liver

largest solid internal organ; RUQ; 2.5% of body weight and approximately 25% of cardiac output

hepatocytes, sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, cholangiocytes

major cell types of the liver

glucose regulation, protein synthesis, immune surveillance, drug and toxin metabolism, hormone regulation, bile acid synthesis and secretion

key functions of the liver

hepatic artery

25% oxygen rich

portal vein

75% nutrient rich, oxygen poor

portal

gateway between intestine and systemic blood

space of disse

contains stellate cells and lymph drainage

hepatic artery and portal vein -> sinusoids -> central vein -> hepatic veins -> inferior vena cava

hepatic blood flow pathway

basolateral surface

faces sinusoids/blood

apical surface

faces bile canaliculi

tight junctions

prevents bile leakage

smooth ER

detoxification and metabolism

rough ER

protein synthesis

mitochondria

high ATP demand

stored glycogen, iron, B12, and lipids

additional functions of the liver

Kupffer cells

resident macrophages

stellate cells

quiescent vitamin A storage; activated after injury, deposit collagen, fibrosis/cirrhosis

glycogenesis

stores glucose as glycogen

glycogenolysis

releases glucose during fasting

gluconeogenesis

synthesize glucose from amino acids and other precursors

lipids

convert excess glucose -> triglycerides -> VLDL; produce cholesterol, uptake of LDL, synthesis of HDL

cholesterol

produced for membranes, hormones, vitamins, and bile acids

HDL

synthesized for reverse cholesterol transport

amino acids

metabolized for gluconeogenesis substrate supply; synthesize proteins, breakdown plasma and metabolic proteins

plasma proteins (albumin), coagulation factors, complement proteins, carrier proteins, antioxidants and regulatory proteins, thrombopoietin

major hepatic protein products

water, bile salts, phospholipids, bilirubin, excreted toxins

what makes up bile composition

hepatocytes

location for bile synthesis

cystic duct of gallbladder

storage of bile

toxic ammonia -> water soluble urea

ammonia detoxification process

hepatic encephalopathy

result of hyperammonemia

lactulose

reduces pH and ammonia absorption, increases stool nitrogen excretion

reduce neurotoxicity

goal of managing hyperammonemia

heme -> biliverdin -> UBil + albumin -> liver -> conjugated with glucuronide -> excreted in bile

bilirubin metabolism

albumin

bound to UBili to transport to liver

glucuronide

essential for conjugation and excretion of bili

urobilinogen

gives stool its brown color

hemolysis

increased unconjugated bilirubin cause

bile duct obstruction

increased conjugated bilirubin cause

liver failure

increased conjugated and unconjugated bilirubin cause

cytochrome P450

phase 1 drug metabolism enzyme

phase 1 drug metabolism

oxidation reduction and hydrolysis; may activate prodrugs or create toxic metabolites

phase 2 drug metabolism

conjugation with glucuronic acid, sulfate, acetyl groups; increases water solubility (renal excretion); detoxification of previous intermediates

polymorphisms

fast vs slow metabolizers

enzyme induction vs inhibition

factors of major drug to drug interactions

first pass effect

oral drug metabolizers before systemic circulation; reduce bioavailability

sublingual, IV, and transdermal

which drugs bypass the liver