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High Yield Path - ChemPath > ChemPath: Calcium Metabolism > Flashcards

ChemPath: Calcium Metabolism Flashcards

Review calcium metabolism and homeostasis, recognising the importance of a fixed calcium level on nerve and muscle function. Common calcium disorders Hypercalcaemia Hypocalcaemia Common metabolic bone disorders Osteporosis Osteomalacia / Rickets Pagets To understand the effects of vitamin D and PTH Renal stones

1
Q

What percent of calcium in the body is stored in bones?

A

99%

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2
Q

What percent of calcium is stored in serum?

A

1%

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3
Q

What are the three forms of serum Calcium?

A
  • Free (“ionised”) ~50% - biologically active
  • Protein-bound ~40% - albumin
  • Complexed ~10% - citrate / phosphate
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4
Q

What is the normal range of total calcium serum?

A

2.2 - 2.6 mmol/L

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5
Q

How is corrected Calcium calculated?

A

serum calcium + 0.02 * (40 – serum albumin in g/L)

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6
Q

Why is control of serum calcium levels so important?

A

Calcium levels important in muscle depolarisation and thus in the control of nerve and muscle

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7
Q

If you have a low albumin, the bound calcium will be ____, but the free calcium will be _____. Thus the corrected calcium tells you that the problem is with the ______ and that the ionised calcium will also be ______.

A

If you have a low albumin, the bound calcium will be low, but the free calcium will be normal. Thus the corrected calcium tells you that the problem is with the albumin and that the ionised calcium will also be normal.

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8
Q

How are circulating calcium levels maintained?

A

Plasma concentration of calcium must be maintained despite calcium and vitamin D deficiency.

Chronic calcium deficiency thus results in loss of calcium from bone in order to maintain circulating calcium.

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9
Q

Describe briefly calcium homeostasis in response to decreased Calcium?

A

Hypocalcaemia is detected by parathyroid gland.

Parathyroid gland releases PTH.

PTH “obtains” Calcium from 3 sources: Bone, Gut (absorption), Kidney (resorption and renal 1 alpha hydroxylase activation)

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10
Q

What are the main roles of PTH?

A
  • Stimulate osteoclasts to release Ca from bone
  • Stimulate renal Ca resorption
  • Stimulates 1,25 (OH)2 Vit D synthesis (1alpha-hydroxylation)
  • Stimulates renal phosphate wasting (Phosphate trashing hormone)
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11
Q

What enzyme does PTH activate in the kidney?

A

1alpha-hydroxylase

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12
Q

Describe Vitamin D synthesis.

A
  1. 7-dehydrocholesterol is converted into cholecalciferol (D3) by UV light.
  2. Cholecalciferol (D3) is converted into 25-hydroxycholecalciferol (25-OH D3) by 25-hydroxylase in the liver.
  3. 25-hydoxycholecalciferol (25-OH D3) is converted by 1,25-dihydroxycholecalciferol (1,25-(OH)2 D3) by 1alpha-hydroxylase in the kidney.
  4. 1,25(OH)2 D3 is the physiologically active form of Vitamin D
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13
Q

What inactive form is Vit D stored in the body as?

A

25-hydroxycholecalciferol

This is what is measured in blood tests as active form of Vit D is immediately used when converted into active

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14
Q

What is the physiologically active form of Vit D?

A

1,25-dihydroxycholecalciferol

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15
Q

Which of these is a plant product?
A. Ergocalciferol (D2)
B. Cholecalciferol (D3)

A

A. Ergocalciferol (D2)

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16
Q

What percent of any absorbed Vit D is hydroxylated at the 25 position in the liver?

A

100%

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17
Q

What enzyme in the liver hydroxylases Vit D at the 25 position?

A

25-hydroxylase

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18
Q

What is the rate limiting step in Vit D activation?

A

1-alpha hydroxylase in the kidney. This enzyme is activated by PTH only when calcium is needed.

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19
Q

Where may 1-alpha hydroxylase sometimes be expressed pathologically?

A

Rarely, it can be expressed in lung cells of sarcoid tissue.

With sarcoidosis, there are macrophages in the lung that may express this enzyme in a non-regulated fashion. This may cause hypercalcaemia but only during the summer time when Vit D levels are increased.

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20
Q

What are the main roles of 1,25 (OH)2 D3?

A
  • Intestinal Ca absoprtion
  • Intestinal Pi absorption (but increase Pi excretion in kidneys)
  • Critical for bone formation

Other:

  • Vit D receptor controls many genes eg for cell proliferation, immune system etc
  • Vit D deficiency associated with cancer, autoimmune disease, metabolic syndrome
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21
Q

What other conditions are Vit D deficiency associated with?

A

Cancer
Autoimmune disease
Metabolic syndrome
TB
Infectious diseases

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22
Q

What effect does PTH have on the bone?

A

Results in bone resorption as PTH activates osteoclasts to release calcium from the bone.

However when used intermittently it causes bone formation. This is because, in response to osteoclast activation, osteoblasts try and build up the bone and pull calcium and phosphate back. Osteoblast activation causes release of ALP.

Overall there is bone remodelling

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23
Q

In the presence of sky high ALP but normal ALT and AST, what pathology does this suggest?

A

Bone disease rather than liver disease

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24
Q

What is the role of the skeleton from an orthopaedic viewpoint?

A 
Structural framework (strong, relatively lightweight, mobile) 
Protects vital organs 
Capable of orderly growth and remodelling
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25
Q

What is the role of the skeleton from a metabolic view point?

A

Metabolic role in calcium homeostasis

Main reservoir of calcium, phosphate and magnesium

26
Q

What does Vit D deficiency cause in adults and children?

A

Osteomalacia and Rickets respectively

Vitamin D deficiency results in defective bone mineralisation due to increased osteoclast action (stimulated by continously raised PTH)

27
Q

What are the risk factors for vitamin D deficiency?

A

Lack of sunlight exposure
Dark skin
Dietary - Malabsorption

28
Q

Why does chappati consumption increase vit D deficiency?

A

Phytic acid

(This chelates vit D in gut and prevents absorption, contributing to the vit D deficiency)

29
Q

What are the clinical features of Osteomalacia?

A
  • Bone and muscle pain
  • Increased fracture risk
  • Looser’s Zones (pseudofractures)
30
Q

What are the clinical features of Rickets?

A
  • Bowed legs
  • Costochondral swelling
  • Widened epiphyses at the wrists
  • Myopathy
31
Q

Is the bone structure in osteomalacia normal or abnormal?

A

Abnormal. Vit D deficiency causes defective bone mineralisation.

32
Q

What is the biochemical picture of Osteomalacia?

A

Low Calcium
Low Phosphate
Raised ALP (due to osteoblasts trying to build up the bone)

33
Q

What type of drug may induce breakdown of Vit D?

A

Anticonvulsants

34
Q

Is bone structure normal or abnormal in osteoporosis?

A

Normal

35
Q

Osteoporosis has ____ loss but with _____ calcium. It is due to a reduction in bone ____ with ____ mineralisation due to _____

A

Osteoporosis has bone loss but with normal calcium. It is due to a reduction in bone density with normal mineralisation due to ageing

36
Q

What are major causes of Osteoporosis?

A

Old age

Lack of oestrogen (menopause!)

Immobilisation

Too many steroids (Cushing’s)

Hyperthyroidism

37
Q

What are lifestyle, endocrine, drugs and other causes of Osteoporosis?

A
  • Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional
  • Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
  • Drugs: steroids
  • Others eg genetic, prolonged intercurrent illness
38
Q

What is the biochemistry of osteoporosis?

A

Normal

39
Q

What T score is used to define osteoporosis and osteopenia?

A

Osteoporosis: T-score < -2.5
Osteopaenia: T-score -1 to -2.5

40
Q

What are the typical fractures seen in osteoporosis?

A

Neck of femur
Vertebral (kyphosis)
Wrist - Colle’s fracture

41
Q

How is osteoporosis diagnosed?

A

DEXA scan (dual energy X-ray absorptiometry)

  • hip (femoral neck etc) & lumbar spine
  • T-score – sd from mean of young healthy population (useful to determine  risk)
  • Z-score – sd from mean of age and gender-matched control (useful to identify accelerated bone loss in younger patients)
42
Q

What are lifestyle treatments for osteoporosis?

A
  • Weight-bearing exercise
  • Stop smoking
  • Reduce EtOH
43
Q

What are drug treatments for osteoporosis?

A
  • Vitamin D/Ca
  • Bisphosphonates (eg alendronate) –↓ bone resorption
  • Teriparatide (PTH derivative) – anabolic
  • Strontium – anabolic + anti-resorptive
  • (Oestrogens – HRT)
  • SERMs eg raloxifene
44
Q

Symptoms of Hypercalcaemia

A

Bones, stones, abdominal groans and psychic moans

  • Bone pain
  • Kidney stones
  • Constipation
  • Confusion, Seizure, Coma, Depression

(low calcium = failure of depolarisation as resting membrane potential becomes more negative therefore harder to reach threshold)

45
Q

How would you interpret a high calcium result in a blood test

A
  1. Repeat blood test
  2. Check PTH:
    - low = adequate response therefore suspect malignancy
    - normal/high = primary hyperparathyroidism (commonest cause of high calcium)

It is important to check albumin as high albumin results in artifically elevated calcium

46
Q

Causes of primary hyperparathyroidism

A

Parathyroid adenoma (80%)
Hyperplasia of PTH gland assocaited with MEN1, 2a

47
Q

Outline the clinical picture of primary hyperparathyroidism

A

Hypercalcaemia symptoms
Increased serum Ca
Increased/Normal serum PTH
Decreased serum phosphate
Increased urine calcium

48
Q

Define Familial hypcalciuric hypercalcaemia

A

Condition arising from Calcium-sensing Receptor (CaSR) gene mutation. This affects the calcium-sensing receptors in the PTH gland and in the kidney.

Due to the effect of CaSR in PTH gland —> decreased PTH sensitivity to calcium, therefore PTH -ve feedback occurs at higher concentrations resulting in mild hypercalcaemia

Due to effect of CaSR in kidneys —-> there is reduced urine calcium as calcium is still being reabsorbed despite being high (this does not occur in primrary hyperparathyrodisim as CaSR in kidney remains intact)

49
Q

3 Types of Cancers which can result in hypercalcamia

A

Squamous cell lung cancer
- releases PTH related peptide which mimics PTH

Bone Mets (often from breast cancer)
- cause local bone osteolysis resulting in release of calcium

Haematological malignancy (myeloma)

50
Q

Outline other causes of non-PTH driven hypercalcaemia

A
  • Sarcoidosis - non renal 1alpha hydroxylation
  • Thyrotoxicosis - thyroxine results in bone resoprtion
  • Hypoadrenalism - impacts renal Ca transport
  • Thiazide diuretics - blocks renal Ca transport causing retention of Ca
  • Excess Vitamin D - sunbeds
51
Q

Treatment for Hypercalcaemia

A
  1. Fluids (0.9% saline 1L/hour) and reasses
  2. Treat underlying cause (if malignancy + bisphosphonates)
  3. Cinacalcet (activates CaSR)
52
Q

Symptom of Hypocalcaemia

A

CATs go Numb - neuromuscular excitability
Convulsions
Arrythmia
Tetany
Paraesthesia

Chvostek’s sign (face)
Trousseau’s sign (blood pressure cuff)
Hyperreflexia

53
Q

Outline how to approach a diagnosis of hypocalcaemia

A
  1. Repeat bloods and make sure its true value
  2. Check PTH levels (high = what to expect normally)
54
Q

Causes of hypocalcaemia

A
55
Q

Is calcium high, normal or low in secondary hyperparathyroidism?

A

Calcium must be low to stimulate PTH

56
Q

What hormone does the placenta make that plays an important role in calcium metabolism in babies?

A

PTHrp

57
Q

Define Paget’s Disease

A

Focal (one specific bone) disorder of bone remodelling

58
Q

Symptoms of Paget’s disease

A

Focal bone PAIN, warmth, deformity, fracture, increased risk of high output cardiac failure

59
Q

What is the calcium level in Paget’s disease?

A

Normal because even though turnover is high the balance of calcium is normal (osteoblasts are working)

ALP will be high

60
Q

Which bones are most commonly affected by Paget’s?

A

Pelvis, femur, skull and tibia

61
Q

What is the gold standard investigation for diagnosing Paget’s disease?

A

IV radiolabelled bisphosphonates

62
Q

How is pain treated in Paget’s disease?

A

Bisphosphonates

High Yield Path - ChemPath (14 decks)

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