Vitamin D deficiency is associated with single gland parathyroid disease

Abstract

Background:

Primary hyperparathyroidism (PHPT) with low preoperative vitamin D levels is thought to be related to 4-gland hyperplasia. We reviewed final parathyroid pathology in relationship to preoperative vitamin D levels.

Methods:

A retrospective review was performed for all PHPT patients undergoing parathyroidectomy from 2001 to 2019. Patient demographics, laboratory studies, and final pathology were reviewed.

Results:

2230 patients were included in the analysis, 78.1% were female with a mean age of 59 years. Patients were stratified into 3 groups based on their preoperative 25-hydroxy vitamin D levels; “deficient” (<20 ng/mL) (n = 319), “insufficient” (20–30 ng/mL) (n = 1108), or “sufficient” (>30 ng/mL) (n = 803). Patients with deficient vitamin D had a higher frequency of single adenoma (71%) compared to sufficient vitamin D patients (62%) (p < 0.001) and fewer hyperplastic glands (19%) compared to sufficient vitamin D level patients (25%) (p < 0.001).

Conclusions:

Vitamin D deficiency is more strongly associated with single-gland parathyroid disease than 4-gland hyperplasia. Further investigation into the complex interplay between vitamin D levels and autonomous parathyroid function is warranted.

1. Introduction

Primary hyperparathyroidism (PHPT) is a common endocrinopathy in the United States.^1,2 It represents the aberrance of a delicate feedback loop among parathyroid hormone (PTH), vitamin D, and calcium, among other hormones/electrolytes. The active form of vitamin D [1,25 (OH2D)] plays a key role in calcium homeostasis and ultimately the secretion of parathyroid hormone (PTH).³ In classical primary hyperparathyroidism, one sees increased serum calcium with inappropriately normal or elevated PTH and increased vitamin D. A less common and unique form of primary hyperparathyroidism presents with vitamin D deficiency or insufficiency without renal failure and is distinct from secondary hyperparathyroidism.⁴

Vitamin D deficiency is common in the developed world and the prevalence is increasing.⁵ This has been shown to have numerous health implications.^3,6 The serum level of 25-hydroxyvitamin D (25OHD) is the most accurate and reliable marker of vitamin D status in an individual.^7,8 The pathophysiology of the combination of vitamin D deficiency and PHPT is opaque, although several theories exist. In addition, vitamin D deficiency in primary hyperparathyroidism has been associated with worsened bone mineral density scores and larger gland sizes when compared to vitamin D sufficient patients.^9–11 Accepted dogma is that vitamin D deficiency in the setting of PHPT may lead to a physiologic imbalance and resultant increased PTH secretion from all 4 parathyroid glands.¹² This unique situation may cause patients to experience more 4- gland hyperplasia or multiple adenomas rather than true single autonomous gland dysfunction as seen in the majority of primary hyperparathyroidism cases.¹³ Of note, this is mostly anecdotal or single-institutional data without large, high-level, studies to support this in the literature.¹⁴ Therefore, the purpose of this study is to review final parathyroid pathology in relationship to preoperative vitamin D levels in patients undergoing parathyroidectomy for PHPT at two large tertiary care centers.

2. Methods

Patients:

IRB approval was obtained by the University of Wisconsin-Madison and the University of Alabama at Birmingham. A retrospective review of all patients with PHPT undergoing parathyroidectomy for primary hyperparathyroidism by two high-volume endocrine surgeons from 2001 to 2019 was performed. Data were collected prospectively from the two academic institutions. The IRB at both institutions approved waiver of consent. Patients were stratified into 3 groups based on their preoperative 25-hydroxy vitamin D levels; “deficient” (<20 ng/ mL), “insufficient” (20–30 ng/mL), or “sufficient” (>30 ng/mL) per Institute of Medicine and Endocrine Society guidelines.^6,8 Patients were not routinely supplemented with vitamin D preoperatively. Patient demographics, pre- and postoperative laboratory studies, imaging reports, operative reports, and final parathyroid pathology were compared amongst groups. Statistical analysis was performed using T-test and Chi-squared analysis, as appropriate. Significance was defined as p <0.05.

Surgical approach:

It is our practice for parathyroid surgery to begin on the side localized for disease with preoperative imaging (if obtained) and to examine the ipsilateral gland. For example, if the right superior parathyroid is abnormal and the right inferior gland is completely normal upon surgical inspection, the procedure is halted until an intraoperative PTH (iOPTH) level measures at least a 50% drop. If no such appropriate drop is identified or both ipsilateral glands appear abnormal, routine bilateral exploration would then be performed.

Our group utilizes a radio-guided approach for all parathyroid surgery, except where contraindicated, as described previously.¹⁵ Preoperatively, patients are injected with 10 mCi of Tc-99 m sestamibi, without post-injection imaging. Intraoperatively, a handheld Neoprobe Gamma Detection System^® (Devicor Medical Products, 2020) is used to obtain background count on the thyroid isthmus. Once diseased parathyroid is removed, an ex vivo count is obtained for each specimen, where a threshold of >20% of background confirms hyperplastic parathyroids and a threshold of >200% of background suggests adenomatous glands.¹⁶ The specimen is then sent for permanent pathology. The absence of persistent disease at 6 months based on our normal laboratory limits is defined as cure (calcium <10.5 mg/dL, PTH<85 pg/mL).

3. Results

Two-thousand two-hundred thirty patients were included in the analysis, the majority of which were female (78.1%) with a mean age of 59 years. Groups were stratified according to vitamin D levels: <20 (n = 319), 20–30 (n = 1108), and >30 (n = 803) (Table 1). Among patients with deficient vitamin D levels, there was a higher rate of males (31%) compared to those with sufficient vitamin D levels (16%, p = 0.008). All groups had a mean creatinine of 1.0 ± 0 mg/dL (p = NS). The median length of stay for all groups was 0 days (p = NS).

Table 1.

Primary Hyperparathyroidism Patient Characteristics Compared by Vitamin D Levels (ng/mL). Values expressed as means ± SD. Parathyroid Hormone = PTH.

Patient Characteristics	Deficient (<20) N = 319 (14.3%)	Insufficient (20–30) N = 1108 (49.7%)	Sufficient (>30) N = 803 (36%)	P-value
Demographics
Age (yrs)	55 ± 1	59 ± 0	62 ± 0	<0.001
Male	98 (31%)	262 (23%)	129 (16%)	0.008
Pie operative Serum Creatinine (mg/dL)	1.0 ± 0	1.0 ± 0	1.0 ± 0	NS
Body Mass Index (BMI)	33 ± 1	35 ± 4	34 ± 4	NS
Preoperative Calcium (rng/dL)	10.9 ± 0.1	10.9 ± 0	10.8 ± 0.1	NS
Preoperative PTH (pg/dL)	161 ± 9	128 ± 3	113 ± 5	<0.001
6-Month Postoperative Calcium (mg/dL)	9.4 ± 0	9.5 ± 0.1	9.4 ± 0	NS
6- Month Postoperative PTH (pg/dL)	63 ± 7	49 ± 1	48 ± 1	<0.001
Pathology
Single Adenoma	226 (71%)	787 (71%)	498 (62%)
Double Adenoma	32 (10%)	111 (10%)	104 (14%)
Hyperplasia	61 (19%)	210 (19%)	202 (25%)	<0.001

Patients with deficient vitamin D had significantly higher preoperative PTH levels (161 ± 9 pg/dL) compared to both the insufficient (128 ± 3 pg/dL) and sufficient groups (113 ± 5 pg/dL; p < 0.001). Similarly, postoperative PTH levels were higher in the deficient vitamin D group (63 ± 7 pg/dL) compared to insufficient (49 ± 1 pg/dL) and sufficient groups (49 ± 1 pg/dL; p < 0.001). There was no difference in pre- or postoperative Ca levels amongst the 3 groups and all groups achieved biochemical cure defined as 6 month post-operative calcium <10.5 and parathyroid hormone <85 pg/mL. Notably, when comparing pathologic diagnoses, patients with deficient vitamin D levels had a significantly higher frequency of a single adenoma (71%) compared to the vitamin D sufficient group (62%; p < 0.001). Hyperplastic glands were pathologically confirmed in fewer deficient or insufficient vitamin D level patients (19% for both) compared to sufficient vitamin D level patients (25%). Over half of all patients (54.8%, n = 1222/2230) underwent a bilateral neck exploration.

4. Discussion

To date, this is the largest cohort of primary hyperparathyroidism undergoing surgery analyzed by vitamin D deficiency. These data contradict anecdotal information regarding a possible trend toward multiple gland hyperplasia in vitamin D deficient patients. This was a surprising result since those patients with normal vitamin D levels were more likely than their vitamin D deficient peers to have multiple adenomas on final pathology.

The pathophysiology of the coexistence of vitamin D deficiency and primary hyperparathyroidism is incompletely understood although several theories exist.¹⁷ Some suggest this is a variant of hyperparathyroidism in which prolonged exposure to hypocalcemia due to vitamin D deficiency has stimulated the development of a parathyroid adenoma. The serum calcium therefore raises to normal or low-normal levels with elevated PTH if vitamin D deficiency is mild or is supplemented.^18,19 Another hypothesis is that hyperparathyroidism accelerates the break-down of vitamin D allowing one to see its effects on elevating calcium but with a lowered serum level.²⁰ Others postulate the cause is a deficiency in calcium sensing receptors in parathyroid tissue that causes persistent hyperparathyroidism even in the presence of vitamin D deficiency.¹¹ Still others believe the vitamin D deficiency could be a completely unrelated but coexisting disease state with primary hyperparathyroidism.²¹ Given that both entities are common it may be a coincidence that they overlap in some patients. Most studies exploring this disease state are small and may suffer from selection bias. All in all, the existence of vitamin D deficiency and PHPT is likely multifactorial and not yet completely understood.

Our data are similar to previously published experiences demon-strating higher preoperative calcium and PTH levels in the vitamin D deficient primary hyperparathyroidism patients.^9,22 This could support the postulate that vitamin D deficiency is a marker of more “severe” primary hyperparathyroidism based on clinical and biochemical profile. More severe biochemical disease does not necessarily correlate with multiple adenomatous or hyperplastic glands as supported by this study. Few studies have specified the rate of multi-gland disease amongst those with vitamin D deficient primary hyperparathyroidism, however this is a common assumption with little data. Beyer et al. examined 110 patients undergoing parathyroidectomy with half having preoperative vitamin D deficiency.⁹ They showed no difference in rates of multiple adenomas resected between the two groups. In addition, Randle, et al. examined patients with primary hyperparathyroidism with and without vitamin D deficiency and demonstrated increased rates of single adenomas in the deficient patients but equivalent cure rates.²³ Both of these patient cohorts were primarily Northeastern or Midwestern populations.²⁴ Our data specifically includes patients from the Southeast who tend to have a different vitamin D biochemical profile due to the geographic latitude and differences in racial/ethnic composition and sun exposure.²⁵

Of note, perioperative care surrounding parathyroidectomy seems to be similar with or without vitamin D deficiency. Preoperative vitamin D deficiency does not affect intraoperative PTH monitoring.^19,26 Vitamin D deficiency may increase rate of transient post-operative hypocalcemia but preoperative supplementation does not seem to affect post-operative hungry bone syndrome or cure.^20,27 For these reasons, our group does not routinely supplement vitamin D preoperatively.

These results may allow surgeons to operate more precisely using evidenced-based surgery. Some surgeons may have been more likely to perform bilateral neck exploration for those with vitamin D deficiency based on a priori suspicion of multi-gland disease. These data do not support this and instead one should likely not base bilateral neck exploration on vitamin D levels alone. Clearly, more work must be done on the pathophysiology of PHPT especially with concomitant vitamin D deficiency to further understand this phenomenon.

There are several limitations to this study. It is a retrospective review of patients cared for by two surgeons. This carries inherent selection bias. We do not have an accurate assessment of how many patients in each group were supplemented with vitamin D preoperatively. However, our institution’s surgeons and endocrinologists do not routinely supplement our vitamin D deficient PHPT patients and there are no guidelines that support this.²⁸ Another limitation is the lack of reported rates of bilateral neck exploration by vitamin D level. It would be interesting to know if certain groups were more likely to undergo bilateral neck exploration and if this played a role in the discovery of multiple adenomatous or hyperplastic glands. However, since our group follows a standard approach to deciding who undergoes bilateral neck exploration, this partially addresses any differences by vitamin D level. Finally, we do not have data on post-operative follow-up times beyond 6 months in this cohort. This would provide the rate of persistent or recurrent PHPT among the groups which would have allowed speculation on if any hyperplastic glands were missed on initial exploration.

5. Conclusions

These results of this large database retrospective review reveal a surprisingly increased association of deficient vitamin D levels with single-gland parathyroid disease instead of hyperplastic disease. Further investigation into the complex interplay between vitamin D levels and autonomous parathyroid function is warranted.