Liver function, jaundice and hepatitis Flashcards
Liver storage
Lglycogen (5% weight) lipids (temporary, until lipoprotein secretion) B12 and folate Vitamin A stored as retinyl palmitate ferritin and hemosiderin
Liver - role in metabolism
carb
amino acids
lipids
Liver - synthesis
plasma proteins
porphyrins (precursor for heme)
bile
hematopoiesis (fetal)
Liver - detox
ammonia converted to urea
CYP450 hydroxylation and oxidation
Glycogen synthesis pathway
- Glucose into cell via GLUT2
- Glucokinase phosphorylation to G1P
- Glycogen synthase
Glycogenolysis pathway
- Glycogen phosphorylase breaks alpha 1-4 linkage
- G1P to G6P
- G6P –> glucose (liver), or glycolysis (liver and skeletal muscle)
Glycolysis pathway
- Glucose to pyruvate
2. Pyruvate to lactate in cytoplasm, or to acetyl-CoA and into mitochondria for TCA cycle
Gluconeogenesis
can use lactate, amino acids (pyruvate or oxaloacetate), or glycerol (to trioses)
only in the liver
Lactate clearance
- Glucose –> lactate in skeletal muscle
- Lactate –> glucose in liver
not energy-efficient
Bile acid content
bile salt electrolyte phospholipids proteins cholesterol bilirubin
Bile acid function
digestion of dietary lipids –> micelles
excretion of waste products/drugs/toxins
Bile salt composition
derived from cholesterol, conjugated to glycine or taurine
Bilirubin production
In reticuloendothelial cells (spleen, liver):
- Heme –> biliverdin, CO, FE
- Biliverdin –> bilirubin
- Bilirubin (insoluble) binds albumin, transported to the liver
Bilirubin metabolism in the liver
- Hepatocytes take up bilirubin without albumin via carrier
- Bilirubin binds ligandin in cytosol
- ER conjugates bilirubin to glucoronic acid, catalyzed by UDPGT
- Conjugated bilirubin diffuses out of ER to canalicular membrane/bile canaliculus (energy-dependent)
Bilirubin metabolism in gut
- Bilirubin in bile drains into duodenum
- In distal ileum & colon: hydrolyzed to unconjugated bilirubin by bacterial glucuronidases
- UC bilirubin reduced to urobilinogens by gut bacteria (colourless)
80-90% excreted in feces as urobilins
10-20% reabsorbed, re-excreted
small portion escapes hepatic uptake, excreted in urine
UC bilirubin is bound to albumin and cannot be filtered - not found in urine
Bile enterohepatic circulation
- Hepatocytes synthesize bile acids using dietary cholesterol
- During interdigestive period, bile acids move down biliary tract, sequestered in gallbladder (sphincter of Oddi contracted, gallbladder wall relaxed)
- DUring digestion, intestinal mucosa simulated to secrete cholecystokinin –> contracts gallbladder wall, relaxes sphincter of Oddi –> bile acids flow into uodenum via ampulla of Vater
- Active transport systems in terminal ileum actively reabsorb bile acids into portal circulation (>90%)
- Bile acid lost replaced by hepatic biosynthesis using cholesterol
Vitamin B12 enterohepatic circulation
- Dietary vitamin B12 released by gastric acid
- B12 binds R-protein
- Pancreatic protease releases B12 from R-protein, binds IF secreted by parietal cells
- Terminal ilem actively takes up IF-B12 into portal circulation
- B12 complexed to transcobalamin
- Tissue takes up B12-TC complex; TC degraded in lysosome, B12 utilized
Primarily stored in the liver (50%) - excreted in bile but reabsorbed
Major transport proteins made by liver
Albumin
Transferrin
Ceruoplasmin
Major protease inhibitors made by liver
a1-antritrypsin
Major coagulation factors made by liver
fibrinogen, all clotting factors except VII
Major immunoproteins made by liver
IgG (plasma cells)
major complement protein made by liver
C3
Regulator of plasma protein synthesis
Low oncotic pressure
acute phase reaction (increase a1-AT, ceruloplasmin, C3, C4, decrease albumin and transferrin)
Estrogen (increase alpha1-AT, ceruloplasmin
Acetaminophen metabolism
- Oxidized by CYP 2E1 –> NAPQI
- Therapeutic> NAPQI –> glutathione, renally excreted
- High dose: binds cellular proteins
Toxicity: oxidative damage, mitochondrial dysfunction, inflammatory response –> injury/death of hepatocytes –> centrilobular liver necrosis
Acetaminophen toxicity management
Most deaths due to cerebral edema (hepatic encephalopathy)
60% survival with liver transplant
N-acetylcysteine infusion - >95% effective if started within 10 hours of ingestion
Jaundice definition
Yellowish pigmentation of the skin, conjunctival membranes over the sclerae and other mucous membranes due to hyperbilirubinemia
Pre-hepatic jaundice pathophys
Due to hemolysis
Conjugating enzyme becomes saturated, UC bilirubin causes yellow skin discolouration
Hepatic jaundice pathophys
Gilberts hepatitis: reduced activity of glucuronyltransferase (conjugates bilirubin)
Viral: inflammation –> liver tissue destroyed and released
Drug: disruption of hepatocyte, transport proteins, cytolytic T_cell activation, apoptosis of hepatocytes, mitochondrial disruption, bile duct injury
Alcohol: hepatocyte death
Cirrhosis: fibrosis - blocks blood flow, liver does not remove enough bilirubin from blood
Post-hepatic jaundice pathophys
Sex hormones
Promazines: obstructive jaundice
Cancer of the bile ducts/head of the pancreas, gallstones: intra/extrahepatic obstruction
Hepatocellular injury labs
ALT and AST
ALT more specific to liver (look at creatinine kinase to differentiate with muscular cause)
>1000 IU/L –> acute viral hepatitis/drug toxicity/ischemic liver injury
Values may be smaller in fulminant due to death of hepatocytes
2)
Biliary obstruction <200
