Biochem of Diarrhoea

Question 1

Define Osmolality, Osmolarity, Tonicity, Solute, Solvent, Isotonic and Oncotic Pressure

Answer 1

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

Question 2

Where are water and electrolytes simultaneously secreted and absorbed?

Answer 2

small intestine

Question 3

What are the two processes that aid in the maintenance of an osmotic gradient?

Answer 3

• Changes in luminal osmotic pressure
• Movement of electrolytes

Question 4

Explain Changes in Luminal Osmolality (3)

Answer 4

• 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

Question 5

What is Secretory Diarrhoea? (5)

Answer 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

Question 6

What is Osmotic Diarrhoea? (5)

Answer 6

• 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

Question 7

Secretory vs Osmotic Diarrhoea (4)

Answer 7

• 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

Question 8

How do you treat diarrhoea? (5)

Answer 8

• 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

Question 9

Diarrhoea may cause a decline in nutritional status and result in weight loss and impaired growth due to: (3)

Answer 9

 Reduced dietary intake
 Decreased nutrient
absorption
 Increased nutritional
requirements

Question 10

Explain Nutrition in Diarrhoea (4)

Answer 10

• 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

Question 11

What is Lactase?

Answer 11

Lactase is a brush-border enzyme coded by the LCT gene and cleaves lactose into glucose and galactose

Question 12

How can intolerance be diagnosed? (4)

Answer 12

 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)

Question 13

How do you treat lactose intolerance? (2)

Answer 13

treated by avoiding dairy or by taking lactase orally with dairy

Question 14

What is secondary lactase deficiency? (3)

Answer 14

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

Question 15

Describe the movement of electrolytes (6)

Answer 15

• 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􏰀

Question 16

Describe Chloride Secretion (6)

Answer 16

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

Question 17

Explain the Chloride Bicarbonate Exchange (5)

Answer 17

-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)

Question 18

What is acute diarrhoea? (5)

Answer 18

• 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-

Question 19

What is chronic diarrhoea? (5)

Answer 19

• Transit is still rapid but prolonged
• There is thus time for 𝑁𝑎􏰀, 𝐾􏰀 and 𝐻􏰀 exchange
• 𝐻􏰃𝑂 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)

Question 20

What is hyperemesis?

Answer 20

severe vomiting

Question 21

Gastric fluid is rich in 𝐻􏰀, 𝐶𝑙􏰄 and 𝐾􏰀 so loss of this fluid
would cause: (4)

Answer 21

 Metabolic alkalosis
 Hypochloraemia
 Hypokalaemia
 Dehydration – due to loss of fluid

Question 22

How can paradoxical acuduria occur? (3)

Answer 22

 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

Question 23

How can hyperemesis be treated? (4)

Answer 23

-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

Question 24

What is steatorrhea? (2)

Answer 24

• The presence of abnormal amounts of fat (triglycerides) in the stool
• The stool appears greasy, floats and is difficult to flush

Question 25

What are the causes of steatorrhea? (5)

Answer 25

• 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

Question 26

What does steatorrhea clinically manifest as?

Answer 26

weight loss and deficiency of fat-soluble vitamins (Vitamins A, D, E, K)

Question 27

What can diagnosis of steatorrhea be made through? (3)

Answer 27

• 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

Question 28

What is isotonic dehydration? (5)

Answer 28

-The loss of 𝑁𝑎􏰀 and 𝐻􏰃𝑂 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

Question 29

What is hypertonic dehydration? (6)

Answer 29

• 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 𝐻􏰃𝑂 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

Question 30

What is hypotonic dehydration? (4)

Answer 30

-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

Question 31

Define pure water, isotonic fluid and primary sodium overloads

Answer 31

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

Question 32

What can over hydration cause?

Answer 32

hyponatraemia and brain oedema

Question 33

What is primary hyperaldosteronism? (3) give one eg

Answer 33

Example is Conns Adenoma 􏰀 • Can cause hypertension due to 𝑁𝑎 and 𝐻􏰃O 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

Question 34

What is secondary hyperaldosteronism? (7)

Answer 34

-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

Question 35

What is SIADH? (7)

Answer 35

-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

Question 36

Explain metabolic acidosis (3)

Answer 36

• 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

Question 37

What can faecal loss result in?

Answer 37

potassium depletion

Question 38

What do we know about potassium depletion? (5)

Answer 38

-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)

Question 39

How do you measure osmolality? (3)

Answer 39

• 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)

Question 40

What two gradients is water movement influenced by?

Answer 40

Starling Forces:  Hydrostatic pressure gradient  Colloid osmotic pressure gradient

Question 41

What system is able to bypass membranes?

Answer 41

lymphatic

Question 42

What is the hydrostatic pressure gradient? (3)

Answer 42

• 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

Question 43

Explain the colloid osmotic pressure gradient (5)

Answer 43

• 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

Question 44

Describe Tonicity (3)

Answer 44

• 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

Question 45

What is the pathological osmotic fluid shift? (6)

Answer 45

-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

Question 46

Explain osmostat (5)

Answer 46

• 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

Question 47

What is potassium homeostasis? (10)

Answer 47

• 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􏰀

Question 48

Potassium has a major impact on excitability of conductive tissue and myocytes and imbalances can lead to arrythmias: (2)

Answer 48

 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

Question 49

What are the causes of hypokaleamia? (5)

Answer 49

- 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

Question 50

What are the symptoms of hypokalaemia? (3)

Answer 50

-Cardiac arrythmias – asystole and ventricular fibrillations • Skeletal muscle weakness and paralysis • GIT smooth muscle weakness causing ileus (lack of intestinal movement)

Question 51

How can hypokalaemia be treated? (2)

Answer 51

• 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

Question 52

What are the causes of hyperkalaemia? (5)

Answer 52

- 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

Question 53

What are the symptoms of hyperkalaemia? (3)

Answer 53

-Cardiac arrythmias – asystole and ventricular fibrillations • Muscle weakness – can lead to respiratory failure • Nausea, vomiting and diarrhoea

Question 54

How is hyperkalaemia diagnosed? (3)

Answer 54

• Tall, peaked T-waves • Loss of P waves • Widening QRS complex

Question 55

Hyperkalaemia is a medical emergency- must be treated to reduce K+ rapidly: (4)

Answer 55

• 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

Question 56

In hyperkalemia, what happens once the patient has stabilised? (3)

Answer 56

• 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