Calcium Homeostasis and Disorders of Calcium Metabolism

Question 1

Movement of calcium in the body?

Answer 1

Calcium is absorbed from the gut (Vitamin D is essential for this) into the blood and shuttles between here and bone

Some calcium is excreted via the kidneys

Question 2

Factors that affect calcium homeostasis?

Answer 2

Diet

Gut absorption, which is affected by:

• Age
• Hormones (pregnancy/lactation)
• Bowel pathology

PTH, which is affected by:

• Hyper/hypoparathyroidism
• Malignant hypercalcaemia (PTHrP)

Vitamin D, which is affected by:

• Diet and absorption
• Renal and liver status
• UVB exposure
• Drugs

Question 3

Effects of PTH?

Answer 3

• Ca2+ release from bone
• Absorption from the gut

These both result in increased serum calcium

Question 4

Regulation of PTH release?

Answer 4

Calcium binds to CaSR on the parathyroid gland, which STOPS PTH release and all of its effects

Question 5

Physiology of vitamin D?

Answer 5

Dehydro-cholesterol (in the skin) is converted, by the sun, into:

• Cholecalciferol (D3) then to
• 25 (OH) vitamin D (in the liver) then to
• 1,25 (OH) vitamin (in the kidneys)

1,25 (OH) vitamin D stimulates:

• PTH release
• Gut absorption
• Bone release of Ca2+
• Kidneys

Question 6

Acute symptoms of hypercalcaemia?

Answer 6

• Thirst, dehydration and polyuria (as hypercalcaemia can induce nephrogenic diabetes mellitus)
• Confusion

Question 7

Chronic symptoms of hypercalcaemia?

Answer 7

• Proximal myopathy
• Osteopaenia and fractures
• Depression
• Hypertension
• Abdominal pain (due to pancreatitis, ulcers and renal stones)

Question 8

Phrase to remember symptoms of hypercalcaemia?

Answer 8

“Stones, groans, bones and psychic moans”

Question 9

Single test requires to assess calcium state?

Answer 9

PTH:

• If normal/high - there is a problem with Ca2+ handling
• If low - there is a bone problem, usually malignancy

Can also check urinary Ca2+:

• If high, likely to be primary/tertiary hyperparathyroidism
• If low - FHH (as, if Ca2+ is high, it would normally be excreted in the urine)

Question 10

Algorithm for hypercalcaemic Ix and diagnoses?

Answer 10

Question 11

Ix for bone pathology (following a result of suppressed PTH and high phosphate)?

Answer 11

Alkaline phosphatase

If high:

• Bone metastases
• Sarcoidosis
• Thyrotoxicosis

If low:

• Myeloma
• Vitamin D excess
• Mild-alkali syndrome (due to, e.g: thyrotoxicosis, sarcoidosis, raised HCO-3)

Question 12

2 main causes of hypercalcaemia?

Answer 12

1. Primary hyperparathyroidism
2. Malignancy

Question 13

Other causes of hypercalcaemia?

Answer 13

Drugs:

• Vitamin D
• Thiazides (stop Ca2+ excretion)

Granulomatous disease, e.g:

• Sarcoidosis
• TB

Familial Hypocalciuric Hypercalcaemia (FHH)

High turnover, e.g:

• Bedridden
• Thyrotoxic
• Paget’s disease

Tertiary hyperparathyroidism

Question 14

What is FHH?

Answer 14

FH (autosomal dominant) of hypercalcaemia, typically assoc. with loss of function mutations in the CaSR (calcium sensing receptor)

Question 15

Ix and result with PRIMARY hyperparathyroidism?

Answer 15

Class triad of:

• Raised serum Ca2+
• Raised serum PTH (or inappropriately normal)
• Increased urine calcium excretion (for this to be accurate, the patient must have correct Vitamin D levels)

Question 16

Mechanisms by which malignancy causes hypercalcaemia?

Answer 16

1. Metastatic bone destruction
2. PTHrp (PTH related protein) from solid tumours, which acts like PTH
3. Osteoclast activating factors

Question 17

Ix and results with hypercalcaemia due to malignancy?

Answer 17

Raised Ca2+ and alkaline phosphatase

X-ray, CT, MRI

Isotope bone scan

Question 18

Acute treatment of hypercalcaemia?

Answer 18

FLUIDS (0.9% saline) - rehydrate with 4-6 l in 24 hours

Once rehydrated, consider loop diuretics (avoid thiazides)

Question 19

Acute treatment of hypercalcaemia?

Answer 19

FLUIDS (0.9% saline) - rehydrate with 4-6 l in 24 hours

Once rehydrated, consider loop diuretics (avoid thiazides)

Bisphosphonates

For sarcoidosis, steroids are used (Prednisolone 40-60 mg/day for)

Salmon calcitonin is rarely used

Chemotherapy, for malignancy, may reduce calcium, e.g: myeloma

Question 20

Use of bisphosphonates to lower Ca2+?

Answer 20

A single dose lowers Ca2+ over 2-3 days

Maximum effect is at 1 week

Question 21

Sestamibi scan?

Answer 21

Shows thyroid and parathyroid uptake, e.g: a pinhole appearance may indicate a parathyroid adenoma (which is benign)

Question 22

Mx of primary hyperparathyoidism?

Answer 22

SURGERY OR NOTHING (surgery is not always required)

Diet and drugs show no proven benefit; however, drinking plenty of fluids reduces risk of renal stones

Cinacalcet is a Ca2+ mimic, so it reduced PTH, and is used in:

• Tertiary hyperparathyroidism
• Parathyroid carcinoma

Question 23

Indications for parathyroidectomy?

Answer 23

End-organ damage:

• Bone disease
• Gastric ulcers
• Renal stones
• Osteoporosis

Very high Ca2+ (>2.85 mmol/l)

<50 years old

eGFR <60 ml/min

Question 24

Types of end-organ complications of bone?

Answer 24

Osteitis Fibrosa et cystica (AKA brown tumours / pepper pot skull appearance on X-ray)

Question 25

What are primary, seconary and tertiary hyperparathyroidism?

Answer 25

Primary: • Primary over-activity of the parathyroid, e.g: with an adenoma Secondary: • Physiological response to low Ca2+ Tertiary: • Parathyroid becomes autonomous after many years of secondary hyperparathyroidism

Question 26

Ix results in primary, secondary and tertiary hyperparathyroidism?

Answer 26

Primary: * PTH raised * Ca2+ raised Secondary: * Ca2+ low * PTH raised Tertiary: * Ca2+ raised * PTH raised

Question 27

Genetic syndromes that are assoc. with hyper hypercalcaemia?

Answer 27

MEN1/2 - have a parathyroid adenoma (consider if the patient is young) FHPT (familial hyperparathyroidism) - this is not the same as FHH

Question 28

Symptoms of FHH?

Answer 28

Usually benign or asymptomatic and tends to be an incidental finding (in which case, the urine Ca2+ excretion must be checked and, if FHH, it will be low)

Question 29

Ix results with FHH?

Answer 29

Mild hypercalcaemia Reduced urine calcium excretion (IF THIS IS THE CASE, WITH NO/FEW SYMPTOMS, THINK FHH) PTH may be marginally elevated Genetic screening

Question 30

Symptoms of HYPOcalcaemia?

Answer 30

Paraesthesia (esp. in the fingers, toes and perianal region) Muscle weakness, cramps and tetany Fatigue Bronchospasm or laryngospasm Fits

Question 31

Signs of HYPOcalcaemia?

Answer 31

Chovsteks sign (tapping over the facial nerve) Trousseau sign (capopedal spasm)

Question 32

Ix and results for hypocalcaemia?

Answer 32

ECG shows QT prolongation (can be fatal if untreated)

Question 33

3 main causes of hypocalcaemia?

Answer 33

1. Hypoparathyroidism 2. Vitamin D deficiency: * Osteomalacia * Rickets 3. Chronic renal failure

Question 34

Other causes of hypocalcaemia?

Answer 34

* Pancreatitis * Hyperventilation * Osteoblastic bone metastases * Rhabdomyolysis

Question 35

Treatment of acute hypocalcaemia?

Answer 35

EMERGENCY IV calcium gluconate - 10ml, 10% over 10 minutes (in 50ml saline/dextrose Infusion - 10ml, 10% in 100ml infusate at 50ml/hour

Question 36

Causes of hypoparathyroidism?

Answer 36

Congenital absence, e.g: in DiGeorge syndrome Destruction, due to e.g: surgery, radiotherapy or malignancy Autoimmune Hypomagnesaemia Idiopathic

Question 37

Long-term Mx of hypocalcaemia?

Answer 37

Ca2+ supplementation: • \>1-2 g per day Vitamin D: * Tablets - 1α-calcidol (0.5-1 mcg) * Depot injection - cholecalciferol (300,000 units 6 monthly)

Question 38

Consqeuences of hypomagnesaema, in terms of calcium?

Answer 38

Calcium release from cells is dependent on Mg; if deficient, intracellular Ca2+ is high, as there is less release PTH release is therefore inhibited (requires Ca2+ binding) Skeletal and muscle receptors become less sensitive to PTH

Question 39

Treatment of hypomagnesaemia, that is causing hypocalacemia?

Answer 39

If low, replace with Ca2+ and Mg

Question 40

Causes of hypomagnesaemia?

Answer 40

Alcohol Drugs: * Thiazide * PPI GI illness Pancreatitis Malabsorption

Question 41

What is pseudohypoparathyroidism?

Answer 41

GENETIC defect in GNAS1 causes dysfunction of the Gs protein α-subunit There is low calcium but PTH conc. is ELEVATED, this this PTH is less effective, due to resistance; the symptoms are the same as in hypoparathyroidism

Question 42

Consequences of pseudohypoparathyroidism?

Answer 42

There is a specific phenotype that has been described (Albright's hereditary osteodystrophy): * Bone abnormalities * Obesity * Subcutaneous calcification * Learning disability * Brachdactyly (shortened 4th metacarpal)

Question 43

What is pseudo-pseudohypoparathyroidism?

Answer 43

Same as Albright's but the CALCIUM is NORMAL Note: patients can shift change from pseudo to pseudo-pseudo

Question 44

Causes of rickets and osteomalacia?

Answer 44

Vitamin D deficiency due to: * Dietary deficiency * Malabsorption, e.g: form gastric surgery, coeliac disease, liver disease, pancreatic failure * Chronic renal failure * Lack of sunlight * Drugs, e.g: anti-convulsants

Question 45

X-ray appearance of Rickets and osteomalacia?

Answer 45

Bow-legged in children Looser zones - wide, transverse lucencies traversing part way through a bone, usually at right angles to the involved cortex; this is surrounded by a sclerotic area

Question 46

Clinical presentation of osteomalacia?

Answer 46

Proximal myopathy and muscle wasting Dental defects (caries, enamel) Bone tenderness, fractures, rib and limb deformity

Question 47

What is Vitamin D resistant rickets?

Answer 47

AKA X-linked hypophosphataemia; both genders can develop this but females develop a less severe form It is due to a PHEX or FGF23 mutation, which regulates phosphate levels in plasma and is secreted by osteocytes (in response to calcitriol), i.e: these people have a low phosphate and a high vitamin D It has the same phenotype as rickets but vitamin D does not help

Question 48

Treatment of vitamin D resistant rickets?

Answer 48

Phosphate and vitamin D supplementation (1,25 - OH vitamin D3) +/- Surgery

Question 49

Consequences of chronic renal disease?

Answer 49

Vitamin D deficiency and secondary hyperparathyroidism They may have high 25-OH vitamin D, as they cannot hydroxylate it into 1,25-OH vitamin D (this must be CHECKED)

Question 50

Treatment of chronic renal disease?

Answer 50

Titrate treatment to PTH levels and do not forget phosphate binders

Question 51

Typical Ix results with osteomalacia?

Answer 51

Low Ca2+ and high PTH Low phosphate High alkaline phosphatase Low vitamin D (25-OH)

Question 52

Long-term effects of vitamin D deficiency?

Answer 52

Bone demineralisation and fractures Osteomalacia/rickets Malignancy (esp. of the colon) Heart disease Diabetes,

Question 53

Chronic treatment of vitamin D deficiency?

Answer 53

Supplement vitamin D: * Vitamin D3 tablets (400-800 IU/day after loading with 3200 IU/day for 12 weeks) * Calcitriol (1,25-dihydroxycholecalciferol) * Alfacalcidol (1α - hydroxycholecalciferol) Combined calcium + vitamin D, e.g: Adcal D3

Question 54

Summary of the biochemistry of each condition?

Answer 54