ChemPath - Calcium handling and metabolism Flashcards
What are the forms of calcium in the body
bone - 99%
Blood/serum - 1%
Free/ionised (50%) - biologically active (important for nerves)
Protein-bound (40%) - bound to albumin
Complexe (10%) - citrate/phosphate
What us calcium needed for
Nerve function
Muscle function
Bone formation and maintenance
What is corrected calcium and how is it calculated
corrected calcium = serum Ca + 0.02(40-serum albumin)
When albumin conc. falls, the calcium is released and so the free calcium level remains the same despite an appearance of low calcium. If albumin is abnormal, this means that the Ca appears abnormal, but the corrected calcium would be NORMAL.
If corrected calcium is still abnormal - problem is not albumin
What is the role of PTH
84aa protein released from the thyroid
- Bone resorption for Ca release (osteoclast stimulation)
- Renal resorption of Ca + phosphate excretion
- Renal 1 a-hydroxylase activation (vit D synthesis)
- Intestinal Ca absorption
Describe the vitamin D’s role in calcium homeostasis
- 7-dehydrocholesterol in the skin is converted to cholecalciferol/vitamin D3 on exposure to UVB light
- Vitamin D from UVB (D3) or the diet (D2) is converted to 25-OH-D3 in the liver via 25 hydroxylase
- Renal 1 𝛼-hydroxylase is stimulated by PTH
- Renal 1 𝛼-hydroxylase converts 25-OH-D3 to calcitriol/1,25(OH)2D3
- Increased Ca reabsorption in the kidney and gut. Increased bone calcium maintenance
- -ve feedback on PTH
What is the difference between ergocalciferol and cholecalciferol
ergo = vit D2, chole = vit D3
Vit D2 - plant product (therefore vegan), Sourced from the diet
vit D3 - synthesised in the skin
Both are active, there is the difference of a double bond between them
What is the role of calcitriol (1,25 dihydroxy-vitamin D)
Active form of vit D
1. Intestinal Ca AND phosphate absorption
2. Renal Ca absorption
3. Bone Ca maintenance
Why might people with sarcoidosis get hypercalcaemia
1-alpha hydroxylase can be expressed unregulated in lung cells of sarcoid tissue → increases renal and intestinal abs. of Ca
Give examples of metabolic bone disease
Osteoporosis (bone normal but weak)
Osteomalacia (vit D deficiency)
Paget’s disease
Parathyroid bone disease
Renal osteodyrstophy
Describe vit D deficiency (what it causes), adults v children, % prevalence)
Defective bone mineralisation
Children - ricketts
Adults - osteomalacia
> 50% of adults have insufficient vit D, and 16% have severe deficiency in Winter and Spring
What are the risk factors for vit D deficiency
Lack of sunlight exposure
Dark skin
Dietary
Malabsorption
Pregnancy
breastfeeding from a mother with vit D deficiency
What are the causes of osteomalacia
Vitamin D deficiency
Renal failure
Anticonvulsants e.g. phenytoin (induces breakdown of active vit D)
Lack of sunlight
Phytic acid (found in Chappati flour)
What are the clinical features of osteomalacia and ricketts
Ricketts
* Bowed legs
* Costochondral swelling (lumps on the chest)
* Widened epiphyses at the wrists
* Myopathy (waddling gait)
Low calcium and phosphate
Osteomalacia
* Bone & muscle pain
* Increased fracture risk
* Looser’s zones (Pseudofractures that will not break until under pressure/trauma)
What are the biochemical features of osteomalacia and Ricketts
High PTH
Low calcium and phosphate
Raised ALP
Describe osteoporosis
Loss of bone mass, while the residual bone structure remains NORMAL
What are the causes of osteoporosis
Lifestyle: Immobility/sedentary, smoking, EtOH, low BMI
Lack of oestrogen (e.g. menopause, anorexia nervosa)
Hyperthyroidism / thyrotoxicosis
Cushing’s syndrome or steroid use
Hyperprolactinaemia (inhibits FSH/LH/Oe)
Failure to attain peak bone mass due to childhood illness or early menopause increases risk of EARLIER fracture
What are the clinical features of osteoporosis
Initial: fracture
- Neck of femur (NOF)
- vertebral
- Wrist (colle’s)
Otherwise asymptomatic
What are the diagnostic markers of osteoporosis
NORMAL biochemistry
Dual energy x-ray absorptiometry (DEXA) of femoral neck and lumbar spine
Bone mineral density >2.5 SDs below the average value for a young health adult (T-score <-2.5)
Osteopenia = -2.5 < T-score < -1
What is the management of osteoporosis
Lifestyle:
- Weight-bearing exercise
- Stop smoking, reduced EtOH
Pharm:
- Vit D/Ca supplements
- Bisphophonates e.g. alendronate
- Teriparatide
- Oestrogens (HRT)
- Selective oestrogen receptor modulators (SERMs) e.g. raloxifene, tamoxifen)
What are the MOAs and SEs for bisphosphonates and SERMs
bisphosphonates e.g. alendronate
Decreases bone resorption as it is much stronger and osteoclasts cannot turnover as quickly
BUT is highly irritative to the stomach
BUT they also bind calcium at the same time - so if taken with milk it would not be absorbed and be inactivated
Taken once a week with plenty of water and nothing else
IV zolendronate is becoming popular as it is only given once a year
SERMs
Tamoxifen - oestrogen antagonist for the breast (so does not increase breast Ca risk) and SERM for bone
BUT Worsens the symptoms of menopause
What are the symptoms of hypercalcaemia
Polyuria/polydipsia (osmotic diuretic effect) + dehydration
Constipation (slows nerves/muscles)
Calcium >3.0mmol/L: Neuro - confusion/seizures/coma
What are the causes of hypercalcaemia
PTH suppressed
- Malignancy
- Sarcoidosis
- vit D excess
- Thyrotoxicosis
- Thiazide diuretics
- Hypoadrenalism
- milk alkali syndrome (excess of Rennie sweet consumption)
PTH not suppressed
- Primary hyperparathyroidism (most common community cause of hyperCa)
- Familial hypocalciuric hypercalcaemia
What are the causes of primary hyperparathyroidism
Parathyroid adenoma (80%)
Parathyroid hyperplasia
Parathyroid carcinoma (0/%)
MEN1 (adenoma) MEN2 (hyperplasia)
What are the clinical features of primary hyperparathyroidism
BONES - PTH bone disease/pain, observe the wrist for Colle’s fractures
STONES - renal calculi
MOANS - abdominal pain due to constipation and pancreatitis
GROANS - psychiatric disturbance e.g. confusion
THRONES - polyuria
i.e. fractured bone, kidney stone, abdominal pain, confusion
What are the biochemical markers of primary hyperparathyroidism
Calcium - raised
PTH - raised or inappropriately normal
Phosphate - low
urine calcium - high
Describe familial benign/hypocalciuric hypercalcaemia (FBH/FHH)
Mutation in CaSR which usually detects the level of Ca for the parathyroid gland
This increases the set point for PTH release → mild hypercalcaemia
Benign condition - do not form kidney stones + reduced urine calcium
Gland removal will not cure it - surgery not required
What are the causes of Hypercalcaemia of malignancy
- Humoral e.g. sq lung cancer releasing PTHrp → dissolves bone
- Bone mets e.g. breast cancer causing local bone osteolysis (most common)
- Haem. malignancy e.g. myeloma
How is hypercalcaemia managed
- Fluid resus (pt will be dehydrated)
- 0.9% saline 1L over the first 1-2 h
- re-measure → 4-6L over 24h - Bisphosphonates if the cause is known to be cancer
- Treat underlying cause e.g. surgery
What are the causes of hypocalcaemia
PTH driven (low PTH)
Surgical e.g. post thyroidectomy
Auto-immune hypoparathyroidism
Congenital absence of parathyroids e.g. DiGeorge syndrome
Mg deficiency (PTH regulation)
non-PTH driven
vitamin D deficiency - dietary, malabsorption, lack of sunlight
CKD (1a-hydroxylase not produced → reduced Ca resorption → hypoCa → PTH stimulated → secondary hyperPTH → hyperCa → tertiary hyperPTH )
PTH resistance (pseudohypoparathyroidism)
What are the clinical features of hypocalcaemia
Neuro-muscular excitability
- Chvosteks sign (fascial nerve excitability, twitching of facial muscles in response to tapping over the facial nerve – 29% sensitive)
- Trousseaus sign (carpopedal spasm induced by pressure - latent tetany – 94% sensitive)
- Hyperreflexia
- Convulsions
- Laryngeal spasm → stridor
- Choked optic disk
- Prolonged QT
- Peri-oral paraesthesia
What is Paget’s disease and what are the clinical features
Focal disorder of bone remodelling
Features:
- Focal pain
- Warmth and tenderness over bone
- Deformity e.g. bowing of tibia, skull enlargement, deafness (CNVIII involvement), kyphosis
- Fracture e.g. fissure fracture
- Malignancy
- Cardiac failure
What are the diagnostic features of Paget’s disease of the bone
ALP: raised
Calcium: normal
Phosphate normal
PTH: normal
Diagnosis is made via X-ray or nuclear medicine scan
Pelvis, femur, skull, and tibia commonly affected
What is renal osteodystrophy
All skeletal changes resulting from chronic renal disease (osteitis fibrosa cytica, osteomalacia, osteosclerosis, growth retardation, osteoporosis)
Secondary hyperparathyroidism and retention of aluminium from dialysis fluid
Calcium: low
Phosphate: high
PTH: high (response to Ca)
ALP: high
What is osteitis fibrosa cystica and what are the characteristic features
Hyperparathyroid bone disease due to hypocalcaemia reducing bone mineralisation and increasing resorption
Shows subperiosteal erosions and brown tumours
What is the difference between T-score and Z-score for osteoporosis DEXA scans
○ T-score sd from mean of young healthy population, useful to determine fracture risk
Z-score sd from mean of aged-matched control, useful to identify accelerated bone loss in younger patients
What are the levels of the following markers for each of these diseases: Calcium, phosphate, PTH, vit D, ALP
Osteoporosis
Osteomalacia/ricketts
Paget’s
Parathyroid bone disease
Renal bone disease
Osteoporosis: Everything normal
Osteomalacia/ricketts: Ca low, Pho PTH high, vit D low, ALP high
Paget’s: ALP high, everything else normal
Parathyroid bone disease: Ca high, Pho low, PTH high, vit D N, ALP N
Renal bone disease: Ca low, Pho high, PTH high, vit D N/low, ALP high
What are the causes of secondary hyperparathyroidism
CKD (renal osteodystrophy)
Vitamin D deficiency
Malabsorption syndromes
What are the causes of tertiary hyperparathyroidism
Prolonged 2° hyperparathyroidism causing unregulated secretion of PTH
Kidney transplant
Describe the clinical steps to understand the cause of hypercalcaemia
- Albumin measurement
Albumin low → measure urea
- Urea low: cuffed specimen
- Urea high: dehydration
Albumin high → measure phosphate
- Phosphate low: primary or tertiary hyperPTH
Phosphate high → measure ALP
ALP normal: myeloma, vit D excess, Sarcoidosis, milk alkali syndrome
ALP high: Bone mets, thyrotoxicosis, sarcoidosis
What is the management for hypocalcaemia
symptomatic, Ca <1.875 → 10% Calcium gluconate IV
Asymptomatic, mild → oral supplementation e.g. SandoCal
Low vit D → vit D supplementation with alfacalcidol (CKD) or vit D2/D3
What are the hypocalcaemia differentiated by phosphate
HIGH PHOSPHATE
CKD
Hypoparathyroidism
Pseudohypoparathryoidism
Hypomagnesaemia
LOW PHOSPHATE
Osteomalacia
Acute pancreatitis
Overhydration
Respiratory alkalosis
What are the risk factors for renal stones
Dehydration
Abnormal urine pH e.g. meat intake, renal tubular acidosis
Increased stone constituents excretion
Urine infection
What are the causes of calcium stones
(most patients normocalcaemic)
Hyperoxaluria (increased intake, absorption etc)
Hypercalciuria (increased intake, renal leak)
What is the management (+investigations) for renal stones
- Urgent CT (US for pregnancy, children, young people)
- IM Diclofenac (analgesia)
- Stones ≤5mm in diameter: Conservative management
- Stones 6-20mm: Lithotripsy/Ureteroscopy
- Stones >20mm: Percutaneous Nephrolithotomy
What is the appearance of the different type of renal stone on X-ray
Calcium mixed (most common): radio-opaque
Calcium oxalate: radio-opaque
Calcium phosphate: radio-opaque
Triple phosphate “Struvite”: Radio-opaque “Staghorn”
Uric acid: radiolucent
Cysteine: radio-opaque (light)
