Hepatic Physiology Flashcards
Liver Functions
Removes potentially toxic byproducts of certain medications
Metabolizes or breaks down nutrients from food to produce energy when needed
Helps body fight infection by removing bacteria from the blood
Prevents nutrient shortages by storing vitamins, minerals, and sugar
Produces most proteins needed by the body
Produces bile a compound necessary to digest fat and absorb vitamins A/D/E/K
Produces clotting factors
How many lobules in the liver?
50,000-10,000
Liver Lobule Structures
HEXAGON CYLINDER Portal vein Sinusoids (capillaries) Central vein Hepatic artery Bile canaliculi & bile duct Space of disse & lymphatic duct Hepatic cellular plates Kupffer cells (macrophages) Interlobular septa
Lymph Production
20mL lymph/day
50% liver
Hepatic Blood Flow
Liver receives its blood supply from the portal vein and hepatic artery
≈ 1,500mL/min (25-30% CO)
8-9 seconds blood to traverse from portal vein to the central vein; promotes sufficient time blood in contact with hepatocytes & Kupffer cells
Portal Vein
Brings blood from the intestines
Supplies 50-55% liver O2 requirement
SaO2 85%
≈ 1,100mL/min (70-75%)
Blood flow dependent on GI tract & spleen (ΔP upstream blood flow)
α1 adrenergic & D1 dopaminergic receptors
Hepatic Artery
Brings fresh blood from the heart Supplies 45-50% liver O2 requirement SaO2 98-100% ≈ 400mL/min (25-30%) Blood flow dependent on metabolic demand Autoregulation α1 β2 adrenergic, D1 dopaminergic, & cholinergic receptors
Portal Vein Pressure
Average 9mmHg
Hepatic Vein Pressure
Average 0mmHg leaving the liver & entering inferior vena cava
Resistance
LOW Δ P / Q 9mmHg / 1,500mL/min ≈ 6mmHg/L/min Cirrhosis ↑resistance to blood flow - Destruction liver parenchymal cells → fibrous tissue that contracts around the blood vessels (bridging fibrosis impedes portal vein blood flow)
Liver Disease Stages
Alcohol-Induced
Fatty liver → fibrosis → cirrhosis
Fat deposits cause liver enlargement; strict abstinence can lead to full recovery
Scar tissue forms; recovery possible but scar tissue remains
Connective tissue growth destroys liver cells; irreversible damage
Cirrhosis CAUSES
Most common = alcoholism Viral hepatitis A/B/C Bile ducts obstruction Bile ducts infection Poison ingestion (Carbon tetrachloride CCl4 - dry cleaning) Non-alcoholic fatty liver disease
Alcoholic Fatty Liver
Lipid deposits w/in hepatocytes
Repeat exposure to toxins can directly lead to fibrosis & cirrhosis
Micronodular cirrhosis - non-functioning liver cells
Non-Alcoholic Fatty Liver Disease
NAFLD
Non-Alcoholic Steatohepatitis
NASH
SNS Activation →
Hepatic artery & mesenteric vessel vasoconstriction ↓hepatic blood flow
Vascular Functions
Blood Reservoir
EXPANDABLE organ
Able to store large quantities of blood in hepatic vessels
Normal liver blood volume ≈ 450mL
Liver expands in response to ↑R atrium pressure → back pressure
0.5-1L blood storage in hepatic veins & sinusoids (commonly occurs w/ CHF)
Low pressure (ex: hemorrhage) blood shifts from hepatic veins & sinusoids into the central circulation as much as 300mL (blood “donation”)
Vascular Functions
Blood Cleansing
Portal vein blood +bacteria
Hepatic macrophages - Kupffer cells
Kupffer cells line hepatic venous sinusoids cleanse the blood
- Phagocytose debris, viruses, proteins, & particulate matter
- Release enzymes, cytokines, & other chemical mediators
Monocyte-macrophage system aka reticuloendothelial system
Vascular Functions
Lymph Flow
Sinusoid pores = extremely permeable & allow easy fluid & protein passage into the spaces of Disse
↑3-7mmHg above normal hepatic venous pressure results in excessive amounts lymph fluid → back-up
Lymph fluid leaks through outer liver capsule surface into the abdominal cavity
↑10-15mmHg hepatic venous pressure ↑lymph flow 20x normal → “sweating” from the liver surface w/ large amounts free fluid entering abdominal cavity = ascites
Portal vein blockage ↑GI tract pressure w/ fluid transudation via gut into the abdominal cavity = ascites
Metabolic Functions
Carbohydrate Metabolism
Glucose metabolism
All cells utilize glucose to produce ATP energy
Glycogen storage
When glycogen storage at max capacity glucose converted to fat
Insulin enhances glycogen storage
Epi & glucagon enhance glycogen breakdown (glycogenolysis)
Hepatic glycogen stores depleted after 24hr fast
Gluconeogenesis (↓glucose → new glucose released from fat breakdown)
Able to convert amino acids, glycerol, pyruvate, & lactate to glucose (all compounds contain carbon)
↑Gluconeogenesis
Glucocorticoids
Catecholamines
Glucagon
Thyroid hormone
↓Gluconeogenesis
Insulin
Metabolic Functions
Fat Metabolism
When carbohydrate storage capacity saturated, the liver converts excess CHOs ingested into fat
Fatty acids used as fuel or stored in the adipose & liver (triglycerides)
Able to used fatty acids directly as energy source
- Fatty acid oxidation to supply energy (derive energy from triglycerides via β oxidation)
- Synthesis of large amounts cholesterol, phospholipids, & lipoproteins
80% cholesterol converted to bile salts & secreted into bile (emulsifies fat) - Fat synthesis from CHO & proteins
After fat synthesized transported in lipoproteins to adipose tissue to be stored
Metabolic Functions
Protein Metabolism
CRITICAL LIVER FUNCTION w/o protein metabolism death will occur w/in days
- Protein deamination - required to utilize energy or before converted to carbohydrates or fats
- Urea formation to remove ammonia from body fluids - w/o urea ammonia plasma concentration will rapidly rise → hepatic coma → death
- Plasma protein formation 90% 15-50g/day - Albumin, α1 antitrypsin, coagulation factors
- Amino acid synthesis & other compound synthesis from amino acids - transamination
Metabolic Functions
Drug Metabolism
Hepatic biotransformation - end products are inactivated or ↑H2O solubility to excrete via urine or bile
Phase 1: CYP450 90% oxidation & reduction (hydrolysis, hydration, dehalogenation)
Phase 2: Conjugation (sulfation, glucoronidation, glutathione conjugation, acetylation, amino acid conjugation, methylation)
CYP450 Induction
Ethanol (alcohol), barbiturates, ketamine, benzodiazepines
↑enzyme production that metabolizes drugs
Enzyme induction → tolerance & cross-tolerance
CYP450 Inhibition
Ranitidine, Amiodarone, & Ciprofloxacin
Prolong other drug effects via CYP450 inhibition
Phase 1 Cytotoxic
Phase 1 reaction products may be more active than the parent compound or rendered cytotoxic
- Acetaminophen → glutathione
- Isoniazid
- Halothane (hepatitis)
Drugs Dependent on Hepatic Blood Flow
Lidocaine, Morphine, Verapamil, Labetalol, & Propranolol high rate hepatic extraction from circulation
↓metabolic clearance typically d/t ↓hepatic blood flow NOT hepatocyte dysfunction
Normal Lidocaine Metabolism
1st pass pulmonary effect
Half-life = 1.8hr
Vd = 1.32L/kg
Clearance = 10mL/kg/min
Liver disease ↑half-life ↑Vd ↓clearance
Phase 2 Reactions
May or may not follow Phase 1 reaction
Substance conjugation w/ H2O soluble metabolite
Most common = glucuronide (large, charged molecule) → polar & water-soluble
Sulfate, taurine, glycine
Conjugated substances are then excreted via urine or bile
Metabolic Functions
MISCELLANEOUS
Vitamin storage site - A, B12, D, E, & K
Fe storage as Ferritin
Coagulation factors - vitamin K required cofactor to synthesis Factors II (prothrombin), VII, IX, & X
Primary degradation site thyroid hormone, insulin, steroid hormones, glucagon, & ADH
Bile Formation
Hepatocytes continuously secrete bile salts, cholesterol, phospholipids, & conjugated bilirubin into the bile canaliculi
Bile ducts form L & R hepatic ducts → hepatic duct → cystic duct → common bile duct
Flow via the common bile duct controlled by Sphincter of Oddi
Gallbladder = bile reservoir
Cholecystokinin - hormone released from intestinal mucosa in response to fat & protein that causes gallbladder contraction, Sphincter of Oddi relaxation, & bile ejection into the small intestine
Bilirubin
Hgb degradation → bilirubin
Excreted into the bile & eliminated via feces
Hemoglobin →
Globin + Heme
Heme →
Fe + Pyrrole rings
Pyrrole Rings →
Biliverdin
Biliverdin →
Free bilirubin
Free Bilirubin →
Bilirubin + Albumin
Unconjugated or indirect bilirubin
Absorbed via hepatocytes & released from Albumin
Bilirubin then conjugated w/ glucuronide & sulfate
Conjugated Bilirubin
Direct bilirubin = TOXIC
Excreted from hepatocytes via active transport process into bile canaliculi & then into intestines
Hemoglobin BINDING
O2 binds to Fe
CO2 binds to Nitrogen
Carbon monoxide preferentially binds to Fe (kicks off oxygen)
- Treatment = hyperbaric chamber ↑atmospheric pressure to drive off CO
Jaundice
Excess bilirubin in the ECF
Total bilirubin >3mg/dL
- Unconjugated or conjugated
Common causes: ↑RBC destruction (hemolytic), bile duct obstruction, or damage to hepatocytes preventing excretion into GI tract (obstructive)
Hemolytic Jaundice
RBCs rapidly hemolyzed
↑bilirubin production ↑unconjugated bilirubin (free/indirect) hepatocytes unable to process (conjugate) d/t overwhelmed
1° ↑unconjugated bilirubin
2° ↑conjugated (direct) bilirubin
Normal excretion
↑urobilinogen formation & urinary excretion
Obstructive Jaundice
Most often d/t common bile duct obstruction (i.e. gallstone or malignancy)
Also caused by damage to hepatic cells (hepatitis - hepatocyte inflammation)
Normal conjugated bilirubin formation but unable to pass from the liver to intestines
Conjugated bilirubin enters blood d/t back-up → rupture bile canaliculi & directly emptying bile into the lymph system
1° plasma bilirubin = conjugated form
↑conjugated (direct) bilirubin
TOTAL obstruction - NO conjugated bilirubin able to reach intestines to be converted into urobilinogen ჻ no urobilinogen reabsorbed into blood & excreted via kidneys → urobilinogen urine test = completely negative
Liver Function Tests
Not sensitive or specific Liver synthetic function: - Serum albumin - Prothrombin time (PT or INR) - Cholesterol - Pseudocholinesterase Large functional reserve ჻ lab tests may be NORMAL in present cirrhosis Parenchymal (hepatocellular dysfunction) vs. obstructive (biliary excretion) disorders
Serum Bilirubin
Total 0.3-1.1 (<1.5mg/dL) reflects balance b/w production & biliary excretion
Unconjugated 0.2-0.7
Conjugated 0.1-0.4 TOXIC
Serum Aminotransferases (Transaminases)
Measurements reflect hepatocellular integrity
Aspartate aminotransferase AST 10-40u/mL
Non-specific (heart, skeletal muscle, kidneys)
Alanine aminotransferase ALT 5-35u/mL
More specific primarily located in the liver
Mild elevations >300iu/L (cholestasis or metastatic disease)
Absolute levels poorly correlated w/ hepatic injury degree in chronic liver disease
Absolute levels in acute liver disease - drug overdose, ischemic injury, or fulminant hepatitis
Serum Alkaline Phosphatase
10-30u/mL
Alkaline phosphatase produced by liver, bone, small bowel, kidneys, & placenta
Excreted via bile
1° circulating comes from bone
Biliary obstruction Alk Phos synthesized & released into circulation
2x normal elevation associated with hepatocellular injury (blockage) or hepatic metastatic disease
↑elevations indicate intrahepatic cholestasis or biliary obstruction
Serum Albumin
Synthetic function
3.5-5.5g/dL
Long half-life (20 days)
Value initially normal in acute liver disease
Serum albumin <2.5 generally indicates chronic liver disease, acute stress, or malnutrition
Hypoalbuminemia also occurs d/t ↑albumin loss via urine (nephrotic syndrome) or GI tract (enteropathy w/ protein loss)
Blood Ammonia
Normal NH3 47-65mmol/L (80-110mg/dL)
↑NH3 reflects hepatic urea synthesis disruption
Marked elevations usually severe hepatocellular damage → hepatic encephalopathy
Ammonium = NH4
Prothrombin Time
12-14sec
PT >3-4sec as compared to control = significant
Corresponds to INR 1.5 (international normalized ratio)
Measures fibrinogen, prothrombin (factor II), factor V, VII, & X
Factor VII short half-life therefore PT useful to evaluate hepatic synthetic function in patients w/ acute or chronic liver disease
Pre-Hepatic
Bilirubin overload
↑unconjugated bilirubin
No change: AST/ALT, alk phos, PT, albumin
Causes: 1° hemolysis, hematoma reabsorption, bilirubin overload (whole blood transfusion)
Intra-Hepatic
Parenchymal/hepatocellular dysfunction
↑conjugated bilirubin
Markedly ↑AST/ALT
No change alk phos (slight ↑ w/ disease progression/duration)
Prolonged PT
↓albumin
Causes: Hepatitis, drugs, sepsis, arterial hypoxemia, CHF, cirrhosis
Post-Hepatic
Cholestasis ↑conjugated bilirubin Normal to slightly ↑ AST/ALT Markedly ↑alk phos No change to prolonged PT No change to ↓ albumin Causes: Cancer, stones, sepsis → inflammation
Anesthesia Effects on Hepatic Function
↓hepatic blood flow (direct & indirect)
Overventilation → vasoconstriction
Anesthetic drugs α1 adrenergic agonist, β adrenergic blockers, vasopressin
Endocrine stress response ↑catecholamines, glucagon, cortisol (response blunted d/t anesthesia)
Carbohydrate & protein stores are mobilized → hyperglycemia & negative nitrogen balance
Opioids cause Sphincter of Oddi spasm ↑biliary pressure
Mild postop liver dysfunction d/t ↓hepatic blood flow, SNS stimulation, & surgical procedure
Most common cause postop jaundice = bilirubin over-production d/t large hematoma reabsorption & RBC breakdown following transfusion
Halothane hepatitis - Methoxyflurane, Enflurane, Isoflurane (typically after second exposure w/in 28 days)
Anesthetic Agent Metabolism
Halothane 20% Enflurane 2.5% Sevoflurane 1% Isoflurane 0.2% Desflurane 0.02%
