1. Calcium metabolism Flashcards
How does calcium enter the body?
Already present in cells or enters via the gut
How is calcium excreted?
Via the kidneys
What percentage of calcium is circulating and is in bones?
1% circulating, 99% in bones
Roles of calcium
- To maintain the body’s skeleton; we can slowly sacrifice bone i.e. osteoporosis to maintain nerve muscle function, however low bone calcium -> increased risk of fractures.
- Metabolic role in action potentials and intracellular signalling.
What are the forms serum calcium is found in?
- Free ionised (50%) -> biologically active. 2. Protein bound (40%) -> mainly albumin, changes in albumin can falsely show a deranged calcium. 3. Complexed (10%) -> citrate or phosphate.
Total serum calcium normal ranges
2.2 - 2.6 mmol/L
Corrected calcium formula:
Serum calcium + 0.02 x (40 - serum albumin in g/L)
What is the corrected calcium if serum calcium is 2.2 and serum albumin is 30 g/L?
2.2 + 0.02 x (40-30) = 2.4 mmol/L = NORMAL
Why is free calcium important for nerve depolarisation?
Bound calcium does not have access
Ionised calcium can also be measured via blood gas, true or false?
True
What happens to bound calcium, free calcium when albumin is low? Thus what happens to correct calcium and ionised calcium when albumin is low?
Bound calcium will be low but free calcium will be normal. Thus corrected calcium will be normal and ionised calcium will be normal. (Formula: serum calcium + 0.02 x (40 - serum albumin in g/L) )
Corrected calcium tells you that the problem is albumin.
What detects hypocalcaemia?
Parathyroid gland
In hypocalcaemia, parathyroid gland releases PTH via autoregulatory mechanisms which obtains calcium from 3 sources:
- Bone - activates osteoclasts initiate bone resorption of calcium phosphate. NOTE osteoblasts build up bone and draw calcium in.
- Gut - increased absorption
- Kidney - resorption from tubule, renal phosphate wasting and 1a-OHxylase activation by PTH converts 25-OH Vitamin D (inactive - liver) to 1,25-(OH)2 Vitamin D (active) which increases intestinal calcium absorption as well
Two key hormones in hypocalcaemia
- PTH - 84 amino acid peptide
- Vitamin D - modified steroid hormone absorbed and unfolded in the skin. Vitamin D3 is an animal substance only, D2 is from plants.
How is vitamin D synthesised?
- 7-dehydrocholesterol in the skin is activated by sunlight to cholecalciferol (vitamin D3)
- Ergocalciferol is from plants. The difference between Vit D2 and D3 is a double bond
- 100% of absorbed vitamin D is converted to 25-OH D3 by 25-OHxylase in the liver, where it is stored
- When needed, activated by PTH in the kidney. PTH activates 1a-OHxylase which converts 25-OH D3 (inactive) into 1,25-di-OH D3 (active)
What is the rate limiting step in vitamin D synthesis?
1a-OHxylation - only occurs when calcium levels need to rise
How does sarcoidosis cause hypercalcaemia?
The macrophages in the lung produce 1a-OHxylase which can cause hypercalcaemia.
Seasonal changes of vitamin D
In summer, lot of vitamin D activation, high vitamin D stores in the liver, so patients become hypercalcaemic. In winter, less skin vitamin D activation, low vitamin D stores in the liver, so become hypocalcaemic.
Roles of 1,25-(OH)2 D3
- Intestinal calcium and phosphate absorption. Critical for bone formation and opposite to PTH in kidney causing phosphate wasting.
- Vitamin D receptor also controls many genes e.g. cell proliferation, immune system, etc.
- Vitamin D deficiency is associated with cancer, autoimmune disease and metabolic syndrome -> reason for this is poverty - poor people have vitamin D deficiency
When is ALP raised (bone causes)?
Post fracture, abnormal PTH secretion, children when growing.
Role of the skeleton from an orthopaedic view:
Structural framework, strong, relatively lightweight and mobile, protects vital organs, capable of orderly growth and remodelling.
Role of the skeleton from an endocrine view:
Metabolic role in calcium homeostasis; main reservoir of calcium, phosphate and magnesium
What is osteoporosis?
Occurs when calcium needs to be taken from bone stores. The bone gets thinner but the bone structure itself is normal. Normal feature of ageing, a consequence of living longer is we are likely to die of a fracture.
What is osteomalacia?
Bones are abnormal due to vitamin D deficiency. There is no vitamin D activated calcification of bone.
What happens in Paget’s disease?
Cause unknown ?virus. Thoughts are the virus is disappearing as very few new cases are appearing. Very active osteoclasts and osteoblasts, resulting in bone pain - cure is bisphosphonates.
Parathyroid bone disease
Tumour of parathyroid gland with very elevated PTH levels. Combination of osteoporosis and osteomalacia as you use up vitamin D as it is continuously being activated by PTH
What is renal osteodystrophy?
Renal failure and lack of vitamin D activation therefore you fail to excrete phosphate
Vitamin D deficiency - defective bone mineralisation. What does it cause in childhood and adulthood?
Rickets and osteomalacia
Vitamin D deficiency in the UK epidemiology
more than 50% of adults. 16% have severe deficiency during winter and spring.
Vitamin D deficiency risk factors
Lack of sunlight exposure, dark skin, dietary, malabsorption
Clinical features of vitamin D deficiency in adults
Osteomalacia: Bone and muscle pain; increased risk of fractures; low calcium, low phosphate and raised ALP; Looser’s zones (pseudofractures)
Clinical features of vitamin D deficiency in children
Rickets: Bowed legs, costochondral swelling, widened epiphyses at wrists, myopathy
Causes of osteomalacia
All causes are due to some form of vitamin D deficiency.
- Renal failure - lack of 1a-OHxylase
- Dietary deficiency
- Anticonvulsants induce breakdown of vitamin D (e.g. phenytoin in children to prevent fits)
- Lack of sunlight
- Phytic acid (found in chappatis) - chelates vitamin D in gut reducing absorption
Can pregnancy cause low vitamin D?
Yes, pregnancy where placenta makes PTHrp to steal calcium from mother for foetal one development, results in low vit D. Calcium is lost during breast feeding. NOTE: cancer cells also make PTHrp which is how they invade bone
What happens in secondary hyperparathyroidism?
- Vitamin D deficiency causes low calcium and phosphate
- parathyroid glands work really hard to release lots of PTH which activate more vitamin D, push out more renal phosphate. Try to absorb calcium but theres none so main cost is losing bone = moth eaten deficiencies in bone a feature of osteomalacia.
- as parathyroid glands work hard, lose bone, high osteoclast activation
What are the causes of osteoporosis?
Results from:
- disuse of bones, immobility, lack of exercise, sedentary lifestyle
- age related decline in bone mass
- congenital osteogenesis imperfecta
- myeloma, leukaemia
- dietary: protein, calcium, or vitamin D deficiency
- deficient anabolism: oestrogen deficiency (post-menopausal statem early menopause) and testosterone deficiency (Kleinfelters syndrome, hypogonadism, castration)
- Excessive catabolism (rapid bone turnover) due to hyperthyroidism, thyrotoxicosis, Cushing’s syndrome, GC excess, administered cortisol or ACTH, steroids
- Long standing diabetes with acidosis
- Liver cirrhosis, alcohol, smoking
- Acromegaly
- Low BMI
- Prolonged recurrent illness (and childhood illness)
Features of osteoporosis
Pathological fractures, tend to occur in the wrist (Colle’s), hip (NOF) and spine. Fractures asymptomatic at first?
Other features: loss of height, kyphosis, back pain, codfish vertebrae, herniation of nucleus pulposus, thin trabeculae, thin skull cortex
Biochemistry of osteoporosis
Calcium and phosphate normal. ALP usually normal unless recent fracture.
How to diagnose osteoporosis
DEXA scan often of hip or lumbar spine
What is the T-score?
In a DEXA scan, the number of SDs from the mean of a young healthy population. Useful to determine fracture risk.
What is the T-score for osteoporosis and osteopaenia?
Osteoporosis T-score = < -2.5
Osteopaenia = -2.5 - -1
What is the Z-score?
Number of SDs from the mean of an age-matched healthy control. Useful to identify accelerated bone loss in younger patients.
What is the treatment for osteoporosis?
Weight bearing exercise, stop smoking, reduce alcohol
What drugs are used in osteoporosis?
- Vitamin D and calcium
- bisphosphonates (alendronate) -> reduce bone resorption
- teriparatide (PTH derivative)
- strontium -> anabolic and anti-resorptive
- oestrogens e.g. HRT, SERMs (raloxifene)
Hypercalcaemia symptoms
Occur when calcium > 3.0 mmol/L.
Polyuria, polydipsia, constipation, confusion, seizures, coma. Symptoms overlap with hyperparathyroidism.
If hypercalcaemia symptoms overlap with hyperparathyroidism, then the normal response is to …
suppress PTH
What to consider when blood test results show hypercalcaemia?
Repeat if in doubt. Is it true hypercalcaemia? What is the PTH?
Causes of hypercalcaemia
- Familial hypocalciuric hypercalcaemia
- malignancy commonly breast or lung cancer
- sarcoidosis where macrophages express 1a-OHxylase in unregulated fashion causing excess vit D activation and calcium release
- milk alkali syndrome
What is an appropriate PTH response to hypercalcaemia? What is a common example?
PTH is suppressed. Common cause is malignancy.
What is an inappropriate PTH response to hypercalcaemia? What is a common example?
PTH is not suppressed. Common cause is primary hyperparathyroidism.
Most common cause of hypercalcaemia
Primary hyperparathyroidism
Causes of primary hyperparathyroidism
Parathyroid adenoma, parathyroid hyperplasia (associated with MEN1), parathyroid carcinoma
Who is primary hyperparathyroidism more common in?
Women
Biochemical features of hyperparathyroidism
increased serum calcium, increased or inappropriately normal PTH, low serum phosphate, increased urine calcium (due to hypercalcaemia)
Clinical features of hyperparathyroidism
BONES (PTH bone disease), STONES (renal calculi), MOANS (abdominal pain due to constipation and pancreatitis), GROANS (psychiatric disturbance e.g. confusion)
What happens in familial benign hypercalcaemia?
Mutation in the calcium sensing receptor (CaSR). PTH gland will detect calcium levels via the CaSR. Mutation increases the set point for PTH release causing mild hypercalcaemia. Benign condition, does not form kidney stones as they also have reduced urine calcium. NOTE: must distinguish this benign condition from hyperparathyroidism which may require surgery
What types of malignancies cause hypercalcaemia?
- Humoral hypercalcaemia of malignancy e.g. small cell lung cancer releasing PTHrp which dissolved bone
- Bone metastases e.g. breast cancer causing local bone osteolysis
- Haematological malignancy e.g. myeloma caused by cytokine involvement
Causes of non-PTH driven hypercalcaemia
Malignancy, sarcoidosis (non-renal 1a-hydroxylase vitamin D activation), thyrotoxicosis (thyroxine increases bone resorption), hypoadrenalism (renal calcium transport), thiazide diuretics (renal calcium transport), excess vitamin D (sunbeds, excess sun tanning).
Treatment of hypercalcaemia
Acute management:
- LOTS OF FLUIDS
- 0.9% saline 1L over first 1-2 hours. Re-measure calcium. Give about 4-6L over 24 hours.
- Bisphosphonates - only if cause known to be cancer to stop it from eating the bone, otherwise avoid
- Treat underlying cause e.g. surgery
Hypocalcaemia clinical signs
Neuromuscular excitability, Chvosteks sign (29% sensitive), Trousseaus sign (carpopedal spasm - latent tetany - 94% sensitive), hyperreflexia, convulsions, laryngeal spasm, choked optic disk, prolonged qt interval on ECG
How to treat hypocalcaemia
Calcium and vitamin D (activated forms)
What to do when results show hypocalcaemia?
Is it a genuine result? Repeat and adjust for albumin. What is the PTH? Is it non-PTH driven or due to low PTH?
What are non-PTH driven causes of hypocalcaemia?
- vitamin D deficiency (dietary, malabsorption, lack of sunlight)
- chronic kidney disease (1a hydroxylation) -> can progress to tertiary hyperparathyroidism!
- PTH resistance (pseudohypoparathyroidism)
What happens to metacarpal in pseudohypoparathyroidism?
Short 4th metacarpal
What are causes of hypocalcaemia due to low PTH?
Surgical (inc. post thyroidectomy), auto-immune hypoparathyroidism, congenital absence of parathyroids (e.g. DiGeorge syndrome), Mg deficiency (PTH regulation)
What happens to PTH in non-PTH driven causes of hypocalcaemia?
PTH will be raised - secondary hyperparathyroidism
What is Paget’s disease?
Focal disorder of bone remodelling. Accelerated osteoclastic and osteoblastic activity, “mosaic bone”
What are the features of Paget’s disease
Focal pain, warmth and tenderness over bones, deformity (bowing of tibia, skull enlargement, deafness if 8th nerve involvement, kyphosis), fracture (E.g. fissure fracture), malignancy, cardiac failure due to increased cardiac output.
Which areas are most commonly affected in Paget’s disease?
Pelvis, femur, skull and tibia
Biochemistry of Paget’s disease
elevated ALP, calcium and phosphate normal, PTH normal
How is Paget’s disease diagnosed?
Nuclear medicine scan or x-ray
Treatment for Paget’s?
Bisphosphonates for pain
Loss of what leads to increased fracture risk in primary hyperparathyroidism?
Cortical bone
What is renal osteodystrophy due to?
Due to secondary hyperparathyroidism and retention of aluminium fromm dialysis fluid
Primary defect in osteoporosis
bone loss
Primary defect in osteomalacia/rickets
low vitamin D
Primary defect in Paget’s
Remodelling
Primary defect in parathyroid bone disease
High PTH
Primary defect in renal bone disease
Low 1a OHxylase and aluminium toxicity
What would calcium, phosphate, PTH, vit D and ALP levels be like in osteoporosis
Calcium - normal Phosphate - normal PTH - normal Vitamin D - normal ALP - normal
What would calcium, phosphate, PTH, vit D and ALP levels be like in osteomalacia/rickets
Calcium - low/normal Phosphate - low/normal PTH - high (secondary hyperparathyroidism) Vitamin D - low ALP - high
What would calcium, phosphate, PTH, vit D and ALP levels be like in Paget’s
Calcium - normal Phosphate - normal PTH - normal Vitamin D - normal ALP - high
What would calcium, phosphate, PTH, vit D and ALP levels be like in parathyroid bone disease
Calcium - high Phosphate - low PTH - high/normal (innapropriate N) Vitamin D - normal ALP - high/normal
What would calcium, phosphate, PTH, vit D and ALP levels be like in renal bone disease
Calcium - low/normal
Phosphate - high (increased phophate retention)
PTH - high (secondary hyperparathyroidism)
Vitamin D - normal (1a is lo though)
ALP - high/normal
1,25-(OH)2 D3 is critical for intestinal calcium and phosphate absorption and thus bone formation. This phosphate aborption is opposite to …
PTH in the kidney which causes phosphate wasting. PTH only increases calcium absorption in kidney
Whenever osteoblasts make bone they leak out …
small amounts of bone ALP
