1. Calcium handling and metabolic bones disease 27 th June 2016 Karim Meeran Chemical Pathology / Metabolic Medicine Please put in your CID now and for EVERY lecture

2. 5% of summative mark is ICA 1% per week for weeks 1 to 3 TBL this Friday (3 rd July) details later on There will be a “retake” on 17 th July for anyone who has authorised absence for any reason 2% for activities in week 4 including TBL, summative exam and path tutorial. Now put in non-Imperial e-mail address

3. Learning objectives 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

4. Calcium handling 1.Ca 2+ homeostasis 2.Hypercalcaemia 3.Hypocalcaemia

5. ECF Ca 2+ ICF 99% body calcium in skeleton Roles of calcium 1.Skeleton 2.Metabolic Action potentials IC signalling

6. Calcium in serum (1%) Serum Ca 2+ in 3 forms –Free (“ionised”) ~50% - biologically active –Protein-bound ~40% - albumin –Complexed ~10% - citrate / phosphate Total serum Ca 2+ 2.2 – 2.6 mmol/L “Adjusted” Ca 2+ usually reported –serum Ca 2+ – 0.02 * (40 – serum albumin in g/L) –Calcium levels important in muscle depolarisation and thus in the control of nerve and muscle Ionised Ca also measured

7. Circulating calcium Important for normal nerve and muscle function Plasma concentration must thus 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

8. Calcium homeostasis – response to ↓Ca Hypocalcaemia detected by parathyroid gland Parathyroid gland releases PTH PTH “obtains” Ca 2+ from 3 sources –Bone –Gut (absorption) –Kidney (resorption and renal 1 alpha hydroxylase activation)

9. Parathyroid hormone (PTH) –from parathyroid gland 1,25 (OH) 2 vit D –from kidney

10. ↑ ECF Ca 2+ ICF Vit D PTH Vit D Hormonal response to hypocalcaemia

11. Two key “hormones” involved in calcium homeostasis 1.PTH 2.Vitamin D (steroid hormone) cholesterol D3

12. CALCIUM HOMEOSTASIS Ca ++ PTH + - 1,25(OH)2D3 + +

13. PTH 84 aa protein Only released from parathyroids Roles –Bone & renal Ca 2+ resorption –Stimulates 1,25 (OH) 2 vit D synthesis (1α hydroxylation) –Also stimulates renal P i wasting

14. Vitamin D Synthesis 1,25 (OH) 2 D3 is the physiologically active form PTH +

15. Which of these is a plant product? A. Ergocalciferol B. Cholecalciferol

16. Synthesis of vitamin D Vitamin D3 is synthesised in the skin (cholecalciferol) Vitamin D2 is a plant vitamin (ergocalciferol) Both are active

17. Wikipedia: D3 and D2

18. Synthesis of vitamin D Next stage in the liver: 100% of any absorbed vitamin D is hydroxylated at the 25 position enzyme: 25 hydroxylase 25 hydroxy vitamin D is inactive This is the stored and measured form of vitamin D

19. Activation of vitamin D Normally happens in kidney enzyme: 1 alpha hydroxylase Rarely, this enzyme can be expressed in lung cells of sarcoid tissue

20. 1 hydroxylase 25 hydroxylase Where is this enzyme (25) found? (SAQ)

21. 1 hydroxylase 25 hydroxylase Where is this enzyme (1) found?

22. Roles of 1,25 (OH) 2 vitamin D Intestinal Ca 2+ absorption Also intestinal P i absorption Critical for bone formation (see later) ? Other physiological effects –Vit D receptor controls many genes eg for cell proliferation, immune system etc –Vit D deficiency associated with cancer, autoimmune disease, metabolic syndrome

23. Vitamin D (100% in liver) 25 hydroxyvitamin D (rate limiting in kidney under PTH control) 1, 25 dihydroxyvitamin D

24. Role of the skeleton (Orthopaedic view) Structural framework Strong Relatively lightweight Mobile Protects vital organs Capable of orderly growth and remodelling

25. Role of skeleton Metabolic role in calcium homeostasis Main reservoir of calcium, phosphate and magnesium

26. Metabolic bone disease biochemical / clinical aspects Osteoporosis Osteomalacia Paget’s disease Parathyroid bone disease Renal osteodystrophy

27. Vitamin D Deficiency Defective bone mineralisation Childhood -> Rickets Adulthood -> Osteomalacia Vitamin D deficiency in the UK –More than 50% adults have insufficient vitamin D –16% have severe deficiency during winter and spring Risk factors –Lack of sunlight exposure –Dark skin –Dietary –malabsorption

28. Clinical features of vit D deficiency Osteomalacia –Bone & muscle pain –  risk –Biochem – low Ca 2+ & P i, raised ALP –Looser’s zones (pseudo  s) Rickets –Bowed legs –Costochondral swelling –Widened epiphyses at the wrists –Myopathy

29. Osteomalacia Bone is demineralised Caused by vitamin D deficiency Renal failure Anticonvulsants induce breakdown of vitamin D Lack of sunlight Chappatis (phytic acid)

31. Osteoporosis Cause of pathological fracture Occurring more often as people live longer Loss of bone mass Bone slowly lost after age 20 Residual bone normal in structure

32. Osteoporosis by comparison has bone loss but with a normal calcium

33. Osteoporosis Reduction in bone density (normal mineralisation) Biochemistry NORMAL Asymptomatic until # (Fracture is the first symptom). Then it is too late… Typical # - neck of femur (NOF), vertebral, wrist (Colle’s)

34. Osteoporosis Diagnosis usually using 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 aged-matched control (useful to identify accelerated bone loss in younger patients) Osteoporosis – T-score <-2.5 Osteopenia – T-score between -1 & -2.5

36. Osteoporosis - causes Skeletal mass Age 20 50 menopause Age-related decline in bone mass  threshold

37. Osteoporosis - causes Childhood illness Skeletal mass Age 20 50 menopause Failure to Attain peak bone mass

38. Osteoporosis - causes Skeletal mass Age 20 50 menopause Early menopause

39. Osteoporosis - causes Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings Drugs: steroids Others eg genetic, prolonged intercurrent illness Skeletal mass Age 20 50 menopause More rapid bone loss during adulthood

40. Treatment 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) SERMs eg raloxifene

41. What is the first symptom of osteoporosis? Answer on mentimeter as text… What is the plasma calcium level in a patient with osteoporosis (MCQ)?

44. Hypercalcaemia

45. Hypercalcaemia - symptoms Polyuria / polydipsia Constipation Neuro – confusion / seizures / coma Unlikely unless Ca 2+ > 3.0 mmol/L Overlap with Sx of hyperPTH (see later)

46. ↓ ECF Ca 2+ ICF Vit D PTH Vit D Hormonal response to hypercalcaemia – PTH release should be suppressed Pathology in these hormonal axes or organ systems can prevent the normal response to hypercalcaemia

47. Hypercalcaemia - aetiology First question: –Is it a genuine result (repeat) Second question: –What is the PTH?

48. Causes of hypercalcaemia

49. Primary Hyperparathyroidism Commonest cause of hypercalcaemia Parathyroid adenoma / hyperplasia / carcinoma Hyperplasia associated with MEN1 Women > men ↑serum Ca, ↑ or inappropriately N PTH, ↓serum P i, urine ↑Ca (due to hypercalcaemia) BONES (PTH bone disease) and STONES (renal calculi) Hypercalcaemia -> abdominal MOANS (constipation, pancreatitis), psychiatric GROANS (confusion)

51. Calcium sensing receptor (CaSR) Parathyroids: regulates PTH release Renal: influences Ca 2+ resorption (PTH independent) Familial hypocalciuric (/benign) hypercalcaemia (FHH / FBH) –CaSR mutation –Higher “set point” for PTH release -> mild hypercalcaemia –Reduced urine Ca 2+ Normal FBH Inactivating Mutation causes R shift of curve PTH release [Ca 2+ ]

52. Causes of hypercalcaemia

53. Hypercalcaemia in malignancy – 3 “types” 1.Humoral hypercalcaemia of malignancy (eg small cell lung Ca) –PTHrP 2.Bone metastases (eg breast Ca) –Local bone osteolysis 3.Haematological malignancy (eg myeloma) –cytokines

54. Other causes of non-PTH driven hypercalcaemia Sarcoidosis (non-renal 1α hydroxylation) Thyrotoxicosis (thyroxine -> bone resorption) Hypoadrenalism (renal Ca 2+ transport) Thiazide diuretics (renal Ca 2+ transport) Excess vitamin D (eg sunbeds…)

55. Hypercalcaemia TREATMENT Acute management –Fluids+++ –Bisphosphonates (if cause known to be cancer) otherwise avoid. Treat underlying cause

56. Hypocalcaemia

57. Clinical Signs of Hypocalcaemia Neuro-muscular excitability Rx: Ca + vit D (usually “activated” ie 1α forms, except simple vit D deficiency)

58. Hypocalcaemia - aetiology First question: –Is it a genuine result Repeat & adjust for albumin Second question: –What is the PTH?

59. Hypocalcaemia *PTH will be raised – secondary hyperparathyroidism **can progress to tertiary hyperparathyroidism!

60. Paget’s Disease Focal disorder of bone remodeling Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure Pelvis, femur, skull and tibia Elevated alkaline phosphatase Nuclear med scan / XR Treatment = Bisphosphonates for pain

62. Single best answer Which has the lowest calcium? A.Primary hyperparathyroidism B.Secondary hyperparathyroidism C.Osteoporosis D.Pagets disease of the bone E.Breast cancer

63. Other metabolic bone disorders In primary hyperparathyroidism –Loss of cortical bone -> # risk –Osteitis fibrosa Renal osteodystrophy –Due to secondary hyperparathyroidism + retention of aluminium from dialysis fluid Both rare due to modern Rx of underlying disorders

64. Biochemistry in metabolic bone disease (and put in CID again)