Therapeutics & Investigations 2 (Part 2) Flashcards
Describe normal metabolic processes in the body, in relation to acid + bases and water
- Normal metabolic processes in the body make 40-80mmol of hydrogen ions, in 24hrs
- Non-volatile acid
- These are then excreted in the urine
- Imbalances = absorbed by buffers.
- Overall acid formation and removal are balanced in health.
What his [H+] a direct measure of
Ø H+ ion concentration is a direct measure of acid base status = this is the direct measure
Ø Other method = pH. Expresses acidity and alkalinity in the reverse way. 1/[H+]
Ø If there is acidosis (too much acid) = pH will drop below 7
Alkalosis = the pH will get higher.
How much CO2 is produced during aerobic oxidation
- 15k mmol/24h of CO2.
- Produces carbonic acid (H2CO3)
- Excreted by the lungs - amount of CO2 is equivalent to 15kmmol/24 of hydrogen ion (volatile acid)
How is the hydrogen ion concentration [H+] of ECF maintained
- Within narrow limits of the 36-44nmol/l (pH 7.35-7.45)
- The intracellular [H+] = a bit higher but is also tightly controlled
- In disease, imbalances between acid formation + removal might develop and persist, which results in acidosis, or alkalosis
Why are the kidneys important in acid-base balance?
- They reabsorb all of the filtered bicarbonate + synthesise additional bicarbonate, to add to blood.
- Produce ammonia - important mechanism for H+ excretion and also use phosphate to excrete H+
What happens in the capillary beds with Co2
- Co2 that is made by tissue respiration diffuses into the RBCs. Forms carbonic acid, in the presence of carbonate hydratase
- Carbonic acid dissociates to form H+ and bicarbonate HCO3-.
- H+ are buffered by deoxygenated Hb.
- HCO3- diffuse outside RBCs in exchange for chloride ions (Cl-), which is chloride shift
- Maintains electrochemical neutrality
What has to be present for co2 to form carbonic acid
- Carbonate hydratase must be present, for CO2 to be able to form carbonic acid
Describe Chloride Shift which occurs in capillary beds
- HCO3- diffuses outside of Red blood cells, in exchange for chloride ions.
- Maintains electrochemical neutrality
Where does the reverse of the chloride shift + where does it happen
- Happens in the alveolar capillaries
- The co2 that is produced is excreted into the alveoli
Ask: so would HCO3- diffuse INTO the Red Blood Cells + then chloride ions would come out? would electrochemical neutrality still be maintained?
What is H ion homoeostasis dependent on?
- Buffering in the tissues + blood stream. Acid excretion by the kidneys
- Expiration of CO2 through the lungs. The blood hydrogen ion concentration is directly proportional to the partial pressure of CO2 (Pco2)
Ø The blood [hydrogen ion] = inversely proportional to the concentration of bicarbonate [HCO3] - Illustrated by the Henderson Hasselbalch equation
Describe the process of metabolic (non-respiratory) acidosis
- When there is either increased production / decreased removal of H+ ions (OTHER than those that come from carbonic acid, or CO2)
- Or both - due to excessive loss of bicarbonate from the body = bicarbonate is the buffer that goes through the blood to deal with too much acid.
- TOO MUCH ACID IN THE BODY
• High H+ ion, and low pH
The markers for metabolic, non-respiratory acidosis- Rise in H+ concentration
- Lower pH value
- Reduced bicarbonate - ranging between 22-33 millimolar
What are the causes of metabolic non respiratory acidosis
- Increased acid production
- Decreased H+ secretion
- Loss of bicarbonate in diarrhoea
What happens to the excess H+ in non respiratory acidosis
- Buffered by bicarbonate, to make CO2. This is lost in expired air.
- Minimises the rise in H+ concentration, or pH drop of the plasma @ the expense of a drop in plasma bicarbonate (alkali reserve)
- Low plasma bicarbonate concentration is marker for presence, and a measure of severity of metabolic acidosis
What will limit respiratory compensation
- Respiratory compensation is limited if respiratory function is compromised - like in COPD, asthma, heart failure.
- If kidney function is normal, XS H+ can be excreted by the kidney
- But a slower rate as compared to the very rapid respiratory component of compensation
What is the clinical presentation of metabolic (non-respiratory) acidosis - Things that are caused by increased [H+]
- Hyperkalaemia with ECG changes • Higher levels of potassium - Increased adrenaline - Decreased myocardial contractility - CNS depression - Hyperventilation = breathing deep and fast because the medulla oblongata, brain stem is triggered.
What is the clinical presentation of metabolic (non-respiratory) acidosis - Things that are caused by increased pCO2
- Peripheral vasodilatation
- Headache
- Bounding pulse
- Papilloedema
- Flapping tremors
- Drowsiness + Coma
How would you achieve complete correction of metabolic acidosis
- Treating the cause. Like insulin + fluids for diabetes ketoacidosis
- Or removal of ethylene glycol in poisoning
• In severe conditions with [H+] of 100nmol/l or above - i.v. bicarbonate (1.26%), 150mmol/L is given in small volumes.
• The effect on arterial H+ regularly checked
• Careful monitoring of Hyperkalaemia + treatment if necessary using glucose and insulin + dialysis
Summary of changes in respiratory compensation?
- [H+] elevated (RR between 35-46nmol/l)
Ø pH is just the minus log, of hydrogen ion concentration - pH decreased (RR between 7.36 - 7.44)
- Pco2 decreased (RR between 4.5 - 6 kPa)
Ø This all means the same thing. - [HCO3-] much reduced (RR between 22-30mmol/L)
How is respiratory acidosis characterised
1. Increased pCo2 Ø Expected to be high = acidosis, expect the hydrogen ion concentration to be high 2. Increased [H+] 3. Decrease in pH 4. Compensatory increase in bicarbonates
What are the causes of respiratory acidosis ?
Airway obstruction
Respiratory centre depression
Neuromuscular diseases
Pulmonary diseases
Thoracic wall diseases
How can respiratory acidosis be corrected?
- By means that will restore the Pco2 back to normal
- If this elevated pCO2 persists the compensation will occur.
- This compensation occurs through increased renal H+ excretion
Give a summary of the acute biochemical changes that occur in respiratory acidosis*
These are important markers to remember!!
1. Acute respiratory acidosis Ø H+ is elevated (RR 35-46nmol/L) Ø pH decreased (RR - 7.36-7.44) Ø PCO2 increased (RR - 4.5-6Kpa) Ø [HCO3-] slightly increased (RR 22-30mmol/L)
- Chronic respiratory acidosis
Ø H+ slightly elevated, or high-normal (RR 35-46nmol/L)
Ø pH slightly decreased, or low (RR - 7.36-7.44)
Ø PCO2 increased (RR 4.5-6Kpa)
Ø HCO3- increased (RR 22-30mmol/L)
What are the management aims of respiratory acidosis
- Lowering Pco2
- Combatting hypoxaemia, by improving vascular ventilation
- Bronchodilators, antibiotics, physiotherapy, artificial ventilation used
- O2 @ high concentration can be used in acute resp failure
• Could be dangerous in chronic respiratory failure because the respiratory centre starts to be insensitive to CO2.
• Hypoxia becomes the main stimulus to respiration
Describe metabolic [non respiratory] alkalosis
- Metabolic = bicarbonate will go up
- Increase in extracellular fluid bicarbonate concentration
- With consequent reduction in [H+] - normally, increased plasma bicarbonate = incomplete renal tubular reabsorption of bicarbonate and increased excretion in the urine
What are the causes of metabolic alkalosis
- ECF volume depletion + hypochloraemia
Ø As in gastric aspiration; repeated vomiting w/ pyloric stenosis
Ø Chloride loss in diarrhoea
Ø Loop and thiazide diuretics (but NOT potassium sparing diuretics)
Ø Loss of sodium and water = contraction of the ECF volume, which will stimulate the renal sodium retention, through stimulating the renin-angiotensin-aldosterone system + increased excretion of potassium and hydrogen ions
Ø Potassium = very low levels in the plasma. Majority of potassium is inside the cells, measure of plasma is a poor indicator.
Ø Potassium kept INSIDE and sodium kept outside. Sodium potassium ATPase, will keep pushing sodium out AGAINST the concentration gradient
Ø That enzyme / pump alone uses 25% of our energy expenditure every day. - Alkali intake as in chronic antacid intake, over treating acidosis
- Potassium depletion
Ø Reduced intake + increased loss
Ø Mineralocorticoid excess like in
○ Cushings, Conns, Barrters, Secondary Hyperaldosteronism
○ Drugs like carbenoxolone
Ø Potassium depletion and the loss of intracellular shift of H+
What does the shift of H+ that is in metabolic
- This shift will cause extracellular alkalosis
- Potassium depletion, will cause more Hydrogen ions to get exchanged (lost in urine), for the reabsorbed sodium ions in the distal convoluted tubules
- Potassium depletion also stimulates ammonia formation by kidney and thus increases acid secretion
What are the biochemical changes in metabolic alkalosis?
Ø Metabolic alkalosis = metabolic condition in which the pH of the tissue is elevated beyond the normal range of 7.35-7.45
Ø This is the result of decreased hydrogen ion concentration
Ø This results in increased bicarbonate concentrations.
- Decreased [H+] (RR 35-46nmol/L)
- Increased pH (RR - 7.36-7.44)
- Increased Pco2 (RR 4.5-6Kpa)
- Much increased [HCO3-] (RR 22-30mmol/L)
What is the expected compensatory change in metabolic non respiratory alkalosis
- Increased PCO2
- Would increase the PCO2 / [HCO3-] and thus [H+] = a low arterial blood [H+] will inhibit the respiratory centre
- Which will cause hypoventilation + increased PCO2
- This is a self-limiting mechanism, because the increased Co2 stimulates respiration and thus it is mainly useful in acute conditions
- In more chronic conditions, the respiratory centre becomes less sensitive to Co2
- If hypoventilation leads to significant hypoxaemia, the low Po2 would be a powerful stimulus of respiration and prevent further compensation
What is the management of metabolic non respiratory alkalosis
- 0.9% (w/v) sodium chloride solution (which is isotonic saline) - used to expand the contracted ECF and correct hypochloraemia
- The corrected hypovolaemia = improves renal perfusion
- And also enhances the excretion of excess bicarbonate
- In presence of potassium depletion, correction of the underlying cause + potassium replacement should be initiated.
What are the common features of respiratory alkalosis?
- Fall in pCo2
- = reduces ratio of pco2 to bicarbonate concentration, thus reduces H+
Ø This is a disturbance in acid + base balance
Ø Due to alveolar hyperventilation
Ø Which leads to a decreased partial pressure of arterial carbon dioxide.
Main causes of respiratory alkalosis
1. Hypoxia + increased respiratory drive
- High altitude, anaemia, pulmonary oedema, pulmonary embolism
- Other causes of increased respiratory drive:
○ Cerebral trauma
○ Infection
○ Tumours
○ Respiratory stimulants (salicylates, liver failure, septicaemia, primary or voluntary hyperventilation and mechanical ventilation)
What are the biochemical features of acute respiratory alkalosis
- Decreased [H+] (RR 35-46 nmol/l)
- Increased pH (RR 7.36-7.44)
- Decreased pCO2 (RR 4.5-6 kPa)
- Slight decrease in [HCO3-] (RR 22-30 mmol/l).
What are the biochemical features of chronic respiratory alkalosis
- Slightly decreased or low-normal [H+] (RR 35-46 nmol/l),
- Slightly increased or high-normal pH (RR 7.36-7.44)
- Decreased pCO2 (RR 4.5-6 kPa)
- Decreased [HCO3-] (RR 22-30 mmol/l)
What determines water distribution
- The osmotic contents of these different compartments
- Kept equal apart from the kidney
- Changes in solute content of a compartment will result in water shift
- Water shift will restore isotonicity
What determines the osmolality of ECF
- Mainly due to sodium (135mmol/L) + its associated anions, chloride and bicarbonate
• + with glucose and urea also contributing
What determines the osmolality of ICF
- Mainly determined by potassium (110mmol/L)
- its associated anions phosphates, proteins and sulfates
Ø The osmotic effect of plasma proteins (the colloid osmotic pressure, or oncotic pressure), is important in determining the water distribution between these compartments
Ø Normally, the amount of water that is taken into the body (fluids, water in solid food + metabolic water) - equals that lost in urine, stools, sweat, and through lungs which is about 1500ml/24h, & is really variable
- its associated anions phosphates, proteins and sulfates
What is the minimal urine volume that is needed for excretion of waste
- 500ml/24h
- Because of obligatory losses through other routes - the minimus daily water intake to maintain balance, is about 1100ml
- This increases with excessive sweating, diarrhoea + diuretic use
What do changes in body water content, independent to amount of solute do to the osmolality?
- Changes in body water content, independent of the amount of solute will alter osmolality, which is normally 280-295 mmol/kg of ECF water.
- Loss of water, as in water deprivation,
• Would increase osmolality and cause water movement from ICF to ECF, thus a slight increase in ECF osmolality occurs.Ø Stimulates thirst centre in hypothalamus, which promotes our desire to drink and stimulate the hypothalamic osmoreceptors
Ø Which will cause the release of ADH (anti diuretic hormone, or vasopressin)
Ø This peptide hormone is synthesized in the hypothalamus + transported to the posterior pituitary to be secreted into the blood
Ø Renders the renal collecting ducts permeable to water - thus permitting water reabsorption and urine concentration.
What happens if ECF osmolality falls
- There will be no thirst sensation
- Vasopressin secretion will be inhibited + urine will be dilute
- This will allow water loss + restoration of normal ECF osmolality
What happens in Diabetes Insipidus?
- Either ADH is not produced by the hypothalamus (Cranial DI = no creation of ADH)
• There are other that produce the hormone
• Tell to reabsorb water and concentrate urine
• Failure of the kidney receptors to respond to the ADH = called insipidus - Or the kidney receptors are resistant to its action (Nephrogenic DI)
• There are 2 types - Very large volume of dilute urine is produced - this is the end result. Like 15 litres rather than a litre and a half.
- This happens at a time when the plasma concentration is expressed as plasma osmolarity
Water balance + distribution
- Vasopressin can also be stimulated by a decrease in plasma or blood volume of 8-10%, even if osmolality is decreased
- Osmolarity is increased and there is linear increase in ADH
- Another factor that influences is the volume of blood - doesn’t have to be blood ; can be loss of fluids (e.g. through a car accident)
- If the blood volume decreases, the dotted line is the response to hypovolemia
- Hyperbolic rise = very fast elevation of ADH
- Even if the plasma is diluted, ADH production is elevated
- Nicotine = stimulates ADH - this is why smokers are less likely to go to the toilet.
Describe the stimulating factors in the control of vasopressin secretion
- Increased ECF osmolality
- Stress, pain, nausea
- Exercise
- Severe hypovolemia
- Drugs: nicotine, morphine, sulphonylureas, carbmezapine, clofibrate, vincristine
Describe the inhibiting factors in the control of vasopressin secretion
- Decreased ECF osmolality
- Hypervolaemia
- Alcohol
Describe the sodium distribution in our bodies
- Body of an adult man = 3000mmol of sodium
- 70% of this freely exchangeable
- 30% is complexed in bone
- ECF sodium concentration is 135-145 mmol/L
- ICF sodium is 4-10mmol/L
- This gradient is maintained by the activity of Na+/K+ ATPase, which uses energy of ATP to pump sodium into the outside of the cells in exchange for potassium = Both against their own concentration gradient!
- Western diet = 100-200mmol of sodium in 24h
- Obligatory sodium loss via kidney, skin + gut is less than 10mmol/24h
- Excess sodium might contribute to hypertension
- Is a PUMP called sodium potassium ATPase
Describe potassium distribution
- Predominant intracellular cation.
- 90% of body potassium = freely exchangeable.
Ø The rest is bound in RBCs, bone + brain, and only 2% (50-60mmol) is located in the ECF - Which transports potassium into the cells, in exchange for sodium, against concentration gradient
- Potassium tends to diffuse down its concentration gradient from the cells into the ECF - this is efficiently opposed by the pumping actions of Na+/K+ ATPase
Sodium + ECF characteristics
- ECF volume depends upon total body sodium content
- Since water intake + loss is regulated to maintain a constant ECF osmolality
- This in turn will depend mainly on sodium concentration
• Facing a variable intake - sodium balance is maintained by the regulation of renal excretion - Normally 70% of filtered sodium gets actively reabsorbed in the proximal convoluted tubules
- With further reabsorption in the Loop of Henle
- Thus less than 5% of filtered sodium reaches the distal convoluted tubules
- Fine control of the distal tubule sodium excretion depends on the activity of aldosterone, secreted by the adrenal cortex in response to activation of the Renin-Angiotensin Aldosterone System
Describe the functional anatomy of the renal system
- Kidney is connected to the heart
- Nephron = 1 million of those in each kidney, collect in the connecting duct and then spill open
- The kidneys filter everything that is smaller in the whole size of the membrane
- Water, glucose, amino acids, potassium - all go in as long as they are small enough
- Red and white cells are larger so cannot get in.
- After that there are secretions - the rest of the tubules fine tunes the rest of the amino acids and glucose
- Adjusts water balance by anti-diuretic hormone
○ All proteins and nucleic acids release nitrogen which are secreted in the form of urea
Outline kidney function
Ø Describe glomerular filtration
- Fluid that is filtered by the glomerular capillary filtration membrane is similar to the blood plasma
- With the exception of proteins, as it is virtually protein free
- The hydrostatic pressure that is within the glomerular capillaries is the major force that drives water + solutes out of the blood capillaries and into the Bowmans capsule
- It is opposed by oncotic pressure - due to plasma proteins of the capillary blood
Outline kidney function
Ø Proximal tubular transport
- In the proximal tubule:
• 70% of filtered sodium, chloride and water
• As well as > 90% of potassium, glucose, bicarbonate, calcium, phosphate, amino acids, and reabsorbed back to the blood - mostly by active transport - Glucose re-absorption has maximum capacity: called renal threshold
Ø If amount of filtered glucose exceeds the renal threshold
Ø Because blood glucose if higher than 10mmol/L as occurs in diabetes mellitus
- Not all glucose can be reabsorbed back to blood, and glucose will appear in the urine
Outline kidney function
Ø Loop of Henle + distal tubular transport
- The loop of Henle + distal and collecting ducts concentrate the urine and conserve water under the influence of ADH
- Also finely adjust the composition of urine under the influence of aldosterone
- This stimulates further sodium reabsorption in exchange for potassium or hydrogen ions
What happens to hydrogen ions (acids) in the kidneys
- Hydrogen ions (acids) are excreted in the distal tubule, which thus contributes to the regulation of acid-base balance
What happens to waste products? + what are they [of the kidneys]?
- Creatinine, urea, uric acid, organic acids are excreted through filtration at the glomerulous + secretion by tubules
What are the 3 renal function tests?
- Plasma creatinine + creatinine clearance
Ø Keeps falling if there is kidney disease
Ø Below certain amount = need dialysis - Blood urea nitrogen (RR=3-7)
- Urine analysis
Ø Microscopic functions of the kidney
- Water depletion could occur due to increased loss form the kidney, in renal disease
- Lost from the skin (e.g. sweating, hyperventilation etc.)
Describe the renal function test:
Ø Plasma creatinine + creatinine clearance
- Creatinine = metabolite of skeletal muscle. Is excreted by the kidney.
- In renal damage = creatinine concentration in the blood is increased above the upper reference level of 140micromol/L
- Elevated creatinine level
• Indicates that a decreased GRF (glomerular filtration rate) - Creatinine clearance is calculated from creatinine level in blood and urine + volume of urine, per minute
Monitoring creatinine clearance allows monitoring the progress of kidney disease + response to therapy estimating the time at which dialysis or renal transplantation would be needed.
Describe the renal function test:
Ø Blood Urea Nitrogen
- Reflects glomerular filtration + urine concentration ability
- Its level increases as GFR decreases
- It also rises in states of dehydration/hypovolemia as it is reabsorbed back to blood
• Weakness, confusion, weight loss. Diabetes insipidus - stays low even when the patient is dehydrated.
• Is dangerous and can affect the brain and cause the brain to shrink
• Lining of the meninges, vessels get stretched and there are atherosclerotic vessels which can break + haemorrhage - It is also sensitive to protein intake
- Normal reference = 3-7mmol/L
Describe the renal function test:
Ø Urine analysis
- Urines physical properties like colour, aspect, odour, pH, volume, specific gravity, chemical properties.
- The presence of the following:
Ø Albumin, glucose, acetone, nitrates
Ø + microscopic picture: pus and red cells, crystals, casts, epithelial cells, parasites ova - These are all useful in diagnosis + management of renal diseases
Describe the properties of ANP, Atrial Natriuritic Peptide
- Secreted by cardiac atria. In response to atrial stretch
- Following a rise in atrial pressure
- ANP acts directly, by inhibiting the distal tubular sodium reabsorption
- also through inhibiting the renin-angiotensin-aldosterone system
- ANP also antagonises the pressor effects of noradrenaline and angiotensin 2
Ø This will cause vasodilatation
How does sodium depletion arise
- Sodium is lost from the body as isotonic, or hypertonic fluid
- Thus decreases ECF volume
- Both vasopressin + aldosterone secretion are stimulated, to retain water and sodium
What is the clinical presentation of sodium depletion?
- Weakness, dizziness, apathy, weight loss, elasticity (skin does not drop again after being pulled out)
- Shortness of breath (dyspnoea), peripheral oedema
- Venous congestion
- Hypertension
- Weight gain
- Pulmonary oedema
Ø These are all due to expansion of ECF volume - Management of this would be to 1. Treat cause 2. Use Diuretics 3. Control Sodium Intake
Describe potassium homeostasis of the kidney
- In kidneys, filtered potassium = almost fully reabsorbed in the proximal tubules
- Some active secretion occurs in the most distal part of the distal convoluted tubules.
- Potassium excretion is mainly a passive process, and togetether with hydrogen ions counterbalance the active sodium reabsorption.
- Aldosterone will stimulate potassium excretion directly @ distale tubule
- Aldosterone will stimulate potassium excretion indirectly by increasing active sodium reabsorption, in distal tubules + collecting ducts
- Aldosterone secretion from the adrenal cortex is stimulated by renin angiontensin system - + by hyperkalaemia
What can potassium and hydrogen do to the membrane potential
- Both potassium and hydrogen ions can neutralise the membrane potential that is generated by active sodium reabsorption
- In acidosis, a lot of Hydrogen ions compete with potassium.
Ø Potassium excretion decreases and its blood level rises (hyperkalaemia) - In alkalosis (which is low hydrogen ion concentration)
Ø Potassium excretion increases.
Ø Potassium blood level decreases (hypokalaemia)
○ Potassium depletion, causes alkalosis
What does potassium depletion cause
- Potassium depletion causes alkalosis
Describe potassium homeostasis of the gut
- Potassium gets excreted in the gastric juice.
- Much of the gastric juice + also dietary potassium gets reabsorbed in the small intestine
- In the colon + rectum, potassium is secreted in exchange for sodium.
Ø This is partly under the control of aldosterone. - Considerable amounts of potassium can be lost in the stools
Ø (in patients that have:
○ chronic diarrhoea
○ or fistulae
○ or in patients that have persistent vomiting / nasogastric aspiration) - Aggressive insulin treatment, of high blood glucose (as in non ketotic- hyperhlycaemia coma) - might induce hypokalaemia.
- Conditions of:
Ø Rapid cell death
Ø or membrane damage (like in leukaemia, lymphoma or crush accidents)
Ø = can cause hyperkalaemia
What stimulates the cellular uptake of potassium
- Insulin stimulates the cellular uptake of potassium.
- In exchange for sodium, co transported with glucose
Describe what happens in potassium depletion
- Normal dietary intake = 60-200mmol/24hours
- This is prevalent in many foods.
What are the causes of hypokalaemia
- Decreased intake (parenteral or oral)
- Transcellular movement
Ø Alkalosis - Increased renal excretion as happens with diuretics
- Increased extra renal excretion
What are the clinical features of hyperkalemia?
- Can kill without warning! Through ventricular fibrillation and cardiac arrest
- ECG changes might precede ventricular fibrillation
What is the management of hyperkalaemia?
- Calcium gluconate - 10ml of 10% solution iv over 1 minute and then repeated
- Iv glucose and insulin
- Dialysis
- Restriction of intake
- Oral ion exchange resin
Describe the anatomy of the hypothalamus-pituitary connections
- Pit gland = base of the brain, just underneath the optic chiasm
- If there are adenomas here then you will present with visual field defects
- Ant. And posterior make it up
○ Posterior = effectively an extension of the brain, has terminals of neurosecretory cells that have their cell bodies in particular parts of the hypothalamus
○ Oxytocin, Vasopressin (ADh)
○ Anterior = not directly neuronally innervated but is under neuronal control. Have neurosecretory cells in the hypothalamus but these do not go into the pituitary but they secrete into the portal circulation
○ Trigger anterior pit cells to stimulate their hormones
Describe the regulation of anterior pituitary hormones - GH
Ø GH-RH - stimulatory
“growth hormone releasing hormone”
Ø Somatostatin - inhibitory, suppresses the anterior pituitary making growth hormone
Describe the regulation of anterior pituitary hormones - Prolactin
Ø PIF (dopamine)
• Prolactin inhibitory factor
Describe the regulation of anterior pituitary hormones - TSH
Thyroid stimulating hormone. Also known as thyrotropin
Ø TRH
Describe the regulation of anterior pituitary hormones - ACTH
Ø Adrenocorticotrophic hormone
Ø CRF - corticotrophin releasing factor
Describe the regulation of anterior pituitary hormones - LH + FSH
GnRH
Regulation of anterior pituitary hormones - anterior pituitary hormones : TSH
Target hormone / action (what is made when it is stimulated)
Ø Thyroxine, T3
Regulation of anterior pituitary hormones - anterior pituitary hormones : ACTH
Target hormone / action (what is made when it is stimulated)
Ø Promotes release of Cortisol, main glucocorticoid
Regulation of anterior pituitary hormones - anterior pituitary hormones : LH, FSH
Target hormone / action (what is made when it is stimulated)
Ø Gonadal Hormones
Regulation of anterior pituitary hormones - anterior pituitary hormones : Growth Hormone
Target hormone / action (what is made when it is stimulated)
Ø IGF-1, insulin like growth factor, when in the circulation they exert negative feedback and release production of pituitary hormone and hypothalamic pathway
• GHRH –> GH –> liver release of IGF1 –> Suppression of GH.
Regulation of anterior pituitary hormones - anterior pituitary hormones : Prolactin
Target hormone / action (what is made when it is stimulated)
Ø Breast Development, lactation
Describe how you would do an investigation of endocrine disorders
- In endocrine disorders, hormone levels = too high, or too low - so you have to measure if in normal range or not.
Ø TOTAL hormone levels (in a radioimmunoassay)
○ = relatively straightforward but depends on protein binding
Ø Free hormone levels. Hormones in circulation = bound to certain proteins.
Ø Hormone release = usually pulsatile, and or circadian
Ø Dynamic function tests
○ This is physiological ability, of endocrine tissue, to stimulate or inhibit hormone release: testing whether it is functionally intact. Do this by inhibiting or stimulating the release of the hormone to see if the system is ok.
§ e.g. checking the release of cortisol by giving ACTH
○ Dynamic = this is over time
Describe the negative regulatory feedback of hormones
THYROID HORMONES
Ø Released by thryroid gland
Ø Then effects rest of the body
- TSH made. Binds to its receptors on the thyroid follicular cells
- This then produces T3 and T4, which then exert negative feedback and maintain levels
Describe the thyroid hormones functions
- Effect on every single cell in the body. Can be divided into:
Ø 1. Normal growth + development in humans and other vertebrates (e.g. metamorphasis in lower animals)- Non developmental = essential for maintaining normal metabolism (BMR) - tends to increase the metabolic rate
- Made in the thyroid via series of enzyme catalysed reactions
• Beginning with the uptake of iodine into gland - Synthesis + release is controlled by TSH
- T4 = main hormone secreted by the thyroid [most abundant]
- T3 = more biologically active. Mostly formed by the peripheral conversion of T4 into T3, @ cellular level within the target tissues.
- These effects are mediated via the activation of nuclear receptor
- Made via iodine uptake by the thyroid gland = 1st step of synthesis
Describe circulating thyroid hormone
- Both T4/T3 = extensively protein bound, principally to TBG
- Free (non- protein bound) fraction physiologically active - taken up, then there is no further release
- Changes in protein binding affect total hormone concentrations
- Accurate measurement : has to be a measurement of free hormones, is not affected by variation in TBG - & so discriminates more reliably between normal + abnormal thyroid function
Describe total and free thyroid hormone concentrations
T4 and T3 in plasma = more than 99% protein bound. The total (all of the T4 or T3 that can be detected) there is a nanomolar concentration. This is a low []. Free one is in the picomolar, very low concentrations of the free form.
Describe disorders of Thyroid function - Hypothalamic-Pituitary Thyroid Axis
- Stimulating hormone from the anterior pituitary, TSH
- Could be a disorder anywhere along this axis
Describe disorders of Thyroid function - Euthyroid, hypothyroid, hyperthyroid
Ø Primary = problem is with the thyroid gland itself
Ø Secondary. Problem is with pituitary regulation. Not enough stimulation or suppression. (this is not direct)
Ø Tertiary = more rare
Ø Could be issue with TRH, which in turn would affect the THs.
Describe hyperthyroidism
- Excessive production of the thyroid hormones (Thyrotoxicosis)
- Not same thing. TTC is the condition that results from elevated thyroid levels.
- Thyrotoxicosis = associated with hyperthyroidism. Is the clinical result
What are the clinical features of hyperthyroidism
Results of thyrotoxicosis
- Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves)
- In extreme: thyroid storm - this is especially sympathetically related: palpitations, excess heart rate, raised body temperature. Bradycardia to the extend where it would be a cardiovascular emergency.
- Presents as a sympathetic overload / excess. Would therefore treat it using Beta Blockers
What are the causes of hyperthyroidism
- Graves = most common due to stimulatory TSH-R antibodies(AUTOantibodies) - antibdoies act as agonists at the TSH receptor and stimulate release.
- Toxic multinodular goitre
- Toxic adenoma
Ø Benign tumour that secretes excess hormone
Ø All of these are primary - Excess TSH secretion (rare)
Ø In this case would be secondary.
What are the actions of TSH
goitre
- Increases iodine uptake
- Stimulates other reactions that are involved with TH synthesis (e.g. TPO)
- Stimulates colloid uptake
- Induces the growth of the thyroid gland - which can lead to goitre
- Stimulates all of the steps, right through to stimualtion of growth of the thyroid gland
- This is why hyperthyroidism can lead to goitre
- Graves = hyperthyroidism. Leads to diffuse goitre. This is enlargement of the hyperthryorid gland which is evenly spread
- Toxic multinodular goitre = some of the thyroid nodules are hyperactive and grow. Goitre that is more lumpy + uneven
Describe hypothyroidism
- Not enough production of thyroid hormones
What are the clinical characteristics of hypothyroidism
- The symptoms are things that you would get through a lowering of metabolic rate.
- Weight gain, cold intolerance, lack of energy, goitre,
- Congenial - developmental abnormalities
- Still would get goitre = if the thyroid is not fully making TH, the TSH levels will increase. The stimulatory effects of TSH on thyroid gland, promote growth and the hypothyroidism can be due to something else breaking in the synthesis pathway
- TSH is trying to compensate and beef up the thyroid gland and get levels back up to normal, therefore is a compensatory response.
- If the hypothyroidism = congenital (from birth), then it will lead to developmental abnormalities, “cretin” = this initially was a description of growth / developmental / learning difficulties that were common in those who lived in low iodine environments
- Clearly demonstrating the need of thyroid hormones to support normal need and development
What are the causes of hypothyroidism?
- Autoimmune thyroiditis (Hashimotos)
Ø Thyroid peroxidase antibodies (Anti - TPO) - anti thyroid peroxidase]
○ Crucial in making thyroid hormones.
Ø DESTRUCTIVE circulating antibodies. Do not act like agonists like with hyper. They are destructive to thyroid function. - Iodine deficiency
Ø Worldwide = the most common cause. Common cause of goitre. - Toxic adenoma
- Pituitary / hypothalamic - lack of TSH
Raised serum TSH would indicated endocrine investigation + thyroid replacement therapy.
Treatment + monitoring of thyroid disorders : HYPERTHRYOIDISM TREATMENTS
- Depends on the actual cause, but mostly will treat the symptoms. In graves, would address the immune issues that cause the symptoms but in the absence of that, it has to be managed.
- Anti thyroid drugs, like carbimazole, partial
- Thyroidectomy - would then need T3 and T4 supplements
- Radioactive iodine for partial or complete destruction of the thyroid gland
- Ft4 levels fall rapidly, with successful treatment, TSH might remain suppressed for several months
- These are not fatal conditions, but they can be in a thyroid storm, but can be awful for the patient
Treatment + monitoring of thyroid disorders : HYPO- THRYOIDISM TREATMENTS
- Thyroxine replacement
- Ft4 might remain a bit raised
- Best monitored by TSH (elevated values indicate under / & suppressed values over replacement), get a stable level of TSH over time = means that there are the right amounts of T4 (thyroxine) involved.
Adrenal steroids characteristics
- The adrenal cortex has 3 zones
- Steroids all come from cholesterols in a series of enzymatic reactions
Characteristics of the 3 adrenal steroids
Ø Aldosterone = main mineralocorticoid that is made in the outer zona glomerulosa
○ Not under control of the HPA. Mostly controlled by the RAAS system. XS ACTH can also lead to aldosterone secretion
Ø Cortisol = principal glucocorticoid that is produced by the zona fasciculata
Ø Glucocorticoids + adrenal androgens are made in the zona fasciculata & zona reticularis
What are the 3 adrenal steroids
- Cortisol 2. Aldosterone 3. Glucocorticoids
Describe the biosynthesis of the adrenal steroid hormones
- Particular enzymes for these reactions are specific for the zones that the blood flows through
- Outer = cholesterol can be carried further to the middle zones
- Intermediate products that flow rather than going to further reactions then encounter a different set of reactions that go through more and make cortisol
- Depends on the presence of the certain enzyme for certain stages, localised to certain zones
Describe the biological effects of adrenal steroids: CORTISOL ALDOSTERONE ANDROGENS - Cortisol "stress hormone"
Ø Controlled by ACTH
Ø NOT only present in stress, essential to life: CVS function, metabolism, protective against hypoglycaemia and promotes increases in insulin
Ø Antagonises the effects of insulin, by enhancing gluconeogenesis
Ø Promotes the central deposition of fat
Ø Increases catabolism of proteins (protein breakdown, feeding them into gluconeogenesis)
Ø Weak mineralocorticoid effects
Ø Anti-inflammatory
Describe the biological effects of adrenal steroids: CORTISOL ALDOSTERONE ANDROGENS - Aldosterone
Ø Increases sodium reabsorption in the renal DCT
Ø Controlled by the RAAS. ACTH additionally has the effect of stimulating adrenal androgen synthesis, especially at higher levels.
Describe the biological effects of adrenal steroids: CORTISOL ALDOSTERONE ANDROGENS - Androgens
Ø Virilising effects when secreted in excess
Describe the control of adrenal steroid secretion?
- The synthesis of cortisol is regulated, by the Hypothalamic-Pituitary Adrenal Axis
- Aldosterone synthesis is controlled by the Renin-Angiotensin System
- Adrenal Androgen Synthesis is regulated by ACTH, not gonadotrophins
- Cortisol can also stimulate aldosterone secretion
Hyperfunction of the adrenal cortex - Ø Can cause CONNS, or CUSHINGS syndrome
describe CONNS
- Excess secretion of aldosterone because of a tumour or hyperplasia of adrenal - sodium retention + other volume problems.
Hyperfunction of the adrenal cortex - Ø Can cause CONNS, or CUSHINGS syndrome
describe Cushing’s syndrome {more common}
- Excess cortisol secretion. This will cause:
Ø Pituitary Tumour (Cushings disease) that results in excess ACTH secretion. This is secondary because it is the pituitary making the ACTH
Ø Ectopic ACTH production
○ Production of ACTH that is other than where it usually happens, i.e. the pituitary. Small cell lung carcinomas have neuroendocrine origins and can start to produce cortisol
Ø Adrenal Tumour
○ Resulted in hyperproduction of cortisol
○ This would be primary
Ø Exogenous administration of steroids
What are the characteristics of Cushings syndrome?
Ø Raise glucose, promote lipogenesis, also promoting proteolysis in muscles as part of its gluconeogenic action as well as its immune functions. Might get raised blood glucose but also:
• Muscle weakness
• Menstrual disturbances+ psychiatric disturbances
• Moon face (rounding of the face due to fat deposition) + truncal obesity
• Striae, Bruising
• Hirsuitsm (ACTH stimulates the adrenal cortex and the secretion of cortisol, and also adrenal androgens which suggests that it is due to ACTH and not definitve factors),
• Acne, hypertension,
• Glucose intolerance (due to raising blood glucose), osteoporosis
Ø Excessive cortisol production by the adrenals.
What are the diagnostic steps of Cushings syndrome
- Demonstration of excessive cortisol production
2. Elucidation of cause
Describe the dynamic tests of endocrine function
Test of endocrine function type 1
Ø Stimulatory test
Test of endocrine function type 2
Ø Suppression test
Ø Investigating endocrine gland hypofunction
Ø Investigation of the suspected hyperfunction
Dexamethasone characteristics
Dexamethasone characteristics
Ø Synthetic glucocorticoid (analogue)
Ø Will not show up in cortisol assay but will stimulate cortisol receptors centrally.
Ø Binds to GC receptors in the pituitary to suppress ACTH release + cortisol secretion from the adrenal
If given to a normal patient
Describe the low dose dexamethasone suppression test
- 1mg of dexamethasone given @ night. Serum cortisol looked @ 9AM the next morning
- Normal subject = cortisol
What would you see in dex suppression test in a normal person
- Decreased cortisol because of the negative feedback.
Describe the high dose dexamethasone suppression test
- 2mg dexamethasone, 6 hourly for 2 days
2. To determine the cause of Cushing’s syndrome
Differential diagnosis of Cushings syndrome
Ø There is a low dose and a high dose version. If the cause is XS ACTH, if you then give the low dose test there might be some suppression of cortisol then ACTH turned up anyway so might not get degree of separation as in a normal person.
Ø If then, in this same person if it IS due to excess ACTH then enough dexamethasone WILL result in suppression. Can suppress pituitary production of ACTH as much as you want if this is not from the pituitary.
What are the causes of adrenocortical insufficiency
- Primary adrenocortical failure
- Addison’s disease, is rare, but the most common cause of adrenal insufficiency. It is due to
Ø Autoimmune disease
Ø TB
Ø Less common: metastases, haemochromatosis, haemorrhage - Secondary to impaired ACTH release
Ø Tumour, head trauma, surgery, rapid withdrawal of steroids - Can have adrenal failure due to lack of cortisol or aldosterone.
Clinical features of adrenocortical insufficiency
Ø Fatigue, weakness, hypoglycaemia, hypotension
Dynamic tests that can be carried out - SHORT synacthen tests
- Certain criteria by which cortisol can arise. Rise of greater than 200 nanmoles from a given peak level, for e.g.
- Assess ability of adrenal to produce cortisol in response to ACTH
- Serum cortisol measured, after giving synacthen (synthetic ACTH )
- (normal response – cortisol increases by >200nmol/L over basal
level with peak of >550nmol/L).
If the adrenal gland is failing to produce cortisol = recovers from lack of production by producing ACTH
If the failure is 2ndary it is failing because the pituitary is not producing enough ACTH.
Dynamic tests that can be carried out - LONG synacthen tests
- 3 day stimulation with 1mg depot synacthen im daily
- In secondary adrenal hypofunction, serum cortisol levels increase to atleast 200nmol/L over baseline values
Other tests of adrenal insufficiences
- ACTH assay
• Increase in primary disease
• Decrease in secondary failure
What is the name for synthetic ACTH
- Synacthen
Congenital adrenal hyperplasia characteristics
- Group of inherited metabolic disorders of the adrenal steroid hormone biosynthesis
- Clinical features depend on the position of the enzyme defect in the metabolic pathway
- 21 hydroxylase deficiency >90% cases, prevalence 1:5000-12k
- Leads to impaired production of cortisol + aldosterone
- Raised ACTH will stimulate production of adrenal androgens
Neonatal manifestation of Congenital adrenal hyperplasia
- There is virilisation of female infants
- Salt wasting + dehydration occurs in first 4 weeks of life
Ø Serum Na 2 days after birth - Needs glucocorticoid + mineralocorticoid replacement
- Treatment monitored by measurement of plasma 17a hydroxyprogesterone or androstenedione
Describe the combined pituitary function test
Ø Destructive lesions of pituitary tend to present with pituitary hypofunction
Ø Thus stimulatory tests are used to assess ability of gland to secrete hormones
Ø When assessing patients with suspected anterior pituitary dysfunction, it is often convenient to test the capacity of the gland, to secrete GH, ACTH, TSH, and the gonadotrophins in a single procedure
• This is the combined pituitary function test
Ø This involves measurement of the anterior pituitary hormones following the administration of:
• TRH, GnRH, insulin
Summary of investigating endocrine disorders
- Hormones of the anterior pituitary, and the target endocrine glands might be measured by immunoassay in order to investigate disorders of endocrine function
- And to distinguish between primary and secondary disease
- Dynamic function tests have greater utility in detecting impaired pituitary function, than measuring the basal hormone concentrations
What are the characteristics of Alkaptonuria?
- Autosomal recessive (AR)
- Urine turns black on standing (homogensitic acid - shown in the container of urine)
• & alkinisation - Black onchrontic pigmentation of cartilage + collagenous tissue
- Arthritis
- Homogentisic acid oxidase deficiency
- Alkapotonuria = ears going black
• If a baby has it, liquid will stay in the Terry nappies - when you try and bleach it, will go extremely black.
What are the characteristics of Cystinuria?
- Autosomal recessive.
- There is defective transport of cysteine + dibasic amino acias through the epithelial cells of renal tubule and intestinal tract
- Cysteine = has low solubility, formation of calculi in the renal tract = children will get kidney stones
- COLA or COAL are the patterns of amino acids
○ Cysteine - Mutations of the SLC3A1 aa transporter gene:
○ (Chr 2p)
○ SLC7A9 (Chromosome 19)
What are the characteristics of Albinism?
- Need to produce melanin, to have pigmentation
- Children with albinism have pink eyes (+ white rabbits with pink eyes)
What are the characteristics of Pentosuria?
- Excrete 1-4 grams of pentose sugar L-XYLULOSE daily (reducing sugar)
- Benign & is almost exclusively Ashkenazi Jews, of Polish Russian Extraction
Describe the one gene - one enzyme concept
- Substrate A going to product B, if there is a defect in the enzyme that takes A to B then the substrate will increase and the product will decrease
• Goes into a secondary metabolic pathway
• And this will start to produce C, which is toxic.
• This is where inborn errors of metabolism arise - That all biochemical processes in organisms = under genetic control
- That these biochemical processes are resolvable into series of stepwise reactions
- Each biochemical reaction is under the ultimate control of a different single gene
- Mutation of a single gene results in an alteration in the ability of a cell to carry out a single primary chemical reaction
Describe the molecular disease concept
- Work on Hb in SCD. Found direct evidence that human gene mutations:
Ø Actually produce an alteration in the primary structure of proteins
Ø Inborn errors of metabolism are caused by mutations in genes which then will produce abnormal proteins, whose functional activities are altered
What are the 5 mechanisms of inheritance?
- Autosomal recessive
- Autosomal dominant
- X linked
- Co dominant
- Mitochondrial
Describe autosomal recessive inheritance?
Ø 1:4 risk
- Both parents = carry mutations that affect same gene
- 1:4 risk each pregnancy
- Consanguity increases risk of autosomal recessive conditions (e.g. marrying a cousin.)
Ø Cystic Fibrosis
Ø Sickle cell disease
Gene from both parents
Describe autosomal dominant inheritance?
- Rare in IEMs
- Dominant condition which is fatal = less likely to survive
- Someone who is heterozygote for AD condition will develop disease
- Might not develop until it is actually reproduced
Ø Huntingtons
○ Neurological conditions
○ Happens in 40s so have already passed on to offspring
Ø Marfans
○ Long limbs
Ø Familial hypercholesterolaemia
○ Buildup in their cholesterol
○ Really early myocardial infarctions
Describe X linked inheritance?
- Characterised by carrier females, passing on the condition to affected sons, there is NO male to male transmission whatsoever
- Female carriers might manifest condition. This is LYONISATION
Ø Random Inactivation of one of the X chromosomes
Ø Common in things like urea cycle defect with OTC.
Ø When female carriers have a baby, involution of the uterus post-delivery = massive protein load and THIS can be the first sighting of this defect; and cause death.
What happens when females get X linked conditions
- Lyonisation
- There is random inactivation of one of the X chromosomes
X linked dominant?
- There is a fragile X
X linked recessive?
- Haemophilia
- Fabrys disease
• Has cardiac involvement
Describe codominant inheritance
- 2 different versions (alleles) of the gene expressed
- Each version makes a slightly different protein
- Both alleles will influence the genetic trait or determine the characteristics of genetic conditions
Ø ABO blood group
Ø (alpha)1AT deficiency (alpha 1 anti-trypsin) - Father has allele for A and O
- Mother allele for B and O
- Variation of what the children can get is shown in the cartoon
Describe mitochondrial influence - this is NOT the same as an X linked disease
- Mitochondrial DNA
• 21 genes that are coded for in the mitochondria - Inherited exclusively from mother
• Only the egg will contribute mitochondria to the developing embryo
○ Sperm does NOT contain mitochondria.
• Only females can pass on their mitochondrial mutations to children = but this is different to X linked although they are both female to male transmission (affects both female and male offspring)
• Fathers do not pass these disorders to their children
Describe mitochondrial DNA replication
- Heteroplasmy = separation of wild type and normal mitochondria
- End up with cell that contains ALL normal, ALL wiltype, ALL mutant or a mix
- Presentation depends on the load of affected mitochondria
- Any inheritance can affect any tissue
- Mix of things occur.
How do inborn errors of metabolism present - Neonatal presentation is often acute
Neonatal presentation is often acute
Ø Things that you do not screen for
Ø Maple syrup urine disease
Ø Tyrosinaemia
Ø OTC (urea cycle defect)
- Often caused by defects in energy metabolism
• Amino acid, organic acid, carbohydrate metabolism
• Urea cycle defects
• Respiratory chain defects
Biochemical abnormalities in IEM
- Hypoglycaemia, hyperammonaemia
- Unexplained metabolic ketoacidosis
- Lactic acidosis
Clinical abnormalities in IEM
- Cognitive decline
- Epileptic encephalopathy
- Floppy baby
- Exercise intolerant
• Glycogen storage diseases affecting the muscle
• Issues with fatty acid metabolism - Cardiomyopathy
- Dysmorphic features
• Mucopolysaccoridosis
• Gargolyism = ears are set @ different angle and eyes are set far apart - SUDI
• Sudden unexplained death in infancy
• Do not know why - if a baby dies quickly, need to get skin biopsy really quickly - Fetal hydrops
Lab investigations of IEM?
Ø General screening
Ø Specific tests to get the diagnosis
1st line lab investigations for IEM
- Blood gas analysis
• Acid base status of the baby (acidotic or alkalotic) - Blood glucose
• Hyperglcaemia or no - Plasma ammonia
• Elevated?
• Urea cycle defect - Liver function test
• Things like bilirubin, alanin transaminase gamma GT
• True test = liver failure, if they can actually clot their blood - this is a true test of if they have synthetic capacity in the blood - Urinary ketones
- Urine reducing substances
• Putting out a lot of galactose or fructose
2nd line investigations for IEM
- Plasma + urine amino acids
- Urinary organic acids
- Urinary orotic acids
- Blood acyl carnites
- Blood lactate and pyruvate
- Urinary glucosaminoglycans
- Plasma very long chain fatty acids
What are the confirmatory investigations of IEM
- Enzymology • Red cell galactose 1 phosphate uridyl transferase • Lysosomal enzyme screening - Biopsy, (muscle and liver) - Fibroblast studies - Complementation studies - Mutation analysis
Describe thin layer chromatography urine reducing sugars
- Pattern that you get on urine chromatography
- Galactose = overloaded and then diluted out.
- Found all the galactose in the urine; very toxic = want to remove lactose from the diet because it is metabolised into the glucose
What are the possible metabolic causes for acute liver disease in neonate
Classical galactosaemia
Hereditary fructose intolerance
Ø Newborn = unlikely because you have to give them fructose in their diet
Ø If getting just fructose from the milk = present with fructosaemia
An organic acidaemia
Tyrosinaemia type 1 = diagnosis
Ø High tyrosine and methionine
Ø Found high levels of succicyl acetate. Do not find them in other forms of liver disease
Ø Increased tyrosine
Ø Ended up with all of the substrates increasing
Ø This also goes with the liver disease
Describe TYPE 1 Tyrosinaemia
- Issues with breaking down tyrosine amino acid from the food that they eat
- If not treated = severe liver problems
- Cause the enzymes to stop working properly
Diagnostic test - liver biopsy
Ø Liver enzymology
Ø Ornithine transcarbamlyase 1.00 (ref range 11.8 - 44.7)
Ø Carbamylphosphate synthase 0.98 (ref range 0.73 - 3.19)
Blood supply to the liver 2
Ø Branches of the hepatic artery and the hepatic vein pull together
Ø Nuclei of the hepatocytes = black
Ø Lipoproteins can be secreted from the liver
Ø Across the “front door” of the liver cells which are call the sinusoid membrane
Ø There is a space (green spot) which is called the canaliculi membrane - a small canal which is called the bile canaliculi
Ø If you were to keep going along this = go from this small canal and it gets larger until you get to the right or left hepatic duct
Ø Which join to form the common bile duct
Describe the biliary passages & the pancreatic duct
- Makes it more alkaline = more appropriate to its function by neutralising the acid that comes from the stomach
- This is important for fat emulsification
- Enzymes are proteins& water soluble.
- Enzymes digest fats @ the interface between water and fats
- Fat digestion is efficient, then absorption is efficient
- Bile acids are not free in the body - they are present as bile salts. [like detergents]
What are the major functions of the liver?
Ø Carbohydrate metabolism Ø Lipid metabolism Ø Protein metabolism Ø Bilirubin metabolism Ø Hormones Ø Xenobiotic Metabolism Ø Storage
Carbohydrate metabolism function of liver?
- Gluconeogenesis
• Production of glucose from non-carbohydrate sources
• This is important in fasting - Glycogen synthesis and degradation
Lipid metabolism function of liver? - Fatty acid synthesis
- Cholesterol synthesis & degradation
• Liver = only organ that can get rid of cholesterol outside the body.
Lipid metabolism function of liver? - LIPOPROTEIN
- Ketogenesis
- VLDLs and the LDL, which are made outside.
- All depends on the clearance of chylomicrons etc.
Lipid metabolism function of liver? - Vitamin D 25-OH
- Vitamin D activation
- Bile acid synthesis + excretion
Protein metabolism function of liver?
- Plasma protein production. Albumin can only be produced in the liver. Oncotic pressure of the plasma - start to have fluid in our stomachs if we have low albumin.
- Normal albumin, between 30-50grams
- Ammonia detoxification happens in liver. Liver takes ammonia in the portal vein, runs it in urea cycle. Ammonia = toxic, and in normal health the liver will detoxify it by changing it into urea which is less toxic- stops ammonia from going into the brain
- Normal urea = 3-7millimolar.
Choleaemia = liver failure
Hormone functions of liver?
- Conjugation of steroid hormones
Ø Sex hormones also
Ø Can cause female hormones to accumulate in men with liver disease
○ Gynaecomastia, balding, feminisation, voice changes etc. accumulation of female sex hormones! - Degradation of peptide hormones
Describe the metabolism of bilirubin
- Bilirubin - bile pigments
- Bile pigments and bile salts are really diff.
- Salts = detergents that work for emulsification.
- Comes from senescent red cells - everything can be recycled apart from porphyrin.
- When the body is left with a porphyrin will break it open into biliverdin, => broken down to be yellow, which is bilrubin
• This is hydrophic. Need a carrier (albumin)
LIVER FUNCTION TESTS: Why are albumin and bilirubin insensitive indicators of disease.
- Liver = has considerable function reserve
- Therefore simple liver function tests, like:
Ø Bilirubin concentrations
Ø Albumin concentrations
○ Has a half-life of 21 days - Are insensitive indicators of disease
- As the cells die they release their contents into the plasma.
What liver function test are more sensitive
- Tests that actually reflect liver cell damage
- Like hepatic enzymes in plasma
What are the true tests of liver functions
- Brom sulphophtalein (BSP)
• See how much time the liver has taken to capture radioactivity
• Enters the different stages of liver circulation
• And then look @ secretion of bile in the intestine - Indocyanin Green
- Caffeine clearance
- Radiolabelled bile acid uptake + clearance tests
Describe the biochemical tests of liver functioning
- Reflect basic pathological processes that are common to lots of conditions
- Rarely provide precise diagnosis: are cheap, non-invasive, can direct other investigations
Ø e.g. liver biopsy and imaging
Ø Useful in detecting presence of liver disease + monitoring process
What are the objectives doing routine liver function tests?
- Aid to establish liver disease, by showing abnormal values
- Inform or help specific diagnosis, by showing different patterns
- Establish the severity of liver damage & provide prognostic insight
- Monitor disease progression
- Assess the response to therapy
Describe the characteristics of Bilirubin and Urobilinogen (the bile pigments)
Ø Derived from the breakdown of HAEM of senescent RBCs
Ø Derived from (to lesser extent) from myoglobin, cytochromes and some enzymes
Ø WATER INSOLUBLE. Transported to the plasma, to the liver by albumin
• At this stage, bilirubin = unconjugated + cannot pass in the urine, even if it is present at a high level
Ø Conjugated bilirubin = direct.
Ø Uncongjugated bilirubin gets taken up by the liver cells, to get conjugated/ link with glucoronic acid
• by the enzyme UDP-glucoronyl transferase,
○ Binds glurononic acid to bilirubin.
○ to produce bilirubin diglucoronide
• Bilirubin glucoronide= water soluble. Is called conjugated bilirubin => secreted into bile.
• Reaches the intestine. Most of it is oxidised by bacteria –> urobilinogen + stercobolin
• Small amount of urobilinogen & bilirubin = reabsorbed through entero-hepatic circulation to be secreted in urine.
Where are bilirubin and urolbilinogen derived from
Ø Derived from the breakdown of HAEM of senescent RBCs
Ø Derived from (to lesser extent) from myoglobin, cytochromes and some enzymes
What happens to uncongjugated bilirubin
- Taken up by the liver cells
- To be conjugated with glucoronic acid
- By the enzyme UDP-glucoronyl transferase
- This produces bilirubin digluoronide, which is water soluble & is called conjugated bilirubin
Describe what happens to conjugated bilirubin
- Also known as bilirubin diglucoronide, (is water soluble)
- Secreted into the bile
- Eventually gets to the intestine where most it is oxidised, by bacterio
- To make 1. urobilinogen and 2. Stercobilin
- Then a small amount of urobilinogen + bilirubin are reabsorbed through the enterohepatic circulation to be secreted in the liver
What is bilirubin reference range
3-17micromoles/L
What is total bilirubin reference range/ changes
- Plasma bilirubin will rise when there is significant liver damage
- Causes yellowish discolouration of skin + mucous membranes (Jaundice)
- This can be clinically detected, at bilirubin level of 50micromolar/L
- Leave bilirubin to go inside brain = will damage brain centres permanently.
When can jaundice be detected
- At a bilirubin level of 50 micromolar/L
What is motoring bilirubin used to do
- Investigate liver diseases + investigated subclinical hyperbilirubinaemia
- Determines need for exchange transfusion in neonatal jaundice
- Assesses surgical treatment of bile duct striature
Ø Duct can be narrow and surgically dilated
Ø Set the liver @ particular rate and if this has not happened then the stricture is not working properly - Determines the correct doses of drugs, e.g. cytotoxic therapy
What is the RR of ALP (alkaline phosphatase)
- 30 to 130 U/I = the RR of ALP (alkaline phosphatase)
• Removes phosphate
• (Group of enzymes that will hydrolyse phosphate esters)
• ALP is also present in the bone and the placenta.
Generally, when will plasma ALP increase
- In presence of obstruction to biliary passages, or cholestasis
- The block could be intrahepatic, as in PBC
- Or block could be due to a stone in the bile duct
- Or pressure by a tumour, e.g. head of pancreas or lymph nodes
- Liver disease = mainly damaging liver cells = AST and ALP will go up.
In which diseases will plasma ALP increase
- Increases in liver + bone disease
- Pregnancy, growing children
- To enhance specificity, ALP isoenzymes can be measured by using electrophoresis
- Or by using different thermal stablities of isoenzymes
- As liver isoenzyme activity drops by 40% after 15 minutes incubation @ 56 degrees
- Bone isoenzyme activity decreases only by 15% of yGT is used
