Vitamin D Deficiency and the Presentation of Primary Hyperparathyroidism: A Mini Review

The clinical presentation of primary hyperparathyroidism (PHPT) has evolved over the years from a symptomatic disorder to a predominantly asymptomatic condition. Altered vitamin D metabolism seems to play a role in the presentation of PHPT and may exacerbate the severity of disease. The epidemiology of PHPT differs in the developing versus the developed world, where more severe phenotypes occur in regions where vitamin D deficiency is common. Although it has been validated that patients with PHPT should be vitamin D sufficient, the threshold to supplement in relation to the severity of PHPT and the degree of vitamin D deficiency remains controversial. This review will highlight some of the controversy regarding vitamin D deficiency and the different phenotypes of PHPT.


Introduction
Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia and is characterized by elevated or inappropriately normal parathyroid hormone (PTH) levels.Tere are three phenotypes of PHPT [1].Tere is classic or symptomatic PHPT which presents with renal or skeletal complications such as nephrolithiasis or osteitis fbrosa cystica.Tere is asymptomatic PHPT which presents with no obvious signs or symptoms but may still have some renal or skeletal involvement.Also, the newest classifcation is normocalcemic PHPT (NPHPT) which is defned by normal albumin-corrected or ionized calcium levels with elevated PTH levels.Patients who ft this category may or may not have renal or skeletal complications.Vitamin D is a fatsoluble secosteroid that plays a central role in calcium homeostasis and bone metabolism through the feedback of calcium, phosphate, and PTH.Vitamin D defciency can cause secondary hyperparathyroidism which must be differentiated from PHPT.Te presentation of vitamin D defciency in PHPT varies geographically.In the Western world, where biochemical screening is common, asymptomatic or NPHPT is more frequently noted.In contrast, symptomatic disease with renal and/or skeletal manifestations is the more predominant phenotype in developing countries [2].As compared to the general population, vitamin D defciency is more common in PHPT patients and has been associated with more severe disease [3,4].Te mechanism behind the association of vitamin D defciency and PHPT is not clear and remains controversial [5].In this article, we aim to review the recent research looking into the relationship between the phenotypes of PHPT and 25(OH)D levels as well as vitamin D-binding protein.

Epidemiology and Prevalence of Vitamin D Defciency in PHPT.
Primary hyperparathyroidism and vitamin D defciency are common conditions, and their efects are interrelated.Te operational defnition of vitamin D defciency as given by the Institute of Medicine is a 25(OH)D level ≤20 ng/ ml (50 nM/l) [6].It has also been suggested to defne vitamin D insufciency as 25(OH)D levels between 20 and 30 ng/mL and defciency as <20 ng/mL [2,4].Tese cutofs are established for optimal bone health and not in the context of PHPT [4].Te likelihood of 25(OH)D insufciency (81%) and 25(OH)D defciency (33%) in PHPT is reported to be much higher than in sex-and age-matched control populations (60% for insufciency and 20% for defciency) and remains so with seasonal variations [7,8].While 25(OH)D levels are highest in the late summer months (July-August) for people with or without PHPT, the average 25(OH)D level is still overall reduced in PHPT patients [7].Recent trends show a decrease in the prevalence of vitamin D defciency in PHPT, possibly from increased supplementation [6,9].It is estimated that the prevalence of vitamin D defciency and insufciency in PHPT has decreased by 50% and 30%, respectively, with a corresponding decline in PTH levels [10].

Geographic Variation of 25(OH)D Levels in PHPT.
With the advent of increased access to population lab screening, developed nations have seen a shift in the clinical presentation of PHPT from a symptomatic disorder to that of a largely asymptomatic condition.In a study comparing PHPT patients in New York to those in Shanghai, the average 25(OH)D levels were found to be signifcantly lower (13 ng/mL) in the Shanghai cohort versus the New York cohort (36.7 ng/mL, p < 0.001) [11].Te patients in the Shanghai cohort also showed biochemical evidence of more severe PHPT with signifcantly higher PTH (402.1 pg/mL vs. 67.5 pg/mL, p < 0.001), alkaline phosphatase (112 U/L vs. 75 U/L, p < 0.001), and serum calcium (11.72 mg/dL vs. 10.6 mg/dL, p < 0.001) levels compared to the New York cohort.Tere were no cases of NPHPT in the Shanghai cohort which was partly attributed to the relatively higher prevalence of vitamin D defciency [11].Similar trends have been noted in other studies done in China, India, and Brazil, where higher rates of symptomatic disease were noted with lower 25(OH)D levels [12][13][14].However, cases of milder or asymptomatic PHPT are rising in developing countries in more recent years [11].One study in 2021 noted that while the majority (>90%) of PHPT patients in India still present with symptomatic disease, there is a rising prevalence of asymptomatic disease with lower PTH levels and an improved vitamin D status [15].

Vitamin D Defciency and Classic PHPT.
Prior to the ubiquitous screening of calcium in the last several decades, classic PHPT was described as a symptomatic condition with renal and/or skeletal manifestations at the time of diagnosis [9].Most notably, osteitis fbrosa cystica, which clinically presents as bone pain and is radiographically characterized by a "salt and pepper" appearance of the skull, brown tumors, subperiosteal bone resorption, and osteolytic lesions, is now considered a very rare complication in the developed world [9,16].Low bone mineral density (BMD) and fragility fractures are now the more common skeletal signs of symptomatic disease.Classic renal manifestations include hypercalciuria, nephrolithiasis, and nephrocalcinosis.
Tere have been several studies that suggest vitamin D defciency (defned as a 25(OH)D level at least <20 ng/mL) is associated with a more severe presentation of PHPT.Tis is thought to be due to higher PTH levels with higher calcium levels, increased bone turnover markers with lower bone mineral density, and increased parathyroid mass [11,12,[17][18][19].Patients who present with osteitis fbrosa cystica have been shown to have signifcantly lower 25(OH) D levels than those with asymptomatic disease (16.7 ± 1.1 ng/ mL versus 29.9 ± 2.9 ng/mL, p < 0.02).Tey also have signifcantly higher PTH levels compared to asymptomatic PHPT patients (1352.8± 297.2 pg/mL versus 145.0 ± 43.7 pg/ mL, p < 0.02) [12].Tis has also been demonstrated in a cohort of patients with PHPT in India where a majority of patients (90%) present with osteitis fbrosa cystica and have severe vitamin D defciency with an average vitamin D level of 8.4 ± 5.1 ng/mL [17].In a study comparing features of PHPT in New York and Shanghai, the patients in China who often presented with symptomatic disease had signifcantly higher calcium and PTH levels as well as lower vitamin D levels [9].In an Italian cohort of PHPT patients, those who had 25(OH)D levels below 20 ng/mL were noted to have signifcantly higher PTH, alkaline phosphatase, and bone turnover markers and signifcantly lower BMD than patients with 25(OH)D levels above 20 ng/mL [18].In another Italian cohort of women with sporadic PHPT, it was found that the lowest quartile of 25(OH)D levels correlated with higher PTH levels, higher bone-specifc alkaline phosphatase levels, and lower estimated glomerular fltration rates (GFRs).No association was found with serum and urine calcium levels, fracture risk, or nephrolithiasis [20].Of note, another study similarly showed that a 25(OH)D level less than 20 ng/mL was associated with higher PTH levels but showed no clinical diference in bone mineral density, osteoporosis, fracture, nephrolithiasis, or urinary calcium [10].

Vitamin D Defciency and Asymptomatic PHPT.
In the 1970s, the clinical presentation of PHPT in the Western world shifted from the symptomatic disorder previously described to an asymptomatic condition likely due to widespread biochemical screening.Asymptomatic PHPT is a unique phenotype characterized by mild hypercalcemia without the classic symptoms.Calcium levels are usually less than 1 mg/dL above the upper limit of normal, and the PTH level is less than 2-fold above the upper range of normal [21].Vitamin D insufciency or defciency is commonly noted in asymptomatic PHPT and is associated with higher PTH levels and higher markers of bone turnover such as bonespecifc alkaline phosphatase [10,22].Low 25(OH)D levels have also been associated with more cortical bone loss and preservation of trabecular bone in these patients [22,23].It is, therefore, recommended that 25(OH)D levels be checked in all cases of asymptomatic PHPT and cautious repletion with vitamin D supplementation be initiated if 25(OH)D levels fall below 20 ng/mL [24,25].In a study that followed patients with asymptomatic PHPT over the course of 15 years, about a third of patients had progressive disease that eventually met criteria for surgery [26].Despite the lack 2 International Journal of Endocrinology of symptoms, patients with seemingly asymptomatic PHPT can still have renal or skeletal involvement which has led to recommendations to continue monitoring asymptomatic disease with radiographic imaging for renal stones, osteoporosis, or fractures [2,27].Vitamin D defciency or insufciency is less prevalent in asymptomatic PHPT patients due to increased routine vitamin D supplementation [24].
Tere may also be a role for vitamin D-binding protein (DBP).One study reported signifcantly lower DBP levels in a cohort of postmenopausal women with PHPT compared to age-and BMI-matched controls.Calculated free 25(OH)D levels and 1,25(OH) 2 D levels were not signifcantly diferent between the two groups [28].
1.5.Vitamin D Defciency and Normocalcemic PHPT.In the early 2000s, NPHPT was recognized as a new entity of PHPT with elevated PTH levels in the absence of hypercalcemia [29].Tese patients have both normal ionized calcium and total albumin-corrected calcium levels.An increase in PTH measurements as part of the workup for low bone mass and diagnosis of osteoporosis helped discover this biochemical phenotype where calcium levels consistently remain normal [9].To evaluate this diagnosis, secondary causes of hyperparathyroidism, such as vitamin D defciency, chronic kidney disease, malabsorption, and medication use such as lithium, diuretics, bisphosphonates, and denosumab, must also be ruled out.It is possible that slightly elevated PTH levels may be a part of the normal distribution curve in the spectrum of PTH ranges.It is estimated that about 2.5% of the normal population can be a part of this spectrum [9].Another perspective is that while the increase in PTH may actually cause an increase in the serum calcium level, the concentration may stay within the normal cutof limits and thus not be detected [30].
Tere is evidence to suggest that NPHPT patients develop complications of PHPT despite having normal calcium levels and that it does not represent a mild, asymptomatic form.One study concluded that patients seen with NPHPT have more substantial skeletal involvement compared to PHPT and develop more complications in the course of the disease [30,31].Another study found higher incidence of kidney stones in NPHPT and similar fracture history in comparison to PHPT.It was hypothesized that NPHPT patients may exhibit resistance to calcium at the bone and kidney levels leading to a higher PTH concentration [32].
Te levels of 25(OH)D that would defne defciency in NPHPT are not fully delineated and both >20 ng/mL or >30 ng/mL have been used to rule out defciency (Table 1).Te Institute of Medicine's current cutof for the diagnosis of vitamin D defciency is 25(OH)D < 20 ng/mL, which applies to the general population as previously discussed.Some experts suggest repletion to 25(OH)D levels above 30 ng/mL (75 nmol/L), as there is evidence that even vitamin D insufciency increases PTH levels [9,33].Once the 25(OH)D level is in the 30-40 ng/ml range, its previous exponential efect on PTH fattens [37].Some have even recommended repletion to >40 ng/mL to see the efects on PTH levels [9,33,37].
A report that studied free versus total 25(OH)D levels in NPHPT showed that measured free 25(OH)D levels were 20% lower in NPHPT patients than in healthy age-, sex-, and BMI-matched controls (5 vs. 6.2 pg/mL, p � 0.013).Te total 25(OH)D levels were >30 ng/dL in both the NPHPT and control groups and were not signifcantly diferent [35].Tis again raised the question of whether total 25(OH)D levels are truly representative of the actual vitamin D status in NPHPT patients and warrants further investigation [37].

Vitamin D Levels in Multiple Endocrine Neoplasia (MEN) Disorders and Familial Hypocalciuric Hypercalcemia (FHH).
It is estimated that about 1-18% of the patients with PHPT have underlying multiple endocrine neoplasia type 1 (MEN1) disease [38].It presents as a multiglandular entity compared to sporadic PHPT that presents as a single gland adenoma 80-85% of the time.It is associated with recurrent hyperparathyroidism even after presumed successful surgery and the recurrence rates can be up to 50% by 12 years [38][39][40].Te MEN1 gene product "menin" directly interacts with the vitamin D receptor (VDR) and enhances gene transcription, leading to lower VDR expression in adenoma cells [41].One study found that 21 out of 31 patients with MEN1 had 25(OH)D levels <10 ng/mL, 9 had levels between 10 and 30 ng/mL, and 1 patient had normal levels, showing the degree of vitamin D defciency in MEN1 [42].In addition, PHPT can occur in 20-30% of typical multiple endocrine neoplasia type 2A (MEN2A) syndrome [43].
Familial hypocalciuric hypercalcemia (FHH) is a rare inherited disorder of the calcium-sensing receptor gene, CASR.FHH can be biochemically similar to PHPT with an elevated calcium level associated with a normal or high PTH level, a normal 25(OH)D level, and a high 1,25dihydroxyvitamin D level.Te 24-hour urinary calcium excretion, however, is low in FHH.Te calculated calcium/creatinine clearance ratio should be <0.01 [9].It is important for patients to be vitamin D replete for diagnosis as the calcium/creatinine ratio can be <0.01 for patients with PHPT and vitamin D defciency.Less conclusive studies suggest that vitamin D supplementation in familial PHPT syndromes may show benefcial efects on serum PTH and bone mineral density (BMD); however, more studies are needed [44].[45].In a study of 88 patients with PHPT matched with related and unrelated family members without PHPT, it was found that 25(OH)D levels as well as International Journal of Endocrinology DBP and free and bioavailable (albumin-bound vitamin D plus free vitamin D) 25(OH)D levels were low in PHPT patients.Te authors suggested that although low DBP is found in PHPT, it alone cannot be responsible for low vitamin D levels [46].However, since most of 25(OH)D is DBP bound, lower DBP may cause low total 25(OH)D levels in asymptomatic PHPT patients [47].
Several studies have shown that although total 25(OH)D levels are lower in PHPT compared to controls, the DBP levels are also lower, so the calculated free 25(OH)D levels remain unchanged [28,47,48].Another report showed that calculated free 1,25(OH) 2 D levels are higher in postmenopausal PHPT patients and correlate better with PTH levels in comparison to total 1,25(OH) 2 D [49].Tese studies raise the question of whether free 25(OH)D levels may be a better indicator of the vitamin D status in PHPT but this needs further exploration.

Potential Mechanisms of Low 25(OH)D in PHPT.
Tere is evidence that vitamin D defciency acts as an inciting factor that worsens the clinical disease status of PHPT [9].Te exact mechanism behind the higher prevalence of low 25(OH)D levels in PHPT is multifactorial, involving low vitamin D intake or production, disturbed 25(OH)D metabolism, and interactions with vitamin D-binding proteins (Figure 1).
PTH enhances the conversion of 25(OH)D to 1,25dihydroxyvitamin D through increased 1-alpha hydroxylase activity in the kidneys via the CYP27B1 activity.Active vitamin D increases serum calcium via its action on vitamin D receptors (VDRs), which is sensed by the calcium-sensing receptor (CaSR) and feeds back to PTH.Active vitamin D regulates VDR levels in the parathyroid and has an ability to prolong VDR half-life.It also regulates the response of the parathyroid gland to calcium by inducing CaSR gene transcription [50].Active vitamin D inhibits 1-alpha hydroxylase and activates 24-alpha hydroxylase via the CYP24A1 activity (in the kidneys) to regulate serum calcium concentrations [51].It can thus be conficting to have low 25(OH)D levels with normal or even high 1,25-dihydroxyvitamin D levels [9].
Te elimination half-life of 25(OH)D is signifcantly shortened in PHPT through increased inactivation of 25(OH)D by 24-hydroxylation to 24,25(OH) 2 D, its inactive form [51]. Tis can be accounted for by an increased excretion of inactivated vitamin D derivatives in the feces [4,51].
In countries such as India, traditional clothing also limits sun exposure and the prevalence of a vegetarian diet adds to nutritional 25(OH)D defciency [52].
Elevated PTH also decreases DBP production in the liver which in turn leads to decreased total 25(OH)D levels.In a study of 50 PHPTpatients, DBP and DBP-bound 25(OH)D levels were found to be lower in PHPT patients compared to healthy controls, while free and bioavailable levels were similar between the groups [47].DBP and 25(OH)D levels have been noted to revert back to normal after parathyroidectomy [47,48].Diferent gene types of DBP can afect total 25(OH)D levels in PHPT patients [46].
Te abovementioned studies provide some insight into the pathophysiology of vitamin D metabolism and lower total 25(OH)D levels in PHPT (Figure 1).Tey confrm that PHPT is associated with lower total vitamin D levels and that these low levels can afect the biochemical presentation.However, there needs to be more studies to assess clinical endpoints such as fracture risk, incidence of nephrolithiasis, and optimal levels of supplementation [4,9,20,46].

Supplementation of Vitamin D in PHPT
As previously discussed, low 25(OH)D levels can be associated with a more severe presentation of PHPT with higher PTH and bone turnover marker levels and a larger parathyroid adenoma size than expected [19,53,54].Several studies have tried to analyze the benefts of 25(OH)D supplementation in PHPT with outcomes ranging from hypercalcemia to no signifcant infuence on serum calcium levels or clinical benefts.In a study investigating the efects of vitamin D repletion in patients with mild PHPT for one year, it was noted that mean serum calcium and phosphate levels did not change with the normalization of serum 25(OH)D levels [55].PTH levels fell by 26% at one year and the serum alkaline phosphatase and urine N-telopeptidelevels were  [55].A metaanalysis of observational studies evaluating the safety of vitamin D replacement in patients with PHPT also showed that vitamin D supplementation can signifcantly reduce PTH levels without a signifcant rise in serum or urinary calcium levels [56].A more recent meta-analysis of over 300 patients with PHPT and vitamin D levels below 30 ng/mL further supported that vitamin D supplementation can signifcantly decrease PTH and alkaline phosphatase levels without exacerbating hypercalcemia or hypercalciuria [57].
In a randomized clinical trial of PHPT patients who were supplemented with 2800 IU cholecalciferol daily for 52 weeks, an increase in 25(OH)D levels from 23 ng/mL to 38 ng/mL was associated with lower PTH and c-telopeptide levels as well as improvement in the lumbar spine bone mineral density (BMD) without signifcant changes in serum or urinary calcium [58].However, in an unblinded study of PHPT patients who were supplemented with calcifediol, 12 out of 27 patients had to stop supplementation due to either hypercalcemia or hypercalciuria [59].Te Fourth International Workshop recommended a threshold 25(OH)D level greater than 20 ng/ml in PHPT [25].However, the same publication acknowledged the controversy regarding what the optimal cutof for 25(OH)D should be in the management of PHPT.More recent consensus guidelines, including the Fifth International Workshop, now suggest the repletion of 25(OH)D levels above 30 ng/mL based on the abovementioned studies [1,60].
We believe that in PHPT with severe hypercalcemia, vitamin D supplementation has to be done with caution to avoid a hypercalcemic crisis.In asymptomatic PHPT patients, vitamin D should be supplemented, while monitoring serum calcium and urinary calcium excretion and with an aim to keep 25(OH)D levels at least between 20 and 30 ng/ml [4,9,53].Vitamin D2 or D3 can be given starting at 1000 IU per day [24].Te repletion of vitamin D to a target level of 40 ng/mL or more may help diagnose NPHPT with more accuracy in select patients.Current guidelines only utilize total 25(OH)D levels, but there have been studies that suggest free 25(OH)D levels may be a better marker for the vitamin D status in NPHPT [35,37].

Supplementation with Vitamin D before and after Parathyroid Surgery.
A recent study compared serum calcium concentrations, PTH levels, calculated free and bioavailable 25(OH)D, and DBP levels before and after parathyroidectomy [48].Te investigators found that serum calcium and PTH levels revert to normal after surgery.DBP as well as DBP-bound 25(OH)D levels increased after surgery likely due to the normalization of PTH.It is important to note that patients in the study received calcitriol after surgery as part of standard postoperative care [48].In International Journal of Endocrinology a retrospective cohort study, it was found that vitamin D repletion in PHPT patients undergoing parathyroidectomy decreases hypocalcemia and reduces the length of hospital stay [61].
Vitamin D levels should be measured and supplemented to adequate levels prior to parathyroid surgery [9].In order to avoid hypocalcemia, we suggest supplementing to a target of 25(OH)D >20 ng/ml for symptomatic patients and to >30 ng/ml for asymptomatic patients.We suggest that the careful repletion of vitamin D to a 25(OH)D level of 40 ng/mL before surgery for NPHPT can be attempted to rule out possible secondary hyperparathyroidism.

Conclusions
In recent years, the presentation of PHPT has shifted in the Western world to a generally asymptomatic condition with less vitamin D defciency.Increased rates of screening and supplementation of vitamin D has changed the prevalence of vitamin D defciency in PHPT and has introduced NPHPT into the clinical spectrum.Vitamin D repletion is recommended in all forms of PHPT, but the threshold to replace to is controversial and should be based on the severity of hyperparathyroidism.Recent studies and meta-analysis suggest that a 25(OH)D threshold level of >30 ng/mL is reasonable to prevent secondary stimulation of PTH secretion and to maintain stable serum and urinary calcium levels.Standard measurements and guidelines only include total 25(OH)D levels, but this may not always be a reliable indicator of the vitamin D status.It may be prudent to also check free 25(OH)D levels along with vitamin D-binding protein levels in the selected patients.Further studies are needed to understand the optimal total 25(OH)D level cutofs in the diferent phenotypes of PHPT.

1. 7 .
Total or Free 25(OH)D and Vitamin D-Binding Protein in PHPT.Total 25(OH)D can be both free or bound to protein.Te vast majority of circulating 25(OH)D is bound to vitamin D-binding protein (DBP) and not biologically available.At present, total 25(OH)D levels are checked to assess the 25(OH)D status and designate defciency or insufciency.Most 25(OH)D is bound to DBP, 10-15% is albumin bound, and <1% is unbound in the serum.Diferent clinical conditions can afect DBP levels, 25(OH)D binding, and total 25(OH)D levels

Table 1 :
NPHPT with 25(OH)D levels: age (yo) is expressed as the range or mean ± SD years old; n � PHPT patients; N � survey subjects; prevalence is expressed as % � n/N; 25(OH)D cutof: diagnostic criteria of vitamin D defciency in the study � expressed as range or mean ± SD ng/dl.