Gastro - week 2 Flashcards
what are the roles of the liver
Largest solid organ in the body • Important metabolic role • Detoxifies metabolites from the gut • Synthesis of digestive enzymes • Production of a variety of proteins • Storing nutrients
how many segments does the liver have
Liver has 8 segments, each of which has its own supply from hepatic artery and portal vein, its own branch of the bile. Each also has a branch of the hepatic vein
compare fasting and feeding
Fasting
• ↓ insulin and ↑ glucagon → normoglycaemia
• Glycogen breakdown in periportal hepatocytes
• Major glucose store in body
• Gluconeogenesis from:
• Lactate, pyruvate, amino acids and glycereol
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
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)
describe ammonia metabolism
Absorbed from the gut but also synthesized in the liver
• Detoxified in the liver by conversion to urea by the Krebs cycle.
describe drug metabolism
• Phase 1
o Oxidation, reduction and hydrolysis
o New compound can have a similar of different activity to the parent molecule, it can be converted from active to relatively inactive and from inactive to active
o Important enzyme in this is CYP450 in the ER
• Phase 2
o Conjugation in cytoplasm of hepatocytes
o Increases their water solubility
o Glucuronidation, sulphation, acetylation and methylation among others
o Most phase 2 reactions inactivate drugs activated by phase 1
• Phase 3
o Secretion of drug into bile
o Excretion is mediated by ATP
what proteins are synthesised by the liver
• Albumin
o 10-12g/day and 55% of circulating protein
o Enables unconjugated materials to be transported in the blood
• Transport proteins
o Caeruoplasmin and Transferrin
Copper and iron transport
• Ferritin
o Iron storage
• Protease inhibitors
o ɑ1 antitrypsin
• CRP
• AFP
• Complement
• Coagulation factors
o Fibrinogen, II, V, VII, IX and X
describe bile secretion
• 600ml/day made up of:
Bile acids primary (made in liver) and secondary (absorbed)
• Allow digestion of dietary fats through emulsification (dysfunction leads to fatty stools which float)
Phospholipids
Cholesterol
Conjugated drugs
Electrolytes: Na+, Cl-, HCO3- and copper
Bilirubin
describe bilirubin
- Breakdown product of RBCs
- Converted to unconjugated bilirubin in the spleen
- Transported to the liver via albumin
- Conjugated with glucuronic acid
- Then excreted in bile
- Then converted to urobilinogen and then some to stercobilin which gives stools their brown colour
- Some urobilinogen is reabsorbed into the blood and travels to the kidneys where it is converted to urobilin to be excreted by the kidneys
describe vitamin and mineral storage
Vitamins
• 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
Minerals
• Iron stored in ferritin and haemosiderin
• Copper
describe the livers immunological function
• “firewall” filtering all blood from gut
• Kupffer cells phagocytose pathogens from gut
• Supply of important chemokines:
• Interleukins
• Tumour necrosis factor
Priming T cell responses
describe liver cirrhosis
- Development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury
- → portal hypertension and end stage liver disease.
- 4000 deaths/year due to cirrhosis
- > 700 transplants
what are some 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
what is the pathology of cirrhosis
• Damage leads to:
o Inflammation damage
o Matrix deposition
o Parenchymal cell death
o Angiogenesis
• This leads to early fibrosis
• The progression of this is down to:
o Genetics
o Epigenetic marks
o Cofactors such as obesity and alcohol
• Reversible
o Removal of underlying cause
o Anti-fibrotic drug or cell therapy
• Continued insult
o Disrupted architecture
o Loss of function
o Aberrant hepatocyte regeneration
- Leads to scarring
- Liver failure, portal hypertension and HCC
what immune response results from hepatocyte injury
Hepatocyte injury leads to recruitment of activated macrophages and activated stellate cells
Phagocytosis leads to production of pro inflammatory and pro fibrotic mediators which leads to differentiation of stellate cells into myofibroblasts – matrix synthesis and deposition
Also decrease in production of matrix metalloproteases
what are the concequences of increased sinusoidal resistance
• Causes portosystemic collaterals
o Blood from portal circulation can pass into
systemic circulation without going through
the liver
• Varices
o Extra blood vessels which form around
oesophagus and stomach which can bleed
• Angiogenesis
o Increases portal venous inflow – exacerbates
portal hypertension
• splanchnic vasodilation
o hypotension and decrease in effective
volume
o sodium and water retention – ascites and
increased cardiac output
o this leads back into increasing portal
hypotension
what are some signs of cirrhosis
• compensated
o liver small or large
o splenomegaly
o loss of body hair
• decompensated
o neurological effects
o ascites
o peripheral oedema
