Primary hyperparathyroidism

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. Its incidence is approximately 1 per 1,000 people (0.1%), while there are 25-30 new cases per 100,000 people per year in the United States. 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, 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.
 * Increased all-cause mortality

The German description of the same symptoms is "Stein-, Bein- und Magenpein", literally "stone, leg, and stomach-pain".

Other signs include proximal muscle weakness, itching, and band keratopathy of the eyes.

Diagnosis
The diagnosis of primary hyperparathyroidism is made by blood tests. Serum calcium levels are elevated.

The serum chloride phosphate ratio is 33 or more in most patients with primary hyperparathyroidism. However, thiazide medications have been reported to causes ratios above 33.

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 resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia (~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:

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.

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.

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. 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.

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.

A consensus statement in 2002 recommended the following indications for surgery in asymptomatic hyperparathyroidism :
 * 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 <&minus;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 :
 * Untreated, asymptomatic primary hyperparathyroidism
 * Serum calcium between 2.60–2.85 mmol/liter (10.4–11.4 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 µmol/liter (<1.47 mg/dl)

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

Non-invasive treatment
The French company Theraclion developed a new device named “TH-One” for the non-invasive treatment (no scars) of fine endocrine targets such as thyroid nodules and parathyroids. TH-One uses High Intensity Focused Ultrasound (HIFU), which is a process that allows the delivery of a large amount of acoustic energy to a confined space resulting in localized tissue necrosis.

The TH-One enables to treat primary hyperparathyroidism by ablating the adenoma. It also allows to lower in a control manner the PTH level for secondary hyperparathyroidism patients. It is scar-less, totally non invasive.

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