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Chemical Pathology > Biochem of Diarrhoea > Flashcards

Biochem of Diarrhoea Flashcards

1
Q

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

A

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

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2
Q

Where are water and electrolytes simultaneously secreted and absorbed?

A

small intestine

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3
Q

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

A
  • Changes in luminal osmotic pressure
  • Movement of electrolytes
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4
Q

Explain Changes in Luminal Osmolality (3)

A
  • 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
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5
Q

What is Secretory Diarrhoea? (5)

A

• 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

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6
Q

What is Osmotic Diarrhoea? (5)

A

• 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

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7
Q

Secretory vs Osmotic Diarrhoea (4)

A

• 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

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8
Q

How do you treat diarrhoea? (5)

A

• 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

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9
Q

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

A

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

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10
Q

Explain Nutrition in Diarrhoea (4)

A

• 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

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11
Q

What is Lactase?

A

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

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12
Q

How can intolerance be diagnosed? (4)

A

 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)

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13
Q

How do you treat lactose intolerance? (2)

A

treated by avoiding dairy or by taking lactase orally with dairy

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14
Q

What is secondary lactase deficiency? (3)

A

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

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15
Q

Describe the movement of electrolytes (6)

A

• 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􏰀

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16
Q

Describe Chloride Secretion (6)

A

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

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17
Q

Explain the Chloride Bicarbonate Exchange (5)

A

-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)

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18
Q

What is acute diarrhoea? (5)

A

• 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-

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19
Q

What is chronic diarrhoea? (5)

A

• 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)

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20
Q

What is hyperemesis?

A

severe vomiting

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21
Q

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

A

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

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22
Q

How can paradoxical acuduria occur? (3)

A

 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

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23
Q

How can hyperemesis be treated? (4)

A

-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

24
Q

What is steatorrhea? (2)

A

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

25
Q

What are the causes of steatorrhea? (5)

A

• 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

26
Q

What does steatorrhea clinically manifest as?

A

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

27
Q

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

A

• 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

28
Q

What is isotonic dehydration? (5)

A

-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

29
Q

What is hypertonic dehydration? (6)

A

• 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

30
Q

What is hypotonic dehydration? (4)

A

-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

31
Q

Define pure water, isotonic fluid and primary sodium overloads

A

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

32
Q

What can over hydration cause?

A

hyponatraemia and brain oedema

33
Q

What is primary hyperaldosteronism? (3) give one eg

A

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

34
Q

What is secondary hyperaldosteronism? (7)

A

-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

35
Q

What is SIADH? (7)

A

-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

36
Q

Explain metabolic acidosis (3)

A

• 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

37
Q

What can faecal loss result in?

A

potassium depletion

38
Q

What do we know about potassium depletion? (5)

A

-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)

39
Q

How do you measure osmolality? (3)

A

• 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)

40
Q

What two gradients is water movement influenced by?

A

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

41
Q

What system is able to bypass membranes?

A

lymphatic

42
Q

What is the hydrostatic pressure gradient? (3)

A

• 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

43
Q

Explain the colloid osmotic pressure gradient (5)

A

• 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

44
Q

Describe Tonicity (3)

A

• 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

45
Q

What is the pathological osmotic fluid shift? (6)

A

-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

46
Q

Explain osmostat (5)

A

• 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

47
Q

What is potassium homeostasis? (10)

A

• 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􏰀

48
Q

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

A

 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

49
Q

What are the causes of hypokaleamia? (5)

A
  • 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
50
Q

What are the symptoms of hypokalaemia? (3)

A

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

51
Q

How can hypokalaemia be treated? (2)

A

• 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

52
Q

What are the causes of hyperkalaemia? (5)

A
  • 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
53
Q

What are the symptoms of hyperkalaemia? (3)

A

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

54
Q

How is hyperkalaemia diagnosed? (3)

A

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

55
Q

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

A

• 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

56
Q

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

A

• 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

Chemical Pathology (2 decks)

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