Approach

Parathyroid surgery is the definitive treatment for primary hyperparathyroidism (PHPT). It is indicated for all symptomatic patients, and is recommended for many asymptomatic patients.[1][2]​​[30]​​​ If the patient is asymptomatic and meets criteria for medical management, declines surgery, or is not a surgical candidate, monitoring is an option.[2][12]

Symptomatic; or asymptomatic with surgical indications

Parathyroidectomy is indicated for all patients with symptomatic hyperparathyroidism.[1][2]​​​​[58]​​[30]​​ Parathyroidectomy is recommended in patients with asymptomatic hyperparathyroidism with evidence of subclinical target organ complications such as bone disease (osteoporosis/fractures) or renal involvement (reduced kidney function, occult stones) and in those at risk of disease progression.[1][2]​​​[30]​​​

In asymptomatic patients with PHPT, advantages of surgery are that it corrects the underlying abnormality, and may improve bone mineral density and inferred fracture-free survival.[59][60]​​​​[61][62]​​ Such findings have been observed in older individuals, reinforcing the case that surgery can be considered in older people with indications.[63]

Patients who are considered to be asymptomatic sometimes report improvements in quality of life following surgery.[28] However, the benefits of parathyroidectomy for non-skeletal/renal outcomes symptoms remains controversial.[58][64][65] [ Cochrane Clinical Answers logo ] ​​​

Indications for surgery in asymptomatic patients, according to some authorities, include:[1]​​[2][12]​​​​

  • Age <50 years

  • Serum calcium >0.25 mmol/L (>1 mg/dL) above normal range

  • Creatinine clearance <60 mL/minute

  • Bone mineral density (BMD) T-score <-2.5 at lumbar spine, total hip, femoral neck, or distal third of radius, and/or vertebral fracture by x-ray, computed tomography (CT), magnetic resonance imaging (MRI), or vertebral fracture assessment (VFA) using dual-energy x-ray absorptiometry (DXA; T-score compares BMD versus the optimal density of a 30- to 40-year-old healthy adult and then assesses the fracture risk)

  • Urinary calcium >250 mg/day in women or >300 mg/day in men

  • Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or CT.

Pre-operative preparation includes adequate hydration and pre-operative localisation tests. Dietary restriction of calcium is not advised, and pre-operative vitamin D replacement is recommended for patients who are vitamin D deficient. Subjective assessment of voice quality is also recommended pre-operatively.[2]

Parathyroidectomy can often be performed on an outpatient basis with same-day discharge. It generally has morbidity and mortality rates of ≤1%.​[66] Potential significant complications include bleeding, haematoma, hoarseness from recurrent laryngeal nerve injury, voice change from superior laryngeal nerve injury, pneumothorax, or hypocalcaemia (transient or permanent).

When imaging studies are positive for location of a solitary adenoma (occurring in approximately 85% of patients with PHPT), the patient is a candidate for a focused or minimally-invasive, directed parathyroidectomy.[67] In people with multiple-gland disease (sporadic or familial), complete cervical exploration with identification of all 4 glands and subtotal resection of parathyroid tissue is the surgical approach.[68] Rarely, the hypercalcaemia of hyperparathyroidism may be severe (>3.5 mmol/L [>14 mg/dL]); for example, in patients with parathyroid carcinoma). These patients require pre-operative medical management for acute severe hypercalcaemia, such as intravenous fluids and furosemide.

If patients decline surgery or are not surgical candidates, serum calcium, vitamin D, and creatinine clearance should be measured every 12 months and bone density measured every 1 to 2 years.​[1]​​ Patients with vitamin D deficiency should be offered supplementation.[1]​ Patients should avoid medications that increase serum calcium levels (e.g., thiazide diuretics, lithium). If symptoms of mental status change or lethargy occur, admission for intravenous hydration and a parathyroidectomy should ensue, if possible. A definitive parathyroidectomy can be performed at any point if the patient agrees and is a surgical candidate.

Bisphosphonates or cinacalcet are adjunctive therapies that may be considered, in addition to monitoring, for patients who do not undergo parathyroidectomy.[1][59][60]​​

  • Bisphosphonates may increase BMD in the lumbar spine at 1 to 2 years and decrease bone turnover, although fracture outcomes are not available.[69][70]​ They may be considered in patients with low BMD and increased risk of fracture.[1]

  • Cinacalcet has been shown to lower serum calcium and serum intact parathyroid hormone (PTH).[70][71] It is a calcimimetic that modulates the activity of the calcium-sensing receptor, the principal regulator of serum intact PTH secretion. Cinacalcet binds to the transmembrane region of the receptor and induces a conformational change that increases the receptor's sensitivity to calcium. The most common adverse effects, nausea and vomiting, lead to poor tolerance and must be monitored very closely. Resulting volume depletion may worsen hypercalcaemia. Previously approved for management of difficult-to-treat secondary hyperparathyroidism and inoperable parathyroid carcinoma, it may now be used in selected cases of primary hyperparathyroidism; for example, in those who are symptomatic but not surgical candidates or who decline surgery.[1][59][60]​​

Surgical approach

Once the diagnosis is confirmed and surgery planned, pre-operative imaging is important to provide accurate localisation of the disease. Given the significant regional variation in imaging accuracy, candidates for parathyroidectomy should be referred to an expert clinician to decide on the best imaging modalities based on their knowledge of local imaging availability.[2][33][34][35] Combining tests is more effective than any one test alone.

Selective parathyroid venous sampling has been suggested as a useful tool in patients with inconclusive preoperative non-invasive imaging, although its invasive nature precludes routine use.[72]

The success rate for surgeons who perform fewer than 10 parathyroidectomies per year is lower than for surgeons with more experience; an inverse correlation exists between volume of operations and risk of complications and length of hospital stay. Therefore, it is recommended that parathyroidectomies are only carried out by surgeons with adequate training and experience specific to PHPT management.[2]

When investigations are positive for location of a solitary adenoma (occurring in approximately 85% of patients with PHPT), the patient is a candidate for a focused or minimally invasive, directed parathyroidectomy.[2][67]​ Compared with 4-gland (bilateral) exploration, a minimally-invasive approach appears to have similar recurrence, persistence, and re-operation rates, but lower overall complication rates and somewhat shorter operative times.[73] The lower rate of complications seen with minimally-invasive surgery relates primarily to a reduced risk of transient postoperative hypocalcaemia and a lower risk of recurrent laryngeal nerve injury due to reduced dissection.[74][66]​ The minimally-invasive procedure may be performed under general or local anaesthesia and various techniques, including video-assisted, endoscopic, radio-guided, or a focused lateral approach.

Intra-operative serum intact PTH serves to inform the operating surgeon that hyperfunctioning tissue has been removed.[75] A decline of >50% from baseline to 5 minutes and 10 minutes post-excision suggests adequate removal of hyperfunctioning tissue.[76] Intra-operative parathyroid hormone monitoring reduces the risk of missing multiple-gland disease during minimally-invasive parathyroidectomy. The cure rate for minimally-invasive parathyroidectomy has been reported to be 97% to 99%, and there is probably an added marginal increase in cure rate in experienced hands.[2]

Intra-operative adjuncts are complementary to pre-operative localisation and assist in localising parathyroid glands, confirming parathyroid tissue and establishing remission. The most widely used surgical adjunct is intra-operative parathyroid hormone monitoring (IOPTH). Other adjuncts can assist with confirmation of resected parathyroid tissue (frozen section analysis, ex vivo parathyroid aspiration), gland visualisation (methylene blue, near infrared fluorescence, or infrared spectroscopy), and gland localisation (intra-operative ultrasonography, bilateral jugular venous sampling, or gamma-probe guidance).[2]

In people with multiple-gland disease (sporadic or familial), complete bilateral cervical exploration with identification of all 4 glands and subtotal resection of parathyroid tissue is the surgical approach.[68] It is also the recommended approach when pre-operative imaging is non-localising or discordant, or when intra-operative parathyroid hormone monitoring is not available.[2] Indications for converting from a minimally-invasive approach to complete cervical exploration are the intra-operative discovery of multiple-gland disease, and failure to achieve an adequate decrease in intra-operative parathyroid hormone levels.[2] Complete cervical exploration has long-term success rates of over 95% when carried out by a skilled endocrine surgeon.[77][78]

If there is suspicion of parathyroid carcinoma during surgery, complete dissection avoiding capsular disruption is recommended and improves the chance of cure. This may involve en bloc resection of adjacent adherent tissue.[2]

Asymptomatic without surgical indications

Patients without specific indications for surgery may be monitored, but there is some epidemiological evidence to suggest that even mild/asymptomatic primary hyperparathyroidism may be associated with multiple negative outcomes, including overall mortality and cardiovascular disease, that in turn may be linked to high baseline parathyroid hormone concentrations.[79][80]

In patients being monitored, serum calcium, vitamin D, and creatinine clearance should be measured every 12 months and bone density measured every 1 to 2 years.​[1]​ Patients should avoid medications that increase serum calcium levels (i.e., thiazide diuretics, lithium). A definitive parathyroidectomy can be performed at any point if symptoms or indications ensue, or if the patient prefers surgery and is a surgical candidate.

Vitamin D repletion in patients with concurrent vitamin D deficiency

Vitamin D supplementation is recommended for patients with PHPT and concurrent vitamin D deficiency.[2][12][1][30]​​​ Definitions for deficiency vary. The Fifth International Workshop on Primary Hyperparathyroidism recommends maintaining levels of >75 nmol/L (>30 ng/mL).[1]​​ Low levels of vitamin D appear to be associated with a greater severity of bone disease in PHPT, and with a greater risk of hungry bone syndrome following parathyroidectomy.[81]​​

Vitamin D replacement may improve bone mineral density in patients with PHPT but the evidence is not conclusive.[82]​​[83]​ A concern is that repleting vitamin D will worsen hypercalcaemia and renal calcium excretion in patients with PHPT.

One systematic review and meta-analysis looking at vitamin D repletion in patients with mild PHPT found that supplementation improved serum 25-hydroxyvitamin D level without worsening of pre-existing hypercalcaemia or hypercalciuria.[84] However, an observational study of 21 patients with mild PHPT treated with vitamin D found that while treatment did not result in a mean increase in serum calcium concentrations across the treatment group, 2 patients experienced an increase in urinary calcium excretion to >400 mg/day. This suggests that some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion. In one patient, serum calcium increased from 2.6 mmol/L to 3.0 mmol/L (10.5 mg/dL to 11.9 mg/dL).[85]​​

On balance, the authors recommend replacement of vitamin D in the setting of deficiency. However, in patients with raised urinary calcium levels, due to a risk of kidney stone formation, caution is recommended to monitor urinary calcium excretion, particularly if parathyroidectomy is not planned during a shorter time frame. Specific treatment regimens based on clinical trial data are not yet available.

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