Heme Catabolism & Bile Salts Flashcards Preview

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Flashcards in Heme Catabolism & Bile Salts Deck (44)
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1
Q

What two things must be dealt with during heme catabolism?

A
  1. Handling the hydrophobic products of porphyrin ring cleavage
  2. Retention, safe mobilization, and re-utilizatoin of iron
2
Q

___% of the total iron is present as heme iron

A

70%

3
Q

Ferrous iron (Fe2+) is an extremely reactive molecule, generating _____ ______ _____

A

Reactive oxygen species

4
Q

Extravascular hemolysis primarily takes place within the macrophages of what two tissues?

A

Red pulp macrophages of the spleen and Kupffer cells in the liver

5
Q

What types of macrophages scavenge hemoglobin-haptoglobin complexes in intravascular hemolysis?

A

CD163(+) macrophages

6
Q

Haptoglobin binds ______ ________

A

free hemoglobin

7
Q

Where is Haptoglobin produced and secreted?

A

Haptoglobin is produced mostly in the liver by hepatocytes and secreted into the blood circulation

8
Q

Describe how haptoglobin functions as an antioxidant

A

Following its release into plasma, hemoglobin dissociates into αß dimers - Oxy-hb dimers are sequestered by haptoglobin preventing both release of free heme and the oxidative damage of heme iron

9
Q

How does the CD163 receptor take up the haptoglobin-hemoglobin complex?

A

Receptor mediated endocytosis

10
Q

What happens when haptoglobin’s buffering capacity is overwhelmed?

A

Hb undergoes a rapid conversion to metHb, liberating heme

11
Q

What happens when metHb liberates the free heme?

A

Free heme then binds to albumin and other plasma components including lipoproteins and is subsequently transferred to hemopexin

12
Q

Describe Hemopexin

  • Type of protein:
  • Production:
  • When do levels increase?
A
  • Hemopexin is an acute phase glycoprotein that binds free heme
  • It is produced mostly in the liver by hepatocytes and secreted into blood circulation
  • Levels markedly increase during acute phase of inflammation in response to inflammatory cytokines and during heme overload
13
Q

What is the CD91 Scavenger receptor?

A

binds the hemopexin-heme complex

14
Q

What happens when the heme complex is engulfed by a macrophage?

A
  1. The globin protein is degraded to amino acids in the lysosome
  2. Heme is transferred to the cytosol where it is catabolized by heme oxygenase-1 (HO1)
15
Q

What causes Jaundice or Icterus

A

Jaundice or Icterus results from accumulation of elevated bilirubin in the skin and sclera, imparting a yellow color to these tissues

16
Q

What is bilirubin?

A
  • Bilirubin, an orange pigment derived from the degradation of heme proteins
  • potentially toxic waste product that is generally harmless because of binding to serum albumin
17
Q

What is the mechanism of heme ring opening in the macrophage? (2 steps)

A
  1. The Ferroprotoporphyrin IX ring is selectively cleaved at the α-methene bridge, catalyzed by heme oxygenase-1 and requires electrons from NADPH cytochrome P450 oxidoreductase (CYPOR)
  2. Nonenzymatic oxidation by molecular oxygen with the elimination of CO- this leads to the release of iron after addition of electrons and the resulting green pigment is biliverdin
18
Q

What converts bivileridin to bilirubin?

A

Biliverdin reductase

19
Q

What are some differences between biliverdin and bilirubin?

A
  • Bilirubin is less polar than biliverdin and crosses membranes more readily
  • Bilrubin is an antioxidant and appears to be particularly important during the neonatal period
20
Q

How do bilirubin and albumin interact?

A
  • Albumin binding plays a critical role in the desposition of bilirubin in the body
    • keeps bilirubin in solution
    • transports it from its primary sites of production to its primary site of excretion
21
Q

What happens to bilirubin once inside the hepatocyte?

A
  1. bilirubin is rapidly removed from the circulation by the liver
    • dissociates from albumin before entering the hepatocyte
  2. ligandins keep bilirubin in solution
    • inhibits the efflux of bilirubin back into the circulation
    • temporary storage
  3. conversion to polar conjugates by esterification of the propionic acid carboxyl groups
  4. Glucuronic acid is the major conjugating group
    • catalyzed uridine diphosphate glucuronosyltransferase (UGT1A1)
  5. Either one or two glucuronic acid moieties of UDP-glucuronic acid are transferred onto bilirubin yielding the mono- (BMG) or diglucuronide (BDG) species
22
Q
  • What is essential for excretion of bilirubin?
  • How is this accomplished?
A
  • Conjugation is essential for bilirubin excretion
  • Mechanism:
    • Energy-dependent and shared with other organic anions, except bile salts
    • ATP-dependent multiorganic anion transporter (MOAT) has been identified in canalicular membranes and is involved in bilirubin excretion
23
Q

Fate of bilirubin in the gastrointestinal tract

A
  • Bilirubin reaches the intestinal tract mainly conjugated and is not substantially readsorbed
  • Rather, bilirubin is degraded by intestinal bacteria into a series of urobilinogen products
  • Urobilinogens are present in the deconjugated state (i.e., lost glucuronic acid)
    • Urobilinogen has anti-oxidant properties
  • Urobilinogen is oxidized to stercobilin
    • Major pigment of feces
24
Q

The hepatic processing of bilirubin involves four distinct, but interrelated stages:

A
  1. uptake from the circulation
  2. intracellular binding and storage
  3. conjugation
  4. biliary excretion
25
Q

How can hyperbilirubinemia be broadly divided? (2)

A
  1. Conjugated
  2. Unconjugated
26
Q

Quantification of bilirubin:

  1. Indirect quantification
  2. Direct quantification
A
  1. Indirect quantification
    • intensity of yellow discoloration of the skin (total bilirubin)
  2. Direct quantification (van den Bergh assay)
    • Only the water soluble, conjugated bilirubin reacts rapidly in this assay, which yields a value for direct bilirubin
    • Indirect bilirubin, corresponding to the unconjugated form, is simply calculated by the difference between total and direct
27
Q
  • When does neonatal jaundice occur?
  • What causes neonatal jaundice?
A
  • About half become clinically jaundiced during the first 5 days of life
  • Combination of three factors:
    1. Low activity of UGT1A1
    2. Decrease excretory capacity of hepatocytes
    3. Increased bilirubin production secondary to accelerated destruction of fetal erythrocytes
28
Q

Neonatal jaundice

  • Serum bilirubin is predominantly _________
  • What can happen if neonatal janudice is untreated?
  • What is Kernicterus?
A
  • Serum bilirubin is predominantly unconjugated
  • If untreated, high bilirubin levels (resulting in intense jaundice) can damage regions of the brain, such as the basal ganglia (yellow discoloration), involved in controlling muscle movement
  • Kernicterus is a specific form of brain damage (“bilirubin encephalopathy”) due to hyperbilirubinemia
    • causing athetoid (writhing) cerebral palsy
    • often hearing loss
29
Q

How is neonatal jaundice treated?

A

Phototherapy is the most common treatment modality.

  • Exposure of bilirubin to light in the blue-green spectrum
  • Changes its configuration to an isomer that can be excreted in bile without conjugation
30
Q

List the inherited uncojugated hyperbilirubinemias (3):

  • How is Hepatic bilirubin UGT affected?
A
  • Crigler-Najjar Syndrome Type I
    • Hepatic bilirubin UGT ⇒ absent
  • Crigler-Najjar Syndrome Type II
    • Hepatic bilirubin UGT ⇒ markedly reduced
  • Gilbert’s Syndrome
    • Hepatic bilirubin UGT ⇒ reduced
31
Q

Conjugated Hyperbilirubinemia:

  • Defects in ….
  • List the syndromes:
    • Appearance of liver
    • Histology of Liver
A
  • Defects of bilirubin secretion
    • Inability of hepatocytes to secrete conjugated bilirubin into the bile canaliculi after it has been formed.
    • Conjugated bilirubin returns to the blood
  • Dubin-Johnson: organic ion transport (MOAT defect)
    • Liver appearance: grossly black
    • Histology: dark pigments; predominately centrilobular
  • Rotor syndrome
    • Liver appearance: normal
    • Histology: normal; no increase in pigmentation
32
Q

Other causes of Jaundice:

  1. Hemolytic (direct or indirect?)
    • Pathogenesis
  2. **Obstructive **(direct or indirect?)
    • Pathogenesis​
  3. Hepatocellular (direct or indirect?)
    • Pathogenesis
A
  1. Hemolytic (increased indirect/unconjugated)
    • Excessive erythrocyte destruction
    • Formation of bilirubin in amounts exceeding the conjugating ability of the liver and hence its excretion into the bile
    • Free bilirubin increases in plasma as a result
  2. Obstructive (increased direct/conjugated)
    • Caused by partial or complete blocking of the bile ducts
    • Conjugated bilirubin is prevented from being excreted into the intestine
    • Increased amounts in the plasma
  3. Hepatocellular (increased indirect/unconjugated)
    • Damage to the liver by toxins, poisons, cardiac failure, or acute or chronic disease
    • Impairs the liver’s capacity to conjugate circulating bilirubin and hence excrete it
33
Q

What two enzymatic processes are involved in cholesterol synthesis?

A
  1. Farnesylation
  2. Glycosylation
34
Q

Cholesterol can be derived from the ___ or _________ de novo in virtually all cells

A

Cholesterol can be derived from the diet or synthesized de novo in virtually all cells

35
Q

Bile acids

  • Synthesis:
  • Secretion:
  • Storage:
  • Function:
A
  • Synthesis: synthesized from cholesterol in the liver
  • Secretion: secreted into bile canaliculi
  • **Storage: **
    • carried to the gallbladder for storage
    • excreted from the small intestine
  • Function:
    • emulsifying agents to prepare dietary triglycerides for hydrolysis by pancreatic lipase
    • facilitate absorption of fat-soluble vitamins from the intestine
36
Q
  • Most abundant bile acids are derivatives of _____ ____
  • How are bile acids a major mechanism by which cholesterol is excreted?
A
  • Most abundant bile acids are derivatives of cholic acid
  • Carbon skeleton of cholesterol is not degraded (oxidized to CO2 and H2O) in humans but is excreted in bile as free cholesterol and as bile acids
37
Q
  • List the primary bile acids:
    • Synthesis:
  • List the primary bile salts:
    • Synthesis:
A
  • Primary bile acids: **cholic acid & chenodeoxycholic acid **
    • synthesized in hepatocytes directly from cholesterol
  • Primary bile acids: **deoxycholic acid & lithocholic acid **
    • converted to secondary bile acids by bacteria in the gut via dehydroxylation reactions
38
Q
  • Where are primary and secondary bile acids absorbed?
  • Why is conjugation important for bile acids?
A
  • Primary and secondary bile acids are reabsorbed by the intestine (lower ileum) into portal blood, and taken up by hepatocytes where they are conjugated to glycine or taurine, forming bile salts.
  • Conjugation is important as it converts the bile acids into molecules (i.e., bile salts) with a lower pKa value
    • renders them more soluble in the small intestine
39
Q

Why is enterohepatic circulation important for bile acid regulation?

A

The capacity of the liver to produce bile acids is insufficient to meet physiological demands, so the body relies on an efficient enterohepatic circulation that carries bile acids from the intestine back to the liver

40
Q

**Familial Hypercholesterolemia (FH): **

  • Clinical Characteristics
  • Genetic Defect
A
  • Clinical Characteristics
    1. elevated concentration of LDL in the plasma
    2. deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas)
    3. inheritance as an autosomal dominant trait with a gene dosage effect (homozygotes are more severely affected than heterozygotes)
  • Genetic Defect:
    • ​mutation in the gene encoding the LDL receptor
41
Q
  • What is the incidence of heterozygotes with FH?
  • What is the treatment for FH?
A
  • Heterozygotes number 1 in 500 persons
  • Treatment is directed at lowering the plasma level of LDL
42
Q
  • What type of endocytosis is exhibted by the LDL receptor?
  • What is the function of the LDL receptor?
A
  • receptor-mediated endocytosis
  • help maintain a constant level of cholesterol within the cell in the face of fluctuations in the supply of lipoproteins
43
Q

What is the dual role of the LDL receptor?

A
  1. Limits LDL production by enhancing the removal of the precursor, IDL (B-100, apo E ⇒ higher affinity for LDL receptor), from the circulation.
  2. LDL receptor enhances LDL degradation by mediating cellular uptake of LDL (apo B-100)
44
Q

What are the treatment options for FH heterozygotes?

A
  1. Bile acid binding resins
    • bind biles acids in the intestinal lumen, preventing their absorption from the ileum.
    • Liver responds to cholesterol deficiency by increasing production of LDL receptors
    • alone, can decrease LDL cholesterol levels by 10-20%
  2. HMG-CoA reductase inhibitors (statins)
    • combined with bile acid binding resins, can decrease LDL cholesterol by >60%
    • drug of choice
  3. Diet low in cholesterol and fats
    • alone, can decrease LDL cholesterol levels by 10-20%