Biochem of Diarrhoea Flashcards
Define Osmolality, Osmolarity, Tonicity, Solute, Solvent, Isotonic and Oncotic Pressure
Osmolality - the concentration (in mmol/l ) of all soluble particles per kilogram of solvent
• Osmolarity – the concentration of all soluble particles per litre of solvent
• Tonicity – a measure of the effective osmotic pressure gradient between two fluid compartments
• Solute – the minor component in a solution ( the dissolved bit)
• Solvent – a substance that dissolves a solute, resulting in a solution
• Isotonic – a solution having the same osmotic pressure as some other solution
• Oncotic pressure – osmotic pressure induced by proteins
Where are water and electrolytes simultaneously secreted and absorbed?
small intestine
What are the two processes that aid in the maintenance of an osmotic gradient?
- Changes in luminal osmotic pressure
- Movement of electrolytes
Explain Changes in Luminal Osmolality (3)
- Ingestion of food and its digestion increases the osmolality of the luminal contents
• For example, when starch, which is not hypertonic, is broken down into monomers, it increases the osmolality of the luminal fluid, drawing water into the gut
• The absorption of these monomers into the bloodstream reduces the osmolality of the intestinal fluid and draws water back into the cells by diffusion
What is Secretory Diarrhoea? (5)
• Commonly caused by infection
• Continual secretion of chloride from crypt cells and/or an impaired or inadequate absorption of sodium by villi
• Bacteria can activate cAMP-dependent CFTR by activating adenyl cyclase and cause diarrhoea – chloride channels will be open causing water to follow the ions over an osmotic gradient
• This causes a net loss of water and electrolytes due to imbalances in the osmotic gradient
• Peptides produced by endocrine tumours like VIP (vasoactive intestinal peptide) or calcitonin can cause diarrhoea by stimulating secretion by epithelial cells
• The diarrhoea does not cease with fasting
What is Osmotic Diarrhoea? (5)
• Results from an osmotic imbalance
• The bowel allows for rapid flow of fluids and ions between the lumen and plasma to maintain an osmotic balance and is highly permeable to water
• Ingested substances which are osmotically active, but the body cannot absorb, like laxatives, increase the osmolality of the lumen and draws water out from cells
• Unabsorbed solutes can have a similar effect – such as when there is a deficiency of lactase or pancreatic enzymes which prevents digestion
• Inflammation of the mucosa and motility disorders can impair absorption leading to increased osmolality in the lumen which would draw water
Secretory vs Osmotic Diarrhoea (4)
• Osmotic and secretory diarrhea can be differentiated through fasting or ceasing ingestion of the causative substance
• Biochemically this can be ascertained by measuring the stool osmolar gap:
𝑠𝑡𝑜𝑜𝑙 𝑜𝑠𝑚𝑜𝑙𝑎𝑙𝑖𝑡𝑦 − 2 × (𝑁𝑎 + 𝐾)
• If the osmolar gap is > 100 it points towards osmotic diarrhoea as the big gap suggests solutes which are unaccounted for (a hypertonic solution)
• If the osmolar gap is < 100 it points towards secretory diarrhoea as the small gap suggests solutes are being lost through secretion thus drawing water out of cells
How do you treat diarrhoea? (5)
• Use Oral Rehydration Therapy (ORT)
• Low osmolality formulas are now recommended
• In SA we currently use a 1𝑙 clean water solution
of tsp salt and 8 tsp sugar
• Recall how SGLT1 requires both sodium and sugar
• If there are acid-base disturbances, sodium bicarbonate should only be administered in severe acidosis
Diarrhoea may cause a decline in nutritional status and result in weight loss and impaired growth due to: (3)
Reduced dietary intake
Decreased nutrient
absorption
Increased nutritional
requirements
Explain Nutrition in Diarrhoea (4)
• Breast feeding should continue
during ORT
• Feeding does not normally
increase stool output
• Lactose is not contraindicated
• They may be increased
nutritional requirements during recovery
What is Lactase?
Lactase is a brush-border enzyme coded by the LCT gene and cleaves lactose into glucose and galactose
How can intolerance be diagnosed? (4)
Excluding lactose from the diet
Ingesting lactose and then monitoring blood
glucose levels
Hydrogen breath test – if lactose is not
digested, it is converted by bacteria in the colon into 𝐶𝑂, SCFAs and 𝐻, some of which is absorbed and breathed out
Stool reducing substance test and TLC (thin light chromatography)
How do you treat lactose intolerance? (2)
treated by avoiding dairy or by taking lactase orally with dairy
What is secondary lactase deficiency? (3)
An example of a cause of osmotic diarrhoea
• Damage to the brush border results in a deficiency
of lactase meaning it cannot be digested and
absorbed
• These new substances increase osmolality in the lumen and draw water
Describe the movement of electrolytes (6)
• The composition of ion like 𝑁𝑎, 𝐶𝑙 and 𝐾 are essential in maintaining ionic and osmotic balance
• They move across cell membranes passively along electrochemical gradients or against them using active transport
• The ECF has higher levels of sodium and chloride than the ICF, but the ICF has more potassium
• Enterocytes actively transport 𝑁𝑎 out of enterocytes into the bloodstream which creates an electrochemical gradient and allows sodium dependent cotransporters to absorb substances from the lumen
• Water follows sodium by moving through special openings in tight junctions
• In the jejunum, chloride ions move by diffusion along the electrochemical gradient, following 𝑁𝑎
Describe Chloride Secretion (6)
Crypt cells actively secrete electrolytes:
• 𝐶𝑙 enters crypt cells via a cotransporter
along with 𝑁𝑎 and 𝐾
• The activation of adenyl cyclase and consequent release of cAMP in the crypt cells activates CFTR channels
• This allows the movement of 𝐶𝑙 into the lumen
• 𝑁𝑎 follows chloride and water is drawn into
the lumen by osmosis
• Bacteria can activate cAMP-dependent CFTR
by activating adenyl cyclase channels and cause diarrhoea – chloride channels will be open causing water to follow the ions over an osmotic gradient
Explain the Chloride Bicarbonate Exchange (5)
-In the ileum and colon, chloride ions are actively absorbed in exchange for bicarbonate ions
• Bicarbonate carries a sodium ion with it
• The sodium bicarbonate secretion is iso-osmotic to water
• The bicarbonate neutralizes acidic products produced by
bacteria
• Bacteria can disrupt this exchange system and cause
diarrhoea (water follows sodium)
What is acute diarrhoea? (5)
• In acute diarrhoea there is a rapid transit of intestinal contents
• There is little time for 𝑁𝑎, 𝐾 and 𝐻 exchange
• A lot of 𝐻2𝑂, 𝐻𝐶𝑂3- and 𝑁𝑎 is thus lost
• The intestinal fluid is isotonic, so loss of water here will lead to isotonic dehydration
• Normal anion-gap metabolic acidosis can occur because of loss of 𝐻𝐶𝑂3-
What is chronic diarrhoea? (5)
• Transit is still rapid but prolonged
• There is thus time for 𝑁𝑎, 𝐾 and 𝐻 exchange
• 𝐻𝑂 and 𝐾 is lost over time
• Dehydration is less severe and there is time to absorb fluid
• Metabolic alkalosis can occur due to 𝐾 depletion (𝐾
and 𝐻 are exchanged in the kidney for 𝑁𝑎 so depletion of 𝐾 will lead to more 𝐻 being lost)
What is hyperemesis?
severe vomiting
Gastric fluid is rich in 𝐻, 𝐶𝑙 and 𝐾 so loss of this fluid
would cause: (4)
Metabolic alkalosis
Hypochloraemia
Hypokalaemia
Dehydration – due to loss of fluid
How can paradoxical acuduria occur? (3)
Sodium is absorbed in exchange for 𝐻 or 𝐾 in the kidney. Hypokalaemia results secretion of a lot of 𝐻 since there is less 𝐾.
Sodium chloride rather than sodium bicarbonate is normally the principal electrolyte in the proximal tubule of the kidney. In this case chloride depletion results in 𝐻𝐶𝑂 absorption making the urine more acidic.
Hypovolaemia causes hyperaldosteronism which results in 𝐻 being secreting in the urine
How can hyperemesis be treated? (4)
-It is treated with 𝑁𝑎𝐶𝑙 and/or 𝐾𝐶𝑙
• The added volume by the solution improves dehydration
which reduces aldosterone, decreasing 𝑁𝑎 absorption proximally in the kidney, allowing for 𝐻 and 𝐾 loss distally
• Chloride will replace the bicarbonate in the kidney and will be reabsorbed with 𝑁𝑎
• This allows excess 𝐻𝐶𝑂 to be excreted which helps to resolve alkalosis
What is steatorrhea? (2)
• The presence of abnormal amounts of fat (triglycerides) in the stool
• The stool appears greasy, floats and is difficult to flush
What are the causes of steatorrhea? (5)
• Infections – giardiasis
• Coeliac disease – damaged mucosa can’t absorb
fats
• Infiltration of the GIT – TB and lymphomas
• Deficiency of pancreatic lipase
• Lack of bile salts
What does steatorrhea clinically manifest as?
weight loss and deficiency of fat-soluble vitamins (Vitamins A, D, E, K)
What can diagnosis of steatorrhea be made through? (3)
• Histologically testing stool for fat globules
• Steatocrit – mixing stool with water and
centrifuging it to measure the proportion of fat
present
• A radioactive 14C triglyceride breath test – the
triglyceride is given orally and 14𝐶𝑂 in the breath is measured to see whether it is being absorbed or not
What is isotonic dehydration? (5)
-The loss of 𝑁𝑎 and 𝐻𝑂 is in the same proportion as that of the ECF
• This results in hypovolaemia due to ECF loss
• The serum osmolality is normal
• This can happen in bleeding, burn wounds, GIT
losses, renal losses and effusions into 3rd spaces
like the peritoneal cavity
• This can result in shock
What is hypertonic dehydration? (6)
• Normally caused by hypertonic, poorly absorbed fluids and not enough water absorption or hypotonic fluid loss
• This results in water moving out of enterocytes into the lumen
• More 𝐻𝑂 is lost than 𝑁𝑎
• The serum 𝑁𝑎 is thus high and so is the serum
osmolality – ECF is hypertonic and fluid shifts
from ICF to ECF
• Shock won’t occur easily – the fluid shift to the
ECF preventing vascular volume dramatically
dropping
• This can occur in sweating, diabetes and decreased water intake
What is hypotonic dehydration? (4)
-Normally caused by drinking large amounts of water with few electrolytes
• This can occur in marathon runner and during inappropriate IV rehydration
• The excess water is absorbed while sodium is lost
• There is a sodium deficit – low serum 𝑁𝑎 and low
serum osmolality
Define pure water, isotonic fluid and primary sodium overloads
Pure water overload – excessive intake such as in endurance athletes who drink too much , beer drinkers potomania and SIADH (produce too much ADH)
• Isotonic fluid overload – hyperaldosteronism
• Primary sodium overload – due to salt intake (sea
water) or iatrogenically from sodium salts which
causes thirst and water intake
What can over hydration cause?
hyponatraemia and brain oedema
What is primary hyperaldosteronism? (3) give one eg
Example is Conns Adenoma
• Can cause hypertension due to 𝑁𝑎
and 𝐻O retention with hypokalaemia and metabolic alkalosis (due to
increased exchange of 𝑁𝑎 with 𝐻/𝐾)
• There is no oedema due to ANP and BNP limiting fluid
retention
• Renin is suppressed
What is secondary hyperaldosteronism? (7)
-Caused by increased renin secretion without ECF volume depletion
• This can occur in renal artery stenosis which will activate the renin angiotensin aldosterone system
• It can also be caused by low oncotic pressure such as in nephrosis, cirrhosis and protein losing enteropathy
• Fluid will shift from the ICF to the ECF which can cause hyponatraemia
• There can be severe peripheral oedema
• High hydrostatic pressure can cause congestive cardiac
failure
• Although there is sodium overload there will be
hyponatraemia due to ADH causing water retention
What is SIADH? (7)
-Syndrome of inappropriate ADH
• A common cause of hyponatraemia – retained water is
shared between ECF and ICF
• Urine 𝑁𝑎 remains high and is concentrated
• Can cause brain oedema
• Treated by restricting water intake, but hyponatraemia is
severe hypertonic saline can be used and mannitol can be
used to pull water out of cells to prevent brain oedema
• Remember that if the 𝑁𝑎 imbalance is corrected too quickly
if hyponatraemia has been longstanding cerebral dehydration
can occur resulting in central pontine myelinosis
• It can be caused by direct stimulation of the hypothalamus,
pulmonary pathology in which volume receptors send incorrect signals, ectopic ADH production, pain and drugs like NSAIDS, morphine and narcotics
Explain metabolic acidosis (3)
• In diarrhoea, large amounts of bicarbonate are lost
• Hypovolaemia can compound this due to lactic acid
production in under perfused tissues
• This can result in metabolic acidosis
What can faecal loss result in?
potassium depletion
What do we know about potassium depletion? (5)
-This has the greatest impact in infants
• This is concerning in individuals with potassium
deficiencies before the onset of diarrhoea
• Metabolic acidosis may mask this depletion as
potassium in the ICF is exchanged for 𝐻 in the ECF as
a compensatory mechanism of acidosis
• This can cause rebound hypokalaemia when acidosis is
treated without addressing 𝐾 depletion
• Signs of potassium depletion include muscle
weakness, cardiac arrythmias and paralytic ileus (obstruction of intestine due to paralysis of muscles)
How do you measure osmolality? (3)
• It can be measured using an osmometer – any bodily fluid can be used
• It can also be calculated using the ECF with the following formula: 2 𝑁𝑎 + 𝐾 + 𝑈𝑟𝑒𝑎 + 𝐺𝑙𝑢𝑐𝑜𝑠𝑒
• We multiply by two to compensate for the negative ions (electrical neutrality)
What two gradients is water movement influenced by?
Starling Forces: Hydrostatic pressure gradient
Colloid osmotic pressure gradient
What system is able to bypass membranes?
lymphatic
What is the hydrostatic pressure gradient? (3)
• Hydrostatic pressure is the pressure fluid exerts on cells
• Water will be pushed away from areas of high
hydrostatic pressure to area of low hydrostatic pressure
• The high hydrostatic pressure at the arteriolar end of
blood vessels pushes water out of the vessel into the interstitial fluid
Explain the colloid osmotic pressure gradient (5)
• Osmotic pressure is the force of solutes in a solution
• Water will be drawn towards a solution with a higher
osmotic pressure
• Plasma proteins cannot cross the capillary barrier
• These osmotically-active solutes have a higher
concentration in the plasma than in the interstitial fluid. The oncotic pressure within the plasma is thus higher than the oncotic pressure of the ICF
• This pulls water lost to intestinal fluid at the arteriolar end back into the vessel
Describe Tonicity (3)
• Tonicity is the measurement of the osmotic pressure gradient between two fluid compartments
• If the ECF is hypotonic compared to the ICF, cells will swell
• If the ECF is hypertonic compared to the ICF cells will shrink
What is the pathological osmotic fluid shift? (6)
-𝑁𝑎 and glucose are the most common cause for large transcellular fluid shits
• This particularly affects the brain which is enclosed
• If brain cells swell (brain oedema), the brain can herniate and the pressure can cause blood vessels to collapse
• If the brain shrinks this can lead to subdural bleeding and central pontine myelinosis in a rapid correction of hyponatremia
• The blood brain barrier (BBB) protects the brain from changes in glucose levels but not rapid changes in Na+ levels
- The brain can adapt to changes in Na+ by increasing or decreasing idiogenic osmoles – this is clinically important as rapid correction in an adapted brain can be lethal
Explain osmostat (5)
• Hypothalamus – it controls thirst and releases ADH
• The hypothalamus is stimulated by substances which do not cross the BBB meaning that they can pull fluid from these osmocytes and cause them to shrink – this shrinking is what activates them
• Examples of these substances are which shrinks osmocytes in
hypotonic fluid loss, glucose which causes thirst in diabetes, and mannitol which is used for cerebral oedema
• Osmocytes are also stimulated by Angiotensin II which causes thirst during hypovolaemia
• Substances such as ethanol and urea do not cross cell membranes easily and do not stimulate the osmostat
What is potassium homeostasis? (10)
• Cells contain a lot of potassium and a lot of the food we eat is cells, so consequently we ingest a lot of 𝐾
• This must be excreted to prevent hyperkalaemia
• Potassium secretion is promoted by aldosterone and is
dependent of sodium reabsorption (exchange)
• Potassium can directly stimulate aldosterone
• Insulin can drive 𝐾 into cells because when glucose
enters cells it is phosphorylated – 𝐾 follows the
negative 𝑃𝑂 into cells • Catecholamines like adrenaline also drive 𝐾
into cells as they cause glycogenolysis which generates more
phosphorylated glucose intermediates
• 𝐻 and 𝐾 compete for negative intracellular binding
sites – this is why acidosis can cause hyperkalaemia
and alkalosis can cause hypokalaemia
• In acidosis excess 𝐻 outcompetes 𝐾 to enter cells
• In alkalosis lack of 𝐻 allows a lot of 𝐾 to enter cells
• Hypokalaemia can cause alkalosis via distal tubular
excretion as lack of 𝐾 means that a lot of 𝐻 is
exchanged for 𝑁𝑎
Potassium has a major impact on excitability of
conductive tissue and myocytes and imbalances can lead to arrythmias: (2)
If ECF 𝐾 is high, 𝐾 will leave cells more slowly because the osmotic gradient is not as big – since less 𝐾 (positive) leaves the cells they will be less negative and thus more excitable
If ECF 𝐾 is low, 𝐾 will leak out of cells quickly making them more negative so the cells will be less excitable
What are the causes of hypokaleamia? (5)
- Increased kidney excretion – primary hyperaldosteronism due to an adenoma like Conn’s adenoma or secondary hyperaldosteronism such as in renal artery stenosis
• Drugs – such as thiazides and loop diuretics cause more 𝑁𝑎 to enter the distal tubule causing more
𝑁𝑎/𝐾 exchange • Metabolic alkalosis – lack of 𝐻
allows a lot of 𝐾
to
enter cells
• Increased GIT secretion – vomiting (direct losses from
fluid and indirect losses through metabolic alkalosis)
and diarrhoea
• Increased sweating – especially exercising in hot
climates
• Drugs - 𝛽2 adrenergic agonists
• Insulin administration
What are the symptoms of hypokalaemia? (3)
-Cardiac arrythmias – asystole and ventricular fibrillations
• Skeletal muscle weakness and paralysis
• GIT smooth muscle weakness causing ileus (lack of intestinal movement)
How can hypokalaemia be treated? (2)
• Diagnoses uses urine 𝐾 to differentiate between GIT and renal losses and looks for flattened or inverted T waves and prominent U waves on an ECG
• Treatment involves administering 𝐾𝐶𝑙
What are the causes of hyperkalaemia? (5)
- Increased intake – rare
• Drugs – 𝛽2 adrenergic antagonists
• Massive cell lysis – releases 𝐾 into ECF such as in
crush injuries, tumour lysis syndrome and
haemolysis
• Hyperosmolarity – osmotic gradient puls water out
of cells increasing ICF concentration of K+ causing it to be pushed out of cells
•Lack of insulin such as in Type I diabetes-𝑁𝑎+ /𝐾+
pump action is decreased
• Acidosis – increased 𝐻 outcompetes 𝐾 to enter
cells
• Acute renal failure – results in no 𝐾+ excretion
What are the symptoms of hyperkalaemia? (3)
-Cardiac arrythmias – asystole and ventricular fibrillations
• Muscle weakness – can lead to respiratory failure
• Nausea, vomiting and diarrhoea
How is hyperkalaemia diagnosed? (3)
• Tall, peaked T-waves
• Loss of P waves
• Widening QRS complex
Hyperkalaemia is a medical emergency- must be treated to reduce K+ rapidly: (4)
• Insulin and glucose – to push 𝐾
• Salbutamol (a 𝛽2-agonist) – to push 𝐾 into cells
• 𝑁𝑎𝐻𝐶𝑂 infusion – alkalosis will push 𝐾 into cells
as a decrease in 𝐻 will allow a lot more 𝐾 to
enter cells
• IV Calcium gluconate – antagonises the effect of
𝐾 on cardiac excitability
In hyperkalemia, what happens once the patient has stabilised? (3)
• 𝑁𝑎𝐶𝑙 infusion with diuretics to increase 𝑁𝑎 delivery to the distal tubules allowed for more 𝐾 exchange to occur
• Haemodialysis
• Polystyrene sulfonate resin PO – this binds oral 𝐾+ in the diet
