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
Describe the process of fibrosis
-Dying hepatocytes and phagocytosis
=Secretion of pro-inflammatory and pro-fibrotic mediators
=Trans-differentiation of stellate cells into activated myofibroblasts
=Matrix synthesis with collagen 1 so matrix deposition
=Reduction in matrix degradation
Removal of cause:
=Decreased production of pro-inflammatory cytokines
=Reduction of matrix metalloproteases
=Reduction in loss of myofibroblasts
Describe Stellate cells
-Important in generation of fibrosis
-Activation of quiescent stellate cells/ portal or perivascular fibroblasts into myofibroblast
=Increased collagen synthesis
=Decrease production of MMP
so collagen accumulation and organ failure
What is the sequelae of collagen deposition?
- Myofibroblasts = 10x increase type 1 and 3 fibrillar collagen
- Decrease metabolite and O2 exchange across Space of Disse= hepatocyte dysfunction
- Increase angiogenesis, sinusoidal remodelling
- Increase sinusoidal resistance and portal hypertension
What are the consequences of increased sinusoidal resistance?
-Portal hypertension
-Systemic effects
=Portosystemic collaterals form so blood can pass from portal circulation to systemic circulation without passing through liver
–Ammonia not detoxification- BBB- encephalopathy
–Varices (extra blood vessels that form around oesophagus, stomach and duodenum= bleeding)
=Angiogenesis- increase portal venous inflow to exacerbate hypertension
-Splanchnic vasodilation= hypotension reduced in effective volume= neurohumoral activation and vasoconstriction and Angiotensin and aldosterone= sodium and water retention increases volume (ascites)= increased cardiac output
What are the general signs of chronic liver disease?
- Jaundice
- Fever
- Loss of body hair (hormones)
What are the signs of compensated chronic liver disease?
- Parotid enlargement
- Spider naevi (released angiogenesis factors)
- Xanthelasma
- Gynaecomastia
- Small (scarring) or large liver
- Splenomegaly (portal hypertension)
- Testicular atrophy (hormones)
- Clubbing
- Dupuytren’s contracture
What are the signs of decompensated chronic liver disease?
- Disorientation (ammonia bypass)
- Drowsy/ coma
- Hepatic flap
- Fetor hepaticus
- Ascites (portal hypertension, increased water tension)
- Dilated veins on abdomen
- Oedema
How do we diagnose fibrosis/ cirrhosis?
-Liver biopsy
=Gold standard, quantitative
=Sampling error, morbidity
-Serum markers
=Widely available, non-invasive
=Nonspecific, gray zone for intermediate fibrosis
-Elastography
=Non-invasive, fast and user friendly, validated in chronic hepatitis
=Cost, confounding factors (body habitus) like obesity
What are the possible results of a biopsy?
- No fibrosis, Ishak stage= 0, METAVIR= F0
- Fibrous expansion of some portal areas +/- short fibrous septa, IS= 1, F1
- Fibrous expansion of most portal areas +/- short fibrous septa, IS 2, F2
- Fibrous expansion of most portal areas with occasional porto-portal bridging, 3, F2
- Fibrous expansion of portal areas with marked porto-portal bridging and porto-central, 4, F3
- Marked bridging P-P and P-C with occasional nodule, 5, F3
- Nodular cirrhosis, 6, F4
What are the serum markers?
-Albumin
=Decreases in end-stage liver disease due to decreased synthesis
=T1/2: 20 days therefore useful in cirrhosis
-Prothrombin time
=Decreased synthesis of clotting factors (I, II, V, VII, X) →↑ PT
=In cirrhosis associated with more advanced disease
-Bilirubin
=Increased in end stage cirrhosis due to decreased clearance
-Platelets
=Decreased in cirrhosis
=Splenomegaly (portal hypertension) →↑ consumption
=Decreased Thrombopoietin production by cirrhotic liver
What is the purpose of composite scores?
- Used to assess risk of patients of having advanced cirrhosis
- Triaging
- Screening tests
What is Fibroscan?
- Liver should be like jelly, elastic
- More fibrosis= less elastic= more solid= probe measure through vibrations
- Liver stiffness
- METAVIR scores
- Varies depending on type of aetiology
- Non invasive measure
What is the Child-Pugh Score?
Assess risk and mortality
- Bilirubin, serum albumin, INR, Ascites, Hepatic encephalopathy
- Class A, B, C with different survival rates