Mineral Metabolism Final Printable

DR. VIC MENDOZA 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

**The diagrams above show the Calcium

DNA and RNA

exchange between different tissue compartments

Functions as covalent modifier of many

in a person ingesting 1000 mg of calcium per day.

enzymes •

Intracellularly, an important anion that +

balances the cations K and Mg •

++

Note:

Most

Calcium

ingested

is

normally

eliminated in the feces, though kidneys also have

Major constituent of the crystalline

the capacity to excrete large amounts by reducing

structure of bone and teeth

tubular reabsorption of Calcium.

 –

85% in skeleton, 6% in muscle

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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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 must be 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 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 new bone 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 the regulators. (Major regulator is actually the parathyroid hormone when it comes to calcium).

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%)

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 Phosphate

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

Metabolism:

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

•

Parathyroid Hormone

in the pancreatic secretion) Therefore, although you

•

Vitamin D

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

•

Calcitonin (concerned with Calcium ONLY)

GIT. This means that in terms of absorption, there is only a 175 mg net absorption of calcium, while

1. PARATHYROID HORMONE

the rest is secreted out.

Target Organs:

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.

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

•

Bones

•

Kidney (because the kidneys are involved in calcium excretion)

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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.

Again: Low ionized serum calcium = High PTH secretion High ionized serum calcium = Low PTH secretion

How is the amount of ionized serum calcium determined 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.

Effect of PTH on Kidneys 1. Promotes calcium reabsorption Therefore, calcium serum levels ELEVATE more. Note: Calcium reabsorption occurs in the distal  nephron

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

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.

albumin levels by about 1mg/deciliter, then the total serum calcium concentration will also be reduced by about 0.8 mg/dL.

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, 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) excitability)

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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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.

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.

Again, in a nutshell:

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!

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 plasma

At the same time, the RANK‐receptor complex causes the formed osteoclasts to live longer by suppressing apoptosis.

calcium levels. (will be further discussed in succeeding text)

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.

•

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.

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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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.

This cholecalciferol is bound to protein (globulin), and upon binding enables it to circulate in the bloodstream. 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!

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 in the skin. The exposure of skin to sunlight (which has UV rays) promotes the conversion of 7‐dehydrocholesterol to Vit. D3, or cholecalciferol .

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 .

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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  phospha te deficiency deficien cy will also cause very high h igh 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

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).

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

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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In a nutshell:

24

VITAMIN D

required].

[when

less

biological

activity

is

Target Organs: •

GIT:

CALCITONIN

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.

•

Produced by the T cells of thyroid gland

•

Reduces bone resorption by inhibiting

Below is a diagram [taken from Harper’s Illustrated

osteoclast function

Biochemistry since the one in the powerpoint is not

o

that clear] that shows the formation and hydroxylation

Effect: Decreased concentrations of Calcium and Phosphate in the

of Vitamin D.

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 •

•

Vitamin D undergoes 25‐hydroxylation in

If

very,

very

HIGH

the liver.

(hypercalcemia)

It is then further hydroxylated in the



kidney in the position 1 [when more

resorption  reduction in serum phosphate.



serum

calcium

level

Calcitonin secretion INCREASE

Osteoblast activity DECREASE



reduced bone

biological reaction is needed] or position

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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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 for life. 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

Calcium

Image above: Schema of how calcium is maintained at a constant level:

reabsorption 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.

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!

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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Vitamin D:

Bone:

PHYSIOLOGY: Hormone Regulation of Mineral Metabolism

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Indirect relationship between PTH secretion and Serum Calcium:

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