POSTOPERATIVE HYPOCALCEMIA FOLLOWING PARATHYROIDECTOMY FOR GIANT PARATHYROID ADENOMA

Abstract

Objective:

Giant parathyroid adenomas (GPAs) are a rare type of parathyroid adenoma (PA) weighing >2 to 3 g. The objective of this manuscript is to report a case of giant parathyroid adenoma and highlight the risk of postoperative hypocalcemia.

Methods:

We describe the presentation and work-up of a woman with GPA confirmed with histopathology as well as management of postoperative hypocalcemia.

Results:

A 66-year-old Caucasian female with chronic fatigue was found to have elevated calcium levels at 13.7 mg/dL (normal, 8.9 to 10.2 mg/dL) and elevated parathyroid hormone levels at 1,240 pg/mL (normal, 12 to 72 pg/mL). Contrast enhanced computed tomography scan of the neck showed a 5.6 cm heterogeneous mass posterior to the right thyroid. The patient underwent right parathyroidectomy and histopathology confirmed the diagnosis of a giant parathyroid adenoma (GPA) weighing 28.7 g. Postoperatively, the patient developed hypocalcemia secondary to hungry bone syndrome and was treated aggressively with intravenous calcium supplementation. At 4 weeks postoperatively, she had normal calcium levels without any calcium supplementation.

Conclusion:

GPAs are a rare variant of PA, and could be a distinct clinical entity with features different from both PA and parathyroid carcinoma. We further postulate that the risk of postoperative hypocalcemia secondary to hungry bone syndrome could be higher among patients with GPA compared to patients with PA. These hypotheses needs to be validated with further studies.

INTRODUCTION

The normal parathyroid gland weighs about 50 to 70 mg. Primary hyperparathyroidism is a common endocrine disorder and is one of the most frequent causes of hypercalcemia. Primary hyperparathyroidism is caused by a single parathyroid adenoma (85 to 90%), multigland disease (10%), and extremely rarely can be due to parathyroid carcinoma (1). Parathyroid adenoma leading to primary hyperparathyroidism extensively varies in size, and adenomas weighing >2 to 3 g are classified as “giant parathyroid adenomas” (2). The largest parathyroid adenoma reported in the literature weighed 110 g. Giant parathyroid adenomas (GPAs) are rare, and in limited studies including case reports and case series have been described to represent a different clinical entity. We report a case of giant parathyroid adenoma presenting with fatigue, polyuria, polydipsia, anorexia, and constipation secondary to longstanding hypercalcemia, who developed post parathyroidectomy symptomatic hypocalcemia requiring prolonged hospitalization.

CASE REPORT

A 66-year-old Caucasian female presented with a chief complaint of gradually progressive fatigue for 4 weeks. The review of systems was positive for polyuria, polydipsia, anorexia, and constipation, but no weight loss, fevers, night sweats, dysphonia, dysphagia, recent nephrolithiasis, or osteoporotic fractures. Her past medical history was significant for a remote history of kidney stones about 20 years before her presentation; however, she had not seen a physician for a prolonged period before her current visit to the hospital. She was not on any medication, and her family history was negative for any known calcium disorders or renal stone. She was tachycardic (103 beats per minute) with normal blood pressure (128/71 mm Hg) and temperature (98.2 °F) on presentation. Her body mass index was 24.3 kg/m². The thyroid gland was unremarkable without any nodule or lymphadenopathy. Laboratory workup (Table 1) showed elevated total calcium 13.7 mg/dL (normal, 8.9 to 10.2 mg/dL) and significantly elevated intact parathyroid hormone (PTH) levels 1,240 pg/mL (normal, 12 to 72 pg/mL). Contrast-enhanced computed tomography (CT) of the neck revealed a heterogeneous 5.6 cm soft tissue mass posterior to the right thyroid lobe in the tracheoesophageal groove, extending into the mediastinum (Fig. 1 A and B). A CT of the chest, abdomen, and pelvis again showed a 5.6 cm heterogeneous mass in the neck, along with multiple calcified mediastinal and hilar lymph nodes, calcifications in the pancreatic head, and bilateral nonobstructing renal calculi. She was diagnosed with PTH-induced hypercalcemia and the differential diagnosis included parathyroid adenoma or parathyroid carcinoma. She was treated aggressively with intravenous fluids and electrolyte replacement, and in the first 24 hours, total calcium levels improved to 10.6 mg/dL. However, 48 hours from presentation, total calcium levels again increased to 14.6 mg/dL, and she was given a dose of intravenous pamidronate 60 mg, following which her calcium levels normalized. On the fifth day of hospitalization, the patient underwent a right inferior parathyroidectomy. Histopathology confirmed the diagnosis of a giant parathyroid adenoma measuring 5.2 cm × 3.1 cm × 1.4 cm in size and weighing 28.7 g (Fig. 2). On postoperative day 0, she developed symptomatic hypocalcemia (total calcium of 8.8 mg/dL). She was started on aggressive calcium replacement with intravenous calcium gluconate. On postoperative day 7, she was discharged on calcitriol 0.5 μg 2 capsules orally 2 times a day, calcium carbonate 500 mg (200 mg elemental calcium) 5 tablets orally 2 times a day, and ergocalciferol 50,000 units orally once a week. The trend of calcium level is shown in Figure 3. At 3 weeks following the parathyroidectomy, total calcium was 12 mg/dL, intact PTH was <10 pg/mL and 25-hydroxyvitamin D was 20.6 ng/mL (normal, 20 to 80 ng/mL). Hence, calcitriol and calcium carbonate was stopped. Calcium levels became normal (9.8 mg/dL) 1 week later. At 6 weeks, laboratory work-up showed a total calcium of 9.4 mg/dL, an intact PTH of 72 pg/mL, a phosphorus level of 3.6 mg/dL (normal, 2.5 to 4.5 mg/dL), a serum creatinine of 1.77 mg/dL (normal, 0.60 to 1.10 mg/dL), and an estimated glomerular filtration rate of 30 mL/min/1.73 m², suggesting secondary hyperparathyroidism in the presence of chronic kidney disease.

Table 1.

Laboratory Results on Admission

Laboratory test	Level	Reference range
WBCs	10.07 K/uL	3.7–10.3 K/uL
RBCs	3.83 M/uL	3.–5.2 M/uL
Hemoglobin	11.4 g/dL	11.2–15.7 g/dL
Hematocrit	34.1%	34–45 %
Platelets	313 K/uL	155–369 K/uL
Plasma glucose	93 mg/dL	74–90 mg/dL
Serum sodium	139 mmol/L	136–145 mmol/L
Serum potassium	2.9 mmol/L	3.7–4.8 mmol/L
Serum bicarbonate	22 mmol/L	22–29 mmol/L
Serum chloride	105 mmol/L	97–107 mmol/L
Serum calcium, total	13.7 mg/dL	8.9–10.2 mg/dL
Ionized calcium	7.5 mg/dL	4.6–5.1 mg/dL
Serum magnesium	1.8 mg/dL	1.9–2.4 mg/dL
Serum phosphorus	2.7 mg/dL	2.5–4.5 mg/dL
Serum albumin	3.6 g/dL	3.3–4.6 g/dL
Blood urea nitrogen	19 mg/dL	0–30 ng/dL
Serum creatinine	1.95 mg/dL	0.60–1.10 mg/dL
Estimated GFR	26 mL/min/1.73 m2	>60 mL/min/1.73 m2
Serum aspartate transaminases	23 U/L	9–36 U/L
Serum alanine transaminases	37 U/L	8–33 U/L
Serum alkaline Phosphatase	243 U/L	46–142 U/L
Serum total protein	7.5 g/dL	6.3–7.9 g/dL
Serum lipase	159 U/L	19–63 U/L
Intact parathyroid hormone	1,240 pg/mL	12–72 pg/mL
Parathyroid hormone–related peptide	1.0 pmol/L	≤4.2 pmol/L
Vitamin D, 25 hydroxy	8.5 ng/mL	20–80 ng/mL
Vitamin 1,25 dihydroxy, total	20.3 pg/mL	20 to 45 pg/mL
Thyroid-stimulating hormone	0.87 uIU/mL	0.4–4.5 uIU/mL
Free T4	1.0 ng/dL	0.8–1.8 ng/dL
Random urine calcium	12.6 mg/dL
Random urine creatinine	17 mg/dL

Abbreviations: GFR = glomerular filtration rate; RBC = red blood cell; T4 = thyroxine; WBC = white blood cell.

Fig. 1.

Contrast-enhanced computed tomography of the neck showing a heterogeneous soft tissue mass at the right tracheoesophageal groove, posterior to the right thyroid lobe and extending into the posterior mediastinum measuring: A, 55.6 mm on sagittal section, and B, 40.5 mm on coronal section.

Fig. 2.

Histologic examination showing proliferation of parathyroid cells, predominantly chief cells, with a solid to follicular growth pattern and a thin fibrous capsule. The cells show no cytologic atypia and there was no evidence of invasion into the soft tissue, necrosis, fibrous bands, and abnormal mitoses. Hematoxylin and eosin stain.

Fig. 3.

Calcium level trend.

DISCUSSION

Giant parathyroid adenomas are defined as parathyroid adenomas >3.5 g (3). GPAs are rare, and their true incidence is unknown. A recent literature review by Al-Hassan et al (4) revealed only 22 cases of GPA between 2009 to 2019.

Clinical presentation of giant parathyroid adenoma is mostly similar to parathyroid adenoma. However, while parathyroid adenomas (PAs) is usually asymptomatic, GPA is mostly symptomatic (4,5). The classic constellation of symptoms is rarely seen these days due to frequent routine chemical assessment and timely intervention. However, our patient did not have a routine health check-up for a prolonged period and presented with symptoms suggestive of chronic hypercalcemia. Rarely, patients can present with severe conditions such as hyperparathyroidism crisis and acute pancreatitis (6,7). GPAs slowly grow over the years; however, occasionally, they can have rapid enlargement due to cystic changes (8).

While both GPA and parathyroid carcinoma are rare entities, parathyroid carcinoma should always be suspected among patients with marked hypercalcemia, extremely high PTH levels, and a neck mass. GPA cannot be reliably differentiated from parathyroid carcinoma based on localization imaging studies; however, local capsular or extracapsular invasion and/or distant metastasis are highly suggestive of parathyroid cancer (9). Invasion beyond the capsule appears to best correlate with the diagnosis of parathyroid cancer (10). Several studies have suggested GPAs to represent a distinct clinical entity compared to PAs with specific genomic aberrations such as mutations in parafibromin, hyperparathyroidism 2 with jaw tumors (HRPT2; CDC73), multiple endocrine neoplasia type 1 (MEN1) and adenomatosis polyposis coli (APC) genes (3,11). Mutation of the HRPT2 (also called CDC73) tumor suppressor gene plays a significant role in the pathogenesis of parathyroid carcinoma and its presence has been found in hyperparathyroidism-jaw tumor syndrome, sporadic parathyroid carcinoma, and isolated familial hyperparathyroidism (12). It is also noteworthy that some studies have proposed that previously resected parathyroid lesions could have been parathyroid carcinoma (13). Besides, head and neck radiation can predispose to future risk of parathyroid carcinoma decades later (14).

Compared to PAs, GPAs have a higher occurrence in males, is mostly a single gland disease (11), and has higher mean preoperative PTH and serum calcium levels (3). A retrospective review of parathyroidectomies between 1996–2006 showed a positive correlation between the size of PA and preoperative PTH (15). The role of fine needle aspiration cytology is limited as it lacks the ability to differentiate between different types of parathyroid disease (16).

Localization of GPA is done following biochemical diagnosis and is most commonly done with a neck ultra-sound and 99mTc-sestamibi scintigraphy (MIBI) scan. Neck ultrasound has a limitation to detect GPA if it is ectopic or extends into the mediastinum, and therefore has a lower accuracy to predict the size (79%), which increases to 82% when it is combined with MIBI, and CT (3). In our patient, preoperative localization was done with contrast enhanced CT scan of neck.

Based on current guidelines for management of PA, our patient met indications to undergo parathyroidectomy (17). Postoperatively, patients with GPA are more likely to develop postoperative hypocalcemia (18). Our patient also developed symptomatic hypocalcemia due to hungry bone syndrome (HBS) on the first postoperative day and needed aggressive intravenous calcium supplementations. HBS is defined as rapid, profound, and prolonged hypocalcemia, associated with hypophosphatemia and hypomagnesemia due to the abrupt withdrawal of PTH following parathyroidectomy in patients with severe PHPT (19). It has a variable incidence ranging from 13 to 87% (19–21). A larger volume of resected parathyroid gland, elderly, elevated blood urea nitrogen, elevated alkaline phosphatase concentrations, or low vitamin D levels and bone disease at the time of diagnosis are known risk factors for HBS (20,21). Various studies have shown the frequent occurrence of 25-hydroxyvitamin D deficiency among patients with primary hyperparathyroidism; however, only a few of those patients develop postoperative hypocalcemia (22). Among risk factors for postoperative hypocalcemia, the size of parathyroid adenoma has consistently been found to be the leading determinant of postoperative hypocalcemia (20,23,24). Therefore, we propose that in our case, the size of parathyroid adenoma was the dominant contributor to the postoperative hypocalcemia, none the less, 25-hydroxyvitamin D deficiency further contributed to it.

HBS can manifest with variable symptoms ranging from neuromuscular irritability, perioral paresthesia to generalized convulsions and rarely can be fatal (19), and therefore, should be aggressively treated. The amount of calcium supplementation to treat HBS can be as high as 6 to 12 g/day (19). Small retrospective studies have suggested the prophylactic role of preoperative bisphosphonate and vitamin D supplementation in preventing HBS among patients with PA, however, larger randomized control trials are lacking (25,26). Furthermore, there is no current evidence on the role of bisphosphonate and vitamin D supplementation among patients with GPAs.

A single center study showing lack of recurrent hypercalcemia following parathyroidectomy among patients with PA suggests a benign pathophysiology (11). Furthermore, studies have shown a similar incidence of recurrent and persistent hyperparathyroidism following parathyroidectomy for PA and GPA (3).

CONCLUSION

GPAs are an uncommon type of PA and represents a distinct clinical entity with features different from both PA and parathyroid carcinoma and can create a diagnostic dilemma. The risk of postoperative hypocalcemia secondary to HBS, could be higher among patients with GPA compared to PA and hence close postoperative monitoring is vital. However, this hypothesis needs be validated with further studies.

Abbreviations

CT

computed tomography

GPA

giant parathyroid adenoma

HBS

hungry bone syndrome

PA

parathyroid adenoma

PTH

parathyroid hormone