Regulation of Calcium Ion

Regulation of Calcium Ion

Level in the Blood

The Total Body Calcium ( 1 100 g):

 MAJORITY - BONES (1 000 000 mg)

 1 % - CELLS (13 000 mg)

 0,1% - EXTRACELLULAR FLUID (1 300 mg):

Phosphate

TOTAL - 500-800 g:

• 85% - BONES

• 14-15% - CELLS

• 1% - EXTRACELLULAR FLUID:

• 3-4 mg/dL (adults)

• 4-5 mg/dL (children)

Calcium

- HPO₄^2--1.05 mmol/L - H₂PO₄^- -0.26 mmol/L

Calcium level : 2,25 – 2,75 mmol/L

(9-11 mg/dL)

Expressed in terms of milligrams of phosphorus per deciliter of blood

Extracellular calcium ion concentration is regulated by hormones:

- Parathyroid hormone (PTH) - 1,25-Dihydroxycholecalciferol

(active form of vitamin D ₃ )

- Calcitonin

Effect of PTH and Calcitonin on Blood Calcium Level

Actions of PTH are coordinated to produce

 an increase in serum [Ca ²⁺ ]

 a decrease in serum [phosphate]

Actions of PTH

Overview of Calcium Distribution - Bone

The bones can serve

as large reservoirs, releasing calcium when extracellular fluid concentration decreases

and storing excess calcium.

(1) Proteolytic enzymes digest or dissolve the organic matrix (2) Acids (citric, lactic) cause

solution of the bone salts.

 Requires several days or weeks to become fully developed

 Osteoclastic reabsorption of the bone itself:

Bone – PTH Action

2. Slow Phase - Activation of Osteoclasts

 Removal of calcium phosphate from hydroxyapatite crystals - Ca₁₀(PO₄)₆(OH)₂

Overview of Calcium Distribution - Bone

 0.4 to 1 per cent –

amorphous (noncrystalline) compounds

Exchangeable calcium

- A rapid buffering mechanism - In equilibrium with the calcium ions in the extracellular fluids.

Calcium salts in bone:

 Majority -

hydroxyapatite crystals,

bound tightly to collagen

fibers

Bone – PTH Action

1. Rapid Phase - Activation of the Osteocytic Membrane System

A system of interconnected cells (osteoblasts and osteocytes) – a membrane that separates the bone itself from the extracellular fluid.

 pumps calcium ions from the bone fluid into the extracellular fluid

 mobilizes exchanchable calcium

 PTH stimulates this pump

- rapid phase begins in minutes, increases progressively for

several hours.

Overview of Calcium Distribution

(99% of filtered )

(1% of filtered )

Kidney

Normally

- the renal tubules reabsorb 99 per cent of the filtered calcium - about 1% -100 mg/day

is excreted in the urine

-Normal calcium excretion –

 4 mg/kg body weidht/day

  200 mg/d (5 mmol/d)

-  4 mg/kg body mass /day – hypercalciuria

Kidney - Calcium Reabsorption in the Renal Tubules

1). Proximal tubule

 Independent on PTH

 Usually parallels sodium and water reabsorption.

 Absorbed 65 per cent of the

filtered calcium

Kidney - Calcium Reabsorption in the Renal Tubules

2). Thick ascending loops of Henle

 Dependent on PTH

 Absorbed 20-35 per cent of

the filtered calcium

Calcium Reabsorption in the Renal Tubules

3). Distal and collecting tubules

 Dependent on PTH

 Absorbed 4-9 per cent of the

filtered calcium

Kidney - Phosphate Reabsorption in the Renal Tubules

Proximal tubule

Phosphate threshold = 0.8 mM/L

 Tm = 0.1 mM/min

PTH

 inhibits phosphate reabsorption

 increases phosphate excretion (phosphaturic effect)

- inhibits Na⁺-phosphate cotransport - lowers Tm

PTH

Ca

PO

Bone resorption

+

PO

X

Excretion of PO

↓

↑

+ 1,25(OH)₂D₃

Kidney – Reabsorption in the Renal Tubules

• reabsortion of magnesium ions, hydrogen ions

• reabsortion of sodium, potassium, and amino

acids

Actions of PTH

Vitamin D Sources

 Diet

- Absorption - small intestine (jejunum) needs bile salts

 Foods rich in vitamin D are not the most popular in Poland

 Foods commonly eaten in Poland have small amounts of vitamin D and usually do not meet daily requirement

Sunlight

7-Dehydrocholesterol → Previtamin D3 → Vitamin D3

(cholecalciferol)

LIVER 25-Hydroxylase Other metabolites 25-Hydroxycholecalciferol

↓ [Ca +], ↑ PTH, ↓ [phosphate]

24-Hydroxylase KIDNEY 1α-Hydroxylase 24,25-Dihydroxycholecalciferol 1,25-Dihydroxycholecalciferol

Intestinal absorption of calcium

Activation of Vitamin D

National Institutes of Health:

 5–30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to sufficient vitamin D synthesis and that the moderate use of commercial tanning beds that emit 2%–6% UVB radiation is also effective

https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

Poland:

 15 minutes of daily sun exposure between 10 AM and 3 PM to 18% body surface without sunscreen is sufficient only from April to September

Skin synthesis

Complete cloud cover reduces UV energy by 50%;

shade (including severe pollution) reduces it by 60%.

Activation of Vitamin D

 [Ca ⁺]

 PTH

 [Phosphate]

+

Activation of Vitamin D

Effect of Plasma Calcium Level on Plasma 1,25-

Dihydroxycholecalciferol Concentration

Vitamin D Production Around the World

• Weber State University, Department of Health Promotion & Human Performance, Nutrition Program

Ogden, Utah

Webr State University, Department of Health Promotion & Human Performance, Nutrition Program, Ogden, Utah

Risk Factors of Vitamin D Deficiency

– Latitude

– Autumn / Winter – Dark skin

– Increased BMI

– Vitamin D poor diet – Breastfed infants

– Life style (garage – work – garage) – Older adults

– Sunscreens with a sun protection factor (SPF) of 8 or more

Levin AD i wsp. Dig Dis Sci. 2011;56:830-6

.

What is true?

Deficiency of vitamin D may lead to/ increases risk of

A. rickets

B. osteomalacia / osteoporosis C. hypertension

D. obesity

E. breast cancer F. prostate cancer G. renal cancer

H. pancreatic cancer I. colon cancer

J. diabetes mellitus type 1 K. diabetes mellitus type 2 L. flu epidemic

M. tuberculosis

N. sclerosis multiplex O. myocardial infarction

What is true?

Deficiency of vitamin D may lead to/ increases risk of

A. rickets

B. osteomalacia / osteoporosis C. hypertension

D. obesity

E. breast cancer F. prostate cancer G. renal cancer

H. pancreatic cancer I. colon cancer

J. diabetes mellitus type 1 K. diabetes mellitus type 2 L. flu epidemic

M. tuberculosis

N. sclerosis multiplex O. myocardial infarction

Vitamin D Deficiency - Ricket

Vitamin D Deficiency - Ricket

Vitamin D

„Extraskeletal” Effects

Receptors for 1,25 (OH)

D are present in most tissues, such as

 heart

 GI Tract

 blood Vessels

 skin

 brain

 gonads

 lymfocytes T and B

Nature Revews Cancer 2014; 14, 342–357

Each extra ng of vitamin D decreases risk of breast cancer

by 16%

• Breast Cancer chance decreased 16 percent for every extra ng of vitamin D – Jan 2013

• Higher Blood 25(OH)D Level May Reduce the Breast Cancer Risk:

• Evidence from a Chinese Population Based Case-Control Study and Meta-Analysis of the Observational Studies.

• PLoS One. 2013;8(1):e49312.

Chen P, Li M, Gu X, Liu Y, Li X, Li C, Wang Y, Xie D, Wang F, Yu C, Li J, Chen X, Chu R, Zhu J, Ou Z, Wang H.

Breast cancer survival doubles

more likely if vitamin D is sufficient

• Breast Cancer survival 2X more likely if vitamin D sufficient – meta-analysis May 2013

• The relationship between serum vitamin D levels and breast cancer prognosis: A meta-analysis.

• Journal of Clinical Oncology, 2013 ASCO Annual Meeting Proceedings (Post- Meeting Edition).

Vol 31, No 15_suppl (May 20 Supplement), 2013: 1521

Using newly available data on worldwide cancer incidence to map cancer rates in relation to proximity to the equator, researchers at the Moores Cancer Center at University of California, San Diego (UCSD) have shown a clear association between deficiency in exposure to sunlight, specifically ultraviolet B (UVB), and kidney cancer.

Renal Cancer Risk

https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ (NIH)

Poland:

 30-50 ng/ml (75-125 nmol/l) – Generally optimal

 50-100 ng/ml (125-250 nmol/l) – High supplementation

  100 ng/ml (250 nmol/l) – Necessary to reduce or stop supplementation

  200 ng/ml (500 nmol/l) – Toxic concentration

https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

Wytyczne suplementacji witaminy D – skrót aktualnych zaleceń. Diabetologia.mp.pl

NIH

1-12 months 1-10 years 11-18 years

Adults or older people Pregnancy or lactation

Obese adults and older obese people

Dose/day

Who needs vitamin D supplements?

Birth – 6 mo 6-12 mo _{1 - 18 yo} ^Children Adults

 400 IU/day Breastfed

 400 IU/day (Supplement +diet)

 400 -800 IU/day Premature Infants (till 40 week)

 400 -600 IU/day  600 -1000 IU/day ( IX-IV )

 1200 -2000 IU/day

Obese children

 800-1000 IU/day (IX-IV)

 800-1000 IU/ day I-XII

 Older people

 1600-4000 IU/day Obese people

 1500 – 2000 IU/day Pregnacy/Lactation

-1000-2000 IU/day Dark skin, night work

40 IU= 1 microgram vitamin D

Gronnigen`s formula Total dose [IU]

= 40 x (75 - 25(OH)D conc. [nmol/l]) x body mass [kg]

Total dose should be divided into 2-3 months

Based on literature data –

standard therapeutic doses do not cause over dosage (even up to 7 000 - 10 000 IU/day).

Toxicity of vitamin D is associated with hypercalcemia, which at the beginning may be manifested as:

 abdominal pain,

 constipation,

 vomiting,

 headache

Vitamin D Toxicity

Effect of PTH and Calcitonin on Blood Calcium Level

HYPOPARATHYROIDISM

Causes - Idiopathic (parathyroid glands absent, hypoplastic), - Surgical hypoparathyroidism (most common)

PTH level 

1,25 (OH)2 D3 

BONE  resorption

URINE  P excretion

Serum [P] 

Serum [Ca²⁺]  - HYPOCALCEMIA

Nervous System  permeability of neuronal membranes to Na ⁺   excitability of nervous system TETANY

Muscular system Muscle cramps, stiffness, contractions – “carpopedal spasm”: “obstetrical hand”, plantar flexion of toes Latent tetany - positive results of provocative tests:

- Chvostek`s sign – a twitch of facial and upper lip muscles produced by a sharp tap given over the facial nerve

- Trousseau`s sign – “carpopedal spasm” induced by a sharp reduction of blood flow obtained with a blood pressure cuff

Thank you