Wk 20 Flashcards
The liver, bile and the biliary tree
The 5 main roles of the Liver
Metabolism= carbs, fats and proteins
Drug= metabolism, detoxification, excretion
Biosynthesis= bile, cholesterol, phospholipids
Immune function: screening of intestinal blood by Kupffer cells
Storage: Vit A, glycogen
Blood from digestive system follows what pathway before entering circulation?
Digestive system –> portal veins –> hepatic venules –> filter through hepatocytes –> drains to central vein –> hepatic vein –> inferior vena cava
Function of bile:
Components of Bile:
Emulsify fats (aids pancreatic lipase)
Water (97%)
Bile salts (0.7%)
Bilirubin (0.2%)
Fats (cholesterol) (0.51%)
Process of bilirubin:
Haem converted to bilirubin and transported to liver to be conjugated, conjugated bilirubin secreted into bile and sent to SI, bacteria in large intestine metabolise bilirubin to sterobilin (gives faeces brown colour)
Waste products excreted in bile: 3
Drugs/ drug metabolites
Calcium
Steroid hormones
How does gall bladder concentrate bile?
What stimulates contraction and secretion of bile into the SI?
Compare non-digestive period to digestive period:
epithelium specialised for water absorption
Contraction mediated by CCK
Non-Digestive period= sphincter of Oddi closed and bile flows from liver to gall bladder
Digestive period= Food triggers CCk release and secretin
- Secretin stimulates hepatic duct cells to release bicarbonate
- CCK triggers relaxation of sphincter of Oddi and contracts gall bladder
- Bile is released into duodenum
What is enterohepatic circulation?
Where is the uptake from the SI and what proteins mediate this?
What happens if this absorption doesn’t occur?
How bile salts are continuously recycled
Terminal Ilium, mediated by sodium-dependent bile salt transporter proteins
Little bit is okay ((degraded by LI bacteria and eliminated in faeces
Lot= Bile acid diarrhoea develops (bile salts draw water into the LI)- watery, osmotic diarrhoea
Explain the 2 functions of the pancreas (endocrine and exocrine)
Endocrine: Produces Insulin (B cells), glucagon (a cells), and somatostatin (released into circulation)
Exocrine: Produces zymogens (activate in duodenum- amylase, lipase, protease) which are released into duodenum through pancreatic duct (exits pancreas via duodenal papilla)
Pancreatic exocrine cells arrange into:
Eventually drains into:
Endocrine cells arrange into:
Acini
Pancreatic duct
Islets of langerhans (little lighter coloured ‘islands’ throughout a sea of darker acini- histology)
What are the major inactive pro-digestive enzymes (zymogens) that the pancreas synthesises and excretes? 6
Why are these zymogens packaged into granules?
- Trypsinogen (to trypsin) for protein digestion
- Chymotrypsinogen (to chymotrypsin) protein digestion
- Proelastase (to elastase) protein digestion
- Procarboxypeptidase (carboxypeptidase) protein digestion
- Prolipase (to lipase) fat digestion
- Active amylase
To avoid digestion of pancreas
What cells are zymogens (pancreatic exocrine digestive enzymes) produced by?
Acinar cells
How is chyme neutralised in duodenum? 2 main mechanisms:
Release of bile from gall bladder (regulated by CCK)
Release of bicarbonate fluid from pancreas
(duodenum is also protected by acidic chyme by a mucus layer)
How are pancreatic zymogens activated in the small intestine?
A brush boarder enzyme in the SI (enteropeptidase/ enterokinase) removes a peptide fragment from trypsinogen –> activated to trypsin
Trypsin then cleaves peptide fragments from the other zymogens and activates them
How is the pancreatic exocrine function regulated? …
Cephalic and gastric phases:
Intestinal phase:
Cephalic (sight, smell, taste of food) and gastric (gastrin produced in stomach) phases trigger vagal signalling –> triggers acinar cells to release zymogen granules and triggers duct epithelial cells to release bicarbonate fluid
Vagovagal reflexes stimulate release of zymogen granules from acinar cells
Stimulation of enteroendocrine cells by luminal contents release CCK and secretin
(CCK and secretin increase zymogen and fluid secretion)
Describe the catabolism of haem, including the sites in which reactions occur and the colour of the intermediates:
1) Breakdown of haem to green biliverdin (unconjugated bilirubin) occurs in macrophages of the spleen and liver (and some tissues) and is taken to liver via blood
2) Conjugated with glucuronic acid in liver and secreted into bile –> SI
3) In SI, glucuronic acid is removed by bacteria –> produces urobilinogen
- Some urobilinogen is reabsorbed from gut and enters portal blood (a portion of this stays in the enterohepatic urobilinogen cycle but the rest is transported via blood to kidney –> oxidised to yellow urobillin and excreted, giving urine its colour
- The urobilinogen that isn’t taken by portal vein stays in intestine and is oxidised by bacteria to brown stercobilin and excreted in faeces
Describe cholesterol’s functional roles in the body: 4
Describe the structure of cholesterol:
- Cell membrane permeability and fluidity
- Vitamin D synthesis
- Steroid hormone synthesis
- Manufacture of bile salts
Structure: it is a sterol because it is made out of alcohol and a steroid
Describe the dietary sources and synthesis of cholesterol:
Dietary sources= animal fat
Synthesis=
- 80% occurs in liver
- Glucose, FAs and AAs make Acetyl CoA which is converted to HMG-CoA
HMG-CoA reductase converts HMG-CoA into Cholesterol (this is the rate limiting step- target of drugs like statins block HMG-CoA reductase so cholesterol can’t be synthesised)
What are bile salts made from and where?
Made from cholesterol and occurs in liver
What are the classes of lipoproteins and the general role of each?
Lipoproteins are classified by density (the amount of lipids, cholesterol and protein)
Chylomicrons= contain so much triglyceride and so little protein= they are lowest in density
Very Low Density Lipoproteins= half TGs= 2nd lowest in density
LDL= half cholesterol= implication in heart disease
HDL= half protein, very high density
General role: transport cholesterol and triglycerides so they can undergo metabolism
Describe the transport of lipids in the blood, including the role of the liver
Triglyceride pathway: TGs are transported to cells by VLDL (from liver) or chylomicrons (from intestine) for energy use or storage (adipose tissue) [chylomicron remnants come back to liver eventually and the liver breaks that down and forms cholesterol (some excreted in bile)+ FAs and lipoproteins and cycle continues]
Cholesterol pathway: Cholesterol is transported to cells by LDL (from liver) for use in plasma membranes and steroid synthesis, while excess cholesterol is moved from cells to liver by HDL to be converted by liver into bile
How is hepatic cholesterol transported to peripheral tissues?
By lipoproteins that contain ApoB100 (VLDL, IDL and LDL)
What factors affect drug absorption after oral administration? 6
- Nature of absorbing surface (stomach or SI)
- Lipid solubility and pH of environment
- Drug formulation: how quickly drug dissolves (sustained release or enteric coating, lipophilic vs hydrophilic)
- Blood flow
- Food in stomach
- Motility of gut
Describe how the preparation of drug affects absorption (e.g. enteric coatings, sustained release, lipophilic vs hydrophilic)
- Lipophilic (fat sol) drugs cross cell membranes easily
- Hydrophilic need help crossing membrane
- Enteric coating: prevents breakdown in stomach and also prevents stomach irritation
- Sustained release: slow, constant absorption of drug for 8 hours or longer
Describe passive and active transport mechanisms for the movement of drugs across cell membranes…
Passive: (what it is and 3 different passive ways to get across membrane)
Active: (what is it and 2 examples)
Passive: movement of drug down concentration/ electrochemical gradient (can be straight through membrane, diffusion through aqueous channel or using a carrier-facilitated diffusion)
Active: carrier mediated transport (against conc gradient)
e.g. ATP binding cassette (ABC) transporters- use ATP (P-glycoprotein and Na/K ATPase are examples)
Describe the interactions of the small intestine epithelium with drugs (absorption, metabolism, exsorption)
Absorption:
- Blood flow (faster blood flow= faster absorption since drug conc kept low in blood)
- Motility (increased gastric emptying= faster drug absorption in SI [dopamine receptor antagonists] and decreased GI motility slows drug absorption [muscarinic receptor antagonists])
- Food (high fat foods= delay gastric emptying)
Metabolism: (reduces amount of drug absorbed)
- Inactivation of drugs by metabolic enzymes before absorption
- Gut microbiota and cytochrome P450 enzymes metabolise drugs
Exsorption: pump drugs back into intestinal lumen= reduces the amount of drug reaching circulation
- P-glycoprotein (ATP binding cassette [ABC] transporters require energy)
What is the structure and replication strategy of Hep A?
Note all Hep A,B and C have Icosahedron shaped capsid
Structure: Non-enveloped RNA genome packaged into a protein shell (capsid)
Replication: After entry into the host cell, the virus loses the capsid and the uncoated RNA induces the host cell to produce the viral polyprotein (primer for transcription) without shutting off the protein synthesis of the cell.
What is the structure and replication strategy of Hep B?
Structure: The virus particle (Dane particle) is a nucleocapsid protein core (with DNA) inside a lipid envelope (derived from host membrane)
Replication strategy: Get in blood (avoid immune system), travel to liver, release DNA and DNA polymerase into hepatocyte nucleus, hepatocyte makes copies of Hep B DNA from messenger RNA, hepatocyte releases copies of the virus into blood to infect other hepatocytes
What is the structure and replication strategy of Hep C?
Structure: RNA genome surrounded by a protein capsid and lipid envelope (derived from host membrane)
Replication: Enters the blood, travels to hepatocyte, replicates itself many times in hepatocyte cytoplasm and is released to infect other hepatocytes
Viral envelope vs just a capsid (non-enveloped) for transmission and replication:
Envelope: (HAV)
- Can survive longer in environment
- Transmission= fecal oral route (via contaminated food and water)
Capsid/ non-enveloped: (HBV and HCV) sensitive to environment, limited survival outside host
- takes longer to replicate
- transmission= directly from host to host (blood/ bodily fluids)
(envelope can integrate surface proteins to hide from immune system)
What does the name Hepatitis mean?
Acute vs chronic hep:
Inflammation of the liver
Acute: self limiting
Chronic: can progress to fibrosis, then cirrhosis and finally hepatocarcinoma
How does chronic hepatitis progress to Hepatocellular carcinoma?
Chronic hepatitis: ongoing inflammation of hepatocytes
Cirrhosis: results from ongoing long-term tissue damage and fibrosis (scar tissue replacement of normal tissue)
Hepatocellular Carcinoma: cancer of liver
How is Hep A transmitted and what are the ‘At risk’ groups who are recommended a vaccination?
Fecal- oral route (through contaminated food, water or person to person)
At risk groups= travelers to endemic areas, ATSI kids and workers in ATSI communities, kids and paeds workers, gay men, IV drug users
What are the treatments for Hep B (2 options) and C? (Hep A has no treatment, only a prevention vaccine)
Hep B:
- Block reverse transcriptase or nucleoside analogue (treatment reduces symptoms but does not cure chronic hep B)
- PEG-interferon a (activate immune antiviral responses)
Hep C: Oral direct acting antivirals (DAAs)
How do the Hep A and B vaccines work? (no Hep C vaccine)
Hep A: 5 Hep A vaccines prepared from different strains of HAV
Hep B: Subunit vaccine containing Hep B surface antigen
