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Gastrointestinal System > Bilirubin Metabolism - Abali 2/22/16 > Flashcards

Bilirubin Metabolism - Abali 2/22/16 Flashcards

1
Q

bile metabolism: related disease

bilirubin metabolism: related disease

A

bile: cholestasis
bilirubin: bilirubinemia/jaundince/icterus

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2
Q

bilirubinemia

A

jauncice, icterus

increased bilirubin in circulation

  • yellowing of eyes, hands
    • if no eyes…might be hyperbetacarotenemia (high levels of beta-carotene : precursor of vit A)
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3
Q

key functions of heme in the body

A
  • hemoglobin: oxygen transport in blood
  • myoglobin: oxygen storage in muscle
  • cytochrome c: e transport chain
  • cytochrome P450s: toxin breakdown
  • catalase: H2O2 breakdown
  • Trp pyrrolase: oxidation of Trp
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4
Q

types of hemolysis

  • proportions, location
A

extravascular (90%): macrophage phagocytosis in liver/spleen

and

intravascular (10%): in vasculature

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5
Q

extravascular hemolysis

A
  • 90% of hemolysis
  • RBCs phagocytized by macrophages in liver and spleen
  • characterized by spherocytes (round cells - not discs)

why?

  • senescent RBCs
  • RBCs with membrane abnormalities (bound Ig)
  • RBCs with physical abnormalities that prevent exit from spleen (sickle cell, thallasemia, PK deficiency)
    *
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6
Q

intravascular hemolysis

A
  • 100% of hemolysis
  • RBC lysis within circulation
  • characterized by fragmented cells called schistocytes

why?

  • trauma
  • complement fixation
  • toxic damage to RBC
  • Favism (G6PD deficiency)
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7
Q

extravascular erythrocyte destruction

A
  • accounts for daily 1% normal RBC turnover
  • reticuloendothelial system is responsible
    • monitors RBCs
    • macrophages of liver, spleen, and bone marrow engulf RBCs before they lyse
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8
Q

salvage of intravascular hemolysis products

A

hemolysys releases RBC contents including Hb and heme

  • Hb binds to haptoglobin
    • Hb-Hp binds to receptor on macrophage, gets endocytosed
  • heme binds to hemopexin
    • ​heme-hemopexin binds to receptor on macrophage, gets endocytosed

in macrophage, Hb and heme undergo lysosomal degredation releasing…

  • CO
  • Fe+2 (recycled)
  • heme → biliverdin → bilirubin
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9
Q

symptom: low/no haptoglobin in circulation

A

potentially hemolysis taking place somewhere → all haptoglobin is bound to hemoglobin that needs to be degraded, so none is free in circulation

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10
Q

heme degradation

A

in the macrophages of the reticuloendothelial system (liver, spleen, bone marrow)

same enzymes whether intra/extravascular hemolysis

heme [purple] → biliverdin [green]

  • via heme oxygenase
  • uses oxygen; gives off Fe+3, CO

biliverdin [green] → bilirubin [red-orange]

  • via biliverdin reductase
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11
Q

bilirubin transport and modification in liver

A

released from site of production (macrophages of RES) into circulation

  • it’s hydrophobic! need something for it to be bound to in circ: albumin

in liver,

  • GST-B (glutathione S transferase B, aka ligandin) traps bilirubin in liver [“indirect”/unconjugated bilirubin]
  • conjugation occurs via UDP-GT (UDP gucuronyl transferase aka UGT1A1)
    • attaches 2 glucoronic acid to bilirubin [“direct” bilirubin-monoglucuronide, “direct” bilirubin-diglucuronide]
  • conjugated bilirubin moves into gallbladder → can be secreted into sm intestine
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12
Q

bilirubin in intestinal tract, fates

A

in colon

  • bacterial enzymes deconjugate bilirubin-diglucuronide back to bilirubin
  • bacterial enzymes take bilirubin → urobilinogen
    • 10% urobilinogen reabs and sent back to liver via hepatic portal circ → central circ to kidney → oxidized to urobilin (yellow, gives urine its color), excreted in urine
    • 90% unabsorbed, further modified to stercobilin, urobilin (gives red-brown color to feces), excreted in feces
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13
Q

urobilinogen: antibiotics and urine concentration

A

oral admin of broad spectrum antibiotics drastically drops production of urobilinogen

high urine concentration of urobilinogen associated with hemolytic disorders/hepatocellular disease

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14
Q

direct vs. indirect bilirubin

A

direct = conjugated

indirect = unconjugated

named based on test, which makes use of van den Bergh rxn in which bilirubin is coupled with diazonium salt to make colored complex

  • direct bilirubin: fraction which complexes with diazonium salt in absence of an accelerator
    • approximates conjugated bilirubin (normal : 0-0.3 mg/dL)
  • total bilirubin: bilirubin which complexes with diazonium salt in presence of an alcohol accelerator
  • indirect bilirubin: diff between total and direct bilirubin
    • ​approximates unconjugated bilirubin (normal : 0.3-1.9 mg/dL)
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15
Q

why is direct bilirubin supposed to be near-absent in circulation?

A

macrophages that bring bilirubin to liver bring it in circulation as indirect bilirubin

conjugation to direct bilirubin occurs in the liver

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16
Q

heme oxygenase

A

enzyme found in macrophages of RES (liver, spleen, bone marrow)

converts heme to biliverdin

  • produces Fe+3 and CO (only rxn that produces CO)
  • uses NADPH
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17
Q

biliverdin

A

heme to biliverdin + CO, catalyzed by heme oxygenase in RES macrophages

  • biliverdin and CO are cytoprotective
    • ​biliverdin = antioxidant
    • CO = signaling mol, vasodilator
18
Q

biliverdin reductase

A

catalyzes biliverdin to bilirubin in RES macrophages

  • uses NADPH
  • bilirubin produced is released from macrophage into circ bound to albumin
19
Q

reactions catalyzed by UDP-GT

consequence of reduced UDP-GT activity

A

UDP-GT conjugates bilirubin with glucoronic acid in liver

  1. bilirubin + UDP-glucoronic acid → BMG
  2. BMG + UDP-glucoronic acid → BDG (conjugated bilirubin)

under normal conds, the second reaction is rate limiting step

  • if there’s a reduction in UDP-GT activity (ex. in genetic conds), you’ll see buildup of BMG
20
Q

bilirubin transport

  • into hepatocytes
  • into bile canaliculi
  • efflux from hepatocytes
  • reuptake by hepatocytes from circ
A

influx

  • unconj bilirubin into hepatocytes: OATP1B1
    • acted on by GST-B to prevent auto-efflux
  • reabs conj bilirubin, into hepatocyltes: OATP1B1, OATP1B3

efflux

  • into bile canaliculi: MRP2
  • sinusoidal efflux: MRP3 [uses ATP]

OATP = organic anion transporting polypeptide

21
Q

jaundice overview

A

French jaune = yellow

= icterus = hyperbilirubinemia

  • consequence of malfunction in heme degradation
  • not a disease!!! indicator that something else might be wrong
    • ​can be a serious problem in newborns
22
Q

jaundice

  • clinical features
  • biochemical features
A

clinical features

  • yellowing of skin and eyes
    • due to affinity of elastin for bilirubin
    • reason why you DO NOT see yellowing of eyes in hyperbetacarotenemia! (sclera x carotene)

biochemical features

  • accumulation of bilirubin in hydrophobic compartments of periph tissues
    • usually in cytoplasmic membranes
  • bilirubin is harmless in older children and adults, not in newborns
    • ​has neurotoxic props in newborns, leads to KERNICTERUS
23
Q

causes of jaundice

A

prehepatic

  • hemolysis : autoimmune or abnormal Hb : rare

intrahepatic

  • infection
  • chemicals/drugs
  • genetic errors : bilirubin metab [4 syndromes]
  • genetic errors : specific proteins (Wilson’s disease/Cu toxicity)
  • autoimmune : chronic active hepatisis
  • neonatal : physiologic : common

posthepatic

  • intrahepatic bile ducts
  • posthepatic bile ducts
24
Q

physiological jaundice

A

newborns achieve adult levels of UDP-GT in approx 1 month

  • premature babies have less to begin with, so it takes them longer to catch up
    • buildup of unconjugated/indirect bilirubin in the catchup period is normal for all babies, but if a baby starts with a lower stock of UDP-GT, the increased buildup can reach dangerous levels
25
Q

kernicterus

A

condition in newborns in which bilirubin accumulates in parts of the brain (kern = nucleus), causes neurotoxicity

yellow-staining of deep nuclei of brain

symptoms

  • early
    • extreme jaundice
    • absent startle reflex
    • poor feeding/sucking
    • extreme lethargy
  • midstage
    • high pitched cry
    • arched back, neck hyperextended
    • bulging fontanel
    • seizures
  • late state (full neurological syndrome)
    • high freq hearing loss
    • intellectual disability
    • muscle rigidity
    • speech difficulty
    • seizures
    • movement disorder
26
Q

treatment for neonatal jaundice

A

bilirubin builds up in part bc it’s so insoluble: making it more soluble would allow it to be excreted in urine

phototherapy (blue light oxidizes bilirubin, makes it into more soluble products: yellow photoisomers and colorless oxidation pdts)

  • photoisomers → excreted in bile (main pathway)
  • oxidation products → excreted in urine (minor pathway)
27
Q

intrahepatic causes of jaundice due to genetic errors in bilirubin metabolism

A
  1. Rotor’s syndrome
    * absence of OATP1B1, OATP1B3 (influx of reabs conj bilirubin)
  2. Gilbert’s syndrome [1 in 20]
    * defect in UDP-GT : normal protein, but less of it
  3. Crigler-Najjar syndrome
    * defect in UDP-GT : either no protein or less protein
  4. Dubin-Johnson syndrome
    * absence of MRP2 (efflux of conj bilirubin from hepatocyte into bile canaliculus)
28
Q

Criggler-Najjar syndrome

Type 1

A
  • complete absence of UDP-GT gene
  • no enzyme activity
  • jaundice: severe, causes kernicterus
29
Q

Criggler-Najjar syndrome

Type 2

A
  • mutation in UDP-GT gene
  • some enzyme activity
  • jaundice: benign
30
Q

Dubin-Johnson syndrome

A
  • mutation in MRP2
    • diffuse deposition of course, dark-brown granular pigment in hepatocytes
  • some enzyme activity
  • jaundice: only symptom

*appears during adolescence/early childhood

*more common in Iranians, Morrocan Jews of Israel

31
Q

Rotor syndrome

A
  • biallelic inactivation mutation of OATP1B1, OATP1B3
  • no enzyme activity
  • jaundice: intermittent; mild conjugated/unconjugated jaundice

*appears shortly after birth/in childhood

32
Q

Gilbert syndrome

A
  • mutation in promoter of UDP-GT gene → reduced transcription
  • some enzyme activity
  • jaundice: mild, with physiologic stress

*appears during/after adolescence

*common (2-10% of pop)

33
Q

types of jaundice overview

A
  • prehepatic: hemolytic
  • intrahepatic
    • neonatal
    • hepatocellular
  • posthepatic
    • ​obstructive
34
Q

hemolytic jaundice

A

prehepatic

  • massive hemolysis : heme released in quantities that overwhelm liver’s capacity to degrade it
    • see increased indirect and increased direct bilirubin
    • buildup in blood and periph tissues
35
Q

neonatal jaundice

A
  • esp in premature infants
    • low levels of hepatic UDP-GT at birth
    • low levels of GST-B
  • increased levels of indirect bilirubin
36
Q

obstructive jaundice

A
  • obstruction of bile duct, prevents passage of conjugated bilirubin into intestines
  • feces have characteristic pale clay color due to absence of stercobilin
37
Q

hepatocellular jaundice

A

more complicated

  • damage to liver cells (via hepatitis, liver disease, alcohol) leading to decrease in normal fx
    • cant handle even normal loads
    • both liver uptake and conjugation can be affected
  • increased unconjugated bilirubin
38
Q

liver function tests:

AST, ALT, alkaline phosphatase

A

AST/ALT will usually work in tandem BUT

  • ALT > AST in viral hep
  • AST > ALT in alcoholic hep

alk phos

highest levels in biliary obstruction, infiltrative liver disease

39
Q

do bilirubin wrapup questions

A
40
Q
A

Gastrointestinal System (35 decks)

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