Hypoparathyroidism


Article Author:
Sonia Hans


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Steven Levine



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Sandeep Sekhon


Updated:
2/18/2019 10:38:54 PM

Introduction

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone (PTH), vitamin D metabolites, and calcitonin on calcium transport in bone, kidneys, and the gastrointestinal tract. Parathyroid hormone deficiency results in hypocalcemia, hyperphosphatemia, and increased neuromuscular irritability with myalgias, muscle spasms, and in extreme cases tetany.[1][2][3][4]

Etiology

Postoperative complication of thyroidectomy and other types of head and neck surgery include transient or permanent:

  • Abnormal development of parathyroid tissue, for example, DiGeorge Syndrome
  • Autoimmune destruction of parathyroid tissue, for example, Polyglandular autoimmune syndrome, Type 1
  • Activation mutations of the calcium-sensing receptor, autosomal dominant hypocalcemia
  • Activating antibodies of the calcium-sensing receptor
  • Hypomagnesemia
  • Infiltration of parathyroid tissue, for example, granulomatous disease, hemochromatosis, metastatic disease
  • Radiation injury
  • Parathyroid Hormone resistance, Pseudohypoparathyroidism[5][6][7]

Epidemiology

The prevalence of hypoparathyroidism in the United States is estimated to be 24 to 37/100,000 person-years, most commonly a complication of a thyroidectomy or head and neck surgery. This complication may be transient or permanent, and the frequency is highly dependent upon the technical skills of the surgeon. Other causes tend to be rare, and the etiology is suspected based on the age of onset, family history, and associated clinical features.

Pathophysiology

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The activity of the calcium-sensing receptor (CaSR), a G-protein coupled receptor, is affected by changes in the concentration of calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Parathyroid hormone activates the PTH receptor, another G-protein coupled receptor, increasing resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihyhroxyvitamin D. Deficient PTH results in hypocalcemia, hyperphosphatemia, while alkaline phosphatase, a marker of bone formation, is normal.

History and Physical

The clinician should determine if there has been any recent or remote thyroid or other types of head and neck surgery, the age of onset, and family history of hypocalcemia. If there is evidence of severe immune deficiency, the patient likely has DiGeorge Syndrome, while autoimmune problems such as adrenal insufficiency, or mucocutaneous candidiasis would suggest the etiology is a polyglandular autoimmune syndrome, type 1. Hypomagnesemia may be the cause if the patient is malnourished, recovering from diabetic ketoacidosis, abuses alcohol, has diarrhea, or been exposed to drugs that cause renal magnesium wasting. Significant hypocalcemia can cause numbness and paresthesias, muscle cramps and carpopedal spasms. When severe it can be life-threatening with laryngospasm, tetany, and seizures.

Hypocalcemia causes positive Chvostek’s and Trousseau signs.

  • Chvostek’s sign is elicited by tapping over the facial nerve as it exits from the parotid gland. The increased neuromuscular irritability leads to ipsilateral twitching of the upper lip and side of the mouth.
  • Trousseau’s sign is sought by inflating a blood pressure cuff 10 mmHg to 20 mmHg over-systolic blood pressure. A positive sign is the development of carpal spasm with flexion of the thumb and adduction of the finger within three minutes. This can be quite painful so the time should be noted and the cuff deflated once the test is positive.
  • Eye and neurological examinations are important since longstanding hypoparathyroidism places patients at a high risk of developing cataracts and calcifications in the brain, primarily in the basal ganglia.
  • Some patients with pseudohypoparathyroidism (Type 1a) have an unusual phenotype known as Albright’s hereditary osteodystrophy characterized by short stature, round face, and shortened fourth metacarpal bones.

Evaluation

Evaluation should include the following tests:

  • Total calcium
  • Albumin
  • Calculation of the “corrected” serum calcium.
    • Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active.
    • Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin)
      • (calcium measured in mg/dL; albumin measured in g/L)
  • Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
  • Parathyroid hormone
  • Phosphorus
  • BUN and creatinine
  • Alkaline phosphatase
  • 25-hydroxyvitamin D
  • Urine calcium and creatinine
  • EKG

Treatment / Management

Chronic Hypoparathyroidism

Traditional treatment of chronic hypoparathyroidism includes supplemental calcium along with active vitamin D metabolites. When replacing calcium it is essential to recognize that many formulations list the weight of the total calcium salt, but clinicians must be aware of the actual content of elemental calcium. For example, calcium carbonate is 40% calcium by weight while calcium gluconate is only 9%. A product stating it is 1250 mg of calcium carbonate has 500 mg of elemental calcium. A 10cc vial of 10% calcium gluconate has 1 gram of calcium gluconate but only 93 mg of elemental calcium.[8][9][10][11]

Patients with hypoparathyroidism have classically been categorized as having "vitamin D resistance."  Historically, this term was applied since normocalcemia can only be achieved by administering extremely large doses of vitamin D (ergocalciferol or cholecalciferol), doses that would likely cause hypercalcemia in normal individuals. In fact, patients with hypoparathyroidism are normally responsive to physiological doses of 1,25-dihydroxyvitamin D but have abnormal vitamin D metabolism.  Conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is stimulated by PTH and low phosphate levels. Since patients with hypoparathyroidism have low levels of PTH and hyperphosphatemia, production of the active vitamin D metabolite (1,25-dihydroxyvitamin D) is markedly reduced. 

 In past years patient were treated with supraphysiological doses of vitamin D (ergocalciferol or cholecalciferol) but the current recommendation is to treat with physiological doses of 1,25-dihydroxyvitamin D (calcitriol) along with supplemental calcium.

  • Supplemental calcium 1-2 grams of elemental calcium in divided doses, as calcium carbonate or calcium citrate
  • Calcitriol 0.25-2.0 mcg daily

Patients with hypoparathyroidism treated with calcium and calcitriol must have calcium, phosphorus, and renal function monitored periodically. When treatment is initiated calcium levels should be checked every few weeks. Once patients are on a stable dose of calcium and calcitriol the frequency of monitoring can be reduced to every 3-6 months. The absence of PTH reduces the renal tubular reabsorption of calcium. Therefore, patients treated for hypoparathyroidism are at risk of urolithiasis, or renal and other soft tissue calcifications. These risks can be minimized by titrating therapy to keep the serum calcium level in the low-normal range. In most cases this will be sufficient to prevent muscle cramps and paresthesias yet limit the risk of extraskeletal calcifications or kidney stones. Urine calcium should periodically be measured to make sure that patients do not develop hypercalciuria. Urine calcium excretion of greater than 250 mg/day should alert the physician to reduce the dose of calcium or vitamin D. An alternative strategy is to add hydrochlorothiazide to decrease urine calcium excretion.

While most with hypoparathyroidism are still treated with calcitriol and calcium, the FDA recently approved daily subcutaneous injections of recombinant human parathyroid hormone (1 to 84) to treat selected patients whose conditions are difficult to control on the more traditional therapy. Parathyroid hormone replacement can reduce the oral calcium and calcitriol requirements, and in some eliminate the need to use calcitriol. Advantages to replacing parathyroid hormone may be lower urine calcium excretion, more physiologic bone turnover, and improved quality of life. Replacement therapy is extremely expensive, and it remains unknown whether there may be long-term adverse effects. Administration of parathyroid hormone increases the risk of osteosarcomas in laboratory animals, although, at present, there is no reported increase in humans.

Acute Hypocalcemia

Acute, symptomatic hypocalcemia should be treated with intravenous calcium. Calcium gluconate is preferred over calcium chloride since the latter can cause tissue necrosis if it extravasates and should only be administered through a central venous line. Each 10cc ampoule of 10% calcium gluconate contains 1 gram of calcium gluconate but only 93 mg of elemental calcium. One-2 ampoules can be diluted in 5% dextrose and infused intravenously over 10 to 20 minutes. The serum calcium should be repeated in several hours and additional doses administered as needed. An alternative is to add 3 g to 5 g of 10% calcium gluconate (279 mg to 465 mg of elemental calcium) to a liter of 5% dextrose and infuse at a rate of 50 mg of calcium/hour. The dose can be adjusted based on subsequent measurements of serum calcium. In most cases, such as following thyroid surgery, it is also appropriate to initiate treatment with calcitriol.

Pearls and Other Issues

Hypomagnesemia

If magnesium depletion is the cause of hypocalcemia effective therapy requires repletion of magnesium stores. Until magnesium levels are normal, treatment with calcium will result in only a temporary improvement in the serum calcium.

Autosomal Dominant Hypocalcemia

Patients with autosomal dominant hypocalcemia due to an activating mutation of the calcium-sensing receptor often have mild hypocalcemia and are asymptomatic. This genetic disorder leads to an increase in urine calcium excretion placing such individuals at high risk of nephrolithiasis and nephrocalcinosis when treated with vitamin D and calcium supplementation. Therefore, practitioners should only consider treatment for those patients who are symptomatic, and the calcium increased only to a point where symptoms are alleviated.

Enhancing Healthcare Team Outcomes

The medical management of hypoparathyroidism is done by a multidisciplinary team that consists of an emergency department physician, endocrinologist, internist, intensivist, general surgeon and a nurse practitioner. In all cases of acute hypocalcemia, intravenous calcium is required if the patient is symptomatic. In chronic cases, life long calcium supplements are necessary. All patients with hypoparathyroidism need monitoring of their calcium, phosphorus, and renal function periodically. When treatment is initiated calcium levels should be checked every few weeks. Once patients are on a stable dose of calcium and calcitriol the frequency of monitoring can be reduced to every 3-6 months.

While most with hypoparathyroidism are still treated with calcitriol and calcium, the FDA recently approved daily subcutaneous injections of recombinant human parathyroid hormone (1 to 84) to treat selected patients whose conditions are difficult to control on the more traditional therapy. Parathyroid hormone replacement can reduce the oral calcium and calcitriol requirements, and in some eliminate the need to use calcitriol. As long as the patient is compliant with therapy the outcomes are good. [12](Level V)


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Hypoparathyroidism - Questions

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A patient undergoes thyroid surgery. At night, she complains of tingling in her hands and complains of spontaneous muscle cramps. What is the initial therapy?



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A patient presents with primary hyperparathyroidism secondary to an adenoma. The patient has the adenoma removed. One week later he presents with weakness, leg cramps, and arm cramps. The patient denies other symptoms. Vital signs are normal. The right arm develops an involuntary muscle spasm lasting 30 seconds after the blood pressure is checked. Percussion over the facial nerve causes the face to twitch. Which of the following is the most likely diagnosis?



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Which of the following electrolyte changes are observed in hypoparathyroidism?



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Which of the following findings is often seen in children with hypoparathyroidism?



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Which of the following lab values would be abnormal in parathyroid hormone deficiency?



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A patient recently had a thyroidectomy and is under observation for hypocalcemia from possible damage to the parathyroid glands. Which of the following symptoms would be of least concern?



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Which of the following lab results does not go a long with a diagnosis of hypoparathyroidism?



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Six hours after a thyroidectomy for follicular carcinoma the patient develops tingling around her mouth and pins-and-needles sensation in her fingers and toes. Her medications include prochlorperazine and morphine sulfate. Subsequently, the patient develops severe hand cramps when her blood pressure is taken. Tapping on her zygomatic arch causes twitching at the corner of her mouth. Select the appropriate management.



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A 7-year-old female has tingling and numbness of the hands. What lab values are most likely?



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Which is not a characteristic of hypoparathyroidism?



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Which set of lab tests would be expected in a patient with pseudohypoparathyroidism (parathyroid hormone resistance)?



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Which of the following is not appropriate management of chronic hypoparathyroidism?



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Sixteen hours after a 47-year-old woman had a total thyroidectomy she complains when the nurse takes her blood pressure that night that her fingers are numb and involuntarily flex. Which of the following would be expected?



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Which of the following is not a cause of hypoparathyroidism?



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A new patient presents to establish care. On physical exam, she curls her hand when the blood pressure cuff is inflated. Further testing reveals facial twitches elicited by the tapping of her face. Which of the following is the most likely lab results in this patient?



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A patient has recently undergone a parathyroidectomy and stopped their teriparatide, calcium, and vitamin D regimen. Which of the following is an expected sign or symptom? Select all that apply.



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Hypoparathyroidism - References

References

D'Asta F,Cianferotti L,Bhandari S,Sprini D,Rini GB,Brandi ML, The endocrine response to severe burn trauma. Expert review of endocrinology     [PubMed]
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Marcucci G,Cianferotti L,Brandi ML, Clinical presentation and management of hypoparathyroidism. Best practice     [PubMed]
Cianferotti L,Marcucci G,Brandi ML, Causes and pathophysiology of hypoparathyroidism. Best practice     [PubMed]
Marcucci G,Brandi ML, Conventional Treatment of Hypoparathyroidism. Frontiers of hormone research. 2019;     [PubMed]
Hakami Y,Khan A, Hypoparathyroidism. Frontiers of hormone research. 2019;     [PubMed]
Rao SD, Epidemiology of parathyroid disorders. Best practice     [PubMed]
Grzegory A,Pomorski L, Perioperative calcium and vitamin D supplementation in patients undergoing thyroidectomy - literature review. Polski przeglad chirurgiczny. 2018 Jun 13;     [PubMed]
Musholt TJ,Bockisch A,Clerici T,Dotzenrath C,Dralle H,Goretzki PE,Hermann M,Holzer K,Karges W,Krude H,Kussmann J,Lorenz K,Luster M,Niederle B,Nies C,Riss P,Schabram J,Schabram P,Schmid KW,Simon D,Spitzweg C,Steinmüller T,Trupka A,Vorländer C,Weber T,Bartsch DK, [Update of the S2k guidelines : Surgical treatment of benign thyroid diseases]. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen. 2018 Sep;     [PubMed]
Di Maio S,Soliman AT,De Sanctis V,Kattamis CC, Current treatment of hypoparathyroidism: Theory versus reality waiting guidelines for children and adolescents. Acta bio-medica : Atenei Parmensis. 2018 Mar 27;     [PubMed]
Zhou HY,He JC,McHenry CR, Inadvertent parathyroidectomy: incidence, risk factors, and outcomes. The Journal of surgical research. 2016 Sep;     [PubMed]

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