Hypoparathyroidism

I. What every physician needs to know.

Primary hypoparathyroidism is a common cause of hypocalcemia. Parathyroid hormone (PTH) secretion is critical to the mobilization of calcium from bone, reabsorption of calcium in the kidneys, and intestinal absorption of calcium (through its stimulating effect on 1 alpha-hydroxylase activity in the kidneys).

Primary hypoparathyroidism can be hereditary or acquired. Genetic disorders, such as DiGeorge syndrome, familial hypoparathyroidism, and other rare disorders will only be suspected with a thorough history. The most common forms of hypoparathyroidism occur due to removal or destruction of parathyroid tissue.

This can occur through surgical removal or damage, autoimmune processes (isolated or part of a syndrome), metastatic infiltration, amyloidosis, or heavy metal deposition (e.g. iron or copper). Finally, magnesium is critical for PTH secretion and receptor activation. Therefore, magnesium deficiency or excess can lead to functional hypoparathyroidism.

Secondary hypoparathyroidism is diagnosed when serum PTH is low in response to a high serum calcium.

II. Diagnostic Confirmation: Are you sure your patient has hypoparathyroidism?

Primary hypoparathyroidism is defined by a low serum PTH and a low calcium level. Secondary hypoparathyroidism is defined by a low serum PTH and an elevated calcium level.

Pseudohypoparathyroidism should be diagnosed in consultation with an endocrinologist. It is characterized by insensitivity to the biological activity of PTH (PTH resistance) with resultant low calcium, high phosphate, and high serum PTH. To make a diagnosis, the skeletal and renal responsiveness to PTH should be assessed. This requires a measurement of changes in phosphorous, calcium, cyclic adenosine monophosphate (cAMP), and calcitriol in response to administration of biosynthetic PTH.

A. History Part I: Pattern Recognition:

A thorough patient and family history is critical to determining the cause of the hypocalcemia and primary hypoparathyroidism. Hypocalcemia can result in severe cardiac and respiratory collapse, or it can be completely asymptomatic. The clinical presentation will be dependent on the underlying etiology of the primary hypoparathyroidism and the level/rate of fall of the calcium.

Secondary hypoparathyroidism will be accompanied by hypercalcemia with the presentation dependent upon the underlying etiology.

Pseudohypoparathyroidism should be distinguished from Vitamin D deficiency which can have a similar biochemical profile. The characteristic findings of AHO will be present if Type 1a is the underlying etiology.

General history for primary hypoparathyroidism:

Is there a family history of hypocalcemia to suggest a genetic disorder?
Is there a history of neck surgery?
Is there evidence to suggest other autoimmune endocrinopathies? (e.g. vitiligo or adrenal insufficiency)
Are there any features to suggest immunodeficiency? (e.g. recurrent infections or candidiasis)
Is there a history of congenital defects? (see DiGeorge Syndrome).
Is hypomagnesemia suspected?
Has there been parenteral magnesium administration or chronic renal failure that would make hypermagnesemia likely?
Is hemochromatosis or transfusion-dependent thalassemia causing iron infiltration into the parathyroid gland?
Is copper infiltration of the parathyroid gland likely, in the setting of Wilson’s Disease?
Is amyloidosis possible?
Is metastatic cancer possible?

B. History Part 2: Prevalence:

Secondary hypoparathyroidism occurs in the setting of hypercalcemia (See Table I).

Primary Hypoparathyroidism: Diagnoses and risk factors.

Pseudohypoparathyroidism is a heterogeneous group of disorders with a similar biochemical profile (hypocalcemia, hyperphosphatemia, and elevated PTH levels). Type 1a has clinical features of Albright hereditary osteodystrophy (AHO) with an autosomal dominant inheritance pattern. Type 1b has no features of AHO. Both Type 1a and Type 1b are caused by mutations in the same gene (GNAS). Type 2 is less common than type 1a or b and can be inherited or sporadic. Its mechanism is unknown.

C. History Part 3: Competing diagnoses that can mimic hypoparathyroidism.

Primary hypoparathyroidism should be distinguished from other causes of hypocalcemia and pseudohypoparathyroidism by the finding of a low serum PTH level.

Secondary hypoparathyroidism is discussed separately in the hypercalcemia section.

Pseudohypoparathyroidism should be distinguished from Vitamin D deficiency which can have a similar biochemical profile (hypocalcemia, hyperphosphatemia, and elevated PTH levels). It is worth noting that Vitamin D deficiency will typically have a low phosphate level (as well as high PTH and low calcium) but it can be elevated due to dietary or diurnal variations.

D. Physical Examination Findings.

The physical exam findings of hypocalcemia and hypercalcemia are described elsewhere. Remember that the severity of symptoms and signs will depend on the level of calcium and the rate of change.

Additional important exam findings include:

Presence of or lack of a surgical scar on the neck
Candidiasis (immunosuppression)
Vitiligo (autoimmune disease)
Signs of liver disease (hemochromatosis, Wilson’s disease)
Features of congenital anomalies or growth retardation

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A diagnosis of primary hypoparathyroidism is usually made when evaluating a patient for hypocalcemia. The most important laboratory testing includes: ionized or adjusted calcium, serum PTH, serum phosphate, 25 hydroxyvitamin D level, assessment of renal function, and a magnesium level.

Primary hypoparathyroidism is defined by a low serum PTH and a low calcium level. Serum phosphate levels are typically elevated.

Secondary hypoparathyroidism is defined by a low serum PTH and an elevated calcium level.

Pseudohypoparathyroidism should be diagnosed in consultation with an endocrinologist. It is characterized by insensitivity to the biological activity of PTH (PTH resistance) with resultant low calcium, high phosphate, and high serum PTH. To make a diagnosis, the skeletal and renal responsiveness to PTH should be assessed. This requires a measurement of changes in phosphorous, calcium, cAMP, and calcitriol in response to administration of biosynthetic PTH.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no radiographic studies needed to make a diagnosis of primary hypoparathyroidism. Certain genetic disorders, such as DiGeorge syndrome can have characteristic findings on imaging.

Appropriate imaging in the setting of secondary hypoparathyroidism is dependent on the underlying etiology of the hypercalcemia.

Pseudohypoparathyroidism with findings of Albright hereditary osteodystrophy (AHO) will have characteristic physical features and radiographic findings.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Measurement of 1,25 dihydroxyvitamin D levels is generally not useful in the work-up of hypocalcemia or hypoparathyroidism.
Serum phosphorous levels can be useful when hypoparathyroidism or pseudohypoparathyroidism is suspected. However, the diurnal and dietary variability in serum levels can occasionally confuse the picture in the initial evaluation of hypocalcemia.
24 hours collections of urinary calcium, magnesium and creatinine can be helpful in the evaluation of hypoparathyroidism. However, these should not be included in the initial testing and probably ordered under the direction of an endocrinologist or nephrologist.
Pseudohypoparathyroidism should be diagnosed in consultation with an endocrinologist. To make a diagnosis, the skeletal and renal responsiveness to PTH should be assessed. This requires a measurement of changes in phosphorous, calcium, cAMP, and calcitriol in response to administration of biosynthetic PTH.
Specialized testing, such as genetic sequencing, should be ordered under the direction of an endocrinologist or geneticist.

III. Default Management.

The management of hypocalcemia and hypercalcemia is described elsewhere. Generally, the goal of therapy is directed by the level of calcium and severity of symptoms.

A. Immediate management.

In the setting of hypocalcemia, severe symptoms should be treated with intravenous (IV) calcium regardless of the degree of decrease in serum calcium.

With severe symptoms (such as volume overload, seizure activity, bronchospasm, laryngospasm, or altered mental status) make sure to obtain an electrocardiography (EKG) and place the patient on telemetry. Support for the patient’s hemodynamics as needed.

B. Physical Examination Tips to Guide Management.

Management should be guided by the serum calcium level and the sign/symptoms that led to the diagnosis of hypocalcemia or hypercalcemia.

For instance, if there is evidence of neuromuscular excitability on presentation with a positive Trousseau’s sign, it would be valuable to ensure cessation with therapy.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Parenteral calcium will only raise the serum calcium level transiently. A continuous infusion is often required. Therapy should be monitored with serial serum calcium levels until symptoms have resolved and values are within the reference range.
Initially, serum calcium levels should be obtained every 1-2 hours while the infusion is adjusted and every 4-6 hours thereafter to ensure stability. Oral calcium can be started concomitantly, if the patient is able to tolerate orally. The calcium infusion should be slowly tapered over 24-48 hours, dependent on the severity of the patient’s presentation and duration of ongoing symptoms.
If a QT abnormality was uncovered on presentation the patient should be placed on telemetry with serial EKGs, until resolution is demonstrated.
There is no value in obtaining serial phosphate levels in the acute setting, but this is important for long-term management.

D. Long-term management.

Primary hypoparathyroidism

Consultation with an endocrinologist is warranted. Endocrinologist consultation is required if use of recombinant human PTH is considered as use of this product requires special certification with the Food and Drug Administration (FDA) prior to prescribing.
Initial management is with calcium and vitamin D supplementation.
Calcium supplementation should be administered in a form and dose that is tailored to the patient’s needs (e.g., calcium acetate in chronic kidney disease or calcium citrate in patients with achlorhydria).
Vitamin D supplementation is critical, but do not use Vitamin D2 or D3. Calcitriol should be administered under the direction of an endocrinologist. A typical starting dose is 0.5 micrograms (mcg) of calcitriol with dosage increases every 4-7 days until serum calcium is in the lower part of the reference range.
Vitamin D intoxication (i.e., hypercalcemia and hypercalciuria) should be avoided. The addition of a thiazide diuretic can help limit hypercalciuria. A thiazide diuretic is usually initiated after a urinary calcium is obtained and is approaching 250 milligram (mg)/24 hours.
Hyperphosphatemia should be avoided. The patient should be instructed on a low phosphorous diet (i.e., limit cola beverages, dairy, meat, and eggs).
Recombinant human PTH is available for use but is often considered second line therapy due to expense and long-term safety has not been fully established. Recombinant PTH has been shown to be efficacious in maintaining serum and urine calcium levels as well as decreasing the total daily dose of calcium supplementation needed. Two forms have been studied, PTH 1-34 and PTH 1-84. PTH 1-84 is available in the United States through the Risk Evaluation and Mitigation Strategy (REMS) program.
Levels of serum calcium, phosphorous, and creatinine should be monitored serially. These should be evaluated weekly to monthly in the beginning, to allow dose adjustments. Once doses are stable, values should be obtained twice a year. Urinary calcium and creatinine levels are also checked twice a year to monitor for hypercalciuria. The desired urinary calcium level is below 300 mg.
The goals of therapy are symptom control and a corrected calcium or ionized calcium that is at the lower end of the normal range, with a calcium-phosphorous product less than 55.
Annual ophthalmology exams are recommended to monitor for cataract formation.

Secondary hypoparathyroidism

Ultimate management is dependent on the underlying etiology.

Pseudohypoparathyroidism

The initial and long-term management is identical to primary hypoparathyroidism. Calcium levels should be maintained within the reference range to suppress PTH levels to normal and avoid hypercalciuria.

E. Common Pitfalls and Side-Effects of Management

Failure to consult endocrinology early when hypoparathyroidism is suspected or diagnosed.

Lack of adequate monitoring to prevent recurrence, morbidity or mortality.

Lack of recognition of the clinical consequences of hypercalciuria once treatment is started (i.e., nephrocalcinosis, nephrolithiasis, adrenal failure).

Calcitriol: 0.25-2 mcg orally or intravenously under the direction of an endocrinologist.
Calcium acetate: Start with 2 tabs/capsules orally with each meal.
Calcium chloride: Use a central line. Calcium gluconate is preferred. 500-1000 mg slow IV every 1-3 days.
Calcium gluconate: 10% (1000 mg/10 milliliter (ml), 4.65 milliequivalents [mEq]/10ml)–10ml over 10 minutes intravenously in symptomatic hypocalcemia. A continuous infusion of calcium gluconate may be necessary. It should be infused at a rate of 50 ml/hour with the expectation that a 10 ml/kilogram (kg) solution will increase the serum calcium by 0.3-0.5 millimole (mmol)/liter over 4-6 hours.
Calcium carbonate or citrate: 1-2 gram (g) elemental calcium daily or more, orally with meals, divided 2-4 times per day.
Ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3), severe deficiency: Not appropriate for use in hypoparathyroidism. Use calcitriol instead.
Magnesium sulfate: 1g of 20% solution intramuscular (IM) every 6 hours for 4 doses or 2 grams IV over 1 hour. May need repeat doses or more aggressive replacement dependent on the severity of the hypomagnesemia.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in initial standard management. Consider early referral to nephrology once treatment is initiated given the resultant hypercalciuria and worsening of renal function. Consider calcium acetate as the oral calcium of choice.