Clincal Biochemistry: Calcium and phosphate metabolism Flashcards
What things help control serum calcium and phopshate levels?
- Bone turnover
- Parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
What is bone turnover?
- Bone turnover is the process of resorption followed by replacement by new bone.
How is calcium distributed within the body?
- 99% of body calcium is in bone
- Most of remaining 1% is intracellular
- <0.1% extracellular
Very briefly describe how calcium balance is maintained
- Hormonal control of the tiny extracellular fraction is what maintains Calcium balance
What % of extracellular calcium is free and what % is potein-bound?
- 50% is free [Ca2+] (physiologically active)
- 50% protein bound (mainly to albumin)
How is phosphate distributed within the body?
- 85% of body phosphorus is in bone
- Remainder is mainly intracellular
- <0.1% extracellular
What forms of phosphate mainly make up extracellular portion of it in the body?
- Dihydrogen phsophate (H2PO4-)
- Hydrogen phosphate (HPO42-)
What are the clinical features of hypercalcemia (high blood calcium)?
- Depression, fatigue, anorexia, nausea, vomiting
- Abdominal pain, constipation
- Renal calcification (kidney stones)
- Bone pain
- Severe symptoms: cardiac arrhythmias, cardiac arrest
What saying can be used to help remeber the symptoms of hpercalcemia?
- “Painful bones, renal stones, abdominal groans, and psychic moans”
What are some of the causes of hypercalcaemia?
- Most common causes:
- Primary hyperparathyroidism
- In hospitalized patients: malignancy
- Less common causes:
- Hyperthyroidism
- Excessive intake of vitamin D
Describe the serum biochemistry of someone suffering from hypercalcaemia
- 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)
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)
- 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
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)
- 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
What are the different types of malignancy that can cause hypercalcaemia?
-
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
What are some causes of hypocalcaemia?
- Most common causes:
- Vitamin D deficiency
- Renal failure
- Less common causes include:
- Hypoparathyroidism
What deficiency is assciated with Rickets and osteomalacia?
- Vitamin D
What is Ricktes and who does it mainly affect?
- Condition that results in failure of bone mineralisation and disordered cartilage formation
- Mainly affects children
What is osteomalacia and who does it mainly affect?
- Condition that results in impaired bone mineralisation
- Mainly affects adults
What are some of the clincial features of Osteomalacia?
- Diffuse bone pain
- Waddling gait
- Muscle weakness
- May see stress fractures on an X-ray
Describe the serum biochemistry of osteomalacia
- 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
What is the difference between Osteoporosis and Osteomalacia?
- Osteoporosis: Loss of bone mass
- Osteomalacia: Loss of bone mineralization
Osteoporosis itself is asymptomatic (no pain associated with loss of bone mass) so what’s the first sign of osteoporosis that someone would notice?
- 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)
What things may contribute to the development of osteoporosis?
- Endocrine causes
- Malignancy
- Drugs
- Renal disease
- Nutritional causes (lack of calcium in diet)
How can osteoporosis be diagnosed?
- 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
What are some endocrine causes of osteoporosis?
- Hypogonadism – notably any cause of oestrogen deficiency
- Excess glucocorticoids – endogenous or exogenous
- Hyperparathyroidism
- Hyperthyroidism
Explain what happen to bone density in women as they age?
- 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
What are some of the treatments for osteopororsis?
- 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
Give a brief history of menopause
- 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
Below is a graph from the WHI study, what does the graph show about the effects of HRT?
- 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
Using results from WHI study what would the relative risk of breast cancer be for Oestrogen+progesterone HRT compared to placebo?
- 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%
What would the absolute risk of breas cancer from Oestrogen+progesterone HRT compared to placebo be from the WHI study?
- Absolute risk = 0.38% vs 0.30%
- This shows quoting relative risk without absolute risk can be misleading
What did further analysis of the WHI results show?
- 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
