Disorders of Calcium Metabolism Flashcards
What are the biological functions of calcium?
-Intracellular Ca2+ is maintained at very low
concentrations (less than 1 μmol/L).
=Reversible increases allow Ca2+ ions to bind to
proteins to influence many key cell processes (proliferation, cell migration and differentiation and apoptosis)
-Extracellular Ca2+ is present at much higher
concentration (about 1 mmol/L).
=To allow normal bone mineralisation
=To maintain normal activity of excitable tissue (neuromuscular tissues have contractility)
What phase of blood is extracellular calcium measured in?
-Liquid (non-cellular) phase of blood i.e. either
o Serum (the liquid phase obtained after blood has
clotted) OR
o Plasma (the liquid phase of non-clotted blood where
the blood sample taken includes an anti-coagulant)
Describe plasma (or serum) calcium (what are the components and concentration)
The concentration measured in plasma (or serum) is within a well defined normal range
• This range is typically 2.1-2.6 mmol/L
• This calcium concentration is made up of 2 components:
o Ionised Ca2+ which is physiologically active
o Ca2+ which is ‘bound’ mainly to albumin and
is not physiologically active
• It is the ionised Ca2+ which is actively regulated
What is the link between albumin and calcium?
- Albumin is the major Ca2+ binding protein in plasma (or serum)
- Abnormal albumin concentration (which is quite common, more likely down than up in infection/inflammation/malignancy) will alter the Ca2+ bound
- Measuring both albumin and total calcium is required to assess extracellular ionised Ca2+ status
How does albumin affect interpretation of plasma calcium?
- Ionised calcium constant
- Bound calcium not constant
- Albumin not constant (less= less capacity to bind calcium)
Describe calcium balance
-Net absorption and excretion both 5mmol/24h
=Diet 25 mmoles
=10 mmoles absorbed from gut
=5 mmoles excreted, other excreted through kidneys
=Bone exchange and turnover (dynamic organ)
How does calcium balance alter throughout life?
- Growth (new bone formation) requires a positive Ca2+ balance
- Adulthood would ideally be associated with neutral balance (Ca2+ in = Ca2+ out)
- The ageing process is associated with a slow phase of negative Ca2+ balance leading to loss of bone density (may lead to osteoporosis)
- Bone loss accelerated after menopause
What is the morphology and function of bone?
• The skeleton makes up ±17% by body weight
• Bone functions
o Support of the body
o Protection of organs
o Leverage system for movement
o Site for haematopoiesis
o Endocrine function (fibroblast growth factor-23;
osteocalcin= basal metabolic rate)
o Regulation of mineral homeostasis
• Bone morphology
o Trabecular Bone (narrow rods, internal)
o Cortical Bone (thicker, outside, strength)
What are the types of bone cells?
- Osteoblasts= cells that make bone
- Osteoclasts= cells that resorb bone
- Osteocytes= most abundant cell type in bone, mechanosensor cell
Describe bone formation by osteoblasts
- Ob precursor
- Ob (osteoblast)
- Osteoid (uncalcified bone matrix, fibrils and collagen, adjacent to osteoblast)
- Calcified bone matrix (phosphate)
- Cell process from osteocyte
- Osteocyte (internal, cell processes for pressure sensing)
Describe bone matrix mineralisation
• Several day delay before osteoid mineralises
• Skeleton contains ~98% of body calcium
• Mineral component is hydroxyapatite: Ca10(PO4)6(OH)2
o Tiny crystals surround collagen fibres
o Provides rigidity, resistance to compression
• Mineralisation of osteoid dependent on calcitriol (active vitamin D);
o Deficiency results in failure to mineralise
o Leads to rickets in children, osteomalacia in adults
• Full mineralisation takes several months
Describe the role of Alkaline phosphatase (ALP) in mineralisation
• Expressed on surface of differentiated osteoblasts; also released into extracellular fluid and circulation (bone formation marker), liver function test
• Releases inorganic phosphate ions (PO4 3-) from diverse molecules (hydrolysis)
• ALP promotes mineralisation (i.e., precipitation of calcium phosphate/ hydroxyapatite) in 2 ways:
o by increasing the local concentration of inorganic phosphate ions
o by hydrolysing pyrophosphate, a key endogenous inhibitor of mineralisation
What is the role of osteoclasts in bone resorption?
o Multinucleate, motile bone-resorbing cells
o Formed by fusion of promonocytic precursors present in marrow and circulation
o “Ruffled border” adjacent to bone surface secretes H+
and enzymes
o Express high levels of carbonic anhydrase II required for H+ generation
Describe the role of RANK-RANKL in osteoclast biology and function
-Bone marrow stromal cell (expresses RANKL) communicates with osteoclast precursor through RANK-RANKL interaction ligands
=Activation of osteoclast precursor
=Mature osteoclast
How do osteoclasts resorb bone?
- Pits on flat surface of bone
- Osteoclast highly motile
What clues indicate osteopetrosis?
• Also known as: ‘Marble bone disease’/ stone bone • Inherited bone disease =shorter • Increased bone mass • Caused by dysfunctional osteoclasts =flat pits
What is the cause of osteopetrosis?
-Failure of matrix degradation by osteoclasts
=CA 2 mutations (carbonic anhydrase)
=TCIRG1 mutations (proton pumps through ruffled border)
=CLCN7 mutations (chloride channel defects, so no HCl)
=Cat K mutations (other protein pumps)
Overview of bone remodelling cycle
- Quiescence of lining cells
- Osteoclast resorption (10 days)
- Osteoblast reversal (osteoblast lays down new osteoid)
- Osteocytes= formation
- Mineralisation 3 months
=4-6 months
Why do we need bone metabolism?
o To grow
o Respond to altered mechanical requirements
o Repair damage (macro / micro fractures)
o Maintenance (failure prevention)
o Calcium deficit
• Skeleton is renewed every ± 7 years
• In health, bone formation and resorption are
balanced
• For bone growth, formation exceeds resorption
Describe bone turnover and metabolism in disease
• Pathological imbalance between formation and
resorption leads to disease
• Most common bone diseases reflect this
imbalance
• Osteoporosis (late stages in life, oestrogen influence, smoking, reduced bone density)
o Most common cause: low oestrogen after menopause
o Main cause of bone loss: increased bone resorption
• Paget’s disease
o Due to overactive osteoclasts (thickened bone, skull can affect neuro-processes, hearing problems and pain)
How is ionised Ca2+ regulated?
• This regulation is endocrine, requiring the
participation of 2 key hormones called
parathyroid hormone (PTH) and calcitriol which
show typical endocrine feedback loops
• PTH is a peptide hormone
• Calcitriol is a steroid hormone which is
synthesised from dietary factor (vitamin D)
• The principal organs involved are gut, bone and
kidney (liver and skin)
What is the physiology of PTH?
• A peptide hormone required for the minute-byminute regulation of ionised calcium levels in
blood
• PTH is secreted as a single chain polypeptide
(84 amino acids) from the parathyroid glands
• PTH secretion is increased in response to falling
Ca2+ and its actions are directed at restoring
Ca2+ levels
• Rising Ca2+ feeds back to the parathyroid glands
and suppresses PTH secretion (negative
feedback loop)
How is PTH secretion regulated?
• PTH secretion is tightly
regulated to maintain Ca2+ in physiological range
• Calcium receptors on cell
sense Ca2+ levels to regulate PTH secretion
• G-protein coupled receptor is activated by binding of calcium
What are the actions of PTH?
oStimulates efflux of Ca2+ from bone
oStimulates renal tubular reabsorption of Ca2+
(distal tubule)
oStimulates formation of calcitriol (indirectly)
promoting intestinal absorption of Ca2+
oPromotes phosphate and bicarbonate loss from
the kidney (proximal tubule, inhibits reabsorption)
Describe calcium, PTH and vitamin D feedback loops
-Rising blood Ca2+
=Suppress PTH
=Decreased bone resorption, increased urinary calcium loss, decreased active vitamin D production
-Falling blood Ca2+
=Stimulate PTH
=Increased bone resorption, decreased urinary calcium loss, increased active vitamin D production
Describe calcitonin
• 32 amino acid polypeptide secreted in response to rising Ca2+ from parafollicular or C-cells of the thyroid gland
• Principal action is to reduce osteoclast activity
• No clear role in calcium homeostasis (e.g. neither total thyroidectomy nor calcitonin-secreting tumours alter calcium homeostasis)
• May be used therapeutically to treat high serum calcium levels
• Also serves as a ‘tumour marker’ (certain thyroid
tumours; some breast cancers)
Describe cholecalciferol
• Fat soluble vitamin (vitamin D)
• Steroid structure
• Produced endogenously by the action of UV light
on skin precursor, 7-dehydrocholesterol
• Dietary sources include oily fish, eggs, butter,
margarine (fortified)= 30%
• Cholecalciferol requires activation by liver and
kidney to produce the active hormone, calcitriol
Describe vitamin D physiology
• Calcitriol is a hormone: it is synthesised in one location (kidney) and acts at many sites
• Vitamin D is distinct from other “classical” vitamins, such as vitamin C, B vitamins, etc., which act as cofactors in biochemical reactions
• Calcitriol is required for the longer-term maintenance of calcium (and phosphate) levels
and is required for normal bone growth and mineralisation
How is vitamin D synthesised (precursor to D3)?
-The precursor for vitamin D synthesis is a sterol in the cholesterol biosynthetic pathway, 7- dehydrocholesterol which is found in skin
• Ultraviolet light (UVB) transforms 7- dehydrocholesterol to vitamin D3 (cholecalciferol)
How is vitamin D synthesised (D3 to 25(OH) vitamin D)?
• Vitamin D3 circulates to the liver, where the microsomal enzyme 25-hydroxylase hydroxylates
it to 25-hydroxy vitamin D (25(OH)vitamin D)= calcidiol
• 25-hydroxylase functions constitutively without
input from blood calcium status or PTH (all the time)
• 25(OH)vitamin D is the best screening test for
vitamin D adequacy
How is vitamin D synthesised (to active form)?
• 25(OH)vitamin D circulates to the kidneys where
it is hydroxylated by 1α-hydroxylase to 1,25(OH)2
vitamin D (calcitriol) = ‘active’ vitamin D
• Renal 1α-hydroxylase is regulated by PTH which
stimulates its activity. PTH is the principle physiologic regulator, although calcium can affect the activity
• Other hydroxylations possible (e.g. at the 24-
position= inactivates vitamin D)
Describe vitamin D metabolism
- 7-DHC= Vitamin D3= 25(OH)D3= 1,25(OH)D3
- Increases calcium and phosphate absorption in gut through calbindin
- Increases bone resorption
What is the mechanism of calcitriol action
• Calcitriol binds to a single vitamin D receptor (VDR)
• The VDR-calcitriol complex acts through a vitamin D-responsive element (new protein synthesis= gene transcription)
o In the intestine, a calcium-binding protein (calbindinD9k) is synthesised which promotes absorption of
both calcium and phosphate
o In bone, stimulates osteoblast differentiation and osteoclast activation via RANK ligand (RANKL)
formation in osteoblasts
What are the actions of calcitriol?
• Calcitriol promotes gut absorption of calcium and
phosphate (requires new protein synthesis)
• Calcitriol, in concert with PTH, stimulates osteoclasts and efflux of Ca2+ from bone
• Calcitriol, in concert with PTH, increases renal Ca2+ reabsorption
• Maintenance of both calcium and phosphate
levels essential for hydroxyapatite formation and normal bone mineralisation
• Calcitriol deficiency has major effects on bone
mineralisation (low calcitriol, high PTH- secondary hypoparathyroidism)
Compare and contrast calcitriol with PTH
- Both maintain ionised Ca2+
- PTH responsible for minute-by-minute plasma Ca2+ regulation
- Calcitriol responsible for longer term plasma Ca2+ regulation
- PTH tends to decrease plasma phosphate
- Calcitriol raises plasma phosphate
What are the effects of 25(OH)D deficiency on calcium metabolism?
- Phosphate wasting (lost from urine)
- Bone resorption
- Reduced calcium absorption from gut
Describe the interactions between PTH and calcitriol
• Co-operativity
o PTH promotes 1α-hydroxylase activity
o PTH and calcitriol both required in vivo for osteoclast activation and distal tubular Ca2+ reabsorption
o Calcitriol deficiency may impair PTH action
• Limitation of action
– Calcitriol stimulates 24-hydroxlase (promotes its own inactivation)
– Calcitriol can switch off PTH gene transcription via
VDR in parathyroid cells, limiting PTH action
Describe regulation of ionised calcium by PTH
-Fall in Ca2+ stimulates parathyroid hormone
-Restores Ca2+ by
=Increasing bone release of Ca2+
=Increasing renal reabsorption of Ca2+
=Stimulating formation of calcitriol
-Rising Ca2+ suppresses PTH
What are the clinical manifestation of hypercalcaemia?
*‘Stones, bones, abdominal moans and psychic groans’
• Muscle weakness (striated and smooth); possible competition with inward Na+ movement
• Central effects (anorexia, nausea, mood change,
depression)
• Renal effects (impaired water concentration, frequent urination; renal stone formation)
• Bone involvement (cause-dependent)
• Abdominal pain
• ECG changes (shortened QT interval= 3-4.5 mmol/L, cardiac arrhythmias and arrest)
What is Factitious hypercalcaemia?
-Non-pathological, clinically fine • Raised [calcium] due to high plasma [albumin] e.g. o Venous stasis (tourniquet applied too long, blood leaks out from vessels to tissues, increase in protein so albumin increases) o Dehydration o IV albumin
Describe the epidemiology of primary hyperparathyroidism
• 1 in 500 to 1 in 1000
• Most common in 6th decade
• Most common aetiology in outpatients
• Women > men, 3:2 ratio (hormonal influence?)
• Many patients found on routine screening
with minimal symptoms
• 90% solitary adenoma; hyperplasia; carcinoma (rare)= growths in parathyroid gland produces too much PTH
What are the types of hyperparathyroidism?
• 1y hyperparathyroidism is an autonomous
and inappropriate overproduction of PTH
leading to hypercalcaemia
=high PTH, high calcium, low phosphate
• 2y hyperparathyroidism is an appropriate increase in PTH in response to hypocalcaemia, chronic kidney disease
=high PTH, low/normal calcium, high phosphate (CKD)
• 3y hyperparathyroidism is rare but refers to the situation where a 2y overactive gland becomes overactive (now autonomously so from appropriate to inappropriate)
=very high PTH, high calcium, high phosphate
Describe the histology of parathyroid adenoma
- No spaces between clusters of cells
- Homogenous
- Overproduction of cell types
Describe the radiology of hyperparathyroidism
- Bones brittle, fragile
- Dark- less bone matrix
- Calculi
How do we diagnose 1y hyperparathyroidism?
• Raised Ca2+ with inappropriately increased
PTH
• Phosphate and bicarbonate tend to be low in serum (increased renal excretion)
• Alkaline phosphatase normal or moderately
increased in more severe disease
• Further investigations:
o Parathyroid imaging scan (Sestamibi,
99mTc-MIBI, adenoma and hyperplasia, isotope scans)
What is the treatment of 1y hyperparathyroidism?
• Acutely, patients may need treatment of their high ionised calcium:
– re-hydration
– drugs
• Definitive treatment is removal of parathyroid
adenoma (surgery- complete removal or adenoma removal)
• Mild cases may be managed by repeated follow-up of serum calcium/PTH
• Where surgery may be difficult (e.g. poor operative risk) drugs to lower calcium levels may be required
What are the available drugs to treat hypercalcaemia?
o Bisphosphonates (inhibit osteoclast action and bone resorption as analogues of pyrophosphate, reduce recruitment and promote apoptosis); after re hydration this is key drug for longer-term control o Furosemide (inhibits distal Ca2+ reabsorption; requires care and patient must be hydrated first) o Calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management- side effects o Glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action)
What are the new drugs that treat hypercalcaemia?
o Calcimimetic drugs which bind to Ca2+ sensor receptor and inhibit PTH release. Restricted use (e.g. parathyroid carcinomas, CKD)
=Cinacalcet
What is the link between malignant disease and hypercalcaemia?
• Commonest cause of hypercalcaemia in hospitalised patients
• Up to 20-30% cancer patients may develop hypercalcaemia during course of illness
• Two broad reasons:
o Endocrine factors secreted by malignant cells acting on bone
o Metastatic tumour deposits in bone locally
stimulating bone resorption via osteoclast activation
What is the frequency of different malignancies as causes of hypercalcaemia?
- Lung= 35%
- Breast= 25%
- Haematological (including myeloma)= 14%
- Head and Neck= 6%
- Renal= 3%
- Prostate= 3%
- Unknown primary= 3%
- Others= 3%
What are the endocrine factors in malignant hypercalcaemia?
• Solid tumours may secrete PTH-related peptide (or PTHrP) (e.g. breast; squamous tumours of lung, head and neck)
• PTHrP shows structural homology to PTH and shares similar actions but is distinct (PTH itself is suppressed due to feedback)
• Where PTHrP is the cause this is known as humoral hypercalcaemia of malignancy
• Some tumours (esp. Hodgkin’s lymphoma)
possess 1-OHase activity and synthesise
calcitriol
Describe how malignant hypercalcaemia is associated with bony metastases
• Approx. 20% cases malignant hypercalcaemia
• Most commonly associated with breast
and lung cancers, multiple myeloma
• Secretion of osteoclast activating cytokines or other factors into the bone
micro-environment is key element
• Metastatic breast tumour may locally produce PTHrP
• Myeloma cells produce cytokines that
activate osteoclasts (RANKL, IL-3, IL-6)
Describe the findings of multiple myeloma
-Bone marrow biopsy
=Increase in plasma cells (abundance, more than 10%)
-Pepper pot skull= lesions in skull, punched out holes
How do we diagnose malignant hypercalcaemia?
• Raised Ca2+ with suppressed PTH
o Phosphate tends to be high
o Alkaline phosphatase may be very high (liver or bone metastases)
o Often clear from previous history of malignant disease
What are the principles of treatment of malignant hypercalcaemia?
• Re-hydrate the patient
• If required, use drugs which lower calcium in the blood
• Treat underlying malignancy (surgery,
chemotherapy)
What are other causes of hypercalcaemia?
- Granulomatous disease e.g. sarcoidosis
- Exogenous vitamin D excess
- Familial hypocalciuric hypercalcemia
- Drugs (e.g. Li, thiazide diuretics)
- Some endocrine diseases (thyrotoxicosis, Addison’s disease)
- Immobilization
What is sarcoidosis?
• Granulomatous disease • Usually affects lung (90%) and skin (10%) • ↑[calcium] with n[PTH] • Hydroxylation of vit D in granulomas =Marker is ACE =Relapsing and remitting pattern
Describe Familial hypocalciuric hypercalcaemia (FHH)
• Rare but interesting
• Ca2+ sensor on parathyroid glands less
sensitive to Ca2+ suppression of PTH
• Altered ‘set-point’ for PTH/Ca2+ interaction
• PTH levels tend to be high normal or slightly
raised
• Plasma ionised calcium increased (mild)
• Urine Ca2+ excretion low (relative to plasma Ca2+)
What are the clinical manifestations of hypocalcaemia?
• Predominantly due to an increase in neuromuscular excitability (increased inward Na+ movement?) • Neuromuscular o Numbness and paraesthesia (‘tingling’) in fingertips, toes, around mouth o Anxiety and fatigue o Muscle cramps, carpo-pedal spasm, bronchial or laryngeal spasm o Seizures • Mental state o Personality change o Mental confusion, psychoneurosis o Impaired intellectual ability • ECG changes, eye problems
What are the signs of hypocalcaemia?
- Chvostek’s sign= tapping facial nerves causes twitching of eye
- Trousseau’s sign= blood pressure inflated so brachial artery completely occluded and makes pinching sign
What is factitious hypocalcaemia?
Consequence of low plasma [albumin] e.g.:
• Acute phase response (low albumin)
• Malnutrition or malabsorption (protein
deficiency in diet)
• Liver disease (reduced liver synthesis
albumin)
• Nephrotic syndrome (albumin lost in urine)
What are the causes of active vitamin D deficiency (amount or action)?
- Lack of sunlight
- Inadequate dietary source
- Malabsorption (crohns, coeliac)
- Chronic renal disease (relatively common)
- Chronic liver disease (rare)
- Defective 1-OHase (v. rare)
- Defective 1,25- D3 receptor (v.rare)
Describe vitamin D deficiency
• Historically, in the UK, poor diet and inadequate sunlight exposure led to many cases of deficiency in children
• Although food (milk, cereals, margarine) is
fortified with vitamin D, the action of sunlight on skin is the main source of vitamin D
• Current risk factors where supplementation may be required:
o Those confined indoors (e.g. elderly)
o Dark skinned individuals at high latitudes
o Lack of sunlight exposure through dress, high factor
sunscreen etc.
What are the biochemical and clinical features of vitamin D deficiency?
-Symptoms related to low Ca2+
-Osteomalacia (bone pain, fractures, disordered growth in children as a consequence of defective mineralisation)
• Low 25-D3 (measured) and 1,25-D3 (usually)
• Low Ca2+ (may be normal in early stages)
• High PTH (2y hyperparathyroidism)
• Phosphate tends to be low
• Often raised ALP (defective mineralisation)
Describe Osteomalacia
- Pathological bone problem classically associated with vitamin D deficiency
- Osteoid laid down by osteoblasts is not adequately calcified
- Osteoid content in bone increases at the expense of normal calcified osteoid (bone matrix)
- Bones are softened, weak and susceptible to fracture
Describe Rickets
- Bone deformity (bowing of long bones widening of cartilage at growth plate)
- Bone pain
- Weakness
What are the inherited causes of osteomalacia/ rickets?
• Deficient 1-hydroxylase (vitamin D-resistant rickets type 1, VDRR type 1)
• Defective receptor for calcitriol (Vitamin D- Resistant rickets type 2, VDRR type 2)
• Other inherited causes of rickets:
o Hypophosphatemic rickets
Low serum phosphate
Impaired mineralisation
Excessive urine phosphate loss
Phosphaturic hormone (FGF23)/PHEX mutations
o Hypophosphatasia (low alkaline phosphatase)
Overall, what are the causes of hypoparathyroidism?
-Acquired
• Surgical damage or removal (relatively common; usually transient)
• Suppressed secretion (e.g. low Mg2+, maternal
hypercalcaemia)
-Inherited
• Developmental parathyroid problems
• Genetic/familial disorders
e.g. DiGeorge syndrome
What is the biochemistry of hypoparathyroidism?
• Low Ca2+
• Inappropriately low PTH
• Phosphate may be
increased
What are the principles of treatment of hypocalcaemia?
• In acute situations IV calcium may be required
• Normally oral calcium and vitamin D are given (Mg sometimes)
• Vitamin D may be given in various forms:
– By injection (IM) if malabsorption is present or
stores require to be replete more quickly
– As the 1OH form if renal function is impaired
• Close monitoring of plasma calcium concentration necessary
Describe osteoporosis
• Commonest bone disease (up to 30% women and 12% men) • Reduced bone mineral density; disruption of microarchitecture • Increased risk of fracture • Routine biochemistry unaffected
How do we assess bone mineral density?
Dual-energy X-ray absorptiometry
(DEXA)
=Scores, average estimate of bone density
Compare and contrast osteoporosis and osteomalacia
Osteoporosis: • Loss of calcified matrix and reduced bone density •‘Less’ bone but histologically normal • Susceptibility to fracture • Essentially normal biochemistry • Defined by bone densitometry (less than 2.5 SD than bone from a young adult)
Osteomalacia: • Abnormal histology with wide seams of uncalcified osteoid • Loss of calcified matrix and reduced bone density • Susceptibility to fracture • Abnormal biochemistry
What is the formula for corrected calcium?
corrected [Ca2+] = measured [Ca2+] + (40 - [albumin] * 0.02)
Why might total serum calcium not represent patient’s ionised calcium status?
-Hypoalbuminaemia
-Acid-base balance disorders can affect the binding of calcium to albumin and inorganic ions.
=In acidosis, albumin becomes protonated which prevents it from binding calcium as effectively, therefore unbound calcium increases.
= On the other hand, in alkalosis albumin can bind calcium more easily, resulting in a reduction in unbound calcium.
-In these situations, there is a change in the proportions of calcium bound and unbound, but the total calcium remains unchanged
How is calcium transported across the intestinal epithelia?
- Calcium diffuses paracellularly (between cells) down its concentration gradient. This occurs only when the concentration of calcium in the gut lumen is greater than the concentration of calcium in the extracellular fluid.
- When calcium levels in the gut lumen are low, calcium can diffuse transcellularly (across cells). First calcium diffuses into the cell (because the intracellular concentration is much lower than the concentration in the gut lumen.
=However, this diffusion cannot go on forever, because calcium is dangerous to the cell. Also, the concentration gradient would be lost, so no more calcium would diffuse in once an equilibrium is reached. - Therefore the cell has calcium binding proteins (such as calbindin) within it. Calcium binds to the proteins. This maintains the concentration gradient of free calcium so more can diffuse into the cell.
- Calcium is then pumped out of the basal membrane of the cell. The Na+/Ca2+ exchange protein pumps calcium out of the cell by using the sodium gradient created by the Na+/K+ pump.
Where is calcium absorbed in the kidney?
- 60% PCT
- 25% ascending limb
- 10% DCT, amount modifiable by hormones
Features of primary hyperparathyroidism progression
-Subperiosteal bone erosion in phalanges
-Osteitis fibrosa cystica
=chronic overstimulation of osteoclasts= excessive bone resorption
=brown tumours (weak patches of immature bone, connective tissue and bone stroma)
How would humoral hypercalcaemia of malignancy present compared to osteolytic bone metastases?
-HHoM
=high calcium, high PTHrP, low PTH, low phosphate
-Bone metastes
=high calcium, low PTH, high phosphate and high alkaline phosphatase
Describe Multiple Myeloma
-Cancer of plasma cells (mature immunoglobulin producing cells that differentiate from B cells)
=secrete paraproteins (abnormal immunoglobulin/ IgG) causes tissue damage
-Common in black elderly people, incurable
What are the symptoms of Multiple Myeloma?
-CRAB
-Calcium= hypercalcaemia
=Renal= kidney damage from paraproteins and hypercalcemia
-Anaemia= disrupt haematopoiesis in marrow
-Bone= resorption
What is Milk-alkali syndrome?
- caused by excess dietary intake of calcium and alkali, for example taking calcium supplements alongside calcium carbonate antacids.
- This can cause hypercalcaemia, a metabolic alkalosis and kidney damage
What symptoms present in chronic hypocalcaemia?
- Cataracts
- Basal ganglia calcification
- Extrapyramidal disorders
What are the causes of hypocalcaemia?
- Vitamin D deficiency
- Hypoparathyroidism
- Chronic kidney disease
- Hypomagnesemia
- Acute pancreatitis
How do we treat secondary hyperparathyroidism?
- Treat CKD
- Ergocalciferol
- Low phosphate diet
- Phosphate binders
