Calcium Homeostasis and Disorders of Calcium Metabolism Flashcards
Movement of calcium in the body?
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
Factors that affect calcium homeostasis?
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
Effects of PTH?
- Ca2+ release from bone
- Absorption from the gut
These both result in increased serum calcium
Regulation of PTH release?
Calcium binds to CaSR on the parathyroid gland, which STOPS PTH release and all of its effects
Physiology of vitamin D?
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
Acute symptoms of hypercalcaemia?
- Thirst, dehydration and polyuria (as hypercalcaemia can induce nephrogenic diabetes mellitus)
- Confusion
Chronic symptoms of hypercalcaemia?
- Proximal myopathy
- Osteopaenia and fractures
- Depression
- Hypertension
- Abdominal pain (due to pancreatitis, ulcers and renal stones)
Phrase to remember symptoms of hypercalcaemia?
“Stones, groans, bones and psychic moans”
Single test requires to assess calcium state?
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)
Algorithm for hypercalcaemic Ix and diagnoses?
Ix for bone pathology (following a result of suppressed PTH and high phosphate)?
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)
2 main causes of hypercalcaemia?
- Primary hyperparathyroidism
- Malignancy
Other causes of hypercalcaemia?
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
What is FHH?
FH (autosomal dominant) of hypercalcaemia, typically assoc. with loss of function mutations in the CaSR (calcium sensing receptor)
Ix and result with PRIMARY hyperparathyroidism?
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)
Mechanisms by which malignancy causes hypercalcaemia?
- Metastatic bone destruction
- PTHrp (PTH related protein) from solid tumours, which acts like PTH
- Osteoclast activating factors
Ix and results with hypercalcaemia due to malignancy?
Raised Ca2+ and alkaline phosphatase
X-ray, CT, MRI
Isotope bone scan
Acute treatment of hypercalcaemia?
FLUIDS (0.9% saline) - rehydrate with 4-6 l in 24 hours
Once rehydrated, consider loop diuretics (avoid thiazides)
Acute treatment of hypercalcaemia?
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
Use of bisphosphonates to lower Ca2+?
A single dose lowers Ca2+ over 2-3 days
Maximum effect is at 1 week
Sestamibi scan?
Shows thyroid and parathyroid uptake, e.g: a pinhole appearance may indicate a parathyroid adenoma (which is benign)
Mx of primary hyperparathyoidism?
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
Indications for parathyroidectomy?
End-organ damage:
- Bone disease
- Gastric ulcers
- Renal stones
- Osteoporosis
Very high Ca2+ (>2.85 mmol/l)
<50 years old
eGFR <60 ml/min
Types of end-organ complications of bone?
Osteitis Fibrosa et cystica (AKA brown tumours / pepper pot skull appearance on X-ray)
What are primary, seconary and tertiary hyperparathyroidism?
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
Ix results in primary, secondary and tertiary hyperparathyroidism?
Primary:
- PTH raised
- Ca2+ raised
Secondary:
- Ca2+ low
- PTH raised
Tertiary:
- Ca2+ raised
- PTH raised
Genetic syndromes that are assoc. with hyper hypercalcaemia?
MEN1/2 - have a parathyroid adenoma (consider if the patient is young)
FHPT (familial hyperparathyroidism) - this is not the same as FHH
Symptoms of FHH?
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)
Ix results with FHH?
Mild hypercalcaemia
Reduced urine calcium excretion (IF THIS IS THE CASE, WITH NO/FEW SYMPTOMS, THINK FHH)
PTH may be marginally elevated Genetic screening
Symptoms of HYPOcalcaemia?
Paraesthesia (esp. in the fingers, toes and perianal region)
Muscle weakness, cramps and tetany
Fatigue
Bronchospasm or laryngospasm
Fits
Signs of HYPOcalcaemia?
Chovsteks sign (tapping over the facial nerve)
Trousseau sign (capopedal spasm)
Ix and results for hypocalcaemia?
ECG shows QT prolongation (can be fatal if untreated)
3 main causes of hypocalcaemia?
- Hypoparathyroidism
- Vitamin D deficiency:
- Osteomalacia
- Rickets
- Chronic renal failure
Other causes of hypocalcaemia?
- Pancreatitis
- Hyperventilation
- Osteoblastic bone metastases
- Rhabdomyolysis
Treatment of acute hypocalcaemia?
EMERGENCY IV calcium gluconate - 10ml, 10% over 10 minutes (in 50ml saline/dextrose
Infusion - 10ml, 10% in 100ml infusate at 50ml/hour
Causes of hypoparathyroidism?
Congenital absence, e.g: in DiGeorge syndrome
Destruction, due to e.g: surgery, radiotherapy or malignancy
Autoimmune
Hypomagnesaemia
Idiopathic
Long-term Mx of hypocalcaemia?
Ca2+ supplementation:
• >1-2 g per day
Vitamin D:
- Tablets - 1α-calcidol (0.5-1 mcg)
- Depot injection - cholecalciferol (300,000 units 6 monthly)
Consqeuences of hypomagnesaema, in terms of calcium?
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
Treatment of hypomagnesaemia, that is causing hypocalacemia?
If low, replace with Ca2+ and Mg
Causes of hypomagnesaemia?
Alcohol
Drugs:
- Thiazide
- PPI
GI illness
Pancreatitis
Malabsorption
What is pseudohypoparathyroidism?
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
Consequences of pseudohypoparathyroidism?
There is a specific phenotype that has been described (Albright’s hereditary osteodystrophy):
- Bone abnormalities
- Obesity
- Subcutaneous calcification
- Learning disability
- Brachdactyly (shortened 4th metacarpal)
What is pseudo-pseudohypoparathyroidism?
Same as Albright’s but the CALCIUM is NORMAL
Note: patients can shift change from pseudo to pseudo-pseudo
Causes of rickets and osteomalacia?
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
X-ray appearance of Rickets and osteomalacia?
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
Clinical presentation of osteomalacia?
Proximal myopathy and muscle wasting
Dental defects (caries, enamel)
Bone tenderness, fractures, rib and limb deformity
What is Vitamin D resistant rickets?
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
Treatment of vitamin D resistant rickets?
Phosphate and vitamin D supplementation (1,25 - OH vitamin D3)
+/-
Surgery
Consequences of chronic renal disease?
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)
Treatment of chronic renal disease?
Titrate treatment to PTH levels and do not forget phosphate binders
Typical Ix results with osteomalacia?
Low Ca2+ and high PTH
Low phosphate
High alkaline phosphatase
Low vitamin D (25-OH)
Long-term effects of vitamin D deficiency?
Bone demineralisation and fractures
Osteomalacia/rickets
Malignancy (esp. of the colon)
Heart disease
Diabetes,
Chronic treatment of vitamin D deficiency?
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
Summary of the biochemistry of each condition?
