Introduction to the Liver and Cirrhosis Flashcards
What are the roles of the liver?
-Important metabolic role
-Detoxifies metabolites from the gut (all blood from gut passes through portal vein)
-Synthesis of digestive enzymes
-Production of a variety of proteins
-Storing nutrients
=80% portal vein (30% 02)
=20% hepatic artery (70% O2)
What does each segment of the liver have?
8 segments, each has:
- Supply from portal vein
- Hepatic artery
- Branch of bile duct
- Segment of hepatic vein back into IVC
What are hepatic lobules?
Each segment -Hepatic lobules =Hepatic artery =Portal vein =Bile duct =Drains into branch of hepatic vein -Hexagonal shape, each corner has above -Central vein in middle draining away -Functions occur along sinusoids
Describe the hepatic sinusoid
-Portal triad
=Portal venous and oxygenated blood mixes
=Liver sinusoidal endothelial cells, allows passage of molecules into Space of Disse (metabolites, plasma proteins, drugs, lipoproteins)
=Hepatocytes= homeostasis
-As blood passes on, metabolic functions change (change in oxygenation)
What are the Liver functions?
- Nutrient metabolism
- Drug Metabolism
- Protein synthesis
- Secretion
- Storage
- Immunological function
Describe glucose metabolism during fasting
↓ insulin and ↑ glucagon → normoglycemia
-Glycogen breakdown in periportal hepatocytes
=Major glucose store in body
-Gluconeogenesis from:
=Lactate, pyruvate, amino acids and glycerol
Describe glucose metabolism during feeding
↑ insulin and ↓ glucagon → hepatic glucose uptake
-Glycogen deposition in hepatocytes
Describe lipid metabolism
-Bile digests lipids in the gut → chylomicrons → liver
-Chylomicrons metabolised by lipoprotein lipase → Cholesterol, phospholipids, triglycerides and free fatty acids
=Chylomicrons travel in lymphatics to liver
Describe the endogenous pathway (LDL)
- VLDL synthesised by liver, fatty acids leaved off= IDL (reuptake via remnant receptor)= more fatty acids cleaved off= LDL (reuptake via LDL receptor
- A residual fraction of LDLs bind to low affinity scavenger receptors on macrophages and are phagocytised
- Foam cells, deposit in atherosclerotic plaques
Describe the Reverse Transport Pathway (HDL)
- HDL synthesised by liver
- Picks up cholesterol in tissues and delivers to tissues that need it or to other lipoproteins
Describe the exogenous pathway (chylomicrons)
- Dietary triglycerides, phospholipids and cholesterol absorbed into enterocytes of the small bowel
- Fatty acids cleaved off
- Reuptake via remnant receptor
Describe protein metabolism
Amino acids are absorbed from the small intestine
-Hepatocytes metabolise proteins via the Krebs or citric acid cycle
→ Hormones, neurotransmitters, plasma proteins, nucleotides (Purine and Pirimidine)
How is ammonia formed?
Absorbed from the gut (formed from bacteria so by product of digestion) but also synthesized in the liver
-Detoxified in theliverby conversion to urea by the Krebs cycle.
HEPATIC ENCEPHALOPATHY IF TOO HIGH
What are the 3 phases of drug metabolism?
-1= Oxidation, reduction and hydrolysis (new compound can have similar or different activity to parent compound; it can be converted from active to relatively inactive compound or vice versa): CYP450 enzyme in the ER
CYP1, CYP2, CYP3 and CYP3A4
-2= Conjugation in cytoplasm of hepatocytes:
→ soluble: glucuronic acid, sulphate, acetate, glycine, glutathione
=Attachment of ionised groups to drug, increases water solubility allowing excretion in bile and urine
-3= Secretion into the bile
=Excretion is mediated by ATP
What proteins are synthesised?
-Albumin
=10-12g/day and 55% of circulating protein
=enables unconjugated insoluble materials to be transported in blood
-Transport proteins
=Caeruoplasmin and Transferrin (transport of iron and copper)
-Ferritin (iron storage)
-Protease inhibitors
=ɑ1 antitrypsin
-CRP (evidence in inflammation and infection)
-AFP (screening in chronic liver disease, carcinomas secrete)
-Complement
-Coagulation factors
=Fibrinogen, II, V, VII, IX and X
=Elevated prothrombin times suggest not able to make them/ normalised doesn’t affect how probe to bleeding a patient is
Describe Bile secretion
600ml/day made up of:
-Bile acids primary (made in liver) and secondary (absorbed)
=Allow digestion of dietary fats through emulsification
-Phospholipids
-Cholesterol
-Conjugated drugs
-Electrolytes: Na+, Cl-, HCO3- and copper
-Bilirubin (also conjugated in liver)
What is Bilirubin?
-Breakdown product of RBCs (Haem)
=RBCs spleen to biliverdin; to unconjugated bilirubin
-Bound to albumin for delivery to liver
-Bilirubin conjugated in liver with glucuronic acid to make soluble
=Bile secreted in small intestine; most absorbed through TI (duodenum)
=Conjugated bilirubin is not absorbed but bile is deconjugated in small bowel and colon (more hydrophobic)
=Converted to urobilinogen then some into Stercobilin (brown colour), some reabsorbed and excreted in urine as urobilin
=Colon bacteria breakdown
What vitamins are stored in the liver?
- Vitamin A, D and B12 are stored in large amounts
- Small amounts of Vitamin K and folate are rapidly depleted with decreased dietary intake
- Metabolises cholecalciferol vitamin D3 → activated 25-(OH) vitamin D
What minerals are stored in the liver?
- Iron stored in ferritin and haemosiderin
- Copper (affected to Wilson’s disease)
Describe the Immunological function of the liver
-“firewall” filtering all blood from gut
-Kupffer cells phagocytose pathogens from gut
-Supply of important chemokines:
=Interleukins
=Tumour necrosis factor
-Priming T cell responses
What is Liver cirrhosis?
Development ofregenerative nodules surrounded by fibrous bandsin response to chronic liver injury
→ portal hypertension and end stage liver disease.
4000 deaths/year due to cirrhosis
>700 transplants
What are the causes of liver cirrhosis?
-Viral infection =Hepatitis B and C -Alcohol -Non Alcoholic Steato-Hepatitis -Autoimmune disorders =AIH -Cholestatic liver disease =PBC and PSC -Metabolic causes
Fibrosis renders the liver more resistant to subsequent acute injury and that type 1 collagen, which predominates in the fibrotic scar, protects hepatocytes against various toxic stimuli
Describe the pathology of cirrhosis
- Chronic injury
- Over time= inflammation, damage, matrix deposition, loss of parenchymal cells, angiogenesis= early fibrosis
- Progression depends on genetics and epigenetic markers, co-factors like obesity and alcohol
- Fibrosis reversible= remove underlying cause, anti-fibrotic drug or cell therapy
- Disrupted architecture, loss of function, aberrant hepatocyte regeneration= cirrhosis, liver transplantation as permanent
- Increased of hepatocellular carcinoma
Describe hepatocyte injury
-Hepatocyte injury
=Apoptosis and necrosis
=Recruitment of activated macrophages
=Activation of hepatic stellate cells
