Liver Physiol Flashcards
Function and dysfunction of stellate and kupffer cells
S - specialised lipocytes in the perisinusoidal space that produce collagen matrix that supports the sinusoids. In health they are responsible for vitamin A storage and homeostasis
Also required for synthesis of ECM of the liver
Activation of these cells is a key event in fibrosis, this is inhibited by wnt antagonism
K - specialised macrophages involved in the metabolism of erythrocyte haemoglobin in health
Globin chains and amino acids are reutilised, Iron is removed and stored
Haeme oxidised to bilirubin.
Express complement receptor required for clearance of complement coated pathogens
Activation of TLRs and production of TNFa can result in contribution to pathogenesis of disease states
Blood flow in liver
Portal venous from abdomen has higher pressure (8-10mmHg) and flows toward central venules in hepatic lobules along the hepatovenous pressure gradient (HPVG) which is about 2-5mmHg difference
If flow in portal venous system increases there is large reserve to prevent pressure increase as well as NO mediated vasodilation and sympathetic mediated reduction in hepatic arterial blood flow.
Cholangiocyte function
secrete water, cations and bicarbonate into the bile
May participate in immune surveillance
Biliary canaliculi are blind tubular structures that by means of osmotic gradient favours flow of bile
Cholangiocytes modify the bile via secretory and reabsorptive processes as it travels along the ducts
Structure of gallbladder and protective mechanisms
single layer of epithelial cells, a lamina propria, a layer of smooth muscle and an outer serosal layer. The gall bladder epithelium concentrates and acidifies bile via absorption of water and electrolytes
Protected from concentrated bile acids via prostaglandin E2 stimulated mucin and bicarbonate secretion
Differences in cat and dog bile duct
In dogs, the CBD and minor pancreatic duct travel through the body of the pancreas in parallel (but separate) and terminate into the sphincter of Oddi
Also have a minor pancreatic duct that opens into minor duodenal papilla
In most cats, the CBD fuses with the major pancreatic duct in an ampulla just before penetrating the duodenum forming the major duodenal papilla
List Functions of Liver
Metabolism of fat, protein, lipids and vitamins
Detoxification of hydrophobic xenobiotics and steroid hormones
Protein synthesis and
Nucleic acid synthesis
Metal storage and homeostasis (Fe, Zn, Cu, Se)
Bilirubin metabolism and excretion
Bile production
Immune surveillance - mostly tolerance induction
Regeneration
What is the urea cycle and what occurs with dysfunction
Ammonia from GIT converted to urea for excretion in urine.
NH3 + CO2 produces carbamoyl phosphate under influence of synthetase I enzyme in the mitochondria the RATE LIMITING ENZYME
Then 3 enzymatic steps:
combined with ornithine –> citrulline
+ Aspatate and ATP
–> Arginosuccinate
–> Arginine which then loses urea and becomes ornithine again
The enzymes involved can be dysfunctional ddue to genetic mutations and result in hyperammonaemia and reduced urea.
In liver failure there is reduced urea cycling and that is what NH3 increases.
Liver role in lipid metabolism and lipoprotein functions
Removes chylomicrons from portal blood and combines into lipoproteins
LDL - delivers cholesterol to tissues
VLDL - delivers fatty acids to tissues (removed by endothelial lipases) and TGs to adipose
HDL - formed by liver to scavenge excess cholesterol
What amino acids are bile acids conjugated to
taurine
(and small amount to glycine in dogs)
How is Cu handled by hepatocytes
Enters liver from portal blood and is immediately bound to glutathione to prevent oxidative damage
–> multiple Cu chaperone proteins bind and transport Cu through hepatocytes for different functions
–> cerumoplasmin is final bound protein which then undergoes exocytosis to excrete Cu into blood or bile.
(this last step is what is dysfunctional in COMMD1 mutation of Bedlington terriers)
Factors required fro hepatic regeneration
TNFa, IL6; TL22 –> priming required prior to response to GFs
TGFa and other GFs promote hepatocyte proliferation from the periportal hepatocytes towards the central venule.
Biliary epithelium has slower regeneration.
Steps in Hgb b/d and bilirubin metabolism
Hgb removed from rbc by RES cells
–> Fe freed, Haema then converted to biliverdin –> bilirubin which enters blood unconjugated and bound to albumin for transport
(small amount of unconjugated bili is conjugated by renal cells and excreted in urine in dogs)
–> Liver absorbs unconjugated bili and conjugates to make it water soluble by glucoronidation
–> ATP dependent active secretion into bile (rate limiting step)
–> GI bact conversiuon to urobilinogen –> urobilin –> stercobilin
How does liver dz cause vomiting and diarrhoea
Vomiting - CRTZ stimulation by build up of toxins
Stretch of CBD/GB or compression of GIT –> vagal stimulation
Diarrhoea - usually small bowel
- lack of bile acids in cholestasis reducing fat metabolism and thus causing osmotic diarrhoea
- portal hypertension –> splanchnic congestion –> reducing GI water reabsorption
- acholic faeces seen with complete biliary obstruction/failure
Common CS from liver disease
vomiting
diarrhoea
PUPD
Abdominal distension from hepatomegaly or ascites
Pallor - rbc sequestration, increased rbc fragility, reduced Fe for Hgb synthesis, secondary IMHA
Pathophys of PUPD in liver disease
more often seen in dogs than cats
Reduced steroid hormone metabolism (inhibited by high bile acids) –> increased cortisol (pseudohyperaldosteronism) –> Na and H2O retention –> pressure diuresis and low K
And reduced sensitivity of tubular cells to ADH due to cortisol induced NDI
HE induced increase in ACTH (abnormal neurotransmission)–> increased cortisol and possibly psychogenic polydipsia
Reduced urea synthesis –> medullary washout
(also increased uric acid excretion by kidneys –> potential uroliths)
Renomegaly and hyperfunction occurs in PSS due to GFs normally only used by liver being present in systemic ciruculation
Nausea
