unit ii – endocrine section calcium metabolism daylily s ooi mbbs, frcpc (med biochemistry) 3973:...

Unit II – Endocrine Section

Calcium Metabolism

Daylily S OoiMBBS, FRCPC (Med Biochemistry)

3973: Describe the function of parathyroid hormone 3974: Explain the physiological actions of PTH on bone kidneys and intestines 3975: Describe Vitamin D action on target tissues3976: Describe the regulation of 1, 25 di-OH vitamin D3977: Explain the regulation of serum calcium3978: Describe the physiological action of calcitonin

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Slides marked with ✪ are modified from Dr. D Liu’s lecture 2014.

Disclosure

Unit II – Calcium Metabolism – DS Ooi

Objectives Additional topics added to this lecture are in blue


Distribution of calcium, phosphate and magnesium in the body3977: Explain the regulation of serum calcium• Organs involved• Hormonal and other regulators

Parathyroid hormone• Production and regulation• 3973: Describe the function of parathyroid hormone • 3974: Explain the physiological actions of PTH on bone, kidneys and intestines

Vitamin D• Forms• Production• 3976: Describe the regulation of 1, 25 di-OH vitamin D• 3975: Describe Vitamin D action on target tissues

Calcitonin• Production• 3978: Describe the physiological action of calcitonin• Clinical uses

Disturbances of calcium homeostasis – causes, symptoms, management• Hypercalcemia• Hypocalcemia• Secondary hyperparathyroidism

Disturbances of Magnesium and Phosphate

Distribution of Calcium

Total body calcium ~ 1kg (25.5 moles)• 99% in Bone (25 moles).

With phosphorus, constitutes 65% of bone by weight.

• Soft tissue - intracellular (25 mmoles)– Very little as cytosolic free calcium (100 nmoles)– 99% is within cellular compartments – bound to inner plasma

membrane of mitochondria, or endoplasmic reticulum

• Extracellular fluid (23 mmoles)


Distribution of calcium in blood

• 45% protein bound (80% albumin, 20% globulins)

• 10% complexed (citrate, lactate, phosphate, bicarbonate)

• 45% free ionized form (physiologically active)Varies with pH

alkaline pH binding free ionized form acid pH binding free ionized Ca


Calcium

Function:

Extracellular• Excitation-contraction in muscles

• Synaptic transmission

• Platelet aggregation and coagulation

Intracellular• Secretion of hormones and other regulators by

exocytosis

• Secondary messenger in cell division, cell motility

✪ Unit II – Calcium Metabolism – DS Ooi

Magnesium

Distribution:Total body magnesium 1 mole (Total body Ca = 25 moles)

– Bone predominantly– Cells– Serum - 30% protein bound (Serum Ca 40% bound)

Function: Neuromuscular conductionParathyroid hormone secretion


Phosphate

Distribution:Total body phosphate 700g (24 moles)• Bone 83% - hydroxyapatite (calcium phospate)

• Cells 16% - organic phosphates (nucleic acid, ATP, phospholipids)

• Extracellular 1% - inorganic phosphates Fluid (H2PO4

- : HPO4= 1:4)

Function:• High energy phosphate bonds• Buffer


Hormones:

Organs involved:• Intestine• Kidneys• Bone

Regulation of calcium metabolism:


Calcium balance over 24 hours

PTH

14 mmoles/d

Vit D

Soft Tissue25 mmoles(1000 mg)

Bone 25 moles

(1000 mg)

Extracellular Fluid23 mmoles(920 mg)

GI Tract

Kidney

20 mmoles (800 mg)

8 mmoles (320 mg)

16 mmoles (640 mg)

4 mmoles (160 mg)

4 mmoles

Vit DGlomerular filtrate270 mmoles PTH


Calcium

Intestine

Absorption process: • Regulated saturable transcellular absorption• Nonsaturable paracellular absorption (dependent on

mineral concentration in lumen)

Main sites:Duodenum and jejunum


Factors affecting intestinal calcium absorption


GIT: Gastro-intestinal tract; diOH: dihydroxy

Kidney: Calcium handling

Filtered Ca270 mmol/24h

Prox Convoluted

Tubule(passive)

Distal Convoluted Tubule(active)

Collecting Duct

Thick Asc

Loop of Henle

70%

20%

8%

(GF:180LConc: 1.5 mmol/L)

98% reabsorbed~ 5 mmol excreted in 24h

<5%


Bones:

PTH

14 mmoles/d

Vit D

Soft Tissue25 mmoles(1000 mg)

Bone 25 moles

(1000 mg)

Extracellular Fluid23 mmoles(920 mg)

GI Tract

Kidney

20 mmoles (800 mg)

8 mmoles (320 mg)

16 mmoles (640 mg)

4 mmoles (160 mg)

4 mmoles

Vit DGlomerular filtrate270 mmoles PTH


Regulation of calcium:

Hormones involved

Parathyroid hormone (PTH, parathyrin) Bone Kidneys Intestines

Vitamin D Intestines Bone Kidneys

Calcitonin Bone Kidneys


Parathyroid hormone (PTH)

Synthesized as preprohoromone that undergoes cleavage before secretion

Continuously synthesized, minimal storage in parathyroid glands

Metabolized by liver & kidneys, plasma t1/2 2 min Laboratory assays measure:

C terminal (long t½), N-terminal (short t½ ) Mid-terminal (long half-life)

Intact PTH – most intact assays, also measure a 7-84aa fragment which accumulates in renal failure

Unit II – Calcium Metabolism – DS Ooi✪

Regulators of Plasma PTH

Plasma calcium Hypocalcemia PTH biosynthesis

Ca-sensing receptor (CaSR) on parathyroid cellsCalcium binding results in PTH synthesis & secretion degradation of stored PTH

Calcitriol 1,25(OH)2D3 PTH gene transcription Hypocalcaemia overrides calcitriol effect on PTH production

Less important regulators: Catecholamines Magnesium - low Mg can cause hypocalcaemia Prostaglandins


PTH secretion vs. Plasma calcium

From Williams Textbook of Endocrinology


Secretion rate of PTH varies inversely with plasma calcium concentation, in a sigmoid fashion

✪

PTH

Actions:

Maintains ionized calcium concentration within narrow range

Bones: Initiates osteoclastic bone resorption– release of calcium from bones

At high concentrations (e.g. 1o or 2o hyperparathyroidism)

– bone resorption >> bone formation

– cortical bone mass

At lower concentrations, especially if episodic release– bone formation >> bone resorption

– trabecular bone mass


PTH

Actions on kidneys:

Kidneys: – calcium reabsorption in distal convoluted tubules

Note: 90% of filtered Ca reabsorbed in proximal tubule and loop of Henle independent of PTH, mostly via passive paracellular route

– phosphate reabsorption in proximal and distal convoluted tubules

– Stimulates 1 a-hydroxylase (calcidiol to calcitriol)

Intestines: effect through vitamin D


Vitamin D


Action:• Binds to nuclear Vitamin D Receptor (VDR) – resulting in regulation of

DNA transcription• Calcitriol has highest affinity

Vitamin D

7-dehydrocholesterol Cholecalciferol

25-OH vitamin D

Calcitriol

PTH

24,25 - D

IntestinesCa & PO4

absorption

Parathyroids¯ PTH Secretion¯ Cell proliferation¯ Gene transcription

BoneMultiple effects

Muscle(deficiency associated with

myopathy)


Hormonal Regulation of Blood Calcium

CalciumAbsorption

GastrointestinalTract

Ca excretion P excretion

Blood Ca

mineralization

Bone loss

Bone resorption

PTH

Parathyroid Glands

Blood calcium


1,25 diOH Vit D

Cholecalciferol (Vit D3)

7-Dehydrocholesterol

Effect of UV on Skin

25-OHcholecalciferol

25 hydroxylase

1 hydroxylase

Legend:

Stimulate

Inhibit

Delayed effects (Stimulation)

Regulation of Blood CalciumWhen blood calcium falls:

Bone resorption

PTH

Blood Ca ++

Parathyroid Glands

Ca excretion Serum Ca

P excretion Serum P

T½ 10 mMetabolised in liver to n-terminal (active, t½ 1-2m) c-terminal fragments (t½1-2h)which are cleared by kidney

Ca P

Serum Ca Serum P


Regulation of Blood Calcium concentrationsIntermediate/Long term

PTH

25-OH D 1,25 diOH Vit D


CalciumAbsorption

Parathyroid Glands



mineralization


Calcitonin


Calcitonin

Production: 32-amino acid peptide hormone Produced by thyroid parafollicular C-cells


Calcitonin

Action: Inhibits osteoclast-mediated bone resorption

(counteracts action of PTH) Renal (at higher concentrations):

Inhibits P reabsorption P excretion Some natriuretic effect mildly Ca excretion

Non-essential & less important than PTHTotal thyroidectomy does not result in hypercalcaemia

High calcitonin in medullary thyroid cancer does not result in hypocalcaemia


Clinical uses of calcitonin

Tumour marker for medullary thyroid carcinoma Therapeutic applications:

Hypercalcemia - administration quickly lowers plasma Ca through reduced osteoclast activity

Osteoporosis - reduces fracture risk & pain associated with fractures (no longer used due to increased risk of malignancy)

Paget disease of bone (bisphosphonates preferred)


Other hormones affect bone

Growth hormone & IGF-1

• bone remodeling

Glucocorticoids• Ca absorption• Long term administration bone

formation

Hyperthyroidism• skeletal growth in children• bone resorption in adults

Insulin • Required for normal growth

Gonadal hormones

• Critical for skeletal development & maintenance


IGF – Insulin-like Growth Factor

Local bone regulators

Cytokines• e.g., interleukins, TNF-, TNF-• bone resorption, formation

TGF- & EGF• Produced by neoplasms• bone resorption

Prostaglandins• Synthesized by many skeletal cells• Affects bone resorption & formation


TNF: Tissue Necrosis Factor, TGF: Transforming Growth Factor, EGF: Epidermal Growth Factor

Hormonal Regulation of Blood Calcium




25-OHCholecalciferol

(Calcidiol)

25 a hydroxylase

1,25 diOH Vit D(calcitriol)

1 a hydroxylase

PTH

Parathyroid Glands

Parafollicular C cells

CalcitoninOsteoclast inhibition bone remodelling

Diet

Ergocalciferol (D2)

25-OHErgocalciferol

1, 25diOH D2

Ca release from bone (permissive)Activates remodelling Ca and phosphate reabsorption Intestinal Ca and P transportInhibition of PTH synthesis

Ca release from bones Bone remodelling (RANKL) DCT Ca reabsorptionPCT and DCT P reabsorptionRenal 1 a hydroxylase activation


Disorders of Calcium homeostasis


Mechanisms for hypercalcemia

• Bone resorption

• Gastrointestinal absorption of calcium

• Renal excretion of calcium


PTH Mediated

• Primary hyperparathyroidism– Sporadic– Inherited variants

• Multiple endocrine neoplasia (MEN1, 2a)• Familial isolated hyperparathyroidism

– Hyperparathyroid-jaw tumour syndrome

• Familial hypocalciuric hypercalcemiaCaSR mutation (AD inheritance)

• Tertiary hyperparathyroidismFollowing prolonged stimulation, part of the parathyroid gland escapes feedback control


Primary Hyperparathyroidism

• F > M, up to 0.4% of F>60y may be affected• Pathology:

– Solitary adenoma 80%– Hyperplasia 15%– Parathyroid carcinoma 1-2%


Non-PTH Mediated

• Malignancy– PTH-related peptide (PTHrP)– Osteolytic bone metastasis and local cytokines– Activation of extrarenal 1 -a hydroxylase

• Vitamin D– Chronic granulomatous disorders (sarcoidosis, TB) 1 -a hydroxylase– Exogenous vitamin D intake

• Drugs:– Milk-alkali syndrome ( Ca absorption, alkalosis renal Ca excretion)– Lithium (renal Ca excretion, ? block Ca feedback on parathyroids)– Thiazides ( Renal Ca excretion)– Vitamin A toxicity– Theophylline toxicity

• Miscellaneous:– Hyperthyroidism– Acromegaly– Adrenal insufficiency– Immobilization


Malignancy-associated hypercalcemia

• The most common cause of hypercalcemia in hospitalized patients

• Incidence: 15 cases/100,000/yr• Common cancers

– squamous cell cancer of lung, breast – renal cell carcinoma– myeloma, lymphoma

Rare in colon, gastric and thyroid cancers


Hypercalcemia – Symptoms/Signs


Bones

Stones

Groans

Moans

Management of Hypercalcemia:

• IV fluids• Loop diuretics (furosemide)• Calcitonin• Steroids• Bisphosphonates• Dialysis• Calcium sensor receptor agonist (Cinacalcet) – for

primary hyperparathyroidism


Hypocalcemia

Causes:

1. Insufficient PTH activity– Hypoparathyroidism (post thyroid surgery)– Hypomagnesemia (Mg required for PTH release)– Pseudoparathyroidism (PTH resistance)

2. Insufficient Vitamin D action– Insufficient Dietary/Exposure to UV rays– 1a-hydroxylase

• Chronic renal failure• Vitamin D dependent rickets

– Vitamin D resistant rickets

3. Sequestration of calcium– Acute pancreatitis

4. Drugs – calcitonin, furosemide


Hypocalcemia – Symptoms/Signs


Management of hypocalcemia

Acute: Replace calcium

Calcium gluconate IV Oral calcium

Treat hypomagnesemia, if present May require vitamin D Correct underlying cause

Long-term High dose vitamin D (D2 50,000 IU daily, calcitriol – up to 2 ug daily)

Adequate calcium intake


Secondary hyperparathyroidism

PTH caused by other conditions• Vitamin D disorders

– Deficiency or malabsorption– Rickets

• Phosphate disorders– Chronic kidney disease– Phosphate depletion– Malabsorption– Aluminium toxicity

• Calcium deficiency


Chronic kidney disease

Parathyroid glands

¯ Ca absorption(passive P absorption)

PTH

PN or Ca2+

1,25 D

+

PTH

+

+

Ca, PP


Hypermagnesemia

Causes:• Chronic renal failure• Intravenous MgSO4 - as antihypertensive, sedative during

parturitionEffects:Usually does not rise to critical concentrations, and not

clinically important.• Sedation• Neuromuscular activity


Hypomagnesemia

Causes:1. Reduce intake

– malabsorption– intake (alcoholics)

2. renal loss– diuretics– alcohol– Renal tubular defects– drugs - gentamicin, amphotericin B

Effects: PTH release (hypocalcemia)


Hyperphosphatemia

Cause: Most often seen in chronic renal failure

Effect: serum calcium

Secondary hyperparathyroidism

Management:• Oral Phosphate binders• Dialysis for CRF patients


Hypophosphatemia

Cause:

1. intake - starvation, malabsorption, Al(OH)3

2. loss• renal tubular leaks• hyperparathyroidism• Vit D resistant rickets (impaired tubular Phosphate

transport)

Effect:1. Loss of RBC membrane integrity (hemolysis)2. Muscle weakness


Key points

Blood calcium is tightly regulated, primarily by PTH & vitamin D. Calcitonin plays a far less important role.

PTH acts on kidneys and bones; Vit D on bones, intestines, kidneys Common clinical conditions:

Hypercalcemia Hypercalcemia in malignancy Primary hyperparathyroidism

Hypocalcemia Post thyroid, parathyroid surgery

Secondary hyperparathyroidism Vitamin D deficiency Renal failure

Remember! Always adjust serum total calcium for albumin concentration (0.2 mmol Ca for every 10 g of albumin)


Appendix: Parathyroid hormone

From Endocrinology: An Integrated Approach, 2001


84 amino acid peptide hormone

Synthesis:

7-84aaBlocks PTH activityAccumulates in CKDMeasured by most intact PTH assays

✪

Vitamin D: Chemical structures

D2 D3

25-OH D31,25(OH)2D3

From www.chm.bris.ac.uk


unit ii – endocrine section calcium metabolism daylily s ooi mbbs, frcpc (med biochemistry) 3973:...

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