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kris Endocrinology > Mineral metabolism > Flashcards

Mineral metabolism Flashcards

1
Q

Describe the Diurnal rhythm of T3/T4/TSH

A

TSH- concentrations are highest midnight to early morning
T3 and T4 don’t really have a rhythm

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2
Q

Where is T3/T4 made?

Which is made in bigger quantity?

A

T4 is made in follicular cells of thyroid
T3 is not only made by thyroid follicles; Deiodinases are spread all over the body
Type 1 and 2 convert T4 into T3-> peripheral tissues also contribute to T3 concentrations
T4 is produced in larger quantities than T3

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3
Q

T4 vs T3: affinity for binding; free form; half life; signalling

A
  • Affinity for binding: T4>T3
  • Free form: T3>T4
    • Only free form is capable of signalling-> Free T3 are higher-> more signalling by T3; but T4 has longer half life
  • Half life: T4>T3
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4
Q

Which organ senses the changes in calcium levels in the body? What is the response?

A

Parathyroid gland; releases parathyroid hormone (PTH) into the circualtion

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5
Q

Which organs does PTH act upon? What is the effect?

A

it can act upon 3 different organs systems: bones, kidney and intestines
1) In bones it increases bone resorption and increases Ca release into the circulation
2) In kidneys, it allows to retain Ca2+ and promotes activation of an inactive form of Vit D to calcitriol, an active form of Vit D
3) Small intestine increases absorption of more Ca from diet
Overall effect: increase Ca levels in the blood
This increased levels is senses by parathyroid gland-> less parathyroid hormone is released

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6
Q

Which cells release calcitonin? Where are they found?

A

C-type cells (clear cells) of thyroid gland are parathyroid cells (which means that they are outside of follicles
They produce calcitonin

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7
Q

What is the effect of calcitonin?

What is the stimuli for calcitonin secretion?

A
  • Stimulates Ca deposition in bones
  • Reduces Ca uptake in kidneys

Overall effect: Ca levels in the circulaiton decrease

Stimuli: rising blood Ca level

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8
Q

What is the Physiological role of calcitonin in humans ?

A

Physiological role of calcitonin in humans is uncertain

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9
Q

When was rickets first described?

A

Rickets was described in children (softening and bending of the bones)

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10
Q

What are the remedies for rickets?

A

Fish liver oil
Sun exposure

UV-irradiation of certain foods

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11
Q

WHat is the active ingredient that result in alleviation of rickets?

Where is it found, what is it’s function and how is it activated>

A

Vitamin D (collective term of a series of related compounds). Promotes absorption of calcium from the gut

Present in fish liver oil
Inactive precursors can be activated by UV

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12
Q

what are the roles of calcium (6)?

A
  • Major structural component of the skeleton
  • Blood clotting (cross-linking of fibrin)
  • Regulation of enzyme activities (induction of conformational changes or co-factor)
  • “Second messenger” of hormones signals
  • Membrane excitability
  • Muscle contraction
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13
Q

How does Ca act as a second mesenger of hormone signals?

A
  • GPCR/IP3

Release of hormones from endoplasmic reticulum

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14
Q

How does Ca participate in membrane excitability?

A
  • via Ca linked channels
  • Secretion of hormone/neurotransmitters
  • Action potential
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15
Q

How does Ca act in muscle contraction?

A

Triggered by the release of Ca++ from the sarcoplasmic reticulum.

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16
Q

Compartements that store Ca, and the % of total Ca stored in each of them

Which compartment is regulated as the overal impact of hormones

A

Skeleton (99%)

Intracellular (1%)

Extracellular (0.1%)- regulated as the overal impact of hormones

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17
Q

__ Ca++ levels are tightly regulated

A

Extracellular and Intracellular Ca++ levels are tightly regulated

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18
Q

Which Ca is the most important?

How is it controlled?

A

The non-complexed Ca++ is readily available and hence is the most important

Controlled by Vit D and PTH

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19
Q

What % of plasma calcium is ionized (free) calcium

A

45%

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20
Q

What are the types of bound plasma calcium?

A
  • Plasma proteins (45%)
  • Anions
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21
Q

Disequilibrium between bound and unbound Ca++ causes __

A

Disequilibrium between bound and unbound Ca++ causes tetany

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22
Q

How doe Disequilibrium between bound and unbound Ca++ cause tetany?

E.g. hyperventilation

A

In hyperventilation, a lot of CO2 is exhaled-> bicarbonate concentrations go down
reduced bicarbonate leads to reduced proton concentration → alkalosis; which causes serum proteins to release their protons to compensate for it
This makes proteins negatively charged -> look for positive ions-> bind positively charged calcium
Since calcium concentration in the circulation are so small, any small change leads to big consequences

Reduction in free serum Ca++ → tetany (spasm of skeletal muscle)

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23
Q

What else, apart from hyperventialtion, can cause tetany?

A

similarly, blood transfusions in which citrate is the anti-coagulant can cause tetany (due to Citrate chelating Ca++)

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24
Q

Where is Ca stored in the cells?

A

Stored in the sarcoplasm

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25
Q

Describe the make up of parathyroid glands

Which part secrets PTH? When?

A

v 4 glands (about 40 mg each) located adjacent to thyroid

v about 15 % of people have a 5th gland

v Chief cells (and oxyphil cells) produce Parathyroid Hormone (PTH)

v PTH is released in response to low levels of ionized Ca in ECF

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26
Q

Which cells produce calcitonin?

A

Parafollicular or C-cells produce calcitonin

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27
Q

Describe steps of PTH production

A
  • produced as a pre-prohormone
  • removal of signalling peptide which occurs as translation occurs converts it to pro-PTH
  • with cleavage of first few fragments-> active parathyroid hormone
  • Parathyroid hormones are stored in granules
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28
Q

PTH is __ conserved

A

PTH is Highly conserved

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29
Q

Does PTH have a short or long half life?

A

Short (2-4 min)

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30
Q

What are the fragments PTH is cleaved into?

A

Cleaved into two fragments (amino and carboxy terminus)

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31
Q

Regulation of PTH secretion by Ca++

A
  • calcium sensing receptor (CaR) located on Chief cell membrane of chief cells detect ECF Ca++
  • Levels of Ca regulate the shape of the receptor
  • High Ca concentrations – Decreased cAMP and increased IP3-> receptor activation leads to inhibiton of PTH secretion

Low Ca concentrations – Increased cAMP and decreased IP3-> no inhibition-> PTH is secreted

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32
Q

Describe the structure of calcium sensing receptor

A
  • Ca receptors on the parathyroid cells
  • Seven-transmembrane domain receptor
  • Coupled with G-protein complex
    • Highly conserved
  • 93 % AA homology between human and bovine receptors
  • Interaction of receptor with Ca
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33
Q

__ is required for cAMP to decrease
__ is required for IP3 to go up

A

Gi protein is required for cAMP to decrease
PLC is required for IP3 to go up

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34
Q

Funciton of PLC

A

Converts IP2 to IP3

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35
Q

PTH effect on the bone

A

PTH increases the resorption of bone by stimulating osteoclasts and promotes the release of calcium and phosphate into the circulation.

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36
Q

Mineral content of bones

A
  • 99% of total Ca+2
  • 90% of total PO4-3
  • 50% of total Mg+2
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37
Q

Cell content of bones

A
  • Osteoprogenitor cells
  • Osteoblasts
  • Osteocytes
  • Osteoclasts
38
Q

Organic matrix content of bones

A
  • Collagen (90-95%)
  • Proteoglycans
  • Glycoproteins
  • Lipids
39
Q

Name 2 important bone proteins

A

Osteocalcin and osteonectin

40
Q

Describe Osteocalcin

A

Secreted by osteoblasts)

1-2% of bone protein

1mg of osteocalcin binds 17 mg of hydroxyapatite

Serum level is indicator of bone growth.

41
Q

Describe Osteonectin

A

Secreted by fibrolasts

Binds collagen and hydroxyapatite

May serve as nucleator for calcium deposition in the bone

forms centres of calcification

42
Q

Long bones vs trabecular bones

A

In contrast to the long bones, other parts of the skeleton are more irregular in their structure (trabecular bone)

43
Q

Process of osteblast differentiation and bone formation

A

Osteoblast differentiationMesenchymal stem cells (fibroblast-like cells located in the bone marrow)

  1. Mesenchymal stem cells (fibroblast-like cells located in the bone marrow)
  2. Osteoprogenitor cells: Attached to bone surface, proliferating
  3. Osteoblasts

Bone formation

  1. Osteoblasts secrete collagen and other proteins to form a matrix (osteoid)
  2. Mineralization (deposition of hydroxyapatite) in two stages: Primary mineralization (60-70%) in 6-12h; Secondary mineralization in 1-2 month
  3. Entombed osteoblasts differentiate into osteocytes. Formation of a network of metabolically active cells
44
Q

What do osteoblasts secrete?

A

can secrete collagen which is the most abundant component of organic matrix
allow for mineralization of the matrix

45
Q

What is an osteocyte

A

osteocyte- a bone cell, formed when an osteoblast becomes embedded in the matrix it has secreted.

46
Q

Compact bone vs woven bone

A

Compact bone: Adult long bones. Regularly arrayed columns of osteons

Woven bone (trabecular bone): Epiphysis, fractures, juvenile bone, bone disorders. Characterized by a haphazard organization of collagen fibers and is mechanically weak.

47
Q

What is the hallmark of adult bone?

A

ossification of epiphysis is the hallmark of an adult bone

48
Q

Epiphysis vs diaphysis

A

epiphysis is more disorganized
diaphysis is very organized

49
Q

Turn over of bones: adults vs kids

A

Turn-over Ca2+ in bone is 100% per year in infants and 18% in adults

50
Q

What carries out bone remodelling?

A

Carried out by bone modeling units: osteoclasts dissolve bone followed by osteoblasts that lay down new bone

51
Q

What are the Factors regulating bone brekd down/building balance

A
  • Mechanical factors
  • Hormonal factors induced by PTH
  • Paracrine factors (i.e. IGF-II produced by osteoblasts) may act on neighboring osteoblasts and osteoclasts.
  • produced locally and act locally
52
Q

WHat are the precursors of osteoclasts?

A

Derived from monocytes (Bone marrow, gives rise to macrophages)

53
Q

What is the function of oestoclasts?

A

Degrade bone and release Ca++

54
Q

How to osteoclasts attach to bones?

A

Attach to bone via integrins and form tight seal

55
Q

How to osteoclasts degrade bone?

A
  • Proton pumps (H+ dependent ATPases) move from endosomes to the cell membrane where they pump out H+
  • Acid pH (~ 4.0) dissolves hydroxyapaptite; acid proteases break down collagen, allowing to free Ca and release into circulation
  • Transcytosis of degradation product and release into the interstitial fluid
56
Q

What can be measured as an index of bone resorption activity

A

Pyridinoline (collagen breakdown product) in urine is an index of bone resorption activity.

High in kids, low in adults

57
Q

Is bone degradation by osteoclasts a fast or a slow responseBone remodeling and its hormonal control

A

Slow response, not involved in acute regulation of calcium homeostasis

58
Q

Bone remodeling and its hormonal control

A
59
Q

WHat is the effect of calcitonin on bone remodelling?

A

Has an inhibitory action, with formation of an inactive osteoclast

60
Q

Effect of PTH and calcitriol on bone remodelling

A

PTH and calcitriol stimulate osteoblasts to produce osteocalst activating factors

61
Q

PTH effect on the kidneys

A

PTH also increases renal reabsorption of Ca from urine and inhibits reabsorption
of phosphate

62
Q

Describe PTHrP

A
  • Parathyroid Related Protein (PTHrP) similar structure to PTH and can bind to PTH receptor but produced by many tissues in fetus and adult
  • required for normal development as a regulator of the proliferation and mineralization of chondrocytes and regulator of placental Ca++ transport
    • important for growth-> thus it is secreted by the fetus (this is when the highest levels of calcification occur)
      *
63
Q

What type of signlling does PTHrP exhibit? Does it ever change?

A

usually acts in paracrine fashion but overexpression by tumour cells can produce severe hypercalcemia by activating PTH receptor

if there is a tumour producing PTHrP- it can go into the general circulation and then act upon the whole body

64
Q

Desribe PTH receptor and it’s ligands and distribution

A

2 G protein coupled receptors for PTH:

  1. PTHR-1 binds PTH and PTHrP with equal affinity
  2. PTHR-2 binds only PTH

receptors have different tissue distributions

PTHR-1 is located in bone and kidney tissues

65
Q

Name and describe 3 Diseases of the bone

A
  1. Osteopetrosis: “marble bone”
    • Increase in bone density due to defective osteoclasts – bones become more brittle and are prone to fracture
    • high calcification, increased caclium deposition
  2. Osteoporosis:
    • Excess osteoclast function-> too much calcium is removed
    • Frequent fractures (areas with trabecular bone: distal forearm, vertebral body, hip)
    • too little caclium -> weak-> break
  3. Involutional Osteoporosis
    • Loss of bone density with age
66
Q

Normal vs osteoporotic trabecular bone

A
67
Q

Calcium through ageing

A

with age, Ca levels in circulation decline with age
plus in menopause levels decline even more due to the absence of estrogen

68
Q

Estrogen effect on osteoclast activity

What are the chnages that occur at menopause?

A
  1. Inhibition of cytokines that stimulate the development of osteoclasts
    (IL-1, IL-6, TNF)-> decreased Osteoclast activity
  2. Stimulation of the cytokine TGFβ that causes apoptosis of osteoclasts-> decreased osteoclast activity

Menopause→ Estrogen levels decrease→ Osteoclast activity increase

69
Q

Drawbacks of estrogen therapy (and to some extent estrogen/progestin therapy) to prevent osteoporosis

A

: Increases myocardial disease and strokes, breast cancer,

70
Q

describe Hyperparathyroidism

frequrency

Characteristics

Etiology

A
  • PTH is released independently of Ca levels
  • Rare disease
  • Affects approximately 100,000 patients a year
  • Primary hyperparathyroidism occurs in 0.1 to 0.3% of the general population and is more common in women (1:500) than in men (1:2000).
  • Primary hyperparathyroidism is characterized by increased parathyroid cell proliferation and PTH secretion which is independent of calcium levels
  • Etiology unknown, but radiation exposure, and lithium implicated, associated with loss of tumor suppressor genes (MENIN) MEN1 and MEN 2A
  • Enlargement of a single gland or parathyroid adenoma in approximately 80% of cases, multiple adenomas or hyperplasia in 15 to 20% of patients and parathyroid carcinoma in 1% of patients

40

71
Q

Signs and symptoms of primary hyperthyrodism

A

Stones, bones, groans and psychic moans

Groans: gastrointestinal conditions

  • abdominal pain
  • constipation
  • decreased appetite
  • nausea
  • peptic ulcer disease
  • vomiting

Stones (kidney-related conditions)

  • flank pain
  • frequent urination
  • kidney stones

Moans (psychological conditions)

  • confusion
  • dementia
  • depression
  • memory loss

Bones (bone pain and bone-related conditions)

  • bone aches and pains
  • curving of the spine and loss of height
  • fractures
72
Q

Hypoparathyroidism

Causes, symtomps, treatment

A

may originate from

  • failure to secrete PTH,
  • altered responsiveness to PTH, Vit. D deficiency or
  • a resistance to Vit. D

problems with PTH may arise from:

  • surgery
  • familial causes
  • autoimmune disorders v idiopathic causes

major clinical symptom is increased neuromuscular excitability (tetany)

treatment: Calcium + Vitamin D

73
Q

What are the hormones that reducehypercalcaemia

A

Calcitonin is the Only known hormone that reduces hypercalcaemia

74
Q

Descrie origins and location of C-cells

A

C-cells derived from neural-crest cells. Dispersed among follicular cells

75
Q

Is calcitonin importnat? What is the proof?

A

May not be physiologically important in humans

  • Overproduction of calcitonin (tumors of the parafollicular cells of the thyroid) → no phenotypic consequences
  • Thyroidectomy → no phenotypic consequences
76
Q

Is calcitonin gene important?

A

gene is important, even though calcitonin might not be

calcitonin gene results in many proteins - calcitonin, CGRP, CGRP-1
CGRP is especially made in the nervous system; speculated to act as a neurotransmitter

CGRP also acts as very potent vasodilator via GPCR receptor

77
Q

How does CGRP act?

A

Acts upon CRLR (GPCR receptro) that activates Adenelyl Cyclase-> cAMP

78
Q

What does vit D deficeincy lead to?

A

Deficiency leads to bone defects and the disease “rickets”, which causes bone deformations and loss of calcium and phosphate from the bones.

79
Q

Where was Vit D common? How is food used to solve this problem?

A
  • deficiency used to be common in northern climates
  • Vitamin D is now commonly added to milk and butter
80
Q

How is Vit D formed in our bodies?

How is it tuned into a hormone?

A
  • Vitamin D can be formed in the skin from 7-dehydrocholesterol in a photochemical reaction requiring sunlight.
  • Vitamin D is converted in the liver and kidney to a hormone that regulates calcium uptake.

conversion occurs at the level of the liver and kidney
liver: D3 is converted to 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3 (one hydroxyl group)
then it is converted into 1, 25-hydroxyvitamin D2 or D3 in the kidney (2 hydroxyl groups) - > calcitrol

81
Q

24, 25-hydroxyvitamin vs 1,25-hydroxyvitamin

A

24, 25-hydroxyvitamin D function remains uncertain
1,25-hydroxyvitamin D form only is capable of signalling

82
Q

What is Vit D2?

A

Vitamin D2 is a pharmaceutical product made by irradiating ergosterol (present in some plants). Used in food fortification such as margarine and milk

83
Q

What does levels of Vit D produced in the skin vary based on?

A

levels of Vit D produced in the skin varies based on the region and time of the day
requires sunlight with more UV radiation
the closer to the equator-> the more Vit D is produced

84
Q

Describe Vitamin D metabolism

A
  • Main circulating derivatives are 25-OH- cholecalciferol (made in the liver; 3-30 ng/ml) and calcitriol (made in the kidney; 20-60 pg/ml)
  • Vitamin D binding protein present in the serum binds 25-OH-cholecalciferol and to a lesser extent calcitriol
  • All physiological effects appear to be due to calcitriol (1,25-(OH)2D3 )
85
Q

What kind of nuclear receptor is Vit D receptor?

A

nuclear

86
Q

What is the cellular impact of Vit D?

A

Vit D leads to gene expression changes; affects various cell types:

  • Increased Osteoblast activity (mineralization)
  • Increased Osteoclast activity
  • Increased Intestinal Ca2+/PO43-absorbtion
  • Increased Renal vitamin D degradation (catabolism)
  • DecreasedParathyroid hormone synthesis
87
Q

Calcitriol mechanim in intestine cells

A
  • Calcitriol promotes active Ca2+ uptake in the intestine by maintaining a Ca2+ gradient
  • as Ca enters the enterocyte through transporters, it gets attached to various structural proteins such as myosin and calmodulin which are calcium binding proteins;
  • Uptake of calcium→binding to myosin/calmodulin complex→ move to the bottom of the microvilli driven by differential binding to proteins → free Ca2+ in cytoplasm is released by exocytosis or pumps
  • Calcitriol induces synthesis of the calbindin protein→ binds Ca2+→ maintenance of the Ca2+ gradient by mopping up all the free at the bottom of the microvilli.
88
Q

Interaction of PTH and vitamin D in controlling plasma calcium

A
89
Q

Vitamin D deficiency causes, consequences and treatment

A
  • inadequate sunlight, nutrition or malabsorption (up to 50-60 % of elderly expecially if institutionalized)
  • cause abnormal mineralization of bone and cartilage:
  • Rickets (children)
  • Osteomalacia (adult form of rickets)

Treatment: Vit D intake

90
Q

Vit D Toxicity: causes, symptoms and treatment

A
  • Overdose either therapeutically or accidently vDifference in storage, catabolism, absorption among individuals influences level required to be toxic
  • Symptoms: weakness, lethargy, headaches, nausea, polyureia due to hypercalcemia and hypercalciuria – may lead to ectopic calcification etc. (kidneys, blood vessels, heart, lungs, skin) with chronic overuse
  • ectopic calcification: calcification of soft tissues
  • Treatment: reduced calcium intake and (Vit. D), rehydration and cortisol (antagonizes action of Vit. D on gut absorption of calcium) + time (slowly cleared from the body)

kris Endocrinology (17 decks)

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