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LMP301 (Winter 2022) > L13 - Calcium, Parathyroid Hormone, Vitamin D > Flashcards

L13 - Calcium, Parathyroid Hormone, Vitamin D Flashcards

1
Q

Calcium Function?

A

Intracellular
• Muscle contraction
• Cell signaling
• Hormone secretion
• Glycogen metabolism
• Cell division

Extracellular
• Maintenanceof intracellular calcium
• Bone mineralization
• Blood coagulation
• Plasma membrane potential
• Extracellular matrix (structure)

Calcium regulation is highly dynamic and tightly regulated constantly between input, exchange, and elimination to maintain homeostasis via endocrine hormones

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2
Q

Distribution of Calcium in the Human Body?

A

99% calcium and phosphate is stored in bone as hydroxyapatite

<0.1% circulates in blood plasma at 2.5 mmol/L

3 plasma fractions:
• Protein bound (albumin and globulin) (40%) (calcium positively charged)
• Complexed to anions (10%) (calcium positively charged)
• Ionized calcium (50%)

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3
Q

Total and Ionized Calcium (iCa)?

A
  • ionized calcium is the biologically active fraction
  • maintained within tight concentration limits
  • laboratory assays can measure total and ionized calcium
  • total calciumis cheaper to run and adequate for most patients
  • ionized calcium is useful in critically ill, abnormal serum protein concentration, acid-base disturbances
  • after blood collection, ionized calcium is sensitive to pH changes and in vitro metabolism
  • special handling of specimens for ionized calcium –transport on ice, do not expose to air, analyze promptly

Reference Ranges:
total calcium: 2.25-2.60 mmol/L (~2.5)
ionized calcium: 1.22-1.37 mmol/L (~1.25)

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4
Q

Hormonal Regulation of Calcium Homeostasis?

A

Hormones:
• Parathyroid Hormone (PTH)
- Acts on bone and kidney
• 1,25 dihydroxy Vitamin D
- Acts on GI and bone
• Calcitonin (insignificant)
- Acts on bone

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5
Q

Parathyroid Hormone?

A
  • 84 amino acid polypeptide hormone
  • produced inChief Cells of the parathyroid gland
  • synthesized as pre-pro-PTH and processed to mature PTH
  • stored in granules
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6
Q

Parathyroid Hormone –Regulation by Calcium?

A
  • PTH secreted in response to a drop in [iCa2+]
  • Release is mediated by calcium sensing receptors (CASRs)
  • Rapidly cleared from plasma with a t1/2 of 5 min by hepatic and renal metabolism – intact PTH required for activity
  • Negative feedback by calcium
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7
Q

Actions of PTH: Bone?

A

**Check slide 10/24

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8
Q

Actions of PTH: Kidney?

A

**Check slide 11/24

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9
Q

Actions of PTH: Intestinal reabsorption?

A
  • PTH upregulates 1-alpha-hydroxlase enzyme activity in the kidney
  • 1-alpha-hydroxylase is responsible for producing the active form of vitamin D, named 1,25 dihydroxy vitamin D
  • 1,25 dihydroxy vitamin D acts on intestinal cells to effect calcium reabsorption
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10
Q

Vitamin D?

A
  • Vitamin D can be synthesized in the body or else be obtained in the diet
  • 1,25 dihydroxy vitamin D is the biologically active form:
  • produced by the activities of cytochrome P450 enzymes
  • Step 1: 25-hydroxylase in the liver to produce 25-hydroxy vitamin D
  • Step 2: 1-alpha-hydroxylase in the kidney to produce 1,25 dihydroxy vitamin D

• Nutritional status of vitamin D is assessed with 25 hydroxy vitamin D test because:

  • Vitamin D is rapidly converted to 25 hydroxy vitamin D
  • 25 hydroxy vitamin D has a long half life (15 days versus 15 hours for 1,25 dihydroxy Vitamin D)
  • 25 hydroxy vitamin D is present in nmol/L versus pmol/L for 1,25 dihydroxy Vitamin D
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11
Q

Actions of 1,25 dihydroxy Vitamin D: Intestinal reabsorption?

A
  • Vitamin D is a lipophilic hormone
  • Crosses membrane and binds to nuclear receptor Vitamin D Receptor = VDR
  • Increases transcription of calbindin gene and protein synthesis
  • Calbindin promotes calcium uptake and calcium vesicles are formed and exocytosed
  • There are also direct effects leading to calcium vesicular formation
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12
Q

Vitamin D Actions: Kidney, Bone, Parathyroid?

A
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13
Q

Calcitonin?

A

32 amino acid peptide hormone produced by C cells in the thyroid gland

Secreted in response to high calcium

Action:
• Bone: Inhibit osteoclast activity
- Used for treatment of postmenopausal osteoporosis, Paget’s disease, etc.
• Kidney: minor effect on calcium handling

In Disease:
• Tumor marker for medullary thyroid carcinoma (tumor of C-cells)

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14
Q

Hypocalcemia?

A

PTH

  • Hypoparathyroidism
  • severe hypomagnesemia
  • autoimmune disease (rare): autoantibody against CASR

Vitamin D
• Deficiency: malabsorption, lack of sun exposure
• Disordered Vitamin D metabolism
- Chronic liver disease
- Renal failure
- Enzyme deficiency (1α-hydroxylase)

Pseudohypoparathyroidism (PTH resistance)
• Mutations in gene encoding G protein S leads to reduced signaling

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15
Q

Hypocalcemia: Clinical Symptoms?

A

Neuromuscular:
• Paresthesia (numbness, tingling)
• Cramps and spasms (tetany)
• Seizure

Cardiovascular:
• Increased QT time
• Arrhythmia

Chvostek’s sign

Trousseau’s sign

**Check slide 17/24

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16
Q

Rickets and Osteomalacia?

A

Defective mineralization in growing bones, children (rickets) or in adults (osteomalacia)

Caused by insufficient Ca, Phosor Vitamin D deficiency
• Acquired:
- Decreased absorption: GI, malnutrition
- Decreased production: Liver, Kidney
• Inherited:
- Defect in 1α-hydroxylase (Rickets type I)
- Defect in Vitamin D receptor (Rickets type II) -resistance

17
Q

Hypercalcemia?

18
Q

Hypercalcemia in disease?

A

Primary Hyperparathyroidism
• Single adenoma or 4-gland hyperplasia
• Leads to excessive bone resorption
• Can present with “Brown’s tumours” in bone radiographs

Hypercalcemia of Malignancy
• Occurs in 20% of all cancer patients (e.g.multiple myeloma)
• 3 mechanisms
- 80% cases -excessive PTH related peptide
- 20% cases -bony metastases leading to release of osteoclast activating factors
- Lymphomas can increase production of 1,25 dihydroxy vitamin D

Granulomatous (immune) disorders e.g.sarcoidosis
• Cells increase production of 1,25 dihydroxy vitamin D

Familial hypocalciuric hypercalcemia (FHH)
• Results from gene mutations in the CASR gene; homozygosity can lead to hyperparathyroidism and severe hypercalcemia, fractures, and failure to thrive

19
Q

Hypercalcemia of Malignancy: PTHrP?

A
  • Homology to PTH
  • Expressed during fetal and neonatal development
  • Produced in uterus and placenta, and in lactating breast
  • No role in endocrine regulation of Ca or PO4

• Causes ‘humoral hypercalcemia of malignancy’ (HHM)

  • squamous cell carcinomas of the lung, esophagus, cervix, skin
  • breast, ovarian and renal
  • bind to PTH receptor and act like PTH except fails to increase enzymatic conversion to 1,25 dihydroxy vitamin D
  • Biochemical
  • High Ca2+
  • Low PO4
  • 1,25 dihydroxy Vit D low to normal
  • PTH low to normal
20
Q

Clinical Symptoms of Hypercalcemia: “Stones, Bones, Groans, and Moans”?

A

Stones: renal stones i.e. nephrolithiasis
Bones: bone pain
Groans: abdominal pain, constipation
Moans: psychiatric overtones, depression, anxiety, confusion
Also, cardiovascular findings: short QT interval, bradycardia

21
Q

Clinical Symptoms of Hypercalcemia: Management?

A
  • Intravenous normal saline
  • Calcitonin
  • Bisphosphonates
  • Diuretics: Loop diuretics (e.g. furosemide)

LMP301 (Winter 2022) (10 decks)

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