W1 - Calcium metabolism Flashcards
What are the roles of calcium in the body?
- skeleton maintenance
- Metabolic - APs and IC signalling (normal nerve and muscle function)
Where is calcium stored in the body?
Skelton (99% of bone calcium)
What are the 3 forms of serum Ca2+?
- Free (ionised) - 50%, biologically active
- Protein-bound - 40%, albumin
- Complexed - 10%, citrate/phosphate
What is the total serum Ca2+ range?
2.2 – 2.6 mmol/L
What is corrected Ca2+?
Corrected calcium takes into account the albumin. E.g., if albumin is really low, then a correction factor is applied.
What is the formula for calculating corrected Ca2+?
serum Ca2+ + 0.02 * (40 – serum albumin in g/L)
Calculate corrected Ca2+ if albumin = 30, calcium = 2.2 mmol/L
Corrected calcium = 2.2 + (0.02 x 10)
= 2.2 + 0.2 = 2.4 mM
What is the physiological response to hypocalcaemia?
Detected by parathyroid gland –> release PTH –> PTH obtains Ca2+ from 3 sources:
- increased bone resorption
- increased intestinal absorption
- increased renal resorption and renal 1 alpha hydroxylase activation (which means increased 1,25-OH Vit D
all these lead to increased ECF Ca2+
what are the key 2 hormones involved in calcium homeostasis?
PTH (84 aa peptide hormone) Vit D (Steroid hormone)
What are the effects of PTH on the kidneys?
- Renal Ca2+ resorption
- Renal Pi wasting
- Stimulates 1,25 (OH)2 vit D synthesis (1α hydroxylation)
what does PTH stand for in terms of Amir Sam?
Phosphate Trashing Hormone
Explain the synthesis of Vitamin D3?
7-dehydrocholesterol (skin) –> sunlight –> cholecalciferol (D3) –> liver –> 25-OH-D3 –> kidney (1a-hydroxylase, with the presence of PTH) –> 1,25-(OH)2-D3 ACTIVE!
What is mammalian and what is plant vitamin D?
mammalian - D3 (cholecalciferol)
plant - D2 (ergocalciferol)
What is the stored and measured form of Vitamin D?
25-OH-D3 (inactive)
What is the rate-limiting step in vitamin D3 synthesis?
1 alpha hydroxylation (b/c it is under the control of PTH)
What happens to any absorbed vitamin d?
100% is hydroxylated at the 25 position in the liver
Where else is 1 alpha hydroxylase expressed?
Rarely, in the lung cells of sarcoid tissue - results in inappropriately raised calcium
What are the roles of 1,25(OH)2 vitamin D in the body?
- Intestinal Ca2+ absorption
- Intestinal Pi absorption
- Bone formation
Name 5 metabolic bone diseases
Osteoporosis
Osteomalacia
Paget’s disease
Parathyroid bone disease
Renal osteodystrophy
Explain Vitamin D deficiency
Defective bone mineralisation
Childhood -> Rickets
Adulthood -> Osteomalacia
What are the risk factors (6) for Vit D deficiency?
- Lack of sunlight exposure
- Dark skin
- Dietary malabsorption
- Anticonvulsants induce breakdown of vit D
- Chappatis (phytic acid)
- Renal failure
What are the symptoms and imaging features of Osteomalacia?
- Bone & muscle pain
- Increased risk of fractures
- Looser’s zones (pseudofractures)
What is the biochemical image of Osteomalacia?
low Ca2+ & Pi, raised ALP
What are the clinical features of rickets?
Bowed legs
Costochondral swelling
Widened epiphyses at the wrists
Myopathy
How does PTHrP act in body?
stimulates bone resorption and renal reabsorption, leading to increased [Ca2+]
How is PTHrP implicated in certain cancers?
Causes hypercalcaemia, and also turns on osteoclasts and provides cancer with opportunity to invade bone
Explain osteoporosis
Normal aging process of bone
- bone slowly lost after age 20
bone is NORMAL in structure, but there is a loss of BONE MASS - normal calcium!!
In osteoporosis, there is a reduction in __________ _________.
In osteoporosis, the calcium is ____ and the phosphate is ________
bone density
normal, normal
What is the first symptom of osteoporosis?
Fracture!!
What are typical fractures in osteoporosis?
neck of femur (NOF), vertebral, wrist (Colle’s)
How is osteoporosis diagnosed? Interpret the results
DEXA (Dual Energy X-ray Absorptiometry)
hip (femoral neck) + lumbar spine
Osteoporosis T Score < -2.5
Osteopenia T score between -1 & -2.5
When does bone mass decline begin?
20-ish, if no childhood illness is present to cause failure to attain peak bone mass
List 4 causes of rapid bone loss in adulthood (leading to osteoporosis) and give examples of each
- Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional
- Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
- Drugs: steroids
- Others eg genetic, prolonged intercurrent illness
What are the treatments for osteoporosis?
- Lifestyle
Weight-bearing exercise
Stop smoking
Reduce EtOH - Drugs
- Vitamin D/Ca
- Bisphosphonates (eg alendronate) –↓ bone resorption
- Teriparatide (PTH derivative) – anabolic
- Strontium – anabolic + anti-resorptive
- Oestrogens – HRT - reduce risk of osteoporosis and hot flushes, increase risk of cancer
- SERMs eg raloxifene, tamoxifen
Symptoms of hypercalcaemia
- Polyuria / polydipsia
- Constipation
- Neuro – confusion / seizures / coma
BONES (PTH bone disease) STONES (renal calculi) MOANS (constipation, pancreatitis), GROANS (confusion)
What is the normal physiological response to hypercalcaemia?
- PTH release suppressed
- Vit D activation suppressed
trying to reduce ECF Ca2+
What is the first thing to look for when Ca2+ is raised?
Is it a genuine result? repeat bloods.
Is the PTH suppressed?
What is the likely cause (5) of hypercalcaemia if PTH is suppressed?
PTH suppressed = appropriate response
causes:
- MALIGNANCY (common)
- sarcoid
- vitamin D excess
- thyrotoxicosis
- Milk alkali syndrome
What is the likely cause of hypercalcaemia if PTH is NOT suppressed?
PTH not suppressed = inappropriate response
causes:
1. Primary hyperparathyroidism (common)
2. familial hypocalciuric hypercalcemia (rare)
What is the commonest cause of hypercalcaemia?
Primary hyperparathyroidism
Primary hyperparathyroidism - what aetiology is most common?
Parathyroid adenoma > hyperplasia > carcinoma
What is parathyroid hyperplasia associated with?
MEN1
Which sex is Primary hyperparathyroidism more common in?
women
What is the biochemistry of Primary hyperparathyroidism?
↑serum Ca
↑ or inappropriately normal PTH
↓serum Pi
↑ urine Ca (due to hypercalcaemia)
What happens with a CaSR mutation? What is the disease called?
Higher setpoint for PTH release –> mild hypercalcaemia, reduced urine Ca2+
Familial hypocalciuric (/benign) hypercalcaemia (FHH / FBH)
Describe the 3 types of hypercalcaemia in malignancy
- Humoral hypercalcaemia of malignancy (eg small cell lung Ca) –> PTHrP
- Bone metastases (eg breast Ca) –> Local bone osteolysis
- Haematological malignancy (eg myeloma) –> cytokines
Describe how each of the following non-PTH driven hypercalcaemias happen:
- sarcoidosis
- thyrotoxicosis
- hypoadrenalism
- thiazide diuretics
- excess vitamin D
Sarcoidosis (non-renal 1α hydroxylation)
Thyrotoxicosis (thyroxine -> bone resorption)
Hypoadrenalism (renal Ca2+ transport)
Thiazide diuretics (renal Ca2+ transport)
Excess vitamin D (excess absorption from gut, reabsorption from kidneys)
Treatment of hypercalcaemia
Acute management
- Fluids+++ (NORMAL SALINE)
- Bisphosphonates (if cause known to be cancer) otherwise avoid.
- bisphosphonates take days to work so you want to GIVE FLUIDS!
Treat underlying cause
Clinical signs of hypocalcaemia
neuromuscular excitability:
- Trousseau’s sign - pressure cuff
- Hyperreflexia
- Convulsions
- Chvostek’s sign - cheek tap
- laryngeal spasm (stridor)
- choked optic disc
Explain how trousseau’s sign happens and what it indicates
Trousseau’s sign – check BP. The albumin in the arm rises because it is squeezing so then the calcium sticks more to the albumin. If its low already and it falls a bit more, you will get the flexion.
- hypocalcaemia
What is the first thing to look for when Ca2+ is low?
- Is it a genuine result? repeat bloods and adjust for albumin
- PTH levels
What are the causes of hypocalcaemia?
PTH high (non-PTH driven):
- Vitamin D deficiency
- CKD (1a hydroxylation)
- PTH resistance (pseudohypoparathyroidism)
raised PTH - secondary hyperparathyroidism
–> can progress to tertiary hyperparathyroidism
PTH low (PTH driven):
- Surgical - post-thyroidectomy
- autoimmune hypoparathyroidism
- Congenital absence of parathyroid (DiGeorge Syndrome)
- Mg deficiency
What is Paget’s disease? Which bones are commonly affected?
Focal disorder of bone remodelling
Pelvis, femur, skull and tibia
What are the clinical features of Paget’s disease?
Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure
What is the biochemistry of Paget’s?
ELEVATED ALKALINE PHOSPHATASE
How to test for Paget’s and how to treat it
Nuclear medicine scan or Xray
treatment - bisphosphonates for pain
Which has the lowest calcium?
A) Primary hyperparathyroidism
B) Secondary hyperparathyroidism
C) Osteoporosis
D) Paget’s disease of the bone
E) Breast cancer
B
