Liver physiology Flashcards
Anatomy ? See picture
- Second largest organ in the body
- Weighs about 1.4-1.6kg
- Divided into right and left lobe by the falciform ligament
- 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
Hepatic blood flow?
- It is 25-30% of CO
- Portal vein supply 75% of blood flow, about 50-60% of oxygen supply
- Hepatic artery 25% of blood supply and 40-55% of oxygen supply
Factors increasing hepatic blood flow?
- Supine position
- Ingestion of food
- Hypercapnia
- Acute hepatitis
- Dugs : Barbiturates and CYP450 enzyme inducers.
Factors decreasing hepatic blood flow?
- Upright position
- IPPV/PEEP & hypocapnia
- Hypoxia
- Cirrhosis
- Drugs: Propofol, volatile agents, beta-blockers
Histology ?
- Lobule is the functional unit of the liver
- The lobule is hexagonal in shape
- It has a central vein and peripheral portal triad (Branches of heptaic artery, portal vein and bile duct).
- Blood enters the lobules through - Portal vein & hepatic artery flowing through sinusoids lined with hepatocytes.
- Metabolically, the functional unit is the hepatic acinus
- Drainage is via the central hepatic vein
Hepatic acinus ?
- Consists of hepatocytes in the area between two adjacent portal triads
- Divided into zones corresponding to their distances from the hepatic artery suuply
- Zones 1&2 best oxygenated and zone 3 poorly oxygenated
Hepatic acinus - Zone 1 (Periportal) ?
- Best perfused and first to regenrate due to proximity to blood supply and nutrition
- First to encounter blood-borne toxins
- Plays a role is oxydative metabolism - Beta-oxidation, gluconeogensis, bile formation, cheolesterol formation and amino acid catabolism
Hepatic acinus - Zone 2 ?
Sits between zones 1 & 3
Hepatic acinus - Zone 3 (Pericentral) ?
- Lowest perfusion due to distance from the portal triad
- Most sensitive to ischaemic injury
- Most sensitive to N-acetyl-p-benzoquinonimine (NAPQI) production in paracetamol OD due to having the highest concentration of CYP2E1 enzymes
- Plays a role in detoxification, biotransformation, ketogenesis, glycolysis, lipogenesis, glycogen synthesis and glutamine formation.
- Bile and blood flow in opposit directions to eachother
Liver functions? See picture
- Biotransformation (Ammonia, Hb, Xenobiotics, drugs, glucose)
- Storage (Lipids, vitamins & glycogen)
- Synthetic function (Albumin, growth factors & urea)
Biotransformation in the liver?
- Phase (I) - Oxidation, reduction & hydrolysis. P450 based drug detoxification
- Phase (II) - Conjugation with second substance to increase polarity.
- Protein and lipid metabolism
- Breakdown of insulin and other hormones
- Conversion of ammonia to urea.
Storage in the liver?
- Glycogen - Release glucose via glycogenolysis
- Storage of Vit A, D and B12
- Iron
- Copper
Synthetic function of the liver?
- Synthesis of amino acids, albumin.
- Cholesterol synthesis
- Lipogenesis, triglycerides and lipoproteins
- Bile production - Emulsification of fat and absorption of Vit K
- Production of insulin-like growth factor 1 - Polypeptide protein hormone - Important role in childhood growth and anabolic effects on adults.
Clotting factors ?
- Fibrinogen (I)
- Prothrombin (II)
- V, VII, IX, X, XI, XIII
- Protein C, protein S and antithrombin
- Vit K dependent ( II, VII, IX, X)
Synthetic fucntion of the liver?
- Albimin levels - Hypoalbuminaemia also occurs in - Malnutrition, nephrotic syndrome, malabsorptive state and later pregnancy.
- Prothrombin time /INR - Measures extrinsic pathway of coagulation - Factor I, II, V, VII & X.
- Prolongation - Deficiencies of Vit K related to - impaired absorption from poor quality bile and abnormality in factor VII production
Markers of hepatic injury ?
- ALT & AST
2. Suggests intrahepatic issues
Markers of billiary obstruction?
- Bilirubin - Haemolysis, billiary stricture, hepatitis, cirrhosis, drugs (antipsychotics and sulphonamides) , Gilbert’s syndrome
- ALP - Present in all tissues in the body - Billiary obstruction, pregnancy and by-product of osteoblast activity ( Paget’s disease)
- GGT - Liver, billiary and pancreatic disease. Acute alcohol ingestion, drugs - Barbiturates, phenytoin and NSAIDs. CCF
Encephalopathy ?
West Haven Grading system - See picture
Ascitis ?
Accumulation of ascitis secondary to portal hypertension.
Grade 1-3
Child-Turcotte-Pugh classification ? Components?
- Encephalopathy
- Ascitis
- Bilirubin
- Albumin
- PT/INR
MELD score - Model for end-stage liver disease?
- Stratification of severity of end-stage liver disease for transplant planning
- 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
- Score ranges from 6-40 . High scores correlating to increased severity of liver dysfunction and higher 3 month mortality
Kings college criteria for liver transplant?
- 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
- 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 )
Kings college criteria for liver transplant?
- 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
- 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)
Paracetamol OD?
- Absorption - 2% excreted with urine unchanged
- About 90% - Phase II metabolism (Non-toxic metabolites) - Conjugation with Gluthatione
- About 5-9% undergo metabolism by CYP2E1 - to toxic metabolite NAPQI
- NAPQI is conjugated with gluthatione in normal situations - GSH dependent pathway - Non-toxic metabolites
- In Paracetamol OD - Phase II enzymes are saturated and a much higher fraction is converted to NAPQI
- Once Gluthatione levels are depleted, the toxic NAPQI accumulates leading to hepatic necrosis
NAPQI?
N-Acetyl-p-Benzoquinone Imine
Definition of ALF?
- Increased PT / INR > 1.5
- Development of hepatic encephalopathy
- In patient without cirrhosis and illness less than 6 months
Causes of ALF?
See picture
Manifestation of ALF?
- Encephalopathy and cerebral oedema
- Coagulopathy - UGIB/DIC
- Renal failure - Low BP/Hepatorenal syndrome
- Metabolic disturbances - Electrolyte disturbances, low BMs and metabolic acidosis
- CVS - Similar to sepsis
- Infection - Immunosuppression
Manifestation of cirrhosis?
- Ascitis & oesophageal varicies
- Resp - Hypoxia, effusion, diaphragmatic splinting
- CVS - Adrenal inssuficiency , cardiomyopathy
- Renal dysfunction
- Haematological changes - Anaemia, coagulopathy
- Metabolic dysfunction - Increased insulin & thyroxine, water retention
7, Altered pharmacokinetics and metabolism.
