Term
| Why do patients with hypercalcemia present with depression, lethargy, coma, muscular weakness and constipation? |
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Definition
As calcium rises, neurons and muscle cells become refractory and cease to function.
1) Neural- Depression, lethargy, coma
2) Muscle weakness- Skeletal muscle
3) Constipation- Intestinal smooth muscle |
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Term
| Why do patients with hypocalcemia present with convulsions, parasthesias, muscle cramps and tetany? |
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Definition
Cellular hyperexcitability.
Low extracellular calcium decreases the potential difference across neural and muscle cell membranes and makes then easier to excite. |
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Term
| What are the 3 primary functions of Ca2+ physiologically? |
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Definition
1) Bone structure- 99% as hydroxyappetite
2) Maintenance of electrical gradients across cell membranes
- Hypo= hyper-excitable.
3) Intracellular signaling
- cAMP-mediated Ca2+ increases that alter transcription |
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Term
| How is calcium homeostasis maintained? |
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Definition
Half is bound to albumin, small amount is complexed with carbonate or phosphate and the rest is "free, ionized" serum calcium.
1) Intestine
- 150-200 mg (out of 800-1200) is absorbed in jejnum under the regulation of 1,25 (OH)2D (stimulates absorption)
- 1,25 (OH)2D is produced in kidney
2) Kidney
- 90% reabsorbed in PT
- 10% in DT (PTH-regulated)
3) Skeleton (supply and sink)
- Osteoclasts resorb bone and produce 500mg/d
- Osteoblasts synthesize unmineralized bone at 500mg/d
- ONLY uncoupled in immobilzation hypercalcemia, malignancy hypercalcemia and RAPID PTH flux |
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Term
| Under what conditions can osteoclast-mediated resorption and osteoblast synthesis be "uncoupled"? |
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Definition
1) Rapid PTH fluctuation
- Osteoclasts respond within hours, while Osteoblasts take days to weeks
2) Uncoupling diseases
- Immobilization hypercalcemia
- Malignancy-assocaited hypercalcemia |
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Term
| What sources is vitamin D intake derived from? |
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Definition
Equipotent sources that are both activated by dihydroxylation ("25" in liver and "1" in kidney)
1) Vitamin D2 (ergocalciferol) in diet
2) Vitamin D3 (cholecalciferol) in skin from dehydrocholesterol in the presence of sunlight |
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Term
| How is vitamin D activated and what is its major action? |
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Definition
Dihydroxylation in liver and kidney.
1) first OH group added at "25" position in liver
- 25 D2 or D3 are used to assess stores and absorption
- Not regulated by PTH
2) second OH group added at "1" position in kidneys to form Calcitrol
- Tightly regulated by PTH (positive) and phosphate (negative)
3) Calcitrol binds jejnunal cells and stimulates calcium absorption
- Also stimulates osteoclast-mediated resorption (minor) |
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Term
| How is PTH synthesized and what are its primary actions? |
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Definition
1) Synthesis
- Pre-pro-PTH is cleaved to Pro-PTH and then to PTH
- PTH is stored in secretory granules until serum [Ca] falls
(Calcium levels determined by GPCR sensor)
2) Metabolized in plasma, liver and kidney
3) Actions
3a) Bone (direct)
- stimulates osteoclasts (acute)
- stimulates osteoblasts (subacute and chronic)
3b) Kidney (Direct)
- stimulates distal calcium reabsorption and inhibits excretion
- stimulates conversion of 25 OHD to Calcitrol (subacute and chronic).
- inhibits proximal tubular phosphorus reabsorption and - stimulates proximal tubular cAMP synthesis and excretion.
3) Intestine (indirect)
- Stimulates calcium absorption in response to rising Calcitrol levels (subacute and chronic) |
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Term
| What are the effects of PTH on the kidney? |
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Definition
Direct: Calcium, Phosphate, and 25OH-D
1) stimulates distal calcium reabsorption and inhibits excretion (acute and chronic)
2) Stimulates conversion of 25 OHD to Calcitrol (subacute and chronic).
3) inhibits proximal tubular phosphorus reabsorption (acute and chronic)
4) stimulates proximal tubular cAMP synthesis and excretion (acute and chronic) |
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Term
| What are the effects of PTH on the intestine? |
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Definition
| Indirect (via 1,25 (OH2)D) increase in jejunal absorption. |
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Term
True or False:
Calcitonin is not a critical hormone in humans. |
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Definition
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Term
| How does the body compensate for Hypocalcemia? |
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Definition
From vitamin D deficiency or infusion with EDTA (lead poisoning)
Conserve...Release.....Absorb (if necessary)
1) Immediate PTH release with inhibition of renal calcium excretion
2) Osteoclastic activity occurs, adding Ca2+ to ECF
3) If hypocalcemia persists, PTH secretion will continue, raising 1,25 (OH)2D levels, which increase intestinal absorption 2X |
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Term
| How does the body compensate for Hypercalcemia? |
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Definition
Flood it out of the kidneys first (PTH decline), and if it persists, stop the absorption in the intestine (Calcitrol decline)
1) Immediate PTH inhibition, with distal tubular "floodgate"
- look for hypercalciura (500 mg/d)
2) Osteoclastic inhibition, leaves osteoblasts unopposed
- Calcium "sink" in unmineralized bone
3) If >3h, 1,25 (OH)2D will decline, which will shut down intestinal absorption |
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Term
| Why are patients with renal dysfunction at first for hypercalcemia? |
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Definition
| Acute compensation relies upon renal "floodgate" response to decreased PTH. |
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Term
What is the clinical utility of each of the following measurements of calcium homeostasis?
1) Fasting calcium excretion
2) 24h urine calcium
3) Renal phosphorus threshold (TmP/GFR)
4) Plasma 25 OH D
5) Plasma 1,25 (OH)2 D
6) Immunoreactive PTH |
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Definition
1) Increased in hypercalcemia (invalidated by foods, diuretics and IV infusions).
2) Best obtained on high calcium intake
3) Increased in hypercalcemia (phosphate inhibits calcium absorption)
4) Good index of total body stores for evaluation of malabsorption
5) Indirect measure of PTH (high means high PTH)
6) Invalid when GFR <30-50 |
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Term
Which of the following is NOT associated with Hypercalcemia?
1) Sarcoidosis
2) Malignancy
3) Hypoparathyroidism
4) Thiazide diuretics
5) Milk alkali syndrome
6) Hyperproteinemia |
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Definition
3- Hypoparathyroidism is associated with HYPOcalcemia
- Low PTH means renal calcium dumping and hypercalciuria
1) Sarcoid (10% of cases): increased production of Calcitrol by macrophages and giant cells that comprise granulomas, which stimulates intestinal absorption.
2) Malignancy (MOST COMMON):
- Secretion of PTHrP causing "humoral hypercalcemia of malignancy" (squamous cell lung cancer)
- Skeletal metastasis with cytokine-mediated osteoclastic activity (treat with Bisphosphonates to prevent resorption)
3) Thiazides prevent calcium excretion
5) High -dose bicarbonate and milk therapy for PUD during 1920-1950 and currently from Calcium Carbonate therapy (passive over-absorption) |
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Term
How does each of the following cause hypercalcemia?
1) Primary hyperparathyroidism
2) Sarcoidosis
3) Malignancy
4) Milk-alkali syndrome |
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Definition
1) Primary Hyperparathyroidism (healthy outpatients)
- 85% from adenoma and 15% from hyperplasia
- Parathyroidectomy
2) Sarcoid (in 10% of cases)
- increased production of Calcitrol by macrophages and giant cells that comprise granulomas, which stimulates intestinal absorption.
3) Malignancy (MOST COMMON overall):
- Secretion of PTHrP causing "humoral hypercalcemia of malignancy" (squamous cell lung cancer)
- Skeletal metastasis with cytokine-mediated osteoclastic activity (treat with Bisphosphonates to prevent resorption)
4) Milk alkali
- 1920s-1950s: High -dose bicarbonate and milk therapy for PUD during
- Currently from Calcium Carbonate therapy (passive over-absorption) |
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Term
| Why might you give a patient with squamous cell lung cancer a bisphosphonate? |
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Definition
| Hypercalcemia from PTHrP release to prevent osteoclast-mediated bone resorption |
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Term
Which of the following is NOT a cause of hypocalcemia?
1) Magnesium deficiency
2) Thiazide diuretics
3) Pancreatitis
4) Hypoparathyroidism
5) ESRD |
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Definition
2- These will cause hypercalcemia
1) Magnesium deficiency (most common in hospital)
- intestinal disease, NPO nutrition or absorption issues
- Mg required for PTH secretion and PTH target organ responses
3) Pancreatitis (obstruction, alcohol, meds, trauma)
- Injury leads to pancreatic lipase release into peritoneal space
- Digested fat produces glycerol and FFA, which bind up calcium into insoluble salts called "calcium soaps"
4) Hypoparathyroidism
- Renal losses
- Intestinal calcium absorption and bone resorption are both lost and cannot compensate
- Give calcium and high-dose Vitamin D
5) ESRD
- No conversion of 25 D to 1,25 VD in kidney
- Similar in live failure, where D can't get to 25 D |
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Term
How do each of the following cause hypocalcemia?
1) Magnesium deficiency
2) Inadequate sun exposure
3) Pancreatitis
4) Hypoparathyroidism
5) ESRD |
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Definition
1) Magnesium deficiency (most common in hospital)
- intestinal disease, NPO nutrition or absorption issues
- Mg required for PTH secretion and PTH target organ responses
2) Loss of cutaneous source
- Other source is diet with intestinal absorption (Calcitrol mediated)
3) Pancreatitis (obstruction, alcohol, meds, trauma)
- Injury leads to pancreatic lipase release into peritoneal space
- Digested fat produces glycerol and FFA, which bind up calcium into insoluble salts called "calcium soaps"
4) Hypoparathyroidism
- Renal losses
- Intestinal calcium absorption and bone resorption are both lost and cannot compensate
- Give calcium and high-dose Vitamin D
5) ESRD
- No conversion of 25 D to 1,25 VD in kidney
- Similar in live failure, where D can't get to 25 D |
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Term
| What are the 7 major forms of metabolic bone disease? |
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Definition
1) Osteoporosis
2) Osteitis Fibrosa Cystica
3) Congenital/genetic skeletal demineralizing disease
4) Skeletal infiltrative/metastasis
5) Osteomalacia/Rickets
6) Renal Osteodystrophy
7) Pagets |
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Term
Which metabolic bone disease is described by each of the following?
1) Chronic elevated levels of PTH
2) Children with un-fused epiphyses that get fractures because of calcium, phosphorus and/or vitamin D deficiency
3) Fractures, bone pain and debility in patients on renal dialysis
4) Focal bone disease of skull, pelvis, lumbar spine, hip or femur due to chronic viral (measles) infection acquired in childhood
5) Hypercalcemia, renal failure and lytic, clean bone lesions. |
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Definition
1) Osteitis Fibrosa Cystica (OFC)
- Treat by treating hyperparathyroidism (remove em)
2) Osteomalacia mineralization defect
- Rickets in adults with fused epiphyses
3) Renal osteodystrophy
- Can be "high turnover" from secondary hyperparathyroidism
- Can be "adynamic" from over-treatment with vitamin D and calcium
- Can be "osteomalacic" from drugs that interfere with mineralization, like aluminum.
4) Paget's disease
- Responds to bisphosphonates
5) Mulitple myeloma |
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Term
| Which metabolic bone disease is associated with Increased numbers of osteoclasts, osteoblasts, fibroblasts, and tetracycline labeling (turnover), with microcysts present in trabecular and cortical bone? |
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Definition
Osteitis Fibrosa Cystica (OFC)
- High PTH- treat hyperparathyroidism |
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Term
What form if renal osteodystrophy is associated with each of the following?
1) Hyperparathyroid bone disease
2) Vitamin D deficiency
3) Aluminum bone disease
4) Vitamin D over-treatment |
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Definition
1) High turnover
2) Osteomalacia
3) Aplastic or Osteomalacia
4) Aplastic |
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