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Gastroenterology > 02: Hepatic Physiology > Flashcards

02: Hepatic Physiology Flashcards

1
Q

What are the major physiological functions of the liver?

A
  1. Conjugation & secretion of bilirubin
  2. Synthesis & secretion of plasma proteins (including clotting factors and albumin)
  3. Metabolism of drugs and alcohol
  4. Carbohydrate metabolism
  5. Protein/nitrogen metabolism
  6. Cholesterol/lipid/bile salt metabolism
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2
Q

Describe the origins of bilirubin.

A
  1. Oxidation of heme via **heme oxygenase **to form biliverdin IX-alpha.
  2. Biliverdin IXalpha is reduced via biliverdin reductase to bilirubin IX-alpha.
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3
Q

What are the sources of bilirubin?

A
  • 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)
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4
Q

What are the major consequences of bilirubin metabolism within the liver?

A
  • 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.
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5
Q

Trace the net movement from blood to bile.

A
  1. Delivery from sinusoid to hepatocyte
  2. Storage in hepatocyte
  3. Biotransformation from lipophilic compound to polar metabolite
  4. Secretion from hepatocyte to canaliculus
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6
Q

Describe the uptake of bilirubin into the hepatocyte.

A
  1. Bilirubin bound to albumin in the blood
  2. Uptake to hepatocyte on basolateral (sinusoidal) surface via OATP-C
  3. Some bilirubin stored in cytosol bound to proteins (ligandin)
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7
Q

Describe the conjugation of bilirubin.

A

Glucoronyl transferase conjugates bilirubin in the ER to mono-glucuronic acid (BMG) or di-glucoronic acid (BDG)

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8
Q

Describe the secretion of bilirubin from the hepatocyte.

A

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.

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9
Q

Describe the enterohepatic circulation of bile pigments.

A
  1. Hydrolyzed in large intestine to free bilirubin and glucoronic acid.
  2. Deconjugation, reduction and oxidation via colon bacteria produce urobilinogen, which is further converted to **stercobilin **and urobilins, which are secreted in stool.
  3. Some urobilinogen enters enterohepatic circulation, being re-absorbed and re-secreted by liver.
  4. Small amount of urobilinogen enters systemic circulation and is excreted by kidneys; converted to urobilin to give urine yellowish color.
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10
Q

Bilirubin in hepatocyte dysfunction

A

↑urobilinogen in urine due to less efficient reabsorption by hepatocytes

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11
Q

Bilirubin in biliary obstruction

A

white/clay-colored stool due to no bilirubin in intestine –> no conversion to stercobilin/urobilin; no urobilinogen in urine

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12
Q

Normal bilirubin levels in blood

A

= 17 uM (1 mg/dL)

~96% unconjugated

NB: Clinical lab will overestimate amount of conjugated bilirubin (up to 30%)

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13
Q

When is **jaundice **seen?

A

[bilirubin] > 35uM (2mg/dL)

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14
Q

What are the causes of primarily unconjugated hyperbilirubinemia?

A
  • 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)
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15
Q

What are the causes of primarily conjugated hyperbilirubinemia?

A
  • 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
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16
Q

What is the cause of physiological neonatal juandice?

A
  • 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
17
Q

What is the treatment of neonatal jaundince?

A
  • Transfusion
  • Phototherapy (produces bilirubin photoisomers w/ ↑aqueous solubility)
18
Q

What plasma proteins are secreted by the liver?

A
  • 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
19
Q

What are the clinical implications of liver dysfunction?

A
  • ↑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
20
Q

Describe the phases of durg and toxin metabolism.

A
  • 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)
21
Q

Describe ethanol metabolism.

A
  1. Ethanol broken down into **acetaldehyde **by three different enzymes:
    1. **Alcohol dehydrogenase **(cytoplasm)
    2. **Catalase **(peroxisome)
    3. **CYP450 2E1 **(ER)
  2. Acetaldehyde converted to acetate in mitochondria via alcohol dehydrogenase 2.
  3. These reactions result in the formation of products contributing to alcohol’s toxic effects:
    1. Acetaldehyde adducts
    2. ↑ROS formation
    3. ↑NADH:NAD+ ratio

NB: With chronic drinking, ↑CYP450 2E1 activity

22
Q

Describe the implications of liver dysfunction on carbohydrate production.

A
  • 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
23
Q

What are the roles of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)?

A
  • 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
24
Q

What is the role of the urea cycle?

A
  • Elimination of excess ammonia via incorporation into organic compounds –> urea
  • In liver failure or pHTN, ammonia not adequately removed from liver –> hepatic encephalopathy
25
Q

Describe the role of the liver in cholesterol/lipid/bile salt metabolism.

A
  • 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

Gastroenterology (10 decks)

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