Introduction and methods
What is the natural history of PHPT with or without parathyroid surgery?
Presentation
Skeletal involvement
Renal involvement
Non-classical manifestations of PHPT
International presentations of PHPT (Table 1)
Overall Incidence/Prevalence | Incidence/Prevalence In Women | Incidence/Prevalence In Men | Comments | |
---|---|---|---|---|
Canada [53] | 0.86% General Population 0.4-3.1% | 34-120 (Mean: 66) * 196 (70–79 Yrs) 3.3% | 13-36 (Mean: 25) * 95 (70–79 Yrs) 1.4% | Higher incidence in Blacks than Caucasians than Asians Predominant presentation: asymptomatic disease 74% postmenopausal |
1.07% 9.95 * Hospitalisation for PHPT: 8.3/100’000 | 1.6% | 0.3% | Increase of prevalence over time Surgery proposed: 32% (Italy), 66% (Spain), 64% (France), 53% (UK) | |
Latin America | 0.78% | Asymptomatic disease: 47-82% (18-44% kidney stones) (6.1% osteitis fibrosa cystica) 90% postmenopausal | ||
60% with radiological signs, 40% kidney stones Asymptomatic disease 20% before 2006 to 50% in 2007-2010 | ||||
Asia – India | Asymptomatic disease: <5% Predominant presenting features: skeletal and renal complications, as well as anemia. Resistance to erythropoietin. Improvement of anemia after PTx. Higher prevalence of GI tract symptoms than in the rest of the world. PTx in >80-90% of PHPT |
Diagnosis and imaging
How is primary hyperparathyroidism diagnosed today?
What is the role of preoperative imaging in PHPT?
99mTc-sestamibi scintigraphy
Washout scintigraphy using a single isotope
Subtraction scintigraphy
Ultrasound of parathyroid glands
11C-Methionine PET/CT scintigraphy
Magnetic resonance imaging
Conventional CT
Selective venous sampling with PTH measurement
Management and treatment
What is the role of surgery in PHPT?
Who should have surgery?
1) Age <50 years. |
2) Serum calcium > 1 mg/dL or >0.25 mmol/L of the upper limit of the reference interval for total calcium and >0.12 mmol/L for Ca2+. |
3) BMD T-score ≤−2.5 at the lumbar spine, femoral neck, the total hip, or the 1/3 radius for postmenopausal women or males >50 yrs. A prevalent low-energy fracture (i.e., in the spine) is also considered an indication for surgery, which requires a routine X-ray of the thoracic and lumbar spine (or vertebral fracture assessment by DXA). |
4) A glomerular filtration rate (GFR) of <60 ml/min. Further evaluation of asymptomatic patients with renal imaging (X-ray, CT or ultrasound) in order to detect silent kidney stones or nephrocalcinosis is advised [2]. A complete urinary stone risk profile should be performed in those individuals whose urinary calcium excretion is > 400 mg/day. If stone(s), nephrocalcinosis, or high stone risk is determined, surgery should be recommended. |
Younger and older populations
Indications for minimally invasive parathyroidectomy
Who should be monitored without surgery and what are the medical options?
Vitamin D
Antiresorptive therapy
Lead author, year | Study design | Patient n | Therapy | Duration Tx | Serum calcium (mmol/L) | Baseline Vit D | BMD | PTH | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Lumbar spine %Δ | Femoral neck %Δ | Total hip %Δ | Radial %Δ | ||||||||
Schmidli, 1990 [111] | Single-blind, placebo controlled, randomized cross-over | 10 | Pamidronate 30 mg or saline infusion | Single infusion, repeated 1–5 weeks post PTx | 2.49±0.0 post ADP vs 2.70±0.062
| NA | NA | NA | NA | NA | 56 ng/L increase |
Reasner, 1993 [112] | Open label (dose blinded) | 19 | Risedronate | 20mg or 40mg/d for one week; repeated after three weeks off | −0.16±2.6; transient rose off Tx | NA | NA | NA | NA | NA | +35 ng/L3; transient rise with decline in Ca+ |
Rossini, 2001 [113] | RCT | 26 | Alendronate 10mg every other day vs no Tx | 24 months | Tx: Transient fall in Ca+, P, UCa+ from 3–6 months | NA | Tx: 8.6±3.0% | NA | Tx: 4.8±3.9% increase | NA | Tx: 13±29% increase after 2 yrs |
Parker, 2002 [114] | Open-label, controlled | 32 | Alendronate 10mg/d | 24 months | No significant change | NA | 7.3±1.7%4
| NA | NA | NA | No significant change |
Chow, 2003 [115] | Double-blinded, RCT | 40 | Alendronate 10mg/d or PBO | 48 w Tx, withdrawal 24 w | −0.09 vs 0.012
| 41.4 nmol.L | 3.79±4.04% vs 0.19±2.80%3
| 4.17±6.01% vs 0.25±3.35%3
| NA | No significant change | No significant change |
Khan, 2009 [116] | Double-blinded, RCT | 9 | Alendronate 10mg/d | 12 months | NA | NA | 4.4%4
| NA | 2.95%3
| 2.13% | No significant change |
Khan, 2004 [117] | Double-blinded, RCT | 44 | Alendronate 10mg/d vs PBO | 2 years; in 2nd yr PBO cross-over to alendronate | No significant change | 46 nmol.L | 6.85±0.94% after 2 yr in Tx group4
| 3.67±1.63% after 2 yr in Tx group3
| 4.01±0.77% after 2 yr in Tx group4
| No significant change | No significant change |
Cinacalcet
Author | Study design | Patient n | Duration of treatment (months) (range) | Final daily dose (mg) (range) | Serum calcium (mg/dL) | Plasma PTH (pg/mL) | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Basal | Final | P | % change | Basal (IQR) | Final (IQR) | P | % change | |||||
Sajid-Corckett et al. [124] | Retrospective chart review | 18 | 8 (1–19) | Median 60 (30–90) | 10.6±0.5 | 9.5±0.3 | <0.001 | −10.8 | 141±78 | 108±64 | 0.007 | −22.9 |
Iglesias et al. [125] | Prospective data collection | 4 | 12 | 60 | 10.8±0.6 c
| 9.5±0.2 c
| NA | −10.2 | 196±83 c
| 191±95 c
| NA | −5.1 |
Arranz Martin et al. [126] | Prospective open label | 17 | 9.4±6.4 | 30-60 | 11.5±0.6 | 9.9±0.9 | <0.001 | −13.9 | 144 (99,82) | 119 (86,167) | <0.001 | −17.4 |
Faggiano et al. [122] | Retrospective data collection | 13 | 12 d
| 30-90 | 11±0.2 c
| 9.7±0.1 c
| NA | −11.8 | 122±14 | 92±12 | NA | −25.4 |
Cetani et al. [127] | Prospective, open label | 6 | Median 12 (3–21) | Median 60 (30–120) | 12.2± 1.2 | 9.7±1.2 | 0.002 | −20.4 | 249±245 | 188±131 | 0.19 | −24.5 |
Filopanti et al. [128] | Prospective, open label | 20 | 3 d
| Median (30–60) | 11.7±0.5 | 9.5±0.4 | <0.001 | −11.8 | 181±115 | 121±39 | 0.032 | −29.8 |
Luque-Fernandez et al. [129] | Prospective, open label | 20 | 12 d
| Mean 60 (30–180) | 11.7±0.8 | 10.2±0.9 | <0.001 | −12.8 | 182±102 | 152±70 | 0.028 | −16.0 |
Saponaro et al. [130] | Retrospective data collection | 100 | Median 9 (1–26) | 15-120 | 11.6±1.1 | 10.2±0.9 | <0.001 | −12% | 164 (109,254)e
| 127 (91,200)e
| 0.038 | −22.5 |
Khan et al. [123] | Double blinded, RCT | 67 | Tx: 5.83 (0.7-7.0) | Mean Tx: 82.7 (17–212) | Tx: 11.7±0.5 | NA | <0.001 | Tx: −15.2% | Tx: 158 (121–186) | NA | <0.001 | Tx: −23.8% |
PBO: 5.83 (0.0-6.7) | Mean PBO: 177 (6–228) | PBO: 11.8±0.5 | NA | PBO: −1.66% | PBO: 167 (136–248) | NA | PBO: −1.0% |
A. Diagnosis
|
1. Confirmed if serum calcium is elevated (total calcium corrected for albumin or elevated ionized calcium) in the presence of an elevated or inappropriately normal PTH in the absence of conditions mimicking PHPT (thiazide diuretics or lithium) and FHH. |
2. FHH – Three variants now identified. Confirmed by DNA analysis of CaSR gene, Gα11 gene or AP2S1 genes. Suspected if CaCrCR <0.01. However in 20% of FHH cases CaCrCR can overlap with PHPT and is 0.01-0.02. |
3. Consider familial PHPT in children and adults <35 years of age and DNA analysis (MEN1 gene, RET oncogene, HRPT2 gene) in the presence of: |
a. Family History of hypercalcemia |
b. Prior unsuccessful parathyroid surgery in patient or relative |
c. Hypercalcemia identified at young age (<25yrs) in patient or relative |
d. Absence of symptoms of hypercalcemia |
e. CaCrCR <0.02 |
B. Imaging: |
1. Imaging is not used for the diagnosis of PHPT, which is based on biochemical profile. |
2. Identification of abnormal parathyroid tissue is enhanced with single photon emission computed tomography (SPECT) study in combination with a computed tomography (CT) study and is particularly valuable in repeat surgical cases. |
3. Ultrasound, 99m Tc-sestamibi scintigraphy continue to be useful localization tools, however, they can miss small adenomas and hyperplasia. |
4. Additional imaging or localization tools for those failing surgery or suspected of having an ectopic parathyroid gland include CT scans, MRI (Magnetic Resonance Imaging), 11C-Methionine PET/CT Parathyroid Scintigraphy. Selective venous sampling should only be performed when required for remedial exploration. |
C. Presentation: |
1. In developed countries – approximately 85% of patients present with asymptomatic disease. Twenty % present with renal complications (kidney stones, nephrocalcinosis), skeletal complications (fracture, osteitis fibrosa cystica, bone pain) or symptomatic hypercalcemia. |
2. In developing countries the majority of patients present with symptomatic disease. |
D. Indications for Parathyroid Surgery
|
1. All symptomatic PHPT |
2. Asymptomatic PHPT – surgery is a valuable option particularly in those meeting criteria for surgical intervention. |
E. Medical Management
|
1. Vitamin D deficiency/insufficiency should be corrected and is effective in lowering serum PTH without further elevating serum calcium. Correct serum 25OHD to >50nmol/L. |
2. Amino-bisphosphonates are effective in preventing decreases in BMD and lowering bone remodelling. |
3. Cinacalcet is effective in lowering serum calcium and should be considered for symptomatic PHPT when surgery is not an option. Amino-bisphosphonates may be used in combination with cinacalcet in selected patients. |
4. Data with medical therapy currently is short-term and insufficient to justify medical therapy as an alternative to surgery. There is no fracture data with any of the existing medical therapies. |