Clincal Biochemistry: Calcium and phosphate metabolism Flashcards

1
Q

What things help control serum calcium and phopshate levels?

A
  • Bone turnover
  • Parathyroid hormone (PTH)
  • Vitamin D (1,25-dihydroxy D3)
  • Calcitonin
  • FGF-23
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2
Q

What is bone turnover?

A
  • Bone turnover is the process of resorption followed by replacement by new bone.
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3
Q

How is calcium distributed within the body?

A
  • 99% of body calcium is in bone
  • Most of remaining 1% is intracellular
  • <0.1% extracellular
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4
Q

Very briefly describe how calcium balance is maintained

A
  • Hormonal control of the tiny extracellular fraction is what maintains Calcium balance
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5
Q

What % of extracellular calcium is free and what % is potein-bound?

A
  • 50% is free [Ca2+] (physiologically active)
  • 50% protein bound (mainly to albumin)
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6
Q

How is phosphate distributed within the body?

A
  • 85% of body phosphorus is in bone
  • Remainder is mainly intracellular
  • <0.1% extracellular
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7
Q

What forms of phosphate mainly make up extracellular portion of it in the body?

A
  • Dihydrogen phsophate (H2PO4-)
  • Hydrogen phosphate (HPO42-)
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8
Q

What are the clinical features of hypercalcemia (high blood calcium)?

A
  • Depression, fatigue, anorexia, nausea, vomiting
  • Abdominal pain, constipation
  • Renal calcification (kidney stones)
  • Bone pain
  • Severe symptoms: cardiac arrhythmias, cardiac arrest
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9
Q

What saying can be used to help remeber the symptoms of hpercalcemia?

A
  • “Painful bones, renal stones, abdominal groans, and psychic moans”
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10
Q

What are some of the causes of hypercalcaemia?

A
  • Most common causes:
    • Primary hyperparathyroidism
    • In hospitalized patients: malignancy
  • Less common causes:
    • Hyperthyroidism
    • Excessive intake of vitamin D
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11
Q

Describe the serum biochemistry of someone suffering from hypercalcaemia

A
  • Serum calcium: Modest to large increase
  • Serum phosphate: Low or low normal - PTH increases renal reabsorption of calcium but also increases phosphate excretion
  • Serum alkaline phosphatase: Raised in 20% of cases
  • Serum creatinine: May be elevated in longstanding disease (kidney damage)
  • Serum PTH: Concentration should be interpreted in relation to calcium as PTH causes increase in serum calcium.
    • This means if calcium is high PTH should be low (inverse relationship)
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12
Q

Use the following information to provide a diagnosis to the patient

A 52 year old woman was investigated for

suspected kidney stones.

Serum investigations:

reference range

Total calcium: 2.82 mmol/L (2.20 - 2.52)

Phosphate: 0.69 mmol/L (0.75 - 1.50)

Albumin: 42 g/L (35 - 48)

Alkaline phosphatase: 135 U/L (30 - 100)

PTH: 7.3 pmol/L (1 - 6.9)

Creatinine: 118 mmol/L (60 - 110)

A
  • Serum investigations show patient has the following:
  • High total calcium level
  • Low phosphate level
  • High alkaline phosphate level
  • Slightly high PTH
  • High creatinine level
  • This all suggests that the patient has hyperparathyroidism as they have raised PTH and calcium
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13
Q

Use the following serum investigations to explain whether hyperparathyroidism should be investigated

reference range

Total calcium: 2.82 mmol/L (2.20 - 2.52)

PTH: 6.8 pmol/L (1 - 6.9)

A
  • Hyperparathyroidism should still be investigated in this case even though PTH levels are within normal range
  • This is because PTH levels are on high end of normal and total calcium is way above normal level
  • This suggests something is wrong as in a normal situation high PTH = low calcium and high calcium = low PTH
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14
Q

What are the different types of malignancy that can cause hypercalcaemia?

A
  • Humoral: E.g. lung carcinoma secreting parathyroid hormone-related peptide (PTHrP)
    • PTHrP will bind to the PTH receptor and cause over-secretion of PTH from parathyroid glands (hyperparathyroidism)
    • This results in hypercalcaemia and can lead to bone lesions in cancer patients
  • Metastatic: Tumour cells grow and release cytokines which promote osteoclast differentiation and therefore bone reabsorption which leads to bone lesions and associated hypercalcaemia
  • Haematological: Tumour originating in haematopoietic cell line, e.g. multiple myeloma, expands and may secrete various cytokines that activate osteoclastogenic factors such as RANK-L which results in bone lesions (in cancer patients) and associated hypercalcaemia
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15
Q

What are some causes of hypocalcaemia?

A
  • Most common causes:
    • Vitamin D deficiency
    • Renal failure
  • Less common causes include:
    • Hypoparathyroidism
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16
Q

What deficiency is assciated with Rickets and osteomalacia?

A
  • Vitamin D
17
Q

What is Ricktes and who does it mainly affect?

A
  • Condition that results in failure of bone mineralisation and disordered cartilage formation
  • Mainly affects children
18
Q

What is osteomalacia and who does it mainly affect?

A
  • Condition that results in impaired bone mineralisation
  • Mainly affects adults
19
Q

What are some of the clincial features of Osteomalacia?

A
  • Diffuse bone pain
  • Waddling gait
  • Muscle weakness
  • May see stress fractures on an X-ray
20
Q

Describe the serum biochemistry of osteomalacia

A
  • Low/normal calcium
  • Low phosphate (Hypophosphataemia)
  • Raised alkaline phosphatase
  • Secondary hyperparathyroidism - due to low calcium levels leading to lack of negative feedback on PTH release
21
Q

What is the difference between Osteoporosis and Osteomalacia?

A
  • Osteoporosis: Loss of bone mass
  • Osteomalacia: Loss of bone mineralization
22
Q

Osteoporosis itself is asymptomatic (no pain associated with loss of bone mass) so what’s the first sign of osteoporosis that someone would notice?

A
  • Fragility fracture - Fracture caused by incident that wouldn’t damage healthy bone
  • Intervertebral fracture - Get a compression fracture of the vertebrae (vertebrae may be more triangular)
23
Q

What things may contribute to the development of osteoporosis?

A
  • Endocrine causes
  • Malignancy
  • Drugs
  • Renal disease
  • Nutritional causes (lack of calcium in diet)
24
Q

How can osteoporosis be diagnosed?

A
  • Measurement of bone mineral density (BMD)
  • Dual-energy X-ray absorptiometry (DEXA or DXA scan) - 2 X-ray beams with different energy levels aimed at patients bone with one measuring bone density and the other measuring bone thickness
  • Bone densites given either a T or Z score:
    • T score - Number of SDs below average for young adult at peak bone density
    • Z score - Matched to age and/or group
25
Q

What are some endocrine causes of osteoporosis?

A
  • Hypogonadism – notably any cause of oestrogen deficiency
  • Excess glucocorticoids – endogenous or exogenous
  • Hyperparathyroidism
  • Hyperthyroidism
26
Q

Explain what happen to bone density in women as they age?

A
  • When women reach menopause oestrogen production stops
  • Menpausal women still have low levels of oestrogen as some adrenal androgens are converted into oestrogen
  • Low levels of oestrogen is one of the contributing factors to osteoporosis (loss of BMD)
  • In normal cases loss of oestrogen due to menopause results in oesteopenia
  • However, in women with early menopause or low bone mass loss of bone density would be more rapid and would result in osteoporosis rather than ostopenia
27
Q

What are some of the treatments for osteopororsis?

A
  • Postmenopausal treatment: Hormone replacement therapy (HRT) - effects well established but safety of long term treatment has been questioned
  • Bisphosphonates – inhibit function of osteoclasts: risedronate, alendronate
  • PTH analogues
  • Denosumab – Antibody against the Receptor activator of nuclear factor kappa-B (RANK) ligand
    • RANK ligand activates pre-osteoclasts causing their differentiation which leads to bone reabsorption
  • Romosozumab - Antibody against sclerostin protein
    • Sclerostin is a protein that puts a break in Wnt signalling pathway that’s required for osteoblast differentiation
28
Q

Give a brief history of menopause

A
  • 1947: US FDA approves Premarin for treatment of hot flushes
  • 1970s: Strong association established between oestrogen therapy and endometrial cancer so use of HRT (oestrogen only) declines
  • 1980s: Combination of progestins with oestrogen used to counter proliferative effects of oestrogen on the endometrial wall, therefore HRT use rises again
  • 2002: Preliminary results from Women’s health initiative (WHI) published
    • Results stated there was no cardiovascular protective effects (possibly the reverse) of HRT and claimed it significantly increased breast cancer risk
29
Q

Below is a graph from the WHI study, what does the graph show about the effects of HRT?

A
  • Both Oestrogen only and Oestrogen+Progesterone HRT showed to decrease fractures comapred to placebo’s used
  • Oestrogen only HRT shown to not cause increase in breast cancer compared to placebo
  • However, Oestrogen+Progesterone HRT shown to cause increase in breast cancer incidence compared with placebo but only very small increase
30
Q

Using results from WHI study what would the relative risk of breast cancer be for Oestrogen+progesterone HRT compared to placebo?

A
  • Placebo = 0.30
  • Oestrogen+progesterone HRT = 0.38
  • Placebo will cause 30 breast cancer cases per 10,000 compared with Oestrogen+progesterone HRT which will cause 38 breast cancer cases per 10,000
  • Increase of 8 cases
  • Relative risk = 8/30 x 100 = 27%
31
Q

What would the absolute risk of breas cancer from Oestrogen+progesterone HRT compared to placebo be from the WHI study?

A
  • Absolute risk = 0.38% vs 0.30%
  • This shows quoting relative risk without absolute risk can be misleading
32
Q

What did further analysis of the WHI results show?

A
  • The WHI participants were older, post-menopausal women (mean age of 64 and 10 years post-menopause)
  • Separate analysis of <10 or >10 yrs post-menopause suggested risks were reduced in group <10 years post menopause
  • Guidelines for HRT modified as a result of study:
    • Short-term therapy (3-5 years) for treating vasomotor symptoms
    • Lowest effective dose to be used
    • Long term use not recommended