• Type Ia 
• • Pseudohypoparathyroidism type Ia results from a decrease in the Gs-alpha protein. In 1942, Albright et al described a disorder, known as Albright hereditary osteodystrophy (AHO), comprised of short stature, mental retardation, obesity, round-shaped face, brachymetacarpia, brachymetatarsia, and subcutaneous bone formation. These somatic features of Albright hereditary osteodystrophy and the presence of the biochemical features of pseudohypoparathyroidism constitute type Ia.
  • Laboratory findings include hypocalcemia, hyperphosphatemia (with normal or high PTH levels), and low calcitriol. Vitamin D may be decreased because of inhibition by elevated levels of phosphorus and by decreased PTH stimulation of the 25-hydroxyvitamin D 1-alpha-hydroxylase. The low calcitriol levels, in turn, may cause the resistance to the hypercalcemic effects of PTH in the bone.
  • The defect of the Gs-alpha protein is not confined to the effects of PTH but also affects other hormonal systems (eg, resistance to glucagon, thyroid-stimulating hormone, gonadotropins). The gene for the Gs-alpha protein is located on chromosome 20. Some family members carry the mutation and display the AHO phenotype but do not have pseudohypoparathyroidism. This is termed pseudo-pseudohypoparathyroidism.
• Type Ib: These patients do not present with the somatic features of Albright hereditary osteodystrophy. These patients have normal Gs-alpha protein, with hormonal resistance to PTH—an impaired cAMP response to PTH, suggesting that the defect lies on the receptor. At what level the receptor is affected is not yet clear.
• Type Ic: Patients with this type present with resistance to multiple hormonal receptors but have normal Gs-alpha protein expression.
• Type II: In patients with this type of pseudohypoparathyroidism, PTH raises cAMP normally but fails to increase levels of serum calcium or urinary phosphate excretion, suggesting that the defect is located downstream of the generation of cAMP. If the patient presents with hypocalcemia, hypophosphaturia, and elevated immunoreactive parathyroid hormone (iPTH) levels, first rule out vitamin D deficiency, which has a similar presentation. In patients with a vitamin D deficiency, all parameters return to normal after vitamin D administration.

Hypomagnesemia   

Severe hypomagnesemia can lead to hypocalcemia, which is resistant to the administration of calcium and vitamin D. The usual cause of hypomagnesemia is due to loss through the kidney (eg, osmotic diuresis, drugs) or the gastrointestinal tract (eg, chronic diarrhea, severe pancreatitis, bypass or resection of small bowel). These patients present with low or inappropriately normal PTH levels in the presence of hypocalcemia. The mechanism of hypocalcemia includes resistance to PTH in the bone and kidneys, as well as a decrease in PTH secretion. Acute magnesium restoration rapidly corrects the PTH level, suggesting the hypomagnesemia affects the release of PTH, rather than its synthesis.

Vitamin D is a necessary cofactor for the normal response to PTH, and deficiency renders PTH ineffective. Poor nutritional intake, chronic renal insufficiency, or reduced exposure to sunlight may cause vitamin D deficiency.

Vitamin D related 

Nutritional deficiency

Current federal guidelines recommend 200-600 IU of vitamin D per day for adults, depending upon age.

Studies have recognized that vitamin D insufficiency can still occur and lead to an increased PTH and subsequent bone turnover. Studies have also shown that dietary intake of vitamin D varies greatly by race and age. In one review of National Health and Nutrition Examination Survey (NHANES) III data, 42% of African American women had low blood levels of vitamin D compared to 4% in Caucasian women. 

Another observational study in elderly adults found that 74% of those studied were deficient in vitamin D, despite adequate intake. The authors of this study suggested that the current guidelines for the elderly be increased to 800-1000 IU per day. The recognition of mild hypovitaminosis D may not be trivial. In an elderly population with an increased PTH and osteoporosis, response to alendronate was attenuated. This attenuation was improved when vitamin D was administered.

Impaired absorption 

Numerous conditions can impair the absorption of vitamin D. Small bowel diseases, such as celiac disease, gastric bypass (particularly long limb Roux-en-Y gastric bypass), steatorrhea, and pancreatic diseases can all lead to low vitamin D levels.

Inheritable conditions

• Pseudovitamin D deficiency rickets (type I) or 1-alpha-hydroxylase deficiency: This condition is secondary to an autosomal mutation of the 1-hydroxylase gene. Ultimately, calcidiol is not hydroxylated to calcitriol and calcium is not absorbed appropriately. This condition is considered pseudovitamin D deficiency because high doses of vitamin D can overcome the clinical and biochemical findings of this disease.
• Hereditary vitamin D resistance rickets: This condition is extremely rare and is caused by a mutation in the vitamin D receptor. Typically, this condition presents within the first 2 years of life.

Hepatic disease 

Liver disease with decreased synthetic function can cause vitamin D deficiency from several sources, as follows: impaired 25-hydroxylation of vitamin D, decreased bile salts with malabsorption of vitamin D, decreased synthesis of vitamin D–binding protein, or other factors. Patients with cirrhosis and osteomalacia have low or normal levels of calcitriol, suggesting that other factors may interfere with vitamin D function or are synergistic with malabsorption or decreased sun exposure. These patients require administration of calcidiol or calcitriol for the treatment of hypocalcemia.

Renal failure

Chronic kidney disease leads to a decrease in the conversion of 25-hydroxyvitamin D to its active form 1,25-dihydroxyvitamin D, particularly when the glomerular filtration rate (GFR) falls below 30 mL/min. This results in an increase in PTH. Ultimately, the increased absorption of phosphorus and calcium can lead to calcium-phosphorus mineral deposition in the soft tissues. In the early stages of renal failure, hypocalcemia can be seen due to the decrease in calcitriol production and a subsequent decrease in the intestinal absorption of calcium.

Critical illness and severe sepsis

A patient with acute illness may experience hypocalcemia for multiple reasons. In one study, the three most common factors identified in patients with hypocalcemia associated with acute illness were hypomagnesemia, acute renal failure, and transfusions. In gram-negative sepsis, there is a reduction in total and ionized serum calcium. The mechanism for this remains unknown but appears to be multifactorial, including elevated levels of cytokines (eg, interleukin-6, interleukin-1, TNF-alpha), hypoparathyroidism, and vitamin D deficiency or resistance. Mortality rates increase among patients with sepsis and hypocalcemia compared to patients who are normocalcemic.
  
Hungry bone syndrome

Surgical correction of primary or secondary hyperparathyroidism may be associated with severe hypocalcemia due to a rapid increase in bone remodeling. Hypocalcemia results if the rate of skeletal mineralization exceeds the rate of osteoclast-mediated bone resorption. A less severe picture is also observed after correction of thyrotoxicosis, after institution of vitamin D therapy for osteomalacia, and with tumors associated with bone formation (eg, prostate, breast, leukemia). All of these disease states result in hypocalcemia due to mineralization of large amounts of unmineralized osteoid.
 
Acute pancreatitis

Pancreatitis can be associated with tetany and hypocalcemia. It is caused primarily by precipitation of calcium soaps in the abdominal cavity, but glucagon-stimulated calcitonin release and decreased PTH secretion may play a role. When the pancreas is damaged, free fatty acids are generated by the action of pancreatic lipase. Insoluble calcium salts are present in the pancreas, and the free fatty acids avidly chelate the salts, resulting in calcium deposition in the retroperitoneum. In addition, hypoalbuminemia may be a part of the clinical picture, resulting in a reduction in total serum calcium. In patients with concomitant alcohol abuse, a poor nutritional intake of calcium and vitamin D, as well as accompanying hypomagnesemia, may predispose these patients to hypocalcemia.
 
Hyperphosphatemia

Hyperphosphatemia (due to renal failure, phosphate administration, or excess tissue breakdown because of rhabdomyolysis or tumor lysis) causes acute hypocalcemia. In acute hyperphosphatemia, calcium is deposited mostly in the bone but also in the extraskeletal tissue. In contrast, in chronic hyperphosphatemia, which is nearly always due to chronic renal failure, calcium efflux from the bone is inhibited and the calcium absorption is low, due to reduced renal synthesis of 1,25-dihydroxyvitamin D. However, other consequences of renal failure, including a primary impairment in calcitriol synthesis, also contribute to hypocalcemia.
  
Medications and other causes

Cinacalcet (calcimimetic agent)

Patients receiving the calcimimetic agent to help control secondary hyperparathyroidism in renal failure may experience hypocalcemia as a result of acute inhibition of PTH release. Clinically significant hypocalcemia occurs in approximately 5% of patients treated with cinacalcet.

Chemotherapy

Hypocalcemia can occur in patients treated with some chemotherapeutic drugs. Cisplatin can induce hypocalcemia by causing hypomagnesemia. Combination therapy with 5-fluorouracil and leucovorin can also cause mild hypocalcemia (65% of patients in one series), possibly by decreasing calcitriol production.
 
Bisphosphonates

Hypocalcemia may result from the treatment of hypercalcemia with bisphosphonates, particularly zoledronic acid, which is significantly more potent than other bisphosphates in suppressing the formation and function of osteoclasts. Patients who are affected appear to lack an adequate PTH response to decreasing serum calcium levels.
 
Anticonvulsant therapy

Hypocalcemia and osteomalacia have been described with prolonged therapy with anticonvulsants, such as phenytoin or phenobarbital.
 
Foscarnet

Foscarnet is a drug used to treat refractory cytomegalovirus and herpes infections in patients who are immunocompromised. It complexes ionized calcium and, therefore, lowers ionized calcium concentrations, potentially causing symptomatic hypocalcemia. Therefore, the ionized calcium concentration should be measured at the end of an infusion of foscarnet.
 
Citrated blood

Symptomatic hypocalcemia during transfusion of citrated blood or plasma is rare, because healthy patients rapidly metabolize citrate in the liver and kidney. However, a clinically important fall in serum ionized calcium concentration can occur if citrate metabolism is impaired due to hepatic or renal failure or if large quantities of citrate are given rapidly, for example, during plasma exchange or massive blood transfusion.
 
Ethylenediaminetetraacetic acid (EDTA)

Some radiographic contrast dyes may contain EDTA, which chelates calcium in serum, thereby reducing serum ionized calcium concentration, resulting in hypocalcemia.
 
Fluoride poisoning

Rarely, an excess intake of fluoride can cause hypocalcemia; this effect is presumably mediated by inhibition of bone resorption. Overfluorinated public water supplies and ingestion of fluoride-containing cleaning agents have been associated with low serum calcium levels. In this case, hypocalcemia is thought to be due to excessive rates of skeletal mineralization secondary to formation of calcium difluoride complex.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum albumin
• • In a patient with hypocalcemia, the serum albumin is essential to the diagnosis of true hypocalcemia, which involves a reduction in ionized serum calcium, or to the diagnosis of "factitious" hypocalcemia, meaning decreased total, but not ionized, calcium.
  • An estimate to correct for hypoalbuminemia is to subtract 0.8 mg/dL from the total serum calcium for each 1.0-g/dL decrease in albumin below 4.0 g/dL.
• Serum ionized calcium: Ionized calcium is the definitive method to help diagnose hypocalcemia.
• Serum phosphorus
• • In healthy kidneys, PTH stimulates phosphate excretion. A patient with hypocalcemia and elevated phosphorus levels suggests hypoparathyroidism, pseudohypoparathyroidism, or magnesium depletion (occasionally). Hypophosphatemia most frequently is associated with the latter, which is caused by nutritional deficiencies.
  • Patients with renal failure and hypocalcemia usually present with hyperphosphatemia and high PTH levels.
  • Hypophosphatemia develops in patients with vitamin D deficiency and hungry bone disease.
• Parathyroid hormone levels: Low-to-normal PTH levels occur in patients with hereditary or acquired hypoparathyroidism and in patients with severe hypomagnesemia; however, patients with ineffective PTH have elevated PTH levels. The PTH elevation is a result of hypocalcemia.
• Serum magnesium: The serum magnesium level always should be checked to determine its potential contribution to the hypocalcemia.
• Vitamin D metabolites
• • If vitamin D deficiency is suspected, measurements of 25(OH) D and 1,25(OH)2 D should be performed.
  • Measurement of a low 25(OH) D level suggests vitamin D deficiency from poor nutritional intake, lack of sunlight, or malabsorption.
  • Low levels of 1,25(OH)2 D in association with high PTH suggest ineffective PTH from a lack of vitamin D, as observed in patients with chronic renal failure, vitamin D–dependent rickets type I (VDDR-I), and pseudohypoparathyroidism.
  • Urinary cAMP may help to differentiate hypoparathyroidism from pseudohypoparathyroidism types I and II.
• Alkaline phosphatase: In patients with PTH deficiencies, alkaline phosphatase levels tend to be normal or slightly decreased. On the other hand, these levels frequently are elevated in patients with osteomalacia and rickets.

Imaging Studies

• Skeletal x-rays
• • Disorders associated with rickets or osteomalacia present with the pathognomonic Looser zones, better observed in the pubic ramus, upper femoral bone, and ribs.
  • Osteoblastic metastases from certain tumors (eg, breast, prostate, lung) can cause hypocalcemia.
• CT scan of the head may show basal ganglia calcification and extrapyramidal neurologic symptoms (in idiopathic hypoparathyroidism).

Other Tests

• Electrocardiogram (ECG): Hypocalcemia leads to a prolonged QT interval and severe ST abnormalities (see Media file 1).

Procedures

• Bone biopsy: If the diagnosis of osteomalacia is suspected, a bone biopsy can determine the final diagnosis.

TREATMENT

Section 6 of 11  

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Medical Care

The treatment of hypocalcemia depends on the cause, the severity, the presence of symptoms, and how rapidly the hypocalcemia developed.

• Acute hypocalcemia
• • Promptly correct symptomatic or severe hypocalcemia with cardiac arrhythmias or tetany with parenteral administration of calcium salts.
  • • Administer 1-2 ampules 10% calcium gluconate (93 mg/10 mL) in 50-100 mL of D5W over 5-10 minutes. Calcium chloride 10% solution (273 mg/10-mL ampule) delivers higher amounts of calcium and is advantageous when rapid correction is needed, but it should be administered via central venous access.
    • Measure serum calcium every 4-6 hours to maintain serum calcium levels at 8-9 mg/dL. If low albumin is also present, ionized calcium should be monitored.
  • Patients with cardiac arrhythmias or patients on digoxin therapy need continuous ECG monitoring during calcium replacement because calcium potentiates digitalis toxicity.
  • Identify and treat the cause of hypocalcemia and taper the infusion.
  • Start oral calcium and vitamin D treatment early. Patients with postparathyroidectomy hungry bone disease, especially those with osteitis fibrosa cystica, can present with a dramatic picture of hypocalcemia.
  • Treatment with calcium and vitamin D for 1-2 days prior to parathyroid surgery may help prevent the development of severe hypocalcemia.
• Chronic hypocalcemia: Treatment of chronic hypocalcemia depends on the cause of the disorder.
• • PTH deficiency: Patients with hypoparathyroidism and pseudohypoparathyroidism can be managed initially with the oral administration of calcium supplements. The hypercalcemic effects of thiazide diuretics may offer some additional benefits. In patients with severe hypoparathyroidism, vitamin D treatment may be required; however, remember that PTH deficiency impairs the conversion of vitamin D to calcitriol. Therefore, the most efficient treatment is the addition of 0.5-2 mcg of calcitriol or 1-alpha-hydroxyvitamin D3.
  • Hypocalcemia in patients on dialysis: Most patients on hemodialysis will be hypercalcemic. However, postparathyroidectomy, patients may have considerable difficulty in maintaining appropriate calcium levels. These levels can be managed several ways. First, oral calcium supplements should be provided. They must be given between meals; otherwise, they will primarily act as phosphate binders. Active vitamin D administration (calcitriol) enhances the absorption of calcium. Finally, the calcium in the dialysate bath can be increased.
  • Nutritional vitamin D deficiency from lack of sunlight exposure or poor oral intake of vitamin D: Ultraviolet light or sunlight exposure can treat these patients. Treat nutritional rickets with vitamin D2. Oral calcium preparations containing 1-2 g of elemental calcium per day can treat patients with a calcium deficiency. For infants who are breastfed, adjust the dose to 30 mg/kg/d. Calcitriol may be used, but it has the disadvantages of a higher price and the possibility of producing hypervitaminosis D with hypercalcemia.

Surgical Care

Parathyroidectomy (subtotal or total) may be indicated in certain patients with severe secondary hyperparathyroidism and renal osteodystrophy.

Diet

• An increase in dietary calcium to greater than 1 g/d is an important part of the treatment of chronic hypocalcemia, particularly in cases of vitamin D deficiency.
• In patients with hypocalcemia and chronic renal failure, the dietary intake of phosphate should be lowered to 400-800 mg/d to prevent hyperphosphatemia.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Electrolytes

Restores serum calcium levels. Calcium chloride delivers 3 times more elemental calcium than calcium gluconate.

Drug Name	Calcium gluconate (Kalcinate)
Description	Moderates nerve and muscle performance, and facilitates normal cardiac function. Can be administered IV initially; then, maintain calcium levels with high calcium diet. Some patients require oral calcium supplementation. One ampule contains 93 mg of elemental calcium.
Adult Dose	100-300 mg elemental calcium IV diluted in 100 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium per kg/h
Pediatric Dose	2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
Contraindications	Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in digitalized patients, respiratory failure, acidosis, and severe hyperphosphatemia

Drug Name	Calcium carbonate (Oystercal, Caltrate)
Description	Indicated to restore and maintain normocalcemia when hypocalcemia is not severe enough to warrant rapid replacement.
Adult Dose	0.5-1 g PO bid/tid
Pediatric Dose	45-65 mg/kg/d PO divided qid
Contraindications	Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; large intakes of dietary fiber may decrease calcium absorption and levels; calcium potentiates digitalis effects
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in digitalized patients, respiratory failure, and acidosis

Drug Category: Vitamins

Restore calcium levels in conditions associated with vitamin D deficiency. Vitamin D helps control hyperparathyroidism in patients with chronic renal failure and end-stage renal disease.

FOLLOW-UP

Section 8 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• After correction of serum calcium, initiate a workup to help diagnose the cause of hypocalcemia.

Further Outpatient Care

• After determining the cause for hypocalcemia, direct the treatment at preventing further episodes of hypocalcemia and avoiding the complications of chronic hypocalcemia.
• Following parathyroidectomy, patients should be seen in 5-7 days for follow-up determination of serum calcium.

In/Out Patient Meds

• Patients with hypocalcemia due to resistance to PTH generally will require long-term therapy with vitamin D and calcium supplementation.
• Patients with hypocalcemia associated with chronic renal failure often require phosphate binders and vitamin D supplementation.

Transfer

• Patients with hypocalcemia and renal failure may require transfer to a facility with hemodialysis available.

Complications

• Complications of chronic hypocalcemia predominantly are those of bone disease.
• • Osteomalacia and rickets result from vitamin D deficiency.
  • Osteitis fibrosis cystica and osteomalacia occur in patients with hypercalcemia and secondary hyperparathyroidism.

Prognosis

• Prognosis usually is favorable and depends on the cause and duration of hypocalcemia.

Patient Education

• The primary component of patient education involves dietary instruction in patients with hypocalcemia.
• Patients with chronic hypocalcemia should be informed about the early symptoms of hypocalcemia, such as paresthesias and muscle weakness, so they can obtain care prior to developing more severe symptoms.

MISCELLANEOUS

Section 9 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Lack of recognition of hypocalcemia as a cause of seizures
• Lack of follow-up determination of calcium levels in patients on drugs that may cause hypocalcemia
• Lack of identification of hypomagnesemia as a cause for hypocalcemia

Special Concerns

• Neonatal hypocalcemia is more likely to occur in infants born of diabetic or preeclamptic mothers. Hypocalcemia also may occur in infants born to mothers with hyperparathyroidism.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Electrocardiogram (ECG) findings of severe hypocalcemia.
	View Full Size Image
Media type:  ECG

REFERENCES

Section 11 of 11

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• Differentials
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• Follow-up
• Miscellaneous
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• References

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Article Last Updated: Jan 15, 2008