine aquaporin-2 and plasma sodium, aldosterone and renin did not differ between groups. FHH patients had a lower urinary volume with an increased osmolality if analyses were restricted to those not on treatments with antihypertensive drugs.

Conclusions

FHH does not seem to be associated with an increased risk of CVD.