Bone Physiology Flashcards
What are the calcium-regulating hormones?
Circulating calcium in the ECF is tightly controlled - this is what is measurable in labs
Normal reference range for total calcium is 2.2-2.6 umol/L
Largely regulated by two hormones:
- PTH
- 1,25(OH)2D (calcitriol - activated vitamin D)
Also regulate phosphate concentration (Ca and P never go up together, one will increase as the other decreases as part of a regulatory mechanism - in CKD or some other diseases this is disrupted)
Calcitonin has a proposed minor role in Ca homeostasis - bigger role in other mammals
Where is PTH produced?
There are four parathyroid glands in the body, each is roughly size of a grain of rice so they are very difficult to localise, but in gland hyperplasia (causes hyperparathyroidism) at least one gland increases to the size of a baked bean (not much easier to locate).
PTH is secreted by each of the parathyroid glands, specifically chief and oxyphil cells. PTH synthesised, stored and secreted by chief cells.
Concentration PTH in plasma determined by its synthesis and secretion by parathyroid glands. Metabolism and clearance determined by liver and kidneys.
What is the function of PTH?
PTH acts:
- directly on bone and kidney
- indirectly on intestine to regulate [Ca] and [PO4]
PTH exerts its influence by interacting with PTH/PTHrP receptors on plasma membrane of target cells. This initiates a cascade of intracellular events:
- Generation of cAMP
- Activation of kinases
- Phosphorylation of proteins
- Increased entry of calcium and intracellular calcium
- Stimulated phospholipase C activity
- Generation of DAG and PI activate enzyme transport systems
- Secretion of lysosomal enzymes
What forms of vitamin D are present and active in the body?
Several forms of Vitamin D (vitamers): D1 – D5
Two major forms are the parent molecules, known collectively as calciferol:
Vitamin D2 – Ergocalciferol
Vitamin D3 – Cholecalciferol
25(OH) Vitamin D
- Precursor to vit D = not active, but what is measured as
deficiency. - Calcidiol, Calcifediol, 25-hydroxycholecalciferol, 25-hydroxyvitamin D
1,25(OH)2D
- Hydroxylated to active form in kidney - kidney issues lead to little vit D
- 1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D, Calcitriol
Alphacalcidol
1-hydroxycholecalciferol
Vitamin D analogue with less of an effect on calcium than calcitriol
Calcichew D3 Forte
Vitamin D3 with calcium
How is vitamin D clinically measured and utilised?
Vitamin D:
Non-hydroxylated parent compounds, short t1/2= 24hrs, conc transient based on recent sun exposure and diet
Very liphophilic and difficult to measure
25(OH) Vitamin D, D2 and D3
Effectively a pre-cursor of active form of Vitamin D
t1/2= 3 weeks
Direct indicator of available Vitamin D
1,25(OH) Vitamin D
Active form, very short t1/2= 4hrs
Limited clinical utility as the stability is too low - still metabolises in the tubes
How is vitamin D involved in the endocrine system?
PTH senses low Ca through Ca sensory receptors.
Causes an increase in PTH which:
- acts directly on the kidney:
- activates vit D by increasing 1a hydroxylase activity leading to
increased active vit D
- this increases calcium resorption and decreased excretion in
the tubules
- acts directly on the bone
- causes a deminarlisation of the top layer of bone
- this releases Ca and P, both of which increases the serum
calcium concentrations. BUT but dont want both P and Ca to
increase at the same time, so PTH is phosphoturic - causes
increased P excretion in urine to maintain balance, and increased
absorption of Ca
- acts indirectly on the gut via activated vitamin D,
- hence if an earlier route to activate vit D is ineffective, this will
be too.
- Increased absorption of active vit D in gut increases calcium
and phosphate.
How does PTH have an effect in the kidneys?
Induces 25-OH Vit D-1α-hydroxylase which increases production of 1,25(OH)2D (active form) which stimulates intestinal absorption of calcium and phosphate
- Increases calcium reabsorption in the DCT - Decreases reabsorption of phosphate in PT
Inhibits Na+-H+ antiporter activity which favours a mild hyperchloremic metabolic acidosis in hyperparathyroid states
- High chloride and low bicarbonate
How does PTH have an effect in the bone?
Effects of PTH are complex as can stimulate bone resorption or bone formation depending on [PTH] and duration of exposure
Chronic exposure to high [PTH] leads to increased bone resorption
- PTH acts directly by altering the activity or number of osteoblasts and
indirectly on osteoclasts
- Bone resorption, a quick response is important for maintenance of
calcium homeostasis
- Delayed effects are important for extreme systemic needs and skeletal
homeostasis - inc number of osteoblasts to increase bone turnover
How is calcium homeostasis affected in Renal failure?
Fall in calcium:
↓ conversion 25(OH)D to 1,25(OH)D = no activation
Increase in phosphate:
Kidneys are not excreting excess
FGF23 role - research tool but early indicator of phosphate homeostasis
Increase in PTH:
Stimulated by low Ca (no activation, and no indirect effect on gut)
Continual stimulation of parathyroid glands leads to 2° hyperparathyroidism (gland takes over and becomes autonomous = no homeostasis)
Patients with end stage renal failure become hypercalcaemiac
Probably due to development of autonomous PTH secretion from prolonged hypocalcaemic stimulus
Such hypercalcaemia may manifest for the first time in a renal transplant patient who becomes able to metabolise vitamin D normally - 3° hyperparathyroidism
How does PTH cause Ca mobilisation?
Integration of direct and indirect effects of PTH lead to alterations in calcium and phosphate in serum and urine
PTH mobilisation of calcium is biphasic:
- A rapid phase involving existing cells
- Long term response dependent on proliferation of osteoclasts
In serum total and free calcium are increased, phosphate decreased
In urine, inorganic phosphate and cAMP are increased
Urinary calcium is usually increased as larger filtered load of calcium from bone resorption and intestinal reabsorption overrides increased tubular reabsorption of calcium
In absence of disease the increase in serum calcium reduces PTH secretion through negative feedback loop maintaining homeostasis
How does PTH affect Phosphate and Mg?
Despite PTH being important in control of phosphate secretion
Changes in phosphate do not directly affect secretion of PTH
Mild hypomagnasaemia stimulates PTH secretion
More severe hypomagnasaemia reduces PTH secretion as it is a Mg dependent process (requires Mg for activation)- cAMP and ATP pathways always have Mg cofactors
What are the functions of bone?
Support:
Framework of body supporting softer connective tissues and muscles
Protection:
Mechanical protection for internal organs
Assisting in movement:
Muscles attached to bones so when they contract bones will move
Mineral storage:
Calcium and phosphate reservoirs
Production of blood cells (haeopoetic system):
Bone marrow inside some long bones
Storage of energy:
With age, bone marrow changes from ‘red’ to ‘yellow’ and is predominantly adipose cells providing a chemical energy reserve
What are the different types of bones?
Long bones
- Greater length than width, shaft (diaphysis) with variable number
of endings, curved for strength
- Predominantly COMPACT bone with lesser amounts of marrow
and spongy bone - Bigger capacity but less weight
- e.g. femur, tibia, ulna and radius
Short bones:
- Roughly cube shaped with approximately equal length and width
- Thin layer of compact bone surrounding SPONGY interior - Absorbing
bones - i.e. jumping
- e.g. ankle and wrist bones
Flat bones:
- Thin structure providing mechanical protection and extensive surface
area for muscle attachment
- TWO parallel layers of COMPACT bone surrounding SPONGY interior
- e.g. cranial bones, sternum, shoulder blades
Irregular bones:
- Complicated shapes due to function they fulfil within body
- Thin layers of compact bone surrounding SPONGY interior
- e.g. vertebrae and some facial bones
Sesamoid bones:
- Develop in some tendons where there is considerable friction, tension
and physical stresses; quantity varies considerably person to person
- e.g. common to all are patellae (kneecaps)
What is the structure of bones?
Long bones grow from the ends and under normal circumstances stop growing in late teens or early 20’s - dictate height
Two main types of (lamellar) bone tissue:
- Compact
- Forms outer shell of bones consisting of very hard bones
arranged in concentric layers (Haversian systems)
- Accounts for 80% of total bone mass of adult- thin but very dense -
hence function - Cancellous (trabecular, spongy bone)
- Located beneath the compact bone
- Consists of a meshwork of bony trabeculae with many interconnecting
spaces containing bone marrow
- Accounts for remaining 20% of total bone mass but nearly 10x surface
area of compact bone
What are the different types of bone cells?
OsteoBlasts (Build bone):
- Produce collagen-based matrix which mineralises to form
‘osteoid’
- Become quiescent and flatten to become lining cells
- Respond to hormonal control to activate osteoclasts
OsteoCYCtes (‘cycle’ - transport minerals)
- Cells inside the bone which sense mechanical stress to initiate
remodelling
- Transports mineral into and out of bone
OsteoClasts (‘Consume’ minerals)
Dissolve bone by solubilising mineral - resorption = demineralise top layer
Effects change in bone structure
What is bone remodelling?
Process of resorption followed by replacement
Lifelong process - but different periods of activity
- In 1st year of life almost 100% of bone is replaced
- In adults approx 10% per year - but no change in overall shape
Little change in shape and occurs throughout life
- Regulates calcium homeostasis
- Repairs micro-damaged bones (everyday stress)
- Shapes and sculptures skeleton during growth
Imbalance leads to metabolic bone disorders
What is the activity of osteoblasts and osteoclasts in the cycle of bone turnover?
Bone is obviously not remineralising all at the same time, occurs in a wave.
- Quiescent stage: lining cells are activated by mechanical or biochemical stimuli (eg PTH), causing them to retract to reveal underlying membrane. Enzymes such as matrix metalloproteinases start to digest that.
- Osteoclasts are attracted and fuse (activation), allowing them to digest the underlying bone - these are the demineralising cells.
- Osteoblasts (builders) move into resorption cavities, relay the matrix that then remineralises.
Timescale - from start to remineralisation can take 160-200 days.
What growth factors and signalling molecules are involved in bone turnover?
Osteoblasts produce RANKL which activates RANK on osteoclast precursor cells
- Stimulates cell to differentiate in mature osteoclast
Activated RANK induces expression of c-Fos which binds to DNA and activates genes required for osteoclast function
c-FOS also activates Interferon-β which prevents further osteoclast differentiation
Osteoprotegerin is soluble protein released from osteoblasts that binds to RANKL preventing RANK activation
What is the molecular structure of bones?
Matrix:
- 40% organic
- Type 1 collagen (tensile strength)
- Proteoglycans (compressive strength)
- Glycoproteins - Osteocalcin / osteonectin
- Growth factors / cytokines
- These are what are synthesised during regrowth
Inorganic:
- 60% inorganic - hydroxyapatite
Organic - cellular elements:
- Osteoblasts / osteocytes / osteoclasts
How does the formation (ossification) of bone occur?
Begins 3rd month foetal life and completed late adolescence - can suddenly see huge increase in ALP = growth spurt (female = 12-13, male = 14-15)
Two processes occur:
- Intramembranous ossification:
- Occurs during flat bone formation - eg head
- Formed from mineralisation of connective tissue rather than cartilage - Endochondral ossification:
- Occurs in long bones
- Endochondral ossifacation:
- Multiplying cartilage cells mature and calcify, followed by deposition of osteoblasts.
- This initial initial hyaline cartilage model continues to grow and
mineralise at the metaphysis to form a growth plate (leaves lines
in bones where each cycle has started and finished)
- When skeletal maturity is reached, bones stop growing in length
and you get epithaseal line.
- Defects in the continued division of these plates can lead to growth
disorders e.g. achondroplasia where there is a defect in cartilage
formation leading to dwarfism (rest of skeleton is fine, but bones are
shorter)
What are common disorders of the bone?
206 bones which can be affected by various diseases and disorders!!!
Osteomalacia – inadequate mineralisation of bone
Rickets in children - because children are playing in doors more
- Insufficient Ca absorption due to lack Ca or Vit D def (kidney?)
- Phosphate deficiency caused by increased renal loss (kidney?)
Osteoporosis – Reduced bone mineral density leading to brittle bones
Pagets disease – excessive resorption and formation leading to weak and misshapen bones - often leads to deafness first as ear bones are mostly affected
Renal osteodystrophy – kidneys fail to maintain Ca and PO4 (excretion or reabsorption)
Rheumatoid osteoarthritis – systemic inflammatory disease (autoimmune)
Malignancy
What are the functions of calcium?
Bone growth and remodeling
Secretion (exocytosis) - cellular excretion of proteins eg ACh
Excitation-contraction coupling
Stabilization of membrane potentials - stabilise heart in tachycardia to prevent MI
Enzyme co-factor (e.g. Reduced blood coagulation)
Second messenger – intracellular signalling
What are the different forms of calcium?
Majority of calcium is in the skeleton (reservoir)
- Serum Calcium 2.20 – 2.60 mmol/L
- Ionised calcium 1.1-1.3 mmol/L
- 45% exists in ionised form (physiologically active form)
- 45% bound to proteins (predominantly albumin)
- 10% complexed with anions (citrate, sulphate, phosphate)
Report adjusted calcium and total calcium
Ionised calcium is difficult to measure – ABG machine, calcium electrode, not readily available, dependent on pH
What is adjusted calcium?
Adj Ca accounts for changes in albumin
Useful when a decrease in albumin may mask hypercalcaemia
Conversely not useful in very low albumin states <20g/L - total calcium might be misrepresented
Interpret with caution in extremes of pH - eg someone in DKA
- Acidosis decreases binding
- Alkalosis increases binding
Standard ACa formula
ACa = Total Ca + 0.02 x (40-[albumin])
More appropriate to develop in-house adjustment formula
Remember it is the unbound calcium which the body regulates and in low protein states ACa may be inaccurate
What affects the biochemical homeostasis of calcium?
Input ————————> blood ————————> output
GI absorption || Urinary
of Ca after || excretion
absorption || of Ca
Internal reservoir = bone
(Not directly measurable)
Hypercalcaemia:
- Increased (input) GI absorption
- Increased bone resorption (into circulation)
- Decreased bone mineralisation (what goes into resovoir)
- Decreased urinary excretion (little output)
Hypocalcaemia:
- Decreased GI absorption (low ca diet)
- Decreased bone resorption (cant deminarilise)
- Increased bone mineralisation (hungry bone syndrome)
- Increased urinary excretion (nephrotic diseases)
What are common aetiologies of HYPERcalcaemia?
Increased GI Absorption:
- Elevated Vitamin D
- Excess exogenous (therapeutic)
- Excess endogenous (e.g. sarcoidosis)
- Elevated PTH - increased activation
- Hypophosphataemia
- Milk-alkali syndrome
Increased bone resorption:
- Increased net bone resorption
- Elevated PTH
- Malignancy
- Increased bone turnover
- Paget’s disease
- Hyperthyroidism - body is increased metabolically so functions
happen at a higher rate
Decreased bone mineralisation:
- Elevated PTH
- Aluminium toxicity - used to happen in dialysis patients, causing
deposition in bone
Decreased urinary excretion:
- Thiazide diuretics
- Elevated Vitamin D
- Elevated PTH
What causes HYPERcalcaemia?
Common Causes:
- Primary hyperparathyroidism (99% ambulant patients)
- Single adenoma (80%) (double is rare)
- Hyperplasia (15%)
- Double adenoma (2%)
- Carcinoma (<1%)
- Malignant disease (99% of ill patients)
- Metastases and myeloma
- PTHrp secreting
- Lymphoma
- PTH secreting (v. rare)
Uncommon Causes:
- Vitamin D excess
- Tertiary hyperparathyroidism - often occurs post transplant
- Hyperthyroidism
Rare Causes:
- Familial hypocaliuric hypercalcaemia - low 24 hour urine sample
What is PTH related Peptide (PTHrP)?
Discovered in 1987 when studying the mechanism by which certain cancers produce humoural hypercalcaemia of malignancy
The N-terminal shows homology with PTH with 8 of first 13 AA matching
Remainder of molecule shows little homology - so first 8/13 must be key for interacting with receptors. So tumours act as PTH.
Turnaround time for assay is too long to have clinical importance = research tool
The common N-terminal explains how PTHrP can interact with PTH/PTHrP receptors, mimicking biological actions of PTH in target tissues such as bone and kidney
Like PTH, PTHrP causes hypercalcaemia and hypophosphataemia and increases urinary cAMP
What are common aetiologies of HYPOcalcaemia?
Decreased GI absorption:
- Poor dietary intake
- Impaired absorption of Ca
- Vitamin D deficiency
- Poor dietary intake of Vit D
- Malabsorption
- Decreased conversion of Vitamin D
- Liver failure
- Renal failure
- Low PTH
- Hyperphosphataemia - tend to maintain each other in
opposite direction
Decreased bone resorption / Increased bone mineralisation
- Hypoparathyroidism
- PTH resistance (pseudohypoparathyroidism)
- Vitamin D deficiency
- Hungry bone syndrome - metabolic process where bone sucks in
all Ca and P
- Osteoblastic metastases
Increased urinary excretion:
- Low PTH
- Thyroidectomy
- I131 treatment
- Autoimmune hypoparathyroidism
- PTH resistance
- Vitamin D deficiency
What causes HYPOcalcaemia?
Always exclude EDTA contamination (causes high K, low Ca and low Mg due to collation - less common with coated tubes)
Multiple transfusions with citrated blood products (stop coagulation) = often see post op
Common causes:
- Acute or chronic renal failure
- Hypoparathyroidism
- Hypomagnesaemia
- Vitamin D deficiency
Parathyroid Causes:
- Parathyroid agenesis
- Isolated
- Part of complex developmental anomaly eg DiGeorge Syndrome
- Parathyroid destruction
- Surgery
- Radiation
- Infiltration: eg haemochromatosis, Wilson’s - Autoimmune
- Isolated
- Polyglandular - Reduced parathyroid function
- PTH gene defects
- Hypomagnesaemia
- Neonatal hypocalcaemia
- Hungry bone disease
Non-parathyroid Causes:
- Vitamin D deficiency
- Vitamin D resistance
- Altered vitamin D metabolism eg phenytoin (reduce 1-Alpha
hydroxylation), ketoconazole
- PTH resistance
- Pseudohypoparathyroidism
- Magnesium deficiency
- Bisphosphonates
- Acute pancreatitis - flair up causes calcium to bind = don't give Ca to
patient!
- Acute rhabdomyolysis
What are symptoms of HYPOcalcaemia?
Neuromuscular irritability:
- Tetany
- Carpopedal spasm
- Muscles cramps
- Seizures – all types
- Prolonged QT interval on ECG
- Bronchospasm
- Laryngospasm
Effect of Ca on muscles and nerves!
Longterm hypocalcaemia: - ectopic calcification eg in basal ganglia causing extrapyramidal neurological symptoms - Cataract, papilloedema - Abnormal dentition
What are the functions of phosphate?
Formation of:
- High energy compounds e.g. ATP, creatinine phosphate
- Second messengers e.g. cAMP, inositol phosphates
Component of:
- DNA/RNA
- Phospholipid membranes
- Bone
Phosphorylation (activation/inactivation) of enzymes - activates/deactivates pathways
Intracellular anion (not a representation of the stores in a serum collection)
How is phosphorus distributed?
85% is within the skeleton and teeth
14% is located within the cells
Only 1% is present in the extracellular fluids - what we measure
Present as organic (phosphoproteins, phospholipids) and inorganic (phosphate)
- Inorganic phosphate component is what we measure
(0.70-1.40 mmol/L)
- Mild deficiency 0.35 – 0.70 mmol/L
- Severe deficiency <0.35 mmol/L - especially in recovery from DKA
and refeeding syndrome
What affects the biochemical homeostasis of phosphorus?
Intracellular redistribution
⬇️⬆️
Delayed separation ⬇️⬆️ Refeeding
Rhabdomyolysis ⬇️⬆️ Recovery from DKA
Renal failure, etc. ⬇️⬆️ Alkalosis, etc.
⬇️⬆️
Input ————————> blood ————————> output
GI ⬇️⬆️ Urinary
absorption Mineralisation ⬇️⬆️ resorption excretion
of PO4 ⬇️⬆️ of PO4
Internal reservoir = bone
(Not directly measurable)
Hyperphosphatemia:
- Increased GI absorption
- Increased bone resorption
- Decreased bone mineralisation
- Decreased urinary excretion
Hypophosphataemia:
- Decreased GI absorption
- Decreased bone resorption
- Increased bone mineralisation
- Increased urinary excretion
What are the causes of HYPERphosphataemia?
Pseudohyperphosphataemia:
- Haemolysed specimen
- Myeloma
- Delayed separation / Old sample
Increased Phosphate Input:
- IV PO4
- Rectal PO4
- Cell death
- Tumour lysis syndrome - cells break down
- Rhadbomyolysis - Jordan muscle trauma, or someone falling and
lying in the same position - crushing muscle cells
- Malignant hyperpyrexia - due to heat
- Heat stroke
Reduced phosphate excretion:
- Reduced eGFR
- Acute renal failure (AKI)
- Chronic renal failure
Increased renal tubule reabsorption:
- Physiological
- Recovery from Vit D def
- Lactation - Pathological
- Reduced PTH or PTH resistance
- Vitamin D toxicity
- Thyrotoxicosis
- Acromegaly
What are the causes of HYPOphosphataemia?
Inadequate phosphate absorption:
- Low dietary intake (v rare)
- Phosphate binders (dialysis patients - causes phosphate to
transiently drop)
- Phosphate binding antacids (rare due to new therapies for peptic
ulcers)
Abnormal urinary phosphate loss:
- Primary and secondary hyperparathyroidism
- Osmotic diuresis e.g. hyperosmolar hyperglycameic state HHS -
equivalent of DKA
- Diuretics
- Fanconi syndrome
- Genetic conditions e.g.X-linked hypophosphataemia
Shifts of phosphate from extracellular fluid into cells:
- <1% in extracellular space
- Recovery from DKA
- Treatment with insulin causes phosphate to move back into cells
- Refeeding syndrome
- Starving or chronically malnourished patients are refed or given IV
glucose
- carbohydrates (initiate glycolysis and pentose phosphate
pathways) stimulate insulin which drives phosphate and glucose
intracellularly
- Cells switch to anabolic state resulting in further depletion of P
- use give IV phosphate during refeeding
- Respiratory alkalosis
- Activating phosphofructokinase which stimulates intracellular
glycolysis
- Increased muscle intake
- Hepatic encephalopathy
- Salicylate toxicity
- Acute leukaemia
- Rapid growing malignancies may consume phosphate preferentially
What is FGF23?
Increased significance in regulation of serum phosphate and 1,25 (OH) Vitamin D (active)
Secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased 1,25(OH)D (active)
In CKD, FGF23 sensitive biomarker of abnormal renal phosphate handling increasing during early stages - can treat before develop serious disease
Raised FGF23 increases fractional phosphate excretion (via NPT2 Na-PO4 cotransporter), reducing phosphate levels
FGF23 suggested to suppress 1α-hydroxylase activity, reducing ability to activate vitamin D
Responsiveness to FGF23 declines as number of intact nephrons reduces
- FGF23 therefore cannot reduce PO4 as effectively and exerts
other off-target effects including premature mortaility
- Lowering PO4 through binding agents reduces FGF23 and may
improve patient outcomes
What are the functions of magnesium?
Cofactor for 300+ enzymes
Mg-ATP complex is a substrate for many ATP requiring enzymes
Critical role for DNA replication, transcription and translation
Maintenance of structure of ribosomes, nucleic acids and some proteins
Interacts with calcium, required for PTH activation
Affects permeability of excitable membranes and their electrical properties
- ECF depletion of Mg causes hyperexcitability
- Post op given Mg, so expect to see high levels in certain wards.
Deliberately raised to prevent hyperexcitabilty for short time
What are the symptoms of HYPOmagnesaemia?
Predominantly intracellular cation
Serum Mg inaccurate way to assess total body Mg stores and can be misleading
Hypomagnesaemia symptoms include:
- Loss of appetite
- Nausea and vomitting
- Fatigue
- Weakness & numbness
- Tingling
- Muscle cramps
- Seizures
- Personality changes
- Hypokalaemia
- Hypocalcaemia
Effects nerves, muscles and gut = same as Ca
What are the symptoms of HYPERmagnesaemia?
Symptoms usually not apparent unless > 2mmol/L
Concomitant HypoCa, HyperK or uraemia exaggerate symptoms of hyperMg
Non-specific symptoms include nausea, vomiting and flushing
Neuromuscular symptoms
- Blockage of neuromuscular transmission
Conduction system symptoms
- Mild decrease in blood pressure
- Higher concentrations lead to symptomatic hypotension
- Heart block >7mmol/L
Hypocalcaemia
What are the causes of HYPOmagnesaemia?
Decreased intake +/- absorption
- Starvation (protein calorie malnutrition)
- Malabsorption syndrome
- Prolonged gastric suction
- Inadequate parenteral nutrition
Loss from body
- Extra renal
- Diarrhoea
- Laxative abuse
- Gut fistula
- Excessive lactation (rare)
Misc
- Acute pancreatitis
- Multiple transfusions, through chelation
- Insulin therapy
- Hungry bone syndrome
Renal : - Alcoholism - Interstitial nephropathy (anything that affects loop of Henle) - Diuresis e.g. DKA, post ATN - Drugs e.g. loop diuretics, cis-platinum (65-75% reabsorbed in Loop of Henle) - Hypercalcaemia - RTA - Bartter’s syndrome, Gitelman’s - Endocrine e.g. hypoparathyroidism, primary hyperaldosteronism, hyperthyroidism - K depletion - PO4 depletion - Post renal Tx - Primary renal Mg wasting
What are the causes of HYPERmagnesaemia?
Significant hypermagnesaemia is uncommon as readily excreted in urine
Cardiac conduction is affected at concentration >2.5-5.0 mmol/L
Very high concentrations >7.5 mmol/L cause respiratory paralysis and cardiac arrest
Generally either - Impaired renal function - Large Mg load - IV Contamination - Post cardiac surgery or in pre-eclampsia where it is used to decrease neuromuscular excitability - Enema / laxative abuse
Rare causes include
- Excessive tissue breakdown
- Lithium therapy (↓ renal excretion)
- Hypothyroidism
- Addison’s disease
- Familial hypocalciuric hypercalcaemia - tubular defect
