Mineral Metabolism Final Printable

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PHYSIOLOGY: Hormone Regulation of Mineral Metabolism 1

SUBJECT: PHYSIOLOGY

TOPIC: Hormone Regulation of Mineral

Metabolism

LECTURER: DR. VIC MENDOZA

DATE: FEBRUARY 2011

Endocrine System:

• Maintains constant concentration of

ionized Calcium in the extracellular fluid

• Responsible for:

o Bone mineralization

o Neuromuscular excitability

o Membrane integrity

o Cellular biochemical reactions

o Stimulus‐secretion coupling

(especially in the GIT)o Blood coagulation

PHOSPHATE

• Critically important to all biological

systems

• Integral component of numerous

intermediates in the metabolism of

carbohydrates, lipids, and proteins

• Forms part of the structure of

– High‐energy transfer and storage

compounds such as ATP and

Creatine Phosphate

– Co‐factors such as NAD, NADP,

and thiamine pyrophosphate

– Second messengers such as

cAMP and inositol triphosphate

– DNA and RNA

• Functions as covalent modifier of many

enzymes

• Intracellularly, an important anion that

balances the cations K+ and Mg++

• Major constituent of the crystalline

structure of bone and teeth

– 85% in skeleton, 6% in muscle

**The diagrams above show the Calcium

exchange between different tissue compartments

in a person ingesting 1000 mg of calcium per day.

Note: Most Calcium ingested is normally

eliminated in the feces, though kidneys also have

the capacity to excrete large amounts by reducing

tubular reabsorption of Calcium.




CALCIUM BALANCE

• Balance means we talk about the amount

of Calcium that goes in the body (input)

and how much Calcium goes out (output).

• Therefore, if we say there's a "balance", it

means that the amount that goes in mustbe the amount that goes out. And if there

is more calcium going in than going out

(input > output), then there will be an

imbalance.

• In terms of Input:

o Basically from our diet, where

calcium intake may vary from

200 mg to 2000 mg per day. But

on average, we take in about

1000 mg. (American diet)

o But not all of this 1000 mg is

absorbed in our system. Only

about 300 mg is absorbed on

average.

NOTE: Calcium is actually absorbed in the ILEUM

• There are 2 processes that allow the

absorption of Calcium

1. Passive Diffusion (10%)

2. Active Transport (90%)

But although 300 mg is absorbed in the GIT, a lot

of calcium is also secreted by the GIT. (e.g. calcium

in the pancreatic secretion) Therefore, although you

absorb 300, as much as 125 mg is secreted by the

GIT. This means that in terms of absorption, there

is only a 175 mg net absorption of calcium, while

the rest is secreted out.

SO how much calcium goes in? 175 mg.

However, there is actually a really huge amount of calcium found in the body (about 1 kg) at any

point in time. 99% of this is found in the skeletal

system. The other 1% is found in soft tissue and

ECF.

About 1% of that in bone (about 10 g) is

exchangeable with that in the ECF.

How does this work?

The bone undergoes constant remodelling or a

continuous resorption of the bone. This means

that part of the bone is destroyed, but with newbone formation at the same time. (Because of this,

they estimated that the skeletal system is

regenerated every 10 years!)

Most of the calcium in the ECF is filtered

(ultrafilterable). But a good portion of the calcium

ECF is reabsorbed. In a day, about 10 g are

filtered. But out of this 10 g, more than 98% is

reabsorbed, while the rest is excreted out through

the urine.

Again, this balance works because of theregulators. (Major regulator is actually the

parathyroid hormone when it comes to calcium).

Recall:

There are 3 cell types in the bones:

1. Osteocytes ‐ the "imprisoned" osteoblasts

surrounded by new bone

2. Osteoblasts ‐ new bone formation

3. Osteoclasts ‐ bone resorption

3 Regulators of Calcium and PhosphateMetabolism:

• Parathyroid Hormone

• Vitamin D

• Calcitonin (concerned with Calcium ONLY)

1. PARATHYROID HORMONE

Target Organs:

• Bones

• Kidney (because the kidneys are involved in

calcium excretion)




How PTH works:

When you have very high levels of PTH, bone

resorption occurs. A high activity of bone

resorption means there will be a release of

calcium and phosphate from the skeletal system.

These go to the ECF.

Therefore, calcium serum level rises, and,

theoretically, phosphate levels should rise too.

However, it was found that when you have high

PTH, there is indeed a rise in calcium levels BUT

phosphate levels seem to decrease. This is due to

the effect of the PTH on the kidneys.

Effect of PTH on Kidneys

1. Promotes calcium reabsorption

Therefore, calcium serum levels ELEVATE more.

Note: Calcium reabsorption occurs in the distal

nephron

2. Promotes phosphate excretion

So you lose a lot of phosphate through the

urine.

This action of the PTH on the kidneys is

greater/more dominant than the effect of PTH on

the bone. Therefore, even if phosphate is released

in the bones too, the net effect is that it causes

your phosphate levels to decrease in the serum.

Reducing phosphate levels is actually very

important because if both calcium and phosphate

are very high in your serum, there is a tendency

for mineralization of bone rather than increasing

serum calcium levels.

What regulates the PTH secretion?

Amount of ionized calcium in the body.

This is a negative feedback effect, wherein if calcium in the serum is high, amount of PTH is

low. But, if serum calcium is low, PTH secretion is

high.

Again:

Low ionized serum calcium = High PTH secretion

High ionized serum calcium = Low PTH secretion

There are also other factors that can change the

amounts of total serum calcium such as change in

acid‐base balance

If in a state of acidosis, the acidosis will displace

calcium from its binding with protein.

On the other hand, alkalosis can enhance the

binding of ionized calcium to protein, thereby

reducing the ionized portion!

Hyperventilation Syndrome:

A case wherein an individual hyperventilates, thus

CO2 is blown off. This induces respiratory alkalosis.

The alkalosis will cause the calcium to bind more,

and therefore the ionized serum calcium level goes

down. As a result, these people present with a form

of muscular tetany .

(Since calcium is involved in muscular excitability)

How is the amount of ionized serum calciumdetermined if we can only measure total serum

calcium?

They found out that about 50% of the total serum

calcium is ionized.

The other 50% is not ionized because 40% is bound to

protein, whereas the other 10% is complexed with

diffusable anions.

So, when there is a change in serum protein levels

(especially albumin, since calcium is really bound to

albumin), there is bound to be a change in the total

serum calcium concentration as well.

They postulated that if there is a decrease in serum

albumin levels by about 1mg/deciliter, then the total

serum calcium concentration will also be reduced by

about 0.8 mg/dL.




Action of PTH in Promoting Calcium

• Of the 3 cell types found in the bones, it is

the osteoclasts that are directly affected

by PTH.

• PTH indirectly affects osteoblasts.

If there is new bone formation, the

osteoblasts draw calcium from the ECF to

incorporate in the new bone. As a result, it will

cause a DECREASE in the amount of calcium in

the ECF.

Remember that there is a relationship between

your osteoblasts and osteoclasts.

Osteoblasts come from the stromal cells (CT

within bone marrow), whereas the osteoclasts

come from macrophages. The osteoblasts secrete

a chemical signal that has an effect on the

differentiation of osteoclasts.

These chemical signals are:

1. RANK Ligand

2. Osteoprotegerin

The RANK Ligand acts on the receptor found on

macrophages. So once this attaches to the

receptor, these macrophages are stimulated to

differentiate into osteoclasts!

At the same time, the RANK‐receptor complex

causes the formed osteoclasts to live longer by

suppressing apoptosis.

The Osteoprotegerin suppresses or inhibits the

development and activity of osteoclasts.

So PTH is supposed to inhibit the bone forming

activity of osteoblasts and stimulate recruitment

of osteoclasts.

Again, in a nutshell:

PARATHYROID HORMONE

• PTH acts directly on bone and kidney to

INCREASE Calcium influx into Plasma.

• By stimulating 1,25 (OH)2‐D synthesis,

PTH also increases calcium absorption

from the gut thus increasing plasmacalcium levels.

(will be further discussed in succeeding

text)

• In contrast, PTH INHIBITS renal tubular

resorption of phosphate, thereby

increasing urinary phosphate excretion.

o This offsets entry from bone and

gut therefore decreasing plasma

phosphate levels.

Among Females

Upon reaching the menopausal stage, females tend to

develop more brittle bones. Osteoporosis becomes a

significant problem. This is because estrogen actually

promotes the secretion of Osteoprotegerin, which

suppresses osteoclast development and activity.

Therefore, in menopause there is more of RANK.




NOTE: There is an inverse relationship between

PTH secretion and plasma ionized concentration

in humans.

The diagram below further reinforces the indirect

relationship between PTH secretion and Serum

Calcium levels.

VITAMIN D

• Derived from cholesterol, therefore can

be classified as a steroid hormone

• Basically, from cholesterol converted

to pregnenolone eventually forming 7‐

Dehydrocholesterol.

7‐Dehydrocholesterol is actually abundant inthe skin. The exposure of skin to sunlight

(which has UV rays) promotes the conversion

of 7‐dehydrocholesterol to Vit. D3, or

cholecalciferol .

This cholecalciferol is bound to protein (globulin),

and upon binding enables it to circulate in thebloodstream. Once it finds its way into the liver,

the cholecalciferol is hydroxylated in the carbon

25 (C25) position. Thus, it becomes the 25‐

hydroxycholecalciferol. (aka 25‐hydroxy vitamin

D3, or the major circulating form of Vit. D).

As it circulates, it will find its way to the kidney

where it will again undergo hydroxylation. This

hydroxy group can attach to 2 positions: C24 and

C1.

If it attaches to C1, it will form 1,25(OH)2‐D3.If it attaches to C24, it will form 24,25(OH)2‐D3.

1,25(OH)2‐D3 is the biologically active form of

vitamin D3!

If there is a high rate of hydroxylation at the C1

position, then the hydroxylation at the C24 will be

very low. (Inversely proportional!)

They also postulated that hydroxylations in C24 is

a form of inactivation when it comes to vitamin D.

What will promote the development of the

active form (1,25(OH)2‐D3)?

Hydroxylation in the C1 position is facilitated by

an enzyme called 1‐alpha‐hydroxylase .




If the activity of this enzyme is very high, then

more of 1,25(OH)2‐D3 (the more biologically active

one) will be formed. But if there is low activity of

1‐alpha‐hydroxylase, then there will be greater

formation of 24,25(OH)2‐D3.

What stimulates the activity of the enzyme 1‐

alpha‐hydroxylase?

1. High levels of PTH

High levels stimulate 1‐alpha‐hydroxylase

so that more of the active form (1,24) will

be formed.

2. Low levels of serum phosphate

3. High levels of 24,25(OH)2‐D3

But, in what situations will you have high levels of

PTH and low levels of serum phosphate?

When you have low serum calcium levels.

If your ionized serum calcium level is low, that will

cause your PTH levels to go up and thus cause

your phosphate levels in the serum to go down.

** Vit. D deficiency, calcium deficiency,

phosphate deficiency will also cause very high

levels of PTH.

What will promote the formation of the

INACTIVE form (24,25(OH)2‐D3)?

1. High levels of active vitamin D

2. Excess calcium

3. Excess phosphate

Action of Vitamin D

• Main target organ: GIT (directly affected)

• Although it also has (indirect) effects on:

‐ Bone

‐ Kidneys

‐ Immune system(Vitamin D actually stimulates

lymphocytes, macrophages)

‐ Skeletal muscle strength

Vitamin D on the Kidneys

Promotes the reabsorption of calcium as well.

PTH, however, has an indirect effect on the GIT by

promoting the synthesis of the active form of

vitamin D. Since a high level of PTH and low level

of serum phosphate stimulate the synthesis of 1,25(OH)2‐D3.

Does vitamin D qualify to be called a hormone?

Yes. The endocrine gland would be the skin. And

as it is produced in the skin, it goes through the

circulation without passing through any ducts.

It's just that it was only discovered first as a

vitamin D and so the name "stuck" as "vitamin D".

Vitamin D deficiency:

‐ Rickets for kids

‐ Osteomalacia for adults

If we are exposed to enough sunlight, there is no

need to take supplemental vitamin D.

The only problem is that nowadays, we are rarely

exposed to enough sunlight since some no longer

want to stay outdoors. This mentality causes us to

need to take in vitamin D supplements, especially

for dark‐skinned individuals (they need more

exposure to the sun to produce the same level of

vitamin D). This is a problem, due to the growing

trend of migration wherein a lot of black people

migrate to areas where there is very little sunlight

(e.g. Scandinavian countries).




In a nutshell:

VITAMIN D

Target Organs:

• GIT:

Promote intestinal calcium absorption

and intestinal phosphate absorption• Bone:

Promotes mineralization of bone

• Kidney:

Facilitates Calcium reabsorption in the

distal nephron

• Immune System:

• Promotes differentiation of monocyte

precursors to monocytes & macrophages

• Skeletal Muscle

**Vitamin D affects both T and B cells, inhibiting

interleukin‐2 production and other effector

functions.

Below is a diagram [taken from Harper’s Illustrated

Biochemistry since the one in the powerpoint is not

that clear] that shows the formation and hydroxylation

of Vitamin D.

• Vitamin D undergoes 25‐hydroxylation in

the liver.

• It is then further hydroxylated in the

kidney in the position 1 [when more

biological reaction is needed] or position

24 [when less biological activity is

required].

CALCITONIN

• Produced by the T cells of thyroid gland

• Reduces bone resorption by inhibiting

osteoclast function

o Effect: Decreased concentrations

of Calcium and Phosphate in the

serum

• Receptors for Calcitonin are found in

bones and kidneys.

• Calcitonin lowers circulating Calcium and

Phosphate levels.

• It exerts its Calcium‐lowering effect by

inhibiting bone resorption.

• It also increases Calcium secretion in

urine.

Regulator of calcitonin levels:

Amount of calcium in the serum

If very, very HIGH serum calcium level

(hypercalcemia) Calcitonin secretion INCREASE

Osteoblast activity DECREASE reduced bone

resorption reduction in serum phosphate.




But calcitonin is not so important as a regulator if

calcium is concerned. It is only important when

there are very, very high levels of serum calcium,

which rarely occurs. In fact, one can do away with

calcitonin.

On the other hand, PTH is said to be essential forlife. So if you take out the parathyroid gland (in

the process of taking out the thyroid, for

example), supplementation of calcium is needed.

In such cases, it will also help to be rich in vitamin

D so as to enhance the absorption of calcium in

the system.

TO SUMMARIZE:

• PTH increases serum calcium levels by

mobilizing calcium from the bone

•

This will increase the Calciumreabsorption in the kidney but may be

offset due to Calcium that is filtered

• Increased PTH will also lead to increased

formation of 1,25‐

dihydroxycholecalciferol.

• 1,25‐dihydroxycholecalciferol will

increase Calcium absorption from the

intestine and increases Calcium

reabsorption in the kidneys.

• Calcitonin will then inhibit bone

resorption and it will increase the amount

of Calcium in the urine.

Image above:

Schema of how calcium is maintained at a

constant level:

Low serum calcium level will induce

increased PTH secretion.

PTH will then act on the bone, causing

resorption

As a result of resorption: Calcium levels

INCREASE, Phosphate levels DECREASE

(since PTH enhances the excretion of

phosphate)

If renal phosphate is low, and PTH is high

= cause the secretion of more active form of

vitamin D Vitamin D will then cause the gut to absorb

more calcium, specifically the active

transport of calcium in the GIT

Therefore the serum calcium level eventually

goes UP

Only if there is an excessive amount of

calcium will the calcitonin act! (very rare

occurrence)

—END OF TRANSCRIPTION—

Please read Guyton or Ganong for a more detailed

discussion.

Good luck BATCH 2014!







Vitamin D:

Bone:




Indirect relationship between PTH secretion and

Serum Calcium:

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Mineral Metabolism Final Printable