Lithium, hypercalcemia (increased serum calcium), and hyperparathyroidism
or
What to do when you’re stable on lithium and your calcium level is high?
Lithium therapy increases the prevalence of hypercalcemia and hyperparathyroidism (http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2013.13081057):
1. 10% absolute risk in 730 lithium-treated patients compared with 730 unexposed
2. Recent case-control study of 112 patients with bipolar disorder found 8.6% prevalence hyperparathyroidism and 24.1% hypercalcemia
3. General population rate: from 0.1-0.7%
Mechanisms:
1. Lithium stimulates calcium reabsorption form renal tubules and bowel
2. Lithium stimulates parathyroid hormone release
3. lithium may affect the set point at which the parathyroid gland slows parathyroid hormone release in response to increasing serum calcium levels
4. Increase in parathyroid gland mass correlates with the duration of lithium therapy, and may lead to “lithium-induced ‘primary’ hyperparathyroidism”, which becomes independent of lithium.
How does parathyroid hormone work? :
1. It regulates the concentration of serum ionized calcium
2. It stimulates the kidneys to reabsorb calcium.
3. It stimulates the gut to reabsorb calcium
4. parathyroid hormone secretion is regulated by a very sensitive calcium sensing receptor on the parathyroid cell surface.
5. Increasing serum ionized calcium inhibits parathyroid hormone secretion.
Classic hypercalcemia/primary hyperparathyroidism presents with “stones, bones, thrones, abdominal groans and psychiatric moans”
1. stones represents kidney stones, diabetes insipidus (polyuria and polydipsia)
2. bones represents bone problems: bone pain, pathological fractures, osteoporosis.
3. abdominal groans represents nausea, vomiting, constipation, peptic ulcers, acute pancreatitis
4. Thrones refers to constipation and polyuria
5. psychiatric moans refers to lethargy, fatigue, and depression
Good news is that “up to 80% of cases (of hypercalcemia and primary hyperparathyroidism have no symptomatic manifestations” (Am J Psychiatry 172: 1, January 2015 p. 13) and go by the name of “asymptomatic primary hyperparathyroidism”.
Female/male prevalence is 2.5/1
Three times more common in patients over age 80 vs patients 20-29
Lithium-associated hypercalcemia/ hyperparathyroidism is different from primary hyperparathyroidism:
1. serum calcium levels are less elevated
2. phosphate levels are normal rather than low.
3. magnesium levels are increased, rather than normal .
4. calcium in the urine is decreased rather than increased (hypocalciuria), so there are lower rates of kidney stones
5. parathyroid hormone levels are lower
6. lithium protects bone
The evidence to date (albeit uncontrolled) suggests that lithium induced calcium elevations cause less risk of damage to the kidney and the bones. However, there are “numerous case reports” of “classical symptomatic hypercalcemic states in lithium treated patients” (AJP page 14)
What are the options?
1. Surgical referral (the standard of care for primary hyperparathyroidism is parathyroidectomy)
2. discontinue lithium (the condition is often reversible)
3. continue lithium and monitor it (“Monitored lithium continuation in asymptomatic cases may be a prudent option for many patients, modeled on commonly practiced asymptomatic primary hyperparathyroidism surveillance. ..Monitored surveillance should proceed cautiously and with an appreciation for nuance. Subtle signs of hypercalcemia/ hyperparathyroidism may mimic underlying psychiatric disorders, with disturbances in mood, energy, and cognition in patients who are otherwise classified as asymptomatic.” )
4. calcimimetic therapy (Cinacalcet, FDA approved has “reversed lithium-associated hypercalcemia/ hyperparathyroidism in…five cases to date”
“In consultation with an endocrinologist, cinacalcet represents an important additional treatment option in symptomatic patients for whom lithium discontinuation poses substantial psychiatric risks, for whom surgical intervention has failed, or for whom surgery is contraindicated.”)
5. cinacalcet problems: high rates of gastrointestinal side effects, high cost
6. Get baseline calcium testing in all patients and follow-up testing at 6 months and annually thereafter
lithium induced hyperparathyroidism
Lithium, hypercalcemia (increased serum calcium), and hyperparathyroidism
or
What to do when you’re stable on lithium and your calcium level is high?
Lithium therapy increases the prevalence of hypercalcemia and hyperparathyroidism (http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2013.13081057):
1. 10% absolute risk in 730 lithium-treated patients compared with 730 unexposed
2. Recent case-control study of 112 patients with bipolar disorder found 8.6% prevalence hyperparathyroidism and 24.1% hypercalcemia
3. General population rate: from 0.1-0.7%
Mechanisms:
1. Lithium stimulates calcium reabsorption form renal tubules and bowel
2. Lithium stimulates parathyroid hormone release
3. lithium may affect the set point at which the parathyroid gland slows parathyroid hormone release in response to increasing serum calcium levels
4. Increase in parathyroid gland mass correlates with the duration of lithium therapy, and may lead to “lithium-induced ‘primary’ hyperparathyroidism”, which becomes independent of lithium.
How does parathyroid hormone work? :
1. It regulates the concentration of serum ionized calcium
2. It stimulates the kidneys to reabsorb calcium.
3. It stimulates the gut to reabsorb calcium
4. parathyroid hormone secretion is regulated by a very sensitive calcium sensing receptor on the parathyroid cell surface.
5. Increasing serum ionized calcium inhibits parathyroid hormone secretion.
Classic hypercalcemia/primary hyperparathyroidism presents with “stones, bones, thrones, abdominal groans and psychiatric moans”
1. stones represents kidney stones, diabetes insipidus (polyuria and polydipsia)
2. bones represents bone problems: bone pain, pathological fractures, osteoporosis.
3. abdominal groans represents nausea, vomiting, constipation, peptic ulcers, acute pancreatitis
4. Thrones refers to constipation and polyuria
5. psychiatric moans refers to lethargy, fatigue, and depression
Good news is that “up to 80% of cases (of hypercalcemia and primary hyperparathyroidism have no symptomatic manifestations” (Am J Psychiatry 172: 1, January 2015 p. 13) and go by the name of “asymptomatic primary hyperparathyroidism”.
Female/male prevalence is 2.5/1
Three times more common in patients over age 80 vs patients 20-29
Lithium-associated hypercalcemia/ hyperparathyroidism is different from primary hyperparathyroidism:
1. serum calcium levels are less elevated
2. phosphate levels are normal rather than low.
3. magnesium levels are increased, rather than normal .
4. calcium in the urine is decreased rather than increased (hypocalciuria), so there are lower rates of kidney stones
5. parathyroid hormone levels are lower
6. lithium protects bone
The evidence to date (albeit uncontrolled) suggests that lithium induced calcium elevations cause less risk of damage to the kidney and the bones. However, there are “numerous case reports” of “classical symptomatic hypercalcemic states in lithium treated patients” (AJP page 14)
What are the options?
1. Surgical referral (the standard of care for primary hyperparathyroidism is parathyroidectomy)
2. discontinue lithium (the condition is often reversible)
3. continue lithium and monitor it (“Monitored lithium continuation in asymptomatic cases may be a prudent option for many patients, modeled on commonly practiced asymptomatic primary hyperparathyroidism surveillance. ..Monitored surveillance should proceed cautiously and with an appreciation for nuance. Subtle signs of hypercalcemia/ hyperparathyroidism may mimic underlying psychiatric disorders, with disturbances in mood, energy, and cognition in patients who are otherwise classified as asymptomatic.” )
4. calcimimetic therapy (Cinacalcet, FDA approved has “reversed lithium-associated hypercalcemia/ hyperparathyroidism in…five cases to date”
“In consultation with an endocrinologist, cinacalcet represents an important additional treatment option in symptomatic patients for whom lithium discontinuation poses substantial psychiatric risks, for whom surgical intervention has failed, or for whom surgery is contraindicated.”)
5. cinacalcet problems: high rates of gastrointestinal side effects, high cost
6. Get baseline calcium testing in all patients and follow-up testing at 6 months and annually thereafter