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Prof. Anil Dhawan MD FRCPCH
Director , King’s Cell Therapy Unit
Director Paediatric Liver GI and Nutrition Centre
Liver disease in Infants
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Neonatal Hepatitis 1970-1990
N=1086
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Neonatal Hepatitis 1992-2005
N=1625
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Neonatal
Cholestasis
~ 1:2700
live
births
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Infantile Cholestasis
Disease specific tests (about 30%)• Metabolic
• Perinatal infections
• Endocrinopathies
• Choledochal cysts
• Others
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Infantile Cholestasis
70% of patients no single test • Biliary atresia
• Idiopathic neonatal hepatitis
• Alagille
• Others
Liver biopsy constitutes a major piece of ZIG SAW
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Infantile Cholestasis
Aim of Investigations
v Identify Treatable Condition
v Recognise Complications
v Early Referral
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Infantile Cholestasis
Clinical Clues
v Cutaneous haemangioma -Liver
haemangioma
v Cystic mass -Choledochal
cyst
v Micropenis -SOD
v White hair -HLH
v Ascites -Spon.perf. of bile
duct Storage
disorder,
congenital heart, HLH,
hypothyroidism, Alpha-
1- anti trypsin def.
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Infantile Cholestasis
Subsequent Investigations
v Alpha-1 antitrypsin phenotype
v Gal-1 phosphate uridyl transferase
v Urine succinyl acetone (delta amino laevulinic acid)
v Serum and urine amino acids
v Serum Cholesterol and triglycerides
v TSH/T4, Cortisol
v Sweat sodium/IRT/Mutational analysis for CF
v TORCH(S) screen
v Hep Bs Ag, hep C Ab, HIV Ab and other viruses
v x-ray long bones and spine
v MRI or CT scan of head
v
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look normal!!
babies with biliary atresia
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Infantile Cholestasis
Prelaparatomy diagnosis of biliary
atresiav Stool colour
v Ultrasound
v Hepatobiliary scintigraphy
v ERCP
v MRCP
v Duodenal aspiration
v Liver biopsy
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prevalence of jaundice in UK
v Incidence.
– 2 - 15% will remain
jaundiced after 14
days.
– 0.2 - 0.4% will be
conjugated.
v 1 in 17,000 live births
will have biliary atresia
Livesey et al. 2009.
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Biliary atresia
Incidence
1:14,000 -1:21,000
Single commonest indication for LTx in children
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Biliary atresia
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1892
John Thompson -
Edinburgh physician
Gallbladder
Bile Duct Remnants
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Classification
Type 2 (~2%)
Type 1 (~8%)
Type 3 (~90%)
JAPS
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Kasai’s operation - 1959
v Morio Kasai
v Surgery for
“uncorrectable”(>80%) type of
biliary atresia
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Liver Transplantation - 1963
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Kasai portoenterostomy
“Complementary
& seamless”Davenport et al. Lancet 2004
Liver transplantation
Early diagnosis - liver biopsy / ERCP
Overt
cirrhosis
current management
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“maximally invasive surgery”
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Biliary atresia
successfu
l
Kasai
portoenterostomy
unsuccessf
ul
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jaundice cleared
jaundice not cleared
pe
rce
nta
ge
su
rviv
al
Biliary atresia
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jaundice cleared
jaundice not cleared
pe
rce
nta
ge
su
rviv
al
Biliary atresia
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Cryptogenic hepatitis
331
Infant Cholestasis
Biliary atresia
337
Alpha-1 anti trypsin deficiency
189Alagille syndrome
61Choledochal cyst
34Others
94Total
1046
King’s Data n=1046
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Infant Cholestasis
Giant cell hepatitis
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Infant Cholestasis
Cryptogenic neonatal hepatitis
progression to chronic liver disease
20%
complete resolution 80%
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Infant Cholestasis
Cryptogenic neonatal hepatitis
Indicators of poor prognosis
cirrhosis/severe fibrosis
at presentation
parental consanguinity
low gGT
positive family history
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Biochemistry
Molecular
genetics
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PC
Hepatocyte
OCT
NTCP OATP
OC
BA OA
MDR2/3
OA
MRP2
BSEP
BA
FIC1
MDR1
PS?
Cholangiocyte
CFTR AE
Cl-
Cl-
Cl-
HCO3-
AQPBA
ASBTH2O
NSC?
Bile
flow
PL
Ch
ABCG5/8
MRPs
*
*
*
*
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Low γGT cholestatic liver disease
progressive familial intrahepatic
cholestasis:
BSEP deficiency
FIC1 deficiency
29% not accounted for
1º or 2º bile acid synthesis defects
= failure of bile acid secretion
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Bile salt export pump (BSEP)
deficiency
ABCB11 gene on chromosome
2q24-31
function: major bile salt export
pump
exclusively hepatic phenotype
presents with a neonatal hepatitis
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FIC1 deficiency
protein: P-type
ATPase
ATP8B1 gene on chromosome
18q21
function: aminophospholipid flipase?
hepatic and extrahepatic phenotype:
malabsorption, pancreatitis, growth failure
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Raised γGT cholestasis
primary inflammatory, weak genetic
factors
– PSC, PBC, infective, biliary atresia
cholangitis / cholangiopathy
genetic
– MDR3 deficiency (ABCB4)
– North American Indian childhood
cirrhosis
– neonatal sclerosing cholangitis
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General Management
v MCT rich formulae
v Vitamin K
v Vitamin A, E and D
v ? UCDA and other choleretic agents in selected patients
v Anti-pruritic agents and biliary diversion
v Transplantation
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Paediatric Acute Liver
Failure
Professor Anil Dhawan MD, FRCPCH
Consultant Paediatric Hepatologist
King’s College London School of Medicine
King’s College Hospital
London
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Definition
Multisystem disorder in which severe
acute impairment of liver function
(INR>2)
with or without encephalopathy
occurs in association with hepatocellular
necrosis in a patient with no
recognised underlying chronic liver
disease
Acute liver failure in childhood
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Pediatric ALF: Age of Onset
0
10
20
30
40
50
60
70
80
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Age (years)
(N = 331)
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Aetiology of ALF in children
KCH data
n=236 (1992-2004)
31%
15%
11%
8%
7%
6%
6%
5%
3%3%
3%2% Indeterminate
POD
Infectious
Metabolic
NNH
AILD
Drug induced
Wilson's disease
Hypoxia/ischaemia
HLH
VOD
Miscellaneous
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Neonatal Liver Failure
165
43 1 1 1 1 1
Haemochromatosis
HSV
HLH
Galactosaemia
Tyrosinaemia
OTC def
Sepsis
Paracetamol
Hypocortisolism
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Diagnostic difficulties
• Investigations aimed at-
– Establishing the diagnosis
– Exclude conditions not treatable by liver
transplantation
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Acute Liver Failure
Bone Marrow ExamHLH
ALL
NPC
Pearson
Syn
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Value of liver
biopsy??
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Neonatal Haemochromatosis
Gestational alloimmune liver
disease• Severe liver disease of intrauterine onset
associated with extrahepatic siderosis that
spares reticuloendothelial system.
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Neonatal Haemochromatosis
Gestational alloimmune liver
disease• Prenatal onset
• Rarely affects first born
• Highly recurrent in subsequent
pregnancies
• Associated with maternal antibody to
foetal liver antigen
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‘Liver Dialysis’
bridge to full
recovery
rationale
Auxiliary Liver Transplant
Complete native liver
recovery
Immunusuppression Free
76%
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DISIDA Scan 2 wks after
Tx
DISIDA Scan 1 Year post Tx
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Biopsy at Tx
Biopsy at 1 year after Tx
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Hepatocyte Tx For ALF
• Synthetic and detoxifying function for
few weeks
• No immunosuppression !
• Site that can be accessed in a
coagulopathic patient
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Hepatocytes in Beads
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Equipment Hood in Aseptic Room
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Cannulation
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“Mincing” Digested Tissue
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Repeated Washing and Centrifugation
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Checking Cell No. and Viability(Trypan Blue exclusion technique)
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Hepatocyte Encapsulation
HCs/1.5% alginate
1.2% CaCl2
250µm nozzle
Reaction vessel
~400-450µm
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CELL FUNCTION AND VIABILITY
MTT RESULTS OF MICROENCAPSULATED
HEPATOCYTES CULTURED IN WILLIAM'S E MEDIA
0
0.2
0.4
0.6
0.8
1
1.2
1.4
24Hrs 48Hrs 72Hrs 1 week
Av
era
ge
O.D
. a
t 6
30
nm
pe
r 1
00
mg
Be
ad
s
UREA PRODUCTION OF ENCAPSULATED HEPATOCYTES
CULTURED IN WILLIAM'S E MEDIA
0.0
0.2
0.4
0.6
0.8
1.0
24Hrs 48Hrs 72Hrs 1 Week
Ure
a c
on
ce
ntr
ati
on
(mg
/dL
) p
er
10
0m
g B
ea
ds
FACTOR VII PRODUCTION OF ENCAPSULATED
HEPATOCYTES CULTURED IN WILLIAM'S E MEDIA
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
24Hrs 48Hrs 72Hrs 1 Week
FV
II c
on
ce
ntr
ati
on
(n
g/m
l) p
er
10
0m
g B
ea
ds
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Control 25% 50% 100%
Day 1
Day 7
Day 14
Viability Testing of Encapsulated Hepatocytes
Maintained in Ascitic Fluid
Culture medium only Culture medium + ascitic fluid
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Cell Viability[Confocal Microscopy]
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First in man Hepatocytes in Alginate beads for ALF March
2011
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Microbeads
Before Tx
Retrieved
Microbeads
Albumin Production
[Post-retrieval]
0
100
200
300
400
D1 D7 D14
Days in culture
Alb
um
in (
ng
/mg
pro
tein
)
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Watch for new etiologies !