The Liver Flashcards
Liver Anatomy
- Largest gland in the body: 1-4% total body weight
- 4 main lobes: L (medial, lateral), R (medial, lateral), quadrate, caudate
- Each lobe: own arterial supply, venous drainage, biliary system
Biliary System
GB: absent in horses, rats
Bile duct terminates in duodenum of dog, bovine
Others share common bile ducts with pancreas: cats, horses, SR
Brief Summary Species Differences
–SA: left, right divided into medial, lateral; enlarged caudate lobe that contacts R kidney
–Equine: left divided, entirely within ribcage
–Porcine: deep interlobular fissures (4 lobes - R, L, M, lat) + small caudate lobe that does not contact R kidney
–Bovine: fused lobes, R of midline
–SR: two papillary processes, deeper umbilical fissure
Portal Triad
hepatic arteriole, portal venule, bile duct – define perimeter of lobule
hepatocytes radiate outward from central vein
Hepatic Blood Supply
Portal vein/circulation: receives blood from GIT, supplies majority of blood flow to liver
Hepatic Artery = second blood supply
Portal veins: low PO2, provides O2 DT large volume
Hepatic Blood Flow
Hepatic artery blood enters sinusoid directly or through peribiliary capillary plexus, mixes with portal venous blood in low‐pressure sinusoid microvasculature
Blood from gut, spleen, pancreas –> portal vein –> liver sinusoids –> hepatic vein (central vein) –> cava
Three zones sinusoidal hepatocytes?
Zone 1 = peritubular
Zone 2 = transitional
Zone 3 = centrolobular
Zone 1
peritubular, largest amt of mitochondria/site of most oxidative processes
* Most oxygen
Zone 2
Transitional Zone
Zone 3
centrolobular, large amount of smooth ER/microsomal enzyme activity
* Major role in metabolism
* Least oxygen
Consequences of increased pressure through portal system?
o Increased pressure through portal system –> neovascularization, acquired shunts
MOA Maintenance of Low Portal Pressures
Low basal resistance
Distensible pre, post sinusoid resistance sites
Highly compliant hepatic vasculature
Hepatic artery buffer response (HABR)
HABR
Hepatic artery buffer response (HABR): accumulation of adenosine when blood slows, causes vasodilation of hepatic artery
Blood Supply
o **Receives 20-30% CO, ~12% total blood volume received at any given time **
Portal vein: provides 75% blood flow, relatively low oxygen saturation (from GIT)
Large volume of blood, importance oxygen source for hepatic tissue
Hepatic artery: 25% blood flow
Helps sustain hepatocellular function (majority O2)
Blood enters, mixes with portal blood – sinusoidal delivery or via peribiliary capillary plexus
Regulation of HBF largely depends on preportal factors affecting portal vein BF
What are the 6 reflexes involved in maintenance of HBF autoregulation?
- Pressure flow regulation
- Hepatic artery buffer response
- Hepatorenal reflex
- Metabolic control
- Vascular Escape
- Reduced portal vein pressure (arteries dilate to compensate)
Pressure Flow Regulation
drop in intrahepatic pressure causes liver to expel up to 50% blood volume to increase CO
Hepatorenal reflex
hypotension sensed in liver –> renin release from kidney, angiotensinogen I from liver
Metabolic Control of HBF
high CO2, low O2 increase arterial blood flow
* Hypercapnia = vasodilation
Vascular Escape
arterial VC from SNS stimulation opposed by NO, adenosine release, arterial dilation
Causes Increased HBF
Post prandial, glucagon
Beta agonists
Hypercapnia
P450 enzyme induction (barbiturates)
Hepatitis
Causes Decreased HBF
Upper abdominal sx
Beta blockade, alpha 1 agonism
Hypocapnia, hypoxia
P450 inhibition (H2 blockers)
Cirrhosis
IPPV/PEEP
Function: protein synthesis
Albumin: major contributor to plasma oncotic pressure, transport, binding
Globulins: 75-90% alpha, 50% beta, Immunoglobulin synthesis = endocrine function
Coag Factors:
▪ Fibrinogen
▪ Prothrombin (FII)
▪ Factors V, VII, IX, X, XI, XII, XIII
▪ Prekallikrein
▪ High molecular weight kininogen
▪ Plasminogen
▪ Plasminogen activator inhibitor -1
▪ Alpha 2 antiplasmin
▪ Antithrombin
▪ Protein C/S
▪ Performs vitamin K dependent carboxylation of 2, 7, 9, 10, protein C/S
Metabolism
Carbohydrates: gluconeogenesis, glucose oxidation
Glycogenesis, glycogenolysis, glycogen store
Lipids: lipogenesis, lipolysis, FA oxidation
Ketogenesis, cholesterol/TG synthesis and breakdown
Lipoprotein synthesis, breakdown
Vitamin absorption, storage, activation
Detoxification, Excretion of Waste Products/Xenobiotics
o Synthesis, degradation of amino acids
o Conversion of ammonia to urea
o Filtration, storage of blood – iron, copper, RBC storage
o Bile acids, bilirubin metabolism
First Pass Metabolism
reduces concentration esp after enteral administration, ultimately decreases bioavailability/amt available to systemic circulation
Phase I Metabolism
introduces polar groups to drugs, typically inactivates but sometimes activates pro drug
Conversation of relatively lipophilic compounds into hydrophilic metabolites = Oxidation, reduction, hydrolysis
CYP450
Induction of CYP450
pentobarb, phenobarb, barbiturates, dexamethasone, omeprazole, rifampin, tramadol
Inhibition of CYP450
diltiazem, amiodarone, erythromycin, ketoconazole, itraconazole, omeprazole, ranitidine
Phase II Metabolism
CYSTOL
conjugation, further hydrophilicity to facilitate drug excretion
Primary mechanism: glucuronidation
* Cats: reduced ability to form glucuronide conjugates DT limited glucuronyl transferases
Role of Kupffer Cells
bacteria, toxins in portal circulation processed by phagocytic Kupffer cells
Hepatic Fetal Circulation
- Oxygenated blood travels from placenta via umbilical vein
- Mostly bypasses liver via ductus venosus
o Closes early in horses, pigs - Flow of blood controlled by sphincter –> enables proportion traveling to heart via liver to be altered
- Closure of DV becomes permanent at 2-3 weeks, remnants form ligamentum venosum
Abnormalities Present with liver dysfunction?
Low serum albumin, glucose, BUN usually present in liver dysfunction +/- coat factors, globulins
ALT
Liver specific cytosolic enzyme – hepatocellular injury in dogs, cats
▪ NOT good indicator of liver dz in LA
o Small amt in kidney, heart, muscle
ALT Increases
- Anticonvulsants, CS in dogs
- Primary, secondary hepatic dz with altered cell permeability (inflammation), necrosis +/- EDO DT toxic effects of retained bile salts on hepatocytes
- Muscle injury in LA (main source in horses = SkM)
- Hyperthyroid cats
AST
Cytosolic enzyme in wide variety of tissues: muscle, heart, kidney, brain, plasma
▪ Indicator for liver +/- muscle injury in LA, SA
▪ Not organ specific: SkM > liver > CaM
Increased AST with normal CK suggestive of hepatic insult
AST Increases
Myopathies – muscle trauma/prolonged recumbency, vitamin E/selenium deficiency, infectious myositis
● Persist for longer than increases in CK activity
Liver dz: similar to ALT, levels not as high as muscle damage
● More sensitive marker of liver dz injury in cats
Mildly increased in hyperthyroid cats
ALP
Produced by bile duct endothelium – BDO increases production, cholestatic marker
▪ Cats: specific indicator of liver dz
▪ Cholestasis in dogs, increases before bilirubin
▪ Less utility in large
Also produced in bone, kidney, intestines, placenta – multiple isoforms
Physiologic ALP Elevations
▪ Age: higher in younger, growing animals, decrease ~3mo, normalize by 15mo – bone isoform, colostrum
▪ Siberian Huskies (familial, benign)
▪ Endogenous corticosteroid release from chronic stress
Drug Related ALP Elevations
▪ Dogs only: Glucocorticoids induce production of isoenzyme of ALP
▪ L-ALP induced by anticonvulsants (pheno, pentobarb), steroids
Pathophysiologic Increases ALP
▪ Hepatobiliary dz in SA – structural cholestasis (extra or intrahepatic), functional cholestatsis
▪ Neoplasia (DT localized cholestasis), non-hepatic neoplasia
▪ Acute hepatocellular injury
▪ Dogs: hyperadrenocorticism
▪ Increased non-neoplastic osteoblastic activity
Sorbitol Dehydrogenase
Cytoplasmic enzyme with highest concentrations in liver, specific indicator of liver dz in all species – indicative of hepatocyte damage
▪ Enzyme of choice for detecting hepatocellular injury in horses, cattle
GGT
o Transmembrane protein, expression restricted to luminal surface
o Increased with bile flow impairment
o Many non hepatic sources: lung, kidney, spleen, intestines, muscle, RBC, mammary gland, repro tract
GGT Increases Assoc with Drugs
increase with steroids in dogs
GGT Physiologic Increases
▪ Neonates – colostrum, sensitive indicator of passive transfer in cattle
▪ Some donkeys, burros have 2-3x GGT of horses
GGT Pathophysiologic Increases
Secondary to biliary hyperplasia - release secondary to damage/necrosis of biliary epithelial cells
SA: sensitive indicator of biliary hyperplasia, structural cholestasis
LA: biliary hyperplasia, structural cholestasis
● Elevated with GI issues, primary liver dz in horses, high GGT syndrome in race horses
Renal injury: expression on membrane of proximal renal tubular epithelial cells, cell injury cases GGT to be shed into urine (not blood)
Hyperadrenocorticism in dogs
Serum Bilirubin
o Ability of hepatocyte to take up unconjugated bilirubin in blood, conjugate it (render it water soluble), excrete into bile – broken down in GIT by bacteria
o Used primarily as a marker of liver dz, supportive evidence of hemolytic anemia
Unconjugated/Indirect Bilirubin
Bound to albumin, dominant form of total bilirubin in blood
Produced in macrophages from breakdown of heme groups (porphyrin ring)
● Normal metabolism or intravascular/extravascular hemolysis
Non-RBC sources ~20% unconjugated bilirubin
Water insoluble DT hydrogen bonds btw hydrophilic groups
What is the rate limiting step with bilirubin conjugation?
excretion into biliary canaliculi
Conjugated/Direct Bilirubin
▪ Renders bilirubin water soluble, normally excreted into bile
● Bile salts form micelles facilitating fat absorption
● Urobilinogen: conjugated bilirubin reduced by bacteria, intestinal enzymes – resorbed, broken down
▪ Form in urine – normal finding in dogs, ferrets
▪ Can pass through glomerular filtration barrier, increase in conjugated bilirubin in blood rapidly spills into urine
DDx Increased Total Bilirubin
▪ Horses: fasting, off feed
▪ Neonates, esp foals
▪ Anorexia – horses, cattle
▪ Hemolytic anemia
▪ Liver disease
▪ Cholestasis
▪ Inherited: some sheep, monkeys, rats
Bile Acids
▪ Steroids synthesized by hepatocytes from cholesterol, excreted into bile
▪ Emulsify fat in intestine, facilitate nutrient absorption – highly conserved
▪ Increased with:
● Hepatocellular dysfunction
● Abnormal portal flow
● Cholestasis
Changes in albumin levels
~80% loss of hepatic function
Ammonia
▪ Produced from dietary amino acids, catabolism of amino acids, amines, nucleic acids, glutamine, glutamate in peripheral tissues
▪ Converted in liver via urea cycle to urea, excreted into GIT and urine
Ddx Increased Ammonia
● Physiologic following high protein means, strenuous exercise
● Decreased uptake of ammonia DT abnormalities in hepatic portal blood flow, hepatic dysfunction
● Decreased conversion to urea: hepatic dysfunction/abnormal blood flow, inherited disorders in urea cycle, lack or decreased availability of urea cycle
● Increased ammonia production
Cholesterol
▪ Most common steroid in body – precursor of cholesterol esters, bile acids, steroid hormones
DDX increased cholesterol
● Increased numbers of cholesterol-rich lipoproteins
● Iatrogenic following exogenous corticosteroids in fasted dogs, cats
● Nephrotic syndrome
● Hypothyroidism
● Cholestasis – normally excreted in bile
● DM
● Hyperadrenocorticism – peripheral insulin resistance
● Pancreatitis
● Excessive negative energy balance
● Inherited lipid metabolism disorders
Ddx decreased cholesterol
● Decreased production, absorption, genetic defect
● Altered metabolism
● Increased uptake lipoproteins
Main Keys for Anesthetizing Liver Patients
Mentation: animals with liver dz may be obtunded (HE) – reversible agents, lower doses, potential for increased context-sensitive half life
ACP
negative effects on platelet aggregation in potentially coagulopathic patient, may increase HBF, vasodilation/hypotension; 99% protein bound
BZD
Advanced liver dz: potential to cause HE DT accumulation of ammonia, NMDA hyperactivity, decreased ATP
Benzos may aggravate – contraindicated in HE
Flumazenil may minimize
Induction Agents
–Only TP avoided
–Ket: decreases HBF/DO2, primarily hepatic metabolism - caution when conduction with benzos
–Propofol: extra hepatic metabolism, maintains HBF
–Etomidate: decreased HBF, DO2 - esterase metabolism
Inhalants
o Impairs autoregulatory functions, alteration of HBF in dose-dependent manner
Decrease in HBF decreased DO2, exacerbated with hypotension
PPV: decrease VR, especially in hypovolemic patients
o Decreased drug clearance, hepatocellular damage
Halothane
HEPATOTOXIC
Ascites
Negative Prognostic indicator with liver dz
Anesthetic Concerns Assoc with Liver Dz
o HE: high concentrations of endogenous benzodiazepine receptor agonists, uniquely sensitive to drugs that exert action on GABA receptors
o Hypokalemia
o Hypoglycemia
o Hypoalbuminemia
o Ascites
o Coagulopathy
o Hypotension
o Impaired drug metabolism
US-Guided BX under sedation
o Ideal to have reversible protocol: benzos +/- opioids +/- a2s
o Monitoring, flow by oxygen important
o Vasovagal hypotension reported after cutaneous liver bx
o Bleeding = risk, should be monitoring
Cholecystectomy, EHBDO
o High morbidity and mortality
o Creatinine, low blood pressure associated with mortality
▪ Especially with pancreatitis and bile peritonitis
o Often hypercoagulable
o Dogs with Cushings often predisposed
Hepatic Neoplasia
o Hemorrhage = concern, consider blood typing/cross matching
o Decisions to transfuse based on several factors: HCT, speed/amt of blood loss, hemodynamic stability
o Venous return should be evaluated: CVP, ABP waveform
o Hepatocellular carcinoma
▪ Increases in ALT/AST negative prognostic indicator
▪ Coagulopathies can complicate
PSS
Anomalous vessels flowing from portal circulation without passing through liver
▪ No liver metabolism when bypassing liver
o Non-specific signs: hypoglycemia, low albumin, coagulopathies, altered drug response
HE, seizures seen with PSS
▪ Humans: flumaz may improve mental status DT intrinsic BDZ like compounds
o CRP may be elevated: supports involvement of inflammatory process
Interventional Radiology
o Must ensure complete immobilization during coil placement for PSS
▪ NMBA: Atricurium or cisatricurium often used
▪ Inspiratory hold may be used as well
o Patients may be hypothermic
o Monitor ABP, CVP; support with IV fluids and inotropes
LAs
Amides: directly metabolized by liver, potential for prolonged effect
Opioids
Humans: morphine causes spasm of sphincter of Oddi, increases pressure in gallbladder - not demonstrated in veterinary patients
o May take longer to metabolize opioids vs healthy patients, analgesic intervals altered
o Remifentanil: plasma esterase hydrolysis, rapid elimination, short context sensitive half life
NSAIDS
All have potential to cause hepatic injury
▪ Intrinsically – aspirin, acetaminophen
▪ Idiosyncratic – Particularly Cox2 selective, unpredictable- not dose related
Unknown if administration safe in patients with preexisting hepatic disease
▪ May also impair coagulation and hemostasis
o Should be avoided or closely monitored
