Liver physiology

Question 1

Anatomy ? See picture

Answer 1

1. Second largest organ in the body
2. Weighs about 1.4-1.6kg
3. Divided into right and left lobe by the falciform ligament
4. Cantile’s line run from gallbladder fossa to the IVC fossa, provides more useful division between the left and right based on the hpatic artery and portal veins

Question 2

Hepatic blood flow?

Answer 2

1. It is 25-30% of CO
2. Portal vein supply 75% of blood flow, about 50-60% of oxygen supply
3. Hepatic artery 25% of blood supply and 40-55% of oxygen supply

Question 3

Factors increasing hepatic blood flow?

Answer 3

1. Supine position
2. Ingestion of food
3. Hypercapnia
4. Acute hepatitis
5. Dugs : Barbiturates and CYP450 enzyme inducers.

Question 4

Factors decreasing hepatic blood flow?

Answer 4

1. Upright position
2. IPPV/PEEP & hypocapnia
3. Hypoxia
4. Cirrhosis
5. Drugs: Propofol, volatile agents, beta-blockers

Question 5

Histology ?

Answer 5

1. Lobule is the functional unit of the liver
2. The lobule is hexagonal in shape
3. It has a central vein and peripheral portal triad (Branches of heptaic artery, portal vein and bile duct).
4. Blood enters the lobules through - Portal vein & hepatic artery flowing through sinusoids lined with hepatocytes.
5. Metabolically, the functional unit is the hepatic acinus
6. Drainage is via the central hepatic vein

Question 6

Hepatic acinus ?

Answer 6

1. Consists of hepatocytes in the area between two adjacent portal triads
2. Divided into zones corresponding to their distances from the hepatic artery suuply
3. Zones 1&2 best oxygenated and zone 3 poorly oxygenated

Question 7

Hepatic acinus - Zone 1 (Periportal) ?

Answer 7

1. Best perfused and first to regenrate due to proximity to blood supply and nutrition
2. First to encounter blood-borne toxins
3. Plays a role is oxydative metabolism - Beta-oxidation, gluconeogensis, bile formation, cheolesterol formation and amino acid catabolism

Question 8

Hepatic acinus - Zone 2 ?

Answer 8

Sits between zones 1 & 3

Question 9

Hepatic acinus - Zone 3 (Pericentral) ?

Answer 9

1. Lowest perfusion due to distance from the portal triad
2. Most sensitive to ischaemic injury
3. Most sensitive to N-acetyl-p-benzoquinonimine (NAPQI) production in paracetamol OD due to having the highest concentration of CYP2E1 enzymes
4. Plays a role in detoxification, biotransformation, ketogenesis, glycolysis, lipogenesis, glycogen synthesis and glutamine formation.
5. Bile and blood flow in opposit directions to eachother

Question 10

Liver functions? See picture

Answer 10

1. Biotransformation (Ammonia, Hb, Xenobiotics, drugs, glucose)
2. Storage (Lipids, vitamins & glycogen)
3. Synthetic function (Albumin, growth factors & urea)

Question 11

Biotransformation in the liver?

Answer 11

1. Phase (I) - Oxidation, reduction & hydrolysis. P450 based drug detoxification
2. Phase (II) - Conjugation with second substance to increase polarity.
3. Protein and lipid metabolism
4. Breakdown of insulin and other hormones
5. Conversion of ammonia to urea.

Question 12

Storage in the liver?

Answer 12

1. Glycogen - Release glucose via glycogenolysis
2. Storage of Vit A, D and B12
3. Iron
4. Copper

Question 13

Synthetic function of the liver?

Answer 13

1. Synthesis of amino acids, albumin.
2. Cholesterol synthesis
3. Lipogenesis, triglycerides and lipoproteins
4. Bile production - Emulsification of fat and absorption of Vit K
5. Production of insulin-like growth factor 1 - Polypeptide protein hormone - Important role in childhood growth and anabolic effects on adults.

Question 14

Clotting factors ?

Answer 14

1. Fibrinogen (I)
2. Prothrombin (II)
3. V, VII, IX, X, XI, XIII
4. Protein C, protein S and antithrombin
5. Vit K dependent ( II, VII, IX, X)

Question 15

Synthetic fucntion of the liver?

Answer 15

1. Albimin levels - Hypoalbuminaemia also occurs in - Malnutrition, nephrotic syndrome, malabsorptive state and later pregnancy.
2. Prothrombin time /INR - Measures extrinsic pathway of coagulation - Factor I, II, V, VII & X.
3. Prolongation - Deficiencies of Vit K related to - impaired absorption from poor quality bile and abnormality in factor VII production

Question 16

Markers of hepatic injury ?

Answer 16

1. ALT & AST

2. Suggests intrahepatic issues

Question 17

Markers of billiary obstruction?

Answer 17

1. Bilirubin - Haemolysis, billiary stricture, hepatitis, cirrhosis, drugs (antipsychotics and sulphonamides) , Gilbert’s syndrome
2. ALP - Present in all tissues in the body - Billiary obstruction, pregnancy and by-product of osteoblast activity ( Paget’s disease)
3. GGT - Liver, billiary and pancreatic disease. Acute alcohol ingestion, drugs - Barbiturates, phenytoin and NSAIDs. CCF

Question 18

Encephalopathy ?

Answer 18

West Haven Grading system - See picture

Question 19

Ascitis ?

Answer 19

Accumulation of ascitis secondary to portal hypertension.

Grade 1-3

Question 20

Child-Turcotte-Pugh classification ? Components?

Answer 20

1. Encephalopathy
2. Ascitis
3. Bilirubin
4. Albumin
5. PT/INR

Question 21

MELD score - Model for end-stage liver disease?

Answer 21

1. Stratification of severity of end-stage liver disease for transplant planning
2. Predicts 3 month survival in patients older than 12yo. - TIPS - Transjugular intrahepatic portosystemic shunt - Cirrhotic patients undergoing non-transplant procedures - Acute lcohol hepatitis - Acute variceal haemorrhage
3. Score ranges from 6-40 . High scores correlating to increased severity of liver dysfunction and higher 3 month mortality

Question 22

Kings college criteria for liver transplant?

Answer 22

1. ALF due to acetaminophen toxicity :

A - pH < 7.3 or lactate > 3

or

B - Presence of grade 3or 4 encephalopathy, INR > 6.5 and creatinin > 34

2. ALF due to other causes:

A - INR > 6.5 and encephalopathy of any grade

or

B - Age <10 or >40yo, Jaundice > 7 days before development of encephalopathy, INR > 3.5, Bilirubin > 17, conditons such as ( Wilson’s disease, drug reaction and seronegative hepatitis )

Question 23

Kings college criteria for liver transplant?

Answer 23

1. ALF due to acetaminophen toxicity :

A - pH < 7.3 or lactate > 3

or

B - Presence of grade 3or 4 encephalopathy, INR > 6.5 and creatinin > 34

2. ALF due to other causes:

A - INR > 6.5 and encephalopathy of any grade

or

B - Age <10 or >40yo, Jaundice > 7 days before development of encephalopathy, INR > 3.5, Bilirubin > 17, conditons such as ( Wilson’s disease, drug reaction and seronegative hepatitis)

Question 24

Paracetamol OD?

Answer 24

1. Absorption - 2% excreted with urine unchanged
2. About 90% - Phase II metabolism (Non-toxic metabolites) - Conjugation with Gluthatione
3. About 5-9% undergo metabolism by CYP2E1 - to toxic metabolite NAPQI
4. NAPQI is conjugated with gluthatione in normal situations - GSH dependent pathway - Non-toxic metabolites
5. In Paracetamol OD - Phase II enzymes are saturated and a much higher fraction is converted to NAPQI
6. Once Gluthatione levels are depleted, the toxic NAPQI accumulates leading to hepatic necrosis

Question 25

NAPQI?

Answer 25

N-Acetyl-p-Benzoquinone Imine

Question 26

Definition of ALF?

Answer 26

1. Increased PT / INR > 1.5 2. Development of hepatic encephalopathy 3. In patient without cirrhosis and illness less than 6 months

Question 27

Causes of ALF?

Answer 27

See picture

Question 28

Manifestation of ALF?

Answer 28

1. Encephalopathy and cerebral oedema 2. Coagulopathy - UGIB/DIC 3. Renal failure - Low BP/Hepatorenal syndrome 4. Metabolic disturbances - Electrolyte disturbances, low BMs and metabolic acidosis 5. CVS - Similar to sepsis 6. Infection - Immunosuppression

Question 29

Manifestation of cirrhosis?

Answer 29

1. Ascitis & oesophageal varicies 2. Resp - Hypoxia, effusion, diaphragmatic splinting 3. CVS - Adrenal inssuficiency , cardiomyopathy 4. Renal dysfunction 5. Haematological changes - Anaemia, coagulopathy 6. Metabolic dysfunction - Increased insulin & thyroxine, water retention 7, Altered pharmacokinetics and metabolism.