ChemPath: Calcium Metabolism Flashcards
Review calcium metabolism and homeostasis, recognising the importance of a fixed calcium level on nerve and muscle function. Common calcium disorders Hypercalcaemia Hypocalcaemia Common metabolic bone disorders Osteporosis Osteomalacia / Rickets Pagets To understand the effects of vitamin D and PTH Renal stones
What percent of calcium in the body is stored in bones?
99%
What percent of calcium is stored in serum?
1%
What are the three forms of serum Calcium?
- Free (“ionised”) ~50% - biologically active
- Protein-bound ~40% - albumin
- Complexed ~10% - citrate / phosphate
What is the normal range of total calcium serum?
2.2 - 2.6 mmol/L
How is corrected Calcium calculated?
serum calcium + 0.02 * (40 – serum albumin in g/L)
Why is control of serum calcium levels so important?
Calcium levels important in muscle depolarisation and thus in the control of nerve and muscle
If you have a low albumin, the bound calcium will be ____, but the free calcium will be _____. Thus the corrected calcium tells you that the problem is with the ______ and that the ionised calcium will also be ______.
If you have a low albumin, the bound calcium will be low, but the free calcium will be normal. Thus the corrected calcium tells you that the problem is with the albumin and that the ionised calcium will also be normal.
How are circulating calcium levels maintained?
Plasma concentration of calcium must be maintained despite calcium and vitamin D deficiency.
Chronic calcium deficiency thus results in loss of calcium from bone in order to maintain circulating calcium.
Describe briefly calcium homeostasis in response to decreased Calcium?
Hypocalcaemia is detected by parathyroid gland.
Parathyroid gland releases PTH.
PTH “obtains” Calcium from 3 sources: Bone, Gut (absorption), Kidney (resorption and renal 1 alpha hydroxylase activation)
What are the main roles of PTH?
- Stimulate osteoclasts to release Ca from bone
- Stimulate renal Ca resorption
- Stimulates 1,25 (OH)2 Vit D synthesis (1alpha-hydroxylation)
- Stimulates renal phosphate wasting (Phosphate trashing hormone)
What enzyme does PTH activate in the kidney?
1alpha-hydroxylase
Describe Vitamin D synthesis.
- 7-dehydrocholesterol is converted into cholecalciferol (D3) by UV light.
- Cholecalciferol (D3) is converted into 25-hydroxycholecalciferol (25-OH D3) by 25-hydroxylase in the liver.
- 25-hydoxycholecalciferol (25-OH D3) is converted by 1,25-dihydroxycholecalciferol (1,25-(OH)2 D3) by 1alpha-hydroxylase in the kidney.
- 1,25(OH)2 D3 is the physiologically active form of Vitamin D
What inactive form is Vit D stored in the body as?
25-hydroxycholecalciferol
What is the physiologically active form of Vit D?
1,25-dihydroxycholecalciferol
Which of these is a plant product?
A. Ergocalciferol (D2)
B. Cholecalciferol (D3)
A. Ergocalciferol (D2)
What percent of any absorbed Vit D is hydroxylated at the 25 position in the liver?
100%
What enzyme in the liver hydroxylases Vit D at the 25 position?
25-hydroxylase
What is the rate limiting step in Vit D activation?
1-alpha hydroxylase in the kidney. This enzyme is activated by PTH only when calcium is needed.
Where may 1-alpha hydroxylase sometimes be expressed pathologically?
Rarely, it can be expressed in lung cells of sarcoid tissue.
With sarcoidosis, there are macrophages in the lung that may express this enzyme in a non-regulated fashion. This may cause hypercalcaemia but only during the summer time when Vit D levels are increased.
What are the main roles of 1,25 (OH)2 D3?
- Intestinal Ca absoprtion
- Intestinal Pi absorption (but increase Pi excretion in kidneys)
- Critical for bone formation
Other:
- Vit D receptor controls many genes eg for cell proliferation, immune system etc
- Vit D deficiency associated with cancer, autoimmune disease, metabolic syndrome
What other conditions are Vit D deficiency associated with?
Poverty, Cancer, TB, Infectious diseases
What effect does PTH have on the bone?
PTH activates osteoclasts to release calcium from the bone. It causes resorption of calcium and phosphate stimulated by PTH.
In response to osteoclast activation, osteoblasts try and build up the bone and pull calcium and phosphate back. Osteoblast activation causes release of ALP.
In the presence of sky high ALP but normal ALT and AST, what pathology does this suggest?
Bone disease rather than liver disease
What is the role of the skeleton from an orthopaedic viewpoint?
Structural framework (strong, relatively lightweight, mobile) Protects vital organs Capable of orderly growth and remodelling
What is the role of the skeleton from a metabolic view point?
Metabolic role in calcium homeostasis
Main reservoir of calcium, phosphate and magnesium
What does Vit D deficiency cause in adults and children?
Osteomalacia and Rickets
What are the risk factors for vitamin D deficiency?
Lack of sunlight exposure
Dark skin
Dietary
Malabsorption
Why does chappati consumption increase vit D deficiency?
Phytic acid
(This chelates vit D in gut and prevents absorption, contributing to the vit D deficiency)
What are lifestyle treatments for osteoporosis?
- Weight-bearing exercise
- Stop smoking
- Reduce EtOH
Is the bone structure in osteomalacia normal or abnormal?
Abnormal. Vit D deficiency causes defective bone mineralisation.
What are the clinical features of Osteomalacia?
- Bone and muscle pain
- Increased fracture risk
- Looser’s Zones (pseudofractures)
What are the clinical features of Rickets?
- Bowed legs
- Costochondral swelling
- Widened epiphyses at the wrists
- Myopathy
What is the biochemistry of Osteomalacia?
Low Calcium
Low Phosphate
Raised ALP (due to osteoblasts trying to build up the bone)
What type of drug may induce breakdown of Vit D?
Anticonvulsants
What hormone does the placenta make that plays an important role in calcium metabolism in babies?
PTHrp
Is calcium high, normal or low in secondary hyperparathyroidism?
Calcium must be low to stimulate PTH
Is bone structure normal or abnormal in osteoporosis?
Normal
Osteoporosis has _____ loss but with _____ calcium. It is due to a reduction in bone ____ with ____ mineralisation.
Osteoporosis has bone loss but with normal calcium. It is due to a reduction in bone density with normal mineralisation.
What are major causes of Osteoporosis?
Old age
Lack of oestrogen
Immobilisation
Too many steroids (Cushing’s)
Hyperthyroidism
What is the biochemistry of osteoporosis?
Normal
What T score is used to define osteoporosis and osteopenia?
Osteoporosis: T-score < -2.5
Osteopaenia: T-score -1 to -2.5
What are the typical fractures seen in osteoporosis?
Neck of femur
Vertebral (kyphosis)
Wrist - Colle’s fracture
How is osteoporosis diagnosed?
DEXA scan (dual energy X-ray absorptiometry)
- hip (femoral neck etc) & lumbar spine
- T-score – sd from mean of young healthy population (useful to determine risk)
- Z-score – sd from mean of age and gender-matched control (useful to identify accelerated bone loss in younger patients)
What are lifestyle, endocrine, drugs and other causes of Osteoporosis?
- Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional
- Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
- Drugs: steroids
- Others eg genetic, prolonged intercurrent illness
What are drug treatments for osteoporosis?
- Vitamin D/Ca
- Bisphosphonates (eg alendronate) –↓ bone resorption
- Teriparatide (PTH derivative) – anabolic
- Strontium – anabolic + anti-resorptive
- (Oestrogens – HRT)
- SERMs eg raloxifene
What is the calcium level in Paget’s disease?
Normal because even though turnover is high the balance of calcium is normal
ALP will be high
Recall the symptoms of Paget’s disease
PAIN, warmth, deformity, fracture, increased risk of high output cardiac failure
Which bones are most commonly affected by Paget’s?
Pelvis, femur, skull and tibia
What is the gold standard investigation for diagnosing Paget’s disease?
IV radiolabelled bisphosphonates
How is pain treated in Paget’s disease?
Bisphosphonates
