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M2 GI/Nutrition > Bilirubin Metabolism & Bile Salts - Dahms > Flashcards

Bilirubin Metabolism & Bile Salts - Dahms Flashcards

1
Q

How much hemoglobin is synthesized each day to replace that lost by RBC turnover?

A

6-7g

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2
Q

How much of total body iron is present as RBC heme?

A

70%

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3
Q
  1. What plasma protein conjugates free Hb in the blood?
  2. What is it important for?
  3. Under what circumstances could this protein become depleted?
A
  1. Haptoglobin
  2. Delivering free Hb to macrophages for catabolism
  3. Intravascular hemolysis
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4
Q

What cell do the first steps of heme catabolism occur in?

A

Macrophages, which ingest senescent RBCs and/or Hb+Haptoglobin complexes

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5
Q

What steps of heme catabolism occur in macrophages?

A
  1. Heme ring opening
  2. Conversion of linear heme to biliverdin
  3. Conversion to biliverdin to bilirubin
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6
Q

What carries bilirubin from macrophages to the liver?

A

Albumin

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7
Q

Once bilirubin reaches the liver, what catabolic process occurs there?

A

Bilirubin is conjugated with glucuronic acid & excreted in the bile

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8
Q

What processes of heme catabolism occur in the GI tract?

From the GI tract, what two paths can the heme catabolic products take?

A

Bacteria deconjugate and further convert the conjugated bilirubin into urobilinogen.

Urobilinogen can be:

  1. Oxidized by intenstinal bacteria to stercobilin and excreted in the feces
  2. Reabsorbed into the blood stream from the intestines
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9
Q

How are urobilinogen products excreted from the bloodstream?

A

The kidney converts urobilinogen products to urobilin, which are excreted in the urine.

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10
Q

What is the classic clinical finding of hyperbilirubinemia?

A

Jaundice (icterus)

Yellow discoloration of skin and sclera due to accumulation of elevated bilirubin

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11
Q

Again, what is a normal RBC lifespan?

Senescent RBCs are taken up by what for catabolism? Be specific.

A

120 days

Macrophages of the reticuloendothelial system of the liver & spleen

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12
Q

What percentage of heme catabolism occurs from senescent eryhtrocytes?

What sources make up the remaining percentage?

A

80% from senescent RBCS

Remaining 20% from immature RBC destruction, cytochrome enzyme turnover, etc.

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13
Q

The first step of heme catabolism involves opening of the heme ring.

  1. What enzyme catalyzes this opening?
  2. What specific bond in heme is cleaved?
  3. What is a necessary cofactor for this reaction?
A
  1. HO-1 (Heme oxygenase-1)
  2. The alpha-methene bridge
  3. electrons from NADPH Cytochrome P450 Oxidoreductase (CYPOR)
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14
Q

Once the heme ring is opened, it must be converted to biliverdin.

  1. What enzyme catalyzes this reaction?
  2. What two by-products are liberated by this reaction?
  3. What happens to these by-products?
A
  1. Trick question (sorry) - reaction is believed to be nonenzymatic, catalyzed instead by molecular O2​
  2. CO and Fe2+/3+
    • N.B. Only known rxn in human body to produce CO
  3. Both are toxic compounds in their free forms.
    • CO is bound by Hb
    • Fe2+/3+ is bound by ferritin
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15
Q

During heme catabolism, biliverdin must be converted to bilirubin.

  1. What enzyme catalyzes this reaction?
  2. What cofactor is required?
A
  1. Biliverdin reductase
  2. NADH or NADPH
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16
Q

Compare bilirubin with biliverdin.

A

Bilirubin is less polar than biliverdin, and so can cross membranes more easily.

Bilirubin also appears to be an important antioxidant during the neonatal period.

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17
Q

What is the role of albumin in heme catabolism?

A

Albumin is important for keeping bilirubin soluble and delivering it from its primary site of production (macrophages) to its primary site of excretion (liver).

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18
Q

Once bilirubin is delivered into hepatocytes, what cytosolic proteins temporarily bind bilirubin until it is further processed (conjugated)?

A

Ligandins

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19
Q

Once in the liver, bilirubin is conjugated.

  1. What is the major conjugating group used for bilirubin?
  2. What enzyme is the conjugation catalyzed by?
  3. How can the products of this reaction differ?
A
  1. Glucuronic acid (glucuronidation reaction)
  2. UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1)
  3. Either one or two gluruonic acid moieties can be conjugated, yielding either:
    • mono- (BMG) or
    • diglucuronide (BDG) species
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20
Q

How is bilirubin excreted from hepatocytes?

What cofactor is needed for this process?

A

MOAT (Multiorganic anion transporter), located along the canalicular membranes

ATP-dependent process

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21
Q

Again, what are the major heme breakdown products in:

  1. Urine?
  2. Feces?

What single compound are both of these products derived from?

A
  1. Urobilin (gives urine its yellow color)
  2. Stercobilin (major pigment of feces)

Both are derived from urobilinogen

22
Q

What quantitative assay is there for measuring bilirubin values?

What type of bilirubin does this test measure when run in water? Why?

What type of bilirubin is detected when the test in run in methanol? Why?

A
  1. van den Bergh assay
  2. In water, measures direct (conjugated) bilirubin. Unconjugate bilirubin is insoluble in H2O and is not detected.
  3. In methanol, both conjugated and unconguated bilirubin are soluble, so running the test in MeOH yields total bilirubin

N.B. You can calculate indirect (unconjugated) bilirubin from these two tests with total - direct = indirect

23
Q
  1. What is neonatal jaundice?
  2. How common is it?
  3. When does it occur?
  4. How serious is it?
A
  1. Jaundice due to the neonate’s low liver function at birth.
  2. Every newborn has hyperbiliubinemia by adult standards. About half of newborns become clinically jaundiced.
  3. First five days of life
  4. **Most **cases are innocuous, but severe cases can result in encephalopathy.
24
Q

Is direct or indirect bilirubin responsible for neonatal jaundice?

How does this bilirubin accumulate around birth in the first place?

A

Indirect (unconjugated) bilirubin in the serum is reponsible.

Bilirubin accumulates due to:

  • Low UGT1A1 (conjugating enzyme) activity at birth
  • Low excretory capacity of hepatocytes
  • Increased bilirubin production
    • Due to accerlerated RBC destruction
      • (Not sure what causes this)
25
Q

What is kernicterus?

A

“Bilirubin encephalopathy”

  • The type of encephalopathy seen in neonatal jaundice
  • Causes athetoid (writhing) cerebral palsy
  • Often causes hearing loss
26
Q

Why might neonatal jaundice be an evolved, physiological function?

A
  • Hyperbilirubinemia might be an important antioxidant defense for the newborn
    • Bilirubin can inhibit lipid peroxidation, as it can donate H+
27
Q

If needed, how is neonatal jaundice treated?

Describe the mechanism of action.

A

Phototherapy

Exposure to blue-green light (430-490nm) changes bilirubin’s configuration to an isomer that can be excreted in the bile without conjugation.

28
Q

Name three syndromes that include an inherited unconjugated bilirubinemia.

What serum bilirubin level is typically found in each?

Which is most severe?

A
  1. Crigler-Najjar Syndrome, Type I
    • 20-50mg/dL
  2. Crigler-Najjar Syndrome, Type II
    1. <20mg/dL
  3. Gilbert Syndrome
    • Usually <3mg/dL

Worst: CN Syndrome, Type I. Higher bilirubin = more severe!

29
Q

What deficiency underlies all three inherited unconjugated hyperbilirubinemia syndromes?

A

UGT1A1 expression

Crigler Najjar Type I: Absent

Criggler Najjar Type II: ~20% activity

Gilbert: ~30% activity

30
Q
  1. Name two inherited syndromes that feature conjugated hyperbilirubinemia.
  2. What is the defect in each?
  3. How are they inherited?
A
  1. Dubin-Johnson Syndrome (MOAT defect)
  2. Rotor Syndrome (molecular mechanism unknown)
  3. Both are autosomal recessive
31
Q

What is the prognosis of the inherited conjguated bilirubinemias?

A

Both (Dubin-Johnson and Rotor) hav a benign / mild prognosis.

32
Q

Name three general causes of jaundice that are not inherited diseases.

What type of bilirubin would be increased in each case?

A
  1. Hemolytic (increased indirect)
    • RBC destruction exceeds conjugating ability of liver
  2. Obstructive (increased direct)
    • Partial or complete blockage of the bile ducts
  3. Hepatocellular (increased indirect)
    1. Liver damage due to toxins, poisons, cardiac failure, and acute or chronic disease limit its conjugation ability
33
Q
  1. What is major precursor of bile acids?
  2. What is important about the relationship between bile acids and this precursor?
  3. Where are bile acids synthesized?
A
  1. Cholesterol
  2. Bile acids are a major mechanism for cholesterol excretion from the body
  3. The Liver
34
Q

Describe the passage of bile acids after their synthesis.

Include sites in these locations:

Liver

Biliary tree & Gallbladder

Small Intestine

A
  • Secreted into bile canaliculi (channels between adjacent hepatocytes)
  • Travel through the hepatic duct and up the cystic duct into the gallbladder for storage
  • When needed, is carried through the common bile duct and excreted into the duodenum
  • (Wiki) 95% of bile acids are reabsorbed from the ileum back to the liver, where they can be further modified and secreted into the biliary tree to begin the process anew.
    • The remaining 5% exits the body in the feces.
35
Q

Name two major uses of bile acids

A
  • Emulsify dietary triglycerides for more efficient hydolysis by pancreatic lipase
  • Facilitate absorption of fat-soluble vitamins from the intestine (e.g. Vitamin D)
36
Q
  1. Name two primary bile acids.
  2. What are they directly synthesized from?
  3. What are they synthesized by?
A
  1. Primary bile acids:
    • Cholic acid
    • Chenodeoxycholic acid
  2. Cholesterol
  3. Hepatocytes
37
Q
  1. Name two secondary bile acids.
  2. What are they synthesized from?
  3. What are they synthesized by?
A
  1. Secondary bile acids:
    • Deoxycholic acid
    • Lithocholic acid
  2. Precursors:
    • Deoxycholic is synthesized from cholic
    • Lithocholic is synthesized from chenodeoxycholic
  3. Gut bacteria
38
Q
  1. By what mechanism are bile salts synthesized from bile acids?
  2. Are primary or secondary bile acids converted into salts?
  3. Where does this conversion take place?
A
  1. Conjugation of bile salts with glycine or taurine
  2. Both
  3. Hepatocytes
39
Q

Why is the conjugation of bile acids into bile salts useful?

A

Salts have a lower pKa value, which renders them more soluble in the small intestine (better emulsifying agents than bile acids.)

40
Q

What bacterial enzyme catalyzes the conversion of primary to secondary bile acids?

A

7alpha-hydrogenase

41
Q

What circular blood flow allows for efficient circling and reusing of bile acids?

A

Enterohepatic circulation

42
Q

About how much bile acid (in grams) can be typically stored in the gallbladder?

A

2-4g

43
Q

Familial Hypercholesterolemia

  1. What enzyme deficiency causes FH?
  2. How is it inherited?
  3. How common is it?
A
  1. Defect in gene encoding LDL receptor
  2. Autosomal dominant with **gene dosage **effect
    • Homozygotes more severely affected than heterozygotes
  3. Heterozygotes number 1 in 500 persons
    • One of the most common inborn errors of metabolism
    • Homozygotes are 1:1,000,000
44
Q

Familial Hypercholesterolemia

  1. What is elevated in the plasma?
  2. Where does cholesterol deposit? What are these deposits called?
A
  1. LDL
  2. Deposit sites:
    1. Tendons & skin (xanthomas)
    2. Arteries (atheromas)
45
Q

What is the treatment focused on in Familial Hypercholesterolemia?

A

Reducing plasma LDL levels

(Direct link between high LDL and atherosclerosis)

46
Q

Can you name some examples of cellular functions that are up- or downregulated to control choelsterol levels?

A
  • Synthesis of LDL receptors
    • Recycling of receptors
  • Synthesis of cholesterol
  • Storage of cholesterol esters
  • Synthesis of sterol hormones, vitamins, and bile acids from cholesterol
47
Q

Explain the “dual role” of the LDL receptor and its relation to FH.

A
  1. LDLR limits LDL production by enhancing the removal of LDL’s precursor, IDL.
  2. LDLR enchances LDL degradation by mediating LDL cellular uptake.

In FH, defective LDLR lacks these negative regulatory mechanisms, and so LDL levels increase markedly.

48
Q

Name three specific treatments for HF heterozygotes.

A
  1. Bile acid binding resins
  2. Statins
  3. Low-fat, low-cholesterol diet
49
Q

Name two bile acid binding resins.

Explain their mechanism of action.

Used alone, how much can they lower LDL cholesterol levels?

A
  1. Cholestyramine
  2. Colestipol

Bind bile acids in the intestine and prevent their reabsorption. Increased bile acid excretion prompts an increased conversion of cholesterol to bile acids. The resulting cholersterol deficiency, in turn, stimulates the liver to produce more LDL receptors.

10-20% decrease

50
Q

Recall the mechanism of action of statins.

When combined with bile acid binding resins, how much can LDL cholesterol be decreased?

A

HMG-CoA reductase inhibitors. Decreased cholesterol synthesis promotes synthesis of LDLR.

>60%

51
Q

Alone, how much can a low-fat, low-cholesterol diet be expected to decrease LDL cholesterol levels?

A

10-20%

M2 GI/Nutrition (43 decks)

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