• Vitamin D strongly increases calcium absorption from the intestine.
• It also has important effects on bone deposition and bone resorption.(breaking down old bone and releasing its minerals, especially calcium and phosphate, into the blood.)
• Vitamin D itself is not the final active form.
• It must first be converted through reactions in the liver and kidneys into the active hormone 1,25-dihydroxycholecalciferol, also called:
  • 1,25(OH)₂D₃
  • Calcitriol
• The sequence of vitamin D activation is shown in Fig. 80.9.

Cholecalciferol (Vitamin D3) Is Formed in the Skin

• Several sterol-derived compounds belong to the vitamin D family and have similar functions.
• The most important form is vitamin D₃ (cholecalciferol).
• Vitamin D₃ is formed in the skin when ultraviolet rays from sunlight act on 7-dehydrocholesterol.
• Therefore: 7-dehydrocholesterol + ultraviolet light → cholecalciferol (vitamin D₃)
• Appropriate exposure to sunlight therefore helps prevent vitamin D deficiency.
• Vitamin D obtained from food is functionally similar to the cholecalciferol produced in the skin.

KEY CONCEPT

• Vitamin D → increases intestinal calcium absorption.
• Vitamin D must be activated in the: Liver → kidneys → calcitriol [1,25(OH)₂D₃]
• Skin + sunlight → vitamin D₃ (cholecalciferol).
• Calcitriol = active form of vitamin D.

Conceptual Examples

• Sunlight:
  UV rays act on 7-dehydrocholesterol in skin → vitamin D₃ forms.
• Activation:
  Vitamin D₃ → liver → kidneys → calcitriol.
• Main effect:
  Active vitamin D → intestine → ↑ calcium absorption.

Figure 80.9 — Activation of Vitamin D and Control of Calcium

Easiest Concept

Think of vitamin D₃ as an inactive raw material that must pass through 2 organs to become active:

Skin → Liver → Kidney → Active vitamin D → Intestine → ↑ Blood Ca²⁺

Follow the figure from top to bottom

• Skin
  • Produces cholecalciferol (vitamin D₃).
  • This form is not yet fully active.
• Liver
  • Converts vitamin D₃ → 25-hydroxycholecalciferol.
  • This is the main circulating/storage form of vitamin D.
  • Increased 25-hydroxycholecalciferol feeds back and inhibits further formation in the liver.
• Kidney
  • Converts 25-hydroxycholecalciferol → 1,25-dihydroxycholecalciferol (calcitriol).
  • Calcitriol = active vitamin D.
  • PTH stimulates this kidney activation.

What does active vitamin D do?

Calcitriol acts on the intestinal epithelium and increases:

• Calcium-binding protein → helps carry Ca²⁺ through intestinal cells.
• Calcium-stimulated ATPase → helps pump Ca²⁺ into blood.
• Alkaline phosphatase → assists the calcium-absorbing process.

Result:

↑ Intestinal calcium absorption → ↑ plasma Ca²⁺ concentration

PTH feedback

When blood Ca²⁺ is low:

↓ Ca²⁺ → ↑ PTH → kidney makes more calcitriol → intestine absorbs more Ca²⁺ → blood Ca²⁺ rises

When blood Ca²⁺ rises sufficiently:

↑ Ca²⁺ → inhibits PTH

This prevents calcium from rising too much.

Dashed arrows

• 25-hydroxyvitamin D → liver inhibition = negative feedback.
• ↑ Plasma Ca²⁺ → PTH inhibition = negative feedback.

🔑 KEY CONCEPT

Vitamin D₃ → Liver makes 25-OH D → Kidney makes active 1,25-(OH)₂D → Intestine absorbs more Ca²⁺

And:

Low Ca²⁺ → ↑ PTH → ↑ active vitamin D → ↑ Ca²⁺ absorption

One-line memory

“Skin makes it, liver stores it, kidney activates it, intestine uses it to absorb calcium.”

Cholecalciferol Is Converted to 25-Hydroxycholecalciferol in the Liver

• The first activation step of cholecalciferol (vitamin D₃) occurs in the liver.
• In the liver: Vitamin D₃ → 25-hydroxycholecalciferol
• 25-hydroxycholecalciferol inhibits its own further formation by negative feedback.
• This feedback is important for two main reasons:
  • It keeps plasma 25-hydroxycholecalciferol nearly constant, even when vitamin D₃ intake increases greatly (Fig. 80.10).
  • It prevents rapid conversion of all stored vitamin D₃, helping preserve vitamin D stores in the liver.
• Once vitamin D₃ is converted to 25-hydroxycholecalciferol, it remains in the body for only a few weeks.
• In contrast, vitamin D₃ itself can remain stored in the liver for many months.

Formation of 1,25-Dihydroxycholecalciferol in the Kidneys and Its Control By Parathyroid Hormone

• In the proximal tubules of the kidneys, 25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol (calcitriol) (Fig. 80.9). 25-hydroxycholecalciferol → kidney → 1,25-dihydroxycholecalciferol
• 1,25-dihydroxycholecalciferol is the most active form of vitamin D.
• Earlier vitamin D forms have less than 1/1000 of its activity.
• Therefore, without functioning kidneys, vitamin D loses almost all of its effectiveness.
• This kidney conversion requires parathyroid hormone (PTH).
• Without PTH, almost no 1,25-dihydroxycholecalciferol is produced.
• Therefore, PTH strongly controls the functional activity of vitamin D in the body.

KEY CONCEPT

• Vitamin D activation occurs mainly in two steps: Vitamin D₃ → Liver → 25-hydroxycholecalciferol → Kidney + PTH → 1,25-dihydroxycholecalciferol (calcitriol)
• Liver step → controlled by feedback.
• Kidney step → requires PTH.
• Calcitriol = most active vitamin D form.
• Liver storage protects vitamin D supply for months.

Conceptual Examples

• High vitamin D intake:
  ↑ Vitamin D₃ → feedback limits liver conversion → 25-hydroxycholecalciferol stays near normal.
• Role of kidney:
  25-hydroxycholecalciferol → kidney → active calcitriol.
• Role of PTH:
  ↓ PTH → very little calcitriol formation → vitamin D effects decrease greatly.
• Easy sequence:
  Skin/diet → vitamin D₃ → liver → 25-OH D → kidney + PTH → calcitriol.

Vitamin D₃ Intake vs Plasma 25-Hydroxycholecalciferol

This graph shows one simple idea:

Once vitamin D intake is adequate, increasing vitamin D₃ intake further causes very little increase in plasma 25-hydroxycholecalciferol.

X-axis

Intake of vitamin D₃ (× normal)

• 1.0 = normal intake
• 2.0 = twice normal intake
• 2.5 = 2.5 times normal intake

Y-axis

Plasma 25-hydroxycholecalciferol (× normal)

This is the main circulating storage form of vitamin D produced in the liver.

• 1.0 = normal plasma level
• Below 1.0 = reduced level
• Around 1.0 = maintained near normal

🔴 Red curve

At very low vitamin D intake

The curve is very steep.

So:

Vitamin D₃ intake ↓↓↓ → plasma 25-hydroxycholecalciferol ↓↓↓

This means severe vitamin D deficiency occurs mainly when intake becomes very low.

As vitamin D intake increases

The red curve rises rapidly toward:

≈ 1.0 × normal

So even a relatively modest increase from very low intake quickly restores plasma 25-hydroxycholecalciferol toward normal.

After reaching the plateau

The red line becomes almost flat.

From roughly normal intake up to 2.5 times normal intake:

Vitamin D₃ intake ↑↑

but

Plasma 25-hydroxycholecalciferol changes very little.

This flat part is the key feature of the graph.

Why does the curve flatten?

The liver converts:

Vitamin D₃ → 25-hydroxycholecalciferol

But this conversion is feedback regulated.

When enough 25-hydroxycholecalciferol has formed:

25-hydroxycholecalciferol ↑

→ inhibits further conversion of vitamin D₃

→ plasma level stays relatively stable.

So the body prevents a large rise in 25-hydroxycholecalciferol even when vitamin D intake increases.

“Normal range” bracket

The bracket over the flat portion means:

Over a fairly wide range of vitamin D₃ intake, plasma 25-hydroxycholecalciferol remains close to normal.

So the body has a buffering/protective mechanism.

Easy analogy 🪣

Think of the liver as a factory.

At very low vitamin D supply:

Raw material ↓ → product ↓

But once enough vitamin D is available:

Factory has enough product → factory slows further production

So giving more raw material does not greatly increase the final product.

Whole graph in one flow

Very low vitamin D₃ intake

↓

Very little 25-hydroxycholecalciferol formed

↓

Plasma level falls

But:

Adequate vitamin D₃ intake

↓

25-hydroxycholecalciferol reaches near-normal level

↓

Feedback inhibition limits further conversion

↓

Curve becomes flat

↓

Plasma 25-hydroxycholecalciferol remains nearly constant

⭐ Key Concept

Vitamin D deficiency appears mainly at very low vitamin D intake. Once intake is adequate, increasing vitamin D₃ even several-fold produces little additional rise in plasma 25-hydroxycholecalciferol because its formation in the liver is feedback regulated.

Calcium Ion Concentration Controls the Formation of 1,25-Dihydroxycholecalciferol

• Plasma calcium concentration controls calcitriol formation inversely (Fig. 80.11).
• This means: ↓ Ca²⁺ → ↑ 1,25-dihydroxycholecalciferol
  ↑ Ca²⁺ → ↓ 1,25-dihydroxycholecalciferol
• There are two main reasons:
  • High Ca²⁺ slightly decreases conversion of 25-hydroxycholecalciferol → 1,25-dihydroxycholecalciferol.
  • More importantly, high Ca²⁺ strongly suppresses PTH secretion.
• When plasma calcium is below about 9–10 mg/100 mL:
  • PTH secretion increases.
  • PTH stimulates the kidneys to convert:
  25-hydroxycholecalciferol → 1,25-dihydroxycholecalciferol
• When plasma calcium rises above this level:
  • PTH decreases.
  • Less active 1,25-dihydroxycholecalciferol is formed.
  • Instead, 25-hydroxycholecalciferol is converted mainly into 24,25-dihydroxycholecalciferol.
  • This compound has almost no vitamin D activity.
• When blood calcium is already high, reduced calcitriol formation decreases calcium absorption from:
  • Intestines
  • Bones
  • Renal tubules
• Therefore, plasma Ca²⁺ falls back toward its normal level.

KEY CONCEPT

• Low Ca²⁺ → ↑ PTH → ↑ calcitriol → ↑ calcium absorption.
• High Ca²⁺ → ↓ PTH → ↓ calcitriol → ↓ calcium absorption.
• This provides an important negative-feedback mechanism for maintaining normal blood calcium.

Conceptual Examples

• Low blood calcium:
  ↓ Ca²⁺ → ↑ PTH → kidney makes more calcitriol → more calcium becomes available to the blood.
• High blood calcium:
  ↑ Ca²⁺ → ↓ PTH → ↓ calcitriol → less calcium is absorbed → blood calcium falls toward normal.
• Easy sequence:
  ↓ Ca²⁺ → ↑ PTH → ↑ calcitriol
  ↑ Ca²⁺ → ↓ PTH → ↓ calcitriol.

Plasma Calcium vs Active Vitamin D

This graph shows a powerful calcium-saving feedback system:

When blood calcium falls even slightly below normal, the body greatly increases active vitamin D (1,25-dihydroxycholecalciferol) to help bring calcium back toward normal.

1️⃣ Understand the axes

X-axis = Plasma calcium (mg/100 mL)
Moving right means blood calcium increases.

Y-axis = Plasma 1,25-dihydroxycholecalciferol (× normal)
This is calcitriol—the active form of vitamin D.

• 1 = normal level
• 2 = twice normal
• 6 = six times normal

2️⃣ ⭐ The “Normal” point

The red star is around:

Plasma calcium ≈ 9–10 mg/100 mL

and

Active vitamin D ≈ 1 × normal

So under normal conditions:

Normal Ca²⁺ → normal active vitamin D

3️⃣ 🔴 Red curve — each part explained

Right side: Calcium is normal or high

When plasma calcium is approximately 10 mg/100 mL or higher, the red curve stays very low.

Why?

Because the body already has enough calcium.

Therefore:

Ca²⁺ adequate/high

→ PTH secretion suppressed

→ less kidney conversion to active vitamin D

→ 1,25-dihydroxycholecalciferol ↓

This prevents unnecessary additional calcium absorption.

4️⃣ The steep vertical part is VERY important

Around 9–10 mg/100 mL, the curve changes dramatically.

A small fall in plasma calcium below normal causes a huge increase in active vitamin D.

So:

Ca²⁺ slightly ↓

⬇️

PTH ↑↑

⬇️

Kidneys increase conversion:

25-hydroxycholecalciferol → 1,25-dihydroxycholecalciferol

⬇️

Active vitamin D ↑↑

This is why the red curve rises so steeply.

5️⃣ Left upper plateau

When calcium remains below normal, active vitamin D can become approximately:

5–6 × normal

The curve then plateaus.

The important concept is:

Low calcium strongly stimulates formation of active vitamin D, but the response has a maximum.

6️⃣ Why does LOW calcium increase active vitamin D?

There are two mechanisms, with PTH being the most important.

Main mechanism ⭐

Plasma Ca²⁺ ↓

→ Parathyroid glands detect low Ca²⁺

→ PTH ↑

→ PTH stimulates renal 1α-hydroxylase

→ conversion of 25-hydroxycholecalciferol → 1,25-dihydroxycholecalciferol ↑

Additional effect

Higher calcium itself also tends to reduce conversion toward 1,25-dihydroxycholecalciferol.

So both mechanisms help explain the inverse relationship.

7️⃣ What does increased active vitamin D actually achieve?

The body isn’t increasing active vitamin D just for the sake of it.

Its major purpose here is:

Increase intestinal calcium absorption

So:

Blood Ca²⁺ ↓

→ PTH ↑

→ Active vitamin D ↑↑

→ Intestinal Ca²⁺ absorption ↑↑

→ More calcium enters blood

→ Plasma Ca²⁺ moves back toward normal

This is negative feedback.

8️⃣ Why is the curve so steep near normal calcium?

This is the beautiful physiological point.

Calcium concentration must be kept within a very narrow range because Ca²⁺ is essential for:

• nerve function
• muscle contraction
• cardiac function
• intracellular signaling

Therefore, even a small decrease below normal triggers a large compensatory response.

Small Ca²⁺ ↓ → Big active vitamin D ↑

🧠 Easiest analogy: Calcium thermostat 🌡️

Think of plasma calcium like room temperature.

When temperature is normal:

Heater stays low.

If temperature falls:

Heater switches on strongly.

Similarly:

Normal/high Ca²⁺

→ little need for active vitamin D

But:

Ca²⁺ falls below normal

→ PTH turns up the vitamin-D system

→ intestinal calcium absorption increases

→ calcium is restored.

🎯 Entire graph in one flow

Plasma Ca²⁺ ↓ slightly below normal

↓

PTH ↑

↓

Kidney 1α-hydroxylase ↑

↓

25-OH vitamin D → 1,25-(OH)₂ vitamin D ↑↑

↓

Intestinal Ca²⁺ absorption ↑↑

↓

Plasma Ca²⁺ restored toward normal Key Concept — Figure 80.11

Plasma calcium and active vitamin D have an inverse relationship near the normal calcium level: a slight decrease in plasma calcium causes a large increase in 1,25-dihydroxycholecalciferol, mainly through increased PTH. The increased active vitamin D then greatly increases intestinal calcium absorption and helps restore plasma calcium.

🔑 One-line memory trick

“Calcium falls → PTH rises → active vitamin D rises → gut absorbs more calcium.”

ACTIONS OF VITAMIN D

• The active form of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), acts mainly on the:
  • Intestines
  • Kidneys
  • Bones
• Its overall effect is to increase the movement of calcium and phosphate into the extracellular fluid and help regulate their concentrations.
• Vitamin D receptors are present in many body cells and are located mainly in the cell nucleus.
• The vitamin D receptor has:
  • A hormone-binding domain
  • A DNA-binding domain
• After binding vitamin D, the receptor combines with the retinoid-X receptor.
• This complex binds to DNA and usually increases gene transcription, although in some cases it decreases transcription.
• The vitamin D receptor has about 1000 times greater affinity for 1,25-dihydroxycholecalciferol than for 25-hydroxycholecalciferol.
• Therefore, 1,25-dihydroxycholecalciferol is much more biologically active.

“Hormonal” Effect of Vitamin D to Promote Intestinal Calcium Absorption

• 1,25-Dihydroxycholecalciferol acts like a hormone to increase intestinal calcium absorption.
• Over about 2 days, it increases formation of calbindin, a calcium-binding protein in intestinal epithelial cells.
• Calbindin helps transport calcium from the intestinal lumen into the cell cytoplasm.
• Calcium then crosses the basolateral membrane by facilitated diffusion.
• The amount of calcium absorbed is directly related to the amount of calbindin present.
• Calbindin remains in intestinal cells for several weeks, even after 1,25-dihydroxycholecalciferol is removed.
• Therefore, vitamin D produces a prolonged increase in calcium absorption.
• Calcitriol may also increase:
  • Calcium-stimulated ATPase in the brush border.
  • Alkaline phosphatase in intestinal epithelial cells.
• The exact importance of these additional effects is still unclear.

KEY CONCEPT

• Calcitriol = active vitamin D.
• It acts through a nuclear receptor → DNA → altered gene transcription.
• Its receptor has about 1000× greater affinity for calcitriol than for 25-hydroxycholecalciferol.
• Main intestinal action: Calcitriol → ↑ calbindin → ↑ intestinal Ca²⁺ absorption
• Calbindin remains for weeks, so the calcium-absorbing effect is long lasting.

Conceptual Examples

• Vitamin D action:
  Calcitriol enters target cell → binds nuclear receptor → receptor complex binds DNA → changes protein production.
• Calcium absorption:
  ↑ Calcitriol → ↑ calbindin → more Ca²⁺ enters intestinal cells and then the blood.
• Prolonged effect:
  Calcitriol disappears → calbindin remains for weeks → calcium absorption stays increased for some time.

Vitamin D Promotes Phosphate Absorption By the Intestines

• Phosphate is normally absorbed easily from the intestine.
• Vitamin D further increases intestinal phosphate absorption.
• The active form, 1,25-dihydroxycholecalciferol (calcitriol), increases activity of the sodium-phosphate co-transporter on the luminal membrane of small-intestinal epithelial cells.
• This transporter works similarly to sodium-phosphate co-transporters in the renal tubules.
• This effect is especially important when phosphate availability is low.

Vitamin D Decreases Renal Calcium and Phosphate Excretion

• Vitamin D slightly increases calcium and phosphate reabsorption in the renal tubules.
• Therefore, less calcium and phosphate are lost in the urine.
• However, this renal effect is relatively weak and is not a major regulator of their extracellular concentrations.

Effect of Vitamin D on Bone and Its Relation to Parathyroid Hormone Activity

• Vitamin D has important effects on both bone resorption and bone deposition.
• Excess vitamin D can increase bone resorption.
• Vitamin D is also important for the bone-resorbing action of PTH.
• Without vitamin D, PTH-induced bone resorption is greatly reduced or may be prevented.
• This effect may involve increased calcium transport across cell membranes.
• In smaller amounts, vitamin D promotes bone calcification and mineralization.
• One important mechanism is: Vitamin D → ↑ intestinal Ca²⁺ + phosphate absorption → ↑ minerals available for bone
• Vitamin D can also increase bone mineralization even without increasing intestinal absorption.
• This effect may also involve movement of Ca²⁺ across osteoblast or osteocyte cell membranes.

KEY CONCEPT

• Vitamin D → ↑ intestinal phosphate absorption.
• Vitamin D → slight ↑ renal Ca²⁺ and phosphate reabsorption → ↓ urinary loss.
• High vitamin D → can promote bone resorption.
• Vitamin D is required for much of PTH-induced bone resorption.
• Smaller amounts of vitamin D → promote bone calcification and mineralization.

Conceptual Examples

• Low phosphate availability:
  ↑ Calcitriol → ↑ sodium-phosphate co-transport → more phosphate absorbed from intestine.
• Kidney:
  Vitamin D → ↑ Ca²⁺ and phosphate reabsorption → slightly less lost in urine.
• Bone resorption:
  PTH + adequate vitamin D → greater bone resorption.
• Bone mineralization:
  Vitamin D → ↑ calcium + phosphate availability → better bone calcification.

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