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Year 2 Medicine > Diagnostic Biochemistry of Calcium and Bone Disorders > Flashcards

Diagnostic Biochemistry of Calcium and Bone Disorders Flashcards

1
Q

Calcium Homeostasis

  • Leak: TRPV5 and TRPV6 channels (also known as … - intestine and … - kidney, respectively)
  • Pump: … calcium ATPase, PMCA1b, … calcium per ATP to ADP
    • OR: Basolateral …NA:…CA exhanger, NCX1 extruding calcium (secondarily active mechanism using Na gradient)
  • Regulation: 1,25(OH)2D3 and PTH - what do these stand for?
A
  • Leak: TRPV5 and TRPV6 channels (also known as ECaC2 - intestine and ECaC1 - kidney, respectively)
  • Pump: Basolateral calcium ATPase, PMCA1b, one calcium per ATP to ADP
    • OR: Basolateral 3NA:1CA exhanger NCX1 extruding calcium (secondarily active mechanism using Na gradient)
  • Regulation: 1,25(OH)2D3 and PTH - what do these stand for - activated vitamin D and parathyroid hormone
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2
Q
  • Animal models have demonstrated that ECaC expression is regulated by …
  • Gene transcription upregulated by … …. .; phosphorylation of channels and the insertion of ECaC rich vesicles is also available
  • 1 alpha hydroxylation of Vit D activated in the kidney by … …
A
  • Animal models have demonstrated that ECaC expression is regulated by 1,25 Vit D (activated Vitamin D)
  • Gene transcription upregulated by active vitamin D; phosphorylation of channels and the insertion of ECaC rich vesicles is also available
  • 1 alpha hydroxylation of Vit D activated in the kidney by parathyroid hormone
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3
Q

Calcium Homeostasis - Sites of exchange/control

  • … - Filter v Reabsorption
  • … - Absorption v Secretion
  • … - Formation v Resorption
A
  • Kidney - Filter v Reabsorption
  • GI tract - Absorption v Secretion
  • Bone - Formation v Resorption
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4
Q

Threats to Calcium Homeostasis

  • Disorders of …, … or …
  • Disorders of … gland
  • Abnormal …. metabolism : intake/synthesis/metabolism
A
  • Disorders of gut, kidney or skeleton
  • Disorders of parathyroid gland
  • Abnormal vit D metabolism : intake/synthesis/metabolism
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5
Q

Parathyroid Hormone

  • Secreted as 84aa ‘…’ hormone
    • Active moiety
    • Key plasma measurement (not fragments)
  • Half life approx … mins
  • Low … inhibits release (mimicking ‘hypoparathyroidism’)
  • Stimuli to release:
    • Fall in plasma ionised … (Acute)
    • Rise in plasma … (Chronic)
A
  • Secreted as 84aa ‘intact’ hormone
    • Active moiety
    • Key plasma measurement (not fragments)
  • Half life approx 4 mins
  • Low magnesium inhibits release (mimicking ‘hypoparathyroidism’)
  • Stimuli to release:
    • Fall in plasma ionised calcium (Acute)
    • Rise in plasma phosphate (Chronic)
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6
Q

Parathyroid Hormone vs PTH related peptide

  • Laboratory assay picks up … only, it DOES NOT detect …
  • … secreted by a wide variety of tumours, contributes to the humeral hypercalcaemia of malignancy
  • … acts as a calciotropic hormone in fetal life and in lactation
    • … stimulates the transport of calcium across the placenta
    • … probably contributes to the dramatic but largely reversible bone loss during lactation
A
  • Laboratory assay picks up PTH only, it DOES NOT detect PTHrP
  • PTHrP secreted by a wide variety of tumours, contributes to the humeral hypercalcaemia of malignancy
  • PTHrP acts as a calciotropic hormone in fetal life and in lactation
    • PTHrP stimulates the transport of calcium across the placenta
    • PTHrP probably contributes to the dramatic but largely reversible bone loss during lactation
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7
Q

Vitamin D

  • D… and D… ( light) sources
  • Activation of … via hepatic (25-hydroxylase*) & renal … (1a -hydroxylase) steps
  • *constitutive & this is the measurand
  • When exposed to … 7-dehydrocholesterol undergoes photochemical … forming vitamin D
A
  • Dietary and Dermal ( light) sources
  • Activation of cholecalciferol via hepatic (25-hydroxylase*) & renal hydroxylation (1a -hydroxylase) steps
  • *constitutive & this is the measurand
  • When exposed to UV light 7-dehydrocholesterol undergoes photochemical cleavage forming vitamin D
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8
Q

Vitamin D nomenclature

  • Vitamin D2 (Or …) refers to Vitamin D from … sources and Vitamin D3 (or …) from … sources
  • Product of first hydroxylation (liver)
    • D2 - …-hydroxyvitamin D2 or ercalciferol
    • D3 - …-hydroxyvitamin D3 or calcidiol
  • Product of second hydroxylation (kidney)
    • 1,25-Dihydroxyvitamin D2 or …
    • 1,25-Dihydroxyvitamin D3 or …
A
  • Vitamin D2 (Or ergocalciferol) refers to Vitamin D from plant sources and Vitamin D3 (or cholecalciferol) from animal sources
  • Product of first hydroxylation (liver)
    • D2 - 25-hydroxyvitamin D2 or ercalciferol
    • D3 - 25-hydroxyvitamin D3 or calcidiol
  • Product of second hydroxylation (kidney)
    • 1,25-Dihydroxyvitamin D2 or ercalcitriol
    • 1,25-Dihydroxyvitamin D3 or calcitriol
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9
Q

Calcitonin

  • Main effect: to reduce bone … (direct and reversible effect on …)
  • Role uncertain, thought to protect the skeleton during stressors such as in …
  • Main use: tumour marker for medullary … of the …
A
  • Main effect: to reduce bone resorption (direct and reversible effect on osteoclasts)
  • Role uncertain, thought to protect the skeleton during stresses (growth and pregnancy)
  • Main use: tumour marker for medullary carcinoma of the thyroid
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10
Q

FGF-23

  • Secreted by osteo…, osteo… and osteo… in response to raised serum …
  • Reduces … reabsorption in the renal proximal tubule and inhibits 1-α …
  • May be important in renal … disease
A
  • Secreted by osteocytes, osteoblasts and osteoclasts in response to raised serum phosphate
  • Reduces phosphate reabsorption in the renal proximal tubule and inhibits 1-α hydroxylase
  • May be important in renal bone disease
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11
Q

Total Plasma Calcium - Interpretation?

  • Total plasma calcium is what is measured in the lab – a … method
  • However …% ionised: physiologically active, regulated tightly, measured by blood gas machine
    • …% albumin bound
    • … % complexed
  • Change in … changes the total calcium (lab method).
  • We … therefore and present a range ‘if the albumin were 40 g/L’
A
  • Total plasma calcium is what is measured in the lab – a dye method
  • However 50% ionised: physiologically active, regulated tightly, measured by blood gas machine
    • 40% albumin bound
    • 10 % complexed
  • Change in albumin changes the total calcium (lab method).
  • We adjust therefore and present a range ‘if the albumin were 40 g/L’
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12
Q

‘Adjustment’ of Plasma Calcium Results

  • Method and population specific adjustment to make data fit the range: …-… mmol/L
    • Adjusted calcium = calcium +0.02 x (40-albumin)
  • Consider 3 patients:
    1. Calcium 2.40 Albumin 40 Adjusted Calcium = ?
    2. Calcium 2.16 Albumin 30 Adjusted Calcium = ?
    3. Calcium 2.64 Albumin 50 Adjusted Calcium = ?
A
  • Method and population specific adjustment to make data fit the range: 2.20-2.60 mmol/L
    • Adjusted calcium = calcium +0.02 x (40-albumin)
  • Consider 3 patients:
    1. Calcium 2.40 Albumin 40 Adjusted Calcium = ?
    2. Calcium 2.16 Albumin 30 Adjusted Calcium = ? 2.36
    3. Calcium 2.64 Albumin 50 Adjusted Calcium = ? 2.44
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13
Q

Hypercalcaemia + Suppressed PTH

  • ?parathyroid cause
    • … (E.g. lung, breast or blood)
    • … excess (Activated)
    • Sar…
A
  • Non-parathyroid cause
    • Malignancy (E.g. lung, breast or blood)
    • Vit D excess (Activated)
    • Sarcoidosis
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14
Q

Hypercalcaemia + Raised (or detectable) PTH

  • PTH mediated cause?
    • … hyperparathyroidism
    • … hyperparathyroidism
    • … hyperparathyroidism
    • (+ calcium … defects e.g. FHH)
A
  • PTH mediated cause
    • Primary hyperparathyroidism
    • Secondary hyperparathyroidism
    • Tertiary hyperparathyroidism
    • (+ calcium receptor defects e.g. FHH)
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15
Q

Hypocalcaemia + Increased PTH:

  • ?parathyroid cause
  • Vit D …, mal…
  • … failure
  • (PTH … defect e.g. pseudohypoparathyroidism)
  • (Vit D … defect)
A
  • Non-parathyroid cause
  • Vit D deficiency, malabsorption
  • Renal failure
  • (PTH receptor defect e.g. pseudohypoparathyroidism)
  • (Vit D receptor defect)
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16
Q

Hypocalcaemia + Low/normal PTH:

  • ?Parathyroid cause
    • Such as …
      • … e.g. DiGeorge
      • Post … or …
  • … deficiency (<0.4 mmol/L)
A
  • Parathyroid cause
  • Hypoparathyroidism
  • Congenital e.g. DiGeorge
  • Post surgery or radiotherapy
  • Mg deficiency (<0.4 mmol/L)
17
Q

Normocalcaemic Hyperparathyroidism

  • Primary …
    • adenoma and hyperplasia
  • … deficiency
    • sunlight or dietary deficiency or liver disease
  • C…
    • low 1,25D, high PTH due to hyperphosphataemia, increased PTH fragments
  • … illness
    • pancreatitis, septicaemia, toxic shock, rhabdomyolysis, ITU admission, adrenal crisis
  • M…, / …
    • restrictive/exclusion diets, coeliac, chronic pancreatitis
  • Drugs
    • anti…, bisphoshonates, denosumab, steroids, lithium, PPI, phosphate supplements
A
  • Primary hyperparathyroidism
    • adenoma and hyperplasia
  • Vit D deficiency
    • sunlight or dietary deficiency or liver disease
  • CKD
    • low 1,25D, high PTH due to hyperphosphataemia, increased PTH fragments
  • Acute illness
    • pancreatitis, septicaemia, toxic shock, rhabdomyolysis, ITU admission, adrenal crisis
  • Malabsorption, dietary
    • restrictive/exclusion diets, coeliac, chronic pancreatitis
  • Drugs
    • anticonvulsants, bisphoshonates, denosumab, steroids, lithium, PPI, phosphate supplements
18
Q

Case 1 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Calcium very high - adjusted = 3.24 (for albumin levels 40)
  • Phosphate is low
  • Creatinine is slightly high - look for teritary parathyroidism? - ruled out not high enough
  • PTH is high - driven by this
    • Diagnosis = primary hyperparathyroidism
19
Q

Causes of polyuria (5)

A

Diabetes insipidus, Diabetes Mellitus, CKD, High Ca, Low K

20
Q

Case 2 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Calcium high
  • Albumin low ish (adjusted calcium = 2.72)
  • Creatinine high - kidney injury
  • High ALP - hypoparathyroidism?
  • Next steps - examine breast / prostate , repeat calcium with PTH, FBC, Elctrophoresis and light chains, PSA, ACE, calcium:creatinine clearance ratio, others: DEXA, skeletal surgery, bone marrow biopsy, h pylori
  • Diagnosis - hypercalcaemia confirmed - other tests confirm hyperparathyroidism
21
Q

Case 3 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Calcium low
  • Albumin low (2.04 adjusted calcium)
  • Phosphate high
  • ALP high
  • Creatinine very very high - renal failure
  • PTH very very high - tertiary hyperparathyroidism - very high PTH seen (but secondary because calcium isnt high)
  • Diagnosis - secondary hyperparathyroidism (eventually goes to tertiary - calcium back up - hypercalcaemic)
22
Q

Familial Hypocalciuria hypercalcaemia - LoF CaSR

  • Uncommon condition where calcium ‘set point’ is higher due to insensitivity of the CaSR .
  • Autosomal …, near 100% penetrance, PTH normal or slightly high .
  • To exclude FHH, Ca:Cr ratio should be > …
    • Formula: Urine Calcium (mmol/l) x [Plasma Creatinine (umol/l) / 1000] DIVIDED BY Plasma Calcium (mmol/l) x Urine Creatinine (mmol/l)
  • Condition is …/asymptomatic
  • Identical biochemistry to … …
  • (Ca 2.6-2.9 – only rarely >3.0)
  • Do Not miss as removing parathyroids …
  • … will always have been a bit high
A
  • Uncommon condition where calcium ‘set point’ is higher due to insensitivity of the CaSR .
  • Autosomal dominant, near 100% penetrance, PTH normal or slightly high .
  • To exclude FHH, Ca:Cr ratio should be > 0.01
    • Formula: Urine Calcium (mmol/l) x [Plasma Creatinine (umol/l) / 1000] DIVIDED BY Plasma Calcium (mmol/l) x Urine Creatinine (mmol/l)
  • Condition is benign/asymptomatic
  • Identical biochemistry to primary hyperparathyroidism
  • (Ca 2.6-2.9 – only rarely >3.0)
  • Do Not miss as removing parathyroids won’t help
  • Calcium will always have been a bit high
23
Q

Example of presentation of …

A

_Example of presentation of FHH (_Familial hypocalciuric hypercalcaemi)

24
Q

Primary hyperparathyroidism is commonest in … people. Unusual in ….

A

Primary hyperparathyroidism is commonest in older people. Unusual in younger.

25
Q

Calcitonin

  • Can help to distinguish C cell … from medullary C cell ….
  • There is cross over and therefore ‘pentagastrin-stimulated’ values can be used (more diagnostic).
  • However the specific mutations and family history of age of medullary … are used to guide time of prophylactic …
A
  • Can help to distinguish C cell hyperplasia from medullary C cell carcinoma.
  • There is cross over and therefore ‘pentagastrin-stimulated’ values can be used (more diagnostic).
  • However the specific mutations and family history of age of medullary C cell carcinoma are used to guide time of prophylactic thyroidectomy.
26
Q

Case 4 - Biochemistry of Calcium and Bone Disorders

  • Diagnosis?
A
  • Calcium - low
  • Albumin normal (no adjustment)
  • Phosphate high
  • ALP low
  • Creatinine normal
  • PTH is normal (inappropriate)
    • Diagnosis = hypoparathyroidism
27
Q

Case 5 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Adjusted calcium - bordeline low
  • Phosphate - low
  • Alkaline phosphatase - high
    • Vitamin deficiency
28
Q

Case 6 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Calcium low
  • Albumin high (adjusted calcium 1.81)
  • Phosphate high
  • PTH - quite high
    • diagnosis - pseudohypoparathyroidism
29
Q

Pseudohypoparathyrodism - Albright’s Hereditary Osteodystrophy

  • The syndrome is associated with a specific clinical … (can be very subtle)
    • … stature
    • Shorted 4th +/- 5th … and/or …
    • … faces
    • O…
    • Sometimes .. mental …
A
  • The syndrome is associated with a specific clinical phenotype (can be very subtle)
    • Short stature
    • Shorted 4th +/- 5th metacarpals and/or metatarsals
    • Round faces
    • Obesity
    • Sometimes mild mental retardation
30
Q

Psudohypoparathyroidism - or is it…

  • It was found that some have the physical … but the … is normal. This is an example of genetic …
    • If mutant gene inherited from their mother then manifest pseudo (1a) – … and … features
    • If from father pseudopseudohypoparathyroidism – … features only.
  • Predominantly the maternal gene is expressed in the … …
A
  • It was found that some have the physical phenotype but the biochemistry is normal. This is an example of genetic imprinting.
    • If mutant gene inherited from their mother then manifest pseudo (1a) – biochemical and physical features
    • If from father pseudopseudohypoparathyroidism – physical features only.
  • Predominantly the maternal gene is expressed in the renal tubule
31
Q

Case 6 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Alkaline phosphatase really raised
    • Could be paget’s disease
    • Used to be common - rarely see it now
    • May be macro ALP
32
Q

Case 7 - Biochemistry of Calcium and Bone disorders

  • 67y complains of several months of abdominal pain worse past week plus vomiting 1 to 4 times daily.

Hypertensive Rx Perindopril 4 mg OD, Atorvastatin 10 mg OD and ibuprofen.

Diagnosis?

A
  • Creatinine upper limit of normal
  • high calcium
  • low potassium
  • low magnesium
  • low phosphate
  • normal PTH
    • Gave bisphosphonate to reduce calcium - but then required urgent calcium, potassium, phosphate and magnesium - plus active Vit D - diet issue?
    • Calcium-alkali syndrome - patient used alka-seltzer and milk for dyspepsia - high dose - increasing frequency due to calcium carb for osteoporosis prevention
33
Q

Calcium-Alkali Syndrome

  • Triad is…__​
A
  1. Hypercalcaemia
  2. Metabolic alkalosis
  3. Renal insufficiency
34
Q

The third commonest cause of hypercalcaemia is …

A

calcium-alkali syndrome

35
Q

Case 8 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A
  • Calcium high
  • Albumin low (Adjusted calcium is 2.83)
  • Phosphate high
  • ALLP - high
  • Creatinine - upper limit of normal
  • PTH - low
    • likely diagnosis - cancer
    • Actually a sarcoid - not cancer - so why hypercalcaemia?
      • granulomas - ACE can be be produced by these - activate vit D - no feedback / not PTH controlled
36
Q

Case 9 - Biochemistry of Calcium and Bone disorders

  • Diagnosis?
A

Year 2 Medicine (162 decks)

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