Gastrointestinal Week 2 Flashcards
What is the macroscopic structure of the liver?
- weights ~1.5kg
- situated in R hypochondrium and epigastric region under the diaphragm
- covered by the ribs
- ANTERIOR:
- > right and left lobe, divided by falciform ligament, from which ligamentum teres extends which is a remnant of the umbilical vein
- > along the top edge of the liver is the coronary ligament with a R and L triangular ligament at each end
- > the falciform, coronary and L/R triangular ligaments connect the liver to the diaphragm and anterior abdominal wall
- entire liver covered by fibrous layer called Glisson’s capsule
- FROM ABOVE:
- > bare area of liver on top of R lobe that has Glisson’s capsule but is not covered by peritoneal covering, is in direct contact with the diaphragm
- > IVC towards R lobe, caudate lobe towards left lobe
- POSTERIOR:
- > hepatogastric and hepatoduodenal ligaments emerge from falciform ligament
- > caudate lobe (superior) and quadrate lobe (inferior)
- > GB and porta hepatis can also be seen
What are hepatic recesses and name some clinically relevant ones?
Spaces between liver and surrounding structures where fluid can gather forming an abscess.
1) L/R subphrenic spaces between diaphragm and liver either side of falciform ligament
2) L/R subhepatic spaces between inferior surface of liver and transverse colon
3) Morison’s pouch: the most posterior and superior aspect of the R subhepatic space. It is the deepest part of the peritoneal cavity where fluid is likely to gather in a bed ridden patient. Also known as HEPATORENAL RECESS as it is located between liver and peritoneal surface of right kidney
What is the blood supply and pathway to/through the liver?
Receives blood from 2 sources:
1 - hepatic artery (20-25% of blood) gives O2 blood from coeliac trunk
2 - portal vein (70-75% blood) gives deO2 blood that is nutrient rich from stomach/spleen/intestines
- blood from 1 and 2 mixes in hepatic sinusoids where vascular exchange occurs with the liver hepatic cells
- after passing through sinusoids, blood collects in hepatic veins -> IV -> enters R atrium of heart
How is bilirubin metabolised?
- Every 120 days, RBC’s are phagocytosed by macrophages of RES in the spleen and bone barrow
- the Hb gets broken down into: heme (porphyrin ring), iron which is recycled and globin monomers which are recycled
- Haem —(haem oxygenase)—> biliverdin —(biliverdin reductase)—> bilirubin
- at this stage bilirubin is unconjugated (water insoluble) and so cannot be removed from the body
- the UC bilirubin is bound to albumin and carried in the blood to the liver
- albumin has hydrophilic outside and hydrophobic inside and carries bilirubin by interacting with its hydrophobic part and so transports it in a hydrophilic shell
- in the Space of Disse, the albumin and bilirubin dissociate and the albumin is left behind in the SoD while the bilirubin is carried into hepatocyte cells by sinusoidal bilirubin transporter
- the UC bilirubin is then converted by —(UDP glycoronyl transferase)—> into conjugated bilirubin
- there are two forms of conjugated bilirubin (one of two forms: bilirubin monoglucoronide and bilirubin diglucoronide)
- C bilirubin accumulates in the GB with other components to form bile which is secreted into intestines when needed for fat breakdown
- intestinal bacteria HYDROLYSE CB -> urobilinogen
- intestinal bacteria OXIDISE urobilinogen -> stercobilin (gives faecal colour)
- XS urobilinogen is absorbed into blood and travels to kidneys where it is OXIDISED to urobilin (gives urine colour)
What is portal hypertension and how is it caused?
Increased resistance to blood flow in the portal venous system, due to a sustained increase in portal venous pressure.
- can be caused by various conditions that increase resistance to bloodflow:
- > cirrhosis
- > obstructive thrombosis
- > narrowing of portal vein before it enters iver
- cirrhosis is the main intrahepatic cause, where bands of fibrous tissue and nodules disrupt liver architecture and increase the resistance to blood flow
What complications can develop from portal hypertension?
Oesophageal varices:
- increased pressure causes dilation of venous channels behind the obstruction and collateral channels open, connecting the portal circulation with the systemic venous circulation
Describe briefly what ascites is and how it occurs:
- when amount of fluid in peritoneal cavity increases
- portal hypertension increases hydrostatic pressure causing fluid release
- portal hypertension -> systemic vasodilation -> renal vasoconstriction -> activation of RAAS -> more Na retention -> fluid accumulates
Describe what splenomegaly is and how it occurs:
- spleen progressively enlarges due to shunting of blood into the splenic vein
Describe briefly what oesophageal varices are and how they occur:
- due to portal hypertension and cirrhosis there is obstruction of venous blood flow, so blood tries to find another way back to the heart
- large collateral channels develop between portal veins and systemic veins
- caput medusa form when veins around the umbilicus dilate and open up (i.e. reopening of the foetal umbilical vein which has not been totally obliterated)
- dilated veins at the bottom of the oesophagus form varices
- if these bleed they are very difficult to stop bleeding and can be life threatening
How can you treat bleeding oesophageal varices?
- balloon tamponate
- ligation (band around bleeding vessel)
- B-blockers (propanol) used to reduce BP by lowering blood pressure flow, therefore less pressure in the collateral vessels and the oesophageal vessels that are bleeding
What is the total iron content of the body and where is the iron distributed?
4g
- 3g in bone marrow/RBC’s
- 100mg enzymes
- 200-300mg in myoglobin
- 200-500mg in RES
How is iron balance maintained in the body?
The amount of dietary iron that is absorbed is regulates as there is no excretory mechanism for XS iron in the body
How is iron stored?
Mainly as ferritin (soluble, safe storage and readily available).
Can also be stored as haemosiderin (insoluble conglomerates of ferritin) but in this form iron is slowly available.
How is iron transported in the blood?
Transported in blood by a glycoprotein called transferrin.
- transferrin is synthesised by hepatocytes
- when iron levels are low Tf production increases
- when iron levels are high Tf production decreases
- Tf has two binding sites (Y)
- normal saturation of Tf with Fe is ~30%
- only 4mg iron bound to transferrin at any one time but 50mg of iron are transported by transferrin per day
- the highest concentration of Tf receptors are found on RBC precursors and most iron delivered to erythrocytes is used for haem synthesis by the ALA-S2 protein
What two forms does iron exist in and how are these absorbed?
Haem: in red meat and easily absorbed in the duodenum by enterocytes.
Non-haem: in white meat, green veg and is more difficult to absorb.
- > must be released from food by acid digestion and proteolytic enzymes
- > must be reduced from ferric to ferrous form by DUODENAL CYTOCHROME B1 (taking vitamin C supplements can aid this process)
How is iron absorbed from the blood into enterocytes?
- taken into enterocyte by divalent metal transporter 1 (DMT1) which is an electrogenic pump thats expression is up-regulated in iron deficiency
- once in the enterocyte, ferroportin and hepcidin export the Fe into the circulating plasma
- ferroportin is a transmembrane protein essential for iron release
- hepcidin interacts with ferroportin to increase/decrease iron release into the plasma
What is the RES and what is its function?
- the reticuloendothelial system is part of the immune system with phagocytic cells located in reticular connective tissue
- RES iron is stored as ferritin or haemosiderin
- macrophages store ~500mg iron
- macrophages must obtain their iron by digestion of RBC’s and not through transferrin
Describe iron deficiency anaemia (IDA) and some of its causes:
- when transferrin saturation is only 15%
- RBC’s are hypochromic (pale) and microsytic (small)
- in young females may be due to blood loss of pregnancy
- in IDA there is malabsorption of iron as villi in the duodenum are destroyed by lymphocytes which infiltrate the lamina propria
- common cause of GI blood loss
What is haematinic deficiency?
- deficiency of nutrients like iron, vitamin B12 etc. which are needed for the development of blood cells in bone barrow
- can commonly occur in coeliac disease with deficiencies in:
- > folate
- > iron
- > vitamin B12
What is hereditary haemochromatosis (HHC) and how can it be caused?
- gene mutation (homozygous C282Y mutation of HFE gene)
- autosomal recessive disorder causing iron overload
- HFE (human haemochromatosis protein) is responsible for controlling synthesis of hepcidin
- loss/inappropriate hepcidin expression causes XS GI absorption of iron and increased Tf saturation
- Tf saturation can reach 100% and the danger is that some Fe may be present in the blood that is not bound to Tf = dangerous
Common feature = restrictive cardiomyopathy where walls of heart ventricles become stiffened (not necessarily thickened)
How can HHC be treated?
- (weekly) venesection until normal blood levels of iron return
- 500ml blood removed allowing 250mg of iron to be removed
- Tf saturation and ferritin levels are monitored
Apart from HHC, how else can iron overload occur?
Multiple blood transfusions
After 20 blood transfusions, your iron levels can increase by ~5g
What is sideroblastic anaemia and how can it be caused?
Ringed sideroblasts produced in bone marrow, instead of healthy RBC’s.
In these sideroblasts the iron cannot be transferred from non-haem -> haem and so remains trapped in the mitochondria of developing cells
What is the structure of haemoglobin (Hb)?
4 globin monomers joined together (2 alpha and 2 beta).
4 haem groups are present = an Fe inside a porphyrin ring.
One haem group is inside each globin monomer.
What colour change occurs when bilirubin is oxidised?
Bilirubin is initially orange/yellow but gets oxidised to biliverdin and is then a green pigment
What are bile salts and what is their function?
Bile salts are DERIVED FROM PRIMARY BILE ACIDS and are important for emulsification
Name primary bile acids and how they are synthesised:
What special enzyme is involved?
Primary bile salts are synthesised from cholesterol and include
- > cholic acid
- > chenodeoxycholic acid
Primary bile acids are conjugated to form bile salts
- cholic acid + glycine -> glycocholic acid
- chenodeoxycholic acid + taurine -> chenodeoxytaurocholic acid
The enzyme cholesterol-7-alpha-hydroxylase is involved and when cholic acid is plentiful it inhibits this enzyme working (negative feedback).
How do bile salts carry out emulsification?
Are they recycled and if so how?
- bile salts have a hydrophobic portion which binds to large TAG lipid droplets and disperses them up into micelles (the hydrophilic part of bile salts prevents TAG’s reforming)
- emulsification increases the SA of fats so that lipases can act
- bile salts must be RECYCLED in enterohepatic circulation as there are not enough bile salts to process all the fat in a meal
(95% bile salts recycles in enterohepatic circulation and 5% los in faeces)
- transporters move bile salts from GI tract -> intestinal capillaries -> liver (via portal vein)
- hepatocytes take up bile salts from the blood and increase bile salt secretion into canalculi
How is bile secretion from the GB controlled?
- sphincter of oddi is muscular ring around the duodenal papilla that controls the flow of bile and pancreatic fluid into the duodenum
- in the interdigestive period, sphincter of oddi contracted
- when sphincter is closed, increased pressure in common bile duct causes bile to flow up into GB and be concentrated (epithelial cells reabsorb water and electrolytes)
- after eating, fat in the duodenum causes CCK to be released from I cells in duodenum and jejunum
- CCK causes:
- > contraction of GB
- > relaxation of sphincter of oddi
- > reduced gastric motility
- > increased pancreatic enzyme release
- also after eating, acidic chyme in the duodenum triggers release of secretin from S cells in duodenum and jejunum
- > secretin stimulates bile production and causes liver cells to release bicarbonate into bile
- > secretin also inhibits the activity of G cells, so less gastrin = less HCl made
Define jaundice and its levels of biochemical markers:
- yellowish discolouration of the skin and sclerae caused by elevated levels of bilirubin in the body (hyperbilirubinaemia)
Normal total bilirubin = <21umol/l
Normal conjugated BR = <7umol/l
Jaundice total bilirubin = >30umol/l
Jaundice conjugated BR = >100umol/l
Can be classified into three groups and the proportion of UC/C BR is used to distinguish between the three groups.
What are the three main categories of jaundice?
Pre-hepatic
Hepatic
Post-hepatic
Describe pre-hepatic jaundice and its causes:
There is ELEVATED HAEMOLYSIS and the liver cannot cope with increased levels of unconjugated bilirubin.
Causes: malaria, yellow-fever, genetic disorders associated with haemolysis e.g. sickle cell anaemia
Describe hepatic jaundice and its causes:
Can be 3 issues:
- impaired uptake of UC bilirubin
- impaired conjugation
- impaired transport of C bilirubin into bile canaliculi
Causes: cirrhosis, hepatotoxic drugs (paracetamol overdose), viral hepatitis
Describe post-hepatic jaundice and its causes:
Due to OBSTRUCTION where bile cannot be released into the small intestine causing cholestasis.
Causes: hepatic/cystic/CB duct blockage due to gallstones, pancreatitis or cancerous tumour in head of pancreas.
Where are the three common locations that gallstones can be found?
1 - cystic bile duct -> painful as the GB contracts to try to shift the blockage
2 - common bile duct
3 - duodenal papilla
Describe the levels of the following pigments in their respective locations in pre/post/hepatic jaundice:
a) plasma UC BR
b) plasma C BR
c) urine C BR
d) urine urobilin
e) faeces stercobilin
(see table p8 week 2 lecture notes)
a) prehepatic = very high
hepatic = high
posthepatic = normal
b) prehepatic = high/normal
hepatic = high
posthepatic = high
c) prehepatic = normal
hepatic = high
posthepatic = high
d) prehepatic = high
hepatic = high
posthepatic = none
e) prehepatic = high
hepatic = normal
posthepatic = none
What is the pathophysiology of neonatal jaundice?
How is it treated?
- common and usually harmless
- some babies livers not fully developed and have a lack of UPD glucoronyl transferase
- increased haemolysis occurs as baby’s RBC have shorter lifespan of 70 days
- this along with the lack of UDP glucoronyl transferase means that not all bilirubin gets conjugated and there is a build up of UC BR
- UC BR levels build 3-5 days after birth but normally return to normal within 14 days
- if not self-limiting, then use phototherapy to treat where blue light converts the UC BR into water-soluble form that can be secreted
What is the pathophysiology of haemolytic disease of the newborn?
Mother is Rhesus factor +ve
- Has first baby which is Rh-ve, this baby develops normally but at birth when the mother and baby’s bloods come into contact, the mother’s immune system is sensitised and makes antibodies against Rh-ve
- When second baby is growing which is Rh-ve, the mothers immune system attacks it and the babies blood vessels develop abnormally
- the second child is at risk of kernicterus where bilirubin can cross the blood brain barrier and result in brain damage if not treated
How can you measure bile pigments in serum?
Measuring conjugated BR: add diazo reagent to serum and the conjugated bilirubin will be converted into a blue/purple derivative of bilirubin called azobilirubin (then measure absorbance of solution).
Measuring unconjugated bilirubin: it is water insoluble and so does not react with diazo reagent, so use caffeine to displace UC BR from albumin to measure total Br levels using diazo reagent (again measure absorbance).
Compare the absorbance results with graph of known values of absorbance on Y axis and bilirubin concentration on X axis.
