Hyperparathyroidism overview

# Overview
Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH).  The parathyroid hormone monitors calcium and phosphorus levels and helps to maintain these levels.   Overactivity of one or more of the parathyroid glands causes high calcium levels (hypercalcemia) and low levels of phosphorus in the blood.   Hyperparathyroidism was first described and treated in the 1930s by Fuller Albright of Massachusetts General Hospital, working at the Mallinckrodt General Clinical Research Center.

# Historical Perspective
In 1880, Ivar Sandstrom, a Swedish anatomist, described parathyroids in human following 50 autopsies. In 1924, James Bertram Collip, a Canadian biochemist, discovered and extracted parathyroid hormone and treated tetany with the help of parathyroid extract along with Douglous B Leitch. In 1925, Felix Mandl, a viennese surgeon performed first parathyroidectomy to treat a patient suffering from osteitis fibrosa cystica. In 1959, Howard Rasmussen and Lyman C. Craig at the Rockefeller Institute for Medical Research purified parathyroid hormone. They also isolated the active polypeptide (parathormone B) from bovine parathyroid gland and gave its tentative formula in 1961.

# Classification
Hyperparathyroidism can be classified according to origin of defect into primary, secondary and tertiary. Primary hyperparathyroidism results from a hyperfunction of the parathyroid glands themselves. There is oversecretion of PTH due to adenoma, hyperplasia or, rarely, carcinoma of the parathyroid glands. Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process. Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone (PTH) after a long period of secondary hyperparathyroidism and resulting in hypercalcemia even after treatment of secondary hyperparathyroidism..

# Pathophysiology
Hyperparathyroidism is an increase in serum parathyroid hormone. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedback for secretion of parathyroid hormone. Primary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a primary process in parathyroid gland.Majority of times, increase in secretion of parathyroid hormone is the result of parathyroid adenoma (85%). Calcium-sensing receptor expression is reduced in parathyroid adenoma resulting in an increase in calcium sensing set point. In minority of cases, development of primary hyperparathyroidism is the result of multiple genetic mutations. Genes involved in the pathogenesis of primary hyperparathyroidism include calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene. Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process, most commonly due chronic renal failure. Fibroblast growth factor 23 (FGF-23) concentration increases in chronic renal failure which plays a central role in regulation of phosphate, vitamin D homeostasis and pathogenesis of secondary hyperparathyroidism. Majority of times, tertiary hyperparathyroidism occurs in patients after renal transplantation.Patients with secondary hyperparathyroidism continues to have elevated parathyroid hormone even after renal transplantation. Classically, there is hyperplasia of all four of parathyroid gland. On gross pathology, parathyroid adenoma is a soft, tan nodule which is well-circumscribed by a delicate capsule. Typically, cut surface of parathyroid adenoma is smooth, soft, and reddish brown in color. It should be differentiated from normal parathyroid gland tissue which is yellow-brown color. Parathyroid hyperplasia usually involves multiple glands. Bones and kidney are also commonly involved in hyperparathyroidism. Hypercalcemia due to hyperparathyroidism may cause metastatic calcification in many organs including lungs, heart, blood vessels, stomach. Chief cells are predominant in parathyroid adenoma on microcopy. Adenoma is seperated from a rim of non-neoplastic tissue on the edge by a fibrous capsule. Endocrine atypia (cells with bizarre and pleomorphic nuclei) is often seen in parathyroid adenoma. It should not be mistaken as a sign of malignancy. Majority of times, hyperplasia of chief cells is observed in parathyroid hyperplasia. It may be diffuse or multinodular. Cytologic details are unreliable for diagnosis of parathyroid carcinoma.

# Causes
Hyperparathyroidism is caused by an increase in concentration of parathyroid hormone in serum. There are three type of hyperparathyroidism including primary, secondary and tertiary hyperparathyroidism. There are an array of different causes for all types of hyperparathyroidism. Most common cause of primary hyperparathyroidism is parathyroid adenoma (85%) followed by parathyroid hyperplasia (15%), and parathyroid carcinoma (5%). Most common cause of secondary hyperparathyroidism is chronic renal failure and vitamin D deficiency. Most common cause of tertiary hyperparathyroidism is post renal transplantation.

# Differentiating Hyperparathyroidism from Other Diseases
There are three types of hyperparathyroidism (primary, secondary, and tertiary) and should be differentiated between each other. Hyperparathyroidism should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia other than hyperparathyroidism include familial hypocalciuric hypercalcemia, hypercalcemia related to malignancy, medication-induced hypercalcemia, hypercalcemia due to nutritional disorders, and hypercalcemia related to granulomatous diseases.

# Epidemiology and Demographics
Primary hyperparathyroidism is the 3rd most common endocrine disorder. Highest incidence of primary hyperparathyroidism is in post-menopausal women.The incidence of primary hyperparathyroidism is approximately 0.4 to 21.6 per 100,000 person years. The prevalence of primary hyperparathyroidism is approximately .01 to .07 per 100,000 individuals. The incidence of primary hyperparathyroidism increases with age. Primary hyperparathyroidism usually affects individuals of African-American race. Women are more commonly affected by primary hyperparathyroidism than men. The women to men ratio is approximately 3 to 1. Difference in gender specific incidence of primary hyperparathyroidism becomes more pronounced with advancing age. There is insufficient data on epidemiology and demographics of secondary and tertiary hyperparathyroidism.

# Risk Factors
Common risk factors in the development of primary hyperparathyroidism include postmenopausal women, age group 50-60 year, family history of hyperparathyroidism, and history of familial syndromes. Common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include high serum phosphorus expression levels, low serum creatinine expression levels, low serum calcium expression levels, female gender, and hypertension. Common risk factors in the development of tertiary hyperparathyroidism post renal transplantation include elderly individuals and longer duration of dialysis.

# Screening
There is insufficient evidence to recommend routine screening for hyperparathyroidism.

# Natural History, Complications, and Prognosis
Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone. If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.
Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable. If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.
Tertiary hyperparathyroidism usually develops in post renal transplant patients. If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.
Hyperparathyroidism leads to a variety of complications in various organ systems depending on the type of hyperparathyroidism.
Prognosis is all types hyperparathyroidism is generally good after proper treatment.

# Diagnosis

## History and Symptoms
The majority of patients with primary hyperparathyroidism are asymptomatic. Asymptomatic primary hyperparathyroidism patient is expected to develop signs and symptoms, but most of the patients does not becomes symptomatic with time. The hallmark of primary hyperparathyroidism is asymptomatic hypercalcemia. The classic signs and symptoms of primary hyperparathyroidism are present in a few individuals and are summarized by the mnemonic painful bones, kidney stones, abdominal groans, psychic moans, and fatigue overtones.The majority of patients with secondary hyperparathyroidism have a history of either chronic renal failure or long term vitamin D deficiency.The majority of patients with tertiary hyperparathyroidism have a history of renal transplantation.

## Physical Examination
Physical examination of patients with hyperparathyroidism is usually unremarkable. Patients may have physical findings due to severe hypercalcemia and other complications of hyperparathyroidism.

## Laboratory Findings
An elevated serum calcium on routine biochemical screening in a asymptomatic patient should raise the suspicion of primary hyperparathyroidism. An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyoidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism. Measurement of total serum calcium with automatic techniques has similar or even more reliability than serum ionized calcium measurement. Method of choice for measuring intact parathyroid hormone include Immunoradiometric assay (IMRA) or Immunochemiluminescent assay (ICMA). 24-Hour urinary calcium excretion is used to seperate the patients with familial hypocalciuric hypercalcemia and typical primary hyperparathyroidism. Serum 1,25-dihydroxy vitamin D (calcitriol) concentration are significantly lower in familial hypocalciuric hypercalcemia than primary hyperparathyroidism.

## Electrocardiogram
There are no ECG findings associated with hyperparathyroidism. However, an ECG may be helpful in the diagnosis of cardiac complications of hyperparathyroidism.

## X-ray
X-ray is helpful in diagnosis of hyperparathyroidism. Finding in primary hyperparathyroidism includes subperiosteal bone resorption, endoosteal bone resorption, subchondral resorption, subligamentous resorption, intracortical resorption, osteopenia, brown tumors, salt and pepper sign in the skull (pepper pot skull), and chondrocalcinosis. X-ray is the preferred imaging for diagnosis of secondary hyperparathyroidism as majority of findings are radiological. Findings in secondary and tertiary hyperparathyroidism are often associated with the osteosclerosis of renal osteodystrophy, and the osteomalacia of vitamin D deficiency and includes subperiosteal bone resorption, subchondral resorption, subligamentous resorption, severe osteopenia, osteosclerosis, brown tumor, amyloid deposition, soft tissue and vascular calcification, superior and inferior rib notching, and osteonecrosis.

## CT scan
Good quality preoperative evaluation favors post operative results. 4-dimentional CT scan is an investigation for preoperative localizing of hyper-functioning parathyroid gland. 4D-CT is significantly more sensitive than Tc-99m sestamibi scintigraphy and ultrasound for precise (quadrant) localization of hyper-functioning parathyroid glands. 4D-CT is required to be performed with three phases including non-contrast, arterial, and delayed phase imaging. 4D-CT provides extremely detailed images of neck in multiple planes and enables the visualization of difference in hyper-functioning parathyroid gland compared with normal parathyroid glands and other structures in the neck on the basis on perfusion characteristics ( rapid uptake and washout). 4D-CT is particularly useful in cases of re-operation. The major disadvantage of 4D-CT is significant radiation exposure associated with scanning the patient multiple times.

## MRI
MRI may be helpful in the post-operative evaluation of hyper functioning parathyroid glands, particularly in patients with recurrent or persistent hyperparathyroidism. MRI has similar sensitivity and positive predictive value as Tc-99m sestamibi scintigraphy for post-operative detection of hyper-functioning parathyroid glands. MRI with gadolinium and fat suppression is used for detection of ectopic parathyroid adenoma (particularly those located in mediastinum).

## Ultrasound
Neck ultrasound is used for preoperative localization of hyper-functioning parathyroid gland. Neck ultrasound alone is not a sensitive investigation for this purpose. Neck ultrasound along with Tc-99m sestamibi scintigraphy is most common used diagnostic modality for preoperative localization of hyper-functioning parathyroid gland.

## Other Imaging Findings
Imaging modalities may be helpful in preoperative localization of hyper-functioning parathyroid glands. This includes both non-invasive and invasive modalities.  Non-invasive imaging modalities for preoperative localization of hyper-functioning parathyroid glands include Tc-99m sestamibi scintigraphy (sestamibi or MIBI), single photon emission computed tomography (SPECT), positron emission tomography (PET).  Invasive modalities used for preoperative localization of hyper-functioning parathyroid glands include selective arteriography and angiography. Dual energy X-ray absorptiometry is helpful in detecting low bone mineral density (BMD) caused by hyperparathyroidism.

## Other Diagnostic Studies
Other diagnostic study useful for preoperative localization of hyper-functioning parathyroid glands include super selective venous sampling. Another diagnostic study include measurement of intraoperative parathyroid hormone (IOPTH) by using a modified sensitive assay (immunoradiometric assay). IOPTH is beneficial for predicting long term surgical outcomes.

# Treatment

## Medical Therapy
Surgical therapy is preferred over medical therapy in hyperparathyroidism. However medical therapy is considered in a few circumstances. Patients with primary hyperparathyroidism who do not undergo parathyroidectomy should be monitored for the potential progression of disease. Monitoring includes serum calcium, skeletal monitoring, and renal monitoring. Medical management of primary hyperparathyroidism includes nutritional supplements and pharmacotherapy. Nutritional supplements includes elemental calcium supplements and vitamin D analogs. Pharmacotherapy includes bisphosphonates, calcimimetics, and estrogen receptor-targeted therapy. Medical management of secondary hyperparathyroidism includes calcimimetics, vitamin D analogues, and phosphate binders/phosphate restriction. Medical management of tertiary hyperparathyroidism includes calcimimetics.

## Surgery
Surgery is the mainstay of treatment for hyperparathyroidism. Symptomatic hyperparathyroidism is an indication for surgery. However, there are guidelines for surgery in asymptomatic primary hyperparathyroidism. Surgery for hyperparathyroidism is parathyroidectomy which includes bilateral neck exploration and minimally invasive parathyroidectomy. Most commonly done surgery for hyperparathyroidism is minimally invasive parathyroidectomy (MIP). There are various types of MIP. MIP provides excellent postoperative cure rates comparable to bilateral neck exploration (BNE) with less complications than BNE. This is due to precise preoperative localization of hyper-functioning parathyroid gland and use of intraoperative parathyroid hormone (IOPTH) monitoring for predicting post-surgical success (postoperative normocalcemia).

## Primary Prevention
Effective measures for the primary prevention of secondary hyperparathyroidism in chronic kidney disease include aggressive management of hyperphosphatemia in early stages of chronic kidney disease and prevention and treatment of vitamin D deficiency in stage 3 & 4 chronic kidney disease. There are no established measures for the primary prevention of primary hyperparathyroidism and tertiary hyperparathyroidism.

## Secondary Prevention
Secondary prevention of primary hyperparathyroidism includes monitoring for potential progression of disease in patients who do not undergo parathyroidectomy. There are guidelines for monitoring of patients with asymptomatic hyperparathyroidism not undergoing parathyroidectomy. Effective measures for secondary prevention of secondary hyperparathyroidism include maintain adequate nutrition, proper intake of vitamin D and/or sufficient sunlight exposure, and adequate physical activity.  Effective measures for secondary prevention of tertiary hyperparathyroidism include early detection and treatment of hyperparathyroidism by either calcimimetics or parathyroidectomy.