FACTORS ASSOCIATED WITH SEVERE HYPERCALCEMIA IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

Primary hyperparathyroidism (PHPT) is the most common endocrine pathology after diabetes and hypothyroidism. Its prevalence is 0.3 % in the general population [1, 2]. Due to the increasingly routine dosage of serum calcium, PHPT is nowadays often diagnosed incidentally in the presence of asymptomatic hypercalcemia. In rare cases, however, PHPT may be associated with severe, life-threatening hypercalcemia through predominantly cardiac and neurological complications [3–5]. Few studies have looked at the predictors of severe hypercalcemia in PHPT. The objective of this study was to determine the prevalence of severe hypercalcemia in a hospital cohort of PHPT and to identify its risk factors.


MATERIALS AND METHODS
This is a retrospective study involving the medical records of 123 patients with PHPT collected between January 2000 and December 2019 in the endocrinology department of the Rabta hospital (Tunis -Tunisia). The diagnosis of PHPT was made when serum calcium level was > 2.63 mmol/l associated with high PTH level (> 68 pg/ml). The serum calcium value considered was total serum calcium in the absence of hypoalbuminemia and corrected serum calcium in case of hypoalbuminemia (< 40 g/l). We excluded cases of hypercalcemia with hyperparathyroidism and hypocalciuria and cases of normocalcemic PHPT.
Patients were divided into two groups according to their highest calcium level: • Severe hypercalcemia (SH) patients including the patients with serum calcium level ≥ 3.25 mmol/l. • Moderate hypercalcemia (MH) patients including patients with serum calcium level between 2.63 and 3.25 mmol/l. The two groups of patients were compared according to their socio-demographic, clinical, paraclinical (ECG, laboratory parameters at the time of diagnosis, cervical ultrasound, parathyroid scintigraphy, bone mineral density and renal ultrasound results) and histological (final anatomopathological result in case of surgical treatment) parameters.
The WHO classification was adopted to define osteoporosis and osteopenia [7].
The study was approved by the ethic committee of La Rabta Hospital.
Statistical analysis Study data were analyzed using SPSS version 23 software. Data were expressed as mean ± standard deviation for quantitative variables and percentages for qualitative variables. Student's t test was used to compare means and Pearson's chi squared and Fisher's exact tests were used to compare proportions. Spearman's correlation was used to assess association between calcium level and clinical and paraclinical quantitative variables. The median value of the distribution was used for the determination of the PTH cutoff (300 pg/ml) and the parathyroid adenoma size cutoff (20 mm). A stepwise binary logistic regression model was applied to determine the variables associated with SH. The significance level was p ≤ 0.05 for all tests.

RESULTS AND THEIR DISCUSSION
The mean age of the patients was 57.6 ± 12.4 years. The sex ratio (female / male) was 5.15. The prevalence of severe hypercalcemia was 35.8% (n = 44). The hospital incidence of PHPT was 6.47 patients / year. The hospital incidence of severe hypercalcemia associated with PHPT  Figure 1 shows the distribution of patients according to their serum calcium level. Heart rate, corrected QT (QTc) interval, phosphoremia, parathyroid adenoma size, PTH and 25OHD levels were correlated with calcium level ( Table 1).
In the present study, the prevalence of SH (defined by a calcium level ≥ 3.25 mmol/l) in patients with PHPT was 35.8%. Clinical factors significantly associated with SH were abdominal pain, vomiting and acute pancreatitis. Biological factors associated with SH were higher PTH level and vitamin D deficiency. The parathyroid adenoma size was significantly higher and parathyroid carcinoma was more frequent in patients with SH. After multivariate analysis, the factors independently associated with SH were a parathyroid adenoma size ≥ 20 mm and a PTH level ≥ 300 pg/l (adjusted odds ratios = 12 and 7.7, respectively).
The main limitation of the study is related to its retrospective design. The incidence and prevalence of SH in PHPT is highly variable in the literature. This is mainly related to the Клінічна ендокринологія heterogeneity of the definitions used to characterize SH ( Table 3). The prevalence found in our study was higher than the prevalence of most studies, this can be explained by the fact that the cut-off used to define SH in our study is lower than that used by most studies in the literature. Socio-demographic factors (age and gender), both in our study and in many other studies, were not associated with SH [3,[8][9][10][11][12][13]. Clinically, the presence of digestive symptoms (abdominal pain, vomiting) was associated with SH. The occurrence of acute pancreatitis was observed only in with SH. Calcium excess promotes the formation of stones in the pan creatic ducts and induces the conversion of trypsinogen into trypsin, which is the active form of the pancreatic enzyme responsible for the self-digestion of the pancreas [9,14]. Some cardiac signs such as tachycardia and QT segment shortening were also associated with SH. A positive correlation was objectified between the heart rate and the calcium level, and a negative correlation was found between the corrected QT and the calcium level. The relationship between cardiac manifestations and the severity of hypercalcemia is explained by the fact that calcium excess generates faster depolarization of cardiomyocytes, thus promoting the onset of electrical abnormalities in-cluding shortening of the QT interval [4]. The frequency of neuropsychic disorders is commonly higher in patients with SH [3,11]. This was not verified by our study. This may be linked to the cut-off used to define SH, which is lower than that used in many other studies. In addition, neuropsychic signs depend on the age and neuropsychic history of the patients [15].
Biological factors associated with SH in our study were lower serum phosphorus, higher PTH level, and lower vitamin D level. A PTH level higher than 300 pg/ml (approximately 4.5 times the upper limit of normal) was independently associated with SH with an adjusted OR of 7.7. This association makes sense since PTH is directly responsible for the elevation of serum calcium and the decrease of phosphoremia during PHPT. The association with lower vitamin D levels, however, is less clear. Some studies such as ours have found a relationship between the severity of hypercalcemia in PHPT and the frequency of vitamin D deficiency [12,16]. Several hypotheses have been raised to try to explain this association. One of the most plausible hypotheses would be the increased conversion of 25-OHD to 1,25-dihydroxy-vitamin D. Indeed, PTH stimulates the 1-α-hydroxylase which promotes the conversion of 25-OHD to 1,25-dihydroxy-vitamin D. The Клінічна ендокринологія level of 25-OHD will consequently be reduced [17,18]. We did not find a link between the severity of hypercalcemia and renal or bone complications (renal lithiasis, nephrocalcinosis, chronic renal failure, osteopenia, and osteoporosis). This agrees with several studies in the literature [3,11,16,19,20]. In fact, renal and bone complications of PHPT are more correlated with the duration and the chronicity of the disease than with the severity of hypercalcemia [19,21]. Bone complications are also related to other factors such as age, gender, and vitamin D status [22].
The size of the parathyroid adenoma was positively correlated with the calcium level. A size higher than 20 mm was independently associated with the severity of hypercalcemia with an adjusted OR equal to 12. The correlation between the severity of biological abnormalities and the size of the parathyroid adenoma is controversial [23,24]. It is common to find a relation between the severity of hypercalcemia and the size of the lesion [24].
Histologically, cases of parathyroid carcinoma have only been noted in patients with SH. Most studies, like ours, agree on a higher prevalence of parathyroid carcinoma in patients with SH [3, 8-10, 13, 25]. Compared to parathyroid adenoma, parathyroid carcinoma appears to be larger with an average diameter of 3.4 cm [26]. It tends to be more frequently present when hypercalcemia is higher than 3 mmol/l with a PTH level higher than three times the upper limit of normal [26][27][28][29].

CONCLUSION
Factors independently associated with SH in PHPT were a PTH level higher than 300 pg/ml and a parathyroid adenoma size higher than 20 mm. Cardiac and digestive complications seem to be more frequent when PHPT is associated with SH. Vitamin D deficiency also appears to be more common in these forms of PHPT, justifying its systematic screening and supplementation in case of deficiency. Finally, it is important to fear parathyroid carcinoma and to speed up surgical management when PHPT is associated with SH.