Primary: Hyper functioning of the parathyroid glands themselves leads to primary hyperparathyroidism. Either an adenoma, hyperplasia or in rare instances cancer of the parathyroid gland leads to over secretion of PTH.
In some rare cases, primary hyperthyroidism may also occur as part of a multiple endocrine neoplasia (MEN) syndrome. The two types of MEN those are associated with primary hyperthyroidism include type 1(caused due to a mutation in gene MEN1) and type 2a (caused due to gene RET mutation). Mutations in the genes HRPT2 and CASR have also been linked to parathyroid neoplasia.
The risk of hyperparathyroidism is also increased in bipolar disorder patients who are receiving long-term lithium treatment. 15%-20% of patients who are receiving lithium long-term have been found to have elevated calcium levels. However, significantly increased levels of parathyroid hormone in association with clinical symptoms of hyperparathyroidism are found in only a few of these patients.
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Secondary: When the parathyroid glands secrete parathyroid hormone in response to low levels of blood calcium, a condition also known as hypocalcemia, then the condition is known as secondary hyperparathyroidism. Low serum calcium occurs most commonly in chronic renal failure and deficiency of vitamin D that is often caused due to a deficient diet, lack of sunlight or malabsorption of nutrients).
The absorption of calcium by the intestines is decreased due to lack of vitamin D causing hypercalcemia and over secretion of parathyroid hormone. This leads to increased resorption of bone. In chronic renal failure the kidneys are not able to convert vitamin D to its more active form. The bone disease that occurs as a result of chronic renal failure induced hyperparathyroidism is referred to as renal osteodystrophy.
Tertiary: Patients who have chronic secondary hyperthyroidism develops hyperplasia of the parathyroid glands ultimately leading to no response to serum calcium levels. Such patients are known to have tertiary hyperparathyroidism. This disorder is autonomous and often occurs in patients who suffer from chronic renal failure.
Quaternary and Quintary: These are rare conditions that may occur after the primary hyperparathyroidism has been removed surgically, when renal damage has been caused that leads to a form of secondary or quaternary hyperparathyroidism that may ultimately lead to quintary or autonomy hyperparathyroidism. Quaternary hyperparathyroidism may also result from hungry bone syndrome occurring post parathyroid gland removal.
Signs and symptoms
Each type of hyperparathyroidism presents with different symptoms.
About half of the patients suffering from primary hyperparathyroidism have no symptoms at all, and the disease is discovered as an incidental finding in the form of increased calcium levels or characteristic appearance on the X-Ray. Non-specific symptoms are present in many other patients. Direct symptoms of hypercalcemia are relatively rare and more commonly present in patients suffering from malignant hypercalcemia. If symptoms are present, they are manifested as fatigue and weakness, pain in bones, depression, soreness of muscles (myalgias), reduced appetite, constipation, increased frequency of urination, increased thirst, nausea and vomiting, formation of kidney stones, osteoporosis and impairment of cognitive functions. Clinical examination can very rarely detect parathyroid adenomas. In most of the patients removal of parathyroid gland tumor surgically will eliminate the symptoms.
The parathyroid gland behaves normally in secondary hyperparathyroidism and clinical problems occur due to resorption of bone manifesting as osteomalacia, rickets, and renal osteodystrophy.
Intact PTH: The levels of parathyroid hormone are either elevated or normal (inappropriately) in association with elevated calcium levels in cases of primary hyperparathyroidism. In typical cases, there is a great variation in the PTH levels over time and the levels need to be retested multiple times along with Ca and Ca++ levels to make out the pattern. â€œIntact PTHâ€Â is the currently accepted test for PTH, which detects only biologically active and relatively intact PTH molecules. Other, inactive fragments were also detected by older tests. Inaccurate results of Intact PTH may be obtained in patients suffering from renal dysfunction.
Serum calcium or ionized calcium (Ca++)
Raised PTH lead to increased serum calcium levels (hypercalcemia) in cases of primary hyperparathyroidism or tertiary hyperparathyroidism due to:
Elevated resorption of bone, leading to movement of calcium from bone to blood.
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Decreased renal excretion of calcium.
Increased absorption of calcium from the intestines.
In cases of primary hyperparathyroidism due to decreased reabsorption of phosphates by renal tubules the serum phosphate levels become abnormally low. However, this occurs in only about half of the cases. This finding is in contrast to secondary hyperparathyroidism, where due to renal disease, the serum phosphate levels are generally increased.
In hyperparathyroidism the levels of alkaline phosphate are usually elevated. The levels are within normal range in cases of primary hyperparathyroidism, however, due to the elevated plasma calcium levels these levels are considered â€œinappropriately normalâ€Â.
A procedure in nuclear medicine, a sestamibi scan is done to diagnose hyperparathyroidism or parathyroid adenoma. Surgeons use this scan to locate ectopic parathyroid adenomas, commonly present in the anterior mediastianum.
Parathyroid immunoassay is the main tool of diagnosis. A serum calcium level is obtained to determine whether the hyperparathyroidism is primary or secondary, once an increased parathyroid hormone is found.
When both the PTH and serum calcium levels are high then the likely type is primary hyperparathyroidism. When the PTH levels are high and serum calcium levels are low or normal then the likely type is secondary hyperparathyroidism.
High PTH and serum calcium levels are found in tertiary hyperparathyroidism. A history of chronic kidney failure and secondary hyperparathyroidism differentiates it from primary hyperparathyroidism.
Treatment and monitoring
Hyperparathyroidism is diagnosed by endocrinologists who are trained to diagnose diseases affecting glands. Treatment is done depending on the type of hyperparathyroidism present. Patients suffering from symptomatic primary hyperparathyroidism are treated with removal of the parathyroid tumor (parathyroid adenoma). Surgery is indicated in the following cases:
Hyperparathyroidism with symptoms
Hyperparathyroidism without symptoms with any of the below mentioned findings:
24-hour urinary calcium value greater than 400 mg
Serum calcium levels greater than 1 mg/dL above upper limit of normal
Creatinine clearance greater than 30% below normal for age of patient
Age of patient less than 50 years
Bone density is greater than 2.5 standard deviations for below peak (a T-score of -2.5)
Excessive secretion of PTH occurs as a normal response to decreased calcium levels in patients suffering from secondary hyperparathyroidism. Hence, treatment is directed at rectifying the underlying cause of decreased calcium (Vitamin D deficiency and chronic renal failure in maximum cases). PTH levels become normal if the treatment is successful unless the secretion of PTH becomes autonomous or gets converted into tertiary hyperparathyroidism.
Tests done to detect hyperparathyroidism:
Level of calcium
Bone density test
Vitamin D level
Calcimimetics: This is a new drug that is regarded as potential treatment for some patients suffering from severe hypercalcemia and primary hyperparathyroidism in whom parathyroidectomy cannot be done and also in patients suffering from secondary hyperparathyroidism who are on dialysis. This drug is recognized by your tissues as calcium, thereby tricking the body into thinking that appropriate amounts of calcium are present in blood. This results in decreasing the secretion of PTH from the parathyroid glands, thereby, reducing the levels of blood calcium and phosphorus. The release of PTH from the parathyroid glands is controlled by calcimimetics without elevating the levels of calcium and phosphorus. Calcimimetics may cause some side effects in the form of mild to moderate nausea and vomiting.
Fuller Albright of Massachusetts General Hospital first described and treated hyperparathyroidism in the 1930s while working at the Mallinckrodt General Clinical Research Center. A cadaver from an Early Neolithic cemetery in southwest Germany was the oldest known case found.