Primary hyperparathyroidism

Primary hyperparathyroidism
Classification and external resources

Thyroid and parathyroid.

Primary hyperparathyroidism causes hypercalcemia (elevated blood calcium levels)

through the excessive secretion of parathyroid hormone (PTH), usually by an adenoma
(benign tumors) of the parathyroid glands.

Epidemiology
The incidence of primary hyperparathyroidism is approximately 1 per 1,000 people
(0.1%),[1] while there are 25-30 new cases per 100,000 people per year in the United
States.[2] The prevalence of primary hyperparathyroidism has been estimated to be 3 in
1000 in the general population and as high as 21 in 1000 in postmenopausal women.[3] It
is almost exactly three times as common in women as men.

Signs and Symptoms

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia.
They are classically summarized by the mnemonic "stones, bones, abdominal groans and
psychiatric moans".

"Stones" refers to kidney stones, nephrocalcinosis, and diabetes insipidus

(polyuria and polydipsia). These can ultimately lead to renal failure.
"Bones" refers to bone-related complications. The classic bone disease in
hyperparathyroidism is osteitis fibrosa cystica, which results in pain and
sometimes pathological fractures. Other bone diseases associated with
hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.
"Abdominal groans" refers to gastrointestinal symptoms of constipation,
indigestion, nausea and vomiting. Hypercalcemia can lead to peptic ulcers and
acute pancreatitis. The peptic ulcers can be an effect of increased gastric acid
secretion by hypercalcemia,[4] but may also be part of a multiple endocrine
neoplasia type 1 syndrome of both hyperparathyroid neoplasia and a gastrinoma.
"Psychiatric moans" refers to effects on the central nervous system. Symptoms
include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium,
and coma.
Left ventricular hypertrophy.[5]
Increased all-cause mortality[6]

The German description of the same symptoms is "Stein-, Bein- und Magenpein",
literally "stone, bone, and stomach-pain".
Other signs include proximal muscle weakness, itching, and band keratopathy of the
eyes.
When subjected to formal research, symptoms of depression, pain, and gastric
dysfunction do not correlate with mild cases of hypercalcemia. [7]

Diagnosis
The diagnosis of primary hyperparathyroidism is made by blood tests.
Serum calcium levels are elevated, and the parathyroid hormone level is abnormally high
compared with an expected low level in response to the high calcium. A relatively
elevated parathyroid hormone has been estimated to have a sensitivity of 60%-80% and a
specificity of approximately 90% for primary hyperparathyroidism.[8]
A more powerful variant of comparing the balance between calcium and parathyroid
hormone is to perform a 3 hour calcium infusion. After infusion, a parathyroid hormone
level above a cutoff of 14 ng/l has a sensitivity of 100% and a specificity of 93% in
detecting primary hyperparathyroidism, with a confidence interval of 80% to 100%.[9]
The serum chloride/phosphate ratio is 33 or more in most patients with primary
hyperparathyroidism. However, usage of thiazide medications have been reported to
causes ratios above 33.[10] Studies without any usage of thiazide diuretics have estimated
a serum chloride/phosphate ratio to have a sensitivity of 94%[11] or 95%[12][13] and a
specificity of 96%[11] or 100%.[12]

Urinary cAMP is occasionally measured; this is generally elevated..

Parathyroid hormone activity

Intact PTH levels are also elevated.

Causes
The most common cause of primary hyperparathyroidism is a sporadic, single
parathyroid adenoma[14] resulting from a clonal mutation (~97%). Less common are
parathyroid hyperplasia[14] (~2.5%), parathyroid carcinoma (malignant tumor), and
adenomas in more than one gland (together ~0.5%).
Primary hyperparathyroidism is also a feature of several familial endocrine disorders:
Multiple endocrine neoplasia type 1 and type 2A (MEN type 1 and MEN type 2A), and
familial hyperparathyroidism.
Genetic associations include:
OMIM Name
Gene
145000 HRPT1 MEN1, HRPT2
145001 HRPT2 HRPT2
610071 HRPT3 unknown at 2p13.3-14[15]
In all cases, the disease is idiopathic, but is thought to involve inactivation of tumor
suppressor genes (Menin gene in MEN1), or involve gain of function mutations (RET
proto-oncogene MEN 2a).
Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced
with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive
strontium isotopes.[16]
Primary hyperparathyroidism can also result from pregnancy. It is apparently very rare,
with only about 110 cases have so far been reported in world literature, but this is
probably a considerable underestimate of its actual prevalence in pregnant women.[17]

Complications
The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results
in pain and sometimes pathological fractures. Other bone diseases associated with
hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.

Treatment

Treatment is usually surgical removal of the gland(s) containing adenomas.

Medications
Medications include estrogen replacement therapy in postmenopausal women and
bisphosphonates. Bisphosphonates may improve bone turnover.[18] Newer medications
termed "calcimimetics" used in secondary hyperparathyroidism are now being used in
Primary hyperparathyroidism. Calcimimetics reduce the amount of parathyroid hormone
released by the parathyroid glands. They are recommended in patients in whom surgery is
inappropriate.[19]

Surgery
The symptoms of the disease, listed above, are indications for surgery. Surgery reduces
all cause mortality as well as resolving symptoms. However, cardiovascular mortality is
not significantly reduced.[6]
A consensus statement in 2002 recommended the following indications for surgery in
asymptomatic hyperparathyroidism[20]:

Serum calcium: 1.0 mg/dl above upper limit of normal

24-h urinary calcium >400 mg
Creatinine clearance reduced by 30% compared with age-matched subjects.
Bone mineral density t-score <2.5 at any site
Age <50

More recently, three randomized controlled trials have studied the role of surgery in
patients with asymptomatic hyperparathyroidism. The largest study reported that surgery
showed increase in bone mass, but no improvement in quality of life after one to two
years among patients with[21]:

Untreated, asymptomatic primary hyperparathyroidism

Serum calcium between 2.602.85 mmol/liter (10.411.4 mg/dl)
Age between 50 and 80 yr
No medications interfering with Ca metabolism
No hyperparathyroid bone disease
No previous operation in the neck
Creatinine level < 130 mol/liter (<1.47 mg/dl)

Two other trials reported improvements in bone density and some improvement in quality
of life with surgery.[22][23]

Future therapies
Future developments such as calcimimetic agents (e.g. cinacalcet) which activate the
parathyroid calcium-sensing receptor may offer a good alternative to surgery.

See also

Secondary hyperparathyroidism
Tertiary hyperparathyroidism