Physiology

Question 1

Describe the blood flow to the liver.

Answer 1

Dual blood supply:

Arterial:
1. right and left hepatic artery: 20% of liver blood supply + 50% of the O2
–>usually divides into 2-5 branches that penetrate the different lobes of the liver:
–> RL branch: C + RL
–> RM branch: RM, dorsal part of Q + part of LM
–> L branch: LL + LM, part of Q
–> cystic artery to the gallbladder originates from the L branch of the hepatic artery.

2. portval vein: 80% of blood supply + 50% of O2
   –> created by the confluence of cranial and caudal mesenteric veins at the level of the left pancreatic limb
   –> additional veins entering into the PV: splenic + gastroduodenal veins (absent in cats)

Dogs.
–> divides into a R + L main branch
–> R: CP, RL
–> L: RM, PP –> then devides into LL, LM and Q branch (supply respective lobe)

Cats: 3 main branches—R, central, L –> supply the relevant lobes of the right, central, and left divisions

Venous: 6-8 hepatic veins drain venous blood into CVC

Question 2

How does the SaO2 of the portal blood differ between the fasting and fed state?

Answer 2

Fasting: 85%
fed: 70%

Question 3

What % of CO does the liver receive?

Answer 3

50%

Question 4

How is hepatic blood flow regulated?

Answer 4

1. Intrinsic mechanisms:
   Hepatic artery: autoregulation –> <MAP 60mmHg blood flow becomes pressure dependent

Portal vein: no autoregulation due to small amount of smooth muscle –> blood flow dependent on pressure gradient

2. Extrinsic mechanism: SNS activation –> vasoconstriction
   –> very important for effect on venous (capacitance) vessel (portal vein, hepatic vein, splanchnic veins etc.) –> large reservoir of blood that can be returned to circulation when vasoconstriction (venoconstriction) occurs

Question 5

What is the semi-reciprocal respone of the liver’s vasculature?

Answer 5

= hepatic arterial buffer esponse:

–> if portein vein blood flow falls –> hepatic arteries mainatian overall liver blood flow through adenosine-mediated vasodilation- BUT because portal vein has no autoregulation, if hepatic arterial blood flow falls the portal vein cannot compensate (–> semi-reciprocal)

Question 6

How does the respiratory cycle affect hepatic venous flow? What effect does PEEP have on hepatic venous blood flow?

Answer 6

Inspiration –> increased neagtive intrathoracic pressure –> increased hepatic venous blood flow
expiration –> positive intrathoracic pressure –> decreased hepatic venous blood flow

PPV: vice versa (as inspiration is positive pressure ventilation)
PEEP –> decreased hepatic venous blood flow

Question 7

How do changes in vCO2 affect portal vein flow?

Answer 7

hypocapnia –> reduced portal vein blood flow
hypercapnia –> increased portal vein blood fllw

Question 8

Describe the histological anatomy of the liver

Answer 8

hexagon-shaped lobules with a branch of the hepatic vein in the ventre
–> radiating out from the central vein are colums of hepatocytes and hepatic sinusoids
–> at each of the 6 corners of a lobule is a hepatic triad: hepatic arteriole, portal venule + bile duct

Question 9

Describe the functional anatomy of the liver

Answer 9

elliptical acinus with a terminal branch of the hepativ vein at either end, with 2 portal triad (hepatic artery, portal venule + bile duct) at the midpoint of the flattened sides

–> blood flows from the portal triad towards the terminal vein –> the further a hepatocyyte is away from the portal triad, the lower the O2 tension –> 3 zones:

Zone 1: closest to portal triad –> best oxygenated –> most energy-consuming processes (e.g. gluconeogenesis, b-oxidation of FA)

Zone 2: intermediate

Zone 3: furthest away from portal triad + closest to terminal vein –> lowest O2 tension –> least energy-consuming processes (glycolysis, drug metabolism)

Question 10

Describe the anatomy of the liver

Answer 10

• 4 lobes (left, right, quadrate, and caudate), 4 sublobes, and 2 processes

1. left lobe:
   –> largest: subdivided into LL + LM
   –> substantial cleft separates the two portions –> surgical access to the bases less technically demanding
   –> deep fissure also separates the LM from the Q lobe
2. quadrate lobe
   –> almost on the midline
   –> lateral aspect forms one side of the gallbladder fossa
   –> its attachment to the RM lobe is substantial –> surgical separation challenging
3. right lone
   –> RL + RM
   –> RL fused at its base with C lobe

Caudate lobe:
–> subdivided into the caudate and papillary processes
–> CP = most caudal part of the liver
–> PP extends toward the left side, crossing the midline

Question 11

What is the Pringle maneuver?

Answer 11

hepatic artery + portal vein lie ventral to the epiploic foramen:
–> bounded caudally by mesoduodenum
–> dorsally by the CVC
–> cranially by the liver

–> clamping the hepatoduodenal ligament, which contains the portal triad: Portal vein, hepatic artery + common bile duct –> Temporary inflow occlusion (occluding this site in cause of severe hepatic hemorrhage)

Question 12

What are the different cell types within the liver?

Answer 12

1. Hepatocytes (60%)
2. Kuppfer cells (10%)
3. Sinusoidal cells
4. Peri-sinusoidal cells
5. biliary epithelial cells

Question 13

Describe the liver’s anatomy on a cellular level

Answer 13

hepatocytes arranged in columns -> within columns are small chanenels = bile canaliculi: hepatocytes secrete bile into canaliculi –> bile ductules –> bile ducts –> merge and exit liver as common hepatic duct

hepatic sinusoids = blood filled spaces on either side of hepatocyte colums

Oxygenated blood flow from hepatic arteriole and portal venule –> hepatic vein

Sinusoidal epithelial cells have large fenestration + lack tight junctions –> highly permeable –> substances (nutrients, drugs, toxins etc.) are filtered to peri-sinusoidal spce –> contact with hepatocytes

Kuppfer cells = macrophages –> line walls of hepatic sinusoids –> destroy bacteria, virus, foreign material etc. comming from GIT + remove old RBCs + WBCs

Question 14

What zone incl. its functions is most affected by hypoxic injury?

Answer 14

Hypoxic injury –> centrilobular necrosis –> damage to zone 3: glyolysis, drug metabolism etc.

Question 15

What is the physiological reserve of the liver?

Answer 15

huge reserve –> if 80% is removet it can continue to carry out all functions + can also regenerate via active mitosis back to normal liver mass (in hepatic transplanation 50-60& of donor’s liver is removed –> grows back to normal size within 6-8w; in recipient it takes a bit longer)

Question 16

What are the 7 main functions of the liver

Answer 16

1. metabolic (carbohydrate, fat, protein)
2. exocrine (bile)
3. endocrine (hormones - synthesis, secretion, activation, inactivation)
4. immunological (Kuppfer cells: phagocytosis + cytokines, complement protein syntehsis + CRP)
5. synthetis (haemostatic, plasma-transport proteins, serine protease inhibitors)
6. hepatic clearance (drugs via modification, conjugation + excretion)
7. miscellaneous (storage of iron, copper + fat-solube vitamins, eryhtropoiesis, blood reservoir)

Question 17

What are the metabolic functions of the liver?

Answer 17

• Carbohydrate metabolism
• fat metabolism
• protein metabolism

Question 18

How does the liver contribute to carbohydrate metabolism?

Answer 18

1. Glycolysis: Glucose –> pyruvate (ATP production)
2. Glycogenesis: Insulin stimulates Glucose –> Glycogen (via polymerization)
3. Glycogenolysis: Glucagon stimulates Glycogen –> Glucose
4. Gluconeogenesis: Glucagon stimulates AA, lactate, glycerol –> Glucose

Question 19

Describe the process of Glycolysis

Question 20

Describe the process of Glycogenesis

Question 21

Describe the process of Glycogenolysis

Question 22

Describe the process of Gluconeogenesis

Question 23

How does the liver contribute to fat metabolism?

Answer 23

1. Lipid breakdown via b-oxidation (mitochondria of hepatocytes) –> ATP production
2. Lipid synthesis: triglycerides + excess glucose; Cholesterol syntehsis
3. Lipid processing: Synthesis of Apolipoproteins –> important for packaging of cholesterol + tryglycerides (LDL, HDL, VLDL)

Question 24

What are 3 important functions of cholesterol?

Answer 24

1. part of cell membranes
2. precursor for steroid hormones
3. precursor for bile salt synthesis

Question 25

How does the liver contribute to protein metabolism?

Answer 25

1. Deamination: amino groups are removed from AA --> a keto acid --> ATP production via krebs cycle, transformation into different AA or substrate for gluconeogenesis 2. Urea formation: deamination of AA --> NH3 --> detoxification --> urea or glutamine 3. AA synthesis: Keta acids --> transamination --> non-essential AA 4. Protein synthesis: plasma proteins (exception: immunoglobulins + some hormones)

Question 26

What are the exocine functions of the liver?

Answer 26

Production of bile acids via oxidation of cholesterol, important for: 1. emulsification (surround dietary lipids + fat-soluble vitamins + breaking them down into smaller parts (micelles) so that pancreatic lipase can break them down Bile salts = Na+ and K+ salts of bile acids

Question 27

What are the main constituents of bile?

Answer 27

water, eletrolytes, bile salts, bilirubin, cholesterol, phospholipids

Question 28

What enzyme is important for the conjugation of bilirubin to glucuronic acid? What is the benefit of this process?

Answer 28

glucuronosyltransferase --> makes bilirubin more water-soluble, so that it can be excreted into the bile --> SI

Question 29

Describe the metabolism of bilirubin and the enterohepatic circulation

Answer 29

Question 30

Describe the mechanism leading to prehepatic jaundice

Answer 30

Increased RBC breakdown --> unconjugated bilirubin --> exceeds liver's capacity to conjucate --> high plasma concentrations of unconjugated (indirect) bilirubin

Question 31

Why is the urinary dipstick negative for bilirubin in prehepatic jaundice?

Answer 31

Increased RBC breakdown --> unconjugated bilirubin --> exceeds liver's capacity to conjucate --> high plasma concentrations of unconjugated (indirect) bilirubin Unconjugated bilirubin is water-insoluble --> can't be filtered in glomerulum --> accumulation in blood + no bilirubin in urine

Question 32

Describe the mechanism leading to posthepatic jaundice

Answer 32

Normal route of bilirubin excretion is blocked --> conjugated bilirubin enters systemic circulation (can be transported back into blood from hepatocytes via transporters; but can't be transported back from caniculi) --> urinary excretion

Question 33

Why is the urinary dipstick positive for bilirubin in prehepatic jaundice?

Answer 33

Normal route of bilirubin excretion is blocked --> conjugated bilirubin enters systemic circulation (can be transported back into blood from hepatocytes via transporters; but can't be transported back from caniculi) --> urinary excretion conjugated bilirubin is water-soluble --> can be filtered in the glomerulum --> urinary excretion

Question 34

Describe the mechanism leading to hepatic jaundice

Answer 34

Reduced ability to conjugate and excrete bilirubin --> wether there is more conjugated or unconjugated bilirubin depends on the relative degress of hepatocyte dysfunction compared to biliary duct disruption

Question 35

What are the endocrine functions of the liver?

Answer 35

1. Secretion of hormones: angiotensinogen, thrombopoietin, hepcidin, IGF-1 2. Synthesis of hormone binding proteins: thyroxine-binding globulin, sex hormone-binding globulin 3. Activation of hormones: T4 --> T3 or T4 --> reverse T3 (inactivated); Vitamin D --> 25-hydroxyvitamin D (calcidiol) 4. Inactivation of hormones: aldosterone, ADH, oestrogen, insulin (50% of produced insulin is released into the portal vein --> inactivated before it gets into sytemic circulation)

Question 36

What are the immunological functions of the liver?

Answer 36

1. Phagocytosis via Kuppfer cells (ingested bacteria, viruses, parasites from GIT) 2. Initiation of inflammation via cytokine production from Kuppfer cells 3. Synthesis of complement proteins + CRP

Question 37

Which substances are synthesised by the liver?

Answer 37

1. Haemostatic substances: FI, FII, FV, FVII, FVIX, FX, FXI, AT, protein C, protein S 2. plasma transport proteins: albumin, a-globulins (e.g. haptoglobin, thyroxine-binding globulin), b-globulins (transferrin, sex-hormone binding globulins), a1-acid glycoprotein (transports basic and neutrally charged drugs) 3. Serine protease inhibitors: a1-antitrypsing (protects body against enzymes like neutrophlie elastase)

Question 38

How does the liver metabolize drugs?

Answer 38

3 phases: 1. Modification: cytochrome P450 enzyme system within hepatocytes --> makes drug more polar + therefore more hydrophilic --> main reactoins here: oxidation, reduction, hydrolysis --> if not sufficiently water-soluble to be excreted, then --> phase 2: 2. Conjugation: attachment to a polar molecule which leads to production of water-soluble metabolites, that can then be excreted via bile or urine --> 3 mechanisms: --> glucuronidation: attached to glucuronic acid (less effective in cats) --> acetylation: attached to acetate --> sulphation: attached to sulphate 3. Excretion: ATP-dependent excretion into bile

Question 39

Which drugs induce hepatic enzymes?

Answer 39

1. Phenobarbital 2. rifampicin

Question 40

Which drugs inhibit hepatic enzymes?

Answer 40

1. omeprazole 2. allopurinol 3. erythromycin 4. cimetidine 5. ethanol 6. sulphonamides

Question 41

Why have cats a reduced glucuronidation cypacity?

Answer 41

Glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT) enzymes --> significant deficiency in certain UGT enzymes in cats (esp. UGT1A6, UGT2B) --> limited ability to glucuronidate many substances --> more susceptible to toxicity from drugs and substances that require glucuronidation for clearance (e.g. acetaminophen)

Question 42

What drug metabolism is reduced in neonates (dogs and cats)?

Answer 42

Sulphation

Question 43

Name 3 tests/parameters of liver function

Answer 43

1. Albumin --> half-life 8d --> marker of chronic liver dysfunction 2. PT --> depends on fibrinogen (FI), FII, FV, FVII + FX --> half-life of 24hr --> test of acute liver dysfunction 3. NH3 4. Bile acids ( ±stimulated BA)

Question 44

Name 2 tests of hepatic clearance

Answer 44

1. bilirubin 2. NH3: usually concerted to urea by liver --> NH3 is a small, uncharged, osmotically active moleculs that can pass BBB --> cerebral edema + HE NH3 levels do not correlate particularly well with severity of HE

Question 45

Name 3 hepatic enzyme tests and their location in the liver

Answer 45

1. ALT: cytosol of hepatocytes --> hepatocellular injury 2. ALP: biliary canaliculi membrane of hepatocytes --> disease of biliary system 3. GGT: hepatocytes surrounding biliary canaliculi --> disease of biliary system

Question 46

What are the 4 main ways hepatic dysfunction can manifest biochemically?

Answer 46

1. Decreased uptake or excretion of bilirubin + bile acids (high bilirubin + BA) 2. decreased uptake and conversion of ammonia to urea (low urea, high ammonia) 3. decreased synthetic capacity of liver (hypocholesteromemia, hypoglycemia, reduced clotting factors, recued anticoagulants) 4. reduced immunologic function (reduced clearance via Kuppfer cells --> increased systemic antigenic stimulation --> increase in immunoglobulins = polyclonal gammopathy)

Question 47

Where does bilirubin originate from?

Answer 47

Breakdown product of: 1. Hb 2. myoglobin 3. cytochromes

Question 48

How much of cholesterol is syntesised in the liver?

Answer 48

50%

Question 49

How does choelsterol affect RBCs?

Answer 49

Cholesterol is part of the RBC membrane: Hypocholesterolemia --> RBC membrane defects --> poikilocytes (e.g. acanthocytes), target vells + other different shapes on blood smear

Question 50

How does liver dysfunction cause hypoglycemia?

Answer 50

- reduced gluconeogenesis - reduced glycogen stores - delayed insulin clearence

Question 51

How much of the liver function needs to be lost for hypoglycemia to develop?

Answer 51

70%

Question 52

How much of the liver function needs to be lost for hypoalbumineia to develop?

Answer 52

66-80%

Question 53

What % of the whole protein syntehsis is the liver makes up albumin?

Answer 53

25%

Question 54

What is the half-life of albumin in dogs and cats?

Answer 54

8d

Question 55

What causes hypoalbuminemia in systemic inflammation?

Answer 55

Cytokine-mediated downregulation of albumin, protein C and transferrin production = negative acute phase proteins

Question 56

How many dogs with hepatic failure had a prolongation of their coagulation assays (PT + aPTT) and low fibrinogen?

Answer 56

PT + aPTT: 71% low fibrinogen: 75%

Question 57

What is the half-life of ALT? Where else might ALT be coming from?

Answer 57

dogs: 59hr cats: 2.8-4.4hr --> musculature

Question 58

Where is AST present? What is its half-life in dogs and cats?

Answer 58

liver, skeletal muscle, eryhtrocytes dog: 22hr cat: 78-99min

Question 59

What is the half-life of ALP in dogs and cats?

Answer 59

Depends on the isoenzyme, but liver ALP: Dog: 2-3 days (66 hours) Cat: 6hr

Question 60

Name 6 causes of intrahepatic choestasis

Answer 60

1. hepatocellular swelling: hepatic lipidosis, severe corticosteroid hepatopathy 2. cellular infiltrates: inflammation, neoplasia 3. solid tumors: e.g. cholangiocarcinoma 4. fibrosis around biliary system: chronic inflammation 5. choleliths, parasites (e.g. Fasciola hepatica) 6. bile sludging in canalicule (e.g. severe dehydration in cats)

Question 61

Name 5 causes of extrahepatic cholestasis

Answer 61

1. tumors: pancrea, biliary tract, duodenum 2. inflammation: e.g pancreatitis 3. fibrosis: secondary to recurrent pancreatitis 4. choleliths 5. gall bladder mucocoeles

Question 62

What is functional cholestasis?

Answer 62

= defects in the transporters needed for active transport of bile acids into the canaliculi = ATP-dependent --> excretion is rate-limiting step (often dependent on NA/K ATPase) --> drugs, hormones, cytokines, endotoxins etc. interfere with hepatocyte transporters responsible for bilirubin excretion (MRP2)

Question 63

What hepatocyte transporter is responsible for bilirubin excretion?

Answer 63

MRP2

Question 64

What causes hypokalemia in liver disease?

Answer 64

1. inadequate intake 2. vomiting 3. use of potassium-wasting diuretics for treatment of ascites 4. increased renal excretion due to respiratory alkalosis (if present)

Question 65

What causes hypophosphatemia in liver disease?

Answer 65

centrally induced hyperventilation --> hypocapnia --> shifting of CO2 from intra- to extracellular --> increased intracellular pH --> accerlated use of phosphate for phosphorylation of glucose --> hypophosphatemia

Question 66

How may hyperventilation cause hypophosphatemia?

Answer 66

hyperventilation --> hypocapnia --> shifting of CO2 from intra- to extracellular --> increased intracellular pH --> accerlated use of phosphate for phosphorylation of glucose --> hypophosphatemia

Question 67

What are the 3 isoenzymes of ALP in dogs?

Answer 67

liver bone steroid-induced

Question 68

How may cholestasis cause liver damage?

Answer 68

bile acids have emulsifying effect on cell membranes --> hepatocyte damage --> increased leakage of liver enzymes + unconjugated bilirubin

Question 69

What crystals may be present in liver disease in the urine?

Answer 69

ammonium biurate or urate

Question 70

Why do dogs have bilirubinura in health?

Answer 70

can conjugate bilirubin in small amounts in their renal tubules as well (males > females)

Question 71

Why is bilirubinuria always inappropriate in a cat?

Answer 71

1. cats can't conjugate bilirubin in their renal tubules (unlike dogs) 2. cats have a 9x higher threshold to reabsorb rather than eliminate bilirubin

Question 72

Which hepatocyte cotransporters are responsible for taking up substances from the blood into the hepatocytes (located on sinusoidal or basolateral side)?

Answer 72

1. Sodium taurocholate cotransporter: uptake of conjugated bile acids (80%) + unconjugated bile acids (50%) with Na+ --> driving force = basolateral NA/K ATPase 2. Organic anion transporting polypeptide family (OATP): uptake of unconjugated bile acids, bromshulphthalein, conjugated bilirubin + organic anions --> anion exchange with HCO3- + reduced gluthatione --> OATP can work in the opposite direction when these substances accumulate within the hepatocyte --> regurgitation of bila acids + conjugated bilirubin back into systemic circulation in times of cholestasis

Question 73

Which hepatocyte cotransporters are responsible for excreting substances from the hepatocyte cytoplasma into the blood (circulation)?

Answer 73

Multidrug resistance-associated proteins 3 + 4 (MRP3, MRP4): bile acid afflux from hepatocyte into blood (regurgitation) = protective mechanism against intracellular build up of bile acids (= toxic because the emulsify membranes)

Question 74

Which hepatocyte cotransporters are responsible for excreting substances from the hepatocyte into the biliary canaliculi?

Answer 74

1. Bile salt export pump (BSEP): Na+-independent transporter: excretes bile salts 2. Multidrug resistance-associated protein 2 (MRP2): excretes conjugated bilirubin, conjubated bile acids and organic acids --> bile-salt independent flow 3. Multidrug resistance-gene 1 (MDR1, P-glycoprotein): transports foreign substances (drugs), organic cations + cytotoxins into bile

Question 75

What is bile salt-dependent flow? Which transporter is the principal force for bile salt-dependent bile flow?

Answer 75

bile salts are osmotically active + create a concentration gradien, which water follows = bile-salt dependent flow Bile salt export pump (BSEP)

Question 76

What is bile salt-independent flow? Which transporter is the principal force for bile salt-independent bile flow?

Answer 76

Stimulation of HCO3-/Cl- exchanger leads to transport of HCO3- into the bale --> water follows --> bile salt-independent flow Multidrug resistance-associated protein 2 (MRP2)

Question 77

Why is bile fluidy in the biliary canaliculi system?

Answer 77

bile salts are osmotically active + create a concentration gradien, which water follows = bile-salt dependent flow

Question 78

What can cause defects in the hepatocyte transporter system?

Answer 78

1. Extrahepatic cholestasis: downregulation of transporters on canalicular site + OATP --> increased intracellular accumulation 2. Endotoxins + inflammatory cytokines: downregulation of Ntcp, BSEP + MRP2

Question 79

What causes hypercholesterolemia in cholestasis?

Answer 79

1. decerased clearance of cholesterol in bile 2. increasd production of cholesterol-rich lipoproteins 3. decreased lipoprotein clearance