Liver:

• Largest abdominal solid organ
• 25 % CO at rest. approx 1,500 mls/min
• 15% of total blood volume at rest

Functions of Liver

Gladwin / JC / Bianca 2019

Paracetamol Overdose

Hepatotoxicity

Toxic daily dose > 4-6 g (while lethal dose occurs at > 10-15 g (or > 300 mg/kg LBM)) → but the toxic and lethal doses are lower in “at-risk” groups:

• EtOH abuse (due to CYP450 induction (↑ toxic metabolite produced) and ↓ glutathione stores)
• Malnutrition (due to ↓ glutathione stores)
• Elderly (due to ↓ glutathione stores)
• Preexisting liver dysfunction

Mechanism:

• At therapeutic doses – “N-acetyl-p-amino-benzoquinoneimine” (highly toxic metabolite) is produced in small amounts, but is rapidly conjugated with hepatic glutathione (anti-oxidant) into a harmless metabolite
• BUT with toxic doses – Hepatic conjugation pathway is saturated and ↑↑↑ N-acetyl-p-amino-benzoquinoneimine is produced → this depletes hepatic glutathione stores, causing remaining N-acetyl-p-aminobenzoquinoneimine to then forms covalent bonds with sulphydryl groups on hepatocytes → results in centrilobular hepatic necrosis

Clinical features:

• Generally conscious and c/o N/V, epigastric pain, erythema, sweating → later developing:
  • Acute haemolytic anaemia
  • Develop hepatic failure (Ie. jaundice and cholestasis) after 48 hrs
  • LFT/INR derangements at 3-5 days
  • Fulminant hepatic failure at 3-7 days
• With severe OD, can present with hypotension/shock

Diagnosis :

Serum paracetamol levels → correlate with “nomogram” to predict likelihood of liver damage → used as a guide to dictate therapy

Treatment:

• Activated charcoal/gastric lavage→ limit paracetamol absorption
• Replace hepatic glutathione store within 12 hrs of OD → permits glucuronidation of toxic metabolite
  • Oral methionine → ↑ glutathione synthesis
  • IV N-acetylcysteine → hydrolysed to cysteine (which is a glutathione precursor)
  • Nb. IV NAC is preferred b/c of N/V a/w toxicity (Ie. ↓ oral methionine absorption)
• IV glucose → due to risk of ↓ BGL with liver dysfunction
• Serial monitoring of LFTs and coagulation studies
• Referral to a specialist centre

Gladwin / JC / Bianca 2019

2017B 20: 86% of candidates passed this question.
This is a very straightforward question testing breadth of knowledge rather than depth. It was well answered by the majority of candidates.

2017A 22: 56% of candidates passed this question.
Most candidates attempted a structure however did not expand the answers within the
categories: e.g. a passing mention of glucose homeostasis is insufficient to score full marks for the carbohydrate metabolism category.

2013B 04: 24 candidates passed (88.9%).
This question was generally well answered with a good response being in some structured format, e.g. a mention, followed by a description for each function of the liver. For questions asking to outline a particular topic, a general overview of the topic is expected and not merely a “dot-point” list of the functions of the liver without actually delving into the way the liver does those functions. In general candidates should avoid making broad-brush statements, which do not get them any marks like “the Liver is the major organ in the body”. Candidates were expected to list, and provide an overview for each, function of the liver.

2009B 23: 4 (44%) of candidates passed this question.
For a good answer candidates were expected to at least mention the following —
Formation and secretion of bile
Carbohydrate metabolism (Glycogen synthesis and breakdown, Gluconeogensis)
Lipid metabolism (Fatty acid oxidation, Synthesis of cholesterol and phospholipids, Production of ketoacids)
Protein metabolism Breakdown
Metabolism of toxins, drugs (Phase I reactions – oxidation, reduction, hydrolysis, Phase II reactions- conjugation/glucuronidation)
Storage (Vitamins B12, A, D 2, Iron as ferritin, Glycogen)
Immunity
Endocrine (Synthesis of 25 OH cholecalciferol, Metabolism of steroid hormones, Synthesis of somatomedins, Erythropoietin)
Miscellaneous (Acid base role – lactate metabolism, Blood store)
Syllabus – I2a
Reference: Gannong p485, Power and Kam p185

Liver:

• Largest abdominal solid organ
• 25 % CO at rest. approx 1,500 mls/min
• 15% of total blood volume at rest

Functions of Liver

Gladwin / JC / Bianca 2019

Paracetamol Overdose

Hepatotoxicity

Toxic daily dose > 4-6 g (while lethal dose occurs at > 10-15 g (or > 300 mg/kg LBM)) → but the toxic and lethal doses are lower in “at-risk” groups:

• EtOH abuse (due to CYP450 induction (↑ toxic metabolite produced) and ↓ glutathione stores)
• Malnutrition (due to ↓ glutathione stores)
• Elderly (due to ↓ glutathione stores)
• Preexisting liver dysfunction

Mechanism:

• At therapeutic doses – “N-acetyl-p-amino-benzoquinoneimine” (highly toxic metabolite) is produced in small amounts, but is rapidly conjugated with hepatic glutathione (anti-oxidant) into a harmless metabolite
• BUT with toxic doses – Hepatic conjugation pathway is saturated and ↑↑↑ N-acetyl-p-amino-benzoquinoneimine is produced → this depletes hepatic glutathione stores, causing remaining N-acetyl-p-aminobenzoquinoneimine to then forms covalent bonds with sulphydryl groups on hepatocytes → results in centrilobular hepatic necrosis

Clinical features:

• Generally conscious and c/o N/V, epigastric pain, erythema, sweating → later developing:
  • Acute haemolytic anaemia
  • Develop hepatic failure (Ie. jaundice and cholestasis) after 48 hrs
  • LFT/INR derangements at 3-5 days
  • Fulminant hepatic failure at 3-7 days
• With severe OD, can present with hypotension/shock

Diagnosis :

Serum paracetamol levels → correlate with “nomogram” to predict likelihood of liver damage → used as a guide to dictate therapy

Treatment:

• Activated charcoal/gastric lavage→ limit paracetamol absorption
• Replace hepatic glutathione store within 12 hrs of OD → permits glucuronidation of toxic metabolite
  • Oral methionine → ↑ glutathione synthesis
  • IV N-acetylcysteine → hydrolysed to cysteine (which is a glutathione precursor)
  • Nb. IV NAC is preferred b/c of N/V a/w toxicity (Ie. ↓ oral methionine absorption)
• IV glucose → due to risk of ↓ BGL with liver dysfunction
• Serial monitoring of LFTs and coagulation studies
• Referral to a specialist centre

Gladwin / JC / Bianca 2019

2011B 12: 5 (20%) of candidates passed this question.
A good response to this question required an ordered and well structured response. There are numerous important functions that the liver undertakes (eg bile formation, immunological, protein, lipid, glucose metabolism, storage, endocrine, etc), yet most candidates could not generate a sufficient list. In relation to paracetomol toxicity, a good response required candidates to mention that normal conjugating reactions in the liver are saturated and metabolism diverts to mixed function oxidases, which generate toxic metabolites. These in turn are inactivated by conjugation with glutathione. However when glutathione is depleted, toxic metabolites react with cellular nuclear material, thus causing liver necrosis. Toxic compound depletes sulphydril groups and also causes direct damage via lipid peroxidation. Regeneration of sulphydril groups and glutathione depends on availability of cysteine, thus the need to administer acetylcysteine.
Syllabus: I2a, G2e2c
Recommended sources: Gannong Review of Medical Physiology pg 485; Power and Kam
Principles of Physiology for the Anaesthetist pg185; Stoelting Pharmacology and Physiology in Anesthetic Practice 4th edition pg 285; Rang & Dale Pharmacology 5th Ed pg 244.

Fat

Carbohydrate

Protein

Gladwin 2016

2020B 04: 54% of candidates passed this question.
This question relates to basic hepatic physiology and is well described in the recommended texts.
The mark allocation and division of time was indicated in the question. Better answers used the categorisation in the question as an answer structure. Many candidates gave a good description of beta oxidation, the formation of Acetyl Co A and ketone synthesis. A description of the synthesis of cholesterol, phospholipids, lipoproteins and fatty acid synthesis from proteins and carbohydrates mainly using glycogen, glucose and lactate also received marks. Candidates seem to have a better understanding of fat and glucose metabolism than protein metabolism. Higher scoring candidates appreciated the anabolic and catabolic processes of each component.

2015A 18: 50 % of candidates passed this question.
Most candidates seemed not to have thought about this before and so collated information from answers about insulin and glucagon, and starvation. Many added information about absorption and digestion which was not required.
Metabolic functions of the liver form part of the “standard list” of functions of the liver yet few details could be provided beyond that. It was expected answers would detail the central role of the liver as a “glucostat” and its role in glucose utilization. It has two main roles in lipid metabolism, the synthesis of fatty acids and the partial oxidation of fatty acids to ketone bodies. The liver also plays a central role in protein catabolism and anabolism. It plays a major role in the breakdown of amino acids gluconeogenesis and protein synthesis. The liver also releases amino acids into the blood for utilization by peripheral tissues.

This answer could be structured by splitting the content into major categories. These could be:

• the clearance functions of the liver
• first pass metabolism
• mechanisms of hepatic metabolism
• the effects of liver disease.

The role of the liver in drug clearance

• The role of the liver in pharmacokinetics is as an organ of clearance.
•  The two major determinants of hepatic clearance are the efficiency of drug removal from the blood and the efficiency of blood delivery to the liver.
• Efficiency of drug removal by the liver is described by the hepatic extraction ratio, which is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
• The hepatic extraction ratio is determined largely by the free (unbound) fraction of the drug and by the intrinsic clearance rate, which is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
• The effect of liver blood flow on hepatic clearance depends on the hepatic extraction ratio of the drug.
• With increasing hepatic blood flow, hepatic extraction ratio will decrease for all drugs.
• For drugs with low intrinsic clearance:
  • Hepatic extraction ratio will drop more rapidly with increasing hepatic blood flow
  • Hepatic clearance will not increase significantly with increasing blood flow
• For drugs with high intrinsic clearance:
  • Hepatic clearance will increase in a fairly linear fashion, in proportion to hepatic blood flow
  • Increasing the intrinsic clearance will have diminishing effect on total hepatic clearance 

The effect of the liver on first pass metabolism

• First pass clearance is not just hepatic but is a combination of metabolism by gut bacteria, metabolism by intestinal brush border enzymes, metabolism in the portal blood and metabolism by liver enzymes.
• For drugs with low hepatic extraction ratio:
  • First pass clearance will be low
  • Changes in hepatic enzyme function will have little effect on first pass clearance 
• For drugs with high hepatic extraction ratio:
  • First pass clearance will be high
  • Changes in hepatic enzyme function will have a significant effect on first pass clearance 

Biotransformation in the liver

By convention, the metabolic functions of the liver are divided into Phase I and Phase II reactions

• Phase I reactions:
  • Examples of Phase I reactions:
    • Hydrolysis
    • Reduction
    • Oxidation.
  • Characteristics of Phase I reactions:
    • these reactions expose or introduce a functional group (–OH, –NH2, – SH or –COOH)
    • They usually result in a small increase in hydrophilicity.
• Phase II reactions:
  • Examples of Phase II reactions:
    • Glucuronidation
    • Sulfation
    • Acetylation
    • Methylation
    • Conjugation with glutathione
    • Conjugation with amino acids eg. taurine, glutamine, glycine
  • Characteristics of Phase II reactions:
    • The products are supposed to be significantly more hydrophilic than the original substrate

Effects of changes in liver function

• The effects of changes in synthetic function
  • The liver synthesises plasma proteins; plasma protein binding influences the volume of distribution
  • Low plasma protein levels lead to raised free drug levels (the free fraction increases)
  • This process is therefore synergistic with the concurrent decrease in liver blood flow and hepatic extraction ratio
  • The liver synthesises plasma esterases and peptidases; these metabolise certain drugs
  • Significant liver disease can result in prolonged clearance of drugs which are susceptible to these enzymes (eg. suxamethonium)
• The effect of changes in secretory function
  • Drugs and metabolites which rely on biliary excretion will be retained, and may require dose adjustment
  • Drugs which enjoy enterohepatic recirculation may have decreased halflives due to failure of recirculation
  • High bilirubin levels may result in the displacement of drugs from albumin as it competes for binding sites 
  • Decreased secretion of bile may result in malabsorption 
• The effects of portal hypertension on pharmacokinetics
  • Portal venous hypertension leads to shunting of portal venous blood into the systemic circulation
  • This has the effect of decreasing first pass metabolism

JC 2019

62% of candidates passed this question.

Most candidates structured their answer to this question well – they were aware of first pass metabolism and the effect of protein synthesis upon volume of distribution of drugs. Knowledge concerning Phase I and Phase II reactions was frequently inadequate. Many candidates were aware that these processes as well as inactivating or activating drugs resulted in increased water solubility to aid excretion via bile or urine. Few candidates discussed the significance of the large blood flow to the liver or the implications of high and low extraction ratios especially in relation to liver blood flow.

Pharmacodynamics

• Altered receptor binding
  • Postulated for relative resistance to non-depolarizing NMB in liver failure

Pharmacokinetics

• Absorption
  • Portal hypertension and interstitial oedema reduce absorption of drugs
  • Hepatic dysfunction
    • Increased bioavailability of drugs susceptible to hepatic first pass metabolism (diazepam)
    • Decreased activation of pro-drug (clopidogrel requires CYP2C19 activation)

• Distribution
  • Decreased synthesis of plasma proteins
    • Increases free fraction of protein bound drugs
      → Unbound drug more permeable → increased volume of distribution (amiodarone)
      → Unbound drug more active
  • Hypervolaemia secondary to renal Na⁺ and H₂O retention
    • Increased V_d for drugs distributed to extracellular volume
  • Decreased pH alteres ionization of acids and bases (acids ionized when pH above pKa and bases ionized when pH below pKa)

• Metabolism
  • Decreased hepatic metabolism
    • Increases T_1/2b of hepatically metabolized drug → Accumulation of drug if no alteration
  • Decreased butylcholinesterase production → Decreased metabolism for drugs metabolised by plasma esterases (suxamethonium – however clinically not significant for this drug) – red cell esterases remain therefore no effect for remifentanyl
• Elimination
  • Hepatorenal syndrome → decreased renal clearance
  • However renal drug clearance tends to decrease even in absence of renal impariment (drugs not hepatically converted to more water soluble metabolites)
  • Biliary clearance of drug is reduced

Sakurai 2016

13 (59.1%) of candidates passed.

Good answers were structured using pharmacokinetic and pharmacodynamics headings. They included some mention of changes in absorption, volume of distribution (an increase in Vd in liver failure), altered protein binding, altered metabolism and thus change in clearance, and changes in excretion (decreased biliary excretion of drugs). In respect to pharmacodynamics candidates could have mentioned increased sensitivity and prolonged action of sedative drugs, oral anticoagulants, etc. Good candidates also differentiated for acute (often hepatocellular dysfunction) and chronic liver failure (cirrhosis and changes in liver blood flow). Common problems were not using a logical structure to answer the question and stating an effect but not describing how this affected pharmacology. For example stating decreased albumin production but then not stating the consequence of this on drug distribution. Primary examination questions may often require candidates to integrate knowledge from across different sections of the syllabusor apply basic physiological or pharmacological principles.

Clearance (Cl)

Defined as the volume of plasma from which drug is completely removed per unit time (units – mL/min)

• Drug can be cleared from plasma via two routes:
  • “Elimination” from the body – Drug excreted unchanged (via renal or biliary routes) and/or metabolised (by liver or other organ)
    • Non-compartmental model: Cl = Dose / AUC
    • Compartmental model:  Cl=Vd x Kel = Vd x (ln2/t1/2)
  • “Intercompartmental clearance” (* occurs only in multi-compartment model *) – Drug distributes from the central to peripheral compartment(s) → determined by the rate constant for intercompartmental transfer (k12, k21; k13, k31; Etc.)
• Significance of clearance:
  • Determines maintenance dose rate needed to achieve a plasma [drug] at steady state
• “Maintenance dose rate” = Cl x desired [ ]PLASMA

Hepatic Extraction Ratio

Hepatic extraction ration (HER) – Fraction of drug that is irreversibly removed during 1st pass of blood through the liver → determined by intrinsic clearance (enzyme activity) and (ii) unbound % of drug

where
Q^_H = Hepatic Blood Flow
ER_Hep = Hepatic Extraction Ratio
F_U = fraction of drug unbound in plasma
Cl_Int = hepatic enzymatic capacity

Hepatic clearance

“Hepatic clearance” → determined by Hepatic Blood Flow and Hepatic Extraction Ratio

• Hepatic blood flow (HBF) – Rate at which drug is delivered to the liver
• Hepatic extraction ration (HER) – Fraction of drug that is irreversibly removed during 1st pass of blood through the liver → determined by intrinsic clearance (enzyme activity) and (ii) unbound % of drug

Hepatic clearance = HBF x HER = HBF x [(% unbound) x (intrinsic clearance)]

Important to note:

• Drugs with HER > 0.7 (↑ enzyme activity or “flow-limited”), such as GTN:
  • Hepatic drug clearance is dependent on HBF (“perfusion-dependent elimination”)
    → ↑ HBF will lead to ↑ hepatic drug clearance
  • Changes in HER (intrinsic enzyme activity or unbound %) have minimal effect on hepatic drug clearance as heaps of drug is already removed at a given time
    – i.e. Hepatic clearance ≈ HBF

• Drugs with HER < 0.3 (↓ enzyme activity or “capacity-limited”), such as diazepam:
  • Hepatic drug clearance is dependent on protein binding and intrinsic enzyme activity (“capacity-dependent clearance”)
    → ↑ enzyme activity and/or ↓ protein binding will ↑ hepatic drug clearance
  • Changes in HBF will have minimal effect on hepatic drug clearance as only a small % of drug is ever removed at a given time
    – i.e. Hepatic clearance ≈ HER = (unbound %) x (intrinsic clearance)

Other roles of liver in drug pharmacokinetics

Absorption (First pass metabolism):

• Drugs absorbed from GIT (except buccal and rectal mucosal) enter portal venous blood and pass through liver before entering systemic circulation
• They are metabolised by enzymes within the (i) liver (main) and (ii) gut wall (minor)
• FPM is a main reason why plasma [ ] after an oral dose is less cf. similar IV dose → as a result, it is a key determinant of oral bioavailability
• Significance – Drugs with ↓ FPM are either well-absorbed, stable in GIT, and/or have minimal hepatic metabolism → thus, have ↑ oral bioavailability (and ↑ plasma [ ]). The opposite is true for drugs with ↑ FPM

where,
F_B = Bioavailable fraction
F_A = Fraction absorbed
F_G = Fraction remaining after gut mucosal metabolism
F_H = Fraction remaining after hepatic metabolism

Metabolism:

Metabolism → process of chemically altering a drug within the body
Mainly occurs in liver (by hepatic microsomal enzymes), and few other sites

Effects of metabolism:

• ↓ drug activity (main effect): converts a “pharmacologically active” form of drug (Ie. non-polar and lipid soluble) into a “pharmacologically inactive” form (Ie. more polar and water-soluble) that can be excreted from the body (esp in bile or urine)
• ↑ drug activity: “Prodrug” → active moiety (Eg. enalapril → enalaprilat; parecoxib → valdecoxib)
• Produce metabolites with equal activity to parent compound (Eg. diazepam, propranolol)

Phases of metabolism:

• Phase I (functionalisation or non-synthetic):
  • Alter drug reactivity for phase II reaction and to ↑ drug polarity/water-solubility
  • Oxidation Including Hydroxylation (Eg. propofol), desulphation (Eg. STP), dealkylation (Eg. vecuronium), dehalogenation (Eg. volatiles), deamination, Reduction, Hydrolysis
• Phase II (conjugation or synthetic)
  • ↑ water solubility of drug or its metabolite by conjugating it to a polar endogenous moiety (Eg. sulphate, glucuronyl, methyl, Etc.) → permits excretion in urine or bile
  • Glucuronidation via glucuronosyltransferase (Eg. morphine, propofol)
    • UDP-glucuronic acid is conjugated to the drug → conjugate is inactive and water-soluble → excreted in urine/bile
    • Conjugated undergoes “enterohepatic recirculation” if eliminated in bile → intestinal bacterial glucuronidases hydrolyses glucuronide → liberates free drug which is reabsorbed back into circulation → results in prolonged drug action
  • Other reactions: Sulphation, Acetylation, Methylation, Glutathione via glutathione-S-transferase (Eg. EtOH)
  • Note – All these reactions involve non-microsomal enzymes, EXCEPT for glucuronidation (requires hepatic CYP450 microsomal enzymes)

Source: Bianca’s notes

JC 2019

2019B 15: 70% of candidates passed this question.
Clearance was generally well answered. It is the volume of plasma cleared of a drug per unit time, not the mass of drug cleared.
An equation was helpful in identifying the relevant components of hepatic clearance. ClHep=QH X ERHep ERHep= FU x ClInt / QH + FU x ClInt QH = hepatic blood flow ERHep = hepatic extraction ratio FU = fraction of drug unbound in plasma ClInt = hepatic enzymatic capacity
Many candidates did not describe the effects of hepatic blood flow and intrinsic clearance on drugs with high and low hepatic extraction ratios. Some discussion of Phase I and II reactions was also expected.

Hepatic blood flow

• 1.5l/min
• Anatomy
  • Afferent via Hepatic Artery (branch of ceoliac trunk) contributing 30% and Portal Vein (confluence of inferior mesenteric, superior mesenteric and splenic veins) contributing 70% of hepatic blood flow
    • Hepatic artery supplies 50% of O₂ delivery
    • Portal venous blood has PO₂ of 80% due to mesenteric AV anastamosis
  • Blood flows through low pressure hepatic sinusoidal system to ventral vein
  • Efferent via Hepatic Vein → IVF

Regulation

Intrinsic

• Hepatic arterial and Portal venous pressure – Hepatic venous pressure / Hepatic vascular resistance (low)
• Autoregulation to systolic blood pressure 80mmHg
• Metabolic autoregulation
  • Vasodilation in response to H⁺, CO₂, lactate
• Semi-reciprocal relationship
  • Hepatic arterial blood flow increases when protal venous flow decreases

Extrinsic

• Respiration
  • Diaphragmic contraction → Decreased intrathoracic (and IVC) pressure and increased abdominal pressure → Favours hepatic blood flow
• Post-prandial
  • Increased splanchnic blood flow post-prandially → Increased hepatic blood flow
• Neural
  • Sympathetic
    • α adrenoceptors present in portal vein AND hepatic artery
    • β adrenoceptors only present in hepatic artery
    • Therefore sympathetic input tends to venoconstrict the portal vein and dilate the hepatic artery
• Hormonal
  • Adrenaline
    • α constricts protal veins and decreases HBF
    • β dilates hepatic arteries and increases HBF
  • Glucagon increases hepatic blood flow
  • Vasopressin decreases hepatic blood flow
  • Angiotensin II decreases hepatic blood flow
  • Vasoactive Intestinal Peptide (VIP) and secretin increase hepatic artery flow

Changes to drug metabolism when liver blood flow decreases:

• The two major determinants of hepatic clearance are the efficiency of drug removal from the blood and the efficiency of blood delivery to the liver.
• Efficiency of drug removal by the liver = hepatic extraction ratio
  • fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
  • determined largely by:
    • the free (unbound) fraction of the drug and
    • the intrinsic clearance rate (the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.)
• The effect of liver blood flow on hepatic clearance depends on the hepatic extraction ratio of the drug.

With decreasing hepatic blood flow, hepatic extraction ratio will increase for all drugs.

• For drugs with low intrinsic clearance:
  • Hepatic extraction ratio will increase with decreasing hepatic blood flow
  • Hepatic clearance will not decrease significantly with decreasing blood flow
• For drugs with high intrinsic clearance:
  • Hepatic extraction ratio will increase slowly with decreasing blood flow
  • Hepatic clearance will decrease in a fairly linear fashion, in proportion to hepatic blood flow

Also, Drugs which enjoy enterohepatic recirculation may have decreased half-lives due to failure of recirculation

Sakurai / JC 2019

2016B 13: 55% of candidates passed this question.
A statement regarding the quantum of hepatic blood flow with recognition of the contributions made by the Hepatic Artery and Portal Vein, drainage into the sinusoids before entering the hepatic vein which drains into the IVC would have been a good start. Discussion was then expected to revolve around how the liver blood flow is controlled. Answering this with respect to intrinsic and extrinsic factors along with an understanding of the semi-reciprocal relationship between hepatic arterial and portal venous blood flow would have rounded out a good answer to the first part of the question.
The second part of the question required recognition that hepatic clearance is the product of hepatic blood flow and the hepatic extraction ratio and considering the impact on drugs with a high or a low extraction ratio. Many answers failed to adequately mention how hepatic blood flow was controlled/regulated thus limiting the marks available. Similarly, in the second part of the question, many candidates spent considerable time mentioning the principals of drug metabolism rather than focusing on the question asked.
The concept of hepatic drug clearance as the product of blood flow and its extraction ratio was poorly appreciated.

2013A 18:
The liver has a unique dual supply – a portal venous system, and a hepatic arterial system, that floods the hepatic sinusoids and drain into the hepatic veins and then the inferior venacava. Knowledge of liver blood flow is essential for the understanding of certain pathophysiological mechanisms associated with disease and/or injury states of the liver. These two systems have unique characteristics, which most candidates seemed to have some knowledge of. A common area of weakness was the understanding/omission of the factors/mechanisms involved in the regulation of liver blood flow.

2008A 16: No candidates (0%) passed this question.
A correct description of the vascular anatomy; the contribution and composition of hepatic artery and portal vein flow to total hepatic flow and how this is regulated would be awarded with a pass. An answer that expanded on these main points received additional marks. The interdependence of hepatic artery and portal vein flow was not appreciated by any candidate.
Either candidates knew the answer to this question or they did not. Some candidate(s) tried to guess at what the anatomy might be. This attracted no marks. Many candidates lacked sufficient knowledge to pass this question.
Syllabus I 2 d&g

Blood flow

Regulation

2015B 03: 54% of candidates passed this question.
It was expected candidates would describe the salient features of the anatomy, distribution and content of blood flow and influences on each circulation. Answers with a clear organisation and context for the normal influences of blood flow on the functioning of each organ system scored highly. Anatomy was often sufficiently covered, but candidates often did not take advantage of that by linking the anatomical features to the functional concepts. Figures should be clearly and accurately labelled to score well. Many answers failed to demonstrate a depth of understanding of key concepts. For example tubuloglomerular feedback, relationship between hepatic arterial and portal venous flows and autoregulation within both those systems was often poorly described.

2012A 11: 7 (70%) of candidates passed.
Another fundamental physiology topic that required candidates to understand, and synthesize knowledge from multiple areas. Generally well done with some very good answers. A tabular format worked well. Candidates were expected to mention values for renal and hepatic flow (total flow, % of cardiac output and oxygen consumption), basic anatomical comparisons, distribution (e.g. renal cortex 95% , renal medulla 5%,), two capillary beds (glomerular and peritubular) for renal, and hepatic triad and sinusoids for the liver, function (filtration for renal blood flow and metabolic activity for hepatic) and regulatory mechanisms for each (e.g. myogenic, autonomic, metabolic and humoral for both and tubuloglomerular feedback for renal).

Bile

• dark green solution produced by the liver to facilitate absorption of fat and fat-soluble vitamins (ADEK) through emulsification.
• Liver produces 1 L bile/day → passes into gallbladder for concentration to 20% volume
• Produced by hepatocytes
• Excreted via canaliculus and biliary tree
• Stored and concentrated in the gallbladder
• Bile contains
  1. Bile salts (sodium and potassium salts of bile acids)
  2. Bilirubin
  3. Water and electrolytes: Na, Cl, K, Ca, bicarb
  4. Lipids: Cholesterol, Fatty acids, lecithin
  5. Proteins

Bile Acids:

• Are produced from cholesterol (from diet or from fat metabolism)
• Cholesterol is first converted to cholic acid or chenodeoycholic acid
• These acids combine with glycine and taurine to form glycol- and tauro- conjugated bile acids.
• The salts of these acids (mainly sodium, and potassium) are then secreted into bile.

Bile salts:

• Are amphipathic, and act as emulsifiers of lipid
  • Break up large fat globules into smaller micelles, which can then be absorbed.
• Form micelles
  • help in the absorption of (1) fatty acids, (2) monoglycerides, (3) cholesterol, and (4) other lipids from the intestinal tract.
• Are absorbed in the terminal ileum, and recycled by the portal circulation (Enterohepatic circulation) along with secondary bile salts produced by gut bacteria such as deoxycholate and lithocholic acid

Bilirubin:

• Catabolic product of heme metabolism
  • hemoglobin, myoglobin, cytochromes, catalase, peroxidase, and tryptophan pyrrolase
  • 80% from Hb (250 to 400 mg daily)
  • 20% other heme proteins and a rapidly turning-over small pool of free heme
• Pathway:
  • Haeme + Haem oxygenase → biliverdin
  • Biliverdin + biliverdin reductase → bilirubin
  • Free bilirubin + albumin → transported to hepatocytes
  • Conjugated with glucuronide to ↑ water solubility
  • Excreted to bile canniliculus
  • Secreted to gut at D2 (duodenum)
  • Intestinal flora hydrolyse and reduce → urobilinogen
  • 3 fates:
    • Gut bacteria form the dark pigment stercobilin, which is egested in the faeces
    • Urobilinogen reabsorbed unchanged by the portal system and recycled by the liver
    • Remainder is reabsorbed by the portal system and then excreted in the urine

Formation and Handling

Formation and handling of bile salts:

1. 1° bile acids (cholic acid and chenodeoxycholic acid) are produced in hepatocytes from cholesterol → then conjugated with glycine (75%) and taurine (25%) to ↑ their H2O solubility → then actively excreted in bile
2. They are metabolised by intestinal bacteria (esp large intestines) to form 2° bile acids (deoxycholic acid and lithocholic acid)
3. 1° and 2° bile acids become “Bile salts” when they combine with Na+ or K+
4. 95% of bile salts are reabsorbed in terminal ileum → recirculated to liver via the portal circulation (“enterohepatic circulation”) → so both 1° and 2° bile salts can be found in bile!
5. Only 5% of bile salts are lost in faeces

Turnover of bile salts:

• Rate of hepatic production of bile acid (~0.2-0.5 g/day) EQUALS rate of bile acid loss in the intestines → this low rate of production/loss is due to bile acid recycling via “enterohepatic circulation”
• The body has a “total” storage pool of bile acids of 3 g → during a meal, 9 g of bile salts are needed (Ie. this pool is recycled 3X). Thus, with 3x meals/day the “effective” bile acid pool can ↑ up to 27 g (Ie. this 3g pool is recycled up to 9X)

Release: (relaxation of sphincter of Oddi) takes place via

• negative feed back from bile salt reabsorption in terminal ileum
• acid chyme in duodenum releasing secretin -> increases HCO3- rich secretions from duct cells
• CCK
• gastrin
• nervous control

Functions

1. Facilitate intestinal digestion of lipids → aids pancreatic lipase activity
2. Enhances intestinal absorption of lipids (fat, cholesterol, phospholipids, and fat-soluble vitamins)
   • by emulsifying lipids (by ↓ surface tension → breaks down fat), and
   • forming “micelles” (as it is amphipathic)
3. Keeps cholesterol solubilised within gallbladder (Ie. prevents gallstones!)
4. Induces intestinal motility (Ie. endogenous laxative)
5. Choleretic action → bile salts stimulate the hepatocytes to produce MORE bile (via Bile-dependent biliary secretion)

Bianca / JC 2020

2016A 05: 31% of candidates passed this question.
Bile is produced by hepatocytes, excretion via cannaliculus and biliary tree. It is stored and concentrated in the gallbladder. Bile contains water, bile acids and bile salts, bile pigments and electrolytes. Some detail was expected regarding each of these and comment on “Primary bile acids”, conjugation with taurine and glycine and production of “bile salts”. It was often not appreciated bacteria in gut produce “secondary” bile acids such as deoxycholate and lithocholic acid. Additional credit was given for discussing “Unconjugated bilirubin” being derived from “heme” component of haemoglobin (85%) is carried via albumin to liver for conjugation via UDP-gluconuryl transferase to “conjugated bilirubin” and that gut bacteria generate water soluble urobilinogen, enterohepatic recycling and excretion in urine. The major role of bile is in lipid, cholesterol and lipid soluble vitamin absorption with a minor role in excretion of bile pigments. It was expected candidates would describe the emulsification of fat via bile salts and lipid micelle formation to facilitate absorption.

RBC Destruction

• Globin chains → AA’s 
• Haem → Biliverdin, Fe²⁺, CO

• Biliverdin
  • Haeme + Haem oxygenase → biliverdin
  • Biliverdin + biliverdin reductase → bilirubin
  • Free bilirubin + albumin → transported to hepatocytes
  • Conjugated with glucuronide to ↑ water solubility
  • Excreted to bile canniliculus
  • Secreted to gut at D2 (duodenum)
  • Intestinal flora hydrolyse and reduce → urobilinogen
  • 3 fates:
    1. Gut bacteria form the dark pigment stercobilin, which is egested in the faeces
    2. Urobilinogen reabsorbed unchanged by the portal system and recycled by the liver
    3. Remainder is reabsorbed by the portal system and then excreted in the urine
• Fe2+ → oxidised to Fe3+ → recycled
• CO (only endogenous source of CO)

Hepatic Disease:

• Intrahepatic disease
  • ↓’d conj billi secretion
    • ↑d plasma conjugated bilirubin
    • ↑ urobilinogen in stool
    • ↑ urine bilirubin,
• Posthepatic disease (complete obstruction)
  • ↑ conjugated bilirubin
  • No urobilinogen in stool
  • ↑ urine bilirubin

Gladwin 2016

2008B 18: 3 (60%) candidates passed this question
A good answer for this question required the description of the pathway of bilirubin production beginning with the breakdown of haemoglobin breakdown, then haem to biliverdin by biliverdin reductase, biliverdin to bilirubin, bilirubin transported to liver bound to plasma proteins, bilirubin monoglucuronide and diglucuronide by conjugation, secreted into bile. Secretion into bile is dependent on active transport and is the first to be impaired in inflammation of the liver. Bilirubis metabolized to stercobilinogen which is absorbed and excreted in urine as urobilinogen. The remaining part to this question flowed on from this point, ie Intrahepatic disease – increased conjugated bilirubin, urobilinogen and urine bilirubin, Posthepatic disease – increased conjugated bilirubin, no urobilinogen, increased urine bilirubin
Syllabus: I2c
Reference Text: Guyton Ch 70

Table of LFT values and clinical significance
(LIMITED)

Bianca 2020

Liver Function Tests

Principles of liver function tests (LFTs):

• They indicate presence of liver injury
• They test hypotheses about types of hepatobiliary pathophysiology → BUT do NOT ascertain precise cause of hepatobiliary disease (Ie. need biopsy, serology, Etc.)
• The tests are very sensitive BUT non-specific (Eg. many other causes of derangements)

Table of LFT values and clinical significance

Bianca 2020

2021B 07: 54% of candidates passed this question.
This was a new question and overall, most candidates provided some detail on each component as requested. Those answers that used a simple template for each section generally scored better than those who wrote in a paragraph style for each section. Areas expected to be covered included the following; a definition of the variable to provide context, a normal value and the range of influences that effect the variable both related to liver function and or extrinsic to the liver (attempting to introduce the concepts of sensitivity and specificity for each test). Stronger answers provided some context as to whether the variable was sensitive to acute or chronic changes in liver function and which synthetic/metabolic component of the liver the variable represented.

Liver Function Tests

Principles of liver function tests (LFTs):

• They indicate presence of liver injury
• They test hypotheses about types of hepatobiliary pathophysiology → BUT do NOT ascertain precise cause of hepatobiliary disease (Ie. need biopsy, serology, Etc.)
• The tests are very sensitive BUT non-specific (Eg. many other causes of derangements)

Table of LFT values and clinical significance

Bianca 2020