Hypoparathyroidism

HYPOPARATHYROIDISM by Svetlana Shifrin-Douglas, MD (Endocrinologist in Red Bank, NJ www.endocrinologynj.com)

Hypoparathyroidism is a disorder that causes lower than normal levels of calcium in the blood due to insufficient levels of parathyroid hormone (PTH) or inappropriately low levels of parathyroid hormone (PTH) in the circulation. This condition can be inherited, associated with other disorders or it may result from the remove of the thyroid during neck surgery. Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia and low or inappropriately normal levels of parathyroid hormone (PTH). Causes include autoimmune diseases, genetic abnormalities, destruction or infiltrative disorders of the parathyroids. Impaired secretion of PTH may be seen with hypomagnesemia or hypermagnesemia.

Classification: 1. Congenital Hypoparathyroid Disorders; 2. Autoimmune Hypoparathyroidism 3. Postsurgical Hypoparathyroidism.

Congenital Hypoparathyroid Disorders: Isolated Hypoparathyroidism (Autosomal recessive, Autosomal dominant, X-linked), Hypoparathyroidism With Additional Features (Polyglandular autoimmune syndrome, DiGeorge syndrome, Hypoparathyroidism-retardation-dysmorphism syndrome, Hypoparathyroidism-deafness-renal dysplasia syndrome); Mitochondrial Disorders Associated With Hypoparathyroidism (Kearns-Sayre syndrome, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial trifunctional protein deficiency syndrome); Pseudohypoparathyroidism; Blomstrand chondrodysplasia. These inherited disorders of hypoparathyroidism are often classifiable according to the defined genetic defects, including abnormalities of PTH biosynthesis, PTH secretion, parathyroid gland development, or parathyroid tissue destruction. Genetic defects may also be associated with complex syndromes involving other organ defects.

Autoimmune Hypoparathyroidism

After postsurgical hypoparathyroidism, autoimmune hypoparathyroidism is the next most common form of hypoparathyroidism in adults. Autoimmune hypoparathyroidism may be isolated or part of an autoimmune polyglandular syndrome (APS). Anti-parathyroid gland antibodies were found in 38% of 75 patients with idiopathic hypoparathyroidism, 26% of 92 patients with idiopathic Addison disease, 12% of 49 patients with Hashimoto thyroiditis, and 6% of 245 normal controls

Postsurgical Hypoparathyroidism. The most common acquired cause of hypoparathyroidism in adults is postsurgical hypoparathyroidism. Surgery on the thyroid or parathyroid glands or adjacent neck structures or neck dissection surgery for malignancy may lead to acute or chronic hypoparathyroidism. Postsurgical hypoparathyroidism is usually due to inadvertent or unavoidable removal of or damage to the parathyroid glands and/or their blood supply. While transient hypoparathyroidism after neck surgery is relatively common, often called “stunning” of the glands, chronic partial hypoparathyroidism is less common, and chronic complete hypoparathyroidism relatively rare. The diagnosis of chronic hypoparathyroidism requires that features of hypoparathyroidism persist for at least 6 months after surgery. Most patients with postsurgical hypoparathyroidism recover parathyroid gland function within several weeks to months after surgery and, thus, do not develop permanent disease. Some patients with chronic hypoparathyroidism have a period of being relatively asymptomatic, and their biochemical abnormalities are found in a routine checkup or during the routine investigation of related but nonspecific symptoms (eg, fatigue, muscle aching). The development of postsurgical hypoparathyroidism, years after neck surgery, suggests that age-related compromise of the remaining parathyroid tissue eventually leads to gland hypofunction. The mechanism of this time-related process is not clear but eventual deficiency of the parathyroid blood supply is an attractive possibility.

The rates of postsurgical hypoparathyroidism vary across centers and with different procedures and surgical expertise. Surgical centers with experienced endocrine surgeons and a high case volume report rates of post-thyroid surgical permanent hypoparathyroidism of 0.9-1.6%. Earlier reports had suggested that after thyroid surgery, permanent hypoparathyroidism can occur with a frequency as high as 6.6%. These studies emphasize the importance of expertise and experience. Transient hypoparathyroidism after thyroid surgery occurs with much higher frequency, ranging from 6.9% to 46%. Parathyroid dysfunction after surgical manipulation of neck structures commonly occurs several days to weeks and even years after the procedure. Postoperative hypoparathyroidism is more likely to occur in patients who have undergone more than one neck operation and/or if extensive thyroid resection is required. Surgery for substernal goiter, head or neck malignancies involving the anterior neck structures, or Graves disease have all been shown to increase the risk of postoperative hypoparathyroidism.

Patients with hypoparathyroidism most often present with paresthesia, cramps, or tetany, but the disorder may also manifest acutely with seizures, bronchospasm, laryngospasm, or cardiac rhythm disturbances. In the postsurgical setting, the presentation can be acute with tetany, cramping, tachycardia, and altered mental status dominating the picture. The disorder occurs in both acquired and inherited forms.

Work-up includes a comprehensive history, physical examination, and a relevant biochemical investigation. Treatment of symptomatic or profound asymptomatic hypocalcemia (Corrected Calcium (Ca)

Management

Acute symptomatic hypocalcemia (carpal or pedal spasm, seizures, broncho- or laryngospasm) can be a medical emergency requiring acute intravenous administration of calcium. Intravenous calcium gluconate should be used. Calcium chloride should be avoided because it is irritating and potentially sclerosing to veins. Ten milliliters of 10% calcium gluconate diluted in 100 mL 5% dextrose (D5W) is infused intravenously over 5-10 minutes. This infusion provides 90 mg of elemental calcium and can be followed by a continuous infusion of a larger amount based on body weight: 15 mg/kg of elemental calcium generally translates to approximately 10 ampules (900 mg of elemental calcium) diluted in 1 L of D5W at 50 mL/h. Over 8 hours, this infusion protocol will raise the serum calcium by approximately 2 mg/dL. Magnesium should also be administered.

Chronic Management: oral calcium and vitamin D analogs are critical in the treatment of hypocalcemia. In the long-term management of hypoparathyroidism thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor. The recommended calcium supplements are calcium carbonate and calcium citrate, the latter being more consistently helpful in those with achlorhydria or after gastric bypass procedure. 1,25(OH)2D3 (calcitriol), the active metabolite of vitamin D, maintains serum calcium, in part, by improving the efficiency of intestinal calcium absorption. It can increase serum calcium substantially within 3 days, by using wide dosing range: 0.25-2.0 μg/d. Parathyroid hormone replacement is of great value in improving serum calcium and lowering serum phosphate as well as the doses of calcium and calcitriol supplementation required. Replacement therapy using synthetic human parathyroid hormone, Teriparatide [PTH(1-34)], twice-daily could maintain serum calcium in the low normal or just below the normal range over a several years.

References

Bilezikian JP, Khan A, Potts JT Jr, Brandi ML, Clarke BL, Shoback D, Jüppner H, D'Amour P, Fox J, Rejnmark L, Mosekilde L, Rubin MR, Dempster D, Gafni R, Collins MT, Sliney J, Sanders J. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res. 2011 Oct;26(10):2317-37.

Al-Azem H, Khan AA. Hypoparathyroidism. Best Pract Res Clin Endocrinol Metab. 2012 Aug;26(4):517-22

Thomusch O, Machens A, Sekulla C, et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A multivariate analysis of 5846 consecutive patients. Surgery. 2003;133:180–195.

Zarnegar R, Brunaud L, Clark OH. Prevention, evaluation, and management of complications following thyroidectomy for thyroid carcinoma. Endocrinol Metab Clin North Am. 2003;32:483–502.

Page C, Strunski V. Parathyroid risk in total thyroidectomy for bilateral, benign, multinodular goiter: Report of 351 surgical cases. J Laryngol Otol. 2007;121:237–241.

Shoback D. Clinical practice: Hypoparathyroidism. New Engl J Med. 2008; 359:391–403.

Falk SA, Birken EA, Baran DT. Temporary postthyroidectomy hypocalcemia. Arch Otolaryngol Head Neck Surg. 1998;114:168–174.

Percival RC, Hargreaves AW, Kanis JA. The mechanism of hypocalcemia following thyroidectomy. Acta Endocrinol. 1985;109:220–226.

See ACH, Soo KC. Hypocalcemia following thyroidectomy for thyrotoxicosis. Br J Surg. 1997;84:95–97.

Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. New Engl J Med. 2004;350:2068–2079.

Blizzard RM, Chee D, Davis W. The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin Exp Immunol. 1966;1:119–128.

Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am. 1993;22:363–375.

Murphy E, Williams GR. Hypocalcaemia. Medicine. 2009;37:465–468.

Cooper MS, Gittoes NJL. Diagnosis and management of hypocalcaemia. BMJ. 2008;336:1298–1302.

Rude RK. Hypocalcemia and hypoparathyroidism. Curr Ther Endocrinol Metab. 1997;6:546–551.

Thakker R. Parathyroid Disorders and Diseases Altering Calcium Metabolism. 4. Oxford University Press; Oxford, England, UK: 2003

Shoback D. Hypoparathyroidism. N Engl J Med. 2008;359:391–403.

Winer KK, Yanovski JA, Cutler GB., Jr Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA. 1996;276:631–636. [PubMed]

Winer KK, Yanovski JA, Sarani B, Cutler GB., Jr A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab. 1998;83:3480–3486.

Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: A randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003;88:4214–4220.

Winer KK, Sinaii N, Peterson D, Sainz B, Jr, Cutler GB., Jr Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab. 2008;93:3389–3395.

Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K, Cutler GB. Long-term treatment of 12 children with chronic hypoparathyroidism: A randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab. 2010;95:2680–2688.