359 The Hyperbilirubinemias Flashcards
Enzyme for conjugation of bilirubin
UDP-glucuronosyltransferase
Mutation in Dubin Johnson Syndrome
MRP2
multidrug resistance–associated protein 2
Mutation in Rotor syndrome
MRP3
hemolysis alone cannot result in a sustained hyperbilirubinemia of more than _?
∼68 μmol/L (4 mg/dL)
When hemolysis is the only abnormality in an otherwise healthy individual, the result is a purely unconjugated hyperbilirubinemia, with the direct-reacting fraction as measured in a typical clinical laboratory being___ of the total serum bilirubin.
≤15% of the total serum bilirubin.
Defect in Glibert syndrome
Decreased hepatic bilirubin uptake
Several drugs, including R__, F___, N____, as well as various cholecystographic contrast agents, have been reported to inhibit bilirubin uptake
flavaspidic acid, novobiocin, and rifampin
transient familial neonatal hyperbilirubinemia in which there is a UGT1A1 inhibitor in maternal serum.
Lucey-Driscoll syndrome
marked unconjugated hyperbilirubinemia in the absence of abnormalities of other conventional hepatic biochemical tests, hepatic histology, or hemolysis
marked unconjugated hyperbilirubinemia in the absence of abnormalities of other conventional hepatic biochemical tests, hepatic histology, or hemolysis
Reduction of serum bilirubin concentrations by >25% in response to enzyme inducers such as _______ distinguishes CN-II from CN-I, although this response may not be elicited in early infancy and often is not accompanied by measurable UGT1A1 induction.
phenobarbital
TABlE 359-1
STUDY!
This syndrome is characterized by mild unconjugated hyperbilirubinemia, normal values for standard hepatic biochemical tests, and normal hepatic histology other than a modest increase of lipofuscin pigment in some patients.
Gilbert Syndrome (GS)
Serum bilirubin concentrations are most often ______ in Gilbert Syndrome (GS)
<51 μmol/L (<3 mg/dL),
associated with stress, fatigue, alcohol use, reduced caloric intake, and intercurrent illness, while increased caloric intake or administration of enzyme-inducing agents produces lower bilirubin levels.
Gilbert Syndrome (GS)
IN Gilbert Syndrome: UGT1A1 activity is typically reduced to ______ of normal, and bile pigments exhibit a characteristic increase in bilirubin (mono or di glucoronides?)
10–35%
bilirubin monoglucuronides.
Administration of phenobarbital normalizes both the serum bilirubin concentration and hepatic bilirubin clearance in this syndrome
Gilbert Sydrome
Administration of ______ to patients with GS has resulted in several toxicities, including intractable diarrhea and myelosuppression.
CPT-11
antitumor agent irinotecan (CPT-11), whose active metabolite (SN-38) is glucuronidated specifically by bilirubin-UDP-glucuronosyltransferase
HIV protease inhibitors indinavir and atazanavir (Chap. 226) can inhibit UGT1A1, resulting in hyperbilirubinemia that is most pronounced in patients with preexisting GS.
indinavir and atazanavir
Gene defect in GS
Studies in Europe and the United States found that nearly all patients had normal coding regions for UGT1A1 but were homozygous for the insertion of an extra TA (i.e., A[TA] 7 TAA rather than A[TA] 6 TAA) in the promoter region of the first exon
FAMILIAL DEFECTS IN HEPATIC EXCRETORY FUNCTION (4)
Dubin-Johnson Syndrome (DJS)
Rotor Syndrome
Benign Recurrent Intrahepatic Cholestasis (BRIC)
Progressive Familial Intrahepatic Cholestasis (FIC)
The degree of hyperbilirubinemia may be increased by intercurrent illness, oral contraceptive use, and pregnancy.
DJS or GS
DJS
Patients with DJS are usually asymptomatic, although some may have vague constitutional symptoms.
True
A cardinal feature of ________ is the accumulation in the lysosomes of centrilobular hepatocytes of dark, coarsely granular pigment. As a result, the liver may be grossly black in appearance. This pigment is thought to be derived from epinephrine metabolites that are not excreted normally. The pigment may disappear during bouts of viral hepatitis, only to reaccumulate slowly after recovery.
DJS
Patients with _____ also have a diagnostic abnormality in urinary coproporphyrin excretion.
DJS
Normally, ∼75% of the coproporphyrin in urine is isomer III. In urine from DJS patients, total coproporphyrin content is normal, but >80% is isomer I
The molecular basis of Rotor syndrome results from simultaneous deficiency of which plasma membrane transporters ?
OATP1B1 and OATP1B3
This results in reduced reuptake of conjugated bilirubin that has been pumped out of the cell into the portal circulation by MRP3
This rare disorder is characterized by recurrent attacks of pruritus and jaundice. The typical episode begins with mild malaise and elevations in serum aminotransferase levels, followed rapidly by rises in alkaline phosphatase and conjugated bilirubin and onset of jaundice and itching.
Benign Recurrent Intrahepatic Cholestasis (BRIC)
A gene termed ____ was recently identified and found to be mutated in patients with BRIC.
FIC1
A second phenotypically identical form of BRIC, termed BRIC type 2, has been described resulting from mutations in the _____, the protein that is defective in progressive familial intrahepatic cholestasis type 2
bile salt excretory protein (BSEP)
presents in early infancy as cholestasis that may be initially episodic. However, in contrast to BRIC, ________ progresses to malnutrition, growth retardation, and end-stage liver disease during childhood.
Progressive FIC type 1 (Byler disease)
Progressive Familial Intrahepatic Cholestasis (FIC)
Progressive FIC type 2 is associated with a mutation in the protein originally named sister of p-glycoprotein, now known as _______, which is the major bile canalicular exporter of bile acids.
bile salt excretory protein
Progressive FIC type 3 has been associated with a mutation of _____ a protein that is essential for normal hepatocellular excretion of phospholipids across the bile canaliculus
MDR3
Although all three types of progressive FIC have similar clinical phenotypes, only type _____ is associated with high serum levels of γ-glutamyltransferase activity.
3
