Hyperparathyroidism


Hyperparathyroidism is an increase in parathyroid hormone levels in the blood. This occurs from a disorder either within the parathyroid glands or outside the parathyroid glands. Most people with primary disease have no symptoms at the time of diagnosis. When symptoms occur, they are due to elevated blood calcium. With long-standing elevation, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.
In 80% of cases, primary hyperparathyroidism is due to a single benign tumor known as a parathyroid adenoma. Most of the remainder are due to several of these adenomas. Rarely it may be due to parathyroid cancer. Secondary hyperparathyroidism typically occurs due to vitamin D deficiency, chronic kidney disease, or other causes of low blood calcium. The diagnosis of primary hyperparathyroidism is made by finding elevated calcium and PTH in the blood.
Primary hyperparathyroidism may be cured by removing the adenoma or overactive parathyroid glands. In those without symptoms, mildly increased blood calcium levels, normal kidneys, and normal bone density monitoring may be all that is required. The medication cinacalcet may also be used to decrease PTH levels. In those with very high blood calcium levels, treatment may include large amounts of intravenous normal saline. Low vitamin D levels should be corrected.
Primary hyperparathyroidism is the most common type. In the developed world, between one and four per thousand people are affected. It occurs three times more often in women than men and is typically diagnosed between the ages of 50 and 60. The disease was first described in the 1700s. In the late 1800s, it was determined to be related to the parathyroid. Surgery as a treatment was first carried out in 1925.

Signs and symptoms

Symptoms depend on whether the hyperparathyroidism is the result of parathyroid overactivity or secondary.
In primary hyperparathyroidism, about 75% of people have no symptoms. The problem is often picked up incidentally during blood work for other reasons, and the test results show a higher amount of calcium in the blood than normal. Many other people only have non-specific symptoms.
Symptoms directly due to hypercalcemia are relatively rare, being more common in patients with malignant hypercalcemia. If present, common manifestations of hypercalcemia include weakness and fatigue, depression, bone pain, muscle soreness, decreased appetite, feelings of nausea and vomiting, constipation, polyuria, polydipsia, cognitive impairment, kidney stones and osteopenia or osteoporosis. A history of acquired racquet nails may be indicative of bone resorption. Parathyroid adenomas are very rarely detectable on clinical examination. Surgical removal of a parathyroid tumor eliminates the symptoms in most patients.
In secondary hyperparathyroidism, the parathyroid gland is behaving normally; clinical problems are due to bone resorption and manifest as bone syndromes such as rickets, osteomalacia, and renal osteodystrophy.

Causes

Radiation exposure increases the risk of primary hyperparathyroidism. A number of genetic conditions including multiple endocrine neoplasia syndromes also increase the risk.

Mechanism

Normal parathyroid glands measure the ionized calcium concentration in the blood and secrete parathyroid hormone accordingly; if the ionized calcium rises above normal, the secretion of PTH is decreased, whereas when the Ca2+ level falls, parathyroid hormone secretion is increased.
Secondary hyperparathyroidism occurs if the calcium level is abnormally low. The normal glands respond by secreting parathyroid hormone at a persistently high rate. This typically occurs when the 1,25 dihydroxyvitamin D3 levels in the blood are low and hypocalcemia is present. A lack of 1,25 dihydroxyvitamin D3 can result from a deficient dietary intake of vitamin D, or from a lack of exposure of the skin to sunlight, so the body cannot make its own vitamin D from cholesterol. The resulting hypovitaminosis D is usually due to a partial combination of both factors. Vitamin D3 is converted to 25-hydroxyvitamin D by the liver, from where it is transported via the circulation to the kidneys, and it is converted into the active hormone, 1,25 dihydroxyvitamin D3. Thus, a third cause of secondary hyperparathyroidism is chronic kidney disease. Here the ability to manufacture 1,25 dihydroxyvitamin D3 is compromised, resulting in hypocalcemia.

Diagnosis

The gold standard of diagnosis is the PTH immunoassay. Once an elevated PTH has been confirmed, the goal of diagnosis is to determine whether the hyperparathyroidism is primary or secondary in origin by obtaining a serum calcium level:
Tertiary hyperparathyroidism has a high PTH and a high serum calcium. It is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism.
Hyperparathyroidism can cause hyperchloremia and increase renal bicarbonate loss, which may result in a normal anion gap metabolic acidosis.

Differential diagnosis

can present with similar lab changes. In this condition, the calcium creatinine clearance ratio, however, is typically under 0.01.

Blood tests

Intact PTH

In primary hyperparathyroidism, parathyroid hormone levels are either elevated or "inappropriately normal" in the presence of elevated calcium. Typically, PTH levels vary greatly over time in the affected patient and must be retested several times to see the pattern. The currently accepted test for PTH is intact PTH, which detects only relatively intact and biologically active PTH molecules. Older tests often detected other, inactive fragments. Even intact PTH may be inaccurate in patients with kidney dysfunction.

Calcium levels

In cases of primary hyperparathyroidism or tertiary hyperparathyroidism, heightened PTH leads to increased serum calcium due to:
  1. increased bone resorption, allowing flow of calcium from bone to blood
  2. reduced kidney clearance of calcium
  3. increased intestinal calcium absorption

    Serum phosphate

In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased reabsorption of phosphate in the kidney tubules. However, this is only present in about 50% of cases. This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of kidney disease.

Alkaline phosphatase

levels are usually elevated in hyperparathyroidism. In primary hyperparathyroidism, levels may remain within the normal range, but this is inappropriately normal given the increased levels of plasma calcium.

Nuclear medicine

A technetium sestamibi scan is a procedure in nuclear medicine that identifies hyperparathyroidism. It is used by surgeons to locate ectopic parathyroid adenomas, most commonly found in the anterior mediastinum.

Classification

Primary

results from a hyperfunction of the parathyroid glands themselves. The oversecretion of PTH is due to a parathyroid adenoma, parathyroid hyperplasia, or rarely, a parathyroid carcinoma. This disease is often characterized by the quartet stones, bones, groans, and psychiatric overtones referring to the presence of kidney stones, hypercalcemia, constipation, and peptic ulcers, as well as depression, respectively.
In a minority of cases, this occurs as part of a multiple endocrine neoplasia syndrome, either type 1 or type 2a. Other mutations that have been linked to parathyroid neoplasia include mutations in the genes HRPT2 and CASR.
Patients with bipolar disorder who are receiving long-term lithium treatment are at increased risk for hyperparathyroidism. Elevated calcium levels are found in 15% to 20% of patients who have been taking lithium long-term. However, only a few of these patients have significantly elevated levels of parathyroid hormone and clinical symptoms of hyperparathyroidism. Lithium-associated hyperparathyroidism is usually caused by a single parathyroid adenoma.

Secondary

is due to physiological secretion of parathyroid hormone by the parathyroid glands in response to hypocalcemia. The most common causes are vitamin D deficiency and chronic kidney failure.
Lack of vitamin D leads to reduced calcium absorption by the intestine leading to hypocalcemia and increased parathyroid hormone secretion. This increases bone resorption.
In chronic kidney failure the problem is more specifically failure to convert vitamin D to its active form in the kidney. The bone disease in secondary hyperparathyroidism caused by kidney failure is termed renal osteodystrophy.

Tertiary

is seen in those with long-term secondary hyperparathyroidism, which eventually leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. This disorder is most often seen in patients with end-stage kidney disease and is an autonomous activity.

Treatment

Treatment depends on the type of hyperparathyroidism encountered.

Primary

People with primary hyperparathyroidism who are symptomatic benefit from parathyroidectomy—surgery to remove the parathyroid tumor. Indications for surgery are:
Surgery can rarely result in hypoparathyroidism.

Secondary

In people with secondary hyperparathyroidism, the high PTH levels are an appropriate response to low calcium and treatment must be directed at the underlying cause of this. If this is successful, PTH levels return to normal levels, unless PTH secretion has become autonomous.

Calcimimetics

A calcimimetic is a potential therapy for some people with severe hypercalcemia and primary hyperparathyroidism who are unable to undergo parathyroidectomy, and for secondary hyperparathyroidism on dialysis.
Treatment of secondary hyperparathyroidism with a calcimimetic in those on dialysis for CKD does not alter the risk of early death; however, it does decrease the likelihood of needing a parathyroidectomy. Treatment carries the risk of low blood calcium levels and vomiting.

History

The oldest known case was found in a cadaver from an Early Neolithic cemetery in southwest Germany.