359 The Hyperbilirubinemias

Question 1

Enzyme for conjugation of bilirubin

Answer 1

UDP-glucuronosyltransferase

Question 2

Mutation in Dubin Johnson Syndrome

Answer 2

MRP2

multidrug resistance–associated protein 2

Question 3

Mutation in Rotor syndrome

Answer 3

MRP3

Question 4

hemolysis alone cannot result in a sustained hyperbilirubinemia of more than _?

Answer 4

∼68 μmol/L (4 mg/dL)

Question 5

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.

Answer 5

≤15% of the total serum bilirubin.

Question 6

Defect in Glibert syndrome

Answer 6

Decreased hepatic bilirubin uptake

Question 7

Several drugs, including R__, F___, N____, as well as various cholecystographic contrast agents, have been reported to inhibit bilirubin uptake

Answer 7

flavaspidic acid, novobiocin, and rifampin

Question 8

transient familial neonatal hyperbilirubinemia in which there is a UGT1A1 inhibitor in maternal serum.

Answer 8

Lucey-Driscoll syndrome

Question 9

marked unconjugated hyperbilirubinemia in the absence of abnormalities of other conventional hepatic biochemical tests, hepatic histology, or hemolysis

Answer 9

marked unconjugated hyperbilirubinemia in the absence of abnormalities of other conventional hepatic biochemical tests, hepatic histology, or hemolysis

Question 10

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.

Answer 10

phenobarbital

Question 11

TABlE 359-1

Answer 11

STUDY!

Question 12

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.

Answer 12

Gilbert Syndrome (GS)

Question 13

Serum bilirubin concentrations are most often ______ in Gilbert Syndrome (GS)

Answer 13

<51 μmol/L (<3 mg/dL),

Question 14

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.

Answer 14

Gilbert Syndrome (GS)

Question 15

IN Gilbert Syndrome: UGT1A1 activity is typically reduced to ______ of normal, and bile pigments exhibit a characteristic increase in bilirubin (mono or di glucoronides?)

Answer 15

10–35%

bilirubin monoglucuronides.

Question 16

Administration of phenobarbital normalizes both the serum bilirubin concentration and hepatic bilirubin clearance in this syndrome

Answer 16

Gilbert Sydrome

Question 17

Administration of ______ to patients with GS has resulted in several toxicities, including intractable diarrhea and myelosuppression.

Answer 17

CPT-11

antitumor agent irinotecan (CPT-11), whose active metabolite (SN-38) is glucuronidated specifically by bilirubin-UDP-glucuronosyltransferase

Question 18

HIV protease inhibitors indinavir and atazanavir (Chap. 226) can inhibit UGT1A1, resulting in hyperbilirubinemia that is most pronounced in patients with preexisting GS.

Answer 18

indinavir and atazanavir

Question 19

Gene defect in GS

Answer 19

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

Question 20

FAMILIAL DEFECTS IN HEPATIC EXCRETORY FUNCTION (4)

Answer 20

Dubin-Johnson Syndrome (DJS)
Rotor Syndrome
Benign Recurrent Intrahepatic Cholestasis (BRIC)
Progressive Familial Intrahepatic Cholestasis (FIC)

Question 21

The degree of hyperbilirubinemia may be increased by intercurrent illness, oral contraceptive use, and pregnancy.

DJS or GS

Answer 21

DJS

Question 22

Patients with DJS are usually asymptomatic, although some may have vague constitutional symptoms.

Answer 22

True

Question 23

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.

Answer 23

DJS

Question 24

Patients with _____ also have a diagnostic abnormality in urinary coproporphyrin excretion.

Answer 24

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

Question 25

The molecular basis of Rotor syndrome results from simultaneous deficiency of which plasma membrane transporters ?

Answer 25

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

Question 26

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.

Answer 26

Benign Recurrent Intrahepatic Cholestasis (BRIC)

Question 27

A gene termed ____ was recently identified and found to be mutated in patients with BRIC.

Answer 27

FIC1

Question 28

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

Answer 28

bile salt excretory protein (BSEP)

Question 29

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.

Answer 29

Progressive FIC type 1 (Byler disease) Progressive Familial Intrahepatic Cholestasis (FIC)

Question 30

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.

Answer 30

bile salt excretory protein

Question 31

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

Answer 31

MDR3

Question 32

Although all three types of progressive FIC have similar clinical phenotypes, only type _____ is associated with high serum levels of γ-glutamyltransferase activity.

Answer 32

3