History and exam
Key diagnostic factors
common
incidental finding on biochemical testing
In the US and Europe, most (80%) patients present with asymptomatic disease and are diagnosed on routine tests.[1]
uncommon
family history of hyperparathyroidism or features suggestive of hypercalcemia
A history of family members with PHPT should prompt suspicion of multigland disease. Inherited forms include multiple endocrine neoplasia (MEN) 1, MEN 2, MEN 4, HPT-jaw tumor syndrome, familial hypocalciuric hypercalcemia, and familial isolated hyperparathyroidism.[18] Genetic counseling should be considered for patients with PHPT and a positive family history of PHPT, and for patients with apparent syndromic manifestations.[2]
nephrolithiasis
If the patient has a history of kidney stones composed of calcium oxalate, hypercalciuria is very likely.[45] Nephrolithiasis is found in 10% to 20% of patients in the US with PHPT.[6] Silent nephrolithiasis and/or nephrocalcinosis is an indication for parathyroidectomy even in the absence of symptoms of PHPT.[2]
The incidence of kidney stones has declined over the past decades, but the incidence of hypercalciuria has not.[46] Renal calcium excretion is not directly related to kidney stones, but an evaluation of a patient with PHPT should include a 24-hour urine test for creatinine clearance and calcium level.[2] Hypercalcemia can impair kidney function. Hypercalciuria (24-hour urine calcium level >400 mg/dL) with increased stone risk is an indication for parathyroidectomy even in the absence of symptoms of PHPT.[2]
Other diagnostic factors
common
poor sleep
The prevalence of sleep disturbance in patients with PHPT is between 44% to 62%.[29] Mechanisms of disruption of sleep quality are unknown, but may be related to alterations in circadian rhythm. Sleep disturbance is one of the most common complaints in patients with PHPT, and resolution of insomnia is seen in 70% of patients following parathyroidectomy.[29]
fatigue
Most patients with PHPT have considerable symptomatology compared with healthy people. The most common profound non-specific symptoms is fatigue.[47]
myalgia
Classic PHPT is commonly associated with muscle weakness and high fatigability. This was originally described as a distinct neuromuscular syndrome characterized by atrophy of type II muscle cells. [6]
anxiety
Most patients with PHPT have considerable psychiatric symptomatology compared with healthy people. Rates of anxiety in patients undergoing parathyroidectomy for PHPT are between 43% to 53%.[48] The severity of symptoms was not linearly related to the degree of hypercalcemia or to serum intact PTH levels.[29]
depression
Studies show between 20% to 30% of patients with PHPT met criteria for major depression.[49][50] After treatment (parathyroidectomy or medical treatment of hypercalcemia), there is a decrease in severe depressive symptoms.[51][52] As an isolated symptom, however, depression is not regarded as a clear indication for parathyroidectomy.[1]
memory loss
Neurocognitive impairments were 30% in a US population, with impaired executive functioning present in 13% of patients with PHPT, which decreased to 2% following cure. Impaired cognitive processing speed was detected in 26% of patients preoperatively, but in only 6% after parathyroidectomy.[53] As an isolated symptom, however, neurocognitive impairment is not regarded as a clear indication for parathyroidectomy.[1]
uncommon
overt neuromuscular dysfunction
cardiovascular and metabolic dysfunction
The link between PHPT and cardiovascular disease remains controversial.[1] Published data derived from observational studies exist linking symptomatic and mild PHPT with hypertension, echocardiographic changes, arrhythmias, endothelial dysfunction, glucose metabolism impairment, and metabolic syndrome.[54][55][56][57] However, the data are inconsistent, with little evidence to suggest that parathyroidectomy results in improved outcomes. For this reason, at present cardiovascular involvement is not considered among the criteria required for parathyroidectomy.
gastrointestinal symptoms
The classic gastrointestinal symptoms that were attributed to hypercalcemia, such as anorexia, nausea, vomiting, constipation, and abdominal pain (such as from pancreatitis), are now uncommon and if present are not usually linked to PHPT.[1][28] The exception is gastrointestinal symptoms due to Zollinger-Ellison syndrome associated with MEN 1.[1]
Risk factors
strong
female sex
PHPT is 2 to 3 times more common in women than in men.[2]
age ≥50-60 years
PHPT incidence increases with age, being especially common in postmenopausal women.[6]
multiple endocrine neoplasia (MEN) 1, 2A, or 4
MEN 1, MEN 2A, and MEN 4 all have autosomal dominant inheritance.
PHPT affects over 90% of patients with MEN 1.[7] Clinical features of MEN 1 include multigland parathyroid disease, pancreatic neuroendocrine tumors, and anterior pituitary tumors.[7] In MEN 2A, PHPT occurs in around 20% of patients.[7] MEN 4 is characterized by the occurrence of parathyroid, anterior pituitary, and pancreatic neuroendocrine tumors in association with gonadal, adrenal, renal, and thyroid tumors that have CDNK1B mutations.[18] The PHPT disease is either multigland or an adenoma. Other manifestations of MEN 2A include medullary thyroid cancer and pheochromocytomas.[22] Genetic counseling should be considered for patients presenting with PHPT who have an apparent syndromic manifestation.[2]
current or historical lithium treatment
In patients taking lithium, 10% to 15% have hypercalcemia with or without symptoms of hyperparathyroidism (HPT).[23] Although the precise mechanism has not been elucidated, studies suggest that lithium causes hypercalcemia and HPT by altering feedback inhibition of PTH secretion and raising the "set point" at which serum calcium inhibits PTH secretion.[20] The prevalence of multigland disease in PHPT after chronic lithium therapy is higher than in PHPT due to other causes. The presence of (or potential for) multigland disease is important to be aware of when planning surgery.[2]
hyperparathyroidism-jaw tumor syndrome
Characteristically includes parathyroid adenomas or carcinomas, in association with mandibular or maxillary fibro-osseous lesions, uterine tumors in women, and renal cysts and tumors.[18] Inheritance is autosomal dominant with incomplete penetrance.
Parathyroid carcinomas occur in up to 20% of affected people.[24] It tends to have a more aggressive course, and patients often have more severe hypercalcemia than those with parathyroid adenomas. There is a low threshold for surgical intervention, even if biochemically mild PHPT or normal biochemistry but a parathyroid adenoma identified on imaging.
family history of PHPT
Familial isolated PHPT is a genetic mutation similar to multiple endocrine neoplasia (MEN), but without manifestations of other endocrinopathies.[9][18] Genetic counseling is recommended for patients younger than 40 years old with PHPT and multigland disease, and should be considered for those with a positive family history of PHPT.[2]
weak
history of head and neck irradiation
One study has shown that 14% of patients with exposure to neck irradiation developed PHPT.[25] With irradiation, there is a higher risk of multigland involvement.[26]
Parathyroid adenomas are usually monophenotypic, probably the result of growth from a single genetically dysfunctional cell.[27] The cell dysfunction could be due to a mutation that reflects a consequence of exposure to external mutagens such as irradiation.
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