Abstract
Background
Tertiary hyperparathyroidism, or autonomous parathyroid gland function, is a rare complication of pseudohypoparathyroidism, which is a genetic cause of secondary hyperparathyroidism characterized by PTH resistance at target tissues, particularly the proximal renal tubule. Patients with pseudohypoparathyroidism typically present with symptoms consistent with hypocalcemia and are treated with calcium and vitamin D therapy. Pseudohypoparathyroidism, similar to other longstanding forms of secondary hyperparathyroidism, can progress to tertiary hyperparathyroidism due to chronically decreased serum calcium concentrations.
Summary
We present a report of a patient with longstanding pseudohypoparathyroidism who ultimately developed tertiary hyperparathyroidism. Her tertiary hyperparathyroidism was resistant to bisphosphonate therapy, and she could not afford cinacalcet, resulting in the need for surgical intervention. Therefore, a subtotal parathyroidectomy with cryopreservation was performed, resolving her tertiary hyperparathyroidism.
Conclusion
To our knowledge, this is the first description of a subtotal parathyroidectomy with cryopreservation performed for tertiary hyperparathyroidism secondary to pseudohypoparathyroidism. Additionally, given the genetic nature of this disease, we propose the routine use of a four-gland parathyroid exploration and subtotal parathyroidectomy in similar cases, analogous to other forms of familial hyperparathyroidism.
Key Words
tertiary hyperparathyroidism; pseudohypoparathyroidism; subtotal parathyroidectomy; familial hyperparathyroidism
Abbreviations
PTH: parathyroid hormone
NTx: N-terminal telopeptide
DXA: dual-energy X-ray absorptiometry
SPECT/CECT: single-photon emission computed tomography combined with contrast-enhanced CT
MEN1: multiple endocrine neoplasia type 1
Case Description
Our patient was diagnosed with hypothyroidism at age nine and managed with levothyroxine. Subsequently, she experienced many years of muscle cramps, paresthesias, and intermittent tetany. At 20, her symptoms became so debilitating that she was hospitalized for several weeks. During this hospitalization, she was diagnosed with pseudohypoparathyroidism, which was initially managed with calcium injections and dihydrotachysterol. She was later transitioned to oral calcium and calcitriol supplementation by the early 1990s. Her disease proved difficult to control, and she required frequent dose reductions over the years until her calcium supplementation was eventually discontinued. She recalled her calcium became persistently elevated around the age of 64. She established care with endocrinology at our institution at the age of 70, and her remaining calcitriol prescription was discontinued at that time. Her labs at the time of referral were notable for a significantly elevated parathyroid hormone (PTH) level of 1331 pg/mL, a calcium of 10.4 mg/dL, and an alkaline phosphatase of 152 mg/dL. She had high bone turnover (urine N-terminal telopeptide (NTx) of 209 nmol/mmol creatinine, nl 26-124) and worsening bone density on dual-energy X-ray absorptiometry (DXA) scan (T-score right femoral neck: -2.1, decreased by 15.6% compared to six years prior). She never experienced nephrolithiasis, fractures, seizures, neurocognitive, or gastrointestinal symptoms. Of note, the patient's son also suffers from hypothyroidism and pseudohypoparathyroidism, but other family members, including her mother, sister, and two daughters, are unaffected.
The patient was diagnosed with tertiary hyperparathyroidism due to longstanding secondary hyperparathyroidism. Given her low bone mass and increased bone resorption, alendronate was initiated and slowly titrated up to avoid potential hypocalcemia. Cinacalcet was also prescribed but was never initiated due to cost. After a year of medical therapy, her PTH had worsened (1976 pg/mL), and urine NTx (246 nmol/mmol creatinine) was still elevated. At that point, she was referred to endocrine surgery for her tertiary hyperparathyroidism. Preoperative single-photon emission computed tomography combined with contrast-enhanced CT (SPECT/CECT) imaging demonstrated an enlarged parathyroid inferior to the right thyroid lobe measuring approximately 1.7 × 1.4 × 2.7 cm with focal sestamibi uptake (Figure 1). Surgical clinic ultrasound confirmed the presence of a hypoechoic structure in the corresponding location, which appeared to potentially be two abutting right-sided parathyroid glands (Figure 2). Our clinical practice is to routinely perform preoperative SPECT hybridization with contrast-enhanced CT scanning (SPECT/CECT) to aid in identifying and localizing any ectopic parathyroid glands. We additionally routinely perform an in-office ultrasound to aid in preoperative parathyroid gland localization and rule out concomitant thyroid pathology before taking a patient to the operating room.
Figure 1. SPECT/CECT with Right-Sided Parathyroid Demonstrating Focal Sestamibi Uptake. Published with Permission
Figure 2. Surgical Clinic Ultrasound Findings. A) Right Superior Parathyroid and B) Right Inferior Parathyroid. Published with Permission
A.
After five days of treatment with calcitriol in preparation for surgery, the now 71-year-old patient underwent a four-gland parathyroid exploration. Intraoperatively, she was found to have asymmetric parathyroid hyperplasia, and a subtotal parathyroidectomy (resection of the right superior, left superior, left inferior, and a portion of the right inferior parathyroid glands) with parathyroid cryopreservation was performed. Of note, the large parathyroid seen on SPECT/CT was an enlarged right superior gland (Figure 3).
Figure 3. Enlarged Right Superior Parathyroid. Published with Permission
Intraoperative PTH levels decreased from a baseline of 1086 pg/mL to 34 pg/mL, indicative of an operative cure. She tolerated surgery well without complications. As expected, she required high-dose calcium and calcitriol supplementation postoperatively, carefully titrated to maintain eucalcemia with a normal PTH. Results of a one-year postoperative DXA scan revealed improvement in her bone mineral density from a T score of -2.1 to -1.4. She is currently maintaining eucalcemia with a normal PTH on 0.25 mcg of calcitriol twice daily and calcium 500 mg twice daily at greater than six months after her surgery. She denies symptoms of hypocalcemia and states that she "feels better than ever."
Discussion
Pseudohypoparathyroidism is a genetic cause of secondary hyperparathyroidism due to mutations in the PTH signaling pathway and is characterized by PTH resistance at target tissues, particularly the proximal renal tubule.1,2 This lack of responsiveness to PTH by the kidney results in decreased 1,25 (OH)2 D synthesis as well as decreased calcium resorption, resulting in hypocalcemia and a compensatory elevation in PTH, or secondary hyperparathyroidism. Diagnosis of pseudohypoparathyroidism is typically made in mid to late childhood. It is based on laboratory findings, specifically persistently elevated PTH after appropriate repletion of vitamin D and calcium, and in many cases, can be confirmed with genetic testing demonstrating a mutation in one of several genes involved in the PTH receptor signaling cascade (GNAS, PRKAR1A, PDE4D, or PDE3A).3 Management of pseudohypoparathyroidism is similar to that of primary hypoparathyroidism and is based on calcium and calcitriol supplementation.3,4 However, patients with pseudohypoparathyroidism may have some skeletal responsiveness to PTH, which can lead to osteopenia or osteoporosis.3,4 Rarely pseudohypoparathyroidism, similar to other longstanding forms of secondary hyperparathyroidism, can progress to tertiary hyperparathyroidism due to chronic parathyroid gland hypertrophy from decreased serum calcium concentrations, which become autonomous in function, causing hypercalcemia.
We report the case of a woman with pseudohypoparathyroidism progressing to tertiary hyperparathyroidism and treated with a subtotal parathyroidectomy. Given her high rate of bone turnover, she was at high risk for hungry bone syndrome postoperatively, which was preemptively treated with calcitriol prior to the operation. It is important to recognize that patients with signs of skeletal responsiveness to PTH in the setting of tertiary hyperparathyroidism, regardless of underlying etiology, are at risk for hungry bone syndrome, and preoperative calcitriol can be considered in order to mitigate this anticipated sequela.5 One limitation of initiating treatment with calcitriol in the postoperative setting is its onset of action which may take up to 48 hours.5 Preoperative treatment with a loading dose of calcitriol has been shown to mitigate postoperative hypocalcemia in other forms of secondary hypoparathyroidism. As tertiary hyperparathyroidism secondary to pseudohypoparathyroidism is a rare disease with an increased risk of postoperative hypocalcemia and decreased 1,25 (OH)2 D synthesis, a preoperative loading dose of calcitriol may improve the onset of calcitriol's effects.
While this is an unusual outcome of a rare disease, the recognition of the genetic causes of pseudohypoparathyroidism has only been recently clarified in the literature, with the first mutation associated with pseudohypoparathyroidism (GNAS) described in 1990.3,6 The first international consensus statement on pseudohypoparathyroidism was just released in 2018 and called for "a coordinated and multidisciplinary approach from infancy through adulthood" to best care for these patients.3 As such, it is reasonable to assume that the incidence of similar cases will increase as the disease process becomes more widely diagnosed and more patients are followed lifelong with multidisciplinary management, which may lead to increased recognition of tertiary hyperparathyroidism development in this population.
As this is currently a rare entity and given the longstanding nature of our patient's secondary hyperparathyroidism, we approached the operative treatment of this sequela of her genetic disease much like the treatment of another genetic disease affecting the parathyroid glands, multiple endocrine neoplasia type 1 (MEN1). In a randomized prospective trial comparing subtotal parathyroidectomy to total parathyroidectomy with autotransplantation in patients with MEN1, no difference in outcomes was found with either procedure. Still, subtotal parathyroidectomy was thought to have several advantages due to the need for only one incision as well as the avoidance of an obligate period of transient postoperative hypoparathyroidism.7 Therefore, we elected to proceed with a subtotal parathyroidectomy in our patient, which has led to an operative cure.
Interestingly, the operative approaches used for patients with pseudohypoparathyroidism progressing to tertiary hyperparathyroidism are highly varied in the literature. In search of the literature, only four studies describing eight cases of pseudohypoparathyroidism progressing to tertiary hyperparathyroidism were found.8-11 Of the seven patients who underwent surgery in these case studies, five were treated with either single or double-gland parathyroidectomies, and two underwent total parathyroidectomies (one with autotransplantation into the forearm).8-11 In the case series describing four patients who underwent either single or double-gland parathyroidectomies, all four were eucalcemic at over six months, but two patients had mildly elevated PTH levels.8 Like our patient, these patients were treated with calcium carbonate, calcitriol, and nutritional doses of cholecalciferol postoperatively.8 Notably, the two patients with elevated postoperative PTH levels were the two patients who received single-gland parathyroidectomies.8 Of the other cases identified, the remaining single gland parathyroidectomy did not have more than six months postoperative data, the total parathyroidectomy had "consistently undetectable" PTH, and the total parathyroidectomy with autotransplantation demonstrated surgical cure with over six months of postoperative labs.9-11
Conclusion
Given the underlying genetic predilection of parathyroid hyperplasia in patients with pseudohypoparathyroidism leading to tertiary hyperparathyroidism, we recommend a bilateral neck exploration rather than a focal exploration. Additionally, given the obligate period of transient hypoparathyroidism after total parathyroidectomy with autotransplantation in the setting of a complex endocrine disorder, we recommend performing a subtotal parathyroidectomy in this patient population.
Lessons Learned
Pseudohypoparathyroidism is a genetic cause of secondary hyperparathyroidism, which can progress to tertiary hyperparathyroidism due to chronically decreased serum calcium concentrations. We recommend bilateral neck exploration in these patients, given the likelihood of parathyroid hyperplasia.
Authors
Huffman EMa; Drucker NAa; Econs MJb; McDow ADa
Author Affiliations
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202
Corresponding Author
Elizabeth M. Huffman, MD
Indiana University School of Medicine
545 Barnhill Drive, Emerson Hall 125
Indianapolis, IN 46202
Email: elmahuff@iu.edu
Disclosure Statement
The authors have no conflicts of interest to disclose.
Funding/Support
The authors have no relevant financial relationships or in-kind support to disclose.
Received: March 2, 2021
Revision received: April 21, 2021
Accepted: July 13, 2021
References
- Shoback DM. Disorders of the parathyroids and calcium and phosphorus metabolism. In: Hammer GD, McPhee SJ, eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e. New York, NY: McGraw-Hill Education; 2019.
- Tafaj O, Jüppner H. Pseudohypoparathyroidism: one gene, several syndromes. J Endocrinol Invest. 2017;40(4):347-356. doi:10.1007/s40618-016-0588-4
- Mantovani G, Bastepe M, Monk D, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476-500. doi:10.1038/s41574-018-0042-0
- Linglart A, Levine MA, Jüppner H. Pseudohypoparathyroidism. Endocrinol Metab Clin North Am. 2018;47(4):865-888. doi:10.1016/j.ecl.2018.07.011
- Alsafran S, Sherman SK, Dahdaleh FS, et al. Preoperative calcitriol reduces postoperative intravenous calcium requirements and length of stay in parathyroidectomy for renal-origin hyperparathyroidism. Surgery. 2019;165(1):151-157. doi:10.1016/j.surg.2018.03.029
- Clarke BL, Brown EM, Collins MT, et al. Epidemiology and Diagnosis of Hypoparathyroidism. J Clin Endocrinol Metab. 2016;101(6):2284-2299. doi:10.1210/jc.2015-3908
- Lairmore TC, Govednik CM, Quinn CE, Sigmond BR, Lee CY, Jupiter DC. A randomized, prospective trial of operative treatments for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery. 2014;156(6):1326-1335. doi:10.1016/j.surg.2014.08.006
- Neary NM, El-Maouche D, Hopkins R, Libutti SK, Moses AM, Weinstein LS. Development and treatment of tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1B. J Clin Endocrinol Metab. 2012;97(9):3025-3030. doi:10.1210/jc.2012-1655
- Collins MT, Lindsay JR, Jain A, et al. Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D. J Bone Miner Res. 2005;20(11):1944-1950. doi:10.1359/JBMR.050718
- Eubanks PJ, Stabile BE. Osteitis fibrosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis. Arch Surg. 1998;133(6):673-676. doi:10.1001/archsurg.133.6.673
- Murray TM, Rao LG, Wong MM, et al. Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J Bone Miner Res. 1993;8(1):83-91. doi:10.1002/jbmr.5650080111
