Electrolyte disorders

Question 1

Assessment of electrolyte imbalance

Answer 1

-Laboratory results

-History
=Vomiting (hypokalaemia, metabolic alkalosis), diarrhoea (hypokalaemia, metabolic alkalosis/acidosis), weakness (hypo/hyperkalaemia), confusion (hyponatremia, hypercalcaemia), pain (hypercalcaemia), endocrine and renal disease (excretion), alcohol, diet, supplements

-Physical examination
=BP (potassium in aldosteronism), fluid status, endocrine disease?
-Complete drug history!

Question 2

Why is hyperkalaemia important?

Answer 2

-Life-threatening cardiac dysrhythmia.
-Potassium is freely filtered at the glomerulus; around 65% is reabsorbed in the proximal tubule and a further 25% in the thick ascending limb of the loop of Henle.
-Little potassium is transported in the early distal tubule but a significant secretory flux of potassium into the urine occurs in the late distal tubule and cortical collecting duct to ensure that the amount removed from the blood is proportional to the ingested load.

Question 3

Causes of hyperkalaemia

Answer 3

-AKI
-Drugs:
=potassium sparing diuretics
=ACE inhibitors
=Angiotensin 2 receptor blockers
=Spironolactone
=Ciclosporin
=Heparin
-Metabolic acidosis
-Addison’s disease
-Rhabdomyolysis
-Massive blood transfusion

Question 4

Presentation of hyperkalaemia

Answer 4

-Mild to moderate hyperkalaemia (<6.5 mmol/L) is usually asymptomatic.
-More severe hyperkalaemia can present with progressive muscular weakness, but sometimes there are no symptoms until cardiac arrest occurs.
-Metabolic acidosis is associated with hyperkalaemia as hydrogen and potassium ions compete with each other for exchange with sodium ions across cell membranes and in the distal tubule.

Question 5

Investigation of hyperkalaemia

Answer 5

-ECG: monitor cardiac rhythm serum K >/6.0 mmol/l
=Clinical signs are rare. An ECG may show tall T waves (peaked, 5.8), increased PR interval (6.5) and widened QRS complexes (7+). In severe cases, the P and T waves are absent (7+). A plasma K+ of over 7 mmol/l may lead to cardiac arrest. Sine wave, bradycardia, VT
-Exclude pseudo hyperkalaemia
-Electrolytes, creatinine, bicarbonate
-Plasma sodium concentration in Addison’s

Mild: 5.5-5.9
Moderate: 6-6.4
Severe: >6.5

Rate of rise

Question 6

Management of hyperkalaemia

Answer 6

1. Stabilising cardiac conduction (with intravenous calcium salts, chloride central 10mg 10%/gluconate peripheral 30 10%) IMMEDIATE PRIORITY, repeat every 2-3 minutes
2. Shifting potassium into cells (a temporary holding measure):
   =insulin-dextrose (10 units soluble in 25g glucose: 250ml 10% if no pulmonary oedema, monitor BM, 30 mins for 2 hours then every hour for 6 hours)
   =salbutamol (nebulised 20mg)
   =possibly sodium bicarbonate (cardiac arrest)
   =restore renal function (IV fluids? urinary catheter?)
3. Enhancing potassium removal from the body (in the urine or using renal replacement therapy, IV furosemide? with normal saline)

-For mild-to-moderate hyperkalaemia, it is important to weigh the benefits of potassium-lowering therapy against the iatrogenic risks. =These risks include hypoglycaemia (after insulin therapy) and decompensated heart failure (after stopping RAS inhibitors).

-Longer-term
=Dietary restriction
=Binders
=Diuretics
=Review RASi and other medications

Question 7

Describe giving IV calcium

Answer 7

-Intravenous calcium is necessary only if there is dysrhythmia or severe ECG changes
=10% gluconate or chloride, 10mls over 5 minutes (maximum 2mls/min)

-Give if ECG changes – peaked T-waves, prolonged PR
-Check in 15 minutes and if still abnormal, repeat once or twice
-Does not change [K+]; reduces excitability of membranes

Question 8

Describe giving IV dextrose and insulin

Answer 8

-Intravenous glucose (dextrose)
-50ml 50% (25g) + 5u Actrapid over 20 minutes (i.e., maximum ratio of 5g:1 unit)

-Acts in 30 minutes, peak effect 90 minutes, lasts up to 6 hours
-Lowers [K+] by 0.7-1.6mmol/l
-Can be followed by slow infusion of 10-50% dextrose (give insulin only if glucose high)
-Monitor blood sugar after administration

Question 9

Describe giving salbutamol

Answer 9

-5mg nebulised

-Acts in 60 minutes, peaks 90 minutes, lasts up to 6 hours
-Similar to dextrose in efficacy

Question 10

Describe giving sodium bicarbonate

Answer 10

-Sodium bicarbonate
-50 mmol, usually as 330mls 1.26% (isotonic) (50ml of 8.4%, but this is irritant)

-The least effective intervention and involves sodium load; consider if acidotic and extra sodium tolerable
-Can reduce [K+] by 0.2-0.3mmol/l
-Not routine but may be useful in emergency

Question 11

Describe giving dialysis

Answer 11

-Dialysis
-Only necessary if renal function very poor – working kidneys excrete potassium!

-Note that above treatments do not remove, they only redistribute [K+]
-A standard haemodialysis removes 40-60mmol [K+]
-Haemodialysis lowers [K+] faster than haemofiltration or peritoneal dialysis

Question 12

Describe giving potassium binding resins and compounds

Answer 12

Calcium Resonium is the original. Not useful in acute setting but may be short/medium term option if dialysis not desirable or possible. Unpleasant to take, causes constipation, limited effectiveness. Other more effective and apparently less toxic compounds are in development.

Question 13

Hyperkalaemia in cardiac arrest

Answer 13

1. ALS
2. Identify and treat reversible causes
3. Calcium chloride or calcium gluconate IV bolus (repeat 5-10 mins)
4. Insulin-glucose IV bolus (follow with 10% glucose infusion if BM <7)
5. Sodium bicarbonate IV bolus

ROSC achieved?
=Dialysis
=Monitor serum K and BM
=Post cardiac arrest management, ICU

Question 14

Hyperkalaemia in primary care

Answer 14

5.5-5.9
=Medication review (RAASi, potassium supplements, trimethoprim, NSAID, non-selective beta blockers)
=Low K diet, treat metabolic acidosis, consider diuretic (Patiromer, Sodium Zirconium Cyclosilicate)

6-6.4
=If not acutely ill or AKI, medication review
==Ig CKD 3b-5 or HF, Patiromer or SZC
==Stop RAASi
=If acutely ill, stop RAASi and refer to hospital for emergency treatment

Question 15

(hyper)Potassium homeostasis

Answer 15

-Serum K sensed in adrenal cortex
-Adrenal gland makes aldosterone= reabsorb sodium and excrete potassium (GFR, tubular flow to distal nephron, K secretion exchange for Na so function of collecting duct)
-Shift in plasma potassium: insulin, catecholamines, acid-base, integrity of cells

85% of normal potassium excretion is in urine. Potassium balance depends on regulation of urinary excretion. Endogenous potassium is largely intracellular, hence changes in K+ distribution between ECF and ICF may greatly affect plasma K+ concentration.

Question 16

Causes of hyperkalaemia

Answer 16

-Increased intake (food, IV fluids, potassium supplements)(unlikely to be sole cause)
-Tissue breakdown (e.g. tissue damage, bleeding, haemolysis, rhabdomyolysis, tumour lysis)
-K+ release from cells (e.g. in hyperglycaemia, acidosis)
-Endocrine – Addison’s disease/ adrenal insufficiency (aldosterone)
Impaired excretion in urine (e.g. in renal failure/ advanced CKD, and with drugs – ACE inhibitors, potassium-sparing diuretics, AKI)

DRUGS
-Impaired aldosterone signalling
=ACEi/ARB
=beta blockers
=heparin
-Impaired renal Na/K exchange
=K-sparing diuretics
=Trimethoprim (co-trimoxazole)
=CNI
-Cellular translocation
=Beta-blockers
=Digoxin
=Anaesthetic agents
=Mannitol

Question 17

Low potassium diet

Answer 17

-The usual dietary intake of K+ is about 80 mmol/day.
-Typical daily intake in the UK can vary from 50 to 150mmol. Intake should only be limited if blood tests show it’s necessary, as the fruit and vegetable contribution to potassium intake is important for general health.

Potassium is found in many foods but particularly high in fruit, fruit juice, and potatoes and vegetables which have not been boiled. Salt substitutes (i.e. Contain potassium rather than sodium), bananas, oranges, kiwi fruit, avocado, spinach, tomatoes

CKD – restriction not usually required until GFR<20, unless on ACE inhibitions, and their continuation thought important.
HD – most patients require some restriction.
PD – some patients require restriction.

Question 18

Causes of hypokalaemia

Answer 18

1. SHIFT INTO CELLS
   -catecholamines / beta-agonists
   -insulin treatment of hyperglycaemia
   -re-feeding syndrome
   -hypokalaemic periodic paralysis
   -metabolic alkalosis
2. RENAL POTASSIUM LOSS
   -with metabolic alkalosis
   =vomiting, diuretics, Gitelman, Bartter, mineralocorticoid XS, apparent mineralocorticoid XS
   -with metabolic acidosis
   =renal tubular acidosis types I & II
   =DKA
   -with variable acid-base
   =Mg-depletion
   =non-reabsorbable anion (e.g. high-dose IV penicillins)
3. GASTROINTESTINAL POTASSIUM LOSS
   -with normal acid-base
   =anorexia, tea & toast diet, laxative abuse
   -with metabolic acidosis
   =diarrhoea, villous adenoma, intestinal obstruction

ENDOCRINE: hyperaldosteronism, primary or secondary

-Hypokalaemia with hypertension
=Cushing’s syndrome
=Conn’s syndrome (primary hyperaldosteronism)
=Liddle’s syndrome
=11-beta hydroxylase deficiency*

-Hypokalaemia without hypertension
=Diuretics
=GI loss (e.g. Diarrhoea, vomiting)
=Renal tubular acidosis (type 1 and 2**)
=Bartter’s syndrome
=Gitelman syndrome

-Hypokalaemia with alkalosis
=Vomiting
=Thiazide and loop diuretics
=Cushing’s syndrome
=Conn’s syndrome (primary hyperaldosteronism)

-Hypokalaemia with acidosis
=Diarrhoea
=Renal tubular acidosis
=Acetazolamide
=Partially treated diabetic ketoacidosis

Question 19

Presentation of hypokalaemia

Answer 19

-Patients with mild hypokalaemia (plasma K + 3.0–3.5 mmol/L) are generally asymptomatic
-Lethargy
-Muscle weakness
-Tingling in fingers, paralysis and coma are present in more severe cases.
-Ventricular ectopic beats or more serious arrhythmias may occur and the arrhythmogenic effects of digoxin may be potentiated
-In chronic hypokalaemia there may be nocturia, polyuria or polydipsia.
muscle weakness, hypotonia
hypokalaemia predisposes patients to digoxin toxicity - care should be taken if patients are also on diuretics

Question 20

Investigation in hypokalaemia

Answer 20

-The urine potassium concentration or 24 hr urine potassium excretion can be helpful in distinguishing between renal and extra-renal causes of hypokalaemia. Urine potassium is
=Low (< 20 mM on a spot sample or < 15 – 20 mmoles per day) in extra-renal causes
=High (> 20 mM on a spot sample or > 15 – 20 mmoles per day) in renal causes.

-One important thing to remember here is that vomiting actually promotes renal potassium loss, so expect a high urine potassium concentration after vomiting.

-Plasma electrolytes, bicarbonate, urine potassium, plasma calcium and magnesium, plasma renin?
-Many such cases are associated with metabolic alkalosis, and in this setting the measurement of urine chloride concentration can be helpful. A low urine chloride (<30 mmol/L) is characteristic of vomiting (spontaneous or self-induced, in which chloride is lost in HCl in the vomit), while a urine chloride >40 mmol/L suggests diuretic therapy (acute phase) or a tubular disorder such as Bartter or Gitelman syndromes. Differentiation between occult diuretic use and primary tubular disorders can be achieved by performing a screen of urine for diuretic drugs.

U waves
small or absent T waves (occasionally inversion)
prolong PR interval
ST depression
long QT
=In Hypokalaemia, U have no Pot and no T, but a long PR and a long QT

Question 21

Management of hypokalaemia

Answer 21

-KCl, intravenously in severe cases
-Correcting any associated salt and water imbalance.
-Recurrence is prevented by encouraging a K+ rich diet, but K+ supplementation or a K+-sparing diuretic is advisable if the patient requires diuretics, and supplementation if receiving intravenous fluid treatment.

-In the less common situation where hypokalaemia occurs in the presence of metabolic acidosis, alkaline salts of potassium, such as potassium bicarbonate, can be given by mouth.
-If magnesium depletion is also present, replacement of magnesium may also be required, since low cellular magnesium can promote tubular potassium secretion, causing ongoing urinary losses.
- In some circumstances, potassium-sparing diuretics, such as amiloride, can assist in the correction of hypokalaemia, hypomagnesaemia and metabolic alkalosis, especially when renal loss of potassium is the underlying cause.

Question 22

Why is sodium balance important?

Answer 22

Serum sodium concentration reflects the balance between total body sodium and total body water content. Hence, an assessment of fluid status is key to determining the aetiology and treatment of disorders of sodium concentration. Both hyponatraemia and hypernatraemia can cause cerebral damage, therefore it is important to know the causes and management of disorders of sodium concentration

Question 23

Homeostatic control of sodium

Answer 23

-Plasma tonicity (sensed by osmoreceptors in hypothalamus) is controlled in a negative-feedback loop in which anti-diuretic hormone (ADH) is released from the posterior pituitary in response to rising tonicity.
-ADH acts in the collecting ducts of the kidney, opposing the excretion of water in the urine (make concentrated urine)
-Renal free water excretion depends on: GFR, diluting segment (ascending limb, DCT), ADH-receptor-responsive CDs, osmolar load (amount solute intake)
-Plasma sodium proportional to total body solute content (Na + K)/ total body water

Question 24

Causes of hypernatraemia

Answer 24

-The problem is a deficit in total body water.
=As thirst is such a powerful mechanism, this situation usually only arises in patients who have no access to water (e.g. in the perioperative setting)

1. Reduced water intake (e.g. coma, dysphagia, extreme depression). Because hypernatraemia is an extremely strong stimulus to thirst, reduced water intake is almost always involuntary.
2. And increased losses of hypotonic fluid. Usually both are present, though either alone can be sufficient.
   =increased loss via gut, skin or respiratory tract. Cholera syndromes (likely to be sodium depleted too); severe sweating, etc
   =increased loss in urine caused by impaired ability to concentrate urine (diabetes insipidus, central, nephrogenic or drug-induced)

osmotic diuresis e.g. hyperosmolar non-ketotic diabetic coma
diabetes insipidus
excess IV saline

Question 25

Presentation of hypernatraemia

Answer 25

-Thirst
-Weakness
-Dizziness
-Oliguria and concentrated urine.
-More severe cases may result in confusion and weakness, and possibly tachycardia, and finally hypotension and coma

Question 26

Investigation of hypernatraemia

Answer 26

-Plasma urea is usually elevated due to a low urine flow rate, which is accompanied by increased tubular reabsorption of urea.
-These findings, along with a urine osmolality of over 600 mosm/kg confirm water depletion.
-EGFR, creatinine

Question 27

Management of hypernatraemia

Answer 27

-The treatment is to give enough water to replenish body water stores, accounting for any ongoing water losses.
=This may be given enterally (drinking or NG tube) or parenterally as intravenous 5% glucose.
-Treatment is by oral replacement of water in mild cases; 5% dextrose (i.v.) in moderate cases; and a combination of 5% dextrose and 0.9% (150mmol/l) saline (i.v.) if dehydration is severe, as volume expansion requires salt as well as water.

Hypernatraemia should be corrected with great caution. Although brain tissue can lose sodium and potassium rapidly, lowering of other osmolytes (and importantly water) occurs at a slower rate, predisposing to cerebral oedema, resulting in seizures, coma and death1. Although there are no clinical guidelines by NICE or Royal College of Physicians at present, it is generally accepted that a rate of no greater than 0.5 mmol/hour correction is appropriate1.

Question 28

Causes of hyponatraemia

Answer 28

-Hyponatraemia is a problem of low plasma tonicity. Or you can consider it as a problem of excess body water.

-Translocation of water into the circulation such as in severe hyperglycaemia (in which case plasma tonicity will be normal and there is no risk of cerebral oedema; POsm > 280 mOsm/L)
-POLYDIPSIA: Excessive water intake (relative to kidney function) or low dietary solute (beer potomania, tea and toast) intake (in which the urine will be very dilute: UOsm < 100 mOsm/L)
-Release of ADH in response to hypovolaemia (in which case the renin-angiotensin system will also be activated so that urinary sodium excretion is low: UNa < 30 mM)
-Reduced body sodium: water depletion accompanied by excessive Na+ depletion – e.g. large electrolyte losses replaced largely by water drinking. Seen in Addison’s disease, for example, when kidneys fail to retain sodium.
-Release of ADH in response to what the body perceives as hypovolaemia in low cardiac-output or vasodilated states such as heart failure or portal hypertension in liver cirrhosis (renin-angiotensin system will be activated so UNa < 30 mM)
-Inappropriate release of ADH in euvolaemia in response to drugs, chest and CNS disease, pain, stress or as a paraneoplastic phenomenon = SIADH (UNa > 30 mM)
-Hypovolaemia with manifest UNa >30, impair salt reabsorption within kidney (thiazide, renal salt-wasting, adrenal insufficiency)

Urinary sodium > 20 mmol/l

Sodium depletion, renal loss (patient often hypovolaemic)
diuretics: thiazides, loop diuretics
Addison’s disease
diuretic stage of renal failure

Patient often euvolaemic
SIADH (urine osmolality > 500 mmol/kg)
hypothyroidism

Urinary sodium < 20 mmol/l

Sodium depletion, extra-renal loss
diarrhoea, vomiting, sweating
burns, adenoma of rectum

Water excess (patient often hypervolaemic and oedematous)
secondary hyperaldosteronism: heart failure, liver cirrhosis
nephrotic syndrome
IV dextrose
psychogenic polydipsia

Question 29

Drug causes of hyponatraemia

Answer 29

-Impaired urinary dilution
=Thiazide

-Renal salt wasting
=NSAIDs/ antibiotics, PPIs (if AIN)

-SIADH
=Antidepressants (SSRIs, TCAs)
=Antipsychotics
=Anticonvulsants (carbamazepine)
=Anti-cancer (cisplatin)
=Opioids
=MDMA

-Reset osmostat
=Venlafaxine, carbamazepine

-Excessive thirst
=MDMA

Question 30

Presentation of hyponatraemia

Answer 30

-Moderately severe= nausea, confusion, headache
-Severe= vomiting, CNS, depression, seizures, coma
-Rapid changes in sodium levels or severe hyponatraemia can cause symptoms such as vomiting, drowsiness, headache, seizures, coma, and cardio-respiratory arrest due to cerebral oedema and raised intracranial pressure.
-Chronic mild hyponatraemia can lead to gait instability, falls, and concentration and cognitive deficits.

-Acute hypernatremia (rapid onset)// rapid correction of chronic hyponatraemia= rapid increase in plasma sodium concentration= osmotic demyelination/ Central pontine myelinolysis, causing severe permanent brain damage

-Rapid onset of acute hyponatraemia/ rapid correction of chronic hypernatremia= rapid decrease in plasma sodium concentration= cerebral oedema

Question 31

Diagnosis/ Investigation of hyponatraemia

Answer 31

-History and examination
=Drugs, clinical conditions, intercurrent illness (gastroenteritis), chronic illness (anorexia), fluid intake and nocturnal polyuria
-Serum sodium
-Plasma osmolality (POsm): high= hypertonic, low= hypotonic
-Urine osmolality (UOsm); estimate ADH, low (100)= ADH not acting, high= acting
-Urine sodium concentration (UNa)

Question 32

Classification of hyponatraemia

Answer 32

-Mild (130-135): Debated risks of osteoporosis, neurocognitive defects
-Moderate (125-130)
-Profound (<125) real risks of cerebral oedema and ODS

-Acute= duration known to be <48hrs
-Chronic= duration unknown or >48hrs

-By volume status (deplete, normal, expanded)
-High risk of ODS (osmotic demyelination syndrome)= hypokalaemia, EtOH, malnutrition, liver disease

Question 33

Algorithm of diagnosis of hyponatraemia

Answer 33

1. Exclude hyperglycaemia and other causes of non-hypotonic hyponatremia (translocational): plasma osmolality (<275)
2. Is hypotonic hyponatremia acute or severe symptoms?
   =Yes: medical emergency: consider immediate treatment with hypertonic saline (seek senior help)
3. If not, urine osmolality
   =<100 consider primary polydipsia, low solute intake, beer potomania
   =>100
4. Urine sodium concentration
   =<30 mmol/l: low effective arterial blood volume
   ==If ECF expanded: HF, liver cirrhosis, nephrotic syndrome
   ==If ECF reduced: D&V, third spacing, remote diuretics
   =>30 mmol/l
   ==Diuretics, kidney disease, all other causes
   ==If ECF reduced: vomiting, primary adrenal insufficiency, renal salt wasting, cerebral salt wasting, occult diuretics
   ==If ECF normal: SIAD, secondary adrenal insufficiency, hypothyroidism, occult diuretics

-Duration of hyponatremia: is it acute or chronic?
=acute: develops over a period of < 48 hours
=chronic: develops over a period > 48 hours
-The severity of hyponatremia: what is the sodium level?
=mild: 130-134 mmol/L
=moderate: 120-129 mmol/L
=severe: < 120 mmol/L
-Symptoms: is the patient symptomatic?
=Early symptoms may include: headache, lethargy, nausea, vomiting, dizziness, confusion, and muscle cramps
=Late symptoms may include: seizures, coma, and respiratory arrest
-Suspected aetiology of the hyponatraemia:
=hypovolemic hyponatraemia/clinically =dehydrated: diuretic stage of renal failure, diuretics, Addisonian crisis
=euvolemic hyponatraemia: SIADH
=hypervolaemic hyponatraemia: heart failure, liver failure, nephrotic syndrome

Question 34

Management of hyponatraemia

Answer 34

-Acute symptomatic hyponatraemia= hypertonic saline (seek expert help)
-Primary polydipsia= reduced water intake
-Low solute intake= dietary review, supplemental Na and K
-Hypovolaemia hyponatraemia= ICV 0.9% NaCl. For dehydrated patients, administer 0.9% (isotonic) saline (150 mmol/l NaCl) to replenish volume.
-Volume expanded= loop diuretics (or water restriction)
-SIADH= water restriction (furosemide or V2R antagonists)
-Aim to correct chronic hyponatraemia slowly (5 mM/day, no more than 10)

-Chronic hyponatreamia without severe symptoms
=If a hypovolemic cause is suspected
normal, i.e. isotonic, saline (0.9% NaCl)
this may sometimes be given as a trial
if the serum sodium rises this supports a diagnosis of hypovolemic hyponatraemia
if the serum sodium falls an alternative diagnosis such as SIADH is likely
=If a euvolemic cause is suspected
fluid restrict to 500–1000 mL/day
consider medications:
demeclocycline
vaptans (see below)
=If a hypervolemic cause is suspected
fluid restrict to 500–1000 mL/day
consider loop diuretics
consider vaptans

-Acute hyponatreamia with severe symptoms
=Patients with acute, severe (<120 mmol/L) or symptomatic hyponatraemia require close monitoring, preferably in an HDU or above setting.
=Hypertonic saline (typically 3% NaCl) is used to correct the sodium level more quickly than would be done in patients with chronic hyponatraemia.

Question 35

Describe vasopressin

Answer 35

Vasopressin/ADH receptor antagonists (vaptans):
these act primarily on V2 receptors - antagonism of V2 receptors results in selective water diuresis, sparing the electrolytes
They should be avoided in patients who have hypovolemic hyponatremia
Vasopression/ADH receptor antagonists can stimulate the thirst receptors leading to the desire to drink free water. They can be hepatotoxic in patients with underlying liver disease.

Question 35

Describe complications of hyponatraemia management

Answer 35

-Osmotic demyelination syndrome (central pontine myelinolysis)
=Can occur due to over-correction of severe hyponatremia
=Usually irreversible: dysarthria, dysphagia, paraparesis or quadriparesis, seizures, confusion, and coma
=Patients are awake but are unable to move or verbally communicate, also called ‘Locked-in syndrome’

Question 36

Why is calcium important?

Answer 36

Acute severe hypercalcaemia is a medical emergency because it can cause cardiac dysrhythmia and coma

Question 37

Homeostatic control of calcium

Answer 37

-Detected in parathyroid glands
-PTH acts in bone gut and kidney to mobilise calcium from bone stores and modify excretion
-Vit D activated in liver an kidney: gut promotes absorption
-Calcium receptor in renal tubule: produces dilute urine in hypercalcaemia
=Hypercalcaemia causes the kidney to make a dilute urine. (This effect is mediated in the loop of Henle, mimicking a loop diuretic such as furosemide.)

Question 38

Causes of hypercalcaemia

Answer 38

Hypercalcaemia may be due to excessive PTH secretion (in primary: adenoma or tertiary hyperparathyroidism: chronic kidney disease as glands hyperplastic) or due to other causes such as malignancy, in which PTH levels are suppressed (PTHrP)/ release calcium from bones (osteolytic lesions, myeloma)
-FHH: mutations in calcium sensing receptor= negative feedback at higher set point
-Vit D ingestion, sarcoidosis, lymphoma, TB: granulomatous produces Vit D
-Immobilisation, thyrotoxicosis, milk-alkali

Two conditions account for 90% of cases of hypercalcaemia:
1. Primary hyperparathyroidism: commonest cause in non-hospitalised patients
2. Malignancy: the commonest cause in hospitalised patients. This may be due to a number of processes, including;
PTHrP from the tumour e.g. squamous cell lung cancer
bone metastases
myeloma,: due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells
for this reason, measuring parathyroid hormone levels is the key investigation for patients with hypercalcaemia

Question 39

Drugs causing hypercalcaemia

Answer 39

-Impaired urinary Ca excretion
=Thiazide
=Calcium-containing antacid preps (milk-alkali)
=Lithium

-Increased absorption
=Vitamin preparations
=Calcium-containing antacid preps (milk-alkali)

-Stimulation of PTH secretion
=Lithium

-Reduced bone buffering
=Vitamin A
=Anti-oestrogen

Question 40

Presentation of hypercalcaemia

Answer 40

-Thrones (toilet): polyuria, thirst, volume depletion
-Groans: peptic ulcer, pancreatitis, constipation
-Moans: fatigue, depression, delirium
-Stones: kidney stones, nephrocalcinosis
-Bones: osteoporosis

-Features of malignancy
corneal calcification
shortened QT interval on ECG
hypertension

Question 41

Investigation of hypercalcaemia

Answer 41

-Classification:
<3 mM mild
3-3.5 mM moderate
>3.5 mM severe (cardiac dysrhythmia, seizures)

-History
=Symptoms of hypercalcaemia and duration
=Symptoms of underlying causes, e.g. weight loss, night sweats, cough
=Family history
=Drugs including supplements and over-the-counter preparations
-Examination: volume deplete, malignancy, Assess for cognitive impairment, Fluid balance status. For underlying causes, including neck, respiratory, abdomen, breasts, lymph nodes
-ECG: short QTc
-Bloods: calcium adjusted for albumin, phosphate, PTH, U&E

1. PTH:
   =High/not low in primary hyperparathyroidism
   =-If low or normal then…
2. PTHrP and vitamin D metabolites
   =High PTHrP: malignancy
   =High vit D: granulomatous diseases/ vit D intoxication
   =If normal…
3. Multiple myeloma testing
   =Abnormal: MM
   =Normal: consider milk-alkali syndrome

Question 42

Management of hypercalcaemia

Answer 42

-Volume resuscitation with copious IV 0.9% NaCl (4-6L in 24 hours)
-IV bisphosphonates (takes days to work)
=Zoledronic acid 4mg over 15 mins
-Additional treatments addressing underlying cause

-Second line: glucocorticoids, calcimimetics, parathyroidectomy

The initial management of hypercalcaemia is rehydration with normal saline, typically 3-4 litres/day. Following rehydration bisphosphonates may be used. They typically take 2-3 days to work with maximal effect being seen at 7 days

Other options include:
calcitonin - quicker effect than bisphosphonates
steroids in sarcoidosis

Loop diuretics such as furosemide are sometimes used in hypercalcaemia, particularly in patients who cannot tolerate aggressive fluid rehydration. However, they should be used with caution as they may worsen electrolyte derangement and volume depletion.

Question 43

Causes of hypocalcaemia

Answer 43

The clinical history combined with parathyroid hormone levels will reveal the cause of hypocalcaemia in the majority of cases

Causes
vitamin D deficiency (osteomalacia)
chronic kidney disease
hypoparathyroidism (e.g. post thyroid/parathyroid surgery)
pseudohypoparathyroidism (target cells insensitive to PTH)
rhabdomyolysis (initial stages)
magnesium deficiency (due to end organ PTH resistance)
massive blood transfusion
acute pancreatitis

Question 44

Presentation of hypocalcaemia

Answer 44

As extracellular calcium concentrations are important for muscle and nerve function many of the features seen in hypocalcaemia seen a result of neuromuscular excitability

Features
tetany: muscle twitching, cramping and spasm
perioral paraesthesia
if chronic: depression, cataracts
ECG: prolonged QT interval

Trousseau’s sign
carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and maintaining pressure above systolic
wrist flexion and fingers are drawn together
seen in around 95% of patients with hypocalcaemia and around 1% of normocalcaemic people

Chvostek’s sign
tapping over parotid causes facial muscles to twitch
seen in around 70% of patients with hypocalcaemia and around 10% of normocalcaemic people

Question 45

Investigation of hypocalcaemia

Answer 45

Contamination of blood samples with EDTA may also give falsely low calcium levels.

Question 46

Management of hypocalcaemia

Answer 46

severe hypocalcaemia (e.g. carpopedal spasm, tetany, seizures or prolonged QT interval) requires IV calcium replacement
the preferred method is with intravenous calcium gluconate, 10ml of 10% solution over 10 minutes
intravenous calcium chloride is more likely to cause local irritation
ECG monitoring is recommended
further management depends on the underlying cause