Jaundice and bilirubin

Question 1

Bilirubin metabolism 1

Answer 1

• > 70% from heme breakdown, in nl people virtually all bili is unconjugated
• Jaundice not seen until bili >3mg
• Heme-> biliverdin-> bilirubin
• Unconjugated (not technically indirect, but close enough) bili is carried by albumin to liver, where it gets conjugated w/ glucuronic acid (via UDP-glucuronic acid and UGT1 nz)
• GSTs transport bili from liver cytoplasm to ER where conjugation takes place
• Conjugation (not technically direct bili, but close enough) increases the hydrophilicity of the bili so it can be released across canalicular membrane into the bile (using MRP2 aka ABCC2)

Question 2

Bilirubin metabolism 2

Answer 2

• Excreting conjugated bili into bile is rate limiting step in bili excretion
• Once in colon the conjugated bili is converted to urobilinogen by GI bacteria, and a little of it is reabsorbed into blood to be excreted by kidneys (most is excreted in feces)
• If there are detectable levels of urobilinogen in urine there must be a patent biliary system getting the bili into the colon
• Some bili is unconjugated by bacteria in GI and is reabsorbed

Question 3

Different types of hyperbilirubinemia

Answer 3

• In unconjugated hyperbili almost all of the total bili is indirect (>80%)
• If the amount of direct bili is >20% or 2mg/dl then it is a conjugated/mixed hyperbili
• Unconjugated hyperbili DDx: increased bili load, decreased hepatic uptake, decreased conjugation (UGT1 activity)
• Unconjugated hyperbili for the most part are hemolytic anemias, drugs that reduce hepatic indirect bili uptake (rifampin), gilbert’s syndrome, or crigler-najjar
• Conjugated hyperbilis are usually cholestatic disease, or other genetic diseases (dubin-johnson, rotor’s syndrome)

Question 4

Cirgler-Najjar syndrome 1

Answer 4

• 2 types: type 1 is absent UGT1, type 2 is decreased UGT1 activity
• Type 1: absent UGT1, rare, leads to severe unconjugated hyperbili (15-45)
• Nl liver function labs, but can lead to severe kernicterus in neonates
• Non-responsive to phenobarbital Rx, neonates must be put under continuous photoRx, liver Tx (must be done before irreversible basal ganglia damage)

Question 5

Cirgler-Najjar syndrome 2

Answer 5

• Sx of kernicterus (more common in prematures): cerebral palsy, rigidity, tremors, seizures, hearing loss, oculomotor paralysis
• Type 2: decreased UGT1, more common, moderate unconjugated hyperbili (8-25)
• Nl liver function labs, kernicterus is rare, phenobarbital lowers serum bili by 25-70% in 48 hrs
• Rx is photoRx and phenobarbital

Question 6

Gilbert’s syndrome

Answer 6

• Very common cause of mild unconjugated hyperbili, often becomes apparent in adolescence
• Baseline bili btwn 1-2mg, but can rise 2-3x during fasting, stress, sickness (unconjugated bili usually <4mg)
• 50% reduction in UGT1 activity, due to mutations in promotor region of the gene
• Other liver fxn tests (AST/ALT/PT/alb) all nl
• There is diurnal variation of UGT1 activity (less in afternoon/night)
• Benign d/o that requires no Rx

Question 7

Physiologic jaundice

Answer 7

• Combinaiton of hematologic, hepatic, and intestinal events that are unique to newborns and accentuated in premies, 2 phases
• Due to: increased bili production (lots of RBCs and decreased RBC survival), decreased bili-alb binding, decreased binding to GSTs (bili ligand to get it to UGT1), decreased UGT1 activity, increased enterohepatic circulation of bili
• Phase 1: rapid rise of unconjugated bili to 6-7 at 3 days, then rapid decline to 2mg from days 3-5
• Phase 2: unconjugated bili decreases to adult levels by day 14
• Some nl babies and many premies will have exaggerated phase 1 levels (10-12) and will sustain those levels for longer
• Premies can have a prolonged phase 2

Question 8

Breast milk jaundice and photoRx

Answer 8

• Breast milk jaundice can be early ones (first 3 days) or late onset (after day 4-5)
• Early onset related to caloric deprivation and dehydration, much more common
• Late onset has more severe jaundice but not associated w/ kernicterus, etiology unclear
• Should distontinue breast feeding for 14-48 hrs in late onset
• PhotoRx is used to help convert unconjugated bili to a more water-soluble form by using light
• This reduces kernicterus by reducing amount of lipophilic bilirubin that can cross the BBB

Question 9

Alternate methods of conjugated bili excretion

Answer 9

• A portion of conjugated bili is excreted across the hepatocyte canalicular membrane by MRP2 (aka ABCC2) into bile
• But another portion is regurgitated back into sinusoidal space by ABCC3
• This portion of conjugated bili is take up by downstream hepatocytes by OATP1B transporters, allowing for hepatocytes to work together in increasing amount of bili that can be excreted when challenged w/ high bili load

Question 10

Ddx of conjugated hyperbili

Answer 10

• Hepatocellular dysfxn (liver injury)
• Diseases of biliary tree (cholestasis): PSC, PBC
• Biliary obstruction: stones, neoplasia
• Sepsis
• Paraneoplastic syndrome: due to cytokine release
• Genetic causes: dubin-johnson, rotor’s syndrome

Question 11

Dubin-johnson syndrome (DJS)

Answer 11

• Mutations in MRP2 (ABCC2): autosomal recessive
• Selective loss of conjugated bili transport across canalicular membrane
• Bile secretion does not stop completely, therefore nl cholesterol, synthetic fun, INR, serum bile salts
• The liver is PIGMENTED (dark) on autopsy

Question 12

Rotor’s syndrome

Answer 12

• Conjugated hyperbili w/ alterations in urinary excretion of coproporphyrin isomers (used to differentiate from DJS)
• Differences in urinary excretion of coproporphyrin isomers are used to differentiate from DJS
• Due to mutations in OATP1B (SLCO genes), making hepatocytes unable to reabsorb conjugated bili by downstream hepatocytes
• 89% of coproporphyrin is excreted as coproporphyrin I isomer in DJS, but only 43% is excreted as coproporphyrin I in Rotor’s syndrome
• Liver is NOT PIGMENTED (nl color on autopsy)

Question 13

Work up of unexplained jaundice in adults

Answer 13

• Obstructive profile (AP>ALT w/ conjugated/mixed bili): workup for cholestatic diseases
• Hepatocellular profile (ALT>AP w/ conjugated/mixed bili): workup for liver injury/hepatitis diseases
• Isolated unconjugated hyperbili: probably gilbert’s, workup for hemolytic anemias/crigler nadir type 2 (depending on clinical picture)