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Digestion And Metabolism > Heme Degradation And Jaundice > Flashcards

Heme Degradation And Jaundice Flashcards

1
Q

What is jaundice?

A

Clinical sign characterized by yellowish discoloration of skin, mucous membranes, sclera, and nail beds.
• Binding of bilirubin (Bile pigment) to connective tissue
• Occurs when serum bilirubin levels are greater than 2 mg/dL (hyperbilirubinemia

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2
Q

What are the stages of heme degradation?

A
  1. Formation of bilirubin from heme in reticuloendothelial system
  2. Transport of bilirubin in blood from RES to liver
  3. Uptake and conjugation in liver and excretion into bile
  4. Formation of urobilinogen in large intestine
  5. Formation of stercobilin and loss in feces
  6. Absorption of urobilinogen and excretion of urobilinogen in urine
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3
Q

What is the purpose of heme degradation?

A
  • RBC lifespan about 120 days
    • RES (Spleen, Kupffer cells of liver, macrophages) removes old RBC
    • Hemoglobin = Heme + Globin (amino acid pool)
    • Heme proteins like myoglobin and cytochromes release heme and forms bilirubin
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4
Q

Describe bilirubin formation in macrophages

A

• Heme oxygenase – Fe2+ released
– Porphyrin ring cleaved
– CO formed
– Biliverdin: Green pigment

• Biliverdin reductase
– Bilirubin (bile pigment): Orange- yellow colo

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5
Q

Explain the transport of bilirubin in blood to liver

A
  • Unconjugated (NOT water soluble)
  • Binds albumin for transport in blood
  • Albumin binding prevents excretion in urine

• Drugs (salicylates, sulfonamides) displace
bilirubin from albumin

• Administration of drugs displaces bilirubin
from albumin and free unconjugated bilirubin crosses blood-brain barrier and cause kernicterus in infants

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6
Q

Explain the uptake of bilirubin by liver

A

• Unconjugated bilirubin enters liver by specific transporters on hepatocyte

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7
Q

Describe the conjugation of bilirubin in the liver

A
  • Bilirubin converted to conjugated bilirubin (more water soluble)
  • Addition of two molecules of glucuronic acid
  • Enzyme: Microsomal UDP-glucuronyl transferase
  • Induction by phenobarbital
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8
Q

Explain the secretion of conjugated bilirubin into bile

A
  • Conjugated bilirubin actively transported into bile canaliculus by specific ABC transporters
  • Conjugated bilirubin (Bile pigment) contributes to the Orange-yellow color of bile
  • Bile released into second part of duodenum via common bile duct
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9
Q

Explain formation of urobillinogen in large. Intestine

A

• Conjugated bilirubin acted upon by bacterial flora in large intestine

• Undergoes deconjugation and…
Urobilinogen
converted to urobilinogen
(colorless)

• Urobilinogen not same as unconjugated bilirubin

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10
Q

Explain formation of stercobilin and loss in feces

A
  • Bacterial action on urobilinogen forms stercobilin (brown color)
  • Lost in feces and gives feces a characteristic brown color
  • Some urobilinogen is absorbed from the gut into portal blood
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11
Q

Describe the absorption of urobillinogen and excretion of urobillinogen in urine

A
  • 10% of urobilinogen in intestine absorbed into portal blood and goes to liver
  • Small part re-excreted into bile canaliculus
  • Majority of urobilinogen lost as urine urobilin (light yellow color)
  • Urobilinogen and Urobilin synonymous
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12
Q

What is jaundice? What are the findings of jaundice?

A

• Yellowish discoloration of skin, mucous membranes, sclera, nail beds
• Bilirubin (Bile pigment) binds connective tissue
• Serum bilirubin levels more than 2 mg/dL
(hyperbilirubinemia)

• Normal total serum bilirubin: <1mg/dL; – Unconjugated (80%)
– Conjugated (20%)

• Normal URINE findings:
– Bilirubin absent;
– Urobilinogen (urobilin) is present (Dipstick)

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13
Q

What are the lab tests to detect type of bilirubin?

A

• Van den Bergh reaction
– Bilirubin with diazo reagent forms red colored complex

• Conjugated bilirubin (direct reacting) water soluble reacts rapidly with reagent

• Total bilirubin
– Reaction in presence of methanol, both conjugated and unconjugated bilirubin react
• Unconjugated bilirubin (indirect reacting) water insoluble and reacts in presence of methanol
• Total bilirubin – Direct (conjugated) bilirubin = Indirect (unconjugated) bilirubin

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14
Q

What are the classifications of jaundice?

A

Classification of jaundice (hyperbilirubinemia)

• Based on etiology (cause)
– Prehepatic (hemolytic) jaundice: Increased breakdown of RBCs (Decreased lifespan of RBC)
– Hepatic jaundice: Decreased conjugation capacity of liver and decreased excretion of bilirubin
– Posthepatic (obstructive/ cholestatic) jaundice: Decreased excretion of bilirubin via bile

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15
Q

Describe prehepatic (hemolyric) jaundice

A

Lab findings: serum total bilirubin: increased alot

Serum conjugated bilirubin: N

Serum unconjugated bilirubin: increased alot

Urine bilirubin: absent (acholuric jaundice)

Urine urobilinogrn: increased

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16
Q

What are the changes in bilirubin metabolism in hepatic jaundice

A
  1. RBC Breakdown (hemolysis)
  2. Formation of bilirubin
  3. Increased unconjugated bilirubin in circulation (albumin-bound)
  4. Decreased uptake and conjugation of bilirubin by liver & decreased secretion of conjugated bilirubin (increased conjugated bilirubin in circulation due to regurgitation, leading to loss of bilirubin in urine)
  5. Decreased excretion of conjugated bilirubin into bile and intestine
  6. Decreased formation of urobilinogen in intestine
  7. This leads to decreased excretion of urobilin in urine. Decreased stercobilin in feces
16
Q

What are the changes in bilirubin metabolism in hepatic jaundice

A
  1. RBC Breakdown (hemolysis)
  2. Formation of bilirubin
  3. Increased unconjugated bilirubin in circulation (albumin-bound)
  4. Decreased uptake and conjugation of bilirubin by liver & decreased secretion of conjugated bilirubin (increased conjugated bilirubin in circulation due to regurgitation, leading to loss of bilirubin in urine)
  5. Decreased excretion of conjugated bilirubin into bile and intestine
  6. Decreased formation of urobilinogen in intestine
  7. This leads to decreased excretion of urobilin in urine. Decreased stercobilin in feces
17
Q

Describe the changes in bilirubin metabolism in preheoatic (hemoltyic ) jsundice

A
  1. Increased RBC breakdown (hemolysis)
  2. Increased bilirubin formation
  3. Increased unconjugated bilirubin in circulation (albumin- bound) – Exceeds conjugation capacity of liver
  4. Increased bilirubin uptake and conjugation by liver
  5. Increased excretion of conjugated bilirubin into bile and intestine
  6. Increased formation of urobilinogen in intestine
  7. Increased urobilin in urine+ increased stercobilin in urine
18
Q

What are the laboratory findings in hepatic jaundice?

A
  • Serum conjugated bilirubin elevated due to reduced secretion of conjugated bilirubin into biliary canaliculus. Conjugated bilirubin regurgitates into plasma
  • Serum unconjugated bilirubin elevated: Hepatocellular damage results in lower uptake of unconjugated bilirubin. Also, liver damage reduces conjugating capacity of liver.
  • Additional lab findings: Elevated serum ALT and AST levels (refer Liver function tests lecture)
19
Q

What are the lab findings of posthepatic (obstructivr/cholestatic) jaundice?

A
  • Serum conjugated bilirubin elevated as excretion into biliary canaliculus is reduced due to biliary obstruction. Conjugated bilirubin regurgitates into plasma (Cannot be excreted into bile)
  • Urine urobilinogen absent/ low (indicates extent of obstruction)
  • Additional lab findings: Elevated serum ALP and GGT levels (refer Liver function tests lecture)
20
Q

What are the physiological jaundice in newborn?

A

• Reasons for Jaundice in newborn
– Low hepatic UDP-glucuronyl transferase (premature infants more risk)

• Jaundice 2nd or 3rd day clears by 7th day

• Which type of bilirubin is increased??
Unconjugated bilirubin

  • Phototherapy (about 450nm)
  • Light converts bilirubin to polar, water-soluble isomers (basis of bili-lights)
21
Q

What is the significance of Kernicterus?

A

• Serum bilirubin >25mg/dL

• Unconjugated bilirubin (Lipid soluble) crosses
blood-brain barrier (not developed) deposits in
basal ganglia of brain ‘kernicterus’

• Hypoalbuminemia, low pH, drugs (salicylates,
sulfonamides) increase unconjugated unbound
bilirubin (Increase risk of kernicterus)

• Lethargy, altered muscle tone, high pitched cry

• Severe permanent neurologic symptoms
(choreoathetosis, spasticity, muscular rigidity, ataxia, intellectual impairment)

22
Q

What syndromes lead to inherited unconjugated hyper bilirubinemia?

A
  • Crigler-Najjar syndromes I and II, Gilbert syndrome
  • Varying deficiency of bilirubin UDP-glucuronyl transferase • Unconjugated hyperbilirubinemia
  • Crigler-Najjar syndrome I
  • Most severe; Very low enzyme activity (<5%)
  • Jaundice in neonate or infancy
  • Serum bilirubin levels up to 50 mg/dL (Unconjugated)
  • Kernicterus and developmental delay
  • Daily phototherapy, exchange transfusion to prevent kernicterus • Do NOT respond to phenobarbital
  • Usually fatal (if not treated) due to kernicterus
23
Q

Explain arias syndrome

A

• Crigler-Najjar syndrome II (Arias syndrome)

– Lower activity of bilirubin glucuronyl transferase (10-20%)
– Jaundice, but less severe than type I (serum unconjugated bilirubin levels 6-22mg/dL)

– Respond to phenobarbital (induces enzyme)
– Regular phototherapy in patients with high bilirubin levels

24
Q

What is Gilbert syndrome?

A

Inherited unconjugated hyperbilirubinemia

• Gilbert syndrome
– Present in 3-7% of population
– Adolescents and young adults
– Mild jaundice (2-5 mg/dL) following illness or stress or starvation – Bilirubin UDP-glucuronyl transferase activity 50% of normal
– Mild increase in unconjugated bilirubin
– Normal AST, ALT and ALP levels

25
Q

What is Dubin-Johnson syndrome?

A

• Dubin-Johnson syndrome
– Inherited deficiency of ABC transporter (secretes conjugated bilirubin into biliary canaliculus)

– Adolescents and young adults

– Elevated conjugated (direct) bilirubin – Normal AST, ALT and ALP levels

Digestion And Metabolism (57 decks)

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