Calcium metabolism Flashcards by Georgia Leggett

Calcium in serum exists in 3 forms - what are they and % of each?

Free: ionised, active (50%)
Albumin bound (40%)
Complexed (10%) to citrate/ phosphate

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Normal Ca range?
Corrected Ca2+ calculation?

2.2 - 2.6 mM/L
Serum Ca + 0.02(40-serum albumin g/l)

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What is total calcium confounded by? Give causes of this. What do we use in these cases?

Albumin

Low: Sepsis, burns, low protein, liver/ kidney dysfunction
Gives low total calcium, corrected Ca will be higher

High: dehydration, high protein
Gives high total calcium, corrected Ca will be lower

Use Corrected calcium

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PTH - it is released in response to…?
4 roles of PTH?

Low free Ca in serum
1. GUT: Ca absorption
2. KIDNEY: Ca resorption + Pi excretion + stimulates 1-alpha-hydroxylase
4. BONE: activates osteoclast for Ca resorption

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What is the role of 1-alpha hydroxylase?

Converts 25(OH)D3 to 1,25(OH)2D3 = ACTIVE CALCITRIOL

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Name the organ and condition in which 1-alpha-hydroxylase is expressed ectopically

Sarcoid tissue in lung
Causes hypercalcemia in summer (more vitamin D activation in sun)

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4 Causes of Vit D deficiency

Renal failure (low 1-a-hydroxylase)
Anticonvulsants e.g. Phenytoin in kids
No sun exposure
Chappatis

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5 Features of Rickets

Bowed legs
Costochondral swelling
Widened epiphyses at wrist
Myopathy
Low Ca, Low Pi

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5 features of osteomalacia

Looser’s zones (psuedofractures)
Increased fracture risk
Bone + muscle pain
Low Ca, Low Pi (neither absorbed from gut)
High ALP (osteoblasts trying to make new bone)

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phosphate levels in:

2ndary HyperPTH from CKD
2ndary hyperPTH from vit D deficiency

PO4 levels are:
high in CKD (inability to excrete)

low in vit D deficiency (due to PTH being so high)

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Familial benign hypercalcemia

-Level of urine Ca
- Level of plasma Ca
- Level of PTH

defect in Ca sensing receptor in parathyroid gland + kidneys

urine Ca low
plasma Ca high
PTH high

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pseudohypoparathyroidism
- PTH, Ca and PO4 levels?

PTH resistance

i.e. high levels of PTH, low Ca, high Phosphate

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What pathology is caused by hypercalcaemia?

Failure of depolarisation
Stones: polyuria
Bones
Groans: constipation
Moans: confusion, seizures

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What pathology is caused by hypocalcaemia?

“Trigger happy CNS”
Epilepsy (aberrant firing of nerves + muscles)
CATs go numb
Convulsions
Arrythmias
Tetany
Numbness in hands, feet + perineal

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Describe the importance of maintaining circulating calcium levels

Needed for normal nerve + muscle function
Sacrifice Ca from bone if circulating Ca is low to maintain level
Increases risk of fracture

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Describe the 2 hydroxylation reactions in vitamin D metabolism.

Liver: Cholecalciferol hydroxylated to 25-hydroxycholecalciferol
Kidneys: undergoes 2nd hydroxylation (by 1-alpha-hydroxylase) to 1,25-dihydroxycholecalciferol (calcitriol)

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What is the principle effect of calcitriol?

Increase Ca, Mg + phosphate absorption in the small intestines

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What are the secondary effects of calcitriol?

Increased reabsorption of Ca + decreased reabsorption of phosphate in kidneys (via FGF23)
Stimulates bone formation

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What are the 2 forms of vitamin D?

D3: animals in diet/ synth in skin - cholecalciferol
D2: plants - ergocalciferol

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Describe the action of calcitriol

Enters enterocytes in small intestine to increase activity of calcium channels to absorb more

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What is usually measured to gauge the level of calcitriol? What condition must be fulfilled for this to be a good measure of calcitriol?

25-hydroxycholecalciferol (stored in liver)
Only good in the case of normal renal function

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Describe the diagnostic characteristics of vitamin D deficiency.

Plasma Calcium = LOW
Plasma 25-hydroxycholecalciferol = LOW
Plasma PTH = HIGH (2 to hyperparathyroidism stimulated by the hypocalcaemia)
Plasma Phosphate = LOW
Radiological findings e.g. widened osteoid seams

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Why does ALP rise in fractures or other conditions with high bone turnover?

Osteoblasts release ALP in bone formation

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What would you expect the plasma phosphate level to be in someone with renal failure and why?

HIGH
GFR is low + there is a decrease in plasma excretion via the kidneys

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What would you expect the plasma calcium level to be in someone with renal failure and why?

LOW Not producing as much calcitriol (due to renal failure interfering with 1-alpha hydroxylase) so there is less Ca2+ absorption in the small intestines

What regulates phosphate metabolism?

Fibroblast growth factor 23 (FGF 23)

What happens when phosphate levels rise too high?

FGF 23 is stimulated to reduce circulating phosphate levels Major effect in kidney

What is the difference between Vitamin D and PTH in terms of phosphate absorption?

Vitamin D: increases calcium + phosphate absorption PTH: increases calcium only (phosphate trashing hormone)

Give 3 conditions associated with Vitamin D deficiency

Cancer AI disease Metabolic syndrome

What is the difference between osteoporosis and osteomalacia?

Osteomalacia: defective bone mineralisation. LOW Calcium Osteoporosis: normal bone structure, but weak, less total bone. NORMAL Calcium

How do anticonvulsants cause vitamin D deficiency?

Potent first pass metabolites induce liver enzymes resulting in increased Vitamin D metabolism

How does osteoporosis present?

Asymptomatic until 1st fracture Commonly NOF, Vertebral or Wrist (Colle's)

How can osteoporosis be scored from a DEXA scan?

T: SD from young healthy population of same gender. Fracture risk. Z: SD from mean age-matched control. Identifies in young.

What categories arise from the T score?

< -2.5: OsteoPOROSIS, need tx to prevent fracture -1 to -2.5: OsteoPENIA, at risk

3 Lifestyle changes to reduce fracture risk in osteoporosis

Weight bearing exercise Stop smoking Reduce EtOH

6 Rx for osteoporosis

Vitamin D Bisphosphonates: reduce bone resorption e.g. Alendronate Teriparatide HRT: E2 SERMs: selective estrogen receptor modulator e.g. Tamoxifen Denosumab

How is Alendronate taken? Why is there reluctance to compliance?

PO once per week with plenty of water on an empty stomach Wait 30m before breakfast Stay upright Can irritate stomach SE: Osteonecrosis of jaw

Give an alternative bisphosphonate to alendronate

Zolendronate IV Once per year

Give 4 categories of risk factors for early osteoporosis

Lifestyle: sedentary, EtOH, smoking, low BMI, nutrition Endo: hyperprolactinaemia, thyrotoxicosis, Cushing's Drugs: steroids Other: genetic

How do you determine hypercalcaemia aetiology?

1. Repeat test 2. What is the PTH? If suppressed: cause outside parathyroid If normal/ high: parathyroid gland problem

Give the most common, and 3 rarer causes of hypercalcaemia with low PTH

Metastatic CANCER Sarcoid Vit D excess Thyrotoxicosis

Give the most common, and a rarer causes of hypercalcaemia with normal/ high PTH

Primary Hyperparathyroidism Familial hypocalciuric hypercalcaemia

3 facts about primary hyperparathyroidism

F > M Parathyroid adenoma 80% (mostly single) or hyperplasia/ carcinoma Tx: Remove parathyroid

Parathyroid hyperplasia is associated to which condition

MEN1

What lab findings would be seen in primary hyperparathyroidism?

Serum Ca HIGH Serum Phos LOW PTH N or HIGH Urine Ca HIGH

4 Sx someone with primary hyperparathyroidism may present with

Stones: Renal calculi Bones: Fracture e.g. Colle's Moans: Constipation Groans: Confusion

Pathophysiology of familial hypocalciuric hypercalcaemia

Calcium sensing receptor mutation Reduced sensitivity to calcium Tissue can't "see" high calcium Reduced urine calcium

3 types of hypercalcaemia in malignancy

1. Humoral: SCLC, kidney, breast. PTHrP produced 2. Bone mets: local bone osteolysis (invasion) 3. Haematological e.g. Myeloma

When is production of PTHrP not pathological?

Prior to birth, placenta makes PTHrP to allow foetus to get calcium

5 non-PTH causes of hypercalcaemia

Sarcoidosis: Non renal 1 alpha hydroxylation Thyrotoxicosis: Thyroxine leads to bone resorption Hypoadrenalism: decreased renal excretion Thiazide diuretics: increase reabsorption Excess vit D: Sunbeds

Acute management of hypercalcaemia

FLUIDS: 0.9% Saline 1L/hr 4L daily if no HF IV 1st day at least

When are bisphosphonates given for hypercalcaemia?

if cause KNOWN to be CANCER Alendronate: creates barrier of indestructible bone, can't be invaded by cancer cells

Why would giving bisphosphonates to a patient with primary hyperparathyroidism be problematic?

Bone becomes indestructable Leads to hypocalcaemia post-parathyroidectomy

What is Chvostek's sign?

Twitch of facial muscles on tapping cheek in front of ear

What is Trousseau's sign?

Carpal spasm BP cuff pumped to high pressure, causes albumin to rise, more will bind to ionised calcium, further reducing calcium. Can't open hand

4 signs of hypocalacemia

Chvosteks Trousseau's Hyperreflexia Convulsions/ laryngeal spasm (stridor)

Tx for hypocalcaemia

IV calcium Vitamin D

3 causes of hypocalcaemia that is non PTH driven (secondary hyperparathyroidism- PTH will be high)

Vit D deficiency CKD: lack 1 alpha hydroxylation Pseudohypoparathyroidism

4 causes of hypocalcaemia due to low PTH

Surgical (post thyroidectomy / parathyroidectomy) AI hypoparathyroidism Congenital absence e.g. Di George syndrome Mg deficiency (needed to make PTH)

What characterises Paget's disease?

increased but uncontrolled bone turnover. Primarily a disorder of osteoclasts, with excessive osteoclastic resorption followed by increased osteoblastic activity.

3 bone signs/ sx in Pagets

Focal bone pain Bone warmth Deformity/ fracture

Why do those with Paget's disease develop heart failure?

Bone shunts blood through it Have high throughput of blood through bone Makes heart work harder

3 complications arising from bone causing compression in Pagets

Spinal cord compression Blindness Deafness

What biochemistry is found in Paget's?

HIGH ALP EVERYTHING else is NORMAL Ca + phos normal as osteoclasts + blasts are both active

From lowest to highest calcium level, rank the following conditions: (Breast) Cancer Pagets 2nd HPT Osteoporosis 1st HPT

1. (Breast) Cancer patients 2. 1st HPT 3. Osteoporosis + Pagets have normal so would need distinguishing feature 4. 2nd HPT