Tools
Normocalcemic Hyperparathyroidism
Introduction
Normocalcemic primary hyperparathyroidism (NHPT) is a relatively new classification of primary hyperparathyroidism (PHPT). The definition of NHPT is a disorder in which elevated parathyroid hormone (PTH) levels are the result of autonomous hypersecretion from 1 or more parathyroid glands, and the albumin-adjusted and ionized serum calcium levels are consistently within the normal range when measured at least twice over 6 months.[1][2][3][4] Before establishing a diagnosis of NHPT, all causes of secondary hyperparathyroidism (SHPT) must be excluded.[5][6][7][8][9]
In SHPT, the PTH elevation and parathyroid gland hyperplasia develop in response to a low serum calcium stimulus from diverse causes such as low vitamin D or chronic renal failure.[10] The PTH remains elevated as long as the low calcium stimulus persists and returns to normal as soon as it is corrected. Patients with chronic SHPT typically develop hyperplasia of all 4 parathyroid glands, which can lead to tertiary hyperparathyroidism.[10] Excluding SHPT by a thorough history, physical examination, and directed laboratory investigations is essential before diagnosing NHPT. In those with SHPT, medical treatment is directed at correcting the causes of the reduced serum calcium, which increases PTH. In contrast, the treatment of NHPT is focused on the abnormal parathyroid gland(s), which may include surgical parathyroidectomy.[7][8]
In addition to differentiating NHPT from SHPT, there is a significant overlap between NHPT and PHPT, with the latter characterized by elevated serum calcium. Many patients with NHPT go on to develop PHPT, suggesting that NHPT may be an early presentation of PHPT in some cases. Predicting which patients will develop the hypercalcemia associated with PHPT is impossible. Therefore, clinicians must continue to monitor serum calcium levels. Diagnosis and treatment of NHPT and PHPT are very similar. See StatPearls' companion reference, "Primary Hyperparathyroidism," for more information.
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
NHPT can be caused by a single adenoma, multiple adenomas, or multigland hyperplasia of the parathyroid glands, just as in the classical type of hypercalcemic PHPT. Several studies have shown an increased incidence of multigland adenomas in NHPT.[11] Radiation to the neck increases the incidence of NHPT.[12]
SHPT can be caused by vitamin D deficiency, chronic kidney disease (CKD), intestinal malabsorption syndromes, bariatric surgery, long-term reduced dietary calcium intake, and hypercalciuria.[10] In CKD, reduced vitamin D activation leads to decreased intestinal absorption of calcium. Lower levels of serum calcium then induce a secondary increase in the secretion of parathyroid hormone.[10][13] Treatment of hyperparathyroidism in CKD can include vitamin D supplements, sufficient to maintain a 25-hydroxyvitamin D level of at least 30 ng/mL, calcitriol (ie, activated vitamin D), phosphate binders, and calcimimetics to reduce PTH secretion.[10] Parathyroid surgery is sometimes necessary in patients with severe or refractory disease.[14][15] Other causes of SHPT include older anticonvulsants (eg, phenytoin and phenobarbital), celiac disease, and medications including bisphosphonates, denosumab, diuretics, and lithium. Drug-related SHPT can be verified by stopping the drug for several months and rechecking the PTH level.[10] If a drug elevated the PTH level, then levels should normalize when the medication is withheld. If PTH remains elevated, then another cause is responsible.[9][10]
In 1988, Rao et al first proposed a biphasic progression of hyperparathyroidism.[16] They suggested that PTH levels are elevated during the initial phase, but serum calcium remains within the reference range. This first phase is generally asymptomatic and was not identified as a precursor or early form of hyperparathyroidism until recently. The second phase would include hypercalcemia along with elevated PTH levels and would be considered classic PHPT.[9][16]
Other potential causes of NHPT include partial resistance to parathyroid hormone, decreased production of 1,25-dihydroxyvitamin D in older individuals, and reduced calcium-sensing receptor activation on parathyroid cells by calcium.[9] PTH levels are not generally checked in patients with normal serum calcium levels. Recently, osteoporosis and metabolic bone disease centers have become proactive in evaluating potential risk factors of skeletal disease, leading to identifying patients with NHPT.[9]
A patient with developing PHPT whose baseline calcium is initially 8.9 mg/dL may have an increase of 1 mg/dL in their calcium level to 9.9 mg/dL and PTH to a value that exceeds the upper limit of the reference range. This patient would still have a calcium level within the expected reference range for the general population but would be diagnosed with NHPT due to the PTH elevation. So, clinicians should consider individual baseline values. This fact is essential but very difficult to implement in clinical practice.[17] Another consideration is that the normal value range for PTH in a population is a Gaussian distribution curve. Therefore, approximately 2.5% of the population is expected to have PTH values just outside the upper range of normal yet not have any disease.
Epidemiology
In a recently published prospective study, NHPT comprised 15.4% of all patients with PHPT, with a higher female-to-male ratio.[18] The overall prevalence of NHPT is thought to be between 0.4% and 0.6%.[13] The incidence of asymptomatic hyperparathyroidism may be challenging to assess for the following reasons:
- Because PTH levels are not generally checked in patients with normal serum calcium levels but are more likely to be measured in those with nephrolithiasis and during the evaluation of patients with osteoporosis, a selection bias may be present.
- Different studies have used different cutoffs for 25-hydroxyvitamin D levels and estimated glomerular filtration rate (eGFR) when interpreting PTH values, and the assays have differing accuracy rates.
- Some studies have only measured the total corrected calcium without determining whether the ionized calcium is elevated.
- The lack of a large population prevents prospectively studying the natural history of NHPT.
- Some normocalcemic patients can become hypercalcemic when the calcium is measured on a different day, which changes the classification and diagnosis.[6][7][8][9][19]
Even in patients with NHPT, identifying the patients who will progress to classical PHPT and those who will maintain their normocalcemic status, and for how long, is impossible as all these scenarios have been observed. In addition, the longer the observation period, the greater the number of NHPT patients who will become hypercalcemic, suggesting NHPT may be a precursor of the classical variant. Older age and higher baseline serum and urinary calcium values are more likely to progress to classical PHPT.
Parathyroid incidentalomas were reported in some normocalcemic patients undergoing thyroid surgery.[20] Compared to patients who underwent surgical therapy for proven classical PHPT, the normocalcemic incidentaloma patients were younger and had parathyroid glands that weighed less. Biochemically and histologically, these patients secreted less PTH. The sex distribution, cell type, and disease incidence in multiple glands did not differ, which suggests that NHPT is an earlier form or precursor of classic PHPT.[20]
Pathophysiology
To differentiate it from hypercalcemic PHPT, NHPT is defined as persistently elevated parathyroid hormone levels despite normal corrected serum and ionized calcium measured at least twice over a period that spans 6 months.[4][10] Some suggested pathophysiologic mechanisms include an early form or precursor of classical PHPT, relative hypercalcemia based on an individual patient's baseline, calcium dietary deficiency, and resistance of bone and kidneys to the effects of PTH.[21]
In NHPT, the bone turnover markers and the net calcium release, measured by the urinary calcium/creatinine ratio, are lower than their hypercalcemic counterparts with similar PTH values. The renal tubules are less able to suppress phosphate and promote calcium reabsorption. Thus, for similar PTH concentrations, some patients became hypercalcemic while others did not, confirming tissue resistance to PTH in these patients.[22] A large study comparing patients with NHPT and PHPT found significantly higher levels of 25-hydroxy vitamin D and serum phosphorus in patients with NHPT than in PHPT.
Studies from parathyroid glands of NHPT patients showed similar expression of the calcium-sensing receptor (CaSR), chromogranin A, PTH, and mitotic index (Ki-67) compared to normal parathyroid glands.[23] Glands from those with hypercalcemic hyperparathyroidism had reduced expression of the CaSR. However, decreased vitamin D receptor (VDR) expression and increased cyclin D1 were observed in the glands of both normocalcemic and hypercalcemic patients.[23] Therefore, experts postulated that discordance between CaSR and either VDR or cyclin D1 could result in maintaining normocalcemia in NHPT.[23]
Furthermore, the adequacy of estrogen, even in the postmenopausal period, could reduce the effects of PTH on target tissues and contribute to maintaining normocalcemia.[22] Although PTH levels are lower than classical PHPT, the mild chronic elevation in NHPT is probably sufficient to cause PTH-induced bone resorption. Moreover, while there are conflicting data, some patients with NHPT have been reported to have higher rates of cardiovascular complications, hyperaldosteronism, hypertension, and hyperglycemia due to insulin resistance, muscle tone, and overall quality of life.[1][9]
Additionally, renal calcifications are common in NHPT. They tend to be associated with high serum PTH, increased 1,25-dihydroxy vitamin D levels, and a degree of hypercalciuria.[24] Many patients with NHPT present with nephrolithiasis, which may be silent and found only by imaging studies. Calcium oxalate stones are the most common stone type in the general population, but calcium phosphate is more likely in patients with hyperparathyroidism. The increased nephrolithiasis and bone loss rate is similar between normocalcemic and hypercalcemic patients with hyperparathyroidism.[21] The reasons for this are still unclear.[25] The vast majority of patients with hypercalciuric nephrolithiasis do not have normocalcemic hyperparathyroidism. Hypercalciuria is not consistently found in NHPT, and all patients do not develop renal stones, so other factors must be involved. Contributors to renal calculi other than hypercalciuria include the following:
History and Physical
NHPT is largely asymptomatic, but some have fractures or renal stones. Even asymptomatic patients may have abnormalities in dual-energy x-ray absorptiometry scans (DEXA) or renal ultrasounds. Elevated blood pressure and neuropsychiatric symptoms may accompany NHPT, but whether a direct relationship exists is unclear.
The clinical history should focus on possible causes of SHPT. Clinicians should inquire if any symptoms of celiac disease, gastric surgery, and other malabsorptive disorders are present. Clinicians should obtain an estimated oral calcium intake, an assessment of the risk for vitamin D deficiency, and a thorough medication history checking for any drugs that can cause SHPT. A family history of renal stones or osteoporosis in younger relatives should prompt a search for familial causes of PHPT. Rare case reports of NHPT presenting as acute parathyroid infarction or parathyroid carcinoma have been published.[31][32]
Evaluation
Laboratory Studies
In most cases, a diagnosis of NHPT is made when patients presenting with osteoporosis or renal stones are investigated proactively. In such presentations, initial investigations should include serum calcium and albumin to calculate the corrected calcium phosphorus, eGFR, 25-hydroxyvitamin D level, and urinary calcium excretion. If the corrected calcium is normal, ionized calcium must be measured before establishing a presumptive diagnosis of NHPT. The diagnosis is confirmed if laboratory studies repeated in 6 months have similar findings.[1] These results and a thorough review of the patient's medications exclude SHPT and diagnose NHPT.
The clinical picture dictates the need for other investigations, including liver function tests and serum magnesium. Some have proposed that an increased serum calcium/phosphate ratio might help identify independent parathyroid activity, but prospective studies have not validated this.[33] Two studies looking at this found very high negative predictive values for the albumin-adjusted calcium/phosphorus ratio of 88% and 95%, suggesting that this calculation may be more useful to exclude than diagnose NHPT.[33][34]
A short-term oral calcium challenge has been suggested for patients with presumed NHPT before considering surgery or other therapy. In a recent study, 55% of patients initially diagnosed with NHPT were found to normalize their PTH levels after a clinical trial of oral calcium supplementation, indicating they suffered from SHPT due to relative calcium deficiency. The same study found that 20% of study patients developed hypercalcemia with supplementation, signifying classical PHPT.[35] In complex cases, dynamic testing with a thiazide challenge test to exclude idiopathic hypercalciuria and possibly a calcium loading test to clarify the diagnosis of NHPT may be necessary.[9] When the initial tests are consistent with NHPT, the calcium and PTH must be repeated in 3 to 6 months before a diagnosis of NHPT can be confirmed.
A potentially helpful ratio in the diagnosis of NHPT is the parathyroid function index, a formula specifically designed to differentiate PHPT from SHPT due to vitamin D deficiency. The formula is serum calcium (mmol/L) x PTH (pg/mL)/phosphorus (mmol/L). The cutoff is 34, meaning a higher reading indicates PHPT, while lower results suggest SHPT from low vitamin D levels.[36] The parathyroid function index has a reported sensitivity of 96.9% and specificity of 97.6%, making it potentially very useful.[36] Additional testing in larger populations is required before the parathyroid function index can be formally recommended. Once diagnosed with NHPT, patients must be evaluated using the guidelines established for those with hypercalcemic PHPT, including 3-site DEXA and renal imaging looking for occult calcifications.[37] The following biochemical laboratory studies can be used to establish an NHPT diagnosis:
- Total serum calcium, ionized calcium, and albumin
- Corrected calcium: calculated by measured calcium + 0.8 (4.0-measured albumin)
- Serum intact PTH: second and third-generation assays may be used; third-generation may be more accurate in patients with renal failure
- Serum blood urea nitrogen (BUN) and creatinine, estimated glomerular filtration rate (eGFR): PTH rises when eGFR decreases below 60 ml/min/1.73 m2 [39]
- A 24-hour urine calcium and creatinine
- Repeated serum calcium and intact PTH: performed after a course of supplemental dietary calcium to identify patients with hyperparathyroidism secondary to calcium deficiency [35]
- Celiac disease screening: in selected patients
- Other serum tests: eg, phosphorus, alkaline phosphatase, and magnesium
- Serum 1,25-dihydroxy vitamin D: not routinely measured as levels are normal or even raised in vitamin D deficiency and PHPT
- Selective jugular venous sampling: to localize the diseased glands in rare cases [40]
Imaging Studies
The diagnosis of NHPT is made by biochemical laboratory testing, so imaging should not be used to establish the diagnosis. However, imaging modalities are useful for preoperative localization, especially if minimally invasive surgery is planned, multigland disease is suspected, or reoperation is required. Neck ultrasonography and parathyroid nuclear medicine (Tc-sestamibi) scans are standard imaging tests for the localization of hyperfunctioning parathyroid glands. However, these tests are not considered definitive because there can be false-negative results, and they are generally less helpful in multigland parathyroid disease and NHPT. They should not be ordered unless there are plans for surgery. Imaging is most useful for the surgeon as a "roadmap" in localizing enlarged, hyperfunctioning parathyroid glands.[41]
Cervical ultrasonography
Normal parathyroid glands are rarely visible in ultrasound scans; however, enlarged glands are seen as oval hypoechoic masses with a peripheral vascular ring. The parathyroid glands are seen in inferior or posterior locations to the thyroid gland and are sometimes confused with peripherally situated thyroid nodules. Ultrasound is less efficient in detecting smaller lesions, multi-gland disease, and ectopic adenomas in retro-esophageal, retro-tracheal, and mediastinal locations. Neck ultrasonography is highly operator-dependent but can be very accurate in centers with experience and expertise.
The thyroid gland should also be imaged simultaneously so that any identified abnormalities may be treated in the same surgical setting.[42] Parathyroid incidentalomas are adenomas discovered during surgery or thyroid ultrasound examinations. They are generally smaller, weigh less, and produce less PTH than adenom, causing hyperparathyroidism. Reports of ultrasound-guided fine needle biopsy are reported in the radiology literature, but the surgical guidelines on parathyroid surgery caution about several risks and sequelae. Fine needle biopsy is used almost exclusively for complex and unusual cases.[43]
Radionuclide imaging with Tc 99m sestamibi [44]
Tc 99m is a radiopharmaceutical coupled to 6, sesta meaning 6, units of methoxyisobutylisonitrile (MIBI) ligands that transport it to target organs. Tc 99m is a lipophilic cation that, when injected intravenously, distributes proportionally to blood flow. Cell composition determines the amount of absorption and is directly proportional to its mitochondrial content. Oxyphil cells are rich in mitochondria. Tc 99m is taken up by abnormal parathyroid tissue and retained. The principle behind this modality is that the Tc 99m sestamibi elutes earlier from the thyroid gland than parathyroid adenomas. A delayed scan after 1 to 4 hours will show the adenomatous parathyroid tissue with increased Tc 99m sestamibi uptake and help in its localization. The gamma rays emitted during radionuclide imaging as the isotope decays are imaged with a gamma camera.
Sestamibi scintigraphy with SPECT (single-photon emission computed tomography) adds a 3-dimensional component to the gamma camera images, improving the sensitivity of detecting enlarged parathyroid glands. An earlier washout of the nuclear material from the smaller adenomas or hyperplastic parathyroids can lead to a negative scan, as found in NHPT. In multiple adenomas, a preferential uptake and retention by 1 adenoma over the others may be a reason for not detecting other enlarged glands. Additionally, the presence of p-glycoprotein in the parathyroid cells and calcium channel blocker use are more likely to produce negative scan results.[45] Other confounders are coexisting thyroid lesions that display delayed washout and can result in a false positive scan.
Tc 99m sestamibi scanning complements ultrasound, and together, they successfully localize more lesions than either alone, but even this combination sometimes has poor concordance in NHPT.[46] While positive parathyroid scintigraphy rates are significantly less in normocalcemic than in patients with PHPT (42% vs. 81%), Tc 99m sestamibi scanning is still recommended as a valuable preoperative diagnostic tool even in NHPT.[47] When the parathyroid scan and ultrasound are negative or provide discordant results, a magnetic resonance imaging (MRI) might be considered. However, a four-dimensional computed tomography (4D-CT) scan would probably be preferred.[48][49]
Four-dimensional computed tomography
A 4D-CT scan was initially reported to have a sensitivity of 77%, but more recent studies put this higher (sensitivity 81.3%, specificity 95.5%, positive predictive value 87.1%).[2][41][50][51][52] This modality is particularly good at finding ectopic glands and has a reported 93.3% negative predictive value.[52] Compared to sestamibi scans, 4D-CT was found to have superior sensitivity for both single (92.5% versus 72/1%) and multigland (58.2% versus 30.8%) diseases. A recent meta-analysis of 26 studies comparing 4D-CT and sestamibi-SPECT/CT found 4D-CT to have higher sensitivity and specificity.[53] In the case of parathyroid reoperations, 4D-CT is particularly useful.[54]
Some studies report greater success in NHPT with 4D-CT and novel PET tracers like 11C-methionine, F18-choline, and F18-FDG, but these have to be tested in larger patient populations to be routinely recommended.[41][50][55] Problems with 4D-CT include limited availability, relatively high patient radiation exposure, and somewhat borderline specificity.[56] MRI is not generally used for parathyroid imaging, but it has been reported to have a 79.9% sensitivity in detecting parathyroid adenomas. The sensitivity increases to 91.5% when combined with ultrasound and sestamibi scans.[48] In general, ultrasound and sestamibi scans are the initial imaging procedures. Other imaging modalities should be considered if the results are negative or discordant. During surgery, near-infrared light autofluorescence to locate the parathyroids has been used with some success. More studies are needed to test this localizing modality's sensitivity, specificity, and predictive values.[57] Finally, patients with negative or equivocal scans but a biochemically confirmed diagnosis of NHPT who have indications for surgery will still need surgery by someone highly skilled in performing parathyroidectomies.
Additional imaging studies
DEXA (dual-energy x-ray absorptiometry) scans of the lumbar spine, the hip, and the distal third of the radius determine the T score based on the standard deviation compared to a young healthy adult's bone density.[58] T scores are always negative, reflecting some loss of bone mineral density over time compared to the theoretical optimal level.[58] Although a good measure of bone density, the T score does not indicate bone strength or quality. Fracture sites, arthritis, and degenerative bony changes all influence values and must be considered when interpreting the DEXA data.[58] A T score of -2.5 or lower is generally considered diagnostic of osteoporosis.[58] A trabecular bone score is the most cost-effective way of determining bone quality and is an indirect analysis of trabecular microstructure extracted from data obtained from the DEXA.[59][60] The trabecular bone score demonstrates decreased connectivity of the trabecular spinal microstructure in patients with PHPT, although this may appear normal on the DEXA scan.[60][61]
High-resolution peripheral quantitative computed tomography (HR-pQCT) has been used to study defects in bone microarchitecture even when bone density is not grossly abnormal.[62] This test is still in research settings and is not performed routinely. In NHPT, HR-pQCT may be abnormal when the lumbar spine bone mineral density is not reduced.[62]
Patients with NHPT need renal imaging with ultrasound, plain x-rays, or CT scans to screen for calcifications. Renal ultrasound will document renal size, identify hydronephrosis, and demonstrate nephrolithiasis of stones typically at least 4 mm in size. While renal ultrasound is not ideal for identifying smaller stones, the test is inexpensive, easy to perform, and readily available. The most accurate imaging for detecting renal calculi, calcifications, and nephrocalcinosis is the noncontrast renal CT scan.[29]
Treatment / Management
Medical Management
Patients without an indication for surgery can generally be followed with nonoperative surveillance. Medical therapy is appropriate for those with surgical indications but who have a high operative risk or refuse surgery. Bisphosphonates and calcimimetic medications are typically utilized in these instances. Estrogens increase bone mass density in patients with PHPT. Decisions on whether to prescribe estrogens in postmenopausal female patients must be based on the expected benefit balanced against the potential risks. The only bisphosphonate that has been tried in a study of NHPT with osteoporosis is alendronate.[63] In a study of 15 patients with osteoporosis given alendronate plus vitamin D, 15 matched controls were given vitamin D alone. After treatment, the alendronate group showed a more significant improvement in bone mass density. Serum calcium, phosphorus, and PTH levels were unchanged.[64] Further studies are needed to recommend this therapy routinely, but it can be considered for those whose only complication of NHPT is reduced bone mineral density.[64] In 2 larger, 10-year, randomized, double-blinded multinational studies involving 994 osteoporotic women, alendronate treatment significantly increased bone mineral density, which did not last when the medication was discontinued.[65](A1)
Cinacalcet, a calcimimetic drug, causes allosteric modification of the calcium-sensing receptors in the parathyroid gland and decreases parathyroid hormone secretion. In the renal tubules, cinacalcet reduces calcium reabsorption and is used in parathyroid carcinoma and SHPT due to CKD. Cinacalcet can also be used in those with intractable hypercalcemia in classical PHPT, hypercalcemic patients after failed parathyroid surgery, and those who refuse surgery or are at too high a risk for surgical intervention.[66] Cinacalcet reduces serum calcium, less so in parathyroid hormone levels, but no significant changes in bone mineral density or urinary calcium.[66] A small prospective randomized pilot study involving 10 patients treated for 10 months, which included NHPT patients, showed safety and benefit with cinacalcet in reducing the number and size of renal calculi; however, the study included relatively few patients and was unblinded.[67] More studies with larger numbers in a blinded fashion with a crossover should help address these unanswered questions.
In summary, bisphosphonates can significantly increase bone mineral density but have a relatively minimal effect on serum calcium levels. Calcimimetic agents can effectively lower serum calcium and parathyroid hormone levels but have minimal effect on bone mineral density. If patients need interventions to reduce the serum calcium and treat osteoporosis, they can be treated with cinacalcet and alendronate.
Medical management monitoring
For patients where observation is the selected course of action, periodic monitoring is required. If the hypercalcemia rises, complications develop, or PTH-related symptoms continue, then surgery is recommended.[5] Current guidelines for monitoring patients who do not meet the criteria for surgery include:(A1)
- DEXA scan of 3 sites every 1 to 2 years
- A 24-hour urine calcium excretion, if clinically indicated
- Abdominal imaging for calcifications, if clinically indicated.
- Annual serum calcium, 25-OH vitamin D, and measurement of creatinine clearance or eGFR [68]
- Vertebral x-ray as indicated
Limiting dietary calcium intake can increase parathyroid hormone levels, while supplemental calcium can reduce these.[5][69] The consensus opinion among experts is that dietary calcium intake should follow normal nutritional guidelines. Vitamin D should be supplemented if the 25-hydroxyvitamin D is <30 ng/mL based on studies showing that vitamin D can lower blood parathyroid hormone and improve bone mineral density without significantly increasing serum or urinary calcium levels.[5][70](A1)
Operative Management
Parathyroid surgery is the only definitive treatment for normocalcemic or hypercalcemic PHPT.[15][71][72] Minimally invasive surgical techniques have been developed for this procedure.[73] No known medical treatments can fully reproduce the benefits of a successful parathyroid surgery.[72] Some studies have shown bone mineral density (BMD) improvement after parathyroidectomy.(A1)
The recommendations and indications for parathyroid surgery by the expert panel on Asymptomatic Primary Hyperparathyroidism, including patients aged younger than 50 years, osteoporosis, creatinine clearance <60 ml/min, urinary calcium >300 mg/24 hours in men and >250 mg/24 hours in women, and nephrolithiasis, can be equally applied to NHPT.[5][72][74] Parathyroid surgery performed by experienced parathyroid surgeons tends to have higher success rates, lower complications, and shorter hospital stays.[43] (A1)
Although the risk for recurrent renal calculi is not eliminated, the risk is substantially decreased, and renal function is preserved.[62] The recurrence rate of nephrolithiasis and nephrocalcinosis can be further reduced by performing a 24-hour urine test for kidney stone prevention and optimizing any remaining risk factors.[30] There is not enough evidence yet to attribute any benefit of parathyroid surgery in improving neuropsychiatric symptoms or cardiovascular problems.[5](A1)
Intraoperative PTH monitoring with a rapid assay using the Miami criterion of a 50% drop from baseline to check for completeness of removal of abnormal parathyroid tissue has been tested in NHPT patients and found to be equally predictive as in PHPT.[11] The intraoperative gamma probe relies on tracer retention of >20% in diseased glands and can be used for monitoring. However, this probe is inferior to intraoperative PTH and needs specialized equipment and personnel that are not always available at all centers. The most common surgical finding is a single adenoma, but encountering multiple parathyroid adenomas is more common in normocalcemic (12%) than in hypercalcemic (4%) hyperparathyroidism.[11] There is also a higher rate of reoperation in NHPT.[75](B2)
Differential Diagnosis
SHPT presents with a similar biochemical picture and must be carefully excluded before establishing a diagnosis of NHPT.[10] Causes of SHPT include:
- Calcium deficiency
- Chronic kidney disease
- Hypercalciuria
- Increased fibroblast growth factor-23 with hypophosphatemia
- Malabsorptive disorders
- Bariatric surgery
- Celiac disease
- Inflammatory bowel disease
- Medications
- Anticonvulsants (phenytoin, phenobarbital)
- Bisphosphonates
- Denosumab
- Diuretics
- Lithium
- Obesity
- Paget disease of bone
- Vitamin D deficiency
SHPT caused by hypocalcemia due to hypercalciuria can result from high sodium intake, excess tea or coffee consumption, and loop diuretics like furosemide.[10] A thorough history will exclude these causes. Genetic defects causing hypercalciuria are rare and can be detected by genetic testing.[76]
A thiazide challenge test has been reported to help differentiate PHPT from hypercalciuria. In the thiazide challenge test, 50 mg of hydrochlorothiazide is given orally every day for 2 weeks. Thiazides will decrease urinary calcium excretion, so a patient with SHPT due to hypercalciuria will have a reduction of urinary calcium excretion and decreased or normalized PTH, while a patient with NHPT is likely to become hypercalcemic with only minimal or no reduction in their PTH levels.[77] An oral calcium loading test may help clarify the diagnosis of NHPT in difficult cases. A single 1 g dose of oral calcium is given, and serum calcium and PTH values are measured at regular intervals from 0 to 120 minutes. In patients with NHPT, there is only minimum suppression of PTH from baseline, whereas, in normal individuals and SHPT, there is a marked decrease.[78] Calcium loading can also be done intravenously, and the measurements made.[79] The ratio of the decrease in PTH (which usually happens in 80 to 120 minutes and parallels the increase in calcium after loading) and the baseline PTH is termed the PTH inhibition rate (PTH-IR). The change in calcium levels from baseline to peak concentration after loading is termed the delta calcium. The ratio of these 2 calculated values was used in a study to differentiate the various types of hyperparathyroidism and was also recommended as a test to decide when PTH secretion becomes autonomous in SHPT due to CKD.[10][79] These results are preliminary and need to be confirmed in large-scale studies.[79]
Causes of vitamin D deficiency include inadequate sunlight exposure, diets poor in vitamin D, lack of fortified foods, conditions producing malabsorption including bariatric surgical procedures, various medications that accelerate vitamin D metabolis. High-risk populations include older adults, malnourished children, pregnant and lactating women, and patients with chronic kidney disease, especially in the early stages.[80] Importantly, patients with PHPT may have a coexisting vitamin D deficiency, which masks their hypercalcemia. They would then present with normocalcemic hyperparathyroidism. Depending on the degree of vitamin D deficiency, they may be asymptomatic or present with bone pain, myalgia, and proximal muscle weakness. After the correction of their vitamin D deficiency, hypercalcemia is unmasked. They should then be managed as PHPT patients. They should maintain a normal calcium intake and take vitamin D supplements to achieve and maintain 25-hydroxyvitamin D levels greater than 30 ng/mL.[80][81][82][83]
Lithium can desensitize the parathyroid calcium-sensing receptor to serum calcium, shifting the setpoint to the right, increasing the release of PTH.[84][85] Lithium can unmask and also cause classical PHPT.[86] Single PTH-producing parathyroid adenomas, as well as multigland disease, have been reported with long-term lithium use.[86] Cinacalcet has been shown to be effective in managing lithium-associated hyperparathyroidism.[86][87]
Normocalcemic Primary Hyperparathyroidism and Secondary Hyperparathyroidism in Chronic Renal Disease Differentiation
NHPT can closely mimic SHPT in patients with chronic renal disease. Additionally, PHPT can certainly occur in patients with renal failure and reduced GFR (<60 mL/min), further complicating their differentiation. NHPT requires the elimination of all other causes of hyperparathyroidism, making it difficult or even impossible to differentiate between these 2 diagnoses in CKD when the GFR is less than 60 mL/min. NHPT and SHPT from chronic renal failure may actually be describing the same pathological entity. Notable differences include:
- Patients with PHPT are more likely to have overt hypercalcemia than those with SHPT.
- Vitamin D levels are typically normal or elevated in NHPT but reduced in SHPT from chronic renal disease.
- Serum phosphate is typically low in NHPT but elevated in SHPT from chronic renal disease.
- The parathyroid function index serum calcium (mmol/L) x PTH (pg/mL)/phosphorus (mmol/L) is more than 34 in NHPT and less than 34 in SHPT from chronic renal disease.
- The serum calcium/phosphate ratio tends to be elevated in NHPT but reduced in SHPT from chronic renal disease.
- Serum phosphate levels are likely reduced in NHPT but elevated in SHPT from renal failure.
Prognosis
Surgically managed patients with NHPT generally do well; they avoid complications and increase bone mineral density.[92] The newer minimally invasive surgical parathyroid procedures are less intrusive, with shorter operating times and fewer complications.[71][73] Intraoperative monitoring of serum PTH levels has yielded better outcomes.[71][93] However, even with experienced surgeons, operative failure or early recurrence does occur, given the difficulty in localizing smaller adenomas and a greater incidence of multiple parathyroid adenomas in NHPT. A decrease of PTH of more than 50% from baseline is usually a reliable indicator of surgical success during surgery.[94]
High normal serum calcium, high urinary calcium, and advanced age have been shown to favor progression to classic hypercalcemic PHPT.[6] Current guidelines for monitoring patients with hyperparathyroidism include annual measurement of serum calcium, 25-hydroxyvitamin D, and creatinine clearance with DXA scans repeated every 1 to 2 years.[5] Abdominal imaging and 24-hour urine for calcium should be ordered if clinically indicated.[5]
Complications
Patients with NHPT are more likely to have multigland disease than those with classic hypercalcemic hyperparathyroidism; therefore, they are more likely to require bilateral neck exploration. While uncommon when performed by experienced parathyroid surgeons, complications of parathyroidectomy include injury to the recurrent laryngeal nerve, wound hematoma, and postoperative hypocalcemia.[15] Patients with NHPT undergoing parathyroid surgery tended to have an increased rate of reoperation that is more than double the rate of hypercalcemic patients with PHPT and are more likely to develop permanent hypocalcemia postoperatively (11.4% versus 1.4%).[95] About 25% of patients with NHPT may have nephrolithiasis or nephrocalcinosis.[24][96][97] Those individuals who are not surgical candidates need to be monitored for the development of hypercalcemia and are at risk of developing renal calcifications as well as losing bone mineral density.[9]
Consultations
Specialties that may need to be involved in caring for patients with NHPT include:
- Endocrinology
- Endocrine surgery (otolaryngologists or endocrine surgeons)
- Gastroenterology
- Nuclear medicine
- Radiology
- Urology
Deterrence and Patient Education
Patients with NHPT should be taught in simple language the autonomous nature of the parathyroids in NHPT and the implications of a raised PTH. When surgical treatment is suggested, clinicians should discuss all options with patients with explanations using anatomic models, video lessons of the actual surgery, possible postoperative complications, recovery periods, and a simplified but comprehensive explanation of the technology used.
Patients with NHPT selected for surveillance must receive education on the importance of periodic monitoring, the risks of developing hypercalcemia, the potential complications of parathyroid hormone excess, and the methods to ensure adequate calcium and vitamin D intake. Those requiring treatment with antiresorptive medications need careful instruction on dosage, administration, side effects, therapy duration, follow-up frequency, and required surveillance tests. The health literacy of the individuals involved should be considered in formulating a patient education plan.
Pearls and Other Issues
Key factors to bear in mind when managing NHPT include:
- NHPT is a recognized phenotype and a possible early precursor of PHPT.
- The diagnosis requires both normal ionized and corrected calcium levels measured at least twice over 6 months.
- The diagnosis of NHPT demands the meticulous exclusion of all other possible causes of SHPT.
- The most common causes of SHPT are renal insufficiency with an eGFR <60 ml/min and vitamin D deficiency.
- NHPT and SHPT, when related to chronic renal failure, may be the same disorder.
- A clinical trial of oral calcium supplementation has been suggested for all patients diagnosed with NHPT before starting therapy or considering surgery. This will normalize PTH levels in patients with calcium deficiencies, resulting in SHPT.
- Although asymptomatic for the most part, NHPT is not always an indolent condition.
- Several studies have shown that NHPT can cause end-organ damage even when maintaining normocalcemia.
- Frequent presentations include osteoporosis, osteopenia, nephrolithiasis, and, in some instances, fractures.
- In NHPT, the parathyroid glands are generally smaller, are more likely to involve multiple glands and secrete less PTH than hypercalcemic patients with PHPT.
- A lower secretion of PTH and resistance to its action in the bone and kidneys may explain the maintenance of normocalcemia.
- A trial of oral calcium supplementation should be undertaken before initiating any long-term therapy or surgery for NHPT to evaluate for relative hypocalcemia.
- Some NHPT patients progress to develop overt hypercalcemia, but predicting which ones will progress or when is impossible, so regular follow-up is mandatory.
- Ultrasound and nuclear scans are localizing procedures if surgery is planned but do not have any role in diagnosing NHPT.
- A 4D-CT scan has greater sensitivity in identifying abnormal glands than ultrasound or nuclear scans.
- Indications for surgery are similar to classical PHPT and equally successful in improving bone mineral density and reducing renal problems.
- Serial observation is the rule for patients not willing to undergo or requiring immediate parathyroid surgery or with an unacceptably high surgical risk, with appropriate action taken as needed.
Enhancing Healthcare Team Outcomes
The primary care clinicians should utilize the appropriate laboratory tests to diagnose and differentiate SHPT from NHPT, refer difficult or doubtful cases to the endocrinologist, and coordinate with other specialists as indicated. The radiologist, nuclear medicine physician, and surgeons will need a thorough history, especially what medications the patient takes, any previous surgical procedures, allergies, and the reason for the tests. Each of them will be able to counsel patients appropriately for necessary testing, suggest possible or better alternatives, provide the correct interpretation, and communicate this to the treating physician. Gastroenterologists and bariatric surgeons should be knowledgeable about SHPT and ensure collaboration with endocrinologists in preventing and treating the condition. Endocrine and high-volume parathyroid surgeons (eg, otolaryngologists and endocrine surgeons) tend to have better outcomes.
Parathyroid surgeons should communicate the indications for parathyroidectomy, discuss the pros and cons of various procedures, anticipate complications, and coordinate pre and postoperative medical management with endocrinologists. A close working relationship with the laboratory personnel is paramount when performing intraoperative PTH monitoring. Pharmacists identify correct dosage, drug interactions, contraindications, and signs of toxicity and communicate effectively with endocrinologists and other clinicians. Nurses are skilled in the early identification of complications. They also play an essential part in patient education and instruction. They help prepare patients for various investigations while counseling and allaying concerns, fears, and anxieties. Nurses also provide critical pre and postoperative care and promptly communicate patient condition changes with physicians.
References
Zavatta G, Clarke BL. Normocalcemic Primary Hyperparathyroidism: Need for a Standardized Clinical Approach. Endocrinology and metabolism (Seoul, Korea). 2021 Jun:36(3):525-535. doi: 10.3803/EnM.2021.1061. Epub 2021 Jun 1 [PubMed PMID: 34107603]
Islam AK. Advances in the diagnosis and the management of primary hyperparathyroidism. Therapeutic advances in chronic disease. 2021:12():20406223211015965. doi: 10.1177/20406223211015965. Epub 2021 Jun 11 [PubMed PMID: 34178298]
Level 3 (low-level) evidenceBollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjær T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P, 2021 PARAT Working Group. European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders. European journal of endocrinology. 2022 Feb 1:186(2):R33-R63. doi: 10.1530/EJE-21-1044. Epub 2022 Jan 13 [PubMed PMID: 34863037]
Level 3 (low-level) evidenceBilezikian JP, Khan AA, Potts JT Jr, Third International Workshop on the Management of Asymptomatic Primary Hyperthyroidism. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. The Journal of clinical endocrinology and metabolism. 2009 Feb:94(2):335-9. doi: 10.1210/jc.2008-1763. Epub [PubMed PMID: 19193908]
Bilezikian JP, Khan AA, Silverberg SJ, Fuleihan GE, Marcocci C, Minisola S, Perrier N, Sitges-Serra A, Thakker RV, Guyatt G, Mannstadt M, Potts JT, Clarke BL, Brandi ML, International Workshop on Primary Hyperparathyroidism. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2293-2314. doi: 10.1002/jbmr.4677. Epub 2022 Oct 17 [PubMed PMID: 36245251]
Level 1 (high-level) evidenceEl-Hajj Fuleihan G, Chakhtoura M, Cipriani C, Eastell R, Karonova T, Liu JM, Minisola S, Mithal A, Moreira CA, Peacock M, Schini M, Silva B, Walker M, El Zein O, Marcocci C. Classical and Nonclassical Manifestations of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2330-2350. doi: 10.1002/jbmr.4679. Epub 2022 Oct 17 [PubMed PMID: 36245249]
Level 2 (mid-level) evidenceApplewhite MK, White MG, Tseng J, Mohammed MK, Mercier F, Kaplan EL, Angelos P, Vokes T, Grogan RH. Normohormonal primary hyperparathyroidism is a distinct form of primary hyperparathyroidism. Surgery. 2017 Jan:161(1):62-69. doi: 10.1016/j.surg.2016.03.038. Epub 2016 Nov 17 [PubMed PMID: 27866715]
Cusano NE, Silverberg SJ, Bilezikian JP. Normocalcemic primary hyperparathyroidism. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2013 Jan-Mar:16(1):33-9. doi: 10.1016/j.jocd.2012.12.001. Epub [PubMed PMID: 23374739]
Shaker JL, Wermers RA. The Eucalcemic Patient With Elevated Parathyroid Hormone Levels. Journal of the Endocrine Society. 2023 Feb 9:7(4):bvad013. doi: 10.1210/jendso/bvad013. Epub 2023 Jan 26 [PubMed PMID: 36793479]
Muppidi V, Meegada SR, Rehman A. Secondary Hyperparathyroidism. StatPearls. 2024 Jan:(): [PubMed PMID: 32491754]
Trinh G, Rettig E, Noureldine SI, Russell JO, Agrawal N, Mathur A, Prescott JD, Zeiger MA, Tufano RP. Surgical Management of Normocalcemic Primary Hyperparathyroidism and the Impact of Intraoperative Parathyroid Hormone Testing on Outcome. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2018 Oct:159(4):630-637. doi: 10.1177/0194599818793879. Epub 2018 Aug 14 [PubMed PMID: 30105919]
Rao SD, Frame B, Miller MJ, Kleerekoper M, Block MA, Parfitt AM. Hyperparathyroidism following head and neck irradiation. Archives of internal medicine. 1980 Feb:140(2):205-7 [PubMed PMID: 7352815]
Palermo A, Naciu AM, Tabacco G, Falcone S, Santonati A, Maggi D, D'Onofrio L, Briganti SI, Castellitto D, Casini A, Pedone C, Lelli D, Fabbri A, Bilezikian JP, Napoli N, Pozzilli P, Manfrini S, Cesareo R. Clinical, Biochemical, and Radiological Profile of Normocalcemic Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2020 Jul 1:105(7):. pii: dgaa174. doi: 10.1210/clinem/dgaa174. Epub [PubMed PMID: 32271382]
Pokhrel B, Leslie SW, Levine SN. Primary Hyperparathyroidism. StatPearls. 2024 Jan:(): [PubMed PMID: 28722924]
Wang Y, Ladie DE. Parathyroidectomy. StatPearls. 2024 Jan:(): [PubMed PMID: 33085421]
Rao DS, Wilson RJ, Kleerekoper M, Parfitt AM. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. The Journal of clinical endocrinology and metabolism. 1988 Dec:67(6):1294-8 [PubMed PMID: 3192682]
Bilezikian JP. Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2018 Nov 1:103(11):3993-4004. doi: 10.1210/jc.2018-01225. Epub [PubMed PMID: 30060226]
Gómez-Ramírez J, Gómez-Valdazo A, Luengo P, Porrero B, Osorio I, Rivas S. Comparative prospective study on the presentation of normocalcemic primary hyperparathyroidism. Is it more aggressive than the hypercalcemic form? American journal of surgery. 2020 Jan:219(1):150-153. doi: 10.1016/j.amjsurg.2019.10.032. Epub 2019 Oct 22 [PubMed PMID: 31662196]
Level 2 (mid-level) evidencePawlowska M, Cusano NE. An overview of normocalcemic primary hyperparathyroidism. Current opinion in endocrinology, diabetes, and obesity. 2015 Dec:22(6):413-21. doi: 10.1097/MED.0000000000000198. Epub [PubMed PMID: 26512768]
Level 3 (low-level) evidenceCarnaille BM, Pattou FN, Oudar C, Lecomte-Houcke MC, Rocha JE, Proye CA. Parathyroid incidentalomas in normocalcemic patients during thyroid surgery. World journal of surgery. 1996 Sep:20(7):830-4; discussion 834 [PubMed PMID: 8678958]
Cusano NE, Cipriani C, Bilezikian JP. Management of normocalcemic primary hyperparathyroidism. Best practice & research. Clinical endocrinology & metabolism. 2018 Dec:32(6):837-845. doi: 10.1016/j.beem.2018.09.009. Epub 2018 Sep 28 [PubMed PMID: 30665550]
Maruani G, Hertig A, Paillard M, Houillier P. Normocalcemic primary hyperparathyroidism: evidence for a generalized target-tissue resistance to parathyroid hormone. The Journal of clinical endocrinology and metabolism. 2003 Oct:88(10):4641-8 [PubMed PMID: 14557434]
Yang AH, Hsu CW, Chen JY, Tseng LM, Won GS, Lee CH. Normocalcemic primary hyperparathyroidism in patients with recurrent kidney stones: pathological analysis of parathyroid glands. Virchows Archiv : an international journal of pathology. 2006 Jul:449(1):62-8 [PubMed PMID: 16670929]
Victor F, Pereira Lemos AL, de Holanda Ribas AM, Bandeira L, Pimentel JH, de Andrade Damázio LO, Bandeira F. Occult Renal Calcifications in Patients with Normocalcemic Primary Hyperparathyroidism and Their Association with the Parathyroid Hormone-Vitamin D Axis. International journal of endocrinology. 2022:2022():4558236. doi: 10.1155/2022/4558236. Epub 2022 Apr 8 [PubMed PMID: 35437440]
Dawood NB, Yan KL, Shieh A, Livhits MJ, Yeh MW, Leung AM. Normocalcaemic primary hyperparathyroidism: An update on diagnostic and management challenges. Clinical endocrinology. 2020 Nov:93(5):519-527. doi: 10.1111/cen.14315. Epub 2020 Sep 15 [PubMed PMID: 32803770]
Leslie SW, Bashir K. Hypocitraturia and Renal Calculi. StatPearls. 2024 Jan:(): [PubMed PMID: 33232062]
KC M, Leslie SW. Uric Acid Nephrolithiasis. StatPearls. 2024 Jan:(): [PubMed PMID: 32809561]
Shah A, Leslie SW, Ramakrishnan S. Hyperoxaluria. StatPearls. 2024 Jan:(): [PubMed PMID: 32644413]
Leslie SW, Sajjad H, Murphy PB. Renal Calculi, Nephrolithiasis. StatPearls. 2024 Jan:(): [PubMed PMID: 28723043]
Leslie SW, Sajjad H, Bashir K. 24-Hour Urine Testing for Nephrolithiasis: Interpretation and Treatment Guidelines. StatPearls. 2024 Jan:(): [PubMed PMID: 29494055]
Gosavi A, Kulkarni M, Sulhyan K, Agashe S. An unusual presentation of parathyroid adenoma--a case report. Indian journal of pathology & microbiology. 2005 Apr:48(2):208-10 [PubMed PMID: 16758668]
Level 3 (low-level) evidenceCampennì A, Ruggeri RM, Sindoni A, Giovinazzo S, Calbo E, Ieni A, Calbo L, Tuccari G, Baldari S, Benvenga S. Parathyroid carcinoma presenting as normocalcemic hyperparathyroidism. Journal of bone and mineral metabolism. 2012 May:30(3):367-72. doi: 10.1007/s00774-011-0344-y. Epub 2012 Jan 14 [PubMed PMID: 22246083]
Level 3 (low-level) evidenceMadeo B, De Vincentis S, Repaci A, Altieri P, Vicennati V, Kara E, Vescini F, Amadori P, Balestrieri A, Pagotto U, Simoni M, Rochira V. The calcium-to-phosphorous (Ca/P) ratio in the diagnosis of primary hyperparathyroidism and hypoparathyroidism: a multicentric study. Endocrine. 2020 Jun:68(3):679-687. doi: 10.1007/s12020-020-02276-7. Epub 2020 Mar 31 [PubMed PMID: 32236819]
Madeo B, Kara E, Cioni K, Vezzani S, Trenti T, Santi D, Simoni M, Rochira V. Serum Calcium to Phosphorous (Ca/P) Ratio Is a Simple, Inexpensive, and Accurate Tool in the Diagnosis of Primary Hyperparathyroidism. JBMR plus. 2018 Mar:2(2):109-117. doi: 10.1002/jbm4.10019. Epub 2017 Nov 2 [PubMed PMID: 30283895]
Baugh KA, McCoy KL, Leung JH, Carty SE, Ramonell KM, Yip L. Normocalcemic hyperparathyroidism: Intervention to differentiate primary from secondary hyperparathyroidism. Surgery. 2024 Jan:175(1):166-171. doi: 10.1016/j.surg.2023.06.056. Epub 2023 Nov 18 [PubMed PMID: 37981554]
Guo Y, Wang Q, Lu C, Fan P, Li J, Luo X, Chen D. New parathyroid function index for the differentiation of primary and secondary hyperparathyroidism: a case-control study. BMC endocrine disorders. 2020 Jan 8:20(1):5. doi: 10.1186/s12902-019-0487-8. Epub 2020 Jan 8 [PubMed PMID: 31914999]
Level 2 (mid-level) evidenceKhan AA, Bilezikian JP, Brandi ML, Clarke BL, Gittoes NJ, Pasieka JL, Rejnmark L, Shoback DM, Potts JT, Guyatt GH, Mannstadt M. Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Dec:37(12):2568-2585. doi: 10.1002/jbmr.4691. Epub 2022 Nov 14 [PubMed PMID: 36054621]
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2011 Jul:96(7):1911-30. doi: 10.1210/jc.2011-0385. Epub 2011 Jun 6 [PubMed PMID: 21646368]
Level 1 (high-level) evidenceKidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney international. Supplement. 2009 Aug:(113):S1-130. doi: 10.1038/ki.2009.188. Epub [PubMed PMID: 19644521]
Level 1 (high-level) evidenceTaslakian B, Trerotola SO, Sacks B, Oklu R, Deipolyi A. The Essentials of Parathyroid Hormone Venous Sampling. Cardiovascular and interventional radiology. 2017 Jan:40(1):9-21. doi: 10.1007/s00270-016-1481-4. Epub 2016 Oct 28 [PubMed PMID: 27796535]
Fiz F, Bottoni G, Massollo M, Trimboli P, Catrambone U, Bacigalupo L, Righi S, Treglia G, Imperiale A, Piccardo A. [18F]F-Choline PET/CT and 4D-CT in the evaluation of primary hyperparathyroidism: rivals or allies? The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.... 2023 Jun:67(2):130-137. doi: 10.23736/S1824-4785.23.03514-8. Epub [PubMed PMID: 37232932]
Sung JY. Parathyroid ultrasonography: the evolving role of the radiologist. Ultrasonography (Seoul, Korea). 2015 Oct:34(4):268-74. doi: 10.14366/usg.14071. Epub 2015 Apr 6 [PubMed PMID: 25971897]
Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, Doherty GM, Herrera MF, Pasieka JL, Perrier ND, Silverberg SJ, Solórzano CC, Sturgeon C, Tublin ME, Udelsman R, Carty SE. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA surgery. 2016 Oct 1:151(10):959-968. doi: 10.1001/jamasurg.2016.2310. Epub [PubMed PMID: 27532368]
Hindié E, Zanotti-Fregonara P, Tabarin A, Rubello D, Morelec I, Wagner T, Henry JF, Taïeb D. The role of radionuclide imaging in the surgical management of primary hyperparathyroidism. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2015 May:56(5):737-44. doi: 10.2967/jnumed.115.156018. Epub 2015 Apr 9 [PubMed PMID: 25858040]
Friedman K, Somervell H, Patel P, Melton GB, Garrett-Mayer E, Dackiw AP, Civelek AC, Zeiger MA. Effect of calcium channel blockers on the sensitivity of preoperative 99mTc-MIBI SPECT for hyperparathyroidism. Surgery. 2004 Dec:136(6):1199-204 [PubMed PMID: 15657576]
Level 2 (mid-level) evidenceKiriakopoulos A, Petralias A, Linos D. Classic Primary Hyperparathyroidism Versus Normocalcemic and Normohormonal Variants: Do They Really Differ? World journal of surgery. 2018 Apr:42(4):992-997. doi: 10.1007/s00268-018-4512-2. Epub [PubMed PMID: 29392434]
Gungor S, Dede F, Can B, Keskin H, Aras M, Ones T, Erdil TY, Turoglu HT. The value of parathyroid scintigraphy on lesion detection in patients with normocalcemic primary hyperparathyroidism. Revista espanola de medicina nuclear e imagen molecular. 2022 Mar-Apr:41(2):86-90. doi: 10.1016/j.remnie.2020.12.007. Epub 2021 Jan 2 [PubMed PMID: 35292143]
Kluijfhout WP, Venkatesh S, Beninato T, Vriens MR, Duh QY, Wilson DM, Hope TA, Suh I. Performance of magnetic resonance imaging in the evaluation of first-time and reoperative primary hyperparathyroidism. Surgery. 2016 Sep:160(3):747-54. doi: 10.1016/j.surg.2016.05.003. Epub 2016 Jun 16 [PubMed PMID: 27318765]
Hillyar CR, Rizki H, Begum R, Gupta A, Nagabhushan N, Lee PH, Smith S. A Retrospective Cohort Study of the Utility of Ultrasound, 99mTc-Sestamibi Scintigraphy, and Four-Dimensional Computed Tomography for Pre-Operative Localization of Parathyroid Disease To Facilitate Minimally Invasive Parathyroidectomy. Cureus. 2022 Jan:14(1):e21177. doi: 10.7759/cureus.21177. Epub 2022 Jan 12 [PubMed PMID: 35165625]
Level 2 (mid-level) evidenceCunha-Bezerra P, Vieira R, Amaral F, Cartaxo H, Lima T, Montarroyos U, Bandeira F. Better performance of four-dimension computed tomography as a localization procedure in normocalcemic primary hyperparathyroidism. Journal of medical imaging and radiation oncology. 2018 Apr 15:():. doi: 10.1111/1754-9485.12728. Epub 2018 Apr 15 [PubMed PMID: 29656552]
Hamidi M, Sullivan M, Hunter G, Hamberg L, Cho NL, Gawande AA, Doherty GM, Moore FD Jr, Nehs MA. 4D-CT is Superior to Ultrasound and Sestamibi for Localizing Recurrent Parathyroid Disease. Annals of surgical oncology. 2018 May:25(5):1403-1409. doi: 10.1245/s10434-018-6367-z. Epub 2018 Feb 26 [PubMed PMID: 29484563]
Naqvi SHS, Brooks KA, Knackstedt MI, Eguia AA, Low GM, Jacks AE, Asi KW, Patino MO, Friedman ER, Karni RJ. 4D-CT facilitates focused parathyroidectomy in patients with primary hyperparathyroidism by maintaining a high negative-predictive value for uninvolved quadrants. American journal of otolaryngology. 2020 Nov-Dec:41(6):102683. doi: 10.1016/j.amjoto.2020.102683. Epub 2020 Aug 15 [PubMed PMID: 32862032]
Kattar N, Migneron M, Debakey MS, Haidari M, Pou AM, McCoul ED. Advanced Computed Tomographic Localization Techniques for Primary Hyperparathyroidism: A Systematic Review and Meta-analysis. JAMA otolaryngology-- head & neck surgery. 2022 May 1:148(5):448-456. doi: 10.1001/jamaoto.2022.0271. Epub [PubMed PMID: 35357400]
Level 1 (high-level) evidenceCruz-Centeno N, Longoria-Dubocq T, Mendez-Latalladi W. Efficacy of 4D CT Scan in Re-operative Parathyroid Surgery. The American surgeon. 2022 Jul:88(7):1549-1550. doi: 10.1177/00031348221083938. Epub 2022 Mar 25 [PubMed PMID: 35337197]
Zajíčková K, Zogala D, Kubinyi J. Parathyroid imaging by (18)F-fluorocholine PET/CT in patients with primary hyperparathyroidism and inconclusive conventional methods: clinico-pathological correlations. Physiological research. 2018 Nov 28:67(Suppl 3):S551-S557 [PubMed PMID: 30484682]
Wan QC, Li JF, Tang LL, Lv J, Xie LJ, Li JP, Qin LP, Cheng MH. Comparing the diagnostic accuracy of 4D CT and 99mTc-MIBI SPECT/CT for localizing hyperfunctioning parathyroid glands: a systematic review and meta-analysis. Nuclear medicine communications. 2021 Mar 1:42(3):225-233. doi: 10.1097/MNM.0000000000001331. Epub [PubMed PMID: 33306636]
Level 2 (mid-level) evidenceParas C, Keller M, White L, Phay J, Mahadevan-Jansen A. Near-infrared autofluorescence for the detection of parathyroid glands. Journal of biomedical optics. 2011 Jun:16(6):067012. doi: 10.1117/1.3583571. Epub [PubMed PMID: 21721833]
Sheu A, Diamond T. Bone mineral density: testing for osteoporosis. Australian prescriber. 2016 Apr:39(2):35-9. doi: 10.18773/austprescr.2016.020. Epub 2016 Apr 1 [PubMed PMID: 27340320]
Goel H, Binkley N, Hans D, Leslie WD. Fracture risk gradient assessed by categories of bone mineral density and trabecular bone score: the Manitoba BMD Registry. Archives of osteoporosis. 2023 May 22:18(1):73. doi: 10.1007/s11657-023-01284-0. Epub 2023 May 22 [PubMed PMID: 37213026]
Rajan R, Cherian KE, Kapoor N, Paul TV. Trabecular Bone Score-An Emerging Tool in the Management of Osteoporosis. Indian journal of endocrinology and metabolism. 2020 May-Jun:24(3):237-243. doi: 10.4103/ijem.IJEM_147_20. Epub 2020 Jun 30 [PubMed PMID: 33083262]
Silva BC, Boutroy S, Zhang C, McMahon DJ, Zhou B, Wang J, Udesky J, Cremers S, Sarquis M, Guo XD, Hans D, Bilezikian JP. Trabecular bone score (TBS)--a novel method to evaluate bone microarchitectural texture in patients with primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2013 May:98(5):1963-70. doi: 10.1210/jc.2012-4255. Epub 2013 Mar 22 [PubMed PMID: 23526463]
Level 2 (mid-level) evidenceKhan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L, Thakker R, D'Amour P, Paul T, Van Uum S, Shrayyef MZ, Goltzman D, Kaiser S, Cusano NE, Bouillon R, Mosekilde L, Kung AW, Rao SD, Bhadada SK, Clarke BL, Liu J, Duh Q, Lewiecki EM, Bandeira F, Eastell R, Marcocci C, Silverberg SJ, Udelsman R, Davison KS, Potts JT Jr, Brandi ML, Bilezikian JP. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2017 Jan:28(1):1-19. doi: 10.1007/s00198-016-3716-2. Epub 2016 Sep 9 [PubMed PMID: 27613721]
Level 3 (low-level) evidenceWilkins Parker LR, Preuss CV. Alendronate. StatPearls. 2024 Jan:(): [PubMed PMID: 30252329]
Cesareo R, Di Stasio E, Vescini F, Campagna G, Cianni R, Pasqualini V, Romitelli F, Grimaldi F, Manfrini S, Palermo A. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2015 Apr:26(4):1295-302. doi: 10.1007/s00198-014-3000-2. Epub 2014 Dec 19 [PubMed PMID: 25524023]
Level 1 (high-level) evidenceBone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, Alendronate Phase III Osteoporosis Treatment Study Group. Ten years' experience with alendronate for osteoporosis in postmenopausal women. The New England journal of medicine. 2004 Mar 18:350(12):1189-99 [PubMed PMID: 15028823]
Level 1 (high-level) evidenceJunaid SZS, Patel JB. Cinacalcet. StatPearls. 2024 Jan:(): [PubMed PMID: 32491590]
Brardi S, Ponchietti R, Duranti E. [Nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: focus on calciomimetics]. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2016 Nov-Dec:33(6):. pii: gin/33.6.4. Epub [PubMed PMID: 28134399]
Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. The Journal of clinical endocrinology and metabolism. 2014 Oct:99(10):3561-9. doi: 10.1210/jc.2014-1413. Epub 2014 Aug 27 [PubMed PMID: 25162665]
Jorde R, Szumlas K, Haug E, Sundsfjord J. The effects of calcium supplementation to patients with primary hyperparathyroidism and a low calcium intake. European journal of nutrition. 2002 Dec:41(6):258-63 [PubMed PMID: 12474069]
Level 1 (high-level) evidenceRolighed L, Rejnmark L, Sikjaer T, Heickendorff L, Vestergaard P, Mosekilde L, Christiansen P. Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial. The Journal of clinical endocrinology and metabolism. 2014 Mar:99(3):1072-80. doi: 10.1210/jc.2013-3978. Epub 2014 Jan 13 [PubMed PMID: 24423366]
Level 1 (high-level) evidenceNabata KJ, Wiseman JJ, Wiseman SM. Normohormonal primary hyperparathyroidism: A systematic review and meta-analysis. American journal of surgery. 2023 Aug:226(2):186-196. doi: 10.1016/j.amjsurg.2023.04.004. Epub 2023 Apr 19 [PubMed PMID: 37100740]
Level 1 (high-level) evidenceKulkarni P, Goldenberg D. Surgery for Normocalcemic Hyperparathyroidism. Otolaryngologic clinics of North America. 2024 Feb:57(1):111-116. doi: 10.1016/j.otc.2023.07.012. Epub 2023 Aug 25 [PubMed PMID: 37634986]
Wolfe SA, Fingeret A. Parathyroid Minimally Invasive Surgery. StatPearls. 2024 Jan:(): [PubMed PMID: 29939611]
Bilezikian JP, Silverberg SJ, Bandeira F, Cetani F, Chandran M, Cusano NE, Ebeling PR, Formenti AM, Frost M, Gosnell J, Lewiecki EM, Singer FR, Gittoes N, Khan AA, Marcocci C, Rejnmark L, Ye Z, Guyatt G, Potts JT. Management of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2391-2403. doi: 10.1002/jbmr.4682. Epub 2022 Oct 17 [PubMed PMID: 36054638]
Pandian TK, Lubitz CC, Bird SH, Kuo LE, Stephen AE. Normocalcemic hyperparathyroidism: A Collaborative Endocrine Surgery Quality Improvement Program analysis. Surgery. 2020 Jan:167(1):168-172. doi: 10.1016/j.surg.2019.06.043. Epub 2019 Sep 19 [PubMed PMID: 31543325]
Level 2 (mid-level) evidenceViviani A, Colangelo L, Ciminelli BM, Novelletto A, Sonato C, Occhiuto M, Cipriani C, Diacinti D, De Martino V, Gianni W, Pepe J, Minisola S, Malaspina P. Genetic aspects underlying the normocalcemic and hypercalcemic phenotypes of primary hyperparathyroidism. Endocrine. 2023 Dec:82(3):646-653. doi: 10.1007/s12020-023-03476-7. Epub 2023 Aug 31 [PubMed PMID: 37651007]
Souberbielle JC, Cavalier E, Cormier C. How to manage an isolated elevated PTH? Annales d'endocrinologie. 2015 May:76(2):134-41. doi: 10.1016/j.ando.2015.03.005. Epub 2015 Apr 13 [PubMed PMID: 25882890]
Invernizzi M, Carda S, Righini V, Baricich A, Cisari C, Bevilacqua M. Different PTH response to oral peptone load and oral calcium load in patients with normocalcemic primary hyperparathyroidism, primary hyperparathyroidism, and healthy subjects. European journal of endocrinology. 2012 Oct:167(4):491-7. doi: 10.1530/EJE-12-0362. Epub 2012 Aug 7 [PubMed PMID: 22872468]
Level 1 (high-level) evidenceZhu X, Shan C, Zhu Q, Song L, Zhou Y, Liu J, Zhang K. Clinical value of calcium load test in differential diagnosis of different types of hyperparathyroidism. International journal of clinical and experimental medicine. 2014:7(12):5445-52 [PubMed PMID: 25664054]
Sizar O, Khare S, Goyal A, Givler A. Vitamin D Deficiency. StatPearls. 2024 Jan:(): [PubMed PMID: 30335299]
Shah VN, Shah CS, Bhadada SK, Rao DS. Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature. Clinical endocrinology. 2014 Jun:80(6):797-803. doi: 10.1111/cen.12398. Epub 2014 Jan 28 [PubMed PMID: 24382124]
Level 1 (high-level) evidenceDas G, Eligar V, Govindan J, Bondugulapati LN, Okosieme O, Davies S. Impact of vitamin D replacement in patients with normocalcaemic and hypercalcaemic primary hyperparathyroidism and coexisting vitamin D deficiency. Annals of clinical biochemistry. 2015 Jul:52(Pt 4):462-9. doi: 10.1177/0004563214564400. Epub 2014 Dec 2 [PubMed PMID: 25468998]
Level 2 (mid-level) evidenceSilverberg SJ. Vitamin D deficiency and primary hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007 Dec:22 Suppl 2():V100-4. doi: 10.1359/jbmr.07s202. Epub [PubMed PMID: 18290710]
Haissaguerre M, Vantyghem MC. What an endocrinologist should know for patients receiving lithium therapy. Annales d'endocrinologie. 2022 Aug:83(4):219-225. doi: 10.1016/j.ando.2022.01.001. Epub 2022 Jan 21 [PubMed PMID: 35074396]
Lerena VS, León NS, Sosa S, Deligiannis NG, Danilowicz K, Rizzo LFL. Lithium and endocrine dysfunction. Medicina. 2022:82(1):130-137 [PubMed PMID: 35037871]
Pattan V, Singh B, Abdelmoneim SS, Gopinath C, Sundaresh V. Lithium-Induced Hyperparathyroidism: An Ill-defined Territory. Psychopharmacology bulletin. 2021 Jun 1:51(3):65-71 [PubMed PMID: 34421145]
Craus S, Mifsud EL, Mifsud S, Vella S. Management of lithium-associated hyperparathyroidism with cinacalcet hydrochloride. British journal of hospital medicine (London, England : 2005). 2023 Jan 2:84(1):1-3. doi: 10.12968/hmed.2022.0330. Epub 2023 Jan 3 [PubMed PMID: 36708345]
Corbetta S. Normocalcemic Hyperparathyroidism. Frontiers of hormone research. 2019:51():23-39. doi: 10.1159/000491036. Epub 2018 Nov 19 [PubMed PMID: 30641527]
Schini M, Jacques RM, Oakes E, Peel NFA, Walsh JS, Eastell R. Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History. The Journal of clinical endocrinology and metabolism. 2020 Apr 1:105(4):e1171-86. doi: 10.1210/clinem/dgaa084. Epub [PubMed PMID: 32072184]
Rodríguez-Ortiz ME, Rodríguez M. Recent advances in understanding and managing secondary hyperparathyroidism in chronic kidney disease. F1000Research. 2020:9():. pii: F1000 Faculty Rev-1077. doi: 10.12688/f1000research.22636.1. Epub 2020 Sep 1 [PubMed PMID: 32913635]
Level 3 (low-level) evidenceYuen NK, Ananthakrishnan S, Campbell MJ. Hyperparathyroidism of Renal Disease. The Permanente journal. 2016 Summer:20(3):15-127. doi: 10.7812/TPP/15-127. Epub 2016 Jul 22 [PubMed PMID: 27479950]
Lui MS, Perrier ND. Parathyroidectomy for Normocalcemic Primary Hyperparathyroidism Improves Bone Mineral Density Regardless of Postoperative Parathyroid Hormone Levels. World journal of surgery. 2023 Mar:47(3):830-831. doi: 10.1007/s00268-022-06877-3. Epub 2023 Jan 9 [PubMed PMID: 36622434]
Pereira C. Role of intraoperative parathyroid hormone in guiding parathyroidectomy. Acta bio-medica : Atenei Parmensis. 2023 Apr 24:94(2):e2023040. doi: 10.23750/abm.v94i2.13998. Epub 2023 Apr 24 [PubMed PMID: 37092630]
Trinh G, Noureldine SI, Russell JO, Agrawal N, Lopez M, Prescott JD, Zeiger MA, Tufano RP. Characterizing the operative findings and utility of intraoperative parathyroid hormone (IOPTH) monitoring in patients with normal baseline IOPTH and normohormonal primary hyperparathyroidism. Surgery. 2017 Jan:161(1):78-86. doi: 10.1016/j.surg.2016.10.001. Epub 2016 Nov 15 [PubMed PMID: 27863787]
Ramonell KM, Lindeman B, Chen H, Fazendin J. Parathyroidectomy for Normocalcemic Tertiary Hyperparathyroidism: A 19-Year Experience. The Journal of surgical research. 2022 Aug:276():362-368. doi: 10.1016/j.jss.2022.02.011. Epub 2022 Apr 13 [PubMed PMID: 35429685]
Lemos ALP, Andrade SRL, Pontes LLH, Teixeira PMC, Bandeira E, Bandeira LC, Bandeira F. High Rate of Occult Urolithiasis in Normocalcemic Primary Hyperparathyroidism. Kidney & blood pressure research. 2019:44(5):1189-1195. doi: 10.1159/000502578. Epub 2019 Sep 20 [PubMed PMID: 31542783]
Wu KCJ, Anpalahan M. Normocalcaemic primary hyperparathyroidism: is nephrolithiasis more common than osteoporosis? Internal medicine journal. 2023 Jan:53(1):112-118. doi: 10.1111/imj.15502. Epub 2022 Jul 19 [PubMed PMID: 34435736]