Cholestasis PDF
Cholestasis PDF
Cholestasis PDF
neonatal cholestasis
Clinical Problem - 1
Full term infant; no complications
Jaundice at day 2; resolution by day 9
At 2 months of age
Breastfeeding
Well-infant visit:
Clinical Problem - 2
3.5 yr old boy with jaundice and pruritus
Ht/Wt ~50th%ile
AST: 167 IU/L
AST: 142 IU/
Albumin: 3.6 g/dL
Conjugated bilirubin: 2.6 mg/dL
Serum bile acids: 56; GTP: 22 IU/L
Clinical Problem - 3
6 month old boy with:
Arthrogryposis multiplex congenita
Jaundice
Conjugated bili: 4.3 mg/dL; GTP: 32 IU/L
Normal synthetic function
Renal dysfunction
Renal Fanconi syndrome
Nephrocalcinosis
Liver histology
Giant cell transformation; ductopenia
Cholestasis as a sign/symptom
Neonatal
cholestasis
Childhood
cholestasis
Non-hepatic
syndrome
Cholestasis
Cholestasis
Pigment of my imagination?
PHYSIOLOGIC
Abnormal decrease in biliary flow
HISTOPATHOLOGIC
Histological evidence of bile within
canaliculi or bile ducts
CLINICAL
Accumulation of substances normally
excreted by bile in plasma and extrahepatic
systems
Bile
Unconj. Bili
Aminoacids
Organic anions
Others
Conj. bilirubin
Bile acids
Lipids (cholesterol)
Proteins
Lytes, Vitamins...
Bile
Unconj. Bili
Aminoacids
Organic anions
Others
Conj. bilirubin
Bile acids
Lipids (cholesterol)
Proteins
Lytes, Vitamins...
Intrahepatic cholestasis
12 months
JAUNDICE
COAGULOPATHY
XANTHOMA (?)
RICKETTS (?)
>12 months
JAUNDICE
COAGULOPATHY
XANTHOMA
RICKETTS
NEURO DEFICITS
PRURITUS
Bilirubin
U.B.
U.B.
2 wk
C.B.
4 wk
1970-2000
-INFECTION
-ATRESIA
-A1AT def (met)
-ALAGILLE
-PFIC
-IDIOPATHIC
Clinical Problem - 1
Full term infant; no complications
Jaundice at day 2; resolution by day 9
At 2 months of age
Breastfeeding
Well-infant visit:
A1AT Deficiency
Laboratory studies:
EGF-like
repeats
CYSTEINE
TRANSMEMBRANE
INTRACELLULAR
DOMAIN
JAG1 protein
91%
95%
87%
70%
89%
68%
Poor growth
Inadequate development
Hypogonadism
Bone disease
High-pitched voice
Abnormal vasculature in
central nervous system
50%
60%
<10%
<10%
<10%
?
Bile
JAG1
1970-2000
-INFECTION
-ATRESIA
-METABOLIC
-ALAGILLE
-PFIC
-IDIOPATHIC
2000...
-INFECTION
-ATRESIA
-METABOLIC
-ALAGILLE
-FIC1 DEFECT (PFIC1)
-FIC1 DEFECT (GREENLAND)
-FIC1 DEFECT (BRIC)
-FIC1 DEFECT (FAROE IS.)
-BSEP DEFICIENCY (PFIC2)
-MDR3 DEFICIENCY (PFIC3)
-3HSD DEFICIENCY
-IDIOPATHIC (VARIANTS ?)
ABC Transporters
A lesson in family values
FIC1
MDR3
BSEP
MRP2
PFIC syndromes
MRP2 (Conj. bili)
FIC1 (P-ilserine)
Bile
Mutant 3HSD
FIC1?
PFIC syndromes
Familial cholestasis
Progression to end-stage liver disease
Clinical features
Cholestasis: recurrent or persistent
Autosomal recessive pattern
Variable levels of aminotransferases
Subgroup with low levels of GTP
Typical histologic/EM findings
Neonatal cholestasis
NEONATAL
CHOLESTASIS
Use of LFTs in
to identify PFIC
INFECTION
BILIARY ATRESIA
METABOLIC DISEASE
IDIOPATHIC
GTP
AST/ALT: Elevated
Conjugated bili: Elevated
GTP: ()
Alk Phosph: Elevated
Elevated bile acids ()
Elevated cholesterol ()
FIC1 defect
Bylers disease
FIC1 defect
FIC1 defect
Progressive cholestasis
Pruritus, steatorrhea, poor growth
Gamma-GTP: Normal or low
Histology:
Fibrosis, granular bile (ME)
BSEP deficiency
Clinical features similar to Bylers
Recurrent cholestasis, pruritus
Progression to chronic liver disease
Gamma-GTP: Normal or low
Histology
Giant cell hepatitis, inflammation, progression
to fibrosis, canalicular cholestasis
Molecular defect
Export of bile salt into canalicular
BSEP deficiency
BRIC-2
van Mill et al. Gastroenterology
2004;127:379
Clinical features similar to BRIC
Recurrent cholestasis, pruritus
No evidence of disease progression
Gamma-GTP: Normal or low
Histology
No evidence of severe fibrosis
MDR3 deficiency
High GTP
Histology
Portal inflammation, ductal proliferation
Variable degree of fibrosis
Other diseases
Intrahepatic cholestasis of pregnancy
Cholesterol-rich cholelithiasis
Molecular defect
Impaired export of aminophospholipids
3HSD deficiency
Clinical features similar to Bylers
Deficiency of fat-soluble vitamins
Gamma-GTP: Normal or low
High conjugated bilirubin
Bile acids: Normal/low (cholestasis)
Absence of pruritus
Histology
Portal inflammation, variable fibrosis
MRP2
Dubin-Johnson
FIC1 defect
BSEP deficiency
MDR3 deficiency
FIC1 defect
FIC1
BSEP
MDR3
Mutant
3HSD
FIC1?
JAG1
Cystic fibrosis
BASD
Cl-
CFTR
Alagille synd.
2000...
2005
Intrahepatic cholestasis
Clinical syndromes
Biochemical markers
PT/INR; conj (direct) bili; GTP
Liver biopsy
Molecular diagnosis: not routine
Intrahepatic cholestasis
Treatment
Nutritional support
Calories to promote adequate growth
A,D,E,K vitamin supplementation
Biliary diversion
External biliary diversion
Internal biliary diversion
May halt progression of liver disease
Liver transplantation
2000...
-INFECTION
-ATRESIA
-A1AT def (met)
-ALAGILLE
-FIC1 DEFECT (PFIC1)
-FIC1 DEFECT (GREENLAND)
-FIC1 DEFECT (BRIC)
-FIC1 DEFECT (FAROE IS.)
-BSEP DEFICIENCY (PFIC2)
-MDR3 DEFICIENCY (PFIC3)
-3HSD DEFICIENCY
-IDIOPATHIC (VARIANTS ?)
2005
-INFECTION
-ATRESIA
-A1AT def, CF
-ALAGILLE
-FIC1 defect
-BSEP deficiency
-MDR3 deficiency
-3HSD deficiency
-Unclassified
-Cholestasis and
multi-system Dz
Summation
Present as jaundice, pruritus, and/or
complications of deficiency of ADEK
Neonatal onset; pre- or school age
Biochemistry: bilirubin vs GTP
Liver biopsy: cellular organization,
degree of fibrosis, EM
Nutritional support, ADEK
Treatment of pruritus
Medication
Surgery
Liver transplantation
Unclassified syndromes
Lymphedema-cholestasis syndrome or
Aaganaes syndrome
Lymphedema: mostly lower extremities
Episodic intrahepatic cholestasis
Low GTP
Cholesterol levels may be low
Variable progression of liver disease
Autosomal recessive
Two loci may exist (LCS-1 and LCS-2)
Unclassified syndromes
North-American Indian childhood cirrhosis
(NAIC syndrome)
Severe form of intrahepatic cholestasis
Typically presents with mild neonatal
cholestasis, but progresses to biliary cirrhosis
Liver transplantation: only effective treatment
Mutation in Cirhin (CIRH1A)
Mostly expressed in the embryonic liver
The biological relationship between Cirhin and
cholestasis is unknown
Unclassified syndromes
Neonatal intrahepatic cholestasis caused
by citrin deficiency (NICCD syndrome)
Type II cytrulinemia (adult-onset)
Neonatal cholestasis; micro/macro steatosis
Variable degrees of synthetic dysfunction
Vomiting, poor growth, irritability
Mutation in citrin (SLC25A13), 7q21.3 mitochondrial aspartate-glutamate carrier
Markedly elevated plasma citrullin, high
methionine, hypergalactosemia
Supportive care; improvement by 1 yr of age
Na+
NTCP
FIC1 (P-ilserine)
Bile
OATPs
hOCT1
FIC1?
IBAT
CFTR
AE2
ClClHCO3-
FIC1 (P-ilserine)
Bile
Mutant 3HSD
FIC1?
JAG1