T HE L IVER B ILIRUBIN M ETABOLISM Anson Lowe September 29, 2015.
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THE LIVERBILIRUBIN METABOLISM
Anson Lowe
September 29, 2015
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Overall plan and function of the liverBilirubin physiologyUnderstand bilirubin as biomarker for
liver diseaseBilirubin; liver
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Henry Gray (1825–1861). Anatomy of the Human Body. 1918.
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Gray’s Anatomy
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Liver Functions
Bilirubin metabolism Protein Synthesis
◦ Albumin◦ Coagulation factors (II, V, VII, IX, X)
Bile Salt Metabolism Lipid Metabolism Glycogen storage and gluconeogenesis Drug metabolism/Xenobiotic transformation
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http://minimopar.knizefamily.net/oilfilterstudy.html
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Bile
H20 84%
Bile Salts 11.5%
Phosphatidyl Choline(lecithin)
3.0%
Bile pigments, protein, inorganic ions
1.0%
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BilirubinBreakdown product of heme compoundsNeurotoxic in infants◦Secondary to immature blood-brain barrier
Bilirubin metabolism is used as a marker to localize the site of liver disease
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Bilirubin - Source Breakdown product of hemoglobin from ineffective erythropoiesis and
red blood cell senescence (80%)◦ Reticuloendothelial cells mainly in the spleen and liver represent the major sites
of breakdown◦ Enhanced with increased RBC turnover as seen in the hemoglobinopathies (e.g.
Sickle-cell disease)
Other heme containing compounds (20%)
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Fate of 14C-glycine, a precursor of heme that is metabolized to bilirubin
BilirubinSpecific Acitivity
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RBC breakdown
Turnover of RBC’s in the spleen, liver, bone marrow, and lymph nodes◦Reticuloendothelial cells are phagocytic
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NEJM 344:581 (2001)
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Bilirubin - Plasma Transport
Bilirubin is hydrophobic and thus insoluble in blood◦ It is transported in blood bound to albumin
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Albumin
The major plasma protein◦ Contributes to the total oncotic pressure of blood.
A general carrier for many hydrophobic compounds◦ High capacity for bilirubin◦ Reversible◦ Binding of bilirubin can be compromised by competition from other hydrophobic
compounds
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Competition for Albumin Binding
Drugs: sulfonamides, streptomycin, chloramphenicol, ampicillin, salicylates, diuretics, food additives
Free fatty acids
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Bilirubin - Hepatic Uptake
Bilirubin is unloaded from albumin and transported into the hepatocyte
~30% is taken up with each pass through the liver
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Bilirubin - Intracellular Transport
Intracellular transport is mediated by ligandin, a cytoplasmic protein
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Conjugation
Bilirubin is then conjugated to carbohydrate (glucoronyl moieties) that increases water solubility◦UDP-glucuronyltransferase
Bilirubin mono- and diglucoronide
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Bilirubin Monoglucuronide
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Bilirubin Diglucoronide
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Trauner et al., NEJM (1998) 339:1217
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Excretion of bilirubinC-MOAT transporter (MRP2)◦Member of the mdr family
Transport of conjugated bilirubin◦The most sensitive step in bilirubin metabolism◦Sensitive to estrogens, infections
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Laboratory Assessment
Total bilirubinDirect bilirubin = “conjugated bilirubin”◦Represents that hydrophillic fraction of bilirubin that is
more readily accessible to diazo dyes. To determine the total bilirubin, an accelerator is added make all the bilirubin reactive with the dye
Calculated indirect bilirubin = unconjugatedbilirubin
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36 year old pregnant woman presents with acute right upper quadrant pain◦Total bilirubin = 8.2 (0.1-1.2)◦Direct bilirubin = 7.9
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Normal Values Bile duct obstruction
Hemolytic anemia
Liver Failure
Total bilirubin 0.3-1.3 mg/dl
Direct bilirubin 0.1-0.3 mg/dl nl
Indirect bilirubin
nl
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46 year old man with colon cancer and recently discovered liver metastasis◦Total bilirubin = 15.2 (0.1-1.2)◦Direct bilirubin = 2.3
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Prothrombin time - 15 sec (normal < 12)
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2 - day newborn who is brought back to the hospital jaundiced◦Total bilirubin = 11.0 (0.1-1.2)◦Direct bilirubin = 0.3
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KernicterusBilirubin encephalopathy◦Neonates have an immature blood-brain barrier
Deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei◦Usually 21-50mg/dL
Can result in death or permanent neurological defects
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An 18 year old male presents to the local draft board for his physical exam
He is slightly jaundiced◦Total bilirubin = 3.2 (0.1-1.2)◦Direct bilirubin = 0.2
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His little brother accompanying him says he has been fasting for the last two days
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NEJM (1995) 333:1171
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NEJM (1995) 333:1171
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NEJM (1995) 333:1171
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Gilbert’s Syndrome
Polymorphism in the promoter region affect the expression of UDP-glucoronyltransferase
Patients with (TA)7 instead of (TA)6 have lower UDP-G activity
Exhibit mild elevations of bilirubin that is exacerbated by fasting, stress, or illness.
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Congenital Bilirubin DisordersCrigler-Najjar Syndrome - mutations in the UDP-
glucoronyltransferase gene◦ Type I: Autosomal recessive with complete absence of
activity leading to death◦ Type II: Partial expression with some activity
Dubin-Johnson Syndrome◦Defects in CMOAT (MRP2) resulting in an excretory
defect. Results in pigmented livers
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Liver Function Tests
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Liver Function TestsWhere is the problem?◦Biliary tract
gallstones cholangiocarcinoma
◦Hepatocyte viral or alcoholic hepatitis
◦Mixed hepatocellular carcinoma
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Liver Function TestsIs this an acute or chronic disease?◦Half-life of liver derived proteins◦ If the liver stopped functioning today, how long
would it take to see an abnormality in the blood?
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