Approach

In the US and Europe, most instances of hyperparathyroidism are detected incidentally when routine laboratory tests are done.[1]​ Hypercalcemia and primary hyperparathyroidism (PHPT) are only rarely diagnosed clinically, and the definitive diagnosis relies on laboratory tests.[6]​ In resource-poor countries, the majority of patients present with symptoms.[6]

History and physical examination

Initial assessment should include both a detailed personal and family history.[2] PHPT is 2 to 3 times more common in women than in men.[6] Prevalence increases with age and is especially common in postmenopausal women.[6]

Symptoms of PHPT are most likely not to be related to hypercalcemia itself and instead relate to its effect on key target organs.[28]​ Medical history may reveal a history of skeletal (e.g., osteopenia or osteoporosis) or renal (e.g., kidney stones) involvement.[1]​ There may also be a family history of hyperparathyroidism or, where this was undiagnosed, a family history of conditions suggestive of hypercalcemia or other endocrine gland involvement.[2] Other features such as neuropsychological symptoms (overt neuromuscular dysfunction is now uncommon), cardiovascular disease abnormalities, or gastrointestinal symptoms are considered to be non-specific.​[6]

The following nonspecific features are most common:

  • Fatigue

  • Poor sleep

  • Myalgias

  • Anxiety

  • Depression

  • Memory loss

Gastrointestinal symptoms that can be attributed to hypercalcemia, such as anorexia, nausea, vomiting, constipation, and abdominal pain (such as from pancreatitis), are now uncommon and are rarely linked to PHPT.[1][28]

Non-specific symptoms that may have been previously attributed to other disorders or aging may be attributed to hyperparathyroidism once it is diagnosed. Surgical cure may lead to apparent resolution of symptoms; patients who are considered to be asymptomatic sometimes report improvements in quality of life following surgery.[29]

Physical exam of the neck is usually unremarkable. A palpable neck mass is rare in benign parathyroid disorders, but may be present in up to 70% of patients with parathyroid carcinoma.[3]​​

Laboratory

Diagnosis of PHPT is confirmed with repeat simultaneously matched measurements of serum calcium and serum intact parathyroid hormone (PTH). Repeat measurements are required given that patients with PHPT may occasionally have temporarily normal calcium levels despite being hypercalcemic most of the time.[2] If the patient is being treated with thiazide diuretics, medication should be stopped 2 weeks before calcium measurements. During blood drawing, venous stasis should be avoided to ensure accurate results. Serum calcium levels should be adjusted for the serum albumin concentration.[2][12]​ This is done by adding 0.8 mg/dL (0.20 mmol/L) to the total serum calcium level for every 1 g/dL (10 g/L) the serum albumin concentration is <4 g/dL (40 g/L).

Serum intact PTH (entire 84-amino acid sequence) is measured by the immunoradiometric or immunochemical assay. Of note, if the serum intact PTH level is normal with hypercalcemia, hyperparathyroidism is not excluded, since it is the appropriateness of the PTH level relative to the calcium level that is relevant.[6]

Patients with normocalcemic PHPT have normal serum and ionized calcium levels. Therefore, a normal ionized calcium is necessary to establish the diagnosis of normocalcemic PHPT, but not hypercalcemic PHPT.[2]

The 25-hydroxyvitamin D level should also be assessed because a low vitamin D may lead to a physiologically compensatory elevated PTH level that normalizes on the repletion of the vitamin.[2][12][30]

Alkaline phosphatase levels are not necessary for diagnosis, but they might help in determining the extent of the bone disease. Preoperative elevated alkaline phosphatase levels predict postoperative hypocalcemia following parathyroidectomy.

Serum phosphorous levels might be in the lower range of normal, indicating concomitant electrolyte shifts. Patients with PHPT may have a low or low-normal blood phosphorus level.

In patients with presumed hyperparathyroidism, urinary calcium measurements should be performed with a 24-hour measurement of urinary creatinine and calcium.[2][12]​​​ Hypercalciuria is a marker of renal involvement in PHPT. International PHPT guidelines recommend a urinary calcium level of >250 mg/day in women; >300 mg/day in men as an indication for parathyroidectomy, although the UK National Institute for Health and Care Excellence do not recommend referral for surgery based on urinary calcium measurements.[1][31]​​ Familial hypocalciuric hypercalcemia (FHH) can often be differentiated from PHPT by measuring the renal calcium to creatinine excretion ratio, which generally is much lower in patients with FHH than in patients with PHPT due to other causes. FHH should be considered in patients with long-standing hypercalcemia with urinary calcium levels <100 mg/day, and a calcium to creatinine clearance ratio less than 0.01.[2] FHH can be confirmed with genetic testing.[5]

Radiographic studies

The diagnosis of PHPT is based on biochemical parameters. Parathyroid localization studies serve no purpose in diagnosis, but represent a guide to the operating surgeon once the decision has been made to proceed with parathyroidectomy.[32] These studies should not be a surrogate for diagnosis of PHPT and are often deferred to the surgeon to order based on their preference and local hospital's expertise.

In surgical management, preoperative imaging is used to help localize the suspected adenoma(s). Parathyroid glands are usually located at the 4 poles of the thyroid gland, although they may be found in other locations and can therefore be difficult to locate. Lack of positive imaging is not a reason to avoid carrying out parathyroidectomy in a patient with a clear biochemical diagnosis of PHPT as an experienced parathyroid surgeon will be able to find abnormal parathyroid tissue.[12][33]

Several imaging modalities are available. 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][34][35][36]​​​​

Neck ultrasound is the preferred initial localization study in patients with PHPT.[2][35]​​ Ultrasonography also identifies concomitant thyroid disease, which is present in 12% to 67% of patients with hyperparathyroidism.[2]​ Many institutions use technetium-99m-sestamibi (MIBI) scanning, often in conjunction with ultrasonography.[2][32][31]​​​​ The use of MIBI single-photon emission computed tomography (SPECT)/CT is commonly used in some areas and has a sensitivity of 88%.[32][37]​​​ Four-dimensional CT in combination with ultrasound is also used for initial assessment.[2]​ It appears to have at least a similar diagnostic performance compared to tomographic parathyroid scintigraphy and is particularly useful in the case of negative previous imaging studies or in patients with distorted neck anatomy.[32] Magnetic resonance imaging (MRI) is an option, although this is less commonly used except in certain circumstances such as pregnancy.[2] A systematic review and meta-analysis examined the role of radiolabeled 18F- or 11C-choline PET, combined with CT (PET/CT) or MRI (PET/MRI), for the detection of hyperfunctioning parathyroid glands in patients with primary hyperparathyroidism with encouraging results.[38] Subsequent prospective studies have validated these findings.[39][40][41]​ However, large multicenter and cost-effectiveness studies are still needed to clarify the role of this imaging in a clinical setting.​

Combining functional and anatomic tests is more effective than any one test alone.

Preoperative ultrasound-directed fine-needle aspiration biopsy of parathyroid lesions is not routinely recommended and may only be considered in unusual, difficult, or re-operative cases of PHPT and not in suspected parathyroid carcinoma. This is because it is rarely necessary and is associated with a number of potential adverse effects.[2]

Once diagnosis is confirmed, a dual-energy x-ray absorptiometry (DXA) scan should be completed to assess progression of disease in 3 sites, lumbar spine, hip, and forearm, and serve as a baseline for subsequent postoperative scans. An ultrasound scan of the kidneys will establish whether there is asymptomatic renal calcification. Asymptomatic renal calcification is an indication for parathyroidectomy.[2]

The trabecular bone score (TBS) is an imaging technology adapted directly from the DXA image of the lumbar spine that provides information about skeletal microstructure. Several studies have assessed TBS in patients with PHPT, and their results suggest that TBS may identify trabecular abnormalities not captured by lumbar spine bone mineral density in PHPT.[42]

Machine learning to identify primary hyperparathyroidism

Machine learning is a growing field with many different applications. It involves applying a collection of methods that allow a computer to learn rules from known/existing data sets to make predictions. Research has demonstrated a way to diagnose PHPT without a knowledge of calcium or PTH values.[43] Some researchers are exploring its use to distinguish between multigland disease and single adenomas preoperatively, thereby optimizing operative planning.[44]​​

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