ChemPath 1: Calcium Metabolism Flashcards
Why must the calcium in blood be fixed?
nerves, muscles rely on Ca for depolarisation
What does Hypercalcaemia cause?
- failure of depolarisation –
- stones, bones, groans, moans + nephrogenic DI
What does Hypocalcaemia cause?
- “trigger happy CNS” –
- epilepsy (aberrant firing of nerves and muscles) –
- CATS go numb
What is the normal range of Ca in blood?
- Normal Ca = 2.2 - 2.6mmol/l
What % of calcium is in serum?
1%
Where is the rest of the Calcium in the body?
complexed with phosphate in bones and teeth
What forms is the 1% of Ca in the serum in?
- Free, ionised calcium, biologically active –> 50% à maintain at a fixed level
- Protein-bound as albumin –> 40%
- Complexed with citrate/phosphate –> 10%
What happens to the blood Ca levels if albumin is abnormal?
- An abnormal albumin affects the free calcium (e.g. in sepsis)
- If albumin is low…
- Bound calcium will be low, but free calcium is normal
- Corrected Ca refers to that (the corrected calcium can tell you what is wrong with albumin)
- So, if albumin = 30 and total Ca = 2.2
- Corrected Ca = 2.2 +(0.02 x 10) = 2.4mM
- So, corrected Ca shows if the problem is albumin, and that ionised Ca will be normal
How might you overcome the abnormal Ca caused by abnormal albumin?
- “Corrected ca” reported by labs
- This compensates for albumin
- Serum Ca + 0.02 x (40 – serum albumin (g/l))
- In blood gas machines, ionised Ca can also be measured (around 1.1mmol/L)
What is circulating Ca important for?
- Important for normal nerve, muscle function
What happens in Chronic Ca deficiency?
- loss in Ca from bone to maintain circulating Ca
Which organ detects hypoglycaemia?
- Hypocalcaemia is detected by parathyroid gland
What are the actions of PTH?
Which are the 2 key hormones involved in Ca homeostasis?
- PTH
- Vitamin D (steroid hormone)
What are the 2 forms of vitamin D? What are they activated by?
- D3 → animal product, from sunlight hitting skin → cholecalciferol
- D2 → plants → ergocalciferol
- both activated by 1-alpha hydroxylase
Describe the structure of PTH
84 aa protein
How is vitamin D in the blood measured?
- Measurement = 25-OH Vitamin D3
Where are the 2 forms of Vitamin D synthesised?
- Vitamin D3 is synthesised in the skin – cholecalciferol
- Vitamin D2 is a plant vitamin – ergocalciferol
Name the organs in which Vitamin D is synthesised/processed etc and describe what happens at each
Are vitamin D3 and D2 active?
yes
Describe what happens to whether Vitamin D is active (or not) as it is processed in the body
- (SKIN) D3 → animal product, from sunlight hitting skin → cholecalciferol;
(INTAKE) D2 → plants → ergocalciferol
= ACTIVE - (LIVER) 25-hydroxylase –> 25-hydroxy-Vitamin D3
= INACTIVE - (KIDNEY) 1α hydroxylase –> 1,25-dihydroxy Vitamin D3
= ACTIVE
Which enzyme hydoxylates Vitamin D3 and D2 in the liver?
25 hydroxylase
Which enzyme hydroxylates 25-hydroxy-vitamin D3 in the kidneys?
1α hydroxylase
Where can 1α hydroxylase also be expressed (other than the kidneys)?
- Rarely, this enzyme is expressed in lung cells of sarcoid tissue
- Sarcoid = causes hypercalcemia (seasonal) – summer hypercalcemia
- In sunlight, calcium goes up (more vitamin D activation
What is another name for 25-hydroxy-Vitamin D3?
calcidiol (prior to 1a hydroxylation in the kidneys)
What is another name for 1,25-dihydroxy-Vitamin D3?
What is the role of Role of 1,25 (OH)2 Vitamin D (Calcitriol)?
- Intestinal Ca2+ absorption and intestinal phosphate absorption
- Critical for bone formation (with osteoblasts)
- Other physiological effects
- Vitamin D receptor controls many genes – cell proliferation, immune system
- Vitamin D deficiency associated with cancer, autoimmune disease, metabolic syndrome
What is the cause of rickets/osteomalacia?
- Vitamin D deficiency
What is the cause of osteoporosis?
lack of oestrogen
What does Vit D deficiency cause?
- Defective bone mineralisation
- Childhood → rickets; Adults → osteomalacia
Describe the epidemiology of Vitamin D deficiency in the UK
- More than 50% adults have insufficient vitamin D
- 16% have severe deficiency during winter and spring
What are the risk factors for Vit D deficiency?
- Lack of sunlight exposure
- Dietary
- Dark skin
- Malabsorption
What are the clinical features of Osteomalacia?
- Bone and muscle pain
- Increase fracture risk
- Looser’s zones (pseudo fractures)
What is the biochemistry seen in osteomalacia?
Bio-chem →
- low Ca2+ and phosphate
- raised ALP
What are the clinical feautures of rickets?
- Bowed legs
- Costochondral swelling
- Widened epiphyses at the wrists
- Myopathy (weak muscles)
What is the cause of the features of osteomalacia?
lack of Ca
What are the clinical features of osteomalacia?
- Bone is demineralised
- Caused by vitamin D deficiency
- Renal failure
- Anticonvulsants induce breakdown of Vitamin D (phenytoin)
- Lack of sunlight
- Chappatis – phytic acid (cause osteomalacia)
What is the first clinical feature of osteoporosis?
- pathological fracture (asymptomatic until then)
- (more common as you age, bone lost slowly after 20)
What is the pathogenesis of osteoporosis?
- Loss of bone mass, (Reduction in bone density)
- but residual bone normal in structure (normal mineralisation)
What happens to the biochemistry in osteoporosis?
all normal
- Osteoporosis has bone loss but with a normal calcium
How is osteoporosis diagnosed?
- DEXA scan (Dual energy X-ray absorptiometry):
Where are the common sites of fractures in osteoporosis?
- Hip (femoral neck)
- lumbar spine
Explain T scores and Z scores
- T score – SD from mean of young healthy population – determine fracture (#) risk
- Z score – SD from mean of age-matched control – identify accelerated bone loss in younger people
What are the diagnostic values for osteoporosis and osteopenia? (T scores)
- Osteoporosis – T score
- Osteopenia – T score -1 and -2.5
What is the Tx for osteoporosis?
- Lifestyle
- Weight bearing exercise
- Stop smoking
- Reduce ETOH
- Drugs
- Vitamin D/Ca
- Bisphosphonates (alendronate) – decrease bone resorption – osteonecrosis of jaw
- Teriparatide – PTH derivative – anabolic
- Strontium – anabolic + anti-resorptive
- Oestrogens – HRT
- SERMs (oestrogen-like drug) – raloxifene (like Tamoxifen)
- Denosumab – biologic anti-RANK-L antibody
What are the symptoms of hypercalcaemia?
- Polyuria or polydipsia
- Bones
- Stones
- Abdo - constipation
- Neuro – confusion, seizures, coma
- Unlikely unless Ca >3mmol/L (2.2-2.6)
Overlap with symptoms of hyperPTH
What qs must be asked when bloods come back as hypercalcaemia?
- First Q: is it a genuine result (repeat)
- 2nd Q: what is the PTH?
What can a high albumin in bloods mean in hypercalcaemia?
- High albumin = artificially elevated Ca
What is secondary hyperparathyroidism associated with?
2nd HPT is associated with a LOW calcium due to low vitamin D
What is the commonest cause of hypercalcaemia?
Primary Hyperparathyroidism
What are some causes of primary hyperparathyroidism?
- Parathyroid adenoma (80%)
- Hyperplasia
- associated with MEN1, 2a
- Malignancy of the parathyroid gland (carcinoma)
sWhat blood results will be seen in hypercalcaemia due to primary hyperparathyroidism?
- High serum Ca
- Low serum phosphate
- High PTH - inappropriate
- High urine Ca due to hypercalcemia
What blood results will be seen in hypercalcaemia due to malignancy elsewhere in the body?
- High serum Ca
- Low serum phosphate
- Low serum PTH – appropriate
What different presentations may a patient with primary hyperparathyroidism present with?
bones, urinary stones, abdo moans, psychiatric groans
Which organs have Ca-sensing receptors?
- Parathyroid – regulate PTH
- Renal – influences Ca resorption – PTH independent
What is Familial hypocalciuric hypercalcemia?
- Calcium Sensing Receptors mutation
- Reduced sensitivity to calcium
- Higher set point for PTH release
What bloods and urine results are seen in Familial hypocalciuric hypercalcemia?
- Mild hypercalcaemia
- Reduced urine Ca
What are the 3 causes of hypercalcaemia seen in malignancy?
-
Humoral hypercalcaemia of malignancy – squamous cell lung cancer
- PTHrP released
-
Bone mets – e.g. in breast ca
- Local bone osteolysis
-
Haematological malignancy – myeloma
- Cytokines
What are some other causes of non-PTH driven hypercalcaemia ?
- Sarcoidosis – non renal 1α hydroxylation
- Thyrotoxicosis – thyroxine leads to bone resorption
- Hypoadrenalism – renal Ca transport
- Thiazide diuretics – renal Ca transport
- Excess vitamin D – sunbeds
What is the Tx for hypercalcaemia?
- FLUIDS (0.9% saline, 1L/hour and reassess)
- Treat underlying cause
- Cinacalcet acid – activates Ca sensing receptors
What are the signs & symptoms of hypocalcaemia?
- Neuromuscular excitability –> Chvostek’s sign (face), Trousseau’s sign, hyperreflexia
- Convulsions
What must be done when diagnosing hypocalcaemia?
- 1st –> repeat bloods and adjust for albumin (as the albumin can bind ionised calcium) - i.e. is the hypocalcaemia a genuine result?
- 2nd –> what is the PTH?
What are the non-PTH driven causes of hypocalcaemia?
What are the PTH-driven (due to low PTH) causes of hypocalcaemia?
Which has the lowest calcium out of:
- primary HPT
- secondary HPT
- osteoporosis
- Paget’s
- breast cancer
secondary HPT
What is Paget’s disease?
focal disorder of bone remodelling
What are the signs and symptoms of Paget’s disease?
- Bone pain
- Warmth
- Cardiac failure
- Deformity
- Fracture
- Malignancy
- Compression (blindness, deafness)
Commonly affected bones: Pelvis, femur, skull and tibia
What are the bloods seen in Paget’s disease?
- Elevated alkaline phosphatase
- Ca and PO4 are NORMAL as…
- Osteoclasts and blasts are both active together
What imaging is conducted in ?Paget’s disease?
- Nuclear med scan / XR
What is the Tx of Paget’s disease?
- Bisphosphonates for pain
What:
- Ca
- phosphate
- PTH
- Alk Phos
- Vit D
is seen in the following conditions?
What are some other metabolic bone disorders?
-
renal osteodystrophy
- due to secondary HPT + retention of aluminuim from dialysis fluid
-
osteistis cysitica
- in primary HPT, loss of cortical bone –> fracture risk
both are quite rare due to modern Tx of underlying cause
