Slide 1

Dr Neil A. Bradbury

Overview

[Ca 2+ ] and [P i ] kept within narrow limits

In humans the most important regulators of plasma [Ca 2+ ]

are the calcium mobilizing hormone PTH , and vitamin D

which promotes intestinal absorption of Ca 2+ and P i

Plasma [Ca 2+ ] and [P i ] must be regulated concomitantly

Plasma [Ca 2+ ] is maintained at the expense of bone integrity

Mrs Barnes, a 30 yo female, with advanced renal

failure is receiving peritoneal dialysis while awaiting

transplantation. She is admitted to hospital for

evaluation because she experienced severe bone

pain and itching. Upon admission, she had increased

plasma Pi (hyperphosphataemia), decreased plasma

Ca++ (hypocalcaemia), increased circulation PTH

and decreased calcitriol. Radiological examination

revealed increased bone resorption, osteomalacia

and soft-tissue calcification.

Bone

99% of total body

calcium

Interstitial Fluid

0.1% of total calcium

Mostly Ca 2+

1.5 mM

Plasma

<0.5% of total

45% as Ca 2+

1% of total

Ca 2+ most is

sequestered

in ER/mito or

protein-bound

40% protein

bound

15% unionized

salts (phosphate/

citrate)

0.1-1.0 µ M

2.5 mM

Mostly as complex

calcuim-phosphate salts

Protein

bound

Ionized "free" Ca 2+

Un-ionized

complexes

[H+] (acidosis) [Ca 2+ ]

[H+] (alkalosis) [Ca 2+ ]

H +

Normal Calcium Balance

~1000mg/ day of calcium is ingested

only ~10% is absorbed (100mg) the rest

is excreted

Only ionized Ca 2+ is filtered by the kidney

How plasma Ca 2+ is

controlled

A. Chemical eqlm between bone ECF and

plasma Ca 2+

- Bone is a ppt of phosphate salts immersed in

a saturated soln of Ca 2+ and P i

- When the [Ca 2+ ] and [P i ] exceeds the solubility constant, the

ions will complex and ppt; promotes bone mineralization

- When the [Ca 2+ ] and [P i ] is lower than the solubility constant,

the ions will not complex and salts within the bone will dissolve;

promotes bone de-mineralization

How plasma Ca 2+ is

controlled

B. Hormones

 Parathyroid hormone (PTH)

 Vitamin D

 Calcitonin

 Parathyroid hormone related peptide (PTHrP)

 Calcium

 Steroids

 Glucocorticoids

 CGRP

 Ca 2+

 Parathyroid hormone (PTH)

 Vitamin D

 Calcitonin

 Parathyroid hormone related peptide (PTHrP)

 Calcium

 Steroids

Parathyroid

Hormone (PTH)

is secreted from

the parathyroid

gland !!!!

Downloaded from: StudentConsult (on 14 June 2007 02:44 PM)

© 2005 Elsevier

Remember to distinguish

between plasma Ca ++

and intracellular Ca ++

R

An autosomal dominant genetic disease with mutations in

the Calcium Receptor (CaSR)

Serum Calcium levels are elevated 10-30%

Serum PTH levels are in normal range

Rarely, infants are born

homozygous for the defective

CaSR. They have very high

severe hypercalcemia. A life

threatening condition with

neuronal malfunction, bone

demineralization and soft

tissue ossificiation. Death

results unless parathyroid

tissue is removed.

PTH and the Kidney

(TAL and DCT)

PTH

CaC Po

ATP

cAMP

PTH affects the skeletal system

PTH accelerates removal of Ca ++ from bone

PTH has a 3-phase effect on bone

Osteocyte

Osteoclast

Osteoblast

Osteoclasts have NO PTH

receptors

PTH

cytokines

X

Osteoblasts

Bone

resorption

Osteoclasts

….one more problem

Ca 2+

+

Phosphate

PTH and intestinal Ca 2+ absorption

PTH does no affect intestinal Ca2+ absorption

PTH

Vitamin D

1,25-

dihydroxyvitamin D

Calcium absorption

Proximal Tubule

PTH

X

cAMP

ATP

Control

NaPi transporter

immuno-staining

PTH for 15 min

PTH for 60 min

Pathophysiology of PTH

1. Hormone excess (hyperparathyroidism)

1. Hormone deficiency (hypoparathyroidism)

1. Hormone resistance

(pseudohypoparathyroidism)

Primary Hyperparathyroidism

Usually from a benign parathyroid adenoma

PTH

Plasma [Ca2+]

Bone

Kidney

Intestine

Phosphate reabsorption

Hypercalcaemia hypophosphataemia (phosphaturia)

Urine contains large amounts of phosphate, cAMP and Ca 2+

Secondary hyperparathyroidism

PTH

PTH secreted in response to hypocalcaemia

(chronic renal failure or Vitamin D deficiency

Circulating levels of PTH are high and plasma

[Ca2+] are either low or normal but never high

Pathophysiology of PTH

1. Hormone excess (hyperparathyroidism)

1. Hormone deficiency (hypoparathyroidism)

1. Hormone resistance

(pseudohypoparathyroidism)

Hypoparathyroidism

Most commonly

associated with thyroid

and parathyroid surgery

Low circulating PTH levels

Decreased bone resorption

Decreased renal and

intestinal Ca2+ absorption

Increased renal Pi absorption

Hypocalcaemia and hyperphosphataemia

Pathophysiology of PTH

1. Hormone excess (hyperparathyroidism)

1. Hormone deficiency (hypoparathyroidism)

1. Hormone resistance

(pseudohypoparathyroidism)

Pseudohypoparathyroidism

• An inability of the body to respond to PTH

• Renal cells don’t make cAMP in resonse

to PTH

• Patients have hypocalcaemia,

hyperphosphataemia and increased

circulating PTH levels.

Vitamin D

• “….a hormone wannabe”

Not a “classic hormone”, as it is not secreted by and

endocrine gland.

But:

After modification affects distant target cells

Binds to surface receptors and has mechanisms of

actions like other hormones

Fish,

liver,

irradiated

milk

D 2 /D 3

D 3

Fat sol

so bile

salts

required

for

uptake

Hydroxylase activities regulate

metabolite formation

Vitamin D

Ca 2+

P i

Vitamin D

1-hydroxylase

activity

1-hydroxylase

activity

Vitamin D and bones

Job of vitamin D is to promote bone mineralization

Vitamin D acts synergistically with PTH to

enhance osteoclast activity and increase

release of Ca2+ and phosphate from bone

Vit D

[Ca-Pi]

Vit D resorbs “old” bone

Together with increased

plasma Ca-and Pi helps

to mineralize “new”

bone (bone remodeling)

Rickets

Vitamin D resistance

Reduced or absent

1 α -hydroxylase activity

X

Genetic loss of enzyme

Chronic renal failure

Renal osteodystrophy

Calcitonin

32 amino acid peptide

“C” cells (aka parafollicular cells)

Calcitonin

(all it appears to be ?)

Calcitonin

(all it appears to be ?)

Calcitonin is impt in teleosts

Calcitonin

(all it appears to be ?)

Osteoclasts have no PTH receptors

Osteoclasts have calcitonin receptors

Calcitonin-gene-related-

peptide (CGRP)

Sex Steroid Hormones

and Glucocorticoids

Thick Ascending Limb (TAL)

Ca 2+ as a

hormone?

Ca 2+

activates

the CaSR

in the TAL

Dietary effects

Plasma [Ca 2+ ]

PTH secretion

1 α -hydroxylase activity

Ca 2+ and

phosphate

release from

bone

Stimulus for intestinal

Ca 2+ uptake

Renal Ca 2+ absorption

Dietary Effects

Plasma [Ca 2+ ]

PTH secretion

1 α -hydroxylase activity

Ca 2+ and

phosphate

release from

bone

Stimulus for intestinal

Ca 2+ uptake

Renal Ca 2+ absorption

Dietary Effects

Plasma [phosphate]

Plasma [Ca2+]

due to complex

formation

Bone Ca 2+ and phosphate

mobilization

phospaturia

PTH

1 α -hydroxylase activity

Intestinal

Ca 2+

absorption

• Plasma Ca 2+ and Pi are kept within narrow limits

• Distinguish between intracellular and extracellular Ca 2+

• Plasma Ca2+ and Pi have to be regulated coordinately

• Both “bound” and “free” Ca 2+

• PTH and vitamin D are the major regulators of Ca 2+ and Pi

homeostasis in humans

• PTH increased plasma [Ca 2+ ] and decreases plasma [Pi]

• Vitamin D increases both plasma [Ca 2+ ] and plasma [Pi]

• PTH and vitamin D actions on GI absorption and renal

excretion

• Other hormones play a minor role in Ca 2+ and Pi

homeostasis