Long-term complications in patients with chronic hypoparathyroidism: a cross-sectional study

in European Journal of Endocrinology
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  • 1 Department of Endocrinology, University Hospitals, Leuven, Belgium

Correspondence should be addressed to B Decallonne; Email: brigitte.decallonne@uzleuven.be
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Objective

Chronic hypoparathyroidism and its treatment may lead to symptoms and complications affecting quality of life. We determined complications in chronic hypoparathyroid patients.

Design

Retrospective cross-sectional study of patients with chronic hypoparathyroidism treated with active vitamin D supplements in a tertiary care centre during the year 2015. Primary outcome parameters were history of kidney stones and seizures and presence of renal and cerebral calcifications on imaging. Secondary outcome parameters were current symptoms of paraesthesia/cramps, hospitalization due to hyper/hypocalcaemia and hypercalciuria.

Subjects

One hundred and seventy patients were included – 143 (84%) with post-surgical hypoparathyroidism (PSHP), 16 (9%) with non-surgical hypoparathyroidism (NSHP) and 11 (7%) with pseudo-hypoparathyroidism (PHP).

Results

History of kidney stones and seizures was present in 15 and 9% of patients, respectively. Renal and cerebral imaging was performed in 51 and 26% of the patients, with 22 and 25% of these patients having renal and cerebral calcifications respectively. Both history of seizures and cerebral calcifications were significantly more in NSHP and PHP than in PSHP patients. No association was observed between seizures and cerebral calcifications. Cramps/paraesthesia were present in 16%, and hospitalization related to hypocalcaemia was reported in 5% of the patients. Calciuria was screened in 47% at the time of consultation, and in 76% of the patients during the past 5 years. In 36% of these patients, calciuria was increased.

Conclusions

Patients with chronic hypoparathyroidism frequently develop ectopic calcifications. Non-surgical patients suffer more from seizures and cerebral calcifications than patients that developed hypoparathyroidism post surgery. There is a need for increased screening of long-term complications, according to the guidelines.

Abstract

Objective

Chronic hypoparathyroidism and its treatment may lead to symptoms and complications affecting quality of life. We determined complications in chronic hypoparathyroid patients.

Design

Retrospective cross-sectional study of patients with chronic hypoparathyroidism treated with active vitamin D supplements in a tertiary care centre during the year 2015. Primary outcome parameters were history of kidney stones and seizures and presence of renal and cerebral calcifications on imaging. Secondary outcome parameters were current symptoms of paraesthesia/cramps, hospitalization due to hyper/hypocalcaemia and hypercalciuria.

Subjects

One hundred and seventy patients were included – 143 (84%) with post-surgical hypoparathyroidism (PSHP), 16 (9%) with non-surgical hypoparathyroidism (NSHP) and 11 (7%) with pseudo-hypoparathyroidism (PHP).

Results

History of kidney stones and seizures was present in 15 and 9% of patients, respectively. Renal and cerebral imaging was performed in 51 and 26% of the patients, with 22 and 25% of these patients having renal and cerebral calcifications respectively. Both history of seizures and cerebral calcifications were significantly more in NSHP and PHP than in PSHP patients. No association was observed between seizures and cerebral calcifications. Cramps/paraesthesia were present in 16%, and hospitalization related to hypocalcaemia was reported in 5% of the patients. Calciuria was screened in 47% at the time of consultation, and in 76% of the patients during the past 5 years. In 36% of these patients, calciuria was increased.

Conclusions

Patients with chronic hypoparathyroidism frequently develop ectopic calcifications. Non-surgical patients suffer more from seizures and cerebral calcifications than patients that developed hypoparathyroidism post surgery. There is a need for increased screening of long-term complications, according to the guidelines.

Introduction

Hypoparathyroidism (HP) is an uncommon endocrinological condition. It is characterized by absent or inappropriately low serum levels of parathyroid hormone (PTH) resulting in hypocalcaemia and hyperphosphataemia (1, 2, 3). Most often, it is an acquired condition after neck surgery. Rare causes are autoimmune conditions, severe magnesium deficiency, infiltrative diseases and genetic abnormalities (4). A distinct form is called pseudo-hypoparathyroidism (PHP) in which there is an end-organ resistance to PTH resulting in high serum levels of PTH, but low levels of serum calcium (1, 2). In Denmark, post-surgical hypoparathyroidism (PSHP) has a prevalence of 22/100 000 person-years, while non-surgical hypoparathyroidism (NSHP) and PHP forms are much more rare with a prevalence of 2.3/100 000 person-years and 1.1/100 000 person-years respectively (5, 6, 7). In the United States the estimated prevalence of all-cause HP is 37/100 000 person-years (8). The prevalence in Belgium is not known.

HP is one of the few endocrinopathies in which currently the hormonal deficiency is not treated by substitution of the hormone itself. Conventional treatment includes calcium supplements and active vitamin D analogues (1, 2). Additional therapy may consist of non-active vitamin D supplements and anticalciuretic drugs. Despite its different pathogenesis, the management of PHP patients is largely the same as that of patients with HP. In the meantime, recombinant human PTH 1–84 (rhPTH) has been FDA and EMA approved for use in patients with HP that are not well controlled by conventional therapy (9, 10). Goals of HP treatment consist of controlling the symptoms and minimizing short-term and long-term complications (1). Symptoms are generally those of hypocalcaemia that can, depending on the severity and the acuteness of onset, result in paraesthesia, spasms, tetany, cardiac arrhythmias and/or seizures (2, 4). Well-known complications of chronic HP and its treatment are renal insufficiency, ectopic calcifications in the kidneys and the brain, impaired quality of life and higher risk of seizures (3, 4). Recent studies show a higher mortality in patients with HP (11, 12). Since it is a rare disease, studies describing the features and complications of the disease generally suffer from small numbers of patients. Therefore, the recently published management guidelines are mainly based on clinical expertise (9, 13, 14).

Our aim was to study complications in a recent cohort of patients with chronic HP in follow-up in our institution and compare these results with the available data from literature and recent European and US guidelines for the management of patients with chronic HP.

Subjects and methods

Patient identification

Patients in follow-up for HP who visited the adult outpatient clinic of endocrinology in the University Hospitals Leuven, Belgium, a tertiary care centre, between 1 January 2015 and 31 December 2015 were studied. Hypoparathyroidism was defined as having hypocalcaemia with inappropriately low/normal levels of PTH at the time of diagnosis, necessitating medical treatment with an active vitamin D analogue. PHP was defined as having hypocalcaemia with elevated PTH levels at time of diagnosis. Patients with other causes of elevated serum PTH such as secondary hyperparathyroidism due to vitamin D deficiency were excluded (1). Patients with HP are evaluated at least once yearly in our centre, which is also a condition for reimbursement of the active vitamin D analogue in Belgium. Cases were identified using an electronic search query in the clinical file system of the institution using the following keywords: ‘hypoparathyroidism’, ‘pseudo-hypoparathyroidism’, ‘1 alpha leo’, ‘alfacalcidol’, ‘rocaltrol’ and ‘calcitriol’, resulting in 319 unique patients. After detailed study of the individual clinical files, 83 patients did not meet the criteria for hypoparathyroidism or PHP and were excluded (for example ‘hypoparathyroidism’ was mentioned in a differential diagnostic list of hypocalcaemia or a patient was treated with a vitamin D analogue for another disease). Other exclusion criteria were duration of disease less than 1 year (52 patients) and follow-up less than 1 year in our institution (14 patients). Eventually, the studied cohort consisted of 159 patients with ‘classical’ chronic hypoparathyroidism (post-surgical and non-surgical) and 11 patients with PHP (Fig. 1). The study was approved by the Ethical Committee of the University Hospitals Leuven. Consent has been obtained from each patient after full explanation of the purpose and nature of all procedures used.

Figure 1
Figure 1

Identification of patients with chronic hypoparathyroidism.

Citation: European Journal of Endocrinology 180, 1; 10.1530/EJE-18-0580

Data collection

Patients’ characteristics such as age, gender, disease aetiology, disease duration and hypoparathyroidism-related medical treatment (calcium supplements, active vitamin D analogues, vitamin D3, thiazide diuretics) were retrieved from the clinical files. Disease duration in PHP patients was similar to the patients’ age. In NSHP patients, disease duration was also similar to the patients’ age in case of a genetic cause of the disease. For autoimmune and idiopathic causes, disease duration was calculated from time of HP diagnosis. Medical history was reviewed in detail for the occurrence of kidney stones, cataracts, seizures and hospitalizations due to hypo- or hypercalcaemia after the diagnosis of HP. The following biochemical parameters were registered: serum creatinine, eGFR and 24-h renal calcium excretion on the day of consultation. The CKD-EPI formula was used to calculate eGFR (15). When a 24-h urine collection was not available on the day of the consultation, the most recent 24-h calciuria result was registered provided that this result was less than 5 years old and post incidence date of the HP diagnosis. Furthermore, any imaging of the kidneys (ultrasound/CT/MRI) and brain (CT/MRI) was registered and screened for the presence of calcifications (nephrocalcinosis, renal stones, intracerebral calcifications), provided that these results were less than 10 years old and post incidence. Finally, data on symptoms of paraesthesia and/or cramps during the month prior to the consultation were registered.

Statistical analysis

The Shapiro–Wilk test was used to verify the assumption of symmetrical distribution of all continuous variables. Symmetrical distributed variables and descriptive data are presented as mean ± standard deviation (s.d.), whereas asymmetric variables are presented as median (minimum–maximum). For the analysis of symmetrical distributed variables unpaired t-tests and one-way ANOVA tests with Bonferroni’s multiple test comparison were performed to detect the differences between groups. All non-symmetrical distributed variables were analysed by Mann–Whitney tests and Kruskal–Wallis tests with Dunn’s multiple comparisons tests. For continuous categorical data, presented as %(n), the Pearson’s χ 2-test was used. In case of patient numbers ≤5 the χ 2-test with Yates’s correction for continuity was used. In case of statistically significant differences between the groups, the Tukey’s range test was used for continuous data and Pearson’s χ 2-test for categorical data. A P value of <0.05 was considered as statistically significant.

Results

Patient characteristics

Between 1 January 2015 and 31 December 2015, 170 patients with chronic HP or PHP who met the inclusion criteria were seen at the adult outpatient endocrinology clinic in the University Hospitals Leuven. The patient characteristics are summarized in Table 1. The majority of patients were females. Average age was 58 years. The duration of disease varied from 1 year to 68 years, being on average 17 years. PSHP was the aetiology in the majority of the cases. In most cases, a total thyroidectomy (with or without lymph node dissection) was performed. None of the parathyroidectomies was performed due to hyperparathyroidism in the context of end-stage renal disease. Sixteen patients had NSHP, with the following aetiologies: autoimmune hypoparathyroidism in six patients (of which two patients with autoimmune polyendocrine syndrome type I (APS-1)), Di George syndrome in two patients, an activating calcium sensor receptor (CaSR) mutation in two patients, CHARGE (Coloboma of the eye, central nervous system anomalies; heart defects; atresia of the choanae; retardation of growth and/or development; genital and/or urinary defects; ear anomalies and/or deafness) syndrome in one patient and HDR (hypoparathyroidism-deafness-renal disease) syndrome in one patient. In the remaining four patients, the cause of the hypoparathyroidism was not known, and they were classified as having idiopathic HP. Eleven patients were identified as having PHP. Five patients had PHP type Ia with Albright’s hereditary osteodystrophy, six patients had PHP type Ib. Genetic confirmation of the disease was available in all PHP and NSHP patients, with the exception of the four patients with autoimmune HP without APS-1 and in the four patients with idiopathic HP.

Table 1

Patient characteristics of total cohort. Data are presented as mean ± s.d. or % (n) for quantitative and categorical data respectively.

n = 170
Male sex39.4 (67)
Age (years)58.11 ± 15.65
Duration of disease (years)16.58 ± 14.65
Aetiology
 Post-surgical hypoparathyroidism

  Total thyroidectomy

  Total thyroidectomy + neck dissection

  Hemithyroidectomy

  Parathyroidectomy (partial/total)

  Other types of neck surgery

 Non-surgical hypoparathyroidism

 Pseudo-hypoparathyroidism
84.1 (143)

65.0 (93)

13.3 (19)

8.4 (12)

7.7 (11)

5.6 (8)

9.4 (16)

6.5 (11)
Medical treatment
 Alfacalcidol

  Mean dose (µg)

 Vitamin D3 (± calcium supplement)

  Mean dose (IU)

 Calcium supplement (± vitamin D3)

  Mean dose (mg)

 Vitamin D3 + calcium supplement

 Anticalciuretic
95.9 (163)

1.31 ± 0.74

35.3 (60)

1067 ± 692

78.2 (133)

1035 ± 507

31.8 (35)

14.1 (24)
eGFR (mL/min/1.73 m2)

 Mean
82.9 (141)

71.94 ± 20.85

eGFR, estimated glomerular filtration rate.

All patients were taking active vitamin D analogues as this was an inclusion criterion. The majority of patients were treated with 1-alphahydroxyvitamin D3 (alfacalcidol). Only seven patients were taking 1,25-alphahydroxyvitamine D3 (Rocaltrol). One-third of the patients were also taking vitamin D3 supplements (cholecalciferol). Almost 80% of patients were taking calcium supplements. Fourteen percent of patients were receiving an anticalciuretic drug (thiazide and/or amiloride).

Long-term complications

As shown in Table 2, 27 out of 170 patients had experienced paraesthesia and/or cramps during the past month. Hospitalization due to severe hypocalcaemia had been necessary in eight cases during the total course of the disease. None of the patients was hospitalized due to a hypercalcaemic event. Cataracts were present in 16 and absent in 12 patients. In the remaining 142 patients the presence or absence of cataract was not mentioned in the clinical file. With regard to renal complications, 14.7% had been diagnosed with kidney stones. For 82.9% of patients kidney function was measured at time of consultation with a mean eGFR (CKD-EPI) of 71.94 ± 20.85 mL/min/1.73 m2. In the last 5 years, a 24-h urinary calcium excretion was determined in 76% of the patients, of which 46.5% at the time of last consultation. With the upper limit of calciuria for females being 6.5 mmol/24 h and for males being 7.5 mmol/24 h, 47 out of 129 patients, including patients taking anticalciuretics, exceeded the gender-specific upper limit. Exclusion of patients on thiazide and/or amiloride diuretics resulted in 41 out of 109 patients exceeding the upper limit of 24-h renal calcium excretion. In 51.2% of patients at least one renal imaging in the last 10 years of the disease was performed, of which 21.8% showed kidney stones and/or nephrocalcinosis. Regarding cerebral imaging, which was performed at least once in the last 10 years of the disease in 25.9% of patients, calcifications were observed in 25% of the patients. Finally, 8.8% of patients had a medical history of seizures.

Table 2

Complications in the total cohort. Data are presented as mean ± s.d. or % (n) for quantitative and categorical data, respectively.

n = 170
Paraesthesia and/or cramps15.9 (27)
Urinary calcium excretion75.9 (129)
 Mean renal calcium excretion (mmol/24 h)6.20 ± 3.79
 Exceeding upper limit36.4 (47)
History of seizures8.8 (15)
History of kidney stones14.7 (25)
Hospitalization due to hypocalcaemia4.7 (8)
Renal imaging51.2 (87)
 Nephrocalcinosis and/or stones21.8 (19)
Cerebral imaging25.9 (44)
 Intracerebral calcifications25.0 (11)

Complications according to disease aetiology

Patients were divided by HP aetiology into three groups: PSHP, NSHP and PHP (Table 3) for comparison of patient characteristics, treatment modality and complications of the disease.

Table 3

Patient characteristics and complications according to disease aetiology. Data are presented as % (n) for categorical data. Quantitative data are presented as mean ± s.d. or median (minimum–maximum) for symmetrical and non-symmetrical distributed variables respectively.

HypoparathyroidismP value
Post-surgical (n = 143)Non-surgical (n = 16)Pseudo (n = 11)
Male sex36.4 (52)56.3 (9)54.5 (6)0.3308
Age (years)60.7 (24.8–88.5)52.4 (19.9–83.3)42.7 (23.3–68.2)c<0.001
Duration of disease (years)9.4 (1.0–57.5)20.1 (1.6–56.9)42.7 (23.3–68.2)c<0.001
Medical treatment
 Alfacalcidol

  Median dose (µg)

 Vitamin D3 (±calcium suppl.)

  Median dose (IU)

 Calcium suppl. (±vitamin D3)

  Median dose (mg)

 Vitamin D3 + calcium suppl.

 Anticalciuretic
95.8 (137)

1.3 (0.3–6.0)

33.6 (48)

833 (400–3571)

79.7 (114)

1000 (500–3000)a

32.2 (46)

14.0 (20)
100 (16)

1.3 (0.5–3.3)

31.3 (5)b

833 (800–1760)

81.3 (13)

1000 (500–3000)

31.3 (5)

18.8 (3)
90.9 (10)

1.0 (0.5–2.5)

63.6 (7)c

833 (833–1786)

54.5 (6)

1000 (500–2000)

27.3 (3)

9.1 (1)
0.9777

0.5848

<0.001

0.7075

0.2900

<0.05

0.9999

0.9841
Paraesthesia and/or cramps

Hospitalisation due to hypocalcaemia

History of seizures

History of kidney stones
16.8 (24)

3.5 (5)

4.2 (6)a

15.4 (22)
25 (4)

6.3 (1)

25 (4)

12.5 (2)
9.1 (1)

18.2 (2)

45.5 (5)c

9.1 (1)
0.7411

0.3342

<0.001

0.9889
eGFR (mL/min/1.73 m2)

 Mean
83.9 (120)

69.9 ± 19.79
87.5 (14)

82.2 ± 26.93
63.6 (7)

85.9 ± 10.86
0.4155

<0.05
Urine analysis

 Median renal calcium excretion (mmol/24 h)
75.5 (108)

6.2 (0.7–17.6)
75.0 (12)

3.2 (0.9–14.6)
81.8 (9)

2.4 (0.4–5.4)c
0.9942

<0.01
Imaging
 Renal

  Calcinosis and/or stones

 Cerebral

  Calcifications
47.6 (68)

27.9 (19)

21.7 (31)

6.5 (2)a
75.0 (12)

6.3 (1)

50.0 (8)

75 (6)
63.6 (7)

14.3 (1)

45.5 (5)

60 (3)c
0.0793

0.5312

<0.05

<0.001

Statistical significant differences (P < 0.05) between two different groups separately are illustrated by a,b and c.

aPSHP vs NSHP; bNSHP vs PHP; cPSHP vs PHP.

eGFR, estimated glomerular filtration rate.

There was no difference of gender distribution between the different groups, but PSHP patients were older compared to PHP patients. The disease duration was significantly longer in the PHP group compared to the PSHP group. The median dose of active vitamin D analogues was similar. More PHP patients took non-active vitamin D3 supplements compared to the other two groups, but the amount of substitution did not differ. The proportion of patients taking calcium supplementation did not differ between the different groups, but the amount of substitution was higher in the PSHP group compared to the NSHP group. Recent complaints of paraesthesia and/or cramps were similar, and there was no difference in hospitalization due to hypocalcaemia.

Regarding renal complications, there was no difference in history of kidney stones. The average kidney function, expressed as eGFR, was lower in PSHP patients as compared to NSHP and PHP patients. Median renal calcium excretion was significantly lower in PHP compared to PSHP patients. No difference was observed regarding the performance of renal imaging or the presence of renal calcifications. Cerebral imaging was more often performed in NSHP and PHP patients. Calcifications were visualized in 75 and 60% of patients with NSHP and patients with PHP with cerebral imaging respectively, in contrast with calcifications being present in only 6.5% of imaging in PSHP patients. History of seizures was present in 45.5% of patients with PHP and in 25% of patients with NSHP, which statistically differs from the 4.2% in patients with PSHP (P < 0.001 and P < 0.01).

Seizures and cerebral calcifications

Patients with a history of seizures were younger and their disease duration was longer compared to patients without seizures, and more cerebral imaging was performed in this group (Table 4). However, there was no difference in presence of intracerebral calcifications on imaging.

Table 4

Seizures. Data are presented as % (n) for categorical data. Quantitative data are presented as mean ± s.d. or median (minimum–maximum) for symmetrical and non-symmetrical distributed variables respectively.

History of seizuresP value
Present (n = 15)Absent (n = 155)
Male sex46.7 (7)39.7 (60)0.5471
Age (years)49.29 ± 18.4958.96 ± 15.08<0.05
Duration of disease (years)23.67 (2.08–54.42)10.08 (1.00–68.17)<0.01
Cerebral imaging66.7 (10)21.9 (34)<0.001
 Calcifications20.0 (2)26.5 (9)1.000

Cerebral imaging was performed in 44 patients of the total cohort, of which 11 patients were diagnosed with intracerebral calcifications (Table 5). Patients with intracerebral calcifications were younger and had a longer disease duration than patients without intracerebral calcifications. There was no difference in seizures in their past medical history.

Table 5

Intracerebral calcifications. Data are presented as % (n) for categorical data. Quantitative data are presented as mean ± s.d. or median (minimum–maximum) for symmetrical and non-symmetrical distributed variables respectively.

Cerebral calcificationsP value
Present (n = 11)Absent (n = 33)
Male sex54.5 (6)45.5 (15)0.6011
Age (years)48.08 (19.92–68.42)68.17 (23.33–87.75)<0.01
Duration of disease (years)35.17 (7.83–53.5)9.92 (1.08–43.25)<0.01
Seizures18.2 (2)24.2 (8)1.000

Discussion

This cross-sectional study analyses complications in a cohort of patients with chronic hypoparathyroidism in follow-up at a tertiary endocrine outpatient clinic in Belgium, with particular focus on the role of disease aetiology, risk of renal and cerebral calcifications and risk of seizures. The majority of the patients was female, consistent with other cohorts described in literature (16, 17). A substantial proportion of patients had already long-lasting disease. Neck surgery was the aetiology in more than 80% of patients, which is in agreement with other studies (1, 2, 4).

A substantial part experienced symptoms of the disease. Complaints of paraesthesia and/or cramps in the past month were present in 3 out of 20 cases. Well-being was not being assessed in this study, but previous data showed failure to restore well-being in patients with HP with standard therapy of calcium and vitamin D (18, 19). Therapy with rhPTH 1–84 may help to improve the quality of life in these patients (20). Hospitalization due to hypocalcaemia was rather rare in this study, having occurred in 5% of the cohort, with 75% of the hospitalizations occurring at the time of HP diagnosis and not during follow-up. In 84% of patients the presence or absence of cataracts could not been retrieved from the patient’s file. There is certainly a need for increased screening for this complication in chronic HP patients.

In our cohort in 21.8% of the available renal imaging kidney stones and/or renal calcifications were present. Mitchell et al. described renal calcifications being present in 31% of patients with hypoparathyroidism (16). Of note, mean daily dose of calcium supplements in the latter study was almost two times higher than that in our study (2048 mg vs 1035 mg), which could explain the difference in the prevalence of renal calcification. Postoperative patients are at increased risk (up to five times more) of developing kidney stones and renal calcifications compared to healthy individuals (5, 16).

Results of a 24-h urine collection of the last 5 years were present in three out of four patients with less than half of these collections at time of the consultation. Nevertheless, one out of three patients exceeded the gender-specific upper limit for mean renal calcium excretion, indicating underuse of calciuria screening in the chronic follow-up of HP patients. Hence, the reported frequency of calcifications and hypercalciuria is a minimum estimate. Lopes et al. found no correlation between urinary levels of calcium and presence of calcifications, but 24-h urinary calcium excretion was significantly higher in patients with kidney calcifications compared to patients without calcifications (2, 17).

Cerebral imaging was available in one out of four HP patients, with calcifications observed in one out of four patients. In the study of Mitchell et al. intracerebral calcifications were present in one out of two cases. (16) A possible explanation is the difference in aetiology of the HP, with 84.1% being post-surgical in our study compared to only 66% in the study of Michell et al. In this study history of seizures was present in 8.8% of patients. This result is consistent with the 8% incidence of seizures in the cohort of Mitchell et al. (16).

According to the HP aetiology, several differences were observed. Not unsurprisingly, PHP patients were younger than PSHP patients and had a longer disease duration. So post-surgical patients are generally older at the time of diagnosis, which is consistent with the fact that PSHP is an acquired condition, while PHP is a congenital disease.

The majority of the patients took alfacalcidol (21, 22, 23). The median dose of active vitamin D analogues did not differ between the three groups. PHP patients did however more often combine with non-active vitamin D3 than the other two groups. One might hypothesize that this reflects the prescriber’s reasoning that due to high levels of PTH in patients with PHP, there is a higher potential for conversion into active vitamin D. Streeten et al. found less morbidity from hypocalcaemia treated with vitamin D2 than with calcitriol (24). Combination treatment with rhPTH 1–84 allows for dose reduction of calcium and active vitamin D analogue while maintaining a stable serum calcium level (25, 26, 27).

There was no difference in history of kidney stones or nephrocalcinosis at renal imaging according to HP disease aetiology. There was also no difference in eGFR between the groups, although NSHP patients and PHP patients had the tendency to have higher eGFR than PSHP patients. This is probably due to the aforementioned differences in age between the three groups. It is known that patients with NSHP and PSHP have an increased risk of developing renal insufficiency, while risk of renal disorders in PHP patients is not increased (5, 6, 7). PHP patients also had significant less calciuria than PSHP patients, which is an expected finding as sensitivity to PTH in the tubular and collecting duct of the nephron is intact in PHP (7, 28).

Cerebral imaging was performed in half of the patients with NSHP and PHP. A probable explanation for this finding is the fact that these patients also had a higher incidence of seizures, with cerebral imaging being standard of care in the work-up. The proportion of brain calcifications was also higher in these two groups compared with PSHP patients. Underbjerg et al. reported similar occurrence of seizures in patients with PSHP (3.8%) and NSHP (23.3%); however, the rate in PHP (16.6%) patients was much lower (5, 6, 7). We found no correlation between a history of seizures and the presence of intracerebral calcifications. Basal ganglia calcifications were present in 73.8% of the 145 NSHP patients reported by Goswami et al. (29), and these authors did find a correlation between cerebral calcifications and seizures. Aggarwal et al. found intracerebral calcifications in 88.7% out of the 62 patients with NSHP (30). However, they could not find a correlation between neuropsychological dysfunctions – present in up to one-third of NSHP patients – and intracerebral calcifications. The clinical significance of cerebral calcifications remains unclear.

The strength of this study lies in the number of patients studied in detail, and the analysis according to different HP aetiologies, shedding light on the risk of complications and on the current clinical management of long-standing HP. The limitation of this study is its retrospective, single-centre, cross-sectional design. All patients were treated with active vitamin D analogues (inclusion criterion) which implicates that this cohort includes patients at the more severe side of the spectrum of hypoparathyroidism, excluding patients with mild hypoparathyroidism that are sufficiently controlled with calcium and non-active vitamin D.

Conclusion

Patients with chronic HP frequently experience complications. Non-surgical and pseudo-HP patients have more seizures and cerebral calcifications than post-surgical HP patients. No correlation was found between seizures and cerebral calcifications. There is a need for increased screening for long-term complications of HP. Undoubtedly, the recently published guidelines will be of help in the clinical management of chronic hypoparathyroidism patients. Whether treatment with recombinant PTH will decrease the long-term complications of chronic HP remains to be discussed.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. Journal of Bone and Mineral Research 2013 8 22772285. (https://doi.org/10.1002/jbmr.1979)

    • Search Google Scholar
    • Export Citation
  • 6

    Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. The epidemiology of nonsurgical hypoparathyroidism in Denmark: a Nationwide case finding study. Journal of Bone and Mineral Research 2015 30 17381744. (https://doi.org/10.1002/jbmr.2501)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism – epidemiology, mortality and risk of complications. Clinical Endocrinology 2016 84 904911. (https://doi.org/10.1111/cen.12948)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Clarke BL, Leibson C, Emerson J, Ransom JE, Lagast H. Co-morbid medical conditions associated with prevalent hypoparathyroidism: a population-based study. Journal of Bone and Mineral Research 2011 26 (Supplement 1) (Abstract SA1070).

    • Search Google Scholar
    • Export Citation
  • 9

    Bilezikian JP, Brandi ML, Cusano NE, Mannstadt M, Rejnmark L, Rizzoli R, Rubin MR, Winer KK, Liberman UA, Potts JT Jr. Management of hypoparathyroidism: present and future. Journal of Clinical Endocrinology and Metabolism 2016 101 23132324. (https://doi.org/10.1210/jc.2015-3910)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Abate EG & Clarke BL. Review of hypoparathyroidism. Frontiers in Endocrinology 2017 7 172. (https://doi.org/10.3389/fendo.2016.00172)

  • 11

    Underbjerg L, Sikjaer T & Rejnmark L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case-control study. Journal of Bone and Mineral Research 2018 33 822831. (https://doi.org/10.1002/jbmr.3368)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Almquist M, Ivarsson K, Nordenström E & Bergenfelz A. Mortality in patients with permanent hypoparathyroidism after total thyroidectomy. British Journal of Surgery 2018 105 13131318. (https://doi.org/10.1002/bjs.10843)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W & Dekkers OM. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. European Journal of Endocrinology 2015 173 G1G20. (https://doi.org/10.1530/EJE-15-0628)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Stack BC Jr, Bimston DN, Bodenner DL, Brett EM, Dralle H, Orloff LA, Pallota J, Snyder SK & Wong RJ et al. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: postoperative hypoparathyroidism – definitions and management. Endocrine Practice 2015 21 674685. (https://doi.org/10.4158/EP14462.DSC)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F & Greene T et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009 150 604612. (https://doi.org/10.7326/0003-4819-150-9-200905050-00006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA & Mannstadt M. Long-term follow-up of patients with hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2012 97 45074514. (https://doi.org/10.1210/jc.2012-1808)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Lopes MP, Kliemann BS, Bini IB, Kulchetschki R, Borsani V, Savi L, Borba VZ & Moreira CA. Hypoparathyroidism and pseudohypoparathyroidism: etiology, laboratory features and complications. Archives of Endocrinology and Metabolism 2016 60 532536. (https://doi.org/10.1590/2359-3997000000221)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Arlt W, Fremerey C, Callies F, Reincke M, Schneider P, Timmermann W & Allolio B. Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D. European Journal of Endocrinology 2002 146 215222. (https://doi.org/10.1530/eje.0.1460215)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Underbjerg L, Sikjaer T & Rejnmark L. Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism. Clinical Endocrinology 2018 88 838847. (https://doi.org/10.1111/cen.13593)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Vokes TJ, Mannstadt M, Levine MA, Clarke BL, Lakatos P, Chen K, Piccolo R, Krasner A, Shoback DM & Bilezikian JP. Recombinant human parathyroid hormone effect on health-related quality of life in adults with chronic hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2018 103 722731. (https://doi.org/10.1210/jc.2017-01471)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Kubodera N. A new look at the most successful prodrugs for active vitamin D (D hormone): alfacalcidol and doxercalciferol. Molecules 2009 14 38693880. (https://doi.org/10.3390/molecules14103869)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Halabe A, Arie R, Mimran D, Samuel R & Liberman UA. Hypoparathyroidism – a long-term follow-up experience with 1-alpha-vitamin D3 therapy. Clinical Endocrinology 1994 40 303307. (https://doi.org/10.1111/j.1365-2265.1994.tb03923.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Okano K, Furukawa Y, Morii H & Fujita T. Comparative efficacy of various vitamin D metabolites in the treatment of various types of hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 1982 55 238243. (https://doi.org/10.1210/jcem-55-2-238)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Streeten EA, Mohtasebi Y, Konig M, Davidoff L & Ryan K. Hypoparathyroidism: less severe hypocalcemia with treatment with vitamin D2 compared to calcitriol. Journal of Clinical Endocrinology and Metabolism 2017 102 15051510. (https://doi.org/10.1210/jc.2016-3712)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Mannstadt M, Clarke BL, Vokes T, Brandi ML, Ranganath L, Fraser WD, Lakatos P, Bajnok L, Garceau R & Mosekilde L et al. Efficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomized, phase 3 study. Lancet Diabetes and Endocrinology 2013 1 275283. (https://doi.org/10.1016/S2213-8587(13)70106-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Lakatos P, Bajnok L, Lagast H & Valkusz Z. An open-label extension study of parathyroid hormone RHPTH(1–84) in adults with hypoparathyroidism. Endocrine Practice 2016 22 523532. (https://doi.org/10.4158/EP15936.OR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Andrews EB, Gilsenan AW, Midkiff K, Sherrill B, Wu Y, Mann BH, Masica D. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and finding from the first 7 years. Journal of Bone and Mineral Research 2012 27 24292437. (https://doi.org/10.1002/jbmr.1768)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Stone MD, Hosking DJ, Garcia-Himmelstine C, White DA, Rosenblum D & Worth HG. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 1993 14 727735. (https://doi.org/10.1016/8756-3282(93)90204-N)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Goswami R, Sharma R, Sreenivas V, Gupta N, Ganapthy A, Das S. Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism. Clinical Endocrinology 2012 77 200206. (https://doi.org/10.1111/j.1365-2265.2012.04353.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Aggarwal S, Kailash S, Sagar R, Tripathi M, Sreenivas V, Sharma R, Gupta N & Goswami R. Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium. European Journal of Endocrinology 2013 168 895903. (https://doi.org/10.1530/EJE-12-0946)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

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  • 1

    Shoback D. Clinical practice. Hypoparathyroidism. New England Journal of Medicine 2008 359 391403. (https://doi.org/10.1056/NEJMcp0803050)

  • 2

    Bilezikian JP, Khan A, Potts JT Jr, Brandi ML, Clarke BL, Shoback D, Jüppner H, D’Amour P, Fox J & Rejnmark L et al. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. Journal of Bone and Mineral Research 2011 26 23172337. (https://doi.org/10.1002/jbmr.483)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Clarke BL, Brown EM, Collins MT, Jüppner H, Lakatos P, Levine MA, Mannstadt MM, Bilezikian JP, Romanischen AF & Thakker RV. Epidemiology and diagnosis of hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2016 101 22842299. (https://doi.org/10.1210/jc.2015-3908)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Shoback DM, Bilezikian JP, Costa AG, Dempster D, Dralle H, Khan AA, Peacock M, Raffaelli M, Silva BC & Thakker RV et al. Presentation of hypoparathyroidism: etiologies and clinical features. Journal of Clinical Endocrinology and Metabolism 2016 101 23002312. (https://doi.org/10.1210/jc.2015-3909)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. Journal of Bone and Mineral Research 2013 8 22772285. (https://doi.org/10.1002/jbmr.1979)

    • Search Google Scholar
    • Export Citation
  • 6

    Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. The epidemiology of nonsurgical hypoparathyroidism in Denmark: a Nationwide case finding study. Journal of Bone and Mineral Research 2015 30 17381744. (https://doi.org/10.1002/jbmr.2501)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism – epidemiology, mortality and risk of complications. Clinical Endocrinology 2016 84 904911. (https://doi.org/10.1111/cen.12948)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Clarke BL, Leibson C, Emerson J, Ransom JE, Lagast H. Co-morbid medical conditions associated with prevalent hypoparathyroidism: a population-based study. Journal of Bone and Mineral Research 2011 26 (Supplement 1) (Abstract SA1070).

    • Search Google Scholar
    • Export Citation
  • 9

    Bilezikian JP, Brandi ML, Cusano NE, Mannstadt M, Rejnmark L, Rizzoli R, Rubin MR, Winer KK, Liberman UA, Potts JT Jr. Management of hypoparathyroidism: present and future. Journal of Clinical Endocrinology and Metabolism 2016 101 23132324. (https://doi.org/10.1210/jc.2015-3910)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Abate EG & Clarke BL. Review of hypoparathyroidism. Frontiers in Endocrinology 2017 7 172. (https://doi.org/10.3389/fendo.2016.00172)

  • 11

    Underbjerg L, Sikjaer T & Rejnmark L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case-control study. Journal of Bone and Mineral Research 2018 33 822831. (https://doi.org/10.1002/jbmr.3368)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Almquist M, Ivarsson K, Nordenström E & Bergenfelz A. Mortality in patients with permanent hypoparathyroidism after total thyroidectomy. British Journal of Surgery 2018 105 13131318. (https://doi.org/10.1002/bjs.10843)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W & Dekkers OM. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. European Journal of Endocrinology 2015 173 G1G20. (https://doi.org/10.1530/EJE-15-0628)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Stack BC Jr, Bimston DN, Bodenner DL, Brett EM, Dralle H, Orloff LA, Pallota J, Snyder SK & Wong RJ et al. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: postoperative hypoparathyroidism – definitions and management. Endocrine Practice 2015 21 674685. (https://doi.org/10.4158/EP14462.DSC)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F & Greene T et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009 150 604612. (https://doi.org/10.7326/0003-4819-150-9-200905050-00006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA & Mannstadt M. Long-term follow-up of patients with hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2012 97 45074514. (https://doi.org/10.1210/jc.2012-1808)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Lopes MP, Kliemann BS, Bini IB, Kulchetschki R, Borsani V, Savi L, Borba VZ & Moreira CA. Hypoparathyroidism and pseudohypoparathyroidism: etiology, laboratory features and complications. Archives of Endocrinology and Metabolism 2016 60 532536. (https://doi.org/10.1590/2359-3997000000221)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Arlt W, Fremerey C, Callies F, Reincke M, Schneider P, Timmermann W & Allolio B. Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D. European Journal of Endocrinology 2002 146 215222. (https://doi.org/10.1530/eje.0.1460215)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Underbjerg L, Sikjaer T & Rejnmark L. Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism. Clinical Endocrinology 2018 88 838847. (https://doi.org/10.1111/cen.13593)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Vokes TJ, Mannstadt M, Levine MA, Clarke BL, Lakatos P, Chen K, Piccolo R, Krasner A, Shoback DM & Bilezikian JP. Recombinant human parathyroid hormone effect on health-related quality of life in adults with chronic hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2018 103 722731. (https://doi.org/10.1210/jc.2017-01471)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Kubodera N. A new look at the most successful prodrugs for active vitamin D (D hormone): alfacalcidol and doxercalciferol. Molecules 2009 14 38693880. (https://doi.org/10.3390/molecules14103869)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Halabe A, Arie R, Mimran D, Samuel R & Liberman UA. Hypoparathyroidism – a long-term follow-up experience with 1-alpha-vitamin D3 therapy. Clinical Endocrinology 1994 40 303307. (https://doi.org/10.1111/j.1365-2265.1994.tb03923.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Okano K, Furukawa Y, Morii H & Fujita T. Comparative efficacy of various vitamin D metabolites in the treatment of various types of hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 1982 55 238243. (https://doi.org/10.1210/jcem-55-2-238)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Streeten EA, Mohtasebi Y, Konig M, Davidoff L & Ryan K. Hypoparathyroidism: less severe hypocalcemia with treatment with vitamin D2 compared to calcitriol. Journal of Clinical Endocrinology and Metabolism 2017 102 15051510. (https://doi.org/10.1210/jc.2016-3712)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Mannstadt M, Clarke BL, Vokes T, Brandi ML, Ranganath L, Fraser WD, Lakatos P, Bajnok L, Garceau R & Mosekilde L et al. Efficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomized, phase 3 study. Lancet Diabetes and Endocrinology 2013 1 275283. (https://doi.org/10.1016/S2213-8587(13)70106-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Lakatos P, Bajnok L, Lagast H & Valkusz Z. An open-label extension study of parathyroid hormone RHPTH(1–84) in adults with hypoparathyroidism. Endocrine Practice 2016 22 523532. (https://doi.org/10.4158/EP15936.OR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Andrews EB, Gilsenan AW, Midkiff K, Sherrill B, Wu Y, Mann BH, Masica D. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and finding from the first 7 years. Journal of Bone and Mineral Research 2012 27 24292437. (https://doi.org/10.1002/jbmr.1768)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Stone MD, Hosking DJ, Garcia-Himmelstine C, White DA, Rosenblum D & Worth HG. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 1993 14 727735. (https://doi.org/10.1016/8756-3282(93)90204-N)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Goswami R, Sharma R, Sreenivas V, Gupta N, Ganapthy A, Das S. Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism. Clinical Endocrinology 2012 77 200206. (https://doi.org/10.1111/j.1365-2265.2012.04353.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Aggarwal S, Kailash S, Sagar R, Tripathi M, Sreenivas V, Sharma R, Gupta N & Goswami R. Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium. European Journal of Endocrinology 2013 168 895903. (https://doi.org/10.1530/EJE-12-0946)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation