ChemPath 10: calcium handling and metabolic bone disease Flashcards
Why is the calcium level in the blood so tightly controlled?
Nerves and muscles rely on calcium to cause depolarisation
What are the consequences of high and low plasma calcium for nerve conduction? What is nomal range?
High calcium – failure of depolarisation
Low calcium – trigger happy neurological system leading to epilepsy (reduced AP required for NM depolarisation)
Range: 2.2-2.6 mmol/L
What are the three forms in which calcium is present in the plasma?
Free (ionised) – 50% - biologically active
Protein-bound – 40% - bound to albumin
Complexed – 10% - citrate/phosphate
State the equation for corrected calcium.
Corrected calcium = serum calcium + (0.02 x (40 – serum albumin in g/L))
NOTE: if your albumin level is constant, the total serum calcium will be roughly double the concentration of free calcium
What are the main effects of PTH?
Liberation of calcium from the bone (increased bone breakdown) and kidneys (increased calcium resorption)
Stimulates 1α-hydroxylase activity resulting in increased activated vitamin D
Stimulates renal phosphate excretion
What is the rate-limiting step in vitamin D activation?
1α-hydroxylase
What are the two forms of vitamin D?
Vitamin D2 (ergocalciferol) – from plants
Vitamin D3 (cholecalciferol) – produced when UV hits the skin and converts 7-dehydrocholesterol to cholecalciferol
NOTE: both are active
Outline how 7-dehydrocholesterol is converted to activated vitamin D.
UV converts 7-dehydrocholesterol to cholecalciferol (D3 - as found in fish oils and D3 tablets)
This is then converted by 25-hydroxylase in the liver to Calcifedol (25-hydroxycholecalciferol)
This then gets converted by 1α-hydroxylase in the kidneys to Calcitriol (1,25-dihydroxycholecalciferol)
How can sarcoidosis lead to hypercalcaemia?
Lung cells of sarcoid tissue (macrophages) express 1α-hydroxylase
NOTE: hypercalcaemia tends to be seasonal (i.e. during the summer months when more sunlight means more vitamin D which can be activated)
What are the main roles of vitamin D (calcitriol)?
Increased intestinal calcium absorption
Increased intestinal phosphate absorption
Critical for bone formation
What is ALP?
By-product of osteoblast activity
What is bone a reservoir of? (elements)
Calcium
Phosphate
Magnesium
What disease states does vitamin D deficiency cause?
Osteomalacia
Rickets
List some risk factors for vitamin D deficiency.
Lack of sunlight
Dark skin
Dietary
Malabsorption
Outline some clinical features of osteomalacia.
Bone and muscle pain
Increased fracture risk
Looser’s zones (Pseudofractures - common sites affected include the scapula, pubic rami and proximal femurs)
Outline the biochemical changes in osteomalacia
Low calcium
Low phosphate
High PTH
High ALP
Lsit some clinical features of rickets
Bowed legs
Costochondral swelling
Widened epiphyses of the wrists
Myopathy
Pathophysiology of osteomalacia
Vitamin D deficiency leads to secondary hyperparathyroidism which stimulates the liberation of calcium from the bone (leading to demineralisation of the bone)
How can renal failure cause vitamin D deficiency?
A lack of 1α-hydroxylase means that you are unable to activate vitamin D
Which group of drugs is associated with vitamin D deficiency?
Anticonvulsants – promote the breakdown of vitamin D
Which component of common foods chelates vitamin D in the gut?
Phytic acid – food like chapatis have a high level of phytic acid which chelates vitamin D in the gut and reduces absorption
How does acromegaly lead to osteoporosis?
Causes testosterone deficiency
escribe the changes in serum biochemistry in osteoporosis
Normal
What is the main investigation used for osteoporosis?
DEXA scan
What is a T-score? Z-score?
T-score:
Number of standard deviations from the mean of a young healthy population
Z-score:
Number of standard deviations from the age-matched control
Causes of osteoporosis?
Age-related decline in bone mass
Early menopause
Sedentary lifestyle
Alcohol
Low BMI
Thyrotoxicosis
Hyperprolactinaemia
Cushing’s syndrome
Prolonged recurrent illness
Lifestyle changes recommended in osteoporosis mx?
Weight-bearing exercise
Stop smoking
Reduce alcohol consumption
Drugs useful in mx of osteoporosis?
Vitamin D
Bisphosphonates
Teriparatide (PTH derivative)
Strontium (anabolic and anti-resorptive)
HRT
SERMs (e.g. raloxifene)
Signs of hypercalcaemia?
Moans, Stones, Groans and Bones
Moans - GI related (abdo pain, constipation, decreased appetite, nausea, peptic ulcers + vomiting)
Stones - Increased risk of kidney stones (+ polyuria / dipsia)
Groans - phychological symptoms (confusion, dementia, depression, seizures, coma)
Bones - If due to primary hyperparatyroidism -> bone breakdown
NOTE: these tend to occur when calcium level > 3 mmol/L
What are the main causes of primary hyperparathyroidism?
Parathyroid adenoma
Parathyroid hyperplasia (associated with MEN1)
Parathyroid carcinoma
Outline the serum biochemistry features of primary hyperparathyroidism.
This is PTH driven hence high PTH:
- High calcium
- Inappropriately raised PTH (can be normal as well)
- Low phosphate (‘phosphate trashing hormone’)
Outline the pathophysiology of familial benign hypercalcaemia
A mutation in the calcium-sensing receptor (CaSR) leads to an increase in the set-point for PTH release (leads to mild hypercalcaemia)
TLDR: Same amount of Ca leads to much greater PTH release than in normal individuals
Why don’t patients with familial benign hypercalcaemia get kidney stones?
PTH causes increased renal calcium absorption, thereby reducing urine calcium
What are the three types of hypercalcaemia of malignancy?
Humoral hypercalcaemia of malignancy (e.g. small cell lung cancer) caused by PTHrP release
Bone metastases (e.g. breast cancer) caused by local bone osteolysis
Haematological malignancy (e.g. myeloma) caused by cytokines causing breakdown of bone
List some other non-PTH driven causes of hypercalcaemia + how?
Sarcoidosis
Thyrotoxicosis (increases bone resorption)
Hypoadrenalism (renal Ca2+ transport)
Thiazide diuretics (renal Ca2+ transport)
Excess vitamin D (e.g. sun beds)
Outline the management of hypercalcaemia
Fluids, fluids and more fluids
Bisphosphonates (stops cancer from eating bone - dronates)
Treat the underlying cause
What is measured in vitamin D tests?
Calcifedol (25-hydroxy vitamin D) levels
25-hydroxy vitamin D is stored and converted to the active form when needed under the influence of PTH
What does calcitriol do?
Increases Ca uptake at GI tract +
Increases Phosphate uptake at GI tract
How to categorise causes of HYPERcalcaemia?
PTH causing or correcting:
PTH causing (high PTH):
- Primary hyperparathyroidism (MAIN)
- Familial benign hypercalcaemia
PTH correcting (low PTH): - Malignancy
What level is hypercalcaemia?
What is hypocalcaemia?
>2.6mmol/L
<2.2mmol/L
How to categorise causes of HYPOcalcaemia?
PTH causing or correcting:
PTH causing (low PTH):
Hypoparathyroidism
- Surgical - thyroidectomy
- Immunological - AI Hypoparathyroidism
- Congenital - DiGeorge
Mg Deficiency
PTH correcting (high PTH): Secondary hyperparathyroidism (PTH is high but caused by indirect reason (reduced Ca)) 1. Vit D deficiency (not enough to start the chain\_ 2. CKD (lack of 1a hydroxlase) 3. PTH resistance (known as pseudohyperparathyroidism)
What is tertiary hyperparathyroidism?
Often seen in CKD - PTH has been raised for so long that even after initial hypocalcaemia is fixed it stays raised
This leads to HYPERcalcaemia
Signs seen in HYPOcalcaemia?
Due to NM excitability:
- > Chvostek’s Sign
- > Trousseau’s Sign
- > Hyperreflexia
- > Laryngeal Spasm
- > Convulsions
Mx of HYPOcalcaemia?
Calcium
- > IV Calcium Gluconate 10%
- > Oral Calci-D tablets
Vitamin D
-> Usually the activated form
