Hyperparathyroidism Disease Background

Hyperparathyroidism is caused by excessive parathyroid hormone (PTH) production, which may be due to autonomous overproduction as seen in primary hyperparathyroidism (PHPT) or in response to low serum calcium (hypocalcemia) as seen in secondary hyperparathyroidism. Elevated levels of parathyroid hormone result in increased serum calcium (hypercalcemia). 

Primary hyperparathyroidism is the third most common endocrine disorder after diabetes mellitus and thyroid disorders. The disease is more frequent with advancing age and in populations of Asian or African-American origin.   The higher prevalence rate may be due to greater predisposition to vitamin D deficiency and subsequent secondary hyperparathyroidism.  This mainly occurs in patients >50 years old, with higher prevalence in women.  Symptomatic cases dominate in the Indian continent, Middle East and Southeast Asia, while transitional patterns with predominantly asymptomatic cases are reported in China and Japan.  

Primary hyperparathyroidism is characterized by hypercalcemia and elevated serum levels of parathyroid hormone caused by an excessive production of parathyroid hormones from one or more of the parathyroid glands. The mechanism occurs via the increased renal tubular calcium reabsorption, rapid mobilization of calcium and phosphate from the bone (bone resorption) and increased renal synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D], which increases intestinal calcium and phosphate absorption. 

Most cases of primary hyperparathyroidism are caused by parathyroid adenoma, while secondary and tertiary hyperparathyroidism are commonly precipitated by conditions that cause hypocalcemia (eg renal disease) which in turn causes increased parathyroid hormone secretion. 

Primary Hyperparathyroidism (PHPT)  

Primary hyperparathyroidism is characterized by autonomous parathyroid hormone overproduction commonly resulting from either an adenoma (>80%) or hyperplasia of parathyroid tissue; it is rarely caused by malignancy. Radiation exposure and rare genetic abnormalities associated with primary hyperparathyroidism can be identified in some patients. Two molecular defects that can be seen in sporadic parathyroid adenomas that include cyclin D1 gene inversions, which lead to cyclin D1 overexpression causing cell proliferation, and MEN1 mutations, which account for approximately 20-30% of sporadic parathyroid tumors and are found in familial parathyroid adenomas.  







Genetic syndromes associated with familial parathyroid adenomas are: 

• MEN1 (Werner’s syndrome) and MEN2 (Sipple’s syndrome), which are due to germline mutations of MEN1 and RET 
• Familial hypocalciuric hypercalcemia, which is a rare autosomal dominant disorder caused by a loss-of-function mutation in the parathyroid calcium-sensing receptor gene leading to decreased extracellular calcium sensitivity. 
• Neonatal severe primary hyperparathyroidism, which is a rare disorder developing shortly after birth affecting either homozygous or heterogenous mutation of the calcium-sensing receptor gene 
• Hyperparathyroidism - jaw tumor syndrome, which is an autosomal dominant disorder characterized by fibrosseous jaw tumors and parathyroid adenoma; polycystic kidney disease, renal hamartomas and Wilms tumor can also be observed in affected patients 
• Familial isolated hyperparathyroidism, which has no specific features but is thought to be an occult expression of MEN1 

Primary hyperparathyroidism may occur during pregnancy and causes spontaneous abortion, intrauterine growth restriction, supravalvular aortic stenosis, stillbirth and neonatal tetany. Neonatal tetany is a result of fetal parathyroid gland suppression by high levels of maternal circulation, which readily crosses the placenta during pregnancy and is the most common initial sign of maternal hyperparathyroidism. Functional hypoparathyroidism occurs after birth in infants of mothers with primary hyperparathyroidism due to hypercalcemic states while in utero. The affected infants can develop hypocalcemia and tetany in the first few days of life. The initial symptoms include abdominal symptoms, muscle weakness, disorientation, coma and death. Other complications noted are prematurity, spontaneous abortion, intrauterine growth restriction, and stillbirth. Mild cases can be managed by maintaining good hydration and monitoring calcium levels. A decreased risk of obstetric complication has been seen in patients who undergo surgery for hyperparathyroidism. Surgical intervention can be considered in the second trimester for patients with serum calcium >11 mg/dL and if surgery is not contraindicated. The neonate should be closely monitored for hypocalcemia if surgery is deferred. Surgery should be done after delivery and before a subsequent pregnancy. Bisphosphonates and Denosumab should not be used and limited data are noted on the use of Cinacalcet. 

Secondary Hyperparathyroidism  

Secondary hyperparathyroidism is precipitated by conditions that result in chronic hypocalcemia leading to compensatory parathyroid overactivity and parathyroid hormone overproduction. As parathyroid hormone concentrations rise, calcium is mobilized by increasing intestinal absorption and bone resorption, thus, characterized by elevated parathyroid hormone and normal or low serum calcium. This is usually seen in cases of chronic kidney disease wherein a decrease in phosphate excretion leads to an elevation of serum phosphate levels, which directly depresses serum calcium levels, eventually leading to parathyroid gland stimulation. Other causes of hypocalcemia are vitamin D and/or calcium deficiency, malabsorption syndromes, medications (eg thiazides, Lithium), metabolic abnormalities (eg chronic hyperphosphatemia), congenital disorders (eg transient neonatal hyperparathyroidism), bone resorption inhibition secondary to use of bisphosphonates, post-renal transplantation, and pseudohypoparathyroidism due to parathyroid hormone resistance. Treatment depends on the underlying cause. 

Tertiary Hyperparathyroidism  

Tertiary hyperparathyroidism occurs after long-standing secondary hyperparathyroidism, as seen in patients with end-stage renal disease or renal failure. The development of hypercalcemia is refractory to medical management in patients with secondary hyperparathyroidism.