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Chapter 13
Workup andManagement ofPrimary
Hyperparathyroidism
InsooSuh andKylaWright
Introduction [1–3]
• Primary hyperparathyroidism (PHPT) is a relatively common disorder characterized by excessive secretion of parathyroid hormone (PTH) from one or more
parathyroid glands.
• Loss of normal feedback suppression of serum calcium on the synthesis and
secretion of PTH results in hypercalcemia and elevated or inappropriately
normal PTH.
• In most patients, PHPT is caused by a solitary parathyroid adenoma. Less frequent causes include four-gland hyperplasia, multiple adenomas, and rarely,
parathyroid cancer (Fig.13.1).
• Most cases are sporadic, although some are associated with a personal or family
history of parathyroid disease or endocrinopathies such as the multiple endocrine
neoplasia (MEN) syndromes.
Clinical Presentation [1, 4–7]
• Most patients with PHPT are asymptomatic at presentation and have a mildly
elevated serum calcium level identied incidentally.
I. Suh (*)
Department of Surgery, NYU Langone Health, New York, NY, USA
e-mail: Insoo.Suh@nyulangone.org
K. Wright
NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
e-mail: kyla.wright@nyulangone.org
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_13
111© The Author(s), under exclusive license to Springer Nature
112
Fig. 13.1 Causes of
primary
hyperparathyroidism [1, 2]
Table 13.1 Signs and symptoms of primary hyperparathyroidism by system [1, 4, 5]
System affected Signs and symptoms
Musculoskeletal Bone and joint pain, muscle cramps and weakness, decreased bone mineral
density, fragility fractures, pseudogout
Renal Nephrolithiasis, nephrocalcinosis, hypercalciuria, ank pain, polyuria and
polydipsia, reduced renal function
Gastrointestinal Constipation, anorexia, vomiting, dehydration, peptic ulcer disease,
pancreatitis
Neurocognitive Fatigue, anxiety, poor concentration, sleep disturbances, altered mental status
Cardiovascular Arterial hypertension, left ventricular hypertrophy, shortened QT interval,
palpitations, arrhythmias
I. Suh and K. Wright
• Overt symptoms occur more frequently in patients with more signicant hypercalcemia or those with a rapid rise in serum calcium.
• When present, the classical disease presentation is described by the popular mnemonic—“bones, stones, groans and psychiatric moans”—and reects the combined effects of hypercalcemia and elevated PTH on the musculoskeletal, renal,
gastrointestinal, and neurocognitive systems (Table13.1).
• Osteitis brosa cystica is a severe skeletal condition pathognomonic for hyperparathyroidism characterized clinically by bone pain, skeletal deformities, fractures and radiographically by brown tumors, lytic lesions, subperiosteal bone
resorption, and bone cysts (Fig.13.2). However, it is increasingly uncommon in
PHPT with earlier detection of hypercalcemia.
• Many patients have subtle neurocognitive and gastrointestinal symptoms such as
excessive fatigue, sleep disruption, memory/concentration difculties, mood disorders, dyspepsia, and constipation that are non-specic but can severely affect
daily quality of life.
13 Workup andManagement ofPrimary Hyperparathyroidism
113
Fig. 13.2 Radiographic appearance of osteitis brosa cystica, including multiple brown tumors
(A), subperiosteal resorption (B), and distal phalangeal resorption (C) [7]
Diagnosis andWorkup
Diagnostic Evaluation [8–10]
• PHPT is the most common cause of hypercalcemia in the outpatient setting.
Thus, all patients with elevated serum calcium warrant work-up for PHPT.
• The diagnosis of PHPT is biochemical. It is typically characterized by hypercalcemia and elevated or inappropriately normal PTH.
• Current guidelines recommend patients undergo a biochemical evaluation that
includes serum total calcium, PTH, creatinine, and 25-OH vitamin D levels.
• Serum total calcium should be corrected for serum albumin via the following
equation: corrected calcium (mg/dL) = {0.8 × [4.0 − patient’s albumin (g/
dL)]}+measured calcium (mg/dL).
114
I. Suh and K. Wright
Differential Diagnosis [8–12]
• The differential diagnosis for hypercalcemia is outlined in Table13.2.
• Hypercalcemia of malignancy is the most common cause of hypercalcemia in the
hospitalized patient. It is due to stimulation of osteoclast-mediated bone resorption by production of parathyroid hormone-related peptide (PTHrP) from tumor
cells or osteolysis from bone metastasis.
• PHPT and hypercalcemia of malignancy are differentiated by PTH level: PTH
level is elevated/inappropriately normal in PHPT but is suppressed in hypercalcemia of malignancy.
• Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disorder caused by a mutation in the calcium-sensing receptor (CaSR) associated
with mild, chronic hypercalcemia and normal-to-mildly elevated PTH.
• PHPT and FHH can be differentiated by measuring 24-hour urinary calcium and
creatinine: FHH is characterized by low urine calcium excretion (classically
<100mg/24h) and a Ca/Cr clearance ratio (CCCR) <0.01. PHPT is associated
with normal to high urinary calcium excretion (>150mg/24h) and a CCCR>0.02.
Genetic Testing [8, 13, 14]
• Most patients with PHPT do not require genetic testing.
• Genetic testing may be performed in select patients in whom a familial form of
PHPT is suspected. Current guidelines recommend genetic counseling for
Table 13.2 Differential diagnosis of hypercalcemia [8–12]
Differential
diagnosis Serum Ca Intact PTH Additional laboratory ndings
PHPT Mild-moderately
elevated
FHH Mildly elevated Normal-mildly
Hypercalcemia of
malignancy
Milk alkali
syndrome
Granulomatous
disease
Vitamin D
intoxication
Ca calcium, PTH parathyroid hormone, PHPT primary hyperparathyroidism, FHH familial hypocalciuric hypercalcemia, PTHrP parathyroid hormone-related peptide
Moderateseverely elevated
Elevated Low • Elevated HCO
Elevated Low • Elevated 1,25(OH)2 vitamin D
Elevated Low • Elevated 25-OH vitamin D
Inappropriately
normal/high
elevated
Low to undetectable • Elevated PTHrP in humoral
• Normal/high urinary ca
(>150mg/24h)
• Normal/high Ca/Cr clearance
(>0.02)
• Low urinary Ca
(<100mg/24h)
• Low Ca/Cr clearance (<0.01)
hypercalcemia of malignancy
3
13 Workup andManagement ofPrimary Hyperparathyroidism
115
patients <40years of age with PHPT and multigland disease (MGD). Genetic
counseling should be considered in patients with a family history of PHPT or
clinical ndings suspicious for MEN type 1 or 2A.
Parathyroid Imaging [8, 15, 16]
• Imaging of the parathyroids is not used to establish the diagnosis of PHPT; however, it is performed for localization, to assess for concomitant thyroid pathology,
and for surgical planning purposes.
• The parathyroid glands are typically imaged via a combination of neck ultrasound, and sestamibi-single photon emission computed tomography (SPECT)
scintigraphy or 4-dimensional computed tomography (4DCT).
• Neck ultrasound may localize parathyroid disease and assess for concomitant
thyroid disease. Parathyroid adenomas appear as ovoid-shaped, hypoechoic
structures with uniform echogenicity, echogenic capsule, and hypervascularity
on Doppler (Fig.13.3). Normal parathyroid glands are typically not visible due
to their small size.
• Parathyroid scintigraphy with 99m-technetium sestamibi and fused SPECT is a
molecular imaging approach that detects mitochondria content in parathyroid
adenomas (Fig.13.4). The combination of ultrasound and sestamibi-SPECT is
the most common localization approach for PHPT.
• Four-dimensional computed tomography (4DCT) has emerged as a highly accurate modality in selected experienced centers, with the fourth dimension referring to the pattern of contrast enhancement in parathyroid tissue over time.
Parathyroid adenomas typically demonstrate rapid contrast uptake and washout.
• The benets and limitations of common parathyroid imaging modalities are
described in Table13.3.
a
Fig. 13.3 Sagittal (a) and transverse (b) ultrasound images of a parathyroid adenoma [23]
b
116
Fig. 13.4 Parathyroid scintigraphy with 99m-technetium sestamibi depicting a left lower parathyroid adenoma [23]
Table 13.3 Comparison of parathyroid imaging modalities [8, 15, 16]
Imaging
modality Benets Limitations
Neck
ultrasound
Sestamibi
imaging
4DCT • High resolution
4DCT 4-dimensional computed tomography, BMI body mass index, MGD multigland disease
• No ionizing radiation
• Low cost
• Widely available
• Ability to assess for concomitant
thyroid disease
• Ability to assess for deep cervical
and ectopic glands
• Relatively low exposure to
ionizing radiation
• Functional data
• Can reliably identify normal
parathyroid glands
• Ultrasonographer dependent
• Limited in patients with high BMI
• Variability in characteristics of diseased
glands
• False positives from thyroid pathology
• Poor performance with MGD
• Poor performance with posterior or
low-lying gland location
• Limited resolution
• Inability to assess thyroid gland
• False positives from thyroid pathology
• Poor performance with MGD
• High cost
• Exposure to ionizing radiation
• Lack of availability
I. Suh and K. Wright
Additional Imaging [8, 17, 18]
• PHPT causes site-specic reduction in bone mineral density (BMD). Thus, all
patients with PHPT should be considered for dual-energy x-ray absorptiometry
(DEXA) imaging of the lumbar spine, hip, and distal radius.
13 Workup andManagement ofPrimary Hyperparathyroidism
117
• Patients who are otherwise asymptomatic may have silent nephrocalcinosis or
nephrolithiasis, which are indications for surgical intervention. Renal imaging
(ultrasound or CT) should be considered in all PHPT patients.
Management
Indications forSurgery [8, 19, 20]
• Denitive management of PHPT is via parathyroidectomy.
• Commonly cited consensus indications for parathyroidectomy include symptomatic (i.e., kidney stones, osteitis brosa cystica, hypercalcemic crisis, and
fractures) PHPT, as well as asymptomatic disease with serum calcium ≥1mg/dL
above normal, patient age<50years at diagnosis, or evidence of renal or skeletal
involvement (Table13.4). However, especially in light of mounting evidence on
the long-term benets of parathyroidectomy even in patients with mild or asymptomatic disease, all patients with PHPT should be considered for surgical
treatment.
Preoperative Management [8, 19]
• As described previously, patients planned for parathyroidectomy should undergo
parathyroid imaging in an attempt at localization. However, patients with negative imaging results remain candidates for parathyroidectomy.
• Localization methods may be supplemented with ne needle aspiration biopsy
with PTH measurement of the needle washout. Though this method is highly
Table 13.4 Common indications for parathyroidectomy in primary hyperparathyroidism [8]
1. Symptomatic primary hyperparathyroidism
2. Serum calcium level>1mg/dL above the upper limit of normal
3. Patients 50years of age or younger at diagnosis
4. Evidence of renal involvement:
(a) Silent nephrolithiasis on renal imaging
(b) Nephrocalcinosis
(c) Hypercalciuria (24-h urine calcium levels >400mg/dL)
(d) Impaired renal function (glomerular ltration rate<60mL/min)
5. Patients with osteoporosis (T-score<−2.5), fragility fracture, or evidence of vertebral
compression fracture on spine imaging
6. Patients with suspected parathyroid carcinoma
7. Patients who are unable to adhere to planned observation schedule
8. Patients with cardiovascular disease who may benet from mitigation of potential
cardiovascular sequelae
118
I. Suh and K. Wright
specic, it is not routinely performed outside of selected scenarios such as recurrent/reoperative disease or suspicion of an intrathyroidal parathyroid adenoma.
• Vitamin D is commonly decient in patients with PHPT and may be repleted
preoperatively.
• Restricting calcium is not recommended in PHPT as low dietary calcium can
stimulate PTH secretion and bone demineralization.
• All patients should be evaluated for voice changes or hoarseness preoperatively,
particularly those with prior neck surgery. Based on clinical suspicion, laryngeal
assessment with laryngoscopy or laryngeal ultrasound should be performed
selectively. Preexisting vocal cord paralysis puts the patient at risk for airway
compromise if the contralateral nerve is damaged intraoperatively.
Operative Approach [8, 21, 22]
• Treatment of PHPT due to parathyroid adenoma consists of resection of the
adenoma(s). In contrast, four-gland hyperplasia is treated with subtotal parathyroidectomy, during which 3.5 glands are removed and the remnant gland is left
in situ. In certain centers with the capability, a portion of resected glands can be
cryopreserved during subtotal parathyroidectomy in case reimplantation is
needed later due to hypoparathyroidism.
• Bilateral neck exploration is the historical gold-standard approach to parathyroidectomy and consists of examining each of the parathyroid glands prior to
deciding on which gland(s) to excise. In contrast, focused parathyroidectomy is
unilateral and image-directed.
• The choice of bilateral neck exploration vs focused parathyroidectomy is at the
discretion of the surgeon based on individual case features and experience.
• With improvements in preoperative imaging and availability of intraoperative
PTH (IOPTH) monitoring, focused parathyroidectomy has become the most
common surgical approach for patients with sporadic PHPT and suspected parathyroid adenoma on preoperative imaging.
• Because MGD occurs in approximately 15% of patients, focused parathyroidectomy guided solely by imaging can miss MGD and lead to higher failure rates.
Thus, IOPTH monitoring is frequently performed after resection of the suspected
adenoma to ensure all hyperfunctioning parathyroid tissue has been removed.
• Focused parathyroidectomy is not recommended for patients with non-localizing
preoperative imaging and those with suspected or at high risk of MGD (e.g.,
familial hyperparathyroidism, age<30years).
13 Workup andManagement ofPrimary Hyperparathyroidism
119
Post-Operative Outcomes andManagement [8, 19]
• Complications of parathyroidectomy include post-operative hypocalcemia and
failure to achieve cure. Rarer complications include neck hematoma and permanent vocal cord paralysis.
• Following focused parathyroidectomy, temporary hypocalcemia may result from
suppression of the other glands. During bilateral neck exploration, there is a risk
of inadvertent injury to or loss of the remaining glands resulting in a low but
existent risk of permanent hypoparathyroidism.
• Prophylactic calcium and vitamin D supplementation may be considered for all
patients undergoing parathyroidectomy. Mild post-operative hypocalcemia may
be treated with oral calcium. Patients with severe hypocalcemia may require high
doses of oral calcium, activated vitamin D analogs, and intravenous calcium
supplementation with calcium gluconate.
• Patients are typically monitored for cure and complications as an outpatient for
at least 6months post-operatively. Cure following parathyroidectomy for PHPT
is dened as normalization of calcium homeostasis at 6months and is achieved
in >97% of patients with sporadic PHPT. Failure to normalize calcium levels
6 months post-operatively may indicate operative failure possibly requiring
reoperation. PTH levels may be elevated for up to a year after a successful operation due to bone remodeling.
Non-operative Management [8, 19]
• Asymptomatic patients with PHPT who do not undergo surgery should undergo
surveillance consisting of serum calcium, creatinine, and glomerular ltration
rate (GFR) annually, and DXA examination every 1–2years.
• All patients undergoing non-operative management should receive vitamin D
repletion. Limiting calcium intake is not recommended. Additional pharmacological approaches that may be considered include bisphosphonates such as alendronate and the calcimimetic, cinacalcet.
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I. Suh and K. Wright