Notes on calcium balance in the body
Humans generally take in 1000mg of Ca daily, 30% of which is absorbed in the duodenum to disperse in the serum. The intestine put out an additional 150 mg/day into the GI to be excreted and the kidneys put out 150 mg/day in urine.
Where are calcium-sensing receptors found?
parathyroid, kidney, C cells in the thyroid, and in bone
This is Gs coupled receptor
How do CaSRs work? Drugs to stimulate?
high calcium levels binds to reduce PTH secretion via internal cascade
Drugs to stimulate: Cinacalcet
How should the workup of a patient with hypercalcemia begin?
2) Check albumin and total calcium TWICE to reduce risk of lab error
3) Check PTH
What conditions associated with hypercalcemia are PTH dependent?
-familial hypocalciuric hypercalcemia (FHH)
-Medication-induced (lithum or HCTZ mediated)
What conditions associated with hypercalcemia are PTH independent?
-tumor induced (PTHrP or bone metastases)
-granulomatous diseases (TB, sarcoidosis, lymphoma) associated with increased VitD
Med-induced (vitD/A toxicity, milk-alkali syndrome)
How is primary hyperparathyroidism defined?
high PTH AND high calcium, low phosphate, and increased cAMP in urine
What the main causes of primary hyperparathyroidism?
15% hyperplasia (MEN1/2A, HPT-Jaw Tumor Syndrome, familial HPT)
1% Parathyroid carcinoma
Is sporadic primary hyperparathyroidism more common in men or women?
Risk factors for sporadic primary hyperparathyroidism?
age, race (AA>W>H), female
What are the symptoms of primary hyperparathyroidism?
Stones, abdominal moans (constripation, nausea), psychic groans (depression, memory loss), and bones (osteoporosis/fractures)
the MAJORITY are asymptomatic, or have vague symptoms/general unwellness
What things should be included in a primary hyperPTN workup?
calcium, albumin (or ionized calcium), PTH, 25-OH vitD,
24 hr urine calcium (to differentiate from FHH)
Imaging: thyroid US to start, Tc-sestamibi scan, DEXA scan
What is the preferred Tx of primary parathyroidism?
What criteria would suggest the need for parathyroidectomy?
calcium 1+ mg/dL above UNL
age under 50 yo
How is primary HPT managed?
-maintain vit D range (20-30 ng/mL)
What is an option for patients who can not or do not want surgery and have moderate hypercalcemia?
What causes familial hypocalciuria hypercalcemia (FHH)?
Inactivating mutations in CaSR (100% penetrant) leading to mildly elevated serum Ca and PTH and hypocalciuria.
How does FHH present?
What labs suggest FHH?
elevated PTH and calcium and
24hr urine calcium less than 50-100 mg/24 hr
Tx of FHH?
How does secondary hyperPTH present in labs?
Normal calcium with elevated PTH secondary to the parathyroid gland trying to return calcium to a normal range
What are the major causes of secondary hyperPTH?
What kinds of diseases can produce an inability of the GI to absorb calcium from the GI and thus stimulate secondary hyperPTH?
stomach or intestine bypass for obesity surgery (gastric stapling/bypass)
-celiac or crohn's disease
What causes tertiary hyperPTH?
parathyroid glands develop hyperplasia due to chronic low calcium and/or high phosphorus levels after years of seconday hyperPTH. At one point, these glands become autonomous
How does hypercalcemia of malignancy present?
They will be sick, not with vague symptoms but signs of hypercalcemia (polyuria, dehydration, abdominal and MSK pain) and symptoms of malignancy (weight loss, anemia, etc.)
the PTH level will be suppressed!
What cancers are most associated with paraneoplastic hypercalcemia?
breast, renal, and squamous cell carcinomas
What causes hypercalcemia from malignancy?
Mostly from PTH-related protein (PTHrp) binds to the PTH receptor and function similar to PTH to increase cAMP
-bony metastases can increase calcium levels
-humoral factors (cytokines, TNFa) can activate osteoclasts
-MM can cause significant bone destruction
How do granulomatous diseases cause hypercalcemia?
overexpression of 1,25(OH)2D by MACROPHAGES which causes elevated calcium and phosphate but supressed PTH
How does hypercalcemia lead to dehydration?
calcium inhibits ADH action to express AQP2
How is acute hypercalcemia treated?
-address volume status (hydrate)
-saline diuresis and furosemide after volume status is corrected
calcitonin (only works for 36-48 hrs)
Bisphosphonates (panidronate IV works for 2-3 wks or Zoledronic acid IV-works for 1-3 months)
glucocorticoids (myelona, granulomatous disease, and vitD toxicity) and
What are the signs of hypocalcemia?
Causes of hypocalcemia caused by hypoparathyroidism?
Idiopathic- Abs to PTH
-autoimmune parathyroid agenesis (DIGeorge syndrome)
Other rare causes of hypocalcemia?
acute pancreatitis in which free fatty acids chelate calcium
massive transfusion in which infusion of citrate will complex calcium
TLS or rhabdomyolysis in which phosphate released binds to ionized calcium
Meds- phospahte, bisphosphonates
Hungry bone syndrome
What is Hungry bone syndrome?
in cases of chronic hyperparathyroidism where the bone is continuously being resorbed, when calcium is given, bone very actively tries to take it up resulting in hypocalcemia
Ddx with hypocalcemia and low PTH?
Magnesium deficiency (diarrhea, malabsorption, alcoholism)
Ddx with hypocalcemia and high PTH?
vitD or PTH resistance
What is pseudohypoparathyroidism?
decreased end organ responsiveness to PTH (PTH resistance)
What causes pseudohypoparathyroidism?
molecular defects in the ability of PTH stimulate intracellular signaling pathways due to mutations in Gs alpha subunit (GNAS1) or downstream elements
How does pseudohypoparathyroidism present in labs?
LABS: highly elevated PTH with hypocalcemia, hyperphosphatemia
How does pseudohypoparathyroidism present clinically?
short stature, rounded face, foreshortened 4th/5th metacarpals, obesity (Albright's Hereditary Osteodystrophy)- only some subtypes
What is PHP 1a? MOI?
Defect in Gs alpha subunit signaling causes unresponsiveness of the kidneys to PTH leading to decreased urinary cAMP and PO4, AHO phenotype and other hormonal defects such as decreased mentation, olfaction, TSH, glucagon, and LH/FSH
Defect must be inherited from mother due to imprinting
What is PHP 1b?
Same as PHP 1a but no AHO
What is PHP 1c?
Same as PHP1a but the defect is downstream to Gs alpha subunit. AHO phenotype present
What is Pseudopseudohypoparathyroidism?
physical exam feastures of AHO but without end-organ PTH resistance.
Occurs when defective Gs protein alpha-subunit is inherited from the FATHER
What is PHP2?
Defect in PKA that leads to normal urinary cAMP, decreased urinary phosphate, and no AHO phenotype
How is acute hypocalcemia crises treated in the short term?
–Always correct Magnesium if low
•1 - 2 ampules over ~10 – 20 minutes
•Followed by infusion if indicated
How is hypocalcemia treated in the long term?
–Oral Calcium salts
–Vitamin D replaced
•Ergocalciferol/Cholecalciferol (act in 10-14 days) - effective only if PTH is present
•Calcitriol – active vitamin D
–Hydrochlorothiazide – increases reabsorption of Calcium in the distal tubule