Inborn errors of bilirubin metabolism & wilson disease

2. Bilirubin Metabolism

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

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

26. Wilson’s disease

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

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