Hypercalcemia in Sarcoidosis Flashcards
What are the causes of Hypercalcemia?
- Enhanced Bone Resorption with greater release of calcium a. PTH excess (primary hyperparathyroidism) b. Malignancy (most often caused by PTH related protein (PTHrP); less often other humoral osteolytic factors; presence of bone metastases; rarely ectopic PTH) c. Immobilization d. Hyperthyroidism
- Increased Intestinal Absorption of Calcium a. Vitamin D intoxication b. Sarcoidosis (enhanced activation of vitamin D by granulomatous tissue) c. “Milk-alkali syndrome” (excessive ingestion of calcium – usually calcium carbonate with or without milk)
- Reduced Urinary Excretion a. Thiazide diuretics (enhanced distal tubular calcium reabsorption) b. Familial hypocalciuric hypercalcemia (abnormal calcium sensor gene)
What is the active form of vitamin D? how does it work? Major target? Patients with excess vitamin D?
The active form of vitamin D is 1,25(OH)2 D (calcitriol). Calcitriol functions as a steroid hormone by interacting with a nuclear vitamin D receptor (VDR) to regulate gene transcription.
The major target tissue for calcitriol is the gastrointestinal tract, where it enhances absorption of both calcium and phosphate. Patients with vitamin D excess can develop hypercalcemia due to excessive intestinal absorption of calcium. In such patients, there is a compensatory decrease in PTH.
explain the regulation of PTH? and how the following conditions affect PTH and calcium: Primary Hyperparathyroidism, Hypoparathyroidism, Pseudohypoparathyroidism, Vitamin D excess, Vitamin D deficiency, Secondary hyperparathryoidism, Chronic Mg deficinecy.
What are the two forms of vitamin D?
There are 2 forms of vitamin D: The naturally occurring form (cholecalciferol, vitamin D3) is produced in humans by ultraviolet irradiation of 7-dehydrocholesterol in the skin, or ingested in oils from animals or fish. The other is a synthetic form obtained from plant sterols (ergocalciferol, vitamin D2). Both share common metabolic pathways and undergo conversion to more active metabolites.
First step of vitamin D synthesis? Major circulating form of vitamin D?
In healthy individuals, the first step in vitamin D metabolism occurs in the liver, where vitamin D is converted to 25-hydroxy vitamin D or 25(OH) D by the mitochondrial enzyme 25-hydroxylase (CYP2R1).
Twenty-five-hydroxy vitamin D represents the major circulating metabolite of vitamin D, and this 25(OH) D metabolite is measured to determine “vitamin D status” (whether a patient has vitamin D deficiency).
Conversion to biologically active 1,25 dihydroxy vitamin D occurs where? how?
Conversion to biologically active 1,25-dihydroxy vitamin D (1,25(OH)2 D also known as calcitriol) occurs primarily in the kidney through the action of the mitochondrial enzyme 1-hydroxylase (CYP27B1).
increased PTH does what? what else does this?
Increased PTH and/or hypophosphatemia enhance renal 1-hydroxylase activity, while renal 1-hydroxylase activity is reduced in response to lowering of PTH or an increase in phosphate (see figure and expanded explanation below).
Explain the full metabolism of Vitamin D?
Explain the regulation of kidney 1alpha-hydroxylase by PTH and Phosphate?
In healthy persons, low extracellular calcium stimulates release of parathyroid hormone (PTH), which acts on kidney proximal tubule cells to increase 1α-hydroxylase activity. As a result, more 25(OH) D is converted to 1,25(OH)2 D. The active vitamin D (calcitriol) promotes more intestinal calcium absorption, and as extracellular calcium is restored to normal, PTH secretion decreases completing the feedback loop (a decrease in PTH provides less of a stimulus for additional vitamin D activation by renal 1αhydroxylase).
In addition to PTH, hypophosphatemia also enhances renal 1-hydroxylase activity. As a result, more 25(OH) D is converted to 1,25-(OH)2 D. The active vitamin D (calcitriol) promotes more intestinal absorption of both calcium and phosphate. The increase in extracellular phosphate increases expression of fibroblast growth factor 23 (FGF23) in bone cells. The feedback loop is completed because an increase in FGF23 decreases renal 1α-hydroxylation of 25(OH) D.
Extra renal 1alpha hydroxylase?
Many other tissues are capable of activating vitamin D in smaller amounts, and this locally produced 1,25(OH)2 D may act in an autocrine or paracrine fashion to produce important biologic effects within such tissues.
Explain hypercalcemia in sarcoidosis?
In patients with granulomatous diseases such as sarcoidosis, pulmonary alveolar macrophages can increase their expression of 1alpha-hydroxylase in response to inflammatory cytokines. These activated macrophages continue to convert the 25(OH) D precursor to active calcitriol, which can result in hypercalcemia
Activated macrophages are not capable of responding to the same regulatory feedback signals that control 1α-hydroxylase activity in the kidney. This type of unrestrained expression of 1α-hydroxylase has been described as “constitutive.” Patients with sarcoidosis and hypercalcemia typically have low PTH (PTH is suppressed by high calcium), low parathyroidrelated protein (PTH-rP), normal or increased serum phosphate, and normal 25(OH) D (also called 25-hydroxyvitamin D). Abnormally high calcitriol (also known as 1,25-(OH)2 D) is found in patients with hypercalcemia due to sarcoidosis.
If albumin is low and we are measuring for calcium in sarcoidosis what do we need to consider? why?
Since hypercalcemia can be a complication of sarcoidosis, calcium* should be measured in patients who are believed to have sarcoidosis. If albumin is low, measurement of total calcium may not be sufficient to detect hypercalcemia (see explanation below) unless ionized calcium is measured.
If hypercalcemia is identified what should be measured? what should we look at?
If hypercalcemia is identified, PTH and PTHrP should be measured to exclude other potential explanations for the hypercalcemia. Measurement of 1,25(OH)2 D may be obtained for confirmation that this is the most likely cause of the hypercalcemia. Renal function should be evaluated (BUN, creatinine, urinalysis, and urine calcium excretion), since hypercalcemia increases the filtered load of calcium, which can lead to impaired kidney function and /or nephrolithiasis
Signs and symptoms of hypercalcemia?
Patients with hypercalcemia may have constipation; hyporeflexia; lethargy, somnolence / coma; renal colic (nephrolithiasis); polyuria, nocturia (renal tubular defects).
Dehydration and renal failure may result. Cardiovascular changes may affect the electrocardiogram (shortened QT interval, etc.).
How do we treat hypercalcemia?
(corticosteroids, steroids) reportedly inhibits the 1αhydroxylase mediated conversion of 25(OH) D to calcitriol (the biologically active form of vitamin D).
Glucocorticoids may also antagonize calcitriol effects on the gut (enhanced calcium absorption). Glucocorticoid treatment may alleviate hypercalcemia in patients with sarcoidosis.
