Metabolic Diseases of the Liver

Question 1

Inherited Deficient Conjugation of Bilirubin is also called as……?

Answer 1

Familial Nonhemolytic Unconjugated Hyperbilirubinemia)

Question 2

What is UDPGT

Answer 2

Diphosphoglucuronate glucuronosyltransferase

Question 3

3 genetically and functionally distinct disorders in which UDPGT activity is deficient or altered ……..?

Answer 3

Crigler-Najjar [CN] syndromes type I and II and Gilbert syndrome

Question 4

———is the primary UDPGT isoform needed for bilirubin glucuronidation

Answer 4

UGT1A1

Question 5

CN type 1 and CN type 2 difference….?

Answer 5

Complete absence of UGT1A1 activity causes CN type I,

CN type II is caused by decreased UGT1A1 activity to ~10% of normal.

Question 6

The most common hereditary hyperbilirubinemia

Answer 6

Gilbert syndrome

5–10% of the white population

Question 7

Clinical presentation of Gilbert syndrome…..?

Answer 7

Gilbert syndrome usually occurs after puberty, is not associated with chronic liver disease, and no treatment is required.

Disease manifestations include fluctuating mild elevations in total serum bilirubin concentration from 1 to 6 mg/dL with no evidence of liver injury or hemolysis.

Because UGT1A1 catalyzes watersoluble glucuronidation and detoxification of multiple substrates other than bilirubin

Question 8

Mutations in the UGT1A1 gene predisposes to …..?

Answer 8

Implicated in cancer risk and predispose to drug toxicity and episodic jaundice specifically in cancer chemotherapy.

Question 9

CRIGLER-NAJJAR SYNDROME TYPE I

(GLUCURONYL TRANSFERASE DEFICIENCY)…….

Answer 9

CN type I is a rare
Autosomal recessive
Disease caused by homozygous or compound heterozygous mutations in the UGT1A1 gene
Complete absence of UGT1A1 activity

Question 10

Clinical Manifestationsof CN type 1

Answer 10

Severe unconjugated hyperbilirubinemia develops in homozygous affected infants in the first 3 days of life.

Without treatment, serum unconjugated bilirubin concentrations reach 25-35 mg/dL in the 1st mo, which can cause kernicterus.

Stools are pale yellow.

Persistent unconjugated hyperbilirubinemia at levels >20 mg/dL without hemolysis after the 1st wk of life should suggest the syndrome.

Question 11

Diagnosis of CN type 1…….?

Answer 11

The diagnosis of CN type I is based on the early age of onset and the extreme level of bilirubin elevation in the absence of hemolysis.

Bile contains no bilirubin glucuronide and bilirubin concentration in bile is <10 mg/dL (50-100 mg/dL)

Measuring hepatic glucuronyl transferase activity in a liver specimen obtained by percutaneous liver biopsy

Question 12

Treatment for CN type 1……..?

Answer 12

Requires repeated exchange transfusions and phototherapy in the immediate neonatal period.

Question 13

Drugs for CN type 1……?

Answer 13

Oral calcium phosphate supplementation renders phototherapy more effective as it forms complexes with bilirubin in the gut.

Phenobarbital therapy, through CYP450 enzyme induction, should be considered to determine responsiveness and differentiation between CN types I and II.

In patients with CN type I there is no response to phenobarbital treatment

Question 14

Brain injury beyond the neonatal period are occurs with bilirubin levels….?

Answer 14

Usually >35 mg/dL

Therefore, phototherapy is generally continued through the early years of life.

Question 15

Additional adjuvant therapy using agents that bind photobilirubin products…….?

Answer 15

Cholestyramine or Agar can also be used to interfere with the enterohepatic recirculation of bilirubin.

Question 16

Risk of kernicterus in CN type 1 …..?

Answer 16

All reported patients with CN type I have eventually experienced severe kernicterus by young adulthood.

Question 17

Role of liver transplant in CN type 1……?

Answer 17

Orthotopic liver transplantation cures the disease and has been successful in a small number of patients.

Isolated hepatocyte transplantation has been reported as bridge therapy to liver transplantation, with most but not all patients eventually requiring orthotopic transplantation

Question 18

Other therapeutic modalities for CN type 1….?

Answer 18

Plasmapheresis and limitation of bilirubin production.

The latter option, inhibiting bilirubin generation, is possible via inhibition of heme oxygenase using metalloporphyrin therapy.

Question 19

CRIGLER-NAJJAR SYNDROME TYPE II

(PARTIAL GLUCURONYL TRANSFERASE DEFICIENCY)…

Answer 19

Autosomal recessive

Disease caused by homozygous missense mutations in UGT1A1

Results in reduced (partial) enzymatic activity.

Question 20

How to differentiate between type 1 & 2 CN…..?

Answer 20

Type II disease can be distinguished from type I by the marked decline in serum bilirubin level that occurs in type II disease after treatment with phenobarbital secondary to an inducible phenobarbital response element on the UGT1A1 promoter.

Question 21

Bilirubin levels in CN type 2……?

Answer 21

unconjugated hyperbilirubinemia usually occurs in the first 3 days of life

Range compatible with physiologic jaundice or can be at pathologic levels persisting in a range of 1.5-22 mg/dL

Question 22

Clinical and lab findings in CN type 2 …..?

Answer 22

Development of kernicterus is unusual.

Stool color is normal, and the infants are without clinical signs or symptoms of disease.

There is no evidence of hemolysis.

Liver enzymes, albumin, and PT/INR are typically normal.

Question 23

Long term treatment for CN type 2….?

Answer 23

5 mg/kg/day of oral phenobarbital, with a decrease in serum bilirubin concentration to 2-3 mg/dL in 7-10 days.

Therapy must be lifelong.

Orlistat, an irreversible inhibitor of intestinal lipase, increases fecal fat excretion and may decrease plasma unconjugated bilirubin concentrations (~10%) in patients with CN types I and II.

Question 24

Name the INHERITED CONJUGATED HYPERBILIRUBINEMIA …..?

Answer 24

Dubin-Johnson syndrome

Rotor Syndrome

Question 25

Characteristics features of inherited conjugated hyperbilirubinemia…….?

Answer 25

Autosomal recessive

Asymptomatic mild jaundice

The transfer of bilirubin and other organic anions from the hepatocyte into bile is defective

The results of other routine liver tests are normal.

Question 26

DUBIN-JOHNSON SYNDROME……?

Answer 26

Inherited defect in hepatocyte secretion of bilirubin glucuronide

Not limited to conjugated bilirubin excretion but also involves several organic anions normally excreted from the liver cell into bile

Question 27

Gene defect in Dubin-Johnson syndrome…..?

Answer 27

Disease results from absent function of multiple drugresistant protein 2 (MRP2, encoded by the gene ABCC2), an adenosine triphosphate–dependent canalicular transporter

Question 28

Cholangiography Dubin-Johnson syndrome…..?

Answer 28

fails to visualize the biliary tract and

x-ray of the gallbladder is also abnormal

Liver histology demonstrates normal architecture, but hepatocytes contain black pigment similar to melanin

Question 29

Clinical presentation of Dubin-Johnson syndrome…?

Answer 29

The most commonly reported symptoms are abdominal pain and fatigue, jaundice, dark urine, and slight enlargement of the liver

Jaundice fluctuates in intensity and is aggravated by intercurrent disease.

Rarely, Dubin-Johnson can present in the neonatal period

Question 30

Treatment for Dubin-Johnson syndrome…..?

Answer 30

No treatment is indicated for disease which presents outside of the neonatal period.

Question 31

Rotor Syndrome gene responsible …..?

Answer 31

Inactivating mutations in SLCO1B1 and SLCO1B3 result in functional deficiencies of both OATP1B1 and OATP1B protein

Question 32

Pathophysiology of Neonatal iron storage disease (NISD), (also known as neonatal hemochrombtosis)….?

Answer 32

During gestation, the maternal immune system becomes sensitized to an unknown fetal hepatocyte cell surface antigen.

Maternal immunoglobulin G to this fetal antigen then crosses the placenta and induces hepatic injury via immune system activation

Question 33

The defining feature of gestational alloimmune liver disease……?

Answer 33

It is complement-mediated hepatocyte injury, the evidence for which comes from detection of the C5b-9 complex by immunohistochemistry on liver tissue of affected infants.

Question 34

Why Neonatal iron storage disease (NISD) is not primary iron disease….?

Answer 34

It is thought that fetal liver injury is the primary event leading to the development of the neonatal hemochromatosis phenotype, providing further evidence that this is not a primary iron overload disease.

Question 35

Features of NISD …..?

Answer 35

It is a rapidly fatal, progressive illness characterized by hepatomegaly, hypoglycemia, hypoprothrombinemia, hypoalbuminemia, hyperferritinemia, and hyperbilirubinemia

The coagulopathy is refractory to therapy with vitamin K

Question 36

Prognosis of NISD……?

Answer 36

The prognosis for affected infants is generally poor.

Question 37

Treatment for NISD …….?

Answer 37

Intravenous immunoglobulin (IVIG) combined with double volume exchange transfusion has been shown to remove the injury-causing maternal IgG and improve outcomes in infants with NISD

Liver transplantation should also be an early consideration

Question 38

How to prevent NISD subsequent pregnancy …..?

Answer 38

Recurrences of NISD in subsequent pregnancies may be modified with IVIG administered to the mother once weekly from the 14th wk of gestation until delivery