Alalawi Y, El Werfalli R, Abu Alrob H, et al. MON-LB091 An Overview of the Etiology, Clinical Manifestations, Management Strategies, and Complications of Hypoparathyroidism from the Canadian National Hypoparathyroidism Registry. J Endocr Soc. 2019 Apr 30;3(Suppl 1):MON-LB091. doi: 10.1210/js.2019-MON-LB091. PMCID: PMC6551102.
Khan AA, Koch C, Van Uum SHM, et al. Standards of Care for Hypoparathyroidism in Adults. Eur J Endocrinol. 2018 Dec 1. pii: EJE-18-0609.R1. doi: 10.1530/EJE-18-0609. [Epub ahead of print] PubMed PMID: 30540559; PubMed Central PMCID: PMC6365672.
Husebye ES, Anderson MS, Kämpe O. Autoimmune Polyendocrine Syndromes. N Engl J Med. 2018 Mar 22;378(12):1132-1141. doi: 10.1056/NEJMra1713301. Review. PubMed PMID: 29562162; PubMed Central PMCID: PMC6007870.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of Hypoparathyroidism: Summary Statement and Guidelines. J Clin Endocrinol Metab. 2016 Jun;101(6):2273-83. doi: 10.1210/jc.2015-3907. Epub 2016 Mar 4. Review. PubMed PMID: 26943719.
Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012 Dec;97(12):4507-14. doi: 10.1210/jc.2012-1808. Epub 2012 Oct 5. PubMed PMID: 23043192; PubMed Central PMCID: PMC3513540.
Definition, Etiology, PathogenesisTop
Hypoparathyroidism is a relatively uncommon condition associated with hypocalcemia and hyperphosphatemia in the presence of low or inappropriately normal parathyroid hormone (PTH) levels. It is associated with significant symptoms of hypocalcemia as well as long-term complications of inadequate PTH levels, hypocalcemia, and hyperphosphatemia.
1) Neck surgery is the most common cause of primary hypoparathyroidism, accounting for 75% of all cases. During neck surgery the parathyroid glands may be damaged or deprived of their blood supply. Patients with transient hypoparathyroidism after surgery may recover; however, if the serum calcium level remains low for ≥6 months, the diagnosis of chronic hypoparathyroidism is confirmed.
2) Nonsurgical causes of hypoparathyroidism account for 25% of cases:
a) Autoimmune hypoparathyroidism is the most common cause of nonsurgical primary hypoparathyroidism. It may occur in isolation or as part of autoimmune polyendocrine syndrome type 1 (APS-1). APS-1 is caused by mutations in the AIRE (autoimmune regulator) gene. Among such patients, 80% have only hypoparathyroidism; other major features of APS-1 are adrenal insufficiency and oral or vaginal candidal infections. Individuals with APS-1 should be followed up to ensure that other major or minor features of APS do not develop.
b) Infiltrative causes include destruction of the parathyroid glands secondary to granulomatous infiltration (eg, Riedel thyroiditis, amyloidosis, sarcoidosis).
c) Metastatic cancer can be a rare cause of hypoparathyroidism, with the most common tumors being tumors of the breast, skin, or lung, as well as leukemia, lymphomas, and sarcomas.
d) Radiation destruction can also be a cause, although high doses of ionizing radiation exposure have been rarely associated with hypoparathyroidism.
e) Mineral deposition can result in hypoparathyroidism with iron overload in hemochromatosis or with repeat blood transfusions and can also develop in individuals with thalassemia. Wilson disease with copper deposition in the parathyroid glands has been reported to cause hypoparathyroidism.
f) Transient hypoparathyroidism can be seen in the presence of severe burn injuries and acute illness.
g) Functional hypoparathyroidism is caused by hypomagnesemia as well as hypermagnesemia, both of which impair parathyroid function (Table 6.6-1).
h) Maternal hyperparathyroidism can result in suppressed parathyroid function in infants exposed to hypercalcemia in utero.
i) Idiopathic hypoparathyroidism is confirmed if the cause of hypoparathyroidism is not identified after laboratory and clinical evaluation.
Two additional clinical states have traditionally carried “hypoparathyroidism” as part of their name but are either distinct or not a disease entity. Pseudohypoparathyroidism (PHP) is defined as target organ resistance to PTH. PHP is characterized by elevated PTH levels in association with low serum calcium and high phosphate levels. Secondary hypoparathyroidism is not a disease state but a physiologic response where PTH levels are low in response to a primary process that has caused hypercalcemia (see Hypercalcemia).
Clinical Features and Natural HistoryTop
1. Symptoms of hypocalcemia include muscle cramping; twitching; numbness and tingling in the face, hands, or feet; depression or irritability; seizures; bradyarrhythmias; wheezing; and laryngospasm (Table 6.6-2). On physical examination the Chvostek sign (Figure 6.6-3) and Trousseau sign (Figure 6.6-4) can be somewhat helpful, but they are not sensitive or specific enough for diagnosis and are mostly of historical interest.
2. Target organ damage: In patients with chronic hypoparathyroidism prolonged hypercalciuria and hyperphosphatemia can result in the development of nephrocalcinosis, nephrolithiasis, and renal insufficiency. Renal function and urine calcium losses should be closely monitored with 24-hour urine calcium measurements as well as assessments of renal function. Nephrocalcinosis or nephrolithiasis can be identified using renal imaging such as ultrasonography. The risk for developing renal stones and renal insufficiency in individuals with postsurgical hypoparathyroidism was found to be increased 4.8 times and 3.1 times, respectively, as compared with control populations.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data and increased due to large effect size. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. J Bone Miner Res. 2013 Nov;28(11):2277-85. doi: 10.1002/jbmr.1979. PubMed PMID: 23661265.
Patients with hypoparathyroidism are at risk of developing cataracts, which occur in ~50% of cases.
Intracranial calcification with calcification of the basal ganglia has also been observed in individuals with hypoparathyroidism. This has been associated with elevations in serum phosphate levels and was noted to occur in the presence of a normal calcium phosphate product by the Canadian National Hypoparathyroidism Registry. Intracranial calcification has also been associated with dystonias and parkinsonism. Brain imaging and electroencephalography are helpful tools in evaluating neurocognitive decline, movement disorders, or seizures in individuals with hypocalcemia.
The standards of care for hypoparathyroidism advise lowering urine calcium losses and maintaining serum phosphate levels in the normal reference range to reduce the risk of extra skeletal calcification as well as the risk of renal, neurologic, and ocular complications associated with hypoparathyroidism. The calcium phosphate product should be maintained in the normal reference range; however, renal complications have been observed even in the presence of a normal calcium phosphate product.
3. Quality of life: Hypoparathyroidism is associated with diminished quality of life. Complaints of “brain fog,” myalgias, numbness, paresthesias, fatigue, weakness, anxiety, and depression all contribute to a lower quality of life. Studies assessing the quality of life in patients with hypoparathyroidism using standardized measurements show that patients with hypoparathyroidism have a lower quality of life relative to control populations irrespective of disease duration, etiology, and treatment with activated vitamin D and calcium supplements. Loss of PTH may have significant effects on cognition and overall well-being; this is an area of active research.
For patients with nonsurgical hypoparathyroidism, a detailed family history is required including the presence of consanguinity. Clinical evaluation is used to determine if other features associated with genetic or autoimmune causes of hypoparathyroidism are present. Currently genetic testing is available, enabling a molecular diagnosis of the cause of hypoparathyroidism.
Low serum calcium levels (corrected for low albumin levels if needed) or low ionized calcium levels should be confirmed on ≥2 separate occasions prior to confirming the diagnosis of hypocalcemia. Low PTH levels should also be confirmed on ≥2 occasions. If PTH levels are not clearly elevated in the presence of hypocalcemia, this confirms the diagnosis of hypoparathyroidism, as it indicates an impaired parathyroid response to the low serum calcium levels.
After parathyroid surgery hypoparathyroidism can be acute and transient (present for <6 months after surgery) or chronic and permanent (present for >6 months after surgery). The diagnosis of permanent surgical hypoparathyroidism is confirmed by the presence of hypocalcemia (ionized calcium or low total serum calcium levels corrected for albumin) for ≥6 months after surgery (in the presence or absence of clinical symptoms) and in the presence of low or inappropriately normal PTH levels on 2 separate occasions.
Management requires close monitoring of the biochemical profile and drug therapy in order to minimize symptoms of hypocalcemia while avoiding overtreatment with the development of hypercalcemia. Prevention of long-term complications requires avoidance of hypercalciuria and hyperphosphatemia. Conventional therapy includes calcium and active vitamin D supplementation. PTH replacement therapy is of value in those in whom conventional therapy has failed.
Acute hypocalcemia may require IV calcium, depending on the rate of onset, clinical symptoms, and biochemical severity of hypocalcemia. Symptomatic hypocalcemia requires IV administration of calcium, with the preferred preparation being calcium gluconate. If the total serum calcium level corrected for albumin is <1.75 mmol/L, our advice is that IV calcium should be administered even if the patient is asymptomatic to avoid serious complications of hypocalcemia, including laryngospasm, seizures, or cardiac arrythmias.
A bolus of IV calcium transiently elevates serum calcium for ~2 to 3 hours and a continuous infusion is required to prevent subsequent decreases in serum levels. Calcium gluconate is preferred to avoid local venous irritation, which can be seen with calcium chloride infusions. Electrocardiographic (ECG) monitoring is required for early detection of any cardiac arrythmias that may occur with calcium infusion.
In the presence of acidosis the ionized calcium level is higher, as calcium ions are displaced from binding to albumin by hydrogen ions. It is important to correct serum calcium levels prior to correcting acidosis to prevent significant declines in serum calcium concentration.
Avoid infusing sodium bicarbonate or phosphate in the same IV administration line as calcium to prevent precipitation of calcium carbonate or calcium phosphate.
Following the administration of the initial bolus of IV calcium gluconate, a calcium infusion is initiated. A calcium bolus is given over 10 minutes and consists of a 1-g of calcium gluconate in 10 mL of a 10% solution or 90 mg of elemental calcium. Following the bolus, a calcium infusion is started, with 10 ampoules of calcium gluconate containing 900 mg of elemental calcium in 1 L of 5% glucose (dextrose) or 0.9% saline (1 mg/mL solution). The infusion is started at 50 mL/h and is titrated to normal serum calcium concentration. To elevate serum calcium levels by 0.5 to 0.75 mmol/L, ~15 mg/kg of elemental calcium IV must be administered over 4 to 6 h.
If the patient is able to take oral calcium supplements, these are also started at the same time as the calcium infusion. Oral calcium salts can be given in the form of calcium carbonate, which contains 40% elemental calcium and is easier to comply with as fewer tablets are required orally. Calcium citrate contains 21% elemental calcium and can be useful in the presence of proton pump inhibitors or achlorhydria, as an acidic pH is not required for absorption of calcium citrate (this is a requirement for the absorption of calcium carbonate). Calcium supplements are initiated in doses of 500 mg to 1000 mg taken with food bid to tid. Patients may require up to 9 g daily. Calcitriol supplementation is of great value as it replaces the deficient 1,25(OH)2D, which is also low in the absence of PTH. Calcitriol is started at a dose of 0.25 microg once daily or bid and gradually titrated upwards to a maximum of 2 microg daily. Calcitriol has a rapid onset of action with a peak occurring at 3 to 6 hours of administration and a half-life of 4 to 6 hours. Vitamin D stores must also be replenished with cholecalciferol or ergocalciferol and hypomagnesemia (see Hypomagnesemia) must be corrected.
Treatment goals of chronic management are to reduce symptoms of hypocalcemia and the risk of long-term complications of hypercalciuria and hyperphosphatemia. Conventional therapy includes calcium supplementation, active vitamin D and its analogues, as well as hydrochlorothiazide, which is helpful in enhancing renal calcium reabsorption. Serum magnesium and potassium levels should be closely monitored as renal losses leading to hypomagnesemia and hypokalemia are common with thiazide use. Begin hydrochlorothiazide with low doses of 12.5 mg daily and gradually titrate upwards. Magnesium supplementation is used as necessary to normalize magnesium levels.
Hyperphosphatemia can be controlled by using phosphate binders and by following a low-phosphate diet. Calcium is an ideal phosphate binder and all patients are advised to take calcium supplements with food, as it binds phosphate in the meal and enables loss of phosphate in the stool. A low-salt diet will also lower urinary calcium losses.
Failure of conventional therapy is confirmed in the presence of poor control of serum calcium, complications of hypoparathyroidism, or poor quality of life; in such cases patients can be offered PTH therapy (see below).
Conventional therapy with calcium and active vitamin D supplementation has been associated with worsening hypercalciuria, renal stones, ectopic calcifications, impaired renal function, and nephrocalcinosis. PTH therapy enhances renal calcium reabsorption and contributes to improved renal phosphate clearance.
Recombinant human PTH (rhPTH) (1-84) therapy has been approved as an adjunct to conventional treatments in Europe and in the United States. PTH(1-84) has been shown to lower urinary calcium losses and serum phosphate levels and allows the patient to decrease the dose of calcium and calcitriol required to maintain target serum calcium concentration. It also makes it possible to achieve normal serum phosphate and urine calcium levels. The majority of patients are able to stop or lower the dose of calcium and calcitriol supplementation required to maintain serum calcium concentration in the low-normal reference range.
PTH(1-34) in doses of 20 microg bid resulted in reductions in the dose of calcium and calcitriol required daily and increased serum calcium while lowering serum phosphate.
Replacement therapy with PTH(1-84) resulted in maintenance of serum calcium and phosphate levels in the appropriate range with reduced daily doses of calcium and active vitamin D metabolites.
PTH therapy is well tolerated and has mild and/or transient adverse events. Long-term data is limited, with no long-term studies evaluating the potential benefits and risks of PTH(1-84) therapy. The US Food and Drug Administration (FDA) has approved PTH(1-84) for the treatment of hypoparathyroidism with a “black box” warning due to a potential increased risk of osteosarcoma observed in rats treated with high doses of PTH(1-34). PTH therapy can be considered in the presence of:
1) Poorly controlled serum calcium levels with calcium and calcitriol therapy.
2) Requirements of high doses of oral calcium or vitamin D metabolites (>2.5 g of calcium or >1.5 microg of calcitriol per day).
3) Hypercalciuria, renal stones, nephrocalcinosis, reduced creatinine clearance, or reduced estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m2).
4) Hyperphosphatemia and/or calcium-phosphate product >55 mg2/dL2 (4.4 mmol2/L2).
Recommendations from the standards of care for hypoparathyroidism (the 2018 Canadian and international consensus):
1) Corrected serum calcium levels (albumin-corrected or ionized calcium), phosphorus, magnesium, urea nitrogen, and creatinine should be monitored every 3 to 6 months. If changes are made in the dose of calcium or calcitriol, or if symptoms of hypocalcemia or hypercalcemia occur, serum calcium and phosphate may require weekly evaluation.
2) Annual monitoring of urinary calcium excretion, creatinine, and sodium (either by 24-hour urine collection or random urine collection), and 25(OH)D levels is currently advised.
3) Renal imaging by ultrasonography for the presence of nephrocalcinosis or nephrolithiasis is recommended at baseline and is of particular importance in individuals with persistent hypercalciuria, history of renal stones, abnormal urinalysis, or a decline in eGFR.
4) Signs and symptoms of hypercalcemia and hypocalcemia should be evaluated every 6 months, depending on the stability of hypoparathyroidism.
5) The general health of the patient should also be assessed, as many symptoms of hypoparathyroidism are nonspecific and include brain fog and low energy.
6) Basal ganglia calcification can be assessed with brain computed tomography (CT) or susceptibility-weighted magnetic resonance imaging (MRI).
7) An eye examination is of value to determine if cataracts are present.
8) Bone mineral density (BMD) is usually higher than expected for age and gender as evaluated by dual x-ray absorptiometry (DXA). Spinal radiographs may be completed with exclusion of vertebral fractures in the presence of significant height loss, back pain, or spinal deformity. At this time there is very limited data on the effects of hypoparathyroidism on fracture risk.
Tables and FiguresTop
Low serum magnesium
Decreased intake or absorption
– Decreased intake
– Malabsorption (short bowel syndrome, steatorrhea, diarrhea, vomiting)
– Diuretics (especially thiazides)
– Proton pump inhibitors
– Foscarnet, amphotericin B, aminoglycosides, pentamidine, rapamycin
– Anticancer drugs (cisplatin, carboplatin)
– Immunosuppressants (calcineurin inhibitors: tacrolimus, cyclosporine A)
– EGRF inhibitors (cetuximab)
Rare genetic disorders
– Familial hypomagnesemia with secondary hypocalcemia (TRPM6 gene mutation)
– Autosomal dominant hypocalcemia (activating mutation in the CASR gene)
– Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
High serum magnesium
– Magnesium administration for eclampsia or preeclampsia
– Intake in laxatives or cathartics
– Metabolic syndromes (familial hypocalciuric hypercalcemia)
– Chronic kidney disease
EGFR, epidermal growth factor receptor.
– Numbness, tingling in face, hands and feet
– Muscle spasms or cramps, laryngospasm
– Bradyarrhythmia, heart failure
– Depression, confusion, seizures
– Nausea, vomiting, anorexia
– Polyuria, polydipsia
Figure 6.6-3. Chvostek sign. Illustration courtesy of Dr Shannon Zhang.
Figure 6.6-4. Trousseau sign. Illustration courtesy of Dr Shannon Zhang.