July 11, 2017
Hypoparathyroidism is a rare endocrine disorder characterized by absent or inappropriately low concentrations of circulating parathyroid hormone (PTH), which leads to hypocalcemia, hyperphosphatemia and increased fractional excretion of calcium in the urine.
Bart L. Clarke, M.D., with Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic's campus in Rochester, Minnesota, says: "It is estimated that 60,000 to 115,000 patients in the U.S. have this disorder. Roughly 75 percent of cases of hypoparathyroidism are due to anterior neck surgery, typically for thyroid, parathyroid, or other head or neck disorders. Autoimmune hypoparathyroidism may be isolated or associated with autoimmune polyglandular syndrome type I, which is also associated with chronic mucocutaneous candidiasis, pernicious anemia and other autoimmune conditions.
"Infiltrative disorders that can cause hypoparathyroidism include iron or copper overload, sarcoidosis, and metastatic malignancy affecting the parathyroid glands. Rare cases have been reported after radioactive iodine 131 (131-I) treatment for thyroid disease. In addition, hypomagnesemia may limit PTH secretion by normal parathyroid glands."
Novel molecular biology techniques have improved understanding of parathyroid gland physiology and have led to the reporting of many different genetic defects responsible for familial hypoparathyroidism. These defects include gain-of-function mutations affecting the extracellular calcium-sensing receptor (CaSR), which causes autosomal dominant hypocalcemia, and defects affecting the guanine nucleotide-binding protein subunit alpha-11 (G-protein α-11). Additional defects include loss-of-function mutations affecting essential transcription factors or the PTH gene.
Dr. Clarke explains: "The clinical presentation varies widely from mild disease with tingling paresthesias and muscle cramps to more severe disease that may result in bronchospasm, laryngospasm, seizures, QT interval prolongation leading to cardiac dysrhythmias or, in extreme cases, sudden death. Onset of symptoms after surgery usually occurs within several days. Other causes may have subtle onset over years before they are finally recognized. Most patients have a moderate presentation with variable symptoms over time.
"Diagnosis of patients with suspected hypoparathyroidism requires assessment of fasting serum calcium, phosphorus, creatinine, PTH, 25-hydroxyvitamin D and magnesium. Once the diagnosis is confirmed, measurement of 24-hour urine calcium and creatinine is recommended to assess for baseline hypercalciuria."
Dr. Clarke outlines: "Treatment with oral calcium and active vitamin D in divided doses each day is currently the standard of care, occasionally supplemented with magnesium, thiazide-type diuretics or phosphate binders, but this does not fully replace the functions of the missing PTH and can lead to long-term complications such as nephrocalcinosis, calcium-containing kidney stones, renal dysfunction, basal ganglia calcifications and posterior subcapsular cataracts.
"Of particular concern are increased calcium losses in the urine in the absence of PTH, which are associated with nephrocalcinosis and impaired renal function in the long term. Several clinical studies have also reported decreased quality of life among patients with hypoparathyroidism."
Recent international guidelines published in Journal of Clinical Endocrinology and Metabolism in 2016 recommend six goals for chronic management therapy of patients with hypoparathyroidism, including:
- Prevention of signs and symptoms of hypocalcemia
- Maintenance of serum calcium slightly below normal (no more than 0.5 mg/dL below normal) or in the low-normal range
- Maintenance of the calcium x phosphate product below 55 mg2/dL2 (4.4 mmol2/L2)
- Avoidance of hypercalciuria, maintaining urinary calcium excretion within normal limits
- Avoidance of hypercalcemia
- Avoidance of renal and other extraskeletal calcifications
Dr. Clarke highlights: "Novel treatments are therefore needed, and until recently hypoparathyroidism represented one of the few endocrine deficiency states not treated by replacement of the missing hormone. Recent trials demonstrating the efficacy of recombinant human (rh) PTH(1-84) for the treatment of hypoparathyroidism have led to the approval of rhPTH(1-84) for hypoparathyroidism in the United States in January 2015."
The international guidelines published in Journal of Clinical Endocrinology and Metabolism in 2016 recommended consideration of treatment with rhPTH(1-84) in patients with:
- Variable and inconstant control of the serum calcium with frequent episodes of hypo- and hypercalcemia
- Nephrocalcinosis, reduced creatinine clearance or eGFR < 60 mL/min
- Hypercalciuria or other biochemical indices of renal stone risk or both
- Persistently increased serum phosphate or calcium x phosphate product or both (> 55 mg2/dL2 or 4.4 mmol2/L2)
- Excessive amounts of oral medications required to control symptoms, such as > 2.5 g of calcium or > 1.5 μg of active vitamin D or both
- A gastrointestinal tract disorder that might lead to variable calcium and vitamin D absorption
- Reduced quality of life
The decision to recommend rhPTH(1-84) should take into account the fact that this is currently an expensive drug.
Dr. Clarke notes: "The approval of this agent for treatment of hypoparathyroidism has stimulated research into new treatment modalities and development of PTH analogues. As new therapies become more widely available, evaluation of their effect on disease control, long-term complications and quality of life will be critically important."
For more information
Brandi ML, et al. Management of hypoparathyroidism: Summary statement and guidelines. Journal of Clinical Endocrinology and Metabolism. 2016;101:2273.