Basics
3 hormones regulate calcium conc: PTH, vitamin D, and calcitonin.
PTH and vitamin D increase blood calcium level
Calcitonin decreases blood calcium level.
PTH secretes parathormone in response to low blood calcium. It increases blood calcium level by:
Stimulating osteoclasts to break down bone
Increases reabsorption of calcium by kidneys
Increases conversion of inactive vitamin D to active vitamin D (which increases calcium absorption from the GI tract)
PTH action on the bone results in bone resorption (bone-to-blood shift of calcium and phosphate), hence both calcium and phosphate is released from bone into the blood circulation. However, PTH prevents hyperphosphatemia by decreasing phosphate reabsorption by the kidneys, resulting in phosphate excretion in the urine.
Vitamin D increases blood calcium and phosphate.
Increases absorption of calcium and phosphate from the GIT
Increases bone resorption of calcium and phosphate Hence, blood calcium and phosphate increases
Increases phosphate reabsorption in the kidneys.
Calcitonin is a hormone which is antagonistic to vitamin D and PTH. It is secreted by the C cells of the thyroid in response to high blood calcium levels.
Decreases blood calcium by using calcium to build bone
Decreases renal reabsorption of calcium.
PTH and vitamin D are the main determinants of blood calcium. Increase in either hormone causes hypercalcemia. Decrease in either causes hypocalcemia. Although calcitonin affect calcium metabolism, it does not play a significant role.
Hypercalcemia
Factors that increase blood calcium
Increase calcium intake or absorption
Excess ingestion of milk, calcium carbonate antacids such as Tums (milk-alkali syndrome)
Increase vitamin D
Lymphoma, granulomatous disease like sarcoidosis, milk-alkali syndrome
Increase PTH
Hyperparathyroidism (more likely if ▲Ca is chronic and patient is Asx)
Bone resorption (bone-to-blood-shift)
Hyperparathyroidism, hyperthyroidism, immobilization, secondary metastasis to bone, primary bone tumor, multiple myeloma, Paget's disease)
Renal calcium excretion is decreased
Thiazide diuretics, lithium (▲ PTH)
Other causes
Familial hypocalciuric hypercalcemia - rare, autosomal dominant disorder, mutation of the calcium sensing receptor in parathyroid and kidney → ▲ Ca set point +/- PTH. It is characterized by asymptomatic hypercalcemia from childhood and a family history of hypercalcemia. Rare acquired form due to autoantibodies vs Ca-sensing rcp
Paraneoplastic syndrome (e.g., squamous cell cancer - NSCLC)
Adrenal insufficiency, resulting in hypovolemia > decrease in intravascular volume > hemoconcentration leading to relative hypercalcemia. Glucocorticoids, normally decrease reabsorption of calcium from the kidneys. Thus, in adrenal insufficiency, decreased glucorticoids can result in increased blood calcium.
Primary Hyperparathyroidism: Increase PTH raises blood calcium levels.
Excess secretion by parathyroids - either one (parathyroid adenoma) or all (multiple adenomas in more than one glands or parathyroid hyperplasia in all 4 glands), or parathyroid cancer. It is a common d/o in elderly women.
Lab findings: Elevation in serum calcium, elevated serum PTH, low serum phosphate, high urine phosphate, high urine calcium, high urine cAMP, elevated vitamin D in serum. Alkaline phosphate can be elevated, due to bone resorption.
Alkaline phosphate is usually elevated in any cause of bone resorption/breakdown, biliary obstruction.
Urine calcium is high because of high spillover of calcium from blood, overwhelming the absorptive capacity of kidney, despite of PTH facilitating renal calcium reabsorption.
Increased urinary cAMP. cAMP is part of many receptor stimulated second messenger cascades.
PTH actually increases conversion of vitamin D from the 25-form to the 1,25-form. So, vitamin D is actually increased in primary hyperparathyroidism.
Parathyroidectomy is the treatment for primary hyperparathyroidism.
Secondary Hyperparathyroidism: It is caused by hypocalcemia. PTH is regulated by Ca++ concentration in serum. It is not under the control of the pituitary.
Decrease in blood calcium causes increased PTH secretion. This can be secondary to vitamin D deficiency or renal failure (causes hypocalcemia as a result of decreased vitamin D activation and increased phosphate rentention).
Tertiary Hyperparathyroidism: It occurs when secondary hyperparathyroidism persists inappropriately after the resolution of the renal failure or after renal transplantation. An autonomous nodule usually develops, needing surgery. Parathyroidectomy if often necessary to treat tertiary hyperparathyroidism.
Malignancy: is responsible for most cases of hypercalcemia among hospitalized patients. ▲ Ca is acute. Pts usually have clinically obvious disease. In these pt hypercalcemia may develop from stimulation of osteoclasts bone resorption from tumor producing cells products, tumor derived PTH-Related Protein (PTHrP), and tumor calcitriol production. Common ones are squamous cell lung cancer, breast cancer, kidney, and bladder tumors. PTHrP mimics PTH > bone resorption of calcium > hypercalcemia > inhibition of PTH release by parathyroids.
Cytokines and ▲ 1,25-(OH)2D3 (calcitriol) in hematologic malignancies.
Local osteolysis: breast cancer and multiple myeloma.
Lab findings: elevated serum calcium, low PTH, elevated PTHrP, low serum phosphate, elevated urine phospate, elevated urine cAMP, normal or decreased vitamin D level in serum, elevated alkaline phosphate.
Vitamin D-induced hypercalcemia: Elevation in active vitamin D increased calcium reabsorption, leading to hypercalcemia.
Lymphocytes in lymphoma, granulomas (sarcoidosis, tuberculosis, histoplasmosis, Wegener's etc.) can cause conversion of 25-vitamin D to 1,25-vitamin D (the more active form). This elevation in active vitamin D increase calcium reabsorption, which can lead to hypercalcemia > decreases PTH level via negative feedback. The reverse is not true: PTH actually increases vitamin D levels in serum.
Vitamin D intoxication
Milk-alkali syndrome: describes the acute or chronic development of hypercalcemia, alkalosis, renal failure that may result from the ingestion of large quantities of calcium-containing antacids.
Lab findings: elevated serum calcium, elevated serum phosphate, decreased urine cAMP, decreased PTH, elevated vitamin D.
Bone Breakdown: PTHrP and lymphomas result in hypercalcemia. Metastases to bone > localized bone destruction by their growth > hypercalcemia. Some hematologic malignancies can elaborate various cytokines like osteoclast-activating factors (OAF) > bone destruction.
Lab findings: Elevated serum calcium and phosphate, decreased PTH and vitamin D. Decrease of PTH and vitamin D levels means that their is not much stimulation of their receptors in the kidneys, so Urine cAMP is low.
Consider Paget's disease, hyperthyroidism, and prolonged immobilization in DDx of bone breakdown and hypercalcemia.
Calciphylaxis (calcific uremic arteriopathy): calcification of media of small-to medium-sized blood vessels of the dermis and SC fat → ischemia and skin necrosis. Associated w/ uremia, ▲PTH, ▲Ca, ▲PO4, and ▲ (Ca x PO4) product (nl <40). Poor prognosis.
Dx: Bx.
Tx: Na thiosulfate IV and parathyroidectomy (controversial)
Hypercalcemia: "stones, bones, abdominal groans, moans, and psychiatric overtones." Short QTc.
Tx:
Dilute calcium: IVF
Increase calcium excretion: loop diuretics. No THZ as they cause calcium reabsorption
Inhibit bone resorption: calcitonin and biphosphonates
Treat underlying cause: surgery for hyperparathyroidism, steroids for granulomatous disease.
Hypocalcemia:
Causes:
Decreased intake and absorption of calcium: starvation, malabsorption, chronic illness, sepsis
Decreased vitamin D (decreased intake, malabsorption, decreased sunlight exposure, renal disease, liver disease) must be severe, since resultant secondary hypoparathyroidism often corrects serum calcium levels. Reduced activity in vitamin D activation via 1-alpha-hydroxylase activity can be seen with vitamin D-dependent rickets and chronic renal insufficiency.
Genetic (1alpha-hydroxylase, VDR mutations)
Decreased PTH
Hypoparathyroidism: Causes
Congenital absence of parathyroids (e.g., DiGeorge syndrome is a problem with the 3rd and 4th branchial pouches in which the thymus and parathyroids are absent)
Autoimmune destruction of the parathyroids. Rare diseases such as autoimmune polyglandular syndromes like HAM (hypoparathyroidism, adrenal insufficiency, mucocutaneous candidiasis) and APECED (autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy)
Familial (i.e., genetic) hypoparathyroidism
Surgical damage/removal of parathyroids, for example from thyroid surgery
Magnesium ( a 2+ ion like Ca), which affects the parathyroids' secretion of PTH; hypomagnesema (<1 mg/dL) or hypermagnesemia (>6 mg/dL) can lead to hypocalcemia.
Infiltrative disease of the parathyroids (e.g., Wilson's disease)
Metastases to the parathyroids
Pseudophypoparathyroidism
PTH resistance to PTH due to mutations in a G protein involved in signal transduction from the PTH receptor. PTH level will be high, but to no avail, resulting in hypocalcemia.
Pseudohypoparathyroidism type 1a also have Albright's hereditary osteodystrophy, which includes features such as short stature, obesity, and round face. There is also resistance to TSH, gonadotropins, and glucagon.
Pseudopseudohypoparathyroidism is referred to when patient's with pseudohypoparathyroidism will have features of Albright's hereditary osteodystrophy but maintain PTH-responsive receptors, and so are not actually hypoparathyroid. Ca and PTH are normal.
Decreased shift from bone-to-blood and increased shift from blood-to-bone: Hungry bone syndrome
Increased calcium excretion in urine:
Fanconi syndrome: proximal tubule dysfunction leading to loss of calcium and other electrolytes
Hypercalciuric hypocalcemia
Renal failure: Vitamin D deficiency due to ▼1,25-(OH)2D production, ▲PO4 from ▼ GFR
Binding of calcium in the circulation
Hyperphosphatemia (e.g., rhabdomyolysis)
Pancreatitis (fats released from pancreas bind calcium)
Tumor lysis syndrome (hyperkalemia, hyperphosphatemia, hyperuricemia and hyperuricosuria, hypocalcemia)
Others: hypoalbuminemia
drugs (chemotherapeutic agents like 5-FU/leucovorin, foscarnet, fluoroquinolones, phenytoin, rifampin, ketoconazole,
Lab findings in Calcium d/o
If calcium and PTH are low, a hypoparathyroid state exists. Alternatively, if calcium is low and PTH is high, one of the three scenarios is possible:
Vitamin D deficiency is causing the hypocalcemia, and the parathyroids are responding to that hypocalcemia by secreting PTH.
PTH is abnormal or non-functional.
PTH receptors may be resistant to PTH, thus leading to elevated, albeit ineffective PTH. The condition of having receptors that are non-responsive to PTH is known as pseudohypoparathyroidism.
Physiologically active Ca is free or ionized (Ca++). Sr total Ca = bound + unbound calcium.
Corrected Ca (mg/dL) = measure Ca (mg/dL) + 0.8 x (4 - albumin gm/dL)
Alkalosis will cause more Ca to bind with albumin, thus total Ca may be normal, but ▼Ca++
Best to measure Ca++ (ionized).