Giant Parathyroid Adenoma Masked by Severe Vitamin D Deficiency with Hypocalcemic Presentation: A Case Report

Introduction

Primary Hyperparathyroidism (PHPT) is the leading cause of hypercalcemia in outpatient settings and results from autonomous overproduction of parathyroid hormone (PTH) by one or more parathyroid glands. It typically presents with elevated serum calcium and inappropriately normal or elevated PTH levels.¹ PHPT is most commonly diagnosed in adults between 50 and 70 years of age and is three times more prevalent in women. Most cases are caused by a single parathyroid adenoma (PTA), whereas multiglandular disease is less common, and parathyroid carcinoma accounts for fewer than 1% of cases.² PTAs typically weigh less than 1 g, and adenomas that weigh at least 3.5 g are classified as giant parathyroid adenomas (GPTA), a rare subgroup representing no more than 1.5% of all parathyroid adenomas.^3,4

The diagnosis of parathyroid lesions may present significant challenges within endocrine and head and neck pathology, particularly when biochemical findings are atypical. Distinguishing between benign and malignant parathyroid neoplasms based solely on macroscopic or radiologic features can be unreliable, as large adenomas may mimic carcinoma in both clinical and imaging presentations.^5,6 Accordingly, accurate diagnosis relies on a multimodal approach incorporating laboratory findings, targeted imaging, and definitive histopathological evaluation, with ancillary testing playing a critical role in preventing misclassification and guiding appropriate management. This lines with current international consensus guidelines that emphasize a structured, criteria-based approach to the evaluation and management of PHPT.⁷

Vitamin D deficiency is frequently observed in individuals with PHPT and can alter the classical biochemical presentation of the disease.⁸ Reduced vitamin D levels decrease intestinal calcium absorption, which may maintain normal or even low serum calcium levels despite elevated PTH secretion.³ As a result, severe vitamin D deficiency can mask the hypercalcemia typically associated with PHPT, delay recognition of the underlying disorder, and complicate the diagnostic evaluation.⁹

We present a case of PHPT in a 30-year-old Syrian woman in whom severe vitamin D deficiency produced hypocalcemia, obscured the classical biochemical profile, and delayed the diagnosis of a giant parathyroid adenoma. This case highlights the importance of considering PHPT in patients with elevated PTH levels even when hypercalcemia is not present.

Case Presentation

A 30-year-old Syrian woman presented to the endocrinology department with a nine-month history of progressive fatigue, generalized bone pain, and cervical discomfort. She reported intermittent paresthesia in the fingertips and denied nephrolithiasis, pathological fractures, gastrointestinal symptoms, or psychiatric manifestations. The patient had no history of chronic medical conditions and was not taking any medications known to affect calcium metabolism. There was no reported family history suggesting a hereditary endocrine syndrome. On physical examination, no lymphadenopathy or palpable cervical or thyroid mass was detected. Chvostek’s and Trousseau’s signs were absent, and the remainder of the examination was unremarkable.

Initial laboratory evaluation demonstrated severe vitamin D deficiency (25-hydroxyvitamin D: 25 nmol/L) and hypocalcemia (serum calcium: 1.89 mmol/L; ionized calcium: 1.05 mmol/L) with markedly elevated intact parathyroid hormone levels (PTH: 247 ng/L). Serum albumin was within the normal range (38.2 g/L), indicating that the low calcium level was not attributable to hypoalbuminemia. Serum phosphorus was mildly decreased at 0.71 mmol/L, while renal function remained normal (creatinine: 62.8 µmol/L). Alkaline phosphatase was mildly elevated at 168 U/L. Routine laboratory studies, including complete blood count, were within normal limits. The pattern of hypocalcemia with elevated PTH prompted initiation of calcium and vitamin D supplementation. After six weeks of treatment, vitamin D improved to 75.25 nmol/L and serum calcium normalized to 2.27 mmol/L (ionized calcium: 1.28 mmol/L). However, PTH remained inappropriately elevated at 151 ng/L (Table 1).

Table 1 Laboratory Values at Presentation and After Six weeks of Supplementation

Persistent elevation of PTH despite correction of vitamin D deficiency raised suspicion for primary hyperparathyroidism and prompted further imaging to localize a potential parathyroid source.

Neck ultrasonography performed at two separate centers identified a well-circumscribed, hypoechoic, oval-shaped nodule in the lower pole of the left thyroid lobe measuring approximately 18×18 × 13 mm. However, due to its posterior location and overlapping sonographic characteristics with thyroid tissue, ultrasound could not reliably distinguish whether the lesion originated from thyroid or parathyroid tissue. Given these inconclusive findings, further localization with functional imaging was indicated. A 99mTc-sestamibi scintigraphy demonstrated a distinct focus of radiotracer uptake inferior to the left thyroid lobe on early images, with persistent tracer retention on delayed imaging, a pattern characteristic of a hyperfunctioning parathyroid adenoma (Figure 1).

Figure 1 99mTc-sestamibi Parathyroid Scintigraphy Demonstrating Left Inferior Parathyroid Adenoma. 99mTc-sestamibi parathyroid scintigraphy demonstrating a left inferior hyperfunctioning parathyroid adenoma. Early-phase imaging (left) shows radiotracer uptake in the thyroid gland with a focal area of increased activity in the left inferior neck. Delayed-phase imaging (right) demonstrates persistent radiotracer retention in the same region, consistent with a parathyroid adenoma. Red arrows indicate the site of abnormal uptake.

Subsequently, the patient was referred for surgical management. A focused parathyroidectomy was performed under general anesthesia targeting the left inferior parathyroid gland. The procedure lasted approximately one hour. Intraoperatively, a markedly enlarged left inferior parathyroid gland was identified and excised without complication. A Rodivac drain was placed at the surgical site. The surgical specimen was sent for histopathological analysis. Gross examination revealed a well-circumscribed, tan parathyroid nodule measuring 2×2 × 1 cm and weighing 3.5 g, meeting the weight threshold for a giant parathyroid adenoma. Microscopic evaluation showed proliferation of uniform chief cells arranged in solid and trabecular patterns with a thin rim of compressed normal parathyroid tissue. Malignant features such as capsular invasion, vascular invasion, necrosis, or atypical mitotic activity were absent.

Postoperative laboratory studies obtained four hours after surgery demonstrated biochemical cure, with serum calcium stable at 2.09 mmol/L and PTH suppressed to 7 ng/L (reference range: 10–65 ng/L). The postoperative course was uncomplicated. The patient remained hemodynamically stable, reported no symptoms of hypocalcemia, and showed no evidence of recurrent laryngeal nerve injury. Routine postoperative monitoring was sufficient, and no aggressive calcium or calcitriol supplementation was required. She met criteria for same-day discharge and was released with instructions for close biochemical follow-up. The drain was removed on postoperative day three.

Discussion

Primary hyperparathyroidism is most commonly caused by a solitary adenoma under one gram and typically arises in individuals between fifty and seventy years of age.^1,2 Cases in patients younger than forty are uncommon, making this presentation at age thirty atypical.² Giant parathyroid adenomas are particularly rare and are generally defined as lesions weighing at least 3.5 g.⁴ Several analyses have reported that adenomas of this size can be associated with more pronounced symptoms, including bone pain, musculoskeletal weakness, nephrolithiasis, and neurocognitive complaints although presentations remain variable, and some patients may present with mild or atypical features despite large tumor size.³ Although young age can raise concern for hereditary causes such as MEN1 (Multiple endocrine neoplasia type 1), MEN2A (Multiple endocrine neoplasia type 2A), or CDC73 (Cell division cycle 73 gene)-related syndromes, the solitary nature of the adenoma confirmed on pathology, coupled with the absence of familial history or other syndromic features, makes a sporadic etiology most likely.¹⁰

Severe vitamin D deficiency (25 nmol/L) played a central role in this patient’s atypical biochemical profile. Vitamin D is required for intestinal calcium absorption, renal calcium reabsorption, and normal bone mineralization.^2,3 When levels are low, calcium availability falls, resulting in hypocalcemia despite markedly elevated PTH. This interaction can mask the hypercalcemia of PHPT and produce a biochemical pattern that mimics secondary hyperparathyroidism, a phenomenon frequently reported in regions with high rates of vitamin D deficiency, including the Middle East.^3,8 Emerging evidence also suggests that long-standing vitamin D deficiency may contribute to the development of larger adenomas. Chronic hypocalcemia drives sustained PTH stimulation, and prolonged parathyroid activation may promote cellular hyperplasia and adenoma growth, a mechanism proposed in studies examining giant parathyroid adenomas.³ This hypothesis may help explain the unusually large 3.5 g adenoma identified in this patient.

Localization of the adenoma presented diagnostic challenges in this case. Although ultrasonography is the standard initial imaging modality, its sensitivity is operator dependent and notably reduced for posterior or inferior parathyroid glands.⁹ In contrast, 99mTc-sestamibi scintigraphy demonstrates higher sensitivity for hyperfunctioning parathyroid adenomas and is recommended as an optimal modality for their detection.⁹ In this patient, two separate ultrasound examinations were inconclusive, whereas 99mTc-sestamibi imaging clearly localized the left inferior adenoma through persistent radiotracer retention on delayed images, consistent with the characteristic appearance of a solitary hyperfunctioning parathyroid gland.

Current international guidelines from the Fifth International Workshop on Primary Hyperparathyroidism recommend parathyroidectomy as the definitive treatment when specific clinical criteria are met.⁷ Indications for surgery include symptomatic disease, evidence of skeletal or renal involvement, serum calcium levels significantly above the upper limit of normal, or age younger than 50 years, which alone is considered sufficient justification for surgical management. Importantly, patients are required to meet only one of these criteria to be considered appropriate candidates for surgery. High cure rates have been reported following surgical excision of solitary lesions, including giant adenomas.^7,11

In the present case, surgical intervention was justified because the patient fulfilled this guideline criterion by virtue of her age of 30 years.⁷ In addition, she presented with symptoms including bone pain and paresthesia and demonstrated persistently elevated parathyroid hormone levels despite correction of severe vitamin D deficiency. Functional imaging further localized a solitary hyperfunctioning parathyroid lesion consistent with an adenoma, therefore, observation alone was not considered an optimal management strategy.⁷ Additionally, long term surveillance in young patients with primary hyperparathyroidism may expose them to decades of ongoing parathyroid hormone excess and the potential development of progressive skeletal and renal complications.⁷

Large parathyroid adenomas may clinically or radiologically mimic parathyroid carcinoma, making histopathologic evaluation essential.¹² In this case, the presence of uniform chief cells, preserved lobular architecture, and the absence of capsular or vascular invasion supported the diagnosis of a benign adenoma rather than carcinoma.¹²

Although Hungry Bone Syndrome (HBS) remains a significant postoperative concern in primary hyperparathyroidism, our patient did not meet high-risk criteria. As outlined in recent literature, HBS is most strongly associated with markedly elevated PTH levels (>1000 ng/L), ALP values exceeding 3–4 times the upper limit of normal, and metabolic profiles seen in secondary hyperparathyroidism or dialysis patients.¹³ Our patient’s ALP was corrected pre-operatively, PTH elevation was modest rather than severe, and both calcium and 25-hydroxyvitamin D levels were stable prior to surgery, placing her within the low-risk group.¹³ Rather than aggressive prophylactic therapy, close postoperative monitoring was clinically appropriate and consistent with recommendations reserving high-dose calcium and calcitriol protocols for patients with severe biochemical or skeletal risk factors.¹⁴

This report has several limitations inherent to a single-case design. The findings are not generalizable to all patients with primary hyperparathyroidism, particularly given the rarity of giant parathyroid adenomas and the atypical biochemical presentation observed in this case. In addition, the duration of follow-up was limited, precluding assessment of long-term outcomes such as recurrence or persistent metabolic complications. Finally, while severe vitamin D deficiency appeared to mask the underlying disorder, a causal relationship between vitamin D status and the development, size, or progression of the adenoma cannot be established.

Conclusion

This case highlights the importance of maintaining a high index of suspicion for primary hyperparathyroidism in patients presenting with discordant calcium–PTH patterns, particularly in the setting of severe vitamin D deficiency. It emphasizes the need for reassessment of biochemical parameters following vitamin D and calcium repletion to avoid misclassification as secondary hyperparathyroidism. Additionally, when first line imaging such as ultrasonography is non-diagnostic, functional imaging with 99mTc-sestamibi scintigraphy plays a critical role in accurate localization and surgical planning. From a broader policy and healthcare systems perspective, this case supports the need for increased awareness of atypical presentations of endocrine disorders, especially in regions with a high prevalence of vitamin D deficiency, and highlights the importance of ensuring access to appropriate diagnostic imaging and timely surgical management. Early recognition and intervention remain essential to prevent complications and achieve optimal patient outcomes.