02: Hepatic Physiology Flashcards
What are the major physiological functions of the liver?
- Conjugation & secretion of bilirubin
- Synthesis & secretion of plasma proteins (including clotting factors and albumin)
- Metabolism of drugs and alcohol
- Carbohydrate metabolism
- Protein/nitrogen metabolism
- Cholesterol/lipid/bile salt metabolism
Describe the origins of bilirubin.
- Oxidation of heme via **heme oxygenase **to form biliverdin IX-alpha.
- Biliverdin IXalpha is reduced via biliverdin reductase to bilirubin IX-alpha.
What are the sources of bilirubin?
- 80% from destruction of senescent red cells within the spleen; “late peak” (120 days)
- 20% from ineffective erythropoiesis in bone marrow and turnover of non-erythrocyte heme (liver cytochrome P450’s)
What are the major consequences of bilirubin metabolism within the liver?
- Intramolecular hydrogen bonding blocks exposure of polar groups to aqueous solvents –> bilirubin insoluble in blood –> allows hepatocyte absorption
- Liver metabolism makes it more polar (water soluble), allowing for secretion into the bile canaliculi.
Trace the net movement from blood to bile.
- Delivery from sinusoid to hepatocyte
- Storage in hepatocyte
- Biotransformation from lipophilic compound to polar metabolite
- Secretion from hepatocyte to canaliculus
Describe the uptake of bilirubin into the hepatocyte.
- Bilirubin bound to albumin in the blood
- Uptake to hepatocyte on basolateral (sinusoidal) surface via OATP-C
- Some bilirubin stored in cytosol bound to proteins (ligandin)
Describe the conjugation of bilirubin.
Glucoronyl transferase conjugates bilirubin in the ER to mono-glucuronic acid (BMG) or di-glucoronic acid (BDG)
Describe the secretion of bilirubin from the hepatocyte.
The ATP-binding cassette proteins (ABCC2) MRP2 and cMOAT (rate-limiting step in hepatocyte bilirubin metabolism), secrete BDG & BMG into bile.
Mutation of ABCC2 results in Dubin-Johnson Syndrome.
Describe the enterohepatic circulation of bile pigments.
- Hydrolyzed in large intestine to free bilirubin and glucoronic acid.
- Deconjugation, reduction and oxidation via colon bacteria produce urobilinogen, which is further converted to **stercobilin **and urobilins, which are secreted in stool.
- Some urobilinogen enters enterohepatic circulation, being re-absorbed and re-secreted by liver.
- Small amount of urobilinogen enters systemic circulation and is excreted by kidneys; converted to urobilin to give urine yellowish color.
Bilirubin in hepatocyte dysfunction
↑urobilinogen in urine due to less efficient reabsorption by hepatocytes
Bilirubin in biliary obstruction
white/clay-colored stool due to no bilirubin in intestine –> no conversion to stercobilin/urobilin; no urobilinogen in urine
Normal bilirubin levels in blood
= 17 uM (1 mg/dL)
~96% unconjugated
NB: Clinical lab will overestimate amount of conjugated bilirubin (up to 30%)
When is **jaundice **seen?
[bilirubin] > 35uM (2mg/dL)
What are the causes of primarily unconjugated hyperbilirubinemia?
- Overproduction
- Hemolysis
- Ineffective erythropoesis
- Impaired uptake
- Fasting
- Sepsis
- Drugs (e.g., probenecid)
- Impaired conjugation
- Inherited mutations in UGT1 (Crigler-Najjar syndrome)
- Inherited polymorphisms in UGT1 (Gilbert Syndrome)
What are the causes of primarily conjugated hyperbilirubinemia?
- Hepatocellular disease –> ↓secretion
- Cirrhosis
- Acute hepatitis
- Pregnancy (~1:1,000)
- Drugs (OCPs)
- Inherited Diseases
- **Dubin-Johnson syndrome **(ABCC2 mutation)
- Rotor syndrome (SLCO1B1 & SLCO1B3 mutations)
- Biliary obstruction
- Gallstones
- Tumors
- Primary biliary cirrhosis
- Sclerosin cholangitis
What is the cause of physiological neonatal juandice?
- Immaturity of all steps in bilirubin metabolism
- High [bilirubin] in blood can cross poorly-developed BBB –> **kernicterus **(brain damage due to bilirubin deposition)
- Affects 50% of neonates within first 1-5 days.
- Severe unconjugated hyperbilirubinemia more common in pre-term infants
What is the treatment of neonatal jaundince?
- Transfusion
- Phototherapy (produces bilirubin photoisomers w/ ↑aqueous solubility)
What plasma proteins are secreted by the liver?
- Albumin
- Clotting factors
- Antithrombin III
- Alpha-1-antitrypsin
- Ceruloplasmin
- Complement C3
- C-reactive protein
- Alpha-1-fetoprotein
- Fibrinogen
- Haptoglobin
- Hemopexin
- Alpha-lipoprotein
- Beta-lipoprotein
- Alpha-2-macroglobulin
- Orosomucoid
- Other clotting factors
- Prothrombin
- Transferrin
What are the clinical implications of liver dysfunction?
- ↑serum bilirubin (jaundice)
- ↑prothrombin time (bleeding tendency)
- ↓serum albumin (edema)
- Altered metabolism of drugs/induced liver damage
- Hypoglycemia/other carbohydrate abnormalities
- ↑blood concentration of ammonia and nitrogenous metabolites (encephalopathy)
- Altered blood lipids and elevated bile salts
Describe the phases of durg and toxin metabolism.
- PHASE I: Catalyzed by **oxoreductases **which lead to more polar metabolites:
- CYP450: produce epoxides
- Hydrolase: produce hydroxyls
- PHASE 2: Catalyzed by transferases: addition of groups (e.g., glucoronide)
Describe ethanol metabolism.
- Ethanol broken down into **acetaldehyde **by three different enzymes:
- **Alcohol dehydrogenase **(cytoplasm)
- **Catalase **(peroxisome)
- **CYP450 2E1 **(ER)
- Acetaldehyde converted to acetate in mitochondria via alcohol dehydrogenase 2.
- These reactions result in the formation of products contributing to alcohol’s toxic effects:
- Acetaldehyde adducts
- ↑ROS formation
- ↑NADH:NAD+ ratio
NB: With chronic drinking, ↑CYP450 2E1 activity
Describe the implications of liver dysfunction on carbohydrate production.
- With cirrhosis and acute liver failure, hepatocytes unable to adequately perform glycolysis and gluconeogenesis –> hypoglycemia
- Hyperglycemia also possible due to decreased ability of liver to store glycogen
- Glycogen storage disease: inherited mutation in gene encoding enzymes in glycogen metabolism
What are the roles of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)?
- Transamination of glutamate
- Indicators of approximate hepatocyte damage (leak out into blood)
- Referred to as “liver function tests,” although they do not provide info on function
- NB: AST can also leak out of damaged muscle
What is the role of the urea cycle?
- Elimination of excess ammonia via incorporation into organic compounds –> urea
- In liver failure or pHTN, ammonia not adequately removed from liver –> hepatic encephalopathy
Describe the role of the liver in cholesterol/lipid/bile salt metabolism.
- Major site of FA synthesis and oxidation
- Synthesis in cytosol
- Beta-oxidation in mitochondria
- LDL uptaken by hepatocytes
- Bile salt synthesis in liver, derived from cholesterol
- Primary bile acids converted into secondary bile acids in the intestine, tertiary bile acids in liver second pass
- In liver failure, ↑[bile acid] due to inefficient reabsorption by liver
