4. Inherited Deficient Conjugation of
Bilirubin (Familial Nonhemolytic Unconjugated
Hyperbilirubinemia)
• Bilirubin is metabolic end product of heme.
• Bfr excretion it is glucuronidated by UDP-
glucuronyltransferase
• UDPGT activity is deficient or altered in 3 disorders
CRIGLER-NAJJAR syndromes type 1 & 2
GILBERT syndrome
• Produces congenital nonobstructive, nonhemolytic,
unconjugated hyperbilirubinemia
5. Gilbert syndrome
• Autosomal dominant trait
• The cause of this hyperbilirubinemia is the
reduced activity of the enzyme
glucuronyltransferase which conjugates
bilirubin.
• Usually occurs after puberty
• Not associated with c/c liver ds
• No treatment required
• Total S.bilirubin fluctuates from 1-6mg/dl
6. Crigler-Najjar type-1
• Rare
• Autosomal recessive trait
• Severe deficiency of UDP glucuronyl transferase.
• Often fatal
7. Crigler-Najjar type-1
• Clinical manifestations
Severe unconjugated hyperbilirubinemia develops in the
1st 3 days of life
Without trtmnt, S.unconjugated bilirubin concentrations
of 25-35mg/dl are reached in 1st month.
Kernicterus – universal complication
8. Crigler-Najjar type-1
Stools – pale yellow
Persistence of unconjugated hyperbilirubinemia
>20mg/dl after 1st week of life
In the absence of hemolysis
suggests CN type 1
9. Diagnosis
• Early age of onset
• Extreme level of bilirubin elevation in the absence of
hemolysis
• In the bile, bilirubin conc <10mg/dl (nly 50-100mg/dl)
• Definitive diagnosis- measuring hepatic glucuronyl
transferase activity in liver specimen
• Identification of heterozygous state in parents also strongly
suggests the diagnosis
10. Treatment
• The S.unconjugated bilirubin conc. Should be kept to <20
mg/dl for atleast 1st 2-4 wk of life
• This requires repeated exchange transfusions &
phototherapy in the immediate neonatal period.
• Oral calcium phosphate supplementation renders
phototherapy more effective as it forms complexes with
bilirubin in the gut.
• Phenobarbital therapy thru CYP450 enzyme induction-
determine responsiveness & differentiation btw type 1 & 2 [
CN type1- no response to phenobarbital Rx ]
11. Treatment
• The risk of kernicterus persists into adult life; therefore
phototherapy is continued thru the early yrs of life
• Despite the administration of ↑sing intensities of light for longer
periods, the S.bilirubin response to phototherapy ↓ses with age
• Adjuvant therapy using agents that bind photobilirubin
products such as cholestyramine or agar can also be used
• Orthotopic liver transplantation cures d ds
12. Treatment
• Inhibiting bilirubin production via heme oxygenase inhibitors
– metalloporphyrin therapy
• Prompt trtmnt of intercurrent infections, febrile episodes
might help in preventing later development of kernicterus
13. Crigler-Najjar type-2
• autosomal recessive ds
• characterized by unconjugated hyperbilirubinemia due to
reduced and inducible activity of hepatic bilirubin
glucuronosyltransferase (GT)
• Milder form
• CNS2 can be differentiated from CNS1 by the marked
decline in S.bilirubin level that occurs in type2 ds after Rx
with phenobarbital
14. Clinical manifestations
• Appears in neonatal period
• Unconjugated hyperbilirubinemia occurs in 1st 3 days of life
• Bilirubin level does not exceed 20mg/dl in type 2
• Development of kernicterus is unusual
• Stool color- normal
• Liver enzymes & synthetic function tests are normal
15. Diagnosis
• Respond readily to 5mg/kg/24 hr of oral phenobarbital,
with a decrease in S.bilirubin conc. To 2-3mg/dl in 7-10
days
16. Treatment
• Long term reduction- continued administration of
phenobarbital at 5mg/kg/24hr
• Good prognosis
17. Inherited Conjugated
Hyperbilirubinemia
• Caused by a small no of rare autosomal recessive
conditions
• Characterized by mild jaundice
• The transfer of bilirubin & other organic anions from the
liver cell to bile is defective
• Usually detected during adolescence or early adulthood
18. • Routine liver function tests are normal
• Jaundice can be exacerbated by infection, pregnancy,
OCP, alcohol consumption & surgery
• No morbidity & life expectancy is normal
19. Dubin-Johnson syndrome
• Autosomal recessive
• defective excretion of conjugated bilirubin due to defective
ATP dependent organic anionic transport in bile canaliculi
• There is mutation in the MRP-2 protein ( multi drug-resistant
protein2) which is responsible for transport of conjugated
bilirubin into bile
20. Dubin-Johnson syndrome
• Clinical manifestations
1. Abdominal pain
2. Fatigue
3. Jaundice- fluctuates in intensity & is aggravated by
intercurrent ds
1. Dark urine
2. Slight enlargement of liver
21. Diagnosis
conjugated hyperbilirubinemia
normal liver function findings
Total urinary coproporphyrin excretion is n/l, but coproporphyrin
1 excretion ↑ses to approximately 80% with a concomitant ↓se
in coproporphyrin 3 excretion .[ Nly coproporphyrin 3 is >75%
of the total]
Cholangiography fails to visualize biliary tract & xray gal
bladder is also abnormal
22. Diagnosis
• Liver histology demonstrates n/l architecture, but hepatocytes
contain black pigment similar to melanin
So referred as
BLACK LIVER
JAUNDICE
23.
24. Rotor Syndrome
• Autosomal recessive
• The SLCO1B1 and SLCO1B3 genes are involved in
Rotor syndrome. Mutations in both genes are required
for the condition to occur.
25. Diagnosis
• conjugated hyperbilirubinemia
• Total urinary coproporphyrin excretion is elevated with a
relative ↑se in the amt o the coproporphyrin 1 isomer
• There is no staining of the liver
• The gall bladder is normal by radiography
27. Wilson’s disease (hepatolenticular
degeneration)
Autosomal recessive
Incidence – 1 in 30,000- 1in 50,000 births
worldwide
Abnormal gene- localized to the long arm of
chromosome 13
The Wilson’s ds gene – ATP7B
28. Pathogenesis
The Wilson ds gene encodes a copper transporting P-type
adenosine triphosphatase
Mainly expressed in hepatocytes & is critical for biliary copper
excretion & for copper incoporation into ceruloplasmin
29. Absence/Malfunction of ATP7B → ↓sed biliary copper
excretion & diffuse accumulation of copper in the cytosol of
hepatocytes
↓
Liver cells become overloaded & Cu is redistributed to
other tissues, including brain & kidneys.
30. Absorption & Metabolism
Dietary source - meat, liver, sea food, cereals, nuts & seeds
Approximately 40% of ingested Cu is absorbed in stomach &
small intestine
↓
Transported to the liver bound to albumin
↓
Utilized by hepatocytes for synthesis of ceruloplasmin [8 Cu
atoms/ molecule; accounts for 95% of the ion in blood]
↓
Released into systemic circulation
31. Clinical Manifestations
• HEPATIC
1. Asymptomatic hepatomegaly
2. Subacute or chronic hepatitis
3. Acute hepatic failure
4. Portal hypertension
5. Ascites
6. Edema
7. Variceal bleeding
The younger the pt, the more likely hepatic involvement will
be the predominant feature
32. Clinical Manifestations
• NEUROLOGICAL
1. Intention tremor
2. Dysarthria
3. Rigid dystonia
4. Parkinsonism
5. Choreiform movts
6. Lack of motor coordination
7. Deterioration in school performance
8. Behavioral changes
PSYCHIATRIC MANIFESTATIONS: depression, personality
changes, anxiety, psychosis
33. Clinical Manifestations
• Kayser-Fleischer Ring
KF ring are absent in young pts with hepatic Wilson’s ds up to
50% of the time but are present in 95% of pts with neurologic
symptoms
34. Clinical Manifestations
Coombs-negative hemolytic anaemia may be an initial
manifestation
Due to release of large amts of Cu from damaged hepatocytes
This form is usually fatal
During hemolytic episodes, urinary Cu excretion & serum
copper levels are markedly elevated
35.
36. Diagnosis
• The clinical suspicion is confirmed by study of indices of Cu
metabolism
1. Decreased ceruloplasmin levels (<20mg/dl)
[ Ceruloplasmin may be ↑sed in a/c inflammation, in states of elevated
estrogen such as pregnancy, OCP & may be low in autoimmune hepatitis,
familial aceruloplasminemia ]
2. Serum free copper elevated in early Wilson ds
3. Urinary Cu excretion (usually <40ựg/day)is ↑sed to
>100ựg/day
37. Diagnosis
4. Demonsatration of KF ring
5. Liver biopsy- determine the extent & severity of liver ds &
for measuring hepatic Cu content
Hepatic Cu accumulation is the hallmark of Wilson ds &
measurement of hepatic parenchymal Cu conc. is the
method of choice for diagnosis
>250ựg/g dry wt
Family mebers of pt require screening for pesymptomatic
Wilson ds
38. Treatment
1. Restrict dietary Cu <1mg/day
2. Foods suchs as liver, shellfish, nuts & chocolates should be
avoided
3. Symptomatic pts- CHELATION THERAPY: oral
administration of D-penicillamine in a dose 1g/day in 2
doses bfr meals for adults & 20mg/kg/day for pediatric pts
or
4. Triethylene tetramine dihydrochloride (Ttien,TETA,
trientine) @ 0.5-2g/day for adults & 20mg/kg/day for
children
39. Treatment
• Penicillamine is an antimetabolite of vit B6, so vit
supplementation is necessary.
• Ammonium tetrathiomolybdate is another alternative
chelating agent under investigation for pts with neurologic ds
5. ZINC – used as adjuvant therapy, maintenance therapy or
primary therapy in presymptomatic pts. Zinc acetate is
given in adults @ dose of 25-50mg elemenatl zinc 3 times a
day & 25mg 3 times a day in children >5yrs