Disorders of The Neonatal Liver and Bile Duct - Seminars 2003 PDF

Editorial
Disorders of the Neonatal Liver and Bile Ducts

Liver and biliary tract disorders in the neonate are
relatively rare and often complex. The conse-
quences of delayed diagnosis and inappropriate
management may be fatal. As with so much of
clinical medicine, awareness of the spectrum of
diseases and recognition of the key clinical
features of the various disorders is essential to
optimizing outcome. It is increasingly hard for
today's clinicians to keep up to date when the
pace of change is so great and the relevant litera-
ture so vast. This issue of Seminars in Neonatology
distills the clinical and scientific experience of an
international group of experts in an attempt to
provide the working neonatologist (and other
healthcare workers involved in the care of the
newborn) with a state-of-the-art review of
each topic and a stimulating insight into recent
advances.
Sue Beath from Birmingham Children's Hospital,
UK outlines current concepts of hepatic function
and physiology in the newborn, whilst the fresh
challenges posed by prenatal diagnosis and molecu-
lar genetics are discussed by Mark Davenport and
Dino Hadzic from King's College Hospital, London,
UK. The myriad of disorders which cause conju-
gated hyperbilirubinaemia are neatly and suc-
cinctly dissected by Eve Roberts from The Hospital
for Sick Children in Toronto, Canada. The latter
nicely leads on to a more detailed discussion of
biliary atresia from a combined Japanese and UK
perspective. Stuart Kaufman from The Mount Sinai
Hospital in New York, USA brings us up to date with
the widespread and potentially hazardous problem
of parenteral-nutrition-associated liver disease.
Finally, there are important contributions from
Paddy McClean and Suzanne Davison in Leeds, UK
on the newborn infant with liver failure, and from
Dietrich von Schweinitz in Munich on neonatal
liver tumours; both are rare but extremely taxing
clinical conditions.
With the constraints of space, each section is not
intended to be encyclopaedic but rather, each
expert has provided a readable account combining
a useful blend of practical knowledge and analysis
of current research. I would like to thank all the
contributors. I am also indebted to Sean Duggan,
Managing Editor, and his assistant Ann Smiley for
their assistance and support.
Mark D. Stringer*
St James's University Hospital
Children's Liver and GI Unit
Level 8 Geldhow Wing
Leeds LS9 7TF
UK
*Tel.: +44-1132066689; fax: +44-1132066691
E-mail address: mdstringer@dial.pipex.com (M.D. Stringer).
Seminars in
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Seminars in Neonatology (2003) 8, 335
1084-2756/03/$ - see front matter 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S1084-2756(03)00091-5
Hepatic function and physiology in the newborn
S.V. Beath
*
The Liver Unit, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK
Summary The liver develops from progenitor cells into a well-differentiated organ in
which bile secretion can be observed by 12 weeks' gestation. Full maturity takes up to
two years after birth to be achieved, and involves the normal expression of signalling
pathways such as that responsible for the JAG1 genes (aberrations occur in Alagille's
syndrome), amino acid transport and insulin growth factors. At birth, hepatocytes are
already specialized and have two surfaces: the sinusoidal side receives and absorbs a
mixture of oxygenated blood and nutrients from the portal vein; the other surface
delivers bile and other products of conjugation and metabolism (including drugs) to
the canalicular network which joins up to the bile ductules. There is a rapid induction
of functions such as transamination, glutamyl transferase, synthesis of coagulation
factors, bile production and transport as soon as the umbilical supply is interrupted.
Anatomical specialization can be observed across the hepatic acinus which has
three distinct zones. Zone 1 borders the portal tracts (also known as periportal
hepatocytes) and is noted for hepatocyte regeneration, bile duct proliferation and
gluconeogenesis. Zone 3 borders the central vein and is associated with detoxification
(e.g. paracetamol), aerobic metabolism, glycolysis and hydrolysis and zone 2 is an
area of mixed function between the two zones.
Preterm infants are at special risk of hepatic decompensation because their
immaturity results in a delay in achieving normal detoxifying and synthetic function.
Hypoxia and sepsis are also frequent and serious causes of liver dysfunction in
neonates.
Stem cell research has produced many answers to the questions about liver
development and regeneration, and genetic studies including studies of susceptibility
genes may yield further insights. The possibility that fatty liver (increasingly recog-
nized as non-alcoholic steatohepatitis or NASH) may have roots in the neonatal period
is a concept which may have important long-term implications.
2003 Elsevier Ltd. All rights reserved.
KEYWORDS
Neonatal;
Hepatitis;
Stem cells;
Genetic disorders;
Sinusoidal function;
Zonal differentiation;
Bile acid
transport/physiology;
Prematurity;
Hypoxia;
Sepsis;
Conjugated;
Unconjugated
hyperbilirubinaemia
Introduction
The liver contains a diverse group of cell lines that
remain in a state of some plasticity until at least 12
months after birth. The liver differentiates from
embryonic liver progenitor cells derived from stem
cells, into a mature organ containing hepatocytes,
cholangiocytes and immune cells, all existing in a
stromal network through which approximately one-
quarter of the circulating blood is pumped.
1,2
This process takes place via several important
mechanisms which are only just beginning to be
understood. These include apoptosis, morphogen-
esis, proliferation and polarization.
35
Aberrations
of the normal sequence of embryonic and fetal
gene expression can lead to disease, e.g. the notch
signalling pathway appears to be important in
Alagille's syndrome characterized by cardiac, facial
and hepatic abnormalities
6
(Table 1). The liver may
play an important role in the maintenance of a
healthy feto-placental unit as intra-uterine growth
restriction is associated with reduced expression of
hepatocyte growth factors.
7
External factors such
as the hormonal milieu and hypoxia influence the
expression of genes responsible for the transport of
amino acids across membranes and the production * Tel.: +44-121-333-8259; fax: +44-121-333-8251
Seminars in
NEONATOLOGY
1084-2756/03/$ - see front matter 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S1084-2756(03)00066-6
Table 1 Bile synthesis and transport defectsexamples of genetic causes
Disease Basis of genetic defect(s) Clinical features
Alagille's JAG1, various ligands? Notch signalling pathway Variableincludes paucity of bile ducts, pulmonary artery stenosis,
triangular facies
Alpha-1 antitrypsin
deficiency
Mutation of gene coding for protease inhibitor on chromosome 14 Growth restriction in utero, severe cholestasis often with pale stools, 2%
present with vitamin-K-sensitive coagulopathy
Bile acid synthesis
disorders
Abnormal expression of the following enzymes:
(a) Hydroxy-steroid dehydrogenase (a) Normal GGT, low serum bile acids, no pruritis
(b) Oxosteroid reductase (b) Severe jaundice and coagulopathy
(c) 25-Dihydroxycholanic cleavage enzymes (c) Normal GGT, elevated ALP and cholesterol, pruritis
Cystic fibrosis Mutation in delta 508 or other genes Jaundice, hepatomegaly, meconium ileus, inspissated bile syndrome, pale
stools
CriglerNajjar type 1 Various mutations in exon 15 of B-UGT1 gene coding for bilirubin
glucuronidation
Unconjugated hyperbilirubinaemia 200400 mol/l, needs phototherapy,
phenobarbitone=no effect
CriglerNajjar type 2 Various mutations leading to reduced affinity of the enzyme for substrate Unconjugated hyperbilirubinaemia 100400 mol/l, needs phototherapy,
phenobarbitone effective
Gilbert's disease Mutation in the promoter region of the UDPGT 1 gene Unconjugated hyperbilirubinaemia 100300 mol/l is common and usually
resolves after brief exposure to phototherapy
DubinJohnson syndrome Autosomal recessive Conjugated bilirubin (30400 mol/l), transaminases normal, centri-lobule
pigment granules on liver biopsy
PFIC type 1 Byler's
disease
Mutation of the mixed drug reaction gene 1 (MDR-1) Normal GGT, normal cholesterol, variable jaundice, pruritis
(diarrhoeapancreatitis)
PFIC type 2 Mutation on chromosome 2 of bile salt export pump Normal GGT, no intestinal symptoms, giant cell hepatitis common
PFIC type 3 Mutation in the P-glycoprotein MDR-3 gene Elevated GGT, troublesome pruritis
Rotor syndrome Autosomal recessive Conjugated hyperbilirubinaemia, but no accumulation of bile acids in the
liver and normal liver function tests
Zellweger's Abnormal expression of peroxisome enzymes involved in side chain
modification of bile acids
Accumulation of very long-chain fatty acids (C
27
), large fontanelle, high
forehead, profound hypotonia
PFIC, progressive familial intrahepatic cholestasis; GGT, gamma glutamyl transferase; ALP, alkaline phosphatase; MDR, multidrug-resistant protein.
3
3
8
S
.
V
.
B
e
a
t
h
of insulin growth factors
8,9
(Table 2). An imbalance
in the transport of molecules such as bilirubin and
amino acids can lead to cholestasis and a giant cell
hepatitis.
Fetal development
The liver develops from the foregut which folds into
the mesoderm. The bile ducts and hepatocytes are
derived from stem cells in the endoderm, and
Kupffer cells, blood vessels, including the special-
ized porous endothelium which lines the sinusoids,
and fibrous tissue are all derived from mesoderm.
The stem cells differentiate into progenitor cells
which are then committed to either hepatocyte or
cholangiocyte lineage.
10
The hepatocytes develop
in long cords into the stroma, initially as plates
three to five cells thick. At the time of birth, the
architecture of the liver is well established with
portal tracts connected to the central veins by
plates of hepatocytes in layers which are two cells
thick. The hepatocytes have a sinusoidal surface
over which blood from the portal vein and hepatic
artery flows, and a basolateral canalicular surface
from which bile is secreted.
The space between the canalicular surface of
hepatocytes communicates with biliary cells in the
portal tracts via the canals of Hering which also
contain oval cells. The oval cells are progenitor
cells which proliferate according to normal fetal
development or in response to liver injury.
1
Oval
cells can develop into hepatocytes or cholangi-
ocytes depending on local environmental factors.
2
Hepatic secretion of bile commences early at
around 12 weeks' gestation.
The main serum protein of the fetus is alpha-
fetoprotein which reaches a peak concentration at
the end of the first trimester. Albumin synthesis
begins at around 16 weeks' gestation and reaches
adult levels at the time of birth.
In utero, the liver acts as the main source of red
cell production, and even at birth, foci of active
haematopoiesis are still present in the parenchyma
of the liver. This may explain why disorders of iron
metabolism such as neonatal haemochromatosis
(which have their origins in the fetus) have such a
devastating effect including fulminant liver fail-
ure.
11
These areas of haematopoiesis usually disap-
pear within six weeks of birth being superseded by
the bone marrow. Persistence of extramedullary
haemopoiesis is an indication of disease and may
be seen in haemolytic anaemia and neonatal
hepatitis.
12
Events at birth
Two major physiological events at birth affect the
liver: the pressure in the lungs drops dramatically
Table 2 Environmental and other causes of neonatal jaundice
Disease Clinical features
Environmental
Hypoxia
9,28,29
Sudden rise in AST and ALT up to 20 times baseline, followed by
jaundice (conjugated hyperbilirubinaemia)
Endocrine
(a) Hypothyroidism
8
(a) Jaundice which may be predominantly unconjugated at first,
associated with hepatomegaly and elevated AST and ALT
(b) Hypopituitarism (b) Hypoglycaemia and jaundice, failure to thrive, poor visual fixing
Preterm birth Reduced concentrations of plasma albumin, prolonged coagulation,
hypoglycaemia, delay in conjugation of bilirubin, reduced efficiency in
transporting bilirubin to canaliculus
Interuterine infection, e.g. parvovirus Intra-uterine growth restriction, hepatosplenomegaly, ascites
Postnatal infection, e.g. streptococcus
28
Sudden rise in conjugated bilirubin, low platelets, coagulopathy, rise in
acute-phase proteins
Parenteral nutrition (PN)
32
Early rise in ALP and GGT, jaundice especially during septic episodes,
can lead to liver failure
Uncertainsusceptibility genes may be interacting
with environment
Biliary atresia Normal birth weight, 10% have situs inversus, pale stools, high GGT and
ALP, bilirubin rises steadily from birth
Giant cell hepatitis Growth restriction in utero, ALT and AST may be three to five times
normal, haemolysis occasionally present, congenital infection may be
detected (especially parvovirus)
AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma glutamyl transferase; ALP, alkaline phosphatase.
Hepatic function and physiology in the newborn 339
with the first few breaths; and 50% of the cardiac
output previously going to the placenta is rapidly
re-distributed as blood flow through the umbilicus
ceases. Within minutes, the venous return from
vital organs such as the liver and the small bowel
increases, and the pulmonary circulation becomes
as dynamic as the systemic circulation, producing a
steep rise in dissolved oxygen in arterial blood to
almost 95% saturation. In addition to these events,
a more gradual change in hepatic blood flow
occurs. In the fetus, the ductus venosus connects
the umbilical vein and the inferior vena cava, pro-
viding a functional bypass of the liver for up to 50%
of the oxygenated blood from the placenta. Postna-
tally, the ductus venosus gradually closes within
one to two weeks of birth. Rarely, the ductus fails
to close and this has been linked to the subsequent
development of encephalopathy and liver tumours
in older children.
Increase in portal blood flow and bacterial
colonization
The newborn infant's first feed increases portal
blood flow and exposes the intestinal tract to
micro-organisms for the first time. Within hours of
birth, colonies of bacteria establish themselves
in the intestine and a stable microflora develops
in the large bowel. Although bacterial colonization
may be associated with necrotizing enterocolitis in
premature infants, enteric bacteria have a physio-
logical role in that they produce vitamin K. It takes
around six weeks for the mass of bacteria to pro-
duce sufficient vitamin K, and this is one reason
why haemorrhagic disease of the newborn is very
rare after this time unless a chronic cholestatic
disease is present causing malabsorption of vitamin
K (e.g. alpha-1 antitrypsin deficiency
13
).
Induction of enzyme functions (GGT and
UDPGT)
The rapid assumption of processing functions by the
hepatocyte cell mass requires an induction of
enzymes such as the cytochrome P450 group and
peroxisomal enzymes which were present before
birth.
14
Transferase function
It is normal to see a rise in gamma glutamyl trans-
ferase (GGT) from a low baseline value of around
30 IU/l up to 120150 IU/l for the first few months
of life. A lack of increase in GGT can imply a
disorder of the biliary epithelium and canalicular
aspect of the hepatocyte cell surface (e.g. progres-
sive familial intrahepatic cholestasis (PFIC) types 1
and 2). In a different type of bile transport disor-
der, the GGT may be abnormally high as in PFIC
type 3, in which one of the genes coding for the
bilirubin transporter multidrug-resistant protein 3
(MDR-3) is defective (Table 1). An abnormally high
GGT is also a pointer to abnormal biliary function as
seen in biliary atresia. Plasma levels of alkaline
phosphatase, which is concentrated in the cyto-
plasm just below the bile canaliculus, are also
strikingly elevated in biliary atresia (Table 2).
Conjugation
Conjugation develops from minimal levels to almost
adult levels within two weeks of birth in most
cases. Conjugation reactions are an important step
in detoxifying by-products of metabolism and drugs,
especially relatively insoluble lipid molecules.
15
Bilirubin, which is salvaged from the complex haem
molecule when worn-out red blood cells are
destroyed, is highly lipophilic and cannot easily
cross cytosolic spaces inside the cell. Conjugating
the bilirubin molecule with glucuronide is depen-
dent on the function of the enzyme uridine
diphosphoglucuronyl transferase (UDPGT), which
improves the water solubility of bilirubin. Conjuga-
tion also improves the efficiency of transport of
bilirubin into the canaliculus and reduces its toxic
detergent effect on the bile ducts.
A rise in unconjugated bilirubin in the first two
weeks of life (up to 50% of babies become visibly
jaundiced) may be regarded as almost physiological
as it is usually self-limiting once the conjugation
capacity of the maturing hepatocytes catches up
with the demands of life outside the womb. How-
ever, it is important to confirm that plasma
bilirubin is reducing after 14 days and also to estab-
lish whether the bilirubin is largely unconjugated.
An elevated conjugated bilirubin can never be
regarded as physiological although it may have a
self-limiting cause such as septicaemia.
A delay in achieving normal levels of UDPGT is
frequently seen in preterm and septic babies
who are at risk of developing kernicterus if high
levels of unconjugated bilirubin occur. Other
causes of an elevation in unconjugated bilirubin
are seen in infants experiencing haemolysis, trau-
matic birth, hypoxia and sepsis (see Table 3).
Autosomal-recessive inherited disorders of UDPGT,
CriglerNajjar type 1 and its milder phenotype type
2 are very rare. In contrast, Gilbert's disease
affects up to one in 100 of the population. Fortu-
nately, the defect in UDPGT expression in Gilbert's
disease is mild and only becomes evident under
340 S.V. Beath
conditions of stress, such as birth, or, in adult life,
in association with prolonged fasting or a systemic
illness such as influenza. Babies who are ho-
mozygous for the genetic abnormality of Gilbert's
disease are more likely to be jaundiced in the first
few days of life than unaffected babies.
16
Induction of synthetic functions
At birth, the plasma albumin concentration is
usually near to adult levels (3035 g/l), but the
concentration of plasma proteins involved in coagu-
lation is usually low. In parallel with the rapid
induction of enzymes involved in conjugation, the
coagulation proteins increase to adult levels within
a few days of birth. Caeruloplasmin is also low at
birth and gradually rises during the first three
months of life. This can become grossly elevated
during sepsis or other stresses because, like alpha-1
antitrypsin, it is an acute-phase protein.
12
Sinusoidal physiology and function
It is important to note that a hepatocyte functions
as if it had two surfaces: the sinusoidal surface and
the canalicular surface (Fig. 1). The sinusoidal sur-
face is exposed to two sources of blood: one is rich
in dissolved oxygen (from the hepatic artery), and
the other is rich in glucose, amino acids, free fatty
acids, larger molecules including intact proteins,
insulin, glucagon, free fatty acid binding protein,
cholecystokinin, micro-organisms and immune cells
(from the portal vein). After a meal, the portal vein
delivers approximately twice the volume of blood
as the hepatic artery, equivalent to 600 ml/min in
an adult.
On the other side of a hepatocyte is the canal-
icular surface. This forms a network of canaliculi
bounded by tight junctions, which joins up with bile
ducts in the portal tracts via the canals of Hering.
Bile is actively transported by specialized transport
proteins into the canaliculi and ultimately flows
under positive pressure down the biliary tree.
17
Hepatocytes act as a conduit and processor for
nutrients, initially from the placenta. Within days
of birth, hepatocytes must have the capacity to
deal with an enormous range of hormones, food
antigens, complex molecules and bacteria derived
from the intestinal tract. It is not surprising, there-
fore, that environmental stress (e.g. intra-uterine
infection, respiratory distress, bacterial sepsis) and
genetic factors (abnormal transporters of bilirubin)
frequently result in cholestasis and disruption of
hepatocytes, leading to a giant cell hepatitis (see
Tables 1 and 2).
Maturing physiology
After the initial adaptations to circulatory changes
in the newborn have taken place, the liver starts to
fulfil its role in maintaining homeostasis.
Table 3 Causes of increased plasma unconjugated
bilirubin
Haemolysis
Traumatic birth associated with haemorrhage and tissue
contusion
Neonatal polycythaemia
Congenital hypothyroidism
Sepsis
Hypoxia
Hypoglycaemia
Autosomal-inherited disorders
CriglerNajjar types 1 and 2
Gilbert's disease
Galactosaemia
Fructose intolerance
Canaliculas
Blood-filled
sinusoid
Kuppfer
cell
Specialized
endothelium
Hepatocyte Tight
junction
S
i
n
u
s
o
i
d
Canalicular
surface
Sinusoidal
surface
Fig. 1 Arrangement of hepatocytes and the specialized sur-
faces within the sinusoidal space.
Carbohydrate, lipid and protein metabolism
Newborn babies do not store much glycogen, and
one of the first responses to a feed is a sharp rise in
insulin. This has an anabolic effect generally caus-
ing glucose to enter cells for energy and for storage
as glycogen and triglyceride, especially in the liver.
Newborn babies are prone to hypoglycaemia unless
they receive frequent feeds, and it is an important
physiological adaptation that the cells of the cen-
tral nervous system can utilize ketones if glucose is
not available.
The liver plays a key role in the control of free
fatty acids which may be converted to ketones
during a fast or stored as triglyceride after a feed
when glucose and insulin are plentiful. The lack of
ketone production during a fast is indicative
of abnormal physiology as in disorders of fat
oxidation, e.g. long-chain 3-hydroxyacyl dehydro-
genase deficiency
18
which is a cause of sudden
infant death.
19
The liver is the major organ respon-
sible for the clearance of lactic acid and although
lactate may be above 5 mmol/l shortly after birth,
it should normalize within 6 h. A persistently
elevated lactate should prompt concerns about
sepsis, adequacy of the circulation or mitochondrial
disorders.
11
Amino acids are transported to the liver along
with other nutrients via the portal vein. They are
rapidly taken up by the sinusoidal hepatocytes
where they are de-aminated, transaminated and
enter the urea cycle. Alternatively, amino acids are
utilized to make nearly all of the plasma proteins
except immunoglobulins. Proteins normally found
in high concentrations such as albumin and coagu-
lation factors are reduced in chronic liver disease.
Conversely, acute-phase proteins such as alpha-1
antitrypsin and fibrinogen may be raised because
the diseased liver fails to clear them.
Bile acid formation and the enterohepatic
circulation
The elaboration of bile requires energy at several
points. Bile is a complex fluid derived from
cholesterol, phospholipids and haemoglobin. The
numerous steps involved in cholesterol metab-
olism, phospholipid synthesis and the conjugation
of bilirubin derived from haem requires enzymes
which are dependent on ATPase, as does the trans-
port of these molecules across the canalicular sur-
face of the hepatocyte.
12
Bile is not just a waste
product but is crucial in the activation of some of
the intestinal lipases and in solubilizing dietary
fats. Infants who produce inadequate amounts of
bile are at risk of protein energy malnutrition sec-
ondary to malabsorption of up to half their dietary
fat and also fat-soluble vitamin deficiency (vita-
mins A, D, E and K). For both these reasons, it is not
surprising that there is a physiological mechanism
for retrieving bilirubin known as the enterohepatic
circulation. It is estimated that a single molecule of
bilirubin circulates from hepatocyte to canaliculus
to intestinal lumen via the common bile duct to the
terminal ileum and back to the liver via the portal
vein up to six times a day.
12
Hepatic function by zone
The sinusoidal plates are differentiated in two
axes: the differentiation between the sinusoidal
and canalicular surfaces, and the specialization of
function longitudinally from the portal tract down
to the central vein. The hepatic acinus can be
separated into three zones on the basis of proximity
to the portal tracts or the central vein and specia-
lization of function (Fig. 2). Zone 1 represents the
area around the portal tracts (also known as the
periportal area), zone 3 represents the area around
the central vein (also known as the perivenular
Zone 1
Zone 1
Zone 1
Zone 1
Zone 1
Zone 2
Zone 3
Zone 3
Zone 2
Central vein
(hepatic venule)
Portal tract
containing
artery, portal venule,
bile duct
Zone 1 Zone 2 Zone 3
Fig. 2 Hepatic acinus showing zonal differentiation of hepato-
cytes along an axis between the portal tracts and the central
vein. Zone 1, periportal; zone 2, mid-acinus; zone 3,
perivenular.
342 S.V. Beath
area) and zone 2 is an area of mixed functions in the
centre of the acinus between zones 1 and 3.
The details of zonal function and specialization
are still being elucidated but some generalizations
are outlined in Table 4. Disorders of bile excretion
tend to affect zone 1 where the greatest concen-
tration of bile exists,
20
and where there is the
greatest capacity for chylomicron uptake.
21
Regen-
eration after hepatocyte injury begins in zone 1,
and gluconeogenesis appears to be concentrated in
the periportal hepatocytes.
2224
The fact that zone
3 is rich in detoxification enzymes such as glutath-
ione reductase
25
is important in interpreting the
histological features of paracetamol poisoning, in
which there is a characteristic pattern of necrosis
selectively affecting the hepatocytes around the
central veins. Hypoxic events may be evident in
zone 3 (haemorrhage around the central vein and
apoptosis of neighbouring hepatocytes
26
), which is
furthest away from arterial blood and has the low-
est concentration of dissolved oxygen. Glycolysis
and hydrolysis have also been associated with the
perivenular hepatocytes in zone 3.
23,27
Clinical scenarios
Hypoxia
The neonatal liver is relatively resistant to the
effects of hypoxia, but in conditions of hypoper-
fusion, such as during circulatory collapse caused
by sepsis or blood loss, acute hepatocyte necrosis
may be evident, especially around the central
vein.
28
Over the next 210 days, an increase in
plasma transaminases (alanine transaminase, as-
partate transaminase) and lactate dehydrogenase
are seen which may exceed 500 IU/l,
29
and a coagu-
lopathy may develop. The rise in transaminases is
followed by a rise in conjugated bilirubin. Full
recovery is possible provided that the cause of
hypoperfusion is treated, although the improve-
ment in plasma bilirubin lags behind the
improvement in transaminases and may take many
weeks to resolve.
Septic shock
Liver dysfunction commonly develops secondary to
severe sepsis in the neonate and can resolve if
appropriate antimicrobial treatment is started
promptly. However, infection with herpes simplex
virus, echo viruses, or Gram-negative organisms is
capable of causing fulminant liver failure,
30,31
which may necessitate liver transplantation in ex-
ceptional cases. Other causes of fulminant liver
failure in the neonate are listed in Table 5 and
discussed in detail by McClean and Davison else-
where in this issue. Ultrasound scanning of the
abdomen in septicaemia may show an echo-bright
liver which is considered to be due to hyperplasia of
the reticuloendothelial system. Biliary sludge and
gall stones which may obstruct the biliary tree may
also be seen after an episode of sepsis, particularly
Table 4 Zonal specialization of hepatocyte functions
Zone Functions Marker molecule or enzyme
associated with function
Zone 1 (periportal) Bile duct proliferation
20
Chylomicron uptake
125
I labelled chylomicron remnant
21
Hepatocyte regeneration Ki-67 antigen detection
22
Gluconeogenesis
23,25
PEPCK
24
Insulin growth factors and binding protein IGF-1 and IGFBP-2
24
Zone 2 Induction of microsomal and peroxisomal enzymes P450 4A and bifunctional enzyme
14
Zone 3 (perivenular) Detoxification Glucuronidation
25
Induction of microsomal and peroxisomal enzymes P450 4A and bifunctional enzyme
14
Aerobic metabolism Relatively more intracellular ionized
calcium during aerobic conditions
26
Insulin growth factor binding protein type 1 IGFBP-1
24
Glycolysis Glucose induced release of lactate
23
Hydrolysis of cholesterol esters Cholesterol ester hydrolase
27
Table 5 Causes of fulminant liver failure in babies under
six weeks of age
Bacterial infection (e.g. Escherichia coli, Meningococcus)
Viral infection (e.g. Herpes simplex, adenovirus)
Metabolic (e.g. tyrosinaemia, haemachromatosis,
galactosaemia)
Circulatory collapse (secondary to congenital heart disease
or haemorrhage)
with necrotizing enterocolitis where enteral
starvation exacerbates the problem.
Prematurity
The great advances in the management of respirat-
ory complications in premature babies have led to
an improved survival in younger and more immature
infants. This has brought challenges and limitations
from other organ systems such as the liver and
gastrointestinal tract. Preterm infants are at
considerable risk of hypoxia because of a failure to
establish a properly dynamic pulmonary circula-
tion. Such infants are also vulnerable to infection
via the intestinal tract (e.g. necrotizing enterocoli-
tis) because the surface epithelium of the gut is
very permeable and the lamina propria lacks
depth.
32
Bacterial translocation from the intestine
via the portal vein to the liver can cause direct
infections (micro-abscesses and/or large collec-
tions). The more common effects of bacterial
infection on liver function are indirect, occurring as
a result of the toxicity of lipopolysaccharide, e.g.
impaired cholesterol and bilirubin metabolism and
transport. The detergent properties of bile can be
very damaging, causing further disruption to the
structure and function of internal plasma mem-
branes, such as the Golgi apparatus, and external
membranes, such as the sinusoidal surface of the
hepatocyte. Preterm infants are also at risk of hy-
poglycaemia because of reduced stores of glycogen
and adipose tissue. More importantly, gluconeogen-
esis appears to be ineffective, with energy being
diverted to heat rather than glucose generation.
Summary
Although the blood supply and volume of the liver
change dramatically at birth, together with its
range of required functions, a healthy baby has
sufficient physiological reserve for homeostasis to
be well maintained with only a short-lived period of
mild unconjugated jaundice being apparent. Babies
who are of low birth weight, premature or stressed
for other reasons (e.g. infection, hypoxia or
congenital heart disease) may present with
hypoglycaemia, acidosis and prolonged jaundice.
Provided that external factors are corrected, the
liver has great powers of repair and regeneration
which are located in specific areas of the hepatic
acinus and which can be enhanced with good
nutrition. The future role of malnutrition
on the evolution of non-alcoholic steatohepatitis
(NASH) and the place of cyto-protective agents
such as vitamin E, ursodeoxycholic acid and
N-acetylcysteine are subjects of ongoing research.
Practice points
Infants with prolonged jaundice (greater
than 14 days) are at risk of developing a
vitamin K responsive coagulaopathy and
should receive vitamin K supplements.
Mild visible jaundice is common in babies up
to 14 days after birth.
Always check that bilirubin levels are
reducing from 14 days onwards.
Always measure the type of bilirubin in
visibly jaundiced infants after 14 daysis it
unconjugated or conjugated?
Sick infants who are jaundiced should have
urine saved and frozen, for screening
metabolic disorders.
Sepsis is the most common cause of
non-physiological jaundice in neonates.
Consider rapid treatment with
broad-spectrum antibiotics and acyclovir in
collapsed infants.
Research agenda
There have been considerable advances in
stem cell research, which may ultimately
allow human organs to be produced in the
laboratory without resorting to cadaveric
organ transplantation. Much of this work has
been performed in laboratory rats, but more
recent experiments with tissues obtained
during neonatal surgery and from embryo
research may yield fresh insights.
Another key area of research includes
collaborative European studies on the
genetics of liver disease, and a greater focus
on susceptibility genes which may contribute
to the pathogenesis of rare diseases, such as
biliary atresia and idiopathic reactions to
drugs. In future, a better understanding of
susceptibility genes may allow high-risk
patients to be identified and offered
prophylactic or even pre-emptive treatment.
New treatments may include the more
widespread use of cyto-protective agents
such as vitamin E, ursodeoxycholic acid and
N-acetylcysteine.
33
There is increasing appreciation that the
disorder NASH occurs in childhood and may
344 S.V. Beath
even have its origin prenatally. NASH is
associated with prematurity, intravenous
feeding, obesity and protein calorie
malnutrition, and has the potential to
become the most common indication for liver
transplantation worldwide.
34
The natural
history and management of NASH is the
subject of much current research
activity.
3237
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346 S.V. Beath
Review article
Neonatal hepatitis syndrome
Eve A. Roberts
*
Division of Gastroenterology and Nutrition, Room 8267, Black Wing, The Hospital for Sick Children, and
Departments of Paediatrics, Medicine and Pharmacology, University of Toronto, Ontario, Canada
Summary Conjugated hyperbilirubinaemia in an infant indicates neonatal liver dis-
ease. This neonatal hepatitis syndrome has numerous possible causes, classified as
infective, anatomic/structural, metabolic, genetic, neoplastic, vascular, toxic,
immune and idiopathic. Any infant who is jaundiced at 24 weeks old needs to have
the serum conjugated bilirubin measured, even if he/she looks otherwise well. If
conjugated hyperbilirubinaemia is present, a methodical and comprehensive diag-
nostic investigation should be performed. Early diagnosis is critical for the best
outcome. In particular, palliative surgery for extrahepatic biliary atresia has the
best chance of success if performed before the infant is 8 weeks old. Definitive
treatments available for many causes of neonatal hepatitis syndrome should be
started as soon as possible. Alternatively, liver transplantation may be life saving.
Supportive care, especially with attention to nutritional needs, is important for all
infants with neonatal hepatitis syndrome.
KEYWORDS
Neonatal hepatitis
syndrome;
Conjugated
hyperbilirubinaemia;
Giant-cell hepatitis;
Neonatal liver failure;
Infant;
Metabolic liver disease
Jaundice frequently occurs in the first 3 months of
life. Most jaundiced infants have unconjugated
hyperbilirubinaemia. In contrast, infants with
hepatic dysfunction have conjugated hyper-
bilirubinaemia. This is one of the most important
problems in paediatric hepatology. Many different
liver disorders can cause neonatal hepatitis syn-
drome. Possible treatments and outcomes vary
greatly among these disorders. It is critically
important to find the cause of neonatal hepatitis
syndrome as soon as possible, and in the majority of
infants, the disease is not idiopathic. Any infant
who is still jaundiced at 24 weeks of age requires
investigation. The first test is to determine whether
the hyperbilirubinaemia is conjugated or not. Any
infant with conjugated hyperbilirubinaemia has
neonatal hepatitis syndrome and requires further
investigation.
Nomenclature for neonatal liver disease is not
straightforward. The simplest term neonatal
jaundice leads to confusion with physiological
jaundice in the newborn. The term neonatal
cholestasis is imprecise because in the first
34 months of life, every infant has some degree of
neonatal cholestasis on a physiological basis. This
physiological cholestasis is multifactorial. Uptake
of bile acids and other organic anions by hepato-
cytes is inefficient, leading to high concentrations
of bile acids in blood; hepatocellular pathways of
bile acid conjugation and biliary secretion are also
immature and inefficient. The circulating bile acid
pool is contracted, and ileal uptake of bile acids is
underdeveloped. Hepatic bile canalicular trans-
porters are also regulated developmentally.
1
The
term neonatal hepatitis is inaccurate because
hepatic inflammation is not a feature of every
condition. The term neonatal hepatitis syndrome
is preferred because it emphasizes the uniformity
* Division of Gastroenterology and Nutrition, Room 8267,
Black Wing, The Hospital for Sick Children, 555 University
Avenue, Tronoto, Ontario M5G 1X8, Canada. Tel.:
+1-416-813-7733; fax: +1-416-813-4972
E-mail address: eve.roberts@sickkids.ca (E.A. Roberts).
Seminars in
NEONATOLOGY
doi:10.1016/S1084-2756(03)00093-9
of the clinical presentation as well as the broad
spectrum of causative disease processes.
A subset of the neonatal hepatitis syndrome is a
group of disorders, which is present with liver fail-
ure with coagulopathy and metabolic instability
(including but not limited to encephalopathy,
which may be difficult to evaluate in the newborn)
(see paper by McClean and Davison). Liver failure
can have an acute-pattern with extremely elevated
serum aminotransferases and normal serum
albumin, or it can have a chronic-pattern with
near-normal serum aminotransferases and low
serum albumin, consistent with a prenatal liver
injury. Since the conventional definition of acute
liver failure does not really apply to the newborn
period, it makes sense to use the term neonatal
liver failure for these disorders.
2,3
As there are so many different causes of neo-
natal hepatitis syndrome, it is useful to group
them: infective, anatomic/structural, metabolic,
genetic, neoplastic, vascular, toxic, immune and
idiopathic (Table 1). This review will deal mainly
with entities in the infectious, metabolic, genetic
and immunologic categories, as well as with idio-
pathic neonatal hepatitis. Liver biopsy is often
required to investigate neonatal hepatitis syn-
drome adequately.
4
The hallmark finding in many
neonatal liver disorders is giant-cell hepatitis
characterized by inflammation and large multi-
nucleated hepatocytes in the liver parenchyma.
Structural disorders causing obstruction of large
bile ducts lead to typical features of duct obstruc-
tion in portal tracts and surrounding parenchyma.
Typical changes of various metabolic diseases may
be evident on liver biopsy in the affected infant.
Infection
Toxoplasmosis, rubella, cytomegalovirus,
herpes simplex (TORCH) infections
These congenital infections usually share clinical
similarities such as enlargement of the liver and
spleen, jaundice, pneumonitis, a petechial or pur-
puric rash, and a tendency to prematurity or poor
intra-uterine growth. Clinical presentation with
neonatal liver failure is possible with any of these
agents, but it is most common with Herpes simplex
infection. Whenever possible, direct identification
of viral infection or measurement of specific IgM
antibodies should be sought for rapid diagnosis;
relying on conventional TORCH titres is less
preferable. Polymerase chain reaction (PCR)-based
diagnostic techniques can be extremely useful.
Toxoplasmosis
Congenital toxoplasmosis is rare and is usually
associated with maternal infection in the third tri-
mester. Neonatal hepatitis is prominent. Central
nervous system involvement with chorioretinitis
(with large pigmented scars), hydrocephaly or mi-
crocephaly, and intracranial calcifications usually
occurs, leading to convulsions, nystagmus and signs
of increased intracranial pressure. In older infants,
deafness may occur.
Rubella
Congenital infection with rubella virus may cause
numerous abnormalities including intra-uterine
growth retardation, anaemia/thrombocytopenia,
congenital heart disease (often patent ductus
arteriosus or pulmonary artery stenosis), cataracts,
chorioretinitis (salt and pepper appearance),
mental retardation and sensorineural deafness.
Conjugated hyperbilirubinaemia with hepato-
splenomegaly usually occurs. Liver histology
typically shows giant-cell hepatitis.
Cytomegalovirus
Cytomegalovirus (CMV) is the most common cause
of congenital infection, affecting 12% of new-
borns, most of whom are asymptomatic. Clinical
findings include a petechial rash, hepatospleno-
megaly and jaundice in 6080%. CMV can cause
neonatal liver failure, but this is uncommon. Fetal
ascites is not necessarily a poor prognostic sign.
CMV infection often affects the central nervous
system, producing microcephaly, intracranial
calcification, and chorioretinitis; progressive sen-
sorineural deafness may develop later in childhood.
Conclusive diagnosis requires CMV to be cultured
from the infant within the first 4 weeks of life
(usually in urine).
In most children, CMV hepatitis is mild and
resolves completely. Persisting neurodevelop-
mental abnormalities become the main problem.
A few children develop hepatic fibrosis or
non-cirrhotic portal hypertension. Intrahepatic
calcification has been reported. Rarely, cirrhosis
with chronic cholestasis eventually requires liver
transplantation.
CMV is an important cause of giant-cell hepatitis.
In a study of liver biopsies from infants with neo-
natal hepatitis or biliary atresia, Chang et al.
5
found evidence of CMV DNA in 23 of 50 infants with
neonatal hepatitis by PCR, but in only two of 26
with biliary atresia, and in none of the control
specimens.
358 E.A. Roberts
Table 1 Neonatal hepatitis syndrome: differential diagnosis
Diseases by category Associated with neonatal liver failure?
Infection
Toxoplasmosis (congenital)
Rubella (congenital)
CMV (congenital)
Herpes simplex (congenital) NLFacute
Syphilis (congenital)
HHV-6 NLFacute (rare)
Herpes zoster
Hepatitis B (mainly vertical) NLFacute
Hepatitis C (mainly vertical) NLFacute (rare)
HIV (vertical)
Parvovirus 19 NLFchronic
Syncytial giant cell hepatitis (?paramyxovirus)
Enteric viral sepsis (echoviruses, Coxsackie viruses, adenoviruses) NLFacute
Bacterial infection (extrahepatic or sepsis) NLFacute
Listeriosis
Tuberculosis
Structural
Biliary atresia
Choledochal cyst
Caroli syndrome
Choledocholithiasis
Neonatal sclerosing cholangitis
Hair-like bile duct syndrome
Spontaneous biliary perforation
Non-syndromic duct paucity
Alagille syndrome
Metabolic
1
-Antitrypsin deficiency
Cystic fibrosis
Galactosaemia NLFacute or chronic
Tyrosinaemia, type 1 NLFacute or chronic
Hereditary fructosaemia NLFchronic
Glycogen storage disease, type IV
NiemannPick, type A
NiemannPick, type C NLFchronic
Wolman disease
Gaucher disease
Progressive familial intrahepatic cholestasis (types 1, 2, 3)
North American Indian familial cholestasis
Aagenaes syndrome (cholestasis/lymphedema)
Primary disorders of bile acid synthesis NLFchronic
Peroxisomal disorders (e.g. Zellweger syndrome)
Perinatal haemochromatosis NLFchronic
Citrullinaemia, type II
Panhypopituitarism (septo-optic dysplasia)
Hypothyroidism
X-linked adrenoleukodystrophy NLFchronic
DubinJohnson syndrome
Genetic
Trisomy 18 (biliary atresia)
Cat-eye syndrome (biliary atresia)
Trisomy 21 (fibrosing hepatitis with transient leukaemia) NLFchronic
Neoplasia
Neonatal leukaemia NLFacute
Neuroblastoma NLFacute
Hepatoblastoma
Histiocytosis X
Erythrophagocytic lymphohistiocytosis NLFchronic
Neonatal hepatitis syndrome 359
Herpes simplex
In the newborn, herpes simplex virus (HSV) usually
causes a severe multisystem disorder with encepha-
litis. Either type 1 or type 2 HSV is capable of
causing severe infection, although type 2 virus shed
from the infected cervix at birth is more frequent.
Neonatal liver failure with an acute-pattern of
injury is typical. Liver biopsy shows areas of necro-
sis with viral inclusions in intact hepatocytes;
however, profound coagulopathy may preclude bi-
opsy. Scrapings from vesicular skin lesions typically
show the virus, but herpetic skin, mouth or eye
lesions may not be present. Antiviral treatment
with acyclovir should be administered to avert the
otherwise high mortality. In the child with acute-
pattern neonatal liver failure, acyclovir should
be started immediately, even with results of
diagnostic tests still pending.
Syphilis
Congenital syphilis causes intra-uterine growth
retardation and subsequent failure to thrive,
severe anaemia and thrombocytopenia, nephrotic
syndrome, periostitis, nasal discharge (snuffles),
skin rash, diffuse lymphadenopathy and hepatome-
galy. Central nervous system involvement occurs in
up to 30% of infants. Jaundice may be present
within 24 h of birth or develop after treatment, and
it may be severe.
6
Diagnosis involves serological
testing, including the Venereal Disease Research
Laboratory (VDRL) test and confirmatory testing for
specific antitreponemal antibodies. Radiographs of
long bones may show typical bony abnormalities in
the first 24 h of life and permit diagnosis while the
other tests are still pending. Treatment with peni-
cillin can then be started without delay. Some
babies with congenital syphilis never develop jaun-
dice, but present with a typical rash on the palms
and soles or only with fever, as well as prominent
hepatomegaly.
Varicella
Varicella may occur in newborn infants if maternal
infection occurs within 14 days of delivery. It tends
to be more severe in premature infants. Jaundice is
a feature of severe disease, which typically involves
an extensive rash, pneumonia and multisystem
involvement.
Hepatotropic viruses: hepatitis A, B, C
In general, infection with hepatotropic viruses in
neonates does not cause jaundice unless there is
acute-pattern neonatal liver failure or severe
hepatitis after a typical incubation period.
Hepatitis A
Hepatitis A is rare in the neonatal period. Congeni-
tal infection may occur if the mother is infected
12 weeks before delivery.
Hepatitis B
Vertical (mother-to-infant) hepatitis B infection is
generally subclinical in the neonatal period;
Table 1 (continued)
Diseases by category Associated with neonatal liver failure?
Toxic
TPN-associated cholestasis
Drug-induced (via breast-milk or other)
Vascular
BuddChiari syndrome NLFacute
Severe congestive heart failure
Neonatal asphyxia
Immune
Inspissated bile syndrome
Neonatal lupus erythematosus
Neonatal hepatitis with auto-immune haemolytic anaemia
Idiopathic
Le foie vide (infantile hepatic non-regenerative disorder) NLFchronic
NLFacute, acute-pattern neonatal liver failure; NLFchronic, chronic-pattern neonatal liver failure.
360 E.A. Roberts
prompt administration of both hepatitis B immuno-
globulin and hepatitis B immunization provides
protection against chronic infection in 93% of
infants at risk. Neonatal liver failure may rarely
occur with hepatitis B in neonates.
Hepatitis C
Hepatitis C virus (HCV) has not yet been identified
as a cause of neonatal hepatitis syndrome. Vertical
transmission of HCV is well documented and occurs
at a rate of 47% in mothers who are viraemic and
not co-infected with the human immunodeficiency
virus (HIV)
7
. Women who are co-infected with HCV
and HIV are three to four times more likely to
transmit HCV to the infant.
HIV infection
Neonatal conjugated hyperbilirubinaemia is rare in
infants with congenital HIV infection, although they
may have hepatosplenomegaly. Sometimes, pres-
entation with jaundice and hepatitis occurs later,
at approximately 6 months of age.
8
Parvovirus B19 infection
Congenital parvovirus B19 infection may cause pro-
found anaemia leading to hydrops and fetal death.
It is a cause of chronic-pattern neonatal liver fail-
ure, resembling perinatal haemochromatosis.
9
The
affected infant may have dermal erythropoiesis
(blueberry muffin rash), anaemia and perinatal
distress in addition to conjugated hyperbilirubi-
naemia, hepatomegaly and severe coagulopathy.
Testing by PCR for presence of parvovirus 19 may be
positive when all serological tests are negative;
placental histology may also suggest prenatal
parvovirus infection. Hepatitis has been reported in
young children and a 7-month-old infant.
Human herpesvirus-6 infection
Human herpesvirus-6 (HHV-6) causes exanthem
subitum, a common but usually benign febrile ill-
ness in infants; other HHV-6 infections are common
and self-limiting without a rash. Jaundice and
acute-pattern neonatal liver failure has been
reported in a 3-month-old infant, based on definite
serological evidence for HHV-6 infection and virus
isolated from peripheral blood mononuclear cells.
Enteric viral sepsis (echovirus, Coxsackie
viruses, adenoviruses)
Enteroviruses can cause systemic viral infection in
the newborn period. Severe hepatitis causing
acute-pattern neonatal liver failure may be the
prominent feature. Most infants with enteric viral
sepsis are less than 5 weeks old at presenta-
tion; many are less than 1 week old. The infant
is lethargic and jaundiced, with very high serum
aminotransferases and severe coagulopathy;
meningitis is usually present. Echovirus serotypes 3,
6, 7, 9, 11, 14, 19 and 21 have all been reported in
severe infections with hepatitis.
10
Echovirus sero-
type 11 appears to be most virulent for newborns.
The incidence of echovirus infections is greatest
between late summer and early autumn. The
infant's mother may give a history of abdominal
pain just prior to the onset of labour. Vertical
infection near the time of birth tends to produce
more severe disease in the infant. Coxsackie A and
B viruses are capable of causing an identical clinical
picture, although myocarditis or heart failure is a
clue to Coxsackie virus infection. Adenoviruses
have also been reported to cause acute liver failure
in the perinatal period. Mortality is high with
neonatal liver failure, of the order of 8590%.
Meticulous supportive care is essential. Infants who
recover may progress through a recovery phase
marked by severe cholestatic jaundice. Subsequent
liver function in survivors appears entirely normal.
Bacterial infection outside of the liver
Conjugated hyperbilirubinaemia may occur in con-
junction with sepsis or localized extrahepatic
infection. Serum aminotransferases may be
slightly elevated. The liver and spleen are not
enlarged. In infants, the most common infection
is a urinary tract infection, which is typically
clinically silent.
11
Gram-negative bacterial septi-
caemia is usually implicated with conjugated
hyperbilirubinaemia, but the mechanism in
infants, as in adults, remains unclear. Jaundice
in infants may also occur with streptococcal and
staphylococcal infections.
Listeriosis
Congenital infection with Listeria monocytogenes
typically involves the liver. Although meningitis is
the predominant clinical feature of congenital
listeriosis, infants have hepatosplenomegaly and
are sometimes jaundiced. Liver biopsy may reveal
simply a diffuse hepatitis or, more commonly, dif-
fuse areas of focal necrosis. These micro-abscesses
contain numerous Gram-positive bacilli. Pneumo-
nia is usually present. A history of maternal illness
is common.
Tuberculosis
Congenital tuberculosis is rare. With the world-
wide prevalence of tuberculosis rising, tuberculosis
in infants may occur somewhat more frequently.
Practical criteria for diagnosing congenital tubercu-
losis are a proven tuberculous infection in the
newborn baby and at least one of the following:
lesions in the first week of life; tuberculous infec-
tion of the placenta or maternal genital organs;
primary hepatic complex or caseating granulomas
in the liver; exclusion of postnatal infection.
12
Hepatomegaly is usually found in infants with
tuberculosis. Jaundice occurs with severe disease.
Respiratory distress, poor feeding and fever are
frequent. Mortality approaches 30%. Treatment is a
quadruple antitubercular antibiotic regimen not
including ethambutol.
Structural
Biliary atresia
Confirming or excluding biliary atresia is an import-
ant diagnostic issue, because it is frequently
responsible for neonatal hepatitis syndrome. Early
diagnosis is vital because surgical treatment, the
Kasai portoenterostomy, is less likely to be suc-
cessful the later it is performed.
13
(see paper
by Kobayashi and Stringer.
Biliary atresia involves a progressive destruc-
tion of the extrahepatic bile ducts with scarring,
obliteration and concomitant damage to small and
medium-sized intrahepatic bile ducts. Biliary
atresia is found world-wide in all racial groups, with
an incidence of 1:800015 000 live births. Cur-
rently, biliary atresia is often categorized into two
general patterns: embryonal/fetal or early and
perinatal or late. The majority of infants have the
late pattern. They appear to have had a normal
biliary system, which has become involved in a
fibrosing inflammatory process towards the end
of gestation or shortly after birth. By contrast,
approximately 1020% of infants with biliary atresia
have additional congenital abnormalities including
polysplenia, left atrial isomerism, double-sided left
lung, pre-duodenal portal vein, intestinal mal-
rotation, and/or congenital heart defects.
14,15
This suggests a different pathogenesis: an early,
possibly genetic, developmental abnormality.
The late pattern of biliary atresia may reflect
an acquired inflammatory lesion in originally
normal bile ducts. This inflammatory process is
not necessarily reversed even if bile drainage is
restored after Kasai portoenterostomy. Various
infective agents have been implicated in the
aetiology of biliary atresia in humans. Early studies
suggesting that reovirus-3 infection might be the
initiating infection for idiopathic neonatal hepatitis
and biliary atresia in humans were not confirmed in
later reports.
16
Other studies of liver biopsies and
biliary remnants from infants with late pattern
biliary atresia have not found support for rotavirus
infection.
17
CMV infection is found in a proportion
of infants with biliary atresia, but CMV does not
appear to be an exclusive cause of the condition. In
one report of fraternal twins with congenital CMV
infection, one had hepatitis only and the other
presented with late pattern biliary atresia.
18
In
one series of infants with biliary atresia, 25% had
CMV infection and they tended to be referred later
than those without CMV infection.
19
A more compli-
cated mechanistic explanation for late pattern
biliary atresia is that it occurs when an inflamma-
tory insult sets off an immune-mediated process in
a susceptible infant. In a murine model examining
bile duct allografts, alloreactive lymphocytes
mediated a destructive process histologically
similar to that of biliary atresia.
20
CMV remains a
candidate virus for causing late presentation
biliary atresia because CMV can infect bile duct
epithelial cells directly and result in increased
expression of major histocompatibility complex
class II antigens by these cells. Infants with con-
genital CMV infection and persisting conjugated
hyperbilirubinaemia should be evaluated for biliary
atresia.
Choledochal cyst
Choledochal cyst refers to a group of congenital
malformations of the biliary system. The most com-
mon type is a fusiform, sometimes sausage-shaped,
dilatation of the extrahepatic bile ducts (type 1).
Choledochal cysts are increasingly identified in the
fetus by prenatal sonography and have been found
as early as 1516 weeks' gestation.
21
The diagnosis
should be confirmed soon after birth. The majority
of these infants have conjugated hyperbilirubi-
naemia, and surgery should be performed
promptly.
Spontaneous biliary perforation
This condition may present as a severe acute
illness resembling acute peritonitis with abdominal
pain and distention, jaundice and fever. It can also
present as neonatal hepatitis syndrome, often with
abdominal distention in addition to jaundice and
acholic stools. Biliary ascites is pathognomonic.
362 E.A. Roberts
Bacterial superinfection greatly increases mor-
bidity. Surgical repair is usually curative.
Neonatal sclerosing cholangitis
Neonatal sclerosing cholangitis (NSC) was first
reported in 1987 with a few subsequent
reports.
22,23
The feature which distinguishes NSC
from childhood primary sclerosing cholangitis is
that NSC presents in early infancy with conjugated
hyperbilirubinaemia which then resolves; although
some children present in infancy with primary
sclerosing cholangitis, they have not had early
cholestatic jaundice. After apparent spontaneous
resolution of the neonatal liver disease, NSC
progresses to biliary cirrhosis with recurrence of
jaundice several years later. Liver transplantation
is usually required. NSC may be a metabolic dis-
ease
24
or have immunological features without
persistent jaundice. In one case, non-specific
auto-antibodies were detected.
25
Alagille syndrome
Alagille syndrome has an important structural
feature: paucity of small (portal) bile ducts. It is a
genetic disorder with autosomal-dominant trans-
mission but highly variable expression. The quoted
incidence of 1:100 000 probably exaggerates its
rarity. Mutations in JAG1 on chromosome 20p have
been identified as the genetic basis for Alagille
syndrome. Its major clinical features include
chronic cholestatic liver disease with decreased
numbers of small (portal) intrahepatic bile ducts,
structural cardiovascular disease, skeletal abnor-
malities including butterfly vertebrae, posterior
embryotoxon of the eye, and typical facies. Minor
features include renal abnormalities, small birth
size and/or poor growth, delayed puberty or
hypogonadism, and an abnormal high-pitched cry/
voice. Associated vascular abnormalities have been
noted including decreased intrahepatic portal vein
radicals, coarctation of the aorta and other large
vessel abnormalities, and moya-moya disease.
26
Neurological abnormalities described in early
reports probably were not part of the syndrome
itself but instead due to vitamin E deficiency from
severe chronic cholestasis. Hypothyroidism and
pancreatic insufficiency have also been observed
in affected children, and they are more likely to
get recurrent otitis media.
27
A spectrum of
behavioural problems has been described (mental
retardation, learning difficulties or antisocial
behaviour), but many children are normal socially
and academically.
The majority of patients with clinically import-
ant Alagille syndrome have conjugated hyper-
bilirubinaemia in the neonatal period.
28
Cholestasis
may be sufficiently severe that the stools are
acholic, and hepatobiliary scanning fails to show
evidence of biliary excretion.
29
Liver biopsy usually
shows reduced numbers of small bile ducts with
some giant-cell transformation and cholestasis. The
number of portal tracts may also be reduced. In
some infants, ongoing damage to bile ducts may be
found, or bile ductular proliferation suggestive of
extrahepatic bile duct obstruction. Alagille syn-
drome with a segmental atresia of the common
hepatic duct has been found in several infants.
The characteristic facies, not always evident in
early infancy, has the shape of an inverted triangle
and consists of a broad forehead, deep-set eyes,
mild hypertelorism, a straight nose and a small
pointed chin. The ears may be prominent. The
cardiovascular disease is usually relatively benign
(peripheral pulmonary artery stenosis), but more
severe hypoplasia of the pulmonary artery branches
may occur and other congenital heart disease has
been found.
30
Butterfly vertebrae, due to failure of
the anterior arches of the vertebral body to fuse,
are most commonly found in the thoracic spine. Eye
signs may be very diverse;
31
posterior embryotoxon
is most frequent.
Alagille syndrome seems to be rather benign in
many children. The clinical features of severe
cholestasisjaundice, pruritus, hypercholestero-
laemia with or without xanthomas, elevated serum
bile acids, alkaline phosphatase and -glutamyl
transpeptidase (GGT)resolve or improve during
the first year of life. The hepatic lesion does not
progress inexorably to cirrhosis. However, young
children with protracted jaundice usually have a
poorer prognosis, with progressive liver disease.
Conservative estimates put overall mortality at 20
25%, due to cardiac disease, intercurrent infection
or progressive liver disease. Liver transplantation
for severe hepatic disease is warranted and
catch-up growth may occur afterwards.
32,33
JAG1 is the human homologue of the rat gene
Jagged1. It encodes a ligand of Notch 1, which
is involved in determining cell fate during differ-
entiation, especially in tissues where epithelial
mesenchymal interactions are important. These
include many of the organs that are potentially
abnormal in Alagille syndrome. Haploinsufficiency
of JAG1 causes Alagille syndrome; mutations result
in truncated and thus inactive proteins and residual
gene expression cannot compensate.
34
Many muta-
tions are sporadic. No clear relationship between
genotype and phenotype has been found, although
the Delta/Serrate/Lag-2 (DSL) domain in the JAG1
protein may influence the severity of liver
disease.
3537
Non-syndromic bile duct paucity
In a full-term neonate in whom Alagille syndrome
has been excluded, various other disorders may
cause portal ductopenia (small duct paucity). This
non-syndromic duct paucity may be idiopathic or
associated with other specific conditions (Table 2).
Among congenital infections, CMV is most import-
ant and, in such cases, CMV inclusions may be found
in bile duct epithelial cells. When idiopathic neo-
natal hepatitis is clinically severe, duct paucity
may be present.
Metabolic
1
This is the most common inherited cause of neo-
natal hepatitis syndrome. The protease inhibitor,
1
-antitrypsin, a member of the serpin superfamily,
is produced mainly in the liver.
1
-Antitrypsin binds
and inactivates leukocyte elastase. More than 90
variants have been reported. The deficiency status
is caused by mutations in the
1
-antitrypsin genes
on chromosome 14. Deficiency occurs in 1:1600
2000 live births in North American and European
populations, but it is much less common with other
ethnic backgrounds. Only a small proportion of
individuals with
1
-antitrypsin deficiency ever
develops liver disease, but 8590% of the children
with
1
-antitrypsin deficiency who develop liver
disease present with neonatal hepatitis syndrome.
In most of these infants, liver disease eventually
resolves. Cholestasis may be severe with totally
acholic stools and a non-draining hepatobiliary
scan. Small duct paucity may be present and
portends a poor prognosis. The rare infant has been
reported with both
1
-antitrypsin deficiency and
biliary atresia. The 1015% who do not have
neonatal hepatitis syndrome present later with non-
jaundiced hepatomegaly. Some newborn infants
present with potentially serious haemorrhagic com-
plications associated with severe coagulopathy.
Clinical diagnosis rests upon finding low serum
concentrations of
1
-antitrypsin and identifying an
allelic variant of
1
-antitrypsin. The most common
deficiency variant is Z, a slow-moving protein on
electrophoresis, with a point mutation resulting in
a single amino acid substitution (lysine replacing
glutamic acid at position 342). Some variants such
as M
Malton
and M
Duarte
show only subtle electro-
phoretic differences from the normal M and may
be difficult to recognize. Since
1
-antitrypsin is an
acute-phase reactant, diagnostic low serum con-
centrations may not be found due to hepatic
inflammation. Determining the phenotype (PI
type) by iso-electric focusing or identifying a
specific gene defect by molecular methods such as
PCR is essential to the diagnosis. In individuals with
the Z- or M-variant allele, liver biopsy shows globu-
lar inclusions, which are abnormal
1
-antitrypsin
protein retained in the endoplasmic reticulum.
These globules stain pink with periodic acidSchiff-
diastase (PAS-D) stain. They are not reliably found
in liver biopsies from infants less than 3 months old.
Most infants with
1
-antitrypsin deficiency and neo-
natal hepatitis syndrome have PI type ZZ (although
PI Z/null cannot be excluded without family
studies). Liver disease may occur with PI SZ at a
relatively young age, and with PI FZ and PI MZ later
in adulthood.
38
The long-term outlook for infants with jaundice
and
1
-antitrypsin deficiency is often very good.
Approximately half do well; of these infants, half
are entirely normal and the other half have mildly
abnormal serum aminotransferases, no jaundice
and no enlargement of liver or spleen. The rest go
on to chronic liver disease with cirrhosis or die in
the first year of life. Early prognostication of indi-
vidual infants with
1
-antitrypsin deficiency is dif-
ficult. In one study of children with neonatal
hepatitis, persisting elevation of serum aminotrans-
ferases and serum GGT through 612 months of
Table 2 Causes of non-syndromic paucity of bile ducts
(ductopenia) in infants
Prematurity
Infection
CMV
Rubella
Syphilis
Hepatitis B
Metabolic
1
Cystic fibrosis
Zellweger syndrome
Byler syndrome
Ivemark syndrome
Prune belly syndrome
Hypopituitarism
Genetic: chromosomal disorders
Trisomy 18, 21
Partial trisomy 11
Monosomy X
Immune-related: grafthost disease
Severe idiopathic neonatal hepatitis
Isolated/idiopathic
364 E.A. Roberts
age, or the presence of bile ductular proliferation,
bridging fibrosis or cirrhosis on the initial liver
biopsy presaged rapidly progressive liver disease.
39
Although the severity of jaundice at presentation
may not be predictive of outcome, its duration
appears to be critical. Infants in whom jaundice
resolves within a few months, usually by 6 months
old, are likely to have a good outcome, but those
with prolonged jaundice pursue a downhill course.
Liver transplantation is generally tolerated well,
although attention to potential kidney disease
associated with
1
-antitrypsin deficiency is
required through the early postoperative period.
40
The PI type of the donor effectively replaces the
abnormal phenotype.
Cystic fibrosis
Abnormalities of liver function tests or on liver
biopsy are found in as many as one-third of infants
with cystic fibrosis. However, even in infants,
hepatic pathology is highly variable. The spectrum
of hepatic pathology includes giant-cell hepatitis,
extrahepatic bile duct obstruction by inspissated
bile, massive hepatic steatosis usually without con-
jugated hyperbilirubinaemia, and paucity of small
(portal tract) bile ducts. Neonatal hepatitis is very
uncommon.
41
Many infants who have severe liver
disease also have meconium ileus.
Galactosaemia
The incidence of galactosaemia is approximately
1:50 000. Clinical features are extremely vari-
able in the neonatal period and include vomiting,
diarrhoea, jaundice, poor weight gain and mal-
nutrition. Eye manifestations include cataracts,
intraocular haemorrhage and retinal detachment.
Although mental retardation may occur, many
children have normal intelligence. Some infants
present with septicaemia. Galactosaemia can
present as an acute or chronic type of neonatal liver
failure. A few infants never have any symptoms and
are diagnosed later in childhood. The definitive
diagnostic test is measurement of erythrocyte
galactose-1-phosphate uridyltransferase (GALT),
which must be performed before the infant has had
any blood transfusions. Testing the urine for reduc-
ing substances can be misleading, as reducing
substances may be present in other severe neo-
natal liver disease. Galactosuria may be present in
normal newborns for the first few days of life, and
well into the second week in premature babies.
Conversely, galactosuria may not be present in
an affected infant who is too unwell to take
lactose-containing formula. Cataracts found on
physical examination require definitive assessment
by an ophthalmologist. Oil-drop cataracts are
highly typical of galactosaemia and may resolve
with treatment if the disease is diagnosed early.
Treatment consists of elimination of galactose from
the diet. Liver disease usually improves. Later com-
plications, mainly neurodevelopmental problems,
may develop later despite good dietary control.
Hereditary tyrosinaemia, type 1
Hereditary tyrosinaemia type 1 is an autosomal-
recessive disease of tyrosine metabolism due to
lack of fumaryl acetoacetate hydrolase (FAH),
expressed mainly in the liver and kidneys.
42
The
classic clinical presentation is liver disease with
rickets and aminoaciduria. However, babies with
this disorder may present with neonatal liver fail-
ure in the perinatal period, with classic neonatal
hepatitis syndrome, or at a later age (between 4
and 24 months) with hepatomegaly, ascites and
coagulopathy but no jaundice. Untreated heredi-
tary tyrosinaemia type 1 carries a high mortality in
infancy; the proportion of patients presenting in
later childhood is comparatively small. Children
with hereditary tyrosinaemia type 1 who survive to
mid-childhood have a very high incidence of
hepatocellular carcinoma, with a prevalence
approaching 40% in mid-childhood. The disease is
found world-wide, but it is common in the
SaguenayLac St. Jean region of Canada (1:500),
Pakistan and northern Europe.
Although presentation of hereditary tyrosi-
naemia type 1 as neonatal hepatitis syndrome
may be less common than other presentations,
hereditary tyrosinaemia type 1 has to be considered
in any infant with clinically or histologically severe
neonatal hepatitis (Table 3) or neonatal liver fail-
ure. Coagulopathy may be prominent, attributed in
part to dysfibrinogenaemia. Hypoglycaemia may
occur. The liver biopsy shows parenchymal changes
with inflammation of unusual severity. Typically,
the -fetoprotein level is disproportionately high
Table 3 Diseases causing histologically severe neonatal
hepatitis
1
Hereditary tyrosinaemia, type 1
NiemannPick disease, type C
Syncytial giant cell hepatitis
Primary disorders of bile acid synthesis (mainly
4
-3-oxosteroid 5-reductase deficiency)
Idiopathic neonatal hepatitis
for an infant, often 40 00070 000 g/l. Rickets
may be present at an early age. Laboratory findings
include an abnormal plasma amino acid profile with
elevations of tyrosine, phenylalanine and methio-
nine. Succinylacetone can be detected in the urine
in virtually all patients. Treatment with 2-(2-nitro-
4-trifluoromethyl-benzoyl)-1,3-cyclohexanedione
(NTBC: an inhibitor of 4-hydroxyphenylpyruvate-
dioxygenase), in addition to a low-tyrosine
phenylalanine diet, has revolutionized the
management of this disease and extended sur-
vival dramatically,
43
although a long-term risk of
hepatocellular carcinoma persists.
Hereditary fructosemia
Hereditary fructose intolerance is an autosomal-
recessive disorder and is due to deficiency of
aldolase B (fructose biphosphate aldolase) in the
liver, kidney and intestine. The genetic basis of this
disorder is mutations in the aldolase B gene, lead-
ing to a spectrum of functional changes in the
enzyme.
44,45
Age of presentation depends on
dietary exposure to fructose, not frequent in early
infancy. Sucrose-containing medications or unduly
early introduction of fruit juice or bananas must be
considered. The usual presentation is with vomiting
and hepatomegaly, but jaundice may be present in
nearly half of affected children. Elevated serum
aminotransferases, mild coagulopathy, proteinuria
and aminoaciduria are common. Liver biopsy
reveals macrovesicular fat with fibrosis and patho-
gnomonic changes in hepatocyte cytoplasm (so-
called fructose holes) on electron microscopy.
Aldolase B activity can be measured in the liver
biopsy specimen. Treatment is to remove all
fructose (and sucrose) from the diet.
NiemannPick disease, type A or type C
There are two types of NiemannPick disease
associated with neonatal liver disease.
Type A
Although hepatosplenomegaly is frequently found
with type A (acute neuronopathic) Niemann
Pick disease, due to lysosomal sphingomyelinase
deficiency, jaundice is rare.
Type C
This is a disorder of cholesterol esterification, with
progressive neurological deterioration during child-
hood in most, but not all, cases. The gene product
of NPC1 appears to mediate trafficking of sterols
and various other substrates out of lysosomes to
other subcellular compartments.
46
In addition to
abnormal cholesterol homeostasis, peroxisomal
function may be impaired.
47
In approximately 3060% of cases, NiemannPick
disease type C presents with conjugated hyper-
bilirubinaemia, often with prominent spleno-
megaly. The infants appear neurologically normal,
although subsequent motor and speech develop-
ment may lag.
48
Fetal ascites may occur. Liver
biopsy shows a histologically severe neonatal
hepatitis, with pericellular fibrosis and pseudo-
acinar formation; features suggesting that extra-
hepatic biliary obstruction may be found.
48
Storage
cells typical of NiemannPick disease are often not
found in the liver this early in life. Rectal biopsy
may show foamy macrophages in the lamina pro-
pria, or typical ultrastructural changes (lamellar
cytoplasmic inclusions) in rectal ganglion cells.
Studies of cholesterol esterification in the patient's
cultured fibroblasts are definitive.
Progressive familial intrahepatic cholestasis
Currently, three types of progressive familial
intrahepatic cholestasis (PFIC) are recognized,
which are due to defects in different transporters in
the bile canalicular membrane of the hepatocyte.
The term Byler disease has been replaced by
PFIC-1.
PFIC-1
Clinically, PFIC-1 presents with conjugated hyper-
bilirubinaemia in the first 3 months of life or often
a little later, around 46 months old. The degree of
jaundice may vary. Fat-soluble vitamin defi-
ciencies, and associated rickets, may be severe.
Pruritus is severe and does not respond well to
treatment. Growth retardation may not be evident
initially. Liver biopsy shows little inflammation but
has distinctive canalicular bile plugs. Small duct
paucity may be found. The serum GGT is normal, as
is serum cholesterol. The total serum bile acid
concentration is elevated but the biliary cheno-
deoxycholic acid concentration is extremely low.
49
Children with PFIC-1 have persistent diarrhoea with
fat malabsorption and protein loss, recurrent
pancreatitis, and poor growth leading to short
stature. Sensorineural hearing loss may occur.
Cirrhosis usually develops in early childhood and
liver transplantation is required. After liver trans-
plant, pancreatitis may still occur, and the
diarrhoea may get worse.
Patients with PFIC-1 have a mutation in the gene
FIC1 on chromosome 18q2122.
50
FIC1 encodes a
366 E.A. Roberts
P-type ATPase (ATP8B1) involved in aminophos-
pholipid transport between membrane leaflets.
FIC1 is expressed in numerous tissues including the
gastrointestinal tract, pancreas and lung. Mutations
in FIC1 are also responsible for Greenland Eskimo
cholestasis
51
and for benign recurrent intra-
hepatic cholestasis, a disease mainly of adults but
sometimes symptomatic in childhood.
52,53
PFIC-2
Children with PFIC-2 have mutations in the human
bile salt export pump (BSEP, ABCB11), an ATP-
binding cassette transporter formerly known as
sister of P-glycoprotein (SPGP)
54,55
on chromosome
2q24. They have cholestasis and normal serum
GGT, and more severe hepatic abnormalities than
in PFIC-1, with inflammation, giant-cell transfor-
mation of hepatocytes, fibrosis and ductular pro-
liferation on liver biopsy. Clinical presentation is
like PFIC-1 except that there is no extrahepatic
involvement.
PFIC-3
Affected children have progressive intrahepatic
cholestasis but, in contrast to PFIC-1 and PFIC-2,
children with PFIC-3 have elevated serum GGT.
56
PFIC-3 frequently presents in infancy, or else later
in childhood. Jaundice may be less striking than
pruritus; despite the clinical appearance of biliary
tract obstruction, imaging reveals a normal biliary
tree. Portal fibrosis with or without bile ductular
proliferation is found on liver biopsy. Mutations in
the P-glycoprotein MDR-3 gene (ABCB4) have been
identified, and mutations resulting in a truncated
protein appear to be associated with more severe
disease than mis-sense mutations.
57
The affected
protein is the bile canalicular membrane transloca-
tor of phospholipids. PFIC-3 patients have bile
phospholipid concentrations which are extremely
low, <15% of normal. Most children with severe
disease eventually require liver transplantation.
North American Indian familial cholestasis
(North American Indian childhood cirrhosis)
Chronic cholestatic liver disease was described in
14 North American Indians living in North-west
Quebec, Canada; familial clustering was promi-
nent, and consanguinity was a possible factor. Nine
of the 14 presented with neonatal conjugated
hyperbilirubinaemia, and in these infants, jaundice
disappeared during the first year of life. Chronic
cholestatic disease was similar in all 14; hepato-
splenomegaly, pruritus, facial telangiectasia and,
eventually, cirrhosis and portal hypertension.
Serum GGT was elevated.
58,59
The genetic basis of
this disorder was recently determined; it is due to
mutations in FLJ14728, conventionally called
cirhin, on chromosome 16q22, and it encodes a
protein of unknown function which localizes to
mitochondria.
60
Aagenaes syndrome
Aagenaes syndrome is a very rare disorder with
cholestasis and lower limb oedema. It was initially
reported in a Norwegian kindred but has also been
reported in children of Norwegian descent and in
other ethnic groups. The principal features are
neonatal hepatitis syndrome evolving to a chronic
cholestatic condition and a lymphatic disorder. This
may be localized lower limb lymphedema, a more
subtle disorder with generalized oedema despite
normal serum albumin, or haemangioma(s) and/or
lymphangioma(s). The lymphatic abnormalities
may present clinically somewhat later than the
jaundice. The neonatal hepatitis evolves into a
predominantly cholestatic problem with pruritus
and fat-soluble vitamin deficiencies requiring sup-
plementation. The genetic basis of this familial
cholestatic disorder is not known, but its genetic
locus has been mapped to chromosome 15q.
61
Primary disorders of bile acid synthesis
Inherited defects in some of the enzymes in the
complex process of bile acid synthesis may cause
neonatal hepatitis syndrome or chronic cholestasis
later in childhood. While these diseases are
extremely rare, they can be treated successfully
by supplementation of critical bile acids, if the
diagnosis is made relatively early in the course of
disease.
62
3-Hydroxy-
5
-C
27
-steroid
dehydrogenase/isomerase deficiency
This microsomal enzyme is the second in the bile
acid synthetic pathway. Infants lacking it present
with jaundice and acholic stools in the first few
days of life; neonatal hepatitis may be histologi-
cally severe or the cholestatic disease may be
somewhat more indolent, resembling progressive
intrahepatic cholestasis and presenting later in
childhood. Typically, infants and children with 3-
hydroxy-
5
-C
27
-steroid dehydrogenase/isomerase
deficiency have normal serum GGT and low serum
total bile acid concentrations, but no pruritus. They
produce excessive amounts of C
24
-bile acids with a
3-hydroxy-
5
structure. The currently preferred
treatment strategy is cholic acid with or without
ursodeoxycholic acid.
4
-3-Oxosteroid 5-reductase deficiency
4
-3-Oxosteroid 5-reductase is an important cyto-
solic enzyme in the bile acid synthetic pathway.
The original description of this disorder included
two infants with early severe cholestasis and coagu-
lopathy. Subsequent reports have included infants
with a clinical presentation resembling perinatal
haemochromatosis. Serum GGT is usually, but not
invariably, normal. Liver biopsy may reveal abnor-
mal bile canaliculi in a focal, mosaic pattern. In
this disorder, excess, potentially toxic,
4
-3-oxo
bile acids are produced. Treatment with cholic acid
(with or without ursodeoxycholic acid) appears to
be beneficial in patients without iron overload. The
hereditary disorder has to be distinguished from
acquired deficiency of the enzyme due to severe
liver disease of any cause.
24,25-Dihydroxycholanoic cleavage enzyme
deficiency
Infants have been described with a defect in the
25-hydroxylase pathway.
63
Jaundice and hepato-
megaly were noted in the first week of life; serum
GGT was normal but alkaline phosphatase and
cholesterol were elevated, hepatobiliary scanning
showed no drainage, and pruritus developed later.
Treatment with chenodeoxycholic plus cholic acid
appeared beneficial.
Other bile acid synthesis disorders
This is an evolving field. Two other inborn errors of
bile acid metabolism have recently been described
in single patients presenting with neonatal liver
disease.
64,65
Neonatal hepatitis syndrome with a
defect in bile acid conjugation (ligase deficiency)
has also been observed.
62
Zellweger syndrome
Zellweger syndrome is the prototype of the peroxi-
somal biogenesis disorders, characterized by
multiple abnormalities of peroxisome function.
The molecular and cell biology of these disorders
is complex, involving multiple PEX genes which
encode peroxins, proteins required for peroxisome
assembly. Zellweger syndrome is most often associ-
ated with mutations in PEX1 and PEX6.
6668
Zellweger syndrome is rare, occurring in 1:100 000,
and affects both genders equally. Multiple systems
besides the liver are affected; features include
profound hypotonia, facial dysmorphism with a high
forehead and large fontanelles, developmental
delay, seizures, bony abnormalities such as epi-
physeal calcifications, and cystic malformations in
the brain and kidneys. In the first 3 months of
life, hepatic involvement may not be prominent,
although some babies have persistent conjugated
hyperbilirubinaemia. Others are not jaundiced but
have hepatosplenomegaly with evidence of poor
hepatic synthetic function. Hepatic fibrosis is typi-
cal, and paucity of the small (portal) bile ducts may
be found. Electron microscopy reveals the absence
of peroxisomes in hepatocytes. Mitochondria may
also appear abnormal. These infants may develop
cirrhosis, although extrahepatic features of the
syndrome almost always overshadow the hepatic
disease.
Perinatal haemochromatosis
This disorder is also called neonatal haemochroma-
tosis or neonatal iron storage disease. It is a severe
liver disease with extensive iron overload in the
newborn, suggesting fetal liver injury. It is thought
to be extremely rare, but approximately 120 cases
have been reported. Its pathogenesis remains
uncertain. The dispute as to whether perinatal
haemochromatosis is a single liver disease or a
common clinical presentation for multiple disease
processes is justified. Some cases have a definable
aetiology but pathogenesis remains unclear in a
significant proportion of patients. These appear to
have a hereditary or at least familial pattern.
Most babies present shortly after birth, although
a few have been diagnosed at 23 months of
age.
6971
The affected infant has neonatal liver
failure with a classic chronic-pattern. The bio-
chemical features are those of end-stage cirrhosis:
near-normal serum aminotransferases, low serum
concentrations of proteins produced in the liver
(e.g. albumin), and variable jaundice with conju-
gated hyperbilirubinaemia. Jaundice may be some-
what more prominent in infants presenting at a few
weeks old. Ascites, including fetal ascites, may be
present. Serum iron and transferrin are normal, but
serum ferritin is usually increased to the 2000
3000 g/l range. The liver and certain other organs
(pancreas, kidneys, adrenal glands and heartnot
the reticulo-endothelial system) show iron accumu-
lation.
72
Finding iron deposition in salivary glands
on buccal biopsy or evidence of iron overload
on magnetic resonance imaging supports the
diagnosis.
368 E.A. Roberts
Treatment is supportive in a well-equipped neo-
natal intensive care setting; liver transplantation
may be required for survival. Recently, multiple
drugs aimed at reducing oxidative stress have been
used with some success, if treatment is commenced
very early.
73
This anti-oxidant cocktail includes
anti-oxidants (N-acetylcysteine, selenium and
-tocopheryl polyethylene glycol succinate), a
hepatocytoprotective agent (prostaglandin E
1
,
omitted if a patent ductus arteriosus is present) and
a chelator (desferrioxamine, used until the serum
ferritin is <500 g/l). Not all infants respond to
this regimen, which has never been subjected to
a controlled clinical trial, and there is a risk of
septicaemia complicating desferrioxamine therapy.
Infants surviving the early liver disease appear to
stabilize clinically and may end up with inactive
fibrosis or even no residual liver disease. An inci-
dental hepatocellular carcinoma has been reported
in three infants. Certain clinical patterns associated
with perinatal haemochromatosis are unusually
severe: a renal tubular disorder
74
or
4
-3-
oxosteroid-5-reductase deficiency.
Citrullinaemia, type II
Although jaundice is rare with the classic form of
citrullinaemia (type I, argininosuccinate synthetase
deficiency), infants with neonatal hepatitis syn-
drome were recently described who had type II
citrullinaemia, confirmed by genetic analysis.
7577
A distinguishing feature was the presence of
steatosis and iron deposition histologically. Liver
disease was severe enough in one infant to require
liver transplantation. Type II citrullinaemia is due
to a deficiency in citrin, a carrier protein of
unknown function associated with the urea cycle,
encoded by the gene SLC25A13.
Disorders of bilirubin conjugation
DubinJohnson syndrome is due to mutations in
the human gene MRP2, which encodes the bile
canalicular membrane transporter for anion
conjugates.
78,79
Numerous mutations have been
described, most of which cause functional deficits
through defects in protein maturation and localiz-
ation.
80,81
Neonatal hepatitis syndrome has been
reported rarely in DubinJohnson syndrome.
82
Diagnosis is hampered by the difficulty in recogniz-
ing the typical melanin-containing pigment in the
liver during infancy, as little accumulates until
later in childhood. Treatment of severely affected
neonates with ursodeoxycholic acid may be
beneficial.
Genetic
Trisomy 18
Trisomy 18 is associated with growth retardation,
skeletal abnormalities and complex congenital
heart disease. In a series of 10 infants with cyto-
genetically confirmed trisomy 18, giant-cell hepa-
titis was found in three and biliary atresia in two. In
one infant with trisomy 18, serial liver biopsies
suggested late evolution of neonatal hepatitis to
biliary atresia. Other cytogenetic abnormalities,
including trisomy 13, deletion of the short arm of
chromosome 18 and 49, and XXXXY,
83
have been
reported rarely in association with biliary atresia.
Trisomy 21
An association between trisomy 21 and biliary
atresia is not well substantiated. Severe liver dis-
ease has been reported with Down's syndrome.
Some patients had severe hepatic fibrosis associ-
ated with a transient myeloproliferative disorder,
raising the possibility of hepatic fibrogenesis due to
high concentrations of growth factors derived
from megakaryocytes.
84
Neonatal liver failure
may occur. Treatment with low-dose cytosine
arabinoside may be curative.
85
Immune
Inspissated bile syndrome
The inspissated bile syndrome is the term tradi-
tionally used for conjugated hyperbilirubinaemia
complicating severe jaundice associated with
haemolysis, usually due to Rhesus factor or ABO
incompatibility or erythrocyte abnormalities. Intra-
hepatic cholestasis is found on liver biopsy, and
cholestasis may be due to direct hepatocellular
toxicity of unconjugated bilirubin. A multifactorial
cause cannot be entirely excluded as these infants
are often premature and present complex medical
problems. The outlook is generally good, although
early reports showed cirrhosis in some infants.
Neonatal lupus erythematosus
Neonatal lupus erythematosus is due to passage of
maternal anti-Ro and anti-La antibodies across the
placenta, leading to damage to fetal tissues, which
express Ro and La antigens. The heart, skin and
liver are most likely to be involved, rarely with
thrombocytopenia and leukopenia.
86
Congenital
heart block is the most dramatic cardiac manifes-
tation; a discoid lupus erythematosus rash may be
present in the newborn period or develop some
weeks later. Hepatic involvement, evident in
approximately 10%, is often limited to elevated
serum aminotransferases, but neonatal hepatitis
syndrome is found. Occasionally, this is severe
enough to mimic extrahepatic biliary tract obstruc-
tion, with acholic stools and a non-draining hepato-
biliary scan. One infant with severe liver disease
resembled perinatal haemochromatosis. Transient
unexplained isolated conjugated hyperbilirubi-
naemia in the perinatal period and later presenta-
tion at 23 months old with transient elevations of
serum aminotransferases are other possible clinical
presentations.
87
In most infants, the liver disease
resolves completely between 6 and 12 months of
age, as the maternal antibodies are degraded. Mild
fibrosis was found in one child on repeat liver
biopsy.
The diagnosis of neonatal lupus erythematosus is
difficult in the child who does not have congenital
heart block or a typical skin rash. Some infants have
only transient jaundice and myocarditis with an
abnormal electrocardiogram. If the mother is
known to have systemic lupus erythematosus or
Sjogren's syndrome, the diagnosis should be sus-
pected. Frequently, however, the mother is
asymptomatic and has no obvious rheumatological
disease. Routine methods may fail to detect anti-Ro
and anti-La in the infant, and in any case, these
studies need to be performed at as young an age as
possible. Very high titres of ANA in the infant may
be due to neonatal lupus erythematosus. Deposits
of associated antibodies (anti-Ro and/or anti-La)
may be found in affected liver tissue by immuno-
fluorescence.
88
The risk of neonatal lupus erythe-
matosus in subsequent pregnancies appears
variable, estimated at 1050%.
Idiopathic neonatal hepatitis
In a large proportion of infants presenting with
conjugated hyperbilirubinaemia before 3 months
old, no aetiology is found. Liver biopsy shows an
extensive giant-cell transformation of hepatocytes
with inflammation, but bile ducts appear generally
normal. A few infants with histologically severe
inflammation also have small duct paucity. All
these infants are classified as having idiopathic
neonatal hepatitis, a condition of unknown and not
necessarily unitary aetiology. In one series, babies
with idiopathic neonatal hepatitis accounted for
approximately one-quarter of all infants who
underwent liver biopsy in the first year of life. This
figure probably underestimates the incidence of
idiopathic neonatal hepatitis. An important subset
of idiopathic neonatal hepatitis includes instances
where more than one child in a single family is
affected, accounting for 515% of cases in most
series.
Cholestasis in idiopathic neonatal hepatitis may
be sufficiently severe clinically that supportive
measures, including high-calorie formula feeds
containing medium-chain triglycerides and supple-
mentation of fat-soluble vitamins, are required at
least temporarily. Differentiation from biliary
atresia and other severe cholestatic conditions is
the critically important issue. In general, there are
no easy discriminators between severe idiopathic
neonatal hepatitis and biliary atresia, and thorough
methodical investigation is essential. An operative
cholangiogram may be required, and there is no
evidence that diagnostic laparotomy for assess-
ment of the extrahepatic biliary tree is detrimental
to infants with idiopathic neonatal hepatitis.
Although idiopathic neonatal hepatitis can occur
in preterm babies, some will have cholestasis due
to immaturity of the biliary tree. These infants are
prone to early hypoglycaemia and also have a func-
tionally immature gastrointestinal tract resulting in
difficulties with feeding. Premature babies can also
have congenital infection or biliary atresia. Some
disorders, notably perinatal haemochromatosis,
seem to predispose to premature birth.
The prognosis for idiopathic neonatal hepatitis
is generally good. Mortality runs at 1325%.
89
Predictors of poor prognosis include prolonged
(>6 months) or severe jaundice, acholic stools,
familial occurrence, persistent hepatomegaly and
severe inflammation on biopsy. Peak bilirubin level
is not necessarily predictive of outcome, and the
prognostic importance of ductopenia has not been
rigorously investigated. Sepsis may shift an infant
from a relatively good prognosis to a poor outlook.
The long-term outlook for infants whose liver dis-
ease resolves in the first year of life is very good,
without residual liver disorder.
Management of neonatal hepatitis
syndrome
Management should be supportive and, if possible,
definitive. Generally, treatments involve dietary
manipulation to remove toxins or surgical interven-
tion to relieve obstruction. For some metabolic
disorders, such as hereditary tyrosinemia type 1
and bile acid synthesis disorders, unloading the
metabolic pathway is effective. Orthotopic liver
transplant is often the only definitive treatment for
severe infantile liver disease and can be performed
370 E.A. Roberts
safely in the first year of life, especially if nutrition
is maintained (see paper by McClean and Davison).
It is advisable to place an infant with conjugated
hyperbilirubinaemia on a lactose-free formula until
the results of testing for galactosaemia are known.
However, if the infant is breast-feeding well and
is clinically stable, and if GALT results can be
obtained with little delay, the child may be left
breast-feeding. Brief use of a more restrictive diet
is sometimes justifiable; an infant with severe neo-
natal hepatitis syndrome might be placed on a
lactose-free/low-protein formula (to minimize
aromatic amino acid intake) until the results of
tests for both galactosaemia and hereditary
tyrosinaemia type 1 are available.
All infants with severe cholestatic jaundice
require special formulas to ensure that caloric
intake is adequate. A nearly elemental formula
containing medium-chain triglycerides, which can
be absorbed regardless of luminal concentrations of
bile acids, is preferable. Caloric density can be
increased further by concentrating the formula or
adding starch powder. These formulas are rela-
tively expensive and not particularly palatable,
although many infants take them satisfactorily. An
alternative strategy is to modify a standard infant
formula by adding medium-chain triglyceride liquid
and additional starch. This is often the best
approach for an infant presenting later in the neo-
natal period with jaundice. A more difficult prob-
lem is how to manage the infant who is
satisfactorily breast-feeding; if breast-feeding is
continued, weight gain must be monitored closely.
Should growth falter, supplementation with a
highly digestible high-caloric density formula
should be added, or else the baby should be weaned
and the special formula substituted for breast-
feeding at that point. A breast-feeding device to
provide supplementary formula at the nipple may
be useful. In biliary atresia, resting energy expendi-
ture runs approximately 30% higher than in normal
infants of the same age and sex;
90
an aggressive
approach to feeding is required, including naso-
gastric supplementation if oral feeding cannot
meet caloric needs. In idiopathic neonatal
hepatitis, this type of special formula, along with
fat-soluble vitamin supplementation, may be
required until the jaundice abates, at which point
the baby can be placed on an appropriate regular
diet. Special diets are used life-long for children
with inborn errors of carbohydrate and amino acid
metabolism.
Infants with chronic cholestasis, whether
jaundiced or not, require supplementation of fat-
soluble vitamins. Vitamins A and D are potentially
toxic in high dose. Administration of the more polar
25-hydroxyvitamin D may be more effective than
plain vitamin D because the hydroxylated form of
vitamin D is better absorbed. However, residual
hepatic 25-hydroxylation activity is usually
adequate. Vitamin E transferred via the placenta to
the fetus may keep the infant replete until the age
of 3 months, but the sufficiency of maternal stores
varies greatly. Most babies require supplementa-
tion after 2 months of age or earlier if the baby
was born preterm. Vitamin E attached to poly-
ethylene glycol 1000 through a succinate linkage
(-tocopheryl polyethylene glycol succinate or
TPGS) has been shown to have the best bioavail-
ability in severe cholestasis, since its absorption
depends on simple passive absorption of the poly-
ethylene glycol. Since vitamin E absorption is
exquisitely dependent on luminal bile acids, any
jaundiced infant with deficiency of another fat-
soluble vitamin should be assumed to require extra
vitamin E. Coagulation should be monitored closely
in all infants with cholestasis. Infants with a coagu-
lopathy (measured by prothrombin time or INR)
should receive oral vitamin K daily. An alternate
approach is to use a combination of fat-soluble
vitamin preparation that includes vitamin K daily;
parenteral vitamin K may be needed periodically.
Infants receiving rifampicin for pruritus should
receive extra vitamin K.
Pruritus due to severe cholestasis interferes with
the infant's sleep and compromises social inter-
action and play during waking hours. It is often
difficult to treat. Local measures such as non-
perfumed skin creams and colloidal oatmeal bath
preparations may help. If there is some bile flow, as
in Alagille syndrome, cholestyramine or ursodeoxy-
cholic acid may be effective. Cholestyramine can
cause intestinal obstruction or hypernatraemia in
small infants and therefore must be used carefully
and given with adequate fluids. If bile flow is totally
obstructed, therapeutic choices are more limited.
Phenobarbital is relatively ineffective, causes
sedation and may exacerbate rickets. Rifampicin
(510 mg/kg/day given by mouth in two equally
divided doses) relieves pruritus in at least 50%,
although experience in very young infants is
limited.
91
Side effects include hepatotoxicity in
510% and thrombocytopenia, and the urine turns
to orangered colour. Surgical biliary diversion may
be effective in some conditions, including Alagille
and PFIC syndromes.
92
Specific attention to the infant's developmental
needs is often highly beneficial. Physiotherapy may
improve gross motor development; lower limb
weakness seems to be especially common in older
infants with biliary atresia. Stimulation programs
enhance mental development of infants who
require frequent hospitalization or for those with
syndromes associated with central nervous system
involvement, such as congenital CMV infection.
Practice points
Any infant jaundiced at 24 weeks of age
must be evaluated for conjugated
hyperbilirubinaemia.
Conjugated hyperbilirubinaemia in the first
24 h of life strongly suggests congenital
infection.
Structural abnormalities of the biliary tree
found on prenatal ultrasound require
assessment as soon as possible after birth.

1
-Antitrypsin deficiency is the most
frequent metabolic disease causing neonatal
hepatitis syndrome in Caucasian infants.
Conjugated hyperbilirubinaemia with
cholestasis but a normal GGT suggests PFIC
(types 1 or 2) or a primary disorder of bile
acid synthesis.
Chronic-pattern neonatal liver failure
presents with conjugated
hyperbilirubinaemia, unremarkable AST and
ALT concentrations, a low serum albumin,
and a marked coagulopathy.
Research directions
The role of congenital infection in the
pathogenesis of biliary atresia.
The mechanism for duct paucity in Alagille
syndrome.
The existence of other types of progressive
familial intrahepatic cholestasis.
The mechanism of hepatic fibrosis in trisomy
21 with transient myeloproliferative
syndrome/leukaemia.
The pathogenesis of perinatal
haemochromatosis.
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374 E.A. Roberts
Review article
Neonatal liver failure
Patricia McClean
*
, Suzanne M. Davison
Children's Liver and GI Unit, St James's, University Hospital, Beckett Street, Leeds LS9 7TF, UK
Summary Liver failure in the neonatal period is challenging to diagnose and manage,
and still carries a high mortality. With ongoing developments in the field of metabolic
disorders and antiviral therapy, and the ability to offer liver transplantation to small
babies, an overall survival of 40% has been achieved. Early recognition of liver failure,
good supportive care and prompt referral to a paediatric liver transplant centre are
essential elements in improving the outcome for these babies. Decisions about
contra-indications to and timing of transplantation are complex as many of the disease
processes are still evolving in the neonatal period, and extrahepatic disease, which
cannot be corrected by a transplant, may appear later.
KEYWORDS
Neonatal liver failure;
Viral hepatitis;
Neonatal
haemochromatosis;
Mitochondrial
hepatopathy
Neonatal liver failure (NLF) is rare and may be
difficult to recognize initially, as jaundice can be a
late feature. Coagulopathy, unresponsive to intra-
venous vitamin K, is always present, although this is
not uncommon in ill neonates (Table 1). Some
conditions, such as neonatal haemochromatosis
(NH), are due to chronic in-utero liver disease and
present as decompensated cirrhosis with low
levels of albumin and normal transaminases, whilst
others have the typical features of acute liver fail-
ure of perinatal onset with high transaminases.
1
Hypoglycaemia, hyperammonaemia and encepha-
lopathy (often difficult to define in a neonate) are
common, although these are seen in many sick
infants. The diagnosis of liver failure must be con-
sidered in any neonate with coagulopathy.
2
If other
features of liver dysfunction are absent or non-
specific, measurement of the individual clotting
factors will show low levels of II, V, VII, IX and X,
and normal or elevated levels of factor VIII in
infants where the coagulopathy is due to liver
disease. Fibrinogen and factors XI and XII are
frequently normal but may be decreased.
Aetiology
Table 2 lists most of the recognized causes of NLF.
Published series from paediatric liver centres will
not include cases that resolve spontaneously (e.g.
hypoxic/ischaemic), respond quickly to treatment
(e.g. bacterial infection), or die early.
2,3
Infection
and metabolic disorders are the two main causes of
NLF. Many of these diseases may also present as a
less fulminant neonatal hepatitis syndrome (see
* Corresponding author. Tel.: +44-113-2066689; fax: +44-113-
2088891
E-mail address: patricia.mcclean@leedsth.nhs.uk (P.
McClean).
Table 1 Differential diagnosis of a prolonged prothrombin
time in the neonate
Congenital bleeding disorder
Afibrinogenaemia
Dysfibrinogenaemia
Deficiencies of individual clotting factors
Acquired bleeding disorder
Disseminated intravascular coagulation
Vitamin K deficiency
Antibodies/inhibitors affecting coagulation
NLF
Drug induced
For normal laboratory ranges of clotting parameters in the
newborn see the work by Williams et al.
53
Seminars in
NEONATOLOGY
doi:10.1016/S1084-2756(03)00095-2
paper by Roberts). This paper will only describe
diseases presenting primarily as NLF.
Clinicopathological features
Presentation at birth implies an intra-uterine insult
such as congenital infection, NH or mitochondrial
disorders. A later presentation may be related
to infection or a metabolic condition unveiled by
the introduction of feeding. A detailed obstetric
history, including information on consanguinity,
previous miscarriages and neonatal deaths, is
important.
There are various patterns of presentation which
are not mutually exclusive and may progress to
fibrosis or cirrhosis. Hepatocyte necrosis is the
characteristic pathological feature of infants with
acute viral infections, toxic or ischaemic injury and
some metabolic diseases. This results in initially
high serum transaminases, but as the degree of
necrosis progresses, the transaminase levels
fall, the liver shrinks in size and coagulopathy and
hyperbilirubinaemia worsens. Recovery is heralded
by a sustained fall in prothrombin time in associ-
ation with falling transaminases and bilirubin
levels.
In contrast, in some metabolic conditions, such
as fatty acid oxidation defects and mitochondrial
respiratory chain defects, there is little cell necro-
sis and the liver failure is at a subcellular level.
Histologically, there may be diffuse hepatic steato-
sis and/or swelling of hepatocytes, and clinically
there is hepatomegaly with moderate elevation of
transaminases and minimal to moderate jaundice.
Often, with prompt and appropriate medical treat-
ment, the liver recovers completely, but if the
liver disease is chronic and has progressed to
cirrhosis, as occurs in many mitochondrial
disorders, recovery will not occur.
Infiltrative and storage disorders result in
hepatosplenomegaly with raised transaminases and
bilirubin. Finally, NH is a typical example of decom-
pensated cirrhosis, presenting at birth with a small
liver, normal transaminases, mildly raised bilirubin,
markedly reduced serum albumin and, possibly,
features of portal hypertension.
Investigations
The initial investigations necessary to establish
the cause of NLF are shown in Table 3. It is import-
ant to recognize medically treatable causes early,
such as galactosaemia or tyrosinaemia, before pro-
ceeding to more invasive procedures. Specific in-
vestigations are discussed under the relevant
disease headings. Performing a liver biopsy is
hazardous due to coagulopathy. The potential
benefits must be balanced against this risk. Some
units advocate an open surgical biopsy in these
circumstances following vigorous correction of
coagulopathy.
Management
There are no randomized trials of the following
interventions in neonates. Recommendations are
extrapolated from experience in paediatric prac-
tice. Intravenous dextrose to maintain normogly-
caemia may require concentrations of 2050% via
central venous access. Hyponatraemia usually re-
flects hyperaldosteronism and/or fluid retention:
fluids should be restricted and excessive sodium
Table 2 Aetiology of NLF
Durand et al.
2
(<1 year)
n=80
Aw et al.
3
(<4 weeks)
n=33
Infection
Hepatitis B 6 0
HSV 1 and 2 2 5
HHV6 4 0
Enterovirus 0 0
Bacterial 0 1
Metabolic
Tyrosinaemia 1 12 1
Mitochondrial 17 0
Urea cycle 2 1
Galactosaemia 2 3
Fatty acid oxidation 0 0
HFI 1 0
IE bile salts 0 0
CDGS 0 0
NH 13 16
Infiltrative/storage
HLH 3 4
Leukaemia 1 0
Tumours 0 0
NiemannPick C 0 0
Other
Drugs 1 1
AIH 3 0
Hypocortisolism 0 1
Hypoxic/ischaemic 0 0
Unknown 13 0
Most described causes of NLF are listed in the first column.
Columns 2 and 3 give the number of cases in the series by
Durand et al., who reported all infants under 1 year old
with liver failure and Aw et al. who documented neonatal
cases only. HSV, herpes simplex virus; HHV6, human herpes
virus 6; HFI, hereditary fructose intolerance; IE bile salts,
inborn error of bile salt synthesis; CDGS, congenital
disorder of glycosylation syndrome; HLH, haemophagocytic
lymphohistiocytosis; AIH, autoimmune hepatitis.
394 P. McClean, S.M. Davison
administration should be avoided. Fluid restriction
is also indicated for deteriorating oliguric renal
impairment, which may ultimately require dialysis
support and for control of ascites. Ascites may
respond to optimizing serum albumin (infusing
5 ml/kg of 20% human albumin solution), and di-
uretic therapy [oral spironolactone or intravenous
potassium canrenoate (1 g0.7 g spironolactone)].
If causing respiratory compromise, percutaneous
drainage may be required. Ventilatory support
should be considered early for neurological as well
as respiratory deterioration. Inotropic support
may be required, and as peripheral vasodilation
may accompany liver failure, vasoconstrictors such
as noradrenaline should be considered. Acidosis,
reflecting hepatic and/or renal dysfunction, sepsis
or a metabolic disorder may require bicarbonate
correction.
Hepatic encephalopathy manifests as irritabil-
ity, poor sucking or excessive somnolence. Manage-
ment includes restriction of protein intake to 2 g/
kg/24 h, and enteral lactulose. Cerebral oedema
may accompany encephalopathy; fluid overload
should be strictly avoided. Convulsions or deterio-
rating conscious level should prompt imaging to
exclude intracerebral haemorrhage.
Feeds should be withheld until galactosaemia,
tyrosinaemia and urea cycle defects have been
excluded. Withdrawal of lactose or fructose from
infants with galactosaemia or hereditary fructose
intolerance, respectively, leads to a dramatic im-
provement in clinical symptoms. Enteral feeding
should be recommenced as soon as possible, al-
though this may be compromised by fluid restric-
tion or poor tolerance, necessitating temporary
parenteral nutrition.
Thrombocytopenia, coagulopathy and dissemi-
nated intravascular coagulation contribute to the
risk of bleeding. Ranitidine should be prescribed
for gastric protection. Intravenous vitamin K
(300 g/kg/24 h) is used to ensure adequate sub-
strate for coagulation factors. Active bleeding
requires correction of thrombocytopenia and co-
agulopathy. However, as the trend in the pro-
thrombin time or international normalized ratio
(INR) provides the best indicator of hepatic func-
tion and recovery, coagulopathy is not routinely
corrected, unless severe.
Antibiotics effective against Gram-negative or-
ganisms, streptococci and listeria should be admin-
istered even in the absence of overt sepsis,
together with antifungal prophylaxis. Intravenous
acyclovir (30 mg/kg/24 h) should be continued un-
til herpes simplex virus (HSV) infection has been
excluded.
Intravenous n-acetylcysteine may improve sur-
vival in liver failure by enhancing tissue oxygen-
ation.
4
Although firm evidence is lacking, its use in
supportive therapy is becoming widespread. In pre-
term infants, the pharmacokinetics and excretion
Table 3 General investigation of NLF
Blood
Haematology
Full blood count and film, Blood group and Coombs test
Prothrombin time, partial thromboplastin time, fibrinogen
D dimers/fibrin degradation products
Biochemistry
Urea and electrolytes, creatine kinase, amylase
Bilirubin (unconjugated/conjugated), transaminases, GT,
alkaline phosphatase, albumin
Acidbase balance
Glucose, lactate, ammonia
Cholesterol, triglycerides, free fatty acids, hydroxy
butyrate
Ferritin and transferrin saturation
Plasma amino acids
Galactose-1-phosphate uridyl transferase
Carnitine/acyl carnitines
Cortisol (9am)
Serum bile salts
Transferrin iso-electric focusing
Alpha fetoprotein
Toxicology including paracetamol
Microbiology
Bacterial/viral culture and PCR detection
Viral serology: mother and infant (IgM in infant may be
negative for several weeks)
Other
Storage for DNA
Urine
Biochemistry
Amino acids, organic acids including succinyl acetone,
orotic acid
pH, ketones, reducing substances
Toxicology
Urinary bile salts
Microbiology
Bacterial/viral culture and PCR detection
Other samples for viral culture/PCR viral detection
Stool/rectal swab
Guthrie card blood spots (HSV diagnosis)
28,29
Nasopharyngeal secretions
Vesicle fluid
Cerebrospinal fluid
Eye swab
Ascitic fluid
Radiology
Chest X-ray
Echocardiography
Doppler ultrasound scan of abdomen
PCR, polymerase chain reaction.
Neonatal liver failure 395
of intravenous n-acetylcysteine depend on weight
and gestational age.
5
The role of plasmapheresis has diminished as
techniques in transplantation have advanced. In
one study of 49 children, including neonates, the
major benefit from plasmapheresis was improved
coagulation, with no effect on neurological compli-
cations.
6
There is increasing experience of extra-
corporeal support systems such as the molecular
adsorbent recirculation system (MARS)
7
in children,
but none in the neonatal period.
Liver transplantation
The role of orthotopic liver transplantation (OLT) in
the management of acute liver failure in adults and
children is well established. However, there are
only a few small series describing the particular
medical and surgical challenges of OLT in neonates
or small infants.
8,9
Infants with multi-organ failure,
uncontrolled sepsis, generalized mitochondrial dis-
orders or haemophagocytic lymphohistiocytosis
should not be considered for liver transplantation
because they will succumb to their underlying dis-
ease. Infants with NH or viral-induced liver failure
are currently the most common groups undergoing
OLT.
8,9
In spite of the introduction of techniques
which use part of larger livers (reduced, split or
monosegment grafts), there are still difficulties
obtaining suitable donor organs, and the death rate
on the waiting list remains high; 31% in one series.
3
The mortality after transplant is 4050% compared
with 3040% in older children or adults trans-
planted for acute liver failure. Complications
include vascular thrombosis, sepsis and haemor-
rhage, but the incidence of acute rejection in this
age group is very low.
8,9
Infectious causes of neonatal liver
failure
Enterovirus
Enteroviruses are small, single-stranded RNA vi-
ruses, comprising polio-, Coxsackie A and B and
Echoviruses. Severe infection may occur in neo-
nates with multi-organ involvement, including
hepatic necrosis. Echovirus, particularly serotype
11, is the most frequently identified virus. It
is postulated that Echovirus causes hepatic fail-
ure by vascular rather than direct hepatocyte
damage.
10
Symptoms typically develop between day 4 and
7, with fever, lethargy, poor feeding and abdominal
distension due to hepatosplenomegaly and ascites.
Convulsions may reflect meningoencephalitic
involvement (in one-third of cases).
The outcome ranges from spontaneous recovery
to a rapidly fatal fulminant course. Mortality was
estimated to be as high as 80% in 1986.
11
The role of
the oral antiviral agent pleconaril in neonatal infec-
tion is being evaluated in a multicentre study.
12
Of
three infants with life-threatening enteroviral
hepatitis treated in an open study, two recovered
completely.
13
Herpes simplex virus infection
Herpes simplex virus (HSV) 1 and 2 are usually
acquired due to exposure to infected maternal
genital secretions or lesions at delivery, although
intra-uterine and postnatal infection may occur.
Risk of transmission is highest in seronegative
mothers with primary infection at delivery. Ma-
ternal viral shedding, however, is frequently
asymptomatic. Delivery by Caesarean section sig-
nificantly reduces the risk of neonatal infection.
14
Of 186 neonates with HSV infection, 60% pre-
sented after day 5.
15
HSV infection may involve the
skin, eyes, mucous membranes, brain, lung and
liver. Liver failure may occur with disseminated
disease or as the only manifestation; onset may
be sudden with lethargy, circulatory collapse and
mild jaundice. Absence of typical skin lesions is
common.
15
Standard treatment is intravenous acyclovir
30 mg/kg/24 h in three divided doses for 1021
days. However, there is evidence that 60 mg/kg/
24 h is associated with improved survival.
16
Acyclo-
vir resistance occurs in 0.3% of immunocompetent
and 47% of immunocompromised patients,
17
and
may emerge during therapy.
18,19
Cross-resistance
occurs to penciclovir and famciclovir. Alternative
antiviral agents include foscarnet and cidofovir,
but have increased toxicity. A novel group of anti-
viral agents has been described that inhibit viral
helicaseprimase enzymes; potential advantages
observed in animal models include superior efficacy
and reduced resistance.
20
Despite acyclovir therapy, the clinical course is
often rapid deterioration, with death from multi-
organ failure within days. Of 59 infants with dis-
seminated disease treated with acyclovir between
1981 and 1997, survival was 47%. OLT should be
considered.
Hepatitis B virus infection
Liver failure due to fulminant HBV infection is
now rare due to screening and immunization
policies.
2,21
In the World Health Organization
European Region, 41 of 51 countries have imple-
mented universal immunization.
22
In the UK, where
this has not been implemented, universal HBV
screening of all women during pregnancy since April
2000 has facilitated identification of at-risk infants.
Fulminant HBV infection is particularly associ-
ated with transmission from a low risk surface-
antigen-positive mother who is e-antigen negative
and e-antibody positive. The diagnosis should be
considered irrespective of immunization history.
Diagnosis is made by the detection of HBV DNA in
peripheral blood.
Spontaneous recovery may occur, but progres-
sive deterioration may necessitate consideration
for OLT. Experience of antiviral strategies for
fulminant hepatitis B in infancy and childhood is
limited. In adults, a potential role for lamivudine
in fulminant hepatitis B has been suggested.
23
Pharmacokinetics and safety of lamivudine in
neonates has been established.
24
Human herpes virus 6
Human herpes virus 6 (HHV6) as a cause of neonatal
liver failure (NLF) has been reported occasionally.
Of two infants presenting at day 3 and day 5 of
life,
25
symptoms included fever, hypotonia, leth-
argy and shock. Both had raised hepatic trans-
aminases and thrombocytopenia. One recovered
spontaneously and the other died at day 15. Four
infants with HHV6 in Durand et al's
2
series under-
went OLT. Ganciclovir is effective treatment,
26
although resistance after prolonged exposure may
occur.
27
Other viruses
Adenovirus and parvovirus have also been associ-
ated with NLF. It is likely that other viruses may
also be responsible. In one series, three of nine
infants had nonAnonB liver failure,
8
and in an-
other series, aetiology was undetermined in 13 of
80 (16%) infants.
2
Metabolic causes of NLF
Neonatal haemochromatosis
NH or neonatal iron storage disease is a rare dis-
order of abnormal iron storage presenting as liver
failure within the first weeks of life. Iron accumu-
lates in the fetal liver, pancreas, heart, thyroid
and salivary glands but spares the reticulo-
endothelial system. The aetiology of this condition
is unclear, and it most likely represents a clinico-
pathological endpoint of different in-utero insults
to the fetal liver, including viral infection,
immunological mechanisms and an inherited pre-
disposition.
30
There is no evidence that these babies have the
HFE gene for hereditary haemochromatosis seen in
adults. Family studies have indicated both an auto-
somal recessive and a maternal mode of inherit-
ance. In some families, once a child is born with NH,
all subsequent children have been affected, and
this has occurred irrespective of having different
fathers.
30
Recurrent re-activation of maternal viral
infection or immunological factors have also been
postulated for maternal transmission. Early results
suggest that repeated immunoglobulin admin-
istration during subsequent pregnancies in these
mothers can significantly ameliorate the disease in
the offspring.
31
Infants with NH are often premature and/or
small for dates. The obstetric history may reveal
previous miscarriages or stillborn infants. Oligo-
hydramnios or polyhydramnios can complicate the
pregnancy. The usual presentation is of acute de-
compensation of endstage liver disease in the first
24 h of life with hypoglycaemia, coagulopathy,
hypoalbuminaemia and ascites. Jaundice does de-
velop subsequently, but the serum transaminases
are often within the normal range. Occasionally,
infants present with a more protracted course and a
milder coagulopathy. Abnormalities of serum bile
acids suggestive of delta 4-3-oxosteroid 5-beta-
reductase deficiency have been associated with a
particularly severe presentation of NH with a bad
prognosis. It has been suggested that this may
reflect severe hepatocellular failure per se, and the
infants do not respond to treatment with bile
salts.
32
The diagnosis is reached by excluding other rec-
ognized causes of NLF and demonstrating evidence
of iron overload. Much weight has been placed on
finding high serum ferritin levels in this condition,
but this is a frequent finding in neonatal liver
disease of any aetiology.
33
A 95100% saturation of
transferrin is probably more specific for NH.
34,35
Extrahepatic iron deposition can be demonstrated
in the salivary glands of the lip, although ensuring
an adequate sample is difficult.
36
Decreased signal
intensity on T2-weighted images on magnetic reso-
nance imaging identifies iron in the liver and other
tissues, and demonstrates a lack of siderosis in the
spleen.
37
Liver histology shows varying degrees of
hepatocyte loss, stromal collapse and fibrosis with
regenerative nodules. Grade 34 siderosis with
sparing of the Kupffer cells is a diagnostic
feature.
31
Overall, the prognosis is poor with a mortality
rate of 75% in a recent review.
30
General supportive
management is instigated as soon as the diagnosis
of NLF is recognized. There have been some reports
of spontaneous recovery. Three infants responded
to an anti-oxidant cocktail (Table 4) described in
1993.
38
Success with this treatment may be more
likely in a milder subgroup if commenced early.
39
Liver transplantation has been successful in NH but
with a high mortality on the waiting list (2564%)
and post-transplant (4060%).
30,35,39
Mitochondrial respiratory chain disorders
The mitochondrial respiratory chain consists of
five protein complexes, plus ubiquinone and cyto-
chrome c, located on the inner mitochondrial
membrane. Other oxidative reactions within the
mitochondria (the tricarboxylic acid cycle and fatty
acid oxidation) generate reduced cofactors, such as
flavin adenine dinucleotide (FADH
2
) and nicotina-
mide adenine dinucleotide (NADH), which pass
electrons down the respiratory chain resulting in
the formation of ATP. This process is called oxidat-
ive phosphorylation. NLF has been recognized in
deficiencies of complex I, III and IV, multiple com-
plex deficiencies and in mitochondrial DNA
(mtDNA) depletion syndrome.
Mitochondrial disorders of the electron transport
proteins in the liver can present as NLF or as gradu-
ally progressive liver disease which can suddenly
decompensate.
40
Most infants have extrahepatic
features, although a few patients with respiratory
chain defects isolated to the liver have been de-
scribed.
41
Typically, severe liver failure develops
in the first few weeks of life. Some cases have
evidence of prenatal liver disease. Non-specific
symptoms are common with lethargy, hypotonia,
poor feeding and vomiting. Some of these features
may be early signs of neurological involvement.
More specific features of liver disease are conju-
gated hyperbilirubinaemia, coagulopathy, ascites
and moderately raised transaminases (between two
and 12 times normal). Hypoglycaemia is common
and may be due to secondary inhibition of oxidation
of fatty acids. Involvement of other organs result
in neurological symptoms, myopathy, proximal
renal tubular dysfunction, hypertrophic cardio-
myopathy, and haematological and gastrointestinal
disorders.
42
Elevated blood lactate should raise suspicion of
a respiratory chain defect, particularly if it rises
further either postprandially or following an
intravenous glucose load. In the presence of
renal tubular dysfunction, plasma lactate may be
lower, but urinary lactate is raised. Ketone bodies
are usually raised, with the plasma 3-OH-
butyrate:acetoacetate ratio often greater than 2.
Intermediates of the tricarboxylic acid cycle plus
3-methyl-glutaconic and 3-methylglutaric acid
may be detected in urine.
42
Evidence of involvement of other organs should
be sought by evaluating renal tubular function,
echocardiography, and visual and auditory evoked
responses. Neurological disease may be implied by
a raised cerebrospinal fluid (CSF):plasma lactate
ratio, an elevated CSF protein or abnormalities on
magnetic resonance imaging. Liver histology almost
invariably shows steatosis and fibrosis, which
may have progressed to micronodular cirrhosis.
Cholestasis, hepatocyte necrosis and increased iron
staining may be present. Electron microscopy
reveals increased numbers of abnormal mitochon-
dria. Muscle may be histologically normal or show
steatosis. Ragged red fibres are rare in infancy,
but if present, these are very suggestive of a
respiratory chain defect.
The definitive diagnosis is made by measuring
the enzymatic activity of respiratory chain com-
plexes in affected tissues. Muscle is traditionally
used as it is safer to obtain, and demonstration of
extrahepatic disease in a patient with NLF is a
contra-indication to OLT.
43
However, due to the
variability of abnormal mtDNA within tissues
(heteroplasmy), and the wide range of normal
values, the results can be difficult to interpret.
40
Liver biopsies are potentially hazardous, and ab-
normalities may be artifactual due to the severity
of the liver damage. mt DNA depletion syndrome
is diagnosed by demonstrating a low ratio of
mtDNA to nuclear DNA using Southern blotting
techniques.
Table 4 Anti-oxidant cocktail for NH
N-acetylcysteine 140 mg/kg orally, then 70 mg/kg 4 hourly
for 19 doses
Selenium 23 g/kg/day intravenously over 24 h
Alpha tocopheryl polyethylene glycol succinate
2030 IU/kg/24 h orally
Prostaglandin E1 0.40.6 g/kg/h intravenously for 24
weeks
Desferrioxamine 30 mg/kg/24 h intravenously over 8 h
until ferritin <500 g/l
Supportive treatment is usually the only thera-
peutic option. The use of ubiquinone, riboflavin
and chloroacetate have not been shown to affect
prognosis in patients presenting with NLF. Liver
transplantation has been successful in a few
patients with isolated liver disease and a less fulmi-
nant presentation
41,44
, but many patients succumb
to neurological disease after transplant. Therefore,
Thompson et al.
43
recommend that any evidence
of extrahepatic disease is a contra-indication to
OLT.
Genetic counselling is difficult as many of these
defects are sporadic. However, mtDNA originates
from the ovum and maternal inheritance has been
reported.
45
mtDNA depletion syndrome is probably
due to a defect of a nuclear gene that codes for
replication of the mitochondrial genome. Consan-
guinity is common and the mode of inheritance
appears to be autosomal-recessive.
46
Tyrosinaemia type 1
Hereditary tyrosinaemia type 1 (HT1), a recessive
condition, is caused by a deficiency of fumaryl-
acetoacetate hydoxylase (FAH), resulting in
accumulation of toxic metabolites, fumaryl-
acetoacetate and maleylacetoacetate, and their
reduced derivatives succinylacetoacetate and
succinylacetone. These are thought to be respon-
sible for liver and proximal renal tubular dys-
function, and porphyria-like crises. The clinical
presentation is variable but, in infants less than 6
months old, HT1 causes acute liver failure. Coagu-
lopathy is a dominant feature and has been de-
scribed in the absence of other signs of liver
failure.
47
The serum transaminases are only mildly
raised and some infants do not develop jaundice.
Plasma tyrosine, phenylalanine and methionine
are raised, but these can be elevated in liver
disease. The presence of succinyl acetone in the
urine is diagnostic. Very high levels of alpha feto-
protein (AFP) are typical. The diagnosis can be
confirmed by measuring FAH activity in skin fibro-
blasts or liver cells.
2-(2-Nitro-4-trifluoromethylbenzoyl)-1-3-cyclo-
hexanedione (NTBC), a bleaching herbicide, has
been used to block the formation of toxic metabo-
lites in patients with HT1 since 1992. Plasma tyro-
sine and phenylalanine remain raised unless the
patient's dietary intake is restricted. In 80
patients commenced on NTBC before 6 months of
age, the response rate was 90%, but there are
still concerns that the future risk of developing
hepatocellular carcinoma, a well-recognized
complication of HT1, is not removed.
48
Ongoing
monitoring of plasma amino acids, urinary suc-
cinylacetone, serum AFP, ophthalmological ex-
amination and hepatic imaging are important.
Infants who do not respond to NTBC, or in whom
hepatocellular carcinoma is suspected, are con-
sidered for OLT. This removes the risk of hepato-
cellular carcinoma in the future, and the children
can return to a normal diet, but the renal tubular
defect may not be corrected.
49
Haemophagocytic lymphohistiocytosis
Haemophagocytic lymphohistiocytosis (HLH) is a
rare disorder involving inappropriate activation of
macrophages. It is divided into a primary, familial
form and a secondary form usually triggered by
infection in an immunocompromised host. The pri-
mary form can present as NLF with hepatosplenom-
egaly, markedly abnormal liver function tests and a
high serum ferritin, which may cause confusion
with NH.
50
Other diagnostic clues are fever, raised
triglycerides, hypofibrinogenaemia and cytopenia.
The diagnosis is usually confirmed by evidence
of haemophagocytosis in a bone marrow aspirate.
Initial management includes chemotherapy, usually
dexamethasone and etoposide, but long-term
survival requires a bone marrow transplant.
51
In one series, 5-year survival was 21%.
52
OLT
is contra-indicated due to recurrence in the
graft.
50
Conclusions
NLF is an uncommon but challenging condition. It
must be considered early in the differential diag-
nosis of coagulopathy in the newborn. Infection
and metabolic disorders are the most common
aetiologies. The overall mortality rate in the two
series described in this paper was 60%. Sepsis,
haemorrhage and multi-organ failure were the
main causes of death. In each series, 24% of
patients survived with their native liver following
intensive supportive management and appropriate
specific medical therapy.
2,3
In one series, five of 16
infants listed for a liver transplant died before an
organ became available,
3
but in both series, the
survival after transplant was 50%. Children with
mitochondrial respiratory chain defects may
succumb to previously unrecognized neurological
disease post-transplant. The recognition and man-
agement of these infants require intensive
co-operation between neonatal, hepatology and
transplant teams.
Practice points
NLF should be considered in any neonate
with a coagulopathy which does not respond
to intravenous vitamin K.
Jaundice and raised transaminases are not
always present in infants with in-utero onset
of cirrhosis.
Infection and metabolic diseases are the
most frequent causes of NLF.
Feeds should be withheld until the results of
galactose-1-phosphate uridyl transferase and
urine organic and amino acids are available.
Monitor and maintain normoglycaemia.
Research directions
Genetics of mitochondrial cytopathies. Can
the ratio of mutant to normal mtDNA be
influenced?
Pathogenesis of NH.
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Review article
Parenteral nutrition associated liver disease
Stuart S. Kaufman
a*
, Gabriel E. Gondolesi
b
, Thomas M. Fishbein
c
a
Department of Gastroenterology and Nutrition, Childrens National Medical Center,
111 Michigan Avenue, N.W. Washington, DC 20010, USA
b
Recanti/Miller Transplantation Institute, The Mount Sinai Hospital and School of Medicine,
One Gustave L. Levy Place, Box 1104, New York, NY 10029, USA
c
Department of Surgery, Georgetown University Hospital, 4 PHC 3800 Reservoir Road,
N.W. Washington, DC 20007, USA
Summary Liver disease is relatively common during parenteral nutrition (PN).
Cholestasis predominates in infants, and ranges in severity from mild increases in
plasma conjugated bilirubin to progressive liver failure that results in death of the
patient. Severity of liver disease depends primarily on the magnitude of the under-
lying intestinal problem that indicated PN. Transient ileus resulting from a non-
intestinal disorder usually results in trivial, self-limited liver injury. Removal of a large
segment of the intestinal tract because of necrotizing enterocolitis or a congenital
malformation predicts a more prolonged course with a guarded prognosis, particularly
when initially complicated by sepsis. Pathogenesis of PN-associated liver disease is not
completely understood. There is no proven treatment short of ending PN through
adaptation of remnant intestine or intestinal transplantation, with or without a
concurrent liver graft. Effective interventions that are less radical than transplan-
tation are needed. Research that includes prospective trials of novel therapies in
PN-associated liver disease is the key to improving outcome.
KEYWORDS
Intestine;
Liver disease;
Intestinal failure;
Short bowel syndrome;
Parenteral nutrition;
Transplant
Introduction
Parenteral nutrition (PN) therapy has been avail-
able for infants with inadequate gastrointestinal
tract function for more than 30 years. Hepatobiliary
complications of PN were recognized early in the
experience. PN-associated liver disease (PNALD)
remains the leading cause of neonatal cholestasis
1
and the primary indication for combined liver and
intestinal transplantation in children.
2,3
These
facts emphasize that understanding of the aeti-
ology of PNALD remains incomplete, and that no
preventative measure or treatment has proven
unequivocally to be effective. The early assumption
that a specific shortcoming of PN, e.g. a toxic
excess of one or more nutrients or a critical
deficiency of others, causes liver injury is simplis-
tic. Rather, liver injury during PN therapy results
from the entire clinical setting that prompted
utilization of PN, and for that reason, the term
PN-induced liver disease has largely been dis-
carded in favour of less-biased terms such as
PNALD.
Uncomplicated PNALD
When ileus owing to extreme prematurity and
severe respiratory tract disease is the indication for
PN, incidence of conjugated hyperbilirubinaemia
ranges from around 10 to 25%.
4
Premature infants
receiving PN may be more likely to develop
cholestasis than full-term infants.
5
Conjugated
* Corresponding author. Tel.: +1-202-884-3058; fax:
+1-202-884-4156
E-mail address: skaufman@cnmc.org (S.S. Kaufman).
Seminars in
NEONATOLOGY
doi:10.1016/S1084-2756(03)00094-0
bilirubin and gamma-glutamyl transferase (GGT)
rise within 14 weeks of initiating therapy.
4,6
When
adequate gastrointestinal tract function returns
within 46 weeks, biochemical indications of liver
injury resolve quickly.
4,5
As biochemical abnormalities are not only mild
but also transient, liver biopsy is now performed
rarely. Hepatocellular and canalicular cholestasis,
bile duct proliferation, fibrous expansion of por-
tal tracts (stage 1 fibrosis), and extramedullary
haematopoiesis have been described after 2 weeks
of PN.
7
These lesions are predictably reversible.
Complicated PNALD
When a serious gastrointestinal disorder indicates
PN in the neonate, both incidence and potential
severity of PNALD increase substantially.
810
Incidence of PNALD in surgical patients approxi-
mates 5060%, although improvements in PN may
have reduced the incidence recently.
8
Full-
term infants may be as vulnerable as premature
infants.
9,11
Major intestinal surgery in the newborn
period places affected patients at risk of develop-
ing what is now termed intestinal failure,
12
which
may be defined operationally in infancy when PN
has been required for a minimum of 3 months.
Intestinal failure in neonates is most often the
result of anatomic short bowel syndrome from
severe necrotizing enterocolitis (NEC), and con-
genital malformations such as gastroschisis and
intestinal atresia. Much less commonly, intestinal
failure results from severe functional disturbances
of the gastrointestinal tract, including the intesti-
nal pseudo-obstruction syndromes
13
and congenital
enterocyte transport disorders such as microvillus
inclusion disease and tufting enteropathy.
14,15
Hirschsprung disease is also likely to result in intes-
tinal failure if the aganglionic segment includes
the entire colon and a portion of small bowel, in
which case both loss of gut length and dysmotility
of remnant bowel probably contribute to PN
dependence.
16
In infants with intestinal failure, PNALD fre-
quently becomes apparent with hyperbilirubi-
naemia that begins during an initial bout of sepsis
and continues to rise over the next 1218 months as
PN is continued.
9
Subsequent episodes of bacterae-
mia and fungaemia often worsens hyperbilirubi-
naemia, which may not return to baseline despite
successful treatment.
17
As PN maintains appropri-
ate nutritional status, patients look surprisingly
well except for persistent jaundice. Physical
examination of the abdomen betrays the overall
well appearance of these infants, as it demon-
strates enlargement of the liver and features of
portal hypertension that include progressive
splenomegaly and visible abdominal wall collateral
circulation. Eventually, the liver and spleen may
occupy almost the entire abdominal cavity. Typical
features of portal hypertension that are observed
with normal gastrointestinal anatomy, including
clinically notable ascites and oesophagogastric
varices, are uncommon.
2
In patients with intestinal
failure, severe gastrointestinal bleeding usually
emanates from gastrostomy orifices and the sur-
faces of enterostomies, if present, although dilated
veins are almost never visible.
Laboratory tests demonstrate conjugated hyper-
bilirubinaemia and functional hypersplenism
(thrombocytopenia and, later, neutropenia), which
are of prognostic value. A platelet count of
100 000/l is associated with a 1-year survival of
only about 30%,
18
while a total plasma bilirubin
of about 10 mg/dl predicts death within 6
months.
19
Elevations of other blood tests related
to liver injury and cholestasis, viz. alanine
aminotransferase and GGT, do not correlate with
disease severity, and routine laboratory indications
of impaired synthetic function, e.g. prolongation of
prothrombin time and hypoglycaemia during brief
fasting, occur very late in the evolution of PNALD.
Death most commonly results from multi-organ
failure precipitated by bacterial or fungal sepsis.
While irritability and lethargy consistent with
hepatic encephalopathy and fetor hepaticus are
often observed late in the course of progressive
PNALD, death directly attributable to cerebral
oedema and brain-stem herniation is unusual.
Histopathology of complicated PNALD
Histological changes in progressive PNALD are those
of increasing intracellular and canalicular cholesta-
sis, portal and lobular inflammation, macrophage
hyperplasia, interlobular bile duct proliferation,
and fibrosis. The appearance may simulate mech-
anical biliary tract obstruction, e.g. biliary
atresia.
20
Fibrosis is initially concentrated in portal
areas (stage 1), and later extends as septae into the
hepatic lobule (stage 2). More extensive fibrosis
that connects adjacent portal zones define bridging
fibrosis (stage 3). In the most advanced stage of
fibrosis, i.e. cirrhosis (stage 4), regenerative
nodules are superimposed on extensive bridging.
Cirrhosis has been confirmed after just 4 months of
PN,
7
development of which yields an actuarial
1-year survival of about 2530%.
18
Prospective
376 S.S. Kaufman et al.
studies delineating a relationship between deterio-
rating clinical and laboratory markers of liver func-
tion and portal hypertension vs. liver histology are
not available.
Response of the liver to cessation of PN, made
possible either by adaptation of remnant bowel to
full enteral nutrition or by intestinal transplan-
tation, is variable. Cholestasis associated with
stage 1 or 2 fibrosis is reversible.
21
Cholestasis
often diminishes before complete discontinuation
of PN, although the quantity of enteral calories
that must be delivered or assimilated has not
been established.
9
Despite clinical resolution of
cholestasis and portal hypertension, fibrosis may
not regress completely; the long-term significance
of which is unclear.
20,2224
Infants with stage 3 or 4
fibrosis need a combined liver and intestinal trans-
plant, because this degree of fibrosis is probably
not reversible.
PNALD and indications for
transplantation
Reported mortality of paediatric patients with neo-
natal intestinal failure who are anticipated to
require PN indefinitely varies markedly, between 0
and 90%, depending largely upon how indefinite PN
is defined.
2529
Death usually results from compli-
cations of liver failure. When there is a significant
risk of liver failure with no reasonable prospect of
ending PN, intestinal transplantation should be
considered.
2
Severity of PNALD determines the
type of transplant to be performed. Rapidly pro-
gressive and advanced disease requires combined
liver and intestinal transplantation. Due to the
severe shortage of suitable donor organs, around
50% of infants waiting for a combined liver and
intestinal transplant die before transplant.
18,21,30
This fact, combined with the common uncertainty
about the rate of progression of PNALD in individual
patients, requires early referral and listing for
transplantation, even before it is clear that PNALD
shall progress to end-stage. A plasma bilirubin that
is continuously elevated to more than 34 mg/dl by
age 6 months despite tolerance of some enteral
feeding justifies referral to an intestinal transplant
centre.
2
If cholestasis appears to have resolved
before suitable donor organs become available,
which may take more than a year, transplantation
is deferred or cancelled.
In other infants, PNALD may progress slowly,
albeit relentlessly, and permit isolated intestinal
transplantation. Patients with PNALD who are likely
to tolerate an isolated intestinal transplant gener-
ally have few or no visible abdominal veins, less
marked hepatosplenomegaly, a platelet count
greater than 150 000/l, and total plasma bilirubin
less than 67 mg/dl.
31
There are no data to show
that repeated liver biopsy is superior to ongoing
clinical assessment in establishing the need for liver
replacement during intestinal transplantation.
Pathogenesis and prevention of PNALD
The risk of death from PNALD in infants and young
children is not directly related to the duration of
PN.
9,32
The median age of death on PN in three
recent studies, mainly from liver failure, was only
19 months,
25,26,29
which is similar to the duration
of PN in paediatric patients able to end
therapy.
27,29,33
However, the risk of death and,
hence, the need for referral for transplantation,
can be predicted based on the probability of suc-
cessfully ending PN. This apparent contradiction is
reconciled by the observation that advanced liver
disease rarely develops in infants who, based on
favourable remnant bowel anatomy and related
factors, can be predicted to end PN eventually,
even if the duration of PN is especially long.
24
Factors predicting progressive PNALD include the
following.
Extreme short bowel syndrome
The liver is particularly vulnerable to injury during
PN therapy when loss of small bowel is severe.
34
Most paediatric patients with neonatal-onset
intestinal failure succumbing to liver failure have
no more than 50 cm of small bowel, often much
less.
9,29
Termination of small bowel as a stoma, i.e.
absence of enterocolonic continuity, may place
patients at further risk.
27
Therapeutic implications
Surgery designed to lengthen remnant small bowel
may become technically feasible beyond the neo-
natal period. A bowel-lengthening operation is
most likely to reduce PN requirements when sub-
stantial enteral calories are already tolerated, and
PNALD is absent or mild and non-progressive. As the
length of bowel added is modest, this type of
operation is not likely either to reduce PN require-
ments markedly or forestall liver failure in infants
with less than 3050 cm of remnant small bowel;
the population at greatest risk of progressive
PNALD.
35
These infants should be referred for iso-
lated intestinal transplantation before PNALD
progresses to end-stage.
31
Parenteral-nutrition-associated liver disease 377
Local and systemic sepsis
Infants who develop progressive and ultimately
fatal PNALD are more likely to have experienced
early sepsis in association with bowel resection, on
average within 30 days of birth.
9
They may also
have had an increased frequency of recurrent
sepsis.
17,27
Animal studies indicate that following
massive intestinal resection, intestinal bacteria
and their byproducts, including endotoxins and
peptidoglycans, translocate to the liver via the
portal venous and lymphatic systems.
36
Bacterial
byproducts inhibit hepatocellular bile acid trans-
port and activate hepatic macrophages via locally
produced cytokines such as tumour necrosis factor-
.
37,38
Hepatocellular cholestasis and necrosis,
inflammation and fibrosis then supervene, medi-
ated by factors that include increased levels of
reactive oxygen species.
39
PN may directly con-
tribute to the production of pro-cholestatic
cytokines when other systemic stresses are
present.
40
Furthermore, enteral feeding, that is
essential to intestinal growth (and ending PN) after
major resection, may have the undesirable effect
of promoting overgrowth of potentially toxic gut
flora. The greater the number of potentially toxic
bacteria in the gut lumen, the more deleterious the
potential impact of translocation on the liver.
41
Chronic stasis of intestinal content secondary
either to partial obstruction or dysmotility of rem-
nant small bowel exacerbates bacterial overgrowth
and PNALD.
8
In experimental models, suppression of intestinal
bacteria, particularly of strict anaerobes using
agents such as metronidazole, may be beneficial to
the liver. However, clinical studies have only rarely
indicated benefit.
42
Current animal research
suggests that elevation of hepatic glutathione, by
means of supplementation with dietary precursors
including glutamine, may minimize hepatic
injury associated with PN and, possibly, massive
intestinal resection and intra-abdominal sepsis.
39,43
Similarly, any manoeuvre that reduces the preva-
lence of venous-catheter-associated sepsis may
also spare the livers of PN-dependent patients,
17
although not all clinical experience supports this
assertion.
25
Lack of early enteral feeding
Tolerance of little, if any, enteral nutrition after
major intestinal resection is another risk factor for
fatal PNALD.
9
Enteral feeding may protect the liver
by promoting enterohepatic recirculation of bile
acids, particularly if initiated early and if some
ileum remains after intestinal resection. Enteral
feeding may also promote bile flow by stimulat-
ing gallbladder contraction and by lessening
postresection increases in intestinal permeability.
Lack of enteral nutrition and consequent gall-
bladder stasis are risk factors for gallbladder
disease which includes acalculous cholecystitis,
gallbladder sludge and gallstones.
44
It is unclear
whether failure to tolerate enteral feeding repre-
sents an independent risk for progressive PNALD, or
if prolonged fasting and PNALD are simply co-
dependent consequences of the original surgical
disorder.
17
Early enteral feeding to the extent permitted by
remnant bowel anatomy and function may be
important to promote bile flow and prevent or
retard PNALD. However, overfeeding may exacer-
bate bacterial overgrowth that is potentially
hepatotoxic. Although suppression of bacterial
overgrowth may improve digestive function,
29
beneficial effects on the liver remain uncertain.
Development of gallstones in a jaundiced patient
with PNALD despite some enteral feeding is not
prima facie evidence of biliary tract obstruction,
because advanced liver disease is an independent
risk factor for cholelithiasis. In our experience,
cholestasis is only likely to be improved by
cholecystectomy, a relatively high-risk operation
with advanced liver disease, when the clinical
presentation suggests obstruction, i.e. biliary colic,
pancreatitis or inflammatory disease. These symp-
toms are uncommon in infants with PNALD.
Cholecystokinin (CCK), by means of increasing
intrahepatic bile flow, gallbladder contraction or
both, has been used to prevent and treat PN-
associated hyperbilirubinaemia at a dose of about
0.02 g/kg two or three times daily.
44,45
Whether
CCK therapy reduces fibrosis or affects long-term
outcome of potentially progressive PNALD remains
to be demonstrated. There is no convincing evi-
dence that enterally administered ursodeoxycholic
acid is useful in PNALD.
46
The possibility that poor
absorption inhibits therapeutic efficacy awaits the
availability and testing of a suitable intravenous
preparation.
PN composition and delivery
There is an association between parenteral calorie
intake greater than around 70% of the calculated
energy requirement and an increased propensity
for PNALD. A high percentage of PN may not be an
independent risk factor for PNALD but, rather,
simply reflect the severity of co-existing gut loss.
34
However, parenteral calorie intake consistently
greater than metabolic expenditures may also be
deleterious to the liver.
37
There is no evidence that
intravenous glucose is inherently hepatotoxic, but
intravenous emulsified lipid intake greater than
1 g/kg/day is associated with fatal liver disease.
47
The effect may reflect direct hepatotoxicity of
some components in lipid emulsion.
48
Additionally,
lipid may also provide substrates to fuel the sys-
temic inflammatory response and its deleterious
effect on the liver.
49
Copper and manganese, which are routinely
included in PN, are potentially hepatotoxic.
23,50
As
excretion of copper and manganese is predomi-
nantly biliary, retention of these elements by a
cholestatic liver may produce additional hepatic
injury and justify the monitoring of blood concen-
trations. Taurine may be conditionally essential
in young infants for hepatocellular bile salt conju-
gation and secretion. Although use of taurine-
containing amino acid solutions, e.g. TrophAmine
(Kendall McGaw, Inc., Irvine, CA, USA), in infants

with intestinal failure is logical and without recog-
nized risk, these solutions do not definitively alter
the incidence and severity of PNALD.
51
Carnitine,
which is required for efficient oxidation of long-
chain fatty acids, may also be conditionally essen-
tial in patients receiving long-term PN. Inclusion of
carnitine in PN based on plasma concentrations is
also logical, but there is no evidence that carnitine
constitutes effective prophylaxis against PNALD.
52
Choline deficiency in long-term PN may, like carni-
tine, contribute to PNALD, given the essential
nature of this substance and its requirement for
efficient hepatic lipid metabolism.
53
Whether
routine choline supplementation of PN solutions in
intestinal failure patients reduces the frequency
and severity of potentially severe PNALD is
the subject of current clinical investigation. Inter-
mittent infusion of PN may protect the liver by
promoting efficient energy utilization, particularly
in the presence of hepatotoxic pro-inflammatory
stresses.
54
Benefit is most likely to be obtained
when total bilirubin is less than 10 mg/dl. Optimal
duration of the parenteral fast has not been
established.
55
Conclusion
PNALD remains a relatively common complication
of PN therapy. Prognosis relates primarily to the
type and severity of the underlying intestinal disor-
der that prompted use of PN. Mild and transient
gastrointestinal dysfunction causes trivial and self-
limited liver injury. Major intestinal resection, par-
ticularly in conjunction with abdominal sepsis,
predicts a more prolonged and complicated course
with a guarded prognosis. Prevention of PNALD
remains difficult because the key to successful
prevention requires a better understanding of its
pathophysiology. Although combined liver and
intestinal transplantation may permit survival of
some patients, less drastic and more effective
interventions are needed. Research that includes
prospective trials of novel therapies in PNALD is the
key to improving outcome.
Practice points
Occurrence and prognosis of PNALD is a
function of the severity and chronicity of the
gastrointestinal dysfunction that originally
prompted PN.
Risk of chronic hepatic failure secondary to
PNALD is highest in infants with intestinal
failure.
Apart from jaundice, infants with severe
PNALD and portal hypertension look well
until terminal hepatic decompensation.
Infants requiring indefinite PN with liver
disease that has not improved by age 6
months should be evaluated for intestinal
transplantation.
There remains no proven, effective therapy
for PNALD, but early enteral feeding,
minimization of sepsis, and avoidance of
excess calorie intake may be beneficial.
Research directions
Clarifying the effect of protracted or
recurring abdominal and systemic
inflammation on course of liver disease.
Clarifying inflammatory pathways involved in
producing cholestasis, hepatic necrosis and
fibrosis.
Improving identification of early clinical risk
factors for progressive PNALD to guide
transplant referral.
Investigation of novel anti-inflammatory
therapies for treatment of PNALD.
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Biliary atresia
Hiroyuki Kobayashi
a
, Mark D. Stringer
b*
a
Department of Pediatric Surgery, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo, Japan
b
Children's Liver & GI Unit, St James's University Hospital, Leeds LS9 7TF, UK
Summary Biliary atresia (BA) is a congenital obliterative cholangiopathy of unknown
aetiology, affecting both the intra- and extrahepatic bile ducts. Although relatively
rare, BA must be excluded in any infant with conjugated hyperbilirubinaemia since the
prognosis is improved by early diagnosis and prompt surgery. At least two phenotypes
of BA are currently recognized; the syndromic variety is associated with other
congenital anomalies and a poorer outcome. The results of treatment have steadily
improved and, with a combination of timely expert surgery (Kasai portoenterostomy)
and liver transplantation in specialist centres, good quality long-term survival is now
possible in more than 90% of affected patients. A better understanding of the
aetiology of BA and the pathogenesis of hepatic fibrosis is needed in order to develop
new therapeutic strategies.
KEYWORDS
Biliary atresia;
Neonatal jaundice;
Portoenterostomy
The aims of this article are to focus on important
clinical aspects of biliary atresia (BA) relevant to
routine clinical practice, and to highlight some of
the more recent scientific and clinical advances in
our understanding of this condition.
BA is a congenital obliterative cholangiopathy of
unknown aetiology. It is a major cause of obstruc-
tive jaundice in neonates. Untreated infants suc-
cumb to liver failure within a year or two. In the
late 1950s, Morio Kasai, a Japanese surgeon, re-
ported the presence of patent microscopic biliary
channels at the porta hepatis in young infants with
BA. Exposure of these channels by radical excision
of atretic extrahepatic biliary remnants could re-
sult in effective drainage of bile, especially if the
operation was performed within eight weeks of
birth. The Kasai portoenterostomy operation is now
accepted as the standard operation for the con-
dition. However, despite this procedure, BA re-
mains the foremost indication for liver
transplantation in infants and children.
Incidence
BA is rare. Reliable incidence figures are available
from France (one in 19 500 live births), the UK and
Eire (one in 16 700 live births), Georgia in the USA
and Sweden (one in 14 000 live births).
14
The
highest recorded incidence is in French Polynesia.
1
No significant seasonal variation or clustering was
found in the French study. In most large series,
there is a slight female preponderance.
Aetiology and pathogenesis
Despite intensive interest and investigation, the
cause of BA remains unknown. Two different forms
are described.
5
In syndromic BA (also known as the
embryonic type), there are associated congenital
anomalies such as an interrupted inferior vena
cava, preduodenal portal vein, intestinal mal-
rotation, situs inversus, cardiac defects and poly-
splenia. In this variety, which accounts for about
1020% of all cases, BA is likely to be due to a
developmental insult occurring during differentia-
tion of the hepatic diverticulum from the foregut
of the embryo. A possible relationship between
syndromic BA and maternal diabetes has been
reported.
6
Non-syndromic BA (also known as the
* Corresponding author. Tel.: +44-113-206-6689; fax:
+44-113-206-6691
E-mail address: mdstringer@dial.pipex.com (M.D. Stringer).
Seminars in
NEONATOLOGY
doi:10.1016/S1084-2756(03)00065-4
perinatal type) may have its origins later in gesta-
tion and run a different clinical course.
There is no ideal animal model for BA, and this
has slowed our understanding of its pathogenesis.
Various aetiologic mechanisms have been postu-
lated including intra-uterine or perinatal viral in-
fection, genetic mutation, abnormal ductal plate
remodelling, a vascular or metabolic insult to the
developing biliary tree, pancreaticobiliary ductal
malunion and immunologically mediated inflamma-
tion. Recent observations would suggest that BA is
not a single disease entity.
Viral agents
Reovirus type 3 infection, rotavirus, cytomegalo-
virus, papillomavirus and EpsteinBarr virus have
all been proposed as possible aetiologic agents but
conclusive evidence is lacking. Reovirus type 3 can
cause an inflammatory cholangiopathy in weaning
mice but the condition is not progressive and the
animals recover.
Genetic factors
Generally, BA is not considered to be an inherited
disorder. However, genetic mutations that result
in defective morphogenesis may be important in
syndromic BA. Transgenic mice with a recessive
deletion of the inversin gene have situs inversus and
an interrupted extrahepatic biliary tree.
5,7
Muta-
tions of the CFC1 gene, which is involved in left
right axis determination in humans, have recently
been identified in a few patients with syndromic
BA.
8
Abnormal ductal plate remodelling
Intrahepatic bile ducts are derived from primitive
hepatocytes which form a sleeve (the ductal plate)
around intrahepatic portal vein branches and as-
sociated mesenchyme in early gestation. Remodel-
ling of the ductal plate in fetal life results in the
formation of the intrahepatic biliary system. Tan
et al. (1994) emphasized the similarities in cyto-
keratin immunostaining between the biliary
ductules in BA and normal first-trimester fetal bile
ducts.
9
They suggested that non-syndromic BA
might be caused by a failure of bile duct remodel-
ling at the hepatic hilum, with persistence of fetal
bile ducts poorly supported by mesenchyme.
Immune-mediated mechanisms
Biliary obstruction in non-syndromic BA is progres-
sive. A few such infants even have a history of
pigmented stools at birth. Pathogenesis may
involve an immune-mediated inflammatory de-
struction of intra- and extrahepatic bile ducts.
Several studies have investigated whether bile
duct epithelial cells are susceptible to immune/
inflammatory attack because of abnormal expres-
sion of human leukocyte antigens (HLA) or
intercellular adhesion molecules on their sur-
face.
10,11
Silveira et al. (1993) showed a greater
than three-fold increase in HLA-B12 antigen in BA
patients compared with controls, particularly in
those with no associated malformations; haplo-
types A9B5 and A28B35 were also increased.
12
Aberrant expression of class II HLA-DR antigens on
biliary epithelial cells and damaged hepatocytes in
BA patients may render these tissues more suscep-
tible to immune-mediated damage by cytotoxic T
cells or locally released cytokines.
13
Dillon et al.
(1994) reported increased expression of intercellu-
lar adhesion molecule-1 (ICAM-1) on bile duct epi-
thelium in patients with BA, and suggested that this
might have a role in immune-mediated damage.
11
Kobayashi et al. (2001) found a strong expression of
ICAM-1 on proliferating bile ductules, endothelial
cells and hepatocytes in BA.
14
There was a direct
relationship between the degree of ductular
expression of ICAM-1 and disease severity. They
postulated that ICAM-1 might be important in the
development of cirrhosis.
More recently, interest has focused on co-
stimulatory molecules. Two processes are involved
in the activation of T lymphocytes by antigen pre-
senting cells (APC). One relates to the expression of
major histocompatibility complex class II molecules
which interact directly with T-cell receptors. The
other depends on the expression of B7 antigens on
APC, and provides the second (co-stimulatory)
signal to T lymphocytes through CD28.
15
In post-
operative BA patients with good liver function,
co-stimulatory antigens (B7-1, B7-2 and CD40) are
expressed only on bile duct epithelial cells, whilst
in patients with failing livers, these markers are
found on the surface of Kupffer cells, dendritic
cells, sinusoidal endothelial cells (SEC) and in the
cytoplasm of hepatocytes.
16
This suggests that
the biliary epithelium and hepatocytes in BA are
susceptible to immune recognition and destruction.
Agents that block or prevent co-stimulatory path-
ways might offer a new therapeutic approach to
limiting liver damage.
None of these mechanisms are mutually exclu-
sive. In addition, for some theories, it is not known
whether the observations are primary or secondary
events. One current hypothesis is that in the aeti-
ology of non-syndromic BA, a viral or other toxic
384 H. Kobayashi, M.D. Stringer
insult to the bile duct epithelium induces the ex-
pression of new antigens on the biliary epithelial
cell surface.
17
Coupled with a genetically predeter-
mined susceptibility mediated via histocompatibil-
ity antigens, these neoantigens are recognized by
circulating T lymphocytes, resulting in a cell-
mediated, immune, fibrosclerosing bile duct injury.
Pathology
BA is a cholangiopathic disease affecting both the
intra- and extrahepatic bile ducts. The lumen of
the extrahepatic biliary tree is obliterated by in-
flammatory tissue to a variable extent. There are
three main types of obliteration, of which type 3
(occlusion at the level of the porta hepatis) is the
most common, occurring in almost 90% of cases.
Atresia of the common bile duct (type 1) or com-
mon hepatic duct (type 2) with patent proximal
ducts is much less common but carries a better
prognosis. In type 3, the gallbladder is typically
small and contains clear mucus only. Occasionally,
a cyst is found proximal or distal to the atretic bile
duct but this should not be confused with a true
choledochal cyst. In its early stages, histopatho-
logic examination of a liver biopsy by light
microscopy typically shows portal tract oedema,
cholestasis, bile plugging, ductular proliferation
and a lymphocytic inflammatory infiltrate (pre-
dominantly CD4+); under electron microscopy de-
generate biliary ductular cells containing bile
pigment are also seen.
18
Disease progression results
in hepatic fibrosis and cirrhosis with concomitant
portal hypertension and liver failure.
Clinical features and diagnosis
Although BA may occur in premature infants, birth
weight and gestation are usually normal. Presenting
features include conjugated hyperbilirubinaemia,
dark urine and pale stools. Malabsorption of fat-
soluble vitamin K may lead to coagulopathy and
bleeding (which can be intracranial). On examina-
tion, the liver is usually enlarged and there may be
splenomegaly.
Early diagnosis and prompt surgery improve the
outcome of infants with BA. Neonatal jaundice that
persists beyond two weeks of age demands clinical
assessment and prompt investigation (see paper by
Roberts in this issue). The cardinal biochemical
feature of BA is conjugated hyperbilirubinaemia,
but there is considerable overlap between the clini-
cal, biochemical, radiologic and histologic features
of BA and other causes of the neonatal hepatitis
syndrome. No single pre-operative investigation
can diagnose BA with certainty. However, by using
a combination of tests, it is possible to be reason-
ably certain about the diagnosis in most cases. The
following investigations are particularly helpful.
Investigations to exclude metabolic and infec-
tive causes of conjugated hyperbilirubinaemia.
Hepatobiliary ultrasound will exclude other sur-
gical causes of jaundice such as choledochal
cyst and inspissated bile. In BA, the intrahepatic
ducts are not dilated on ultrasonography be-
cause they are affected by the inflammatory
process. Various sonographic features have
been targeted in attempts to distinguish BA
from other causes of conjugated hyperbili-
rubinaemia in infants
1923
(Table 1). Irrespec-
tive of interobserver variation, failure to
visualize the common bile duct is not diagnostic
of BA because a patent distal common bile duct
can be found in up to 20% of affected infants.
An absent gallbladder or one with an irregular
outline is suggestive of BA.
23
In some cases, a
Table 1 Diagnostic accuracy of ultrasound scanning in biliary atresia
Sonographic feature n BA Sensitivity (%) Specificity (%)
Absent common bile duct
Azuma et al. (2001)
19
30 23 83 71
Triangular cord sign
Park et al. (1999)
20
79 25 84 98
Kotb et al. (2001)
21
65 25 100 100
Tan Kendrick et al. (2003)
22
217 31 84 100
GB absent/irregular shape and wall thickness
Farrant et al. (2000)
23
346 71 90 92
GB triad (length <19 mm, indistinct wall and irregular contour)
Tan Kendrick et al. (2003)
22
217 31 97 100
GB, gallbladder.
Biliary atresia 385
well-defined triangular area of high reflectivity
is seen at the porta hepatis corresponding with
fibrotic ductal remnants (the triangular cord
sign).
20,21
Radionuclide hepatobiliary imaging using
technetium-99m iminodiacetic acid (IDA) de-
rivatives fails to demonstrate bile excretion
into the bowel in BA. Pretreatment with pheno-
barbitone 5 mg/kg/day and a 24 h scan enhance
the accuracy of the test.
Percutaneous needle liver biopsy.
Magnetic resonance cholangiography may be
used to visualize the bile ducts and gallbladders
of infants with cholestatic jaundice without BA.
Han et al. (2002) reported a diagnostic accuracy
of 98%, sensitivity of 100% and specificity of 96%
in the diagnosis of 23 infants with BA.
24
Some centres have found duodenal intubation
and aspiration looking for bile to be an accurate
test, but false-positive and false-negative results
are found in a small proportion of patients.
25
If the
diagnosis remains in doubt, consideration should be
given to endoscopic retrograde cholangiography
which is technically demanding but nevertheless
possible in up to 90% of infants, and gives few false
positives.
26
Alternatively, laparoscopy or mini-
laparotomy and cholangiography may be required
to exclude the diagnosis.
Screening tests
Only 0.040.2% of newborns have conjugated hy-
perbilirubinaemia due to cholestatic hepatobiliary
disease. In an attempt to achieve earlier diagnosis
of BA, various screening tests have been explored
but none has satisfied criteria for widespread use.
The use of tandem mass spectrometry to measure
conjugated bile acids in dried blood spots from
newborn infants has proved disappointing.
27
Gamma-glutamyl transpeptidase (GGT) is a hepatic
enzyme which may be found in amniotic fluid from
the second trimester onwards consequent on fetal
bile production and defaecation. In a large study of
amniotic fluid samples, MacGillivray and Adzick
(1994) showed that infants born with BA had mini-
mal levels of GGT in amniotic fluid dating back to
18 weeks' gestation.
28
A small number of cases of
BA complicated by cyst formation have been de-
tected prenatally on maternal ultrasound scans
(see paper by Davenport in this issue). Other poten-
tial community screening tests, including those
based on stool colour analysis, are under evalu-
ation, but yellow skin pigmentation alone is too
broad a criterion to be practical.
29
Surgery
The diagnosis of BA is confirmed at laparotomy
(Fig. 1). A cholangiogram is performed if there is
doubt about ductal patency. The obliterated extra-
hepatic biliary tract is separated from the under-
lying portal vein and adjacent hepatic artery, and
then transected high in the porta hepatis where
patent microscopic biliary ductules may be
present.
30
Biliary continuity is restored using a Roux
loop of jejunum, which is anastomosed to the
transected tissue (portoenterostomy). Infants tol-
erate the procedure well and early postoperative
complications are uncommon.
Peri-operative antibiotic prophylaxis is given to
try and prevent cholangitis. Some units use choler-
etics such as phenobarbitone and ursodeoxycholic
acid to try and promote bile flow. There is some
evidence from uncontrolled studies that corticos-
teroids might facilitate bile flow postoperatively;
31
this is currently being evaluated by a randomized
controlled trial in the UK. Fat-soluble vitamins (A,
D, E, and K) and formula feeds enriched with
medium-chain triglycerides are also prescribed.
Results of portoenterostomy
The results of surgery have steadily improved dur-
ing the last 30 years. The age at which surgery is
carried out is the single most widely quoted prog-
nostic variable. Resolution of jaundice is more
likely if surgery is performed at less than eight
weeks of age, but this age correlation is not linear.
Results are considerably worse if the infant is older
than 100 days at the time of portoenterostomy
32,33
because the obliterative cholangiopathy and he-
patic fibrosis are more advanced. However, the
Kasai procedure is still worthwhile provided that
the patient does not have cirrhosis with impaired
Figure 1 Operative view of the porta hepatis in a 10-week-old
infant with BA. Note the liver fibrosis and atretic biliary rem-
nants. A stay suture has been placed in the tiny gallbladder.
synthetic liver function or ascites. Types 1 and 2 BA
generally have a good prognosis if treated early. In
the more typical type 3 BA, the presence of larger
bile ductules at the porta hepatis (>150 m in diam-
eter) is associated with a better prognosis. The
subgroup of infants with syndromic BA has a worse
outcome both in terms of clearance of jaundice
and overall mortality.
1,6
The latter is related to
associated malformations, particularly congenital
heart disease, a predisposition to developing the
hepatopulmonary syndrome and possibly immune
compromise from functional hyposplenism. There is
anecdotal evidence to suggest that infants with
concomitant cytomegalovirus infection fare less
well after the Kasai procedure.
In the UK, a survey of all infants with BA con-
ducted between 1993 and 1995 demonstrated that
outcome was also related to centre experience.
2
Consequently, in 1999, the management of BA in
England and Wales was centralized to three supra-
regional paediatric liver units. Approximately 60%
of all infants undergoing portoenterostomy for BA
in these centres now achieve clearance of jaundice
(plasma bilirubin <20 mol/l). Another measure of
success after Kasai portoenterostomy is survival
with the native liver; this is currently about 50% at
five years in the UK. In common with other series
from specialist units around the world, this figure is
likely to decrease to around 3040% at 10 years.
Infants who fail to clear their jaundice after
portoenterostomy and those who develop compli-
cated or end-stage chronic liver disease despite an
initially successful Kasai procedure require liver
transplantation. BA is the most common indication
for liver transplantation in children, and the
majority of affected children will eventually come
to transplant. Most of these cases require a trans-
plant in the first few years of life.
The timing of transplant is dictated by liver
function, nutritional status, symptoms and the
presence of complications. A high hepatic artery
resistance index measured on Doppler ultrasound is
an ominous sign and an indication for relatively
urgent transplantation.
34
For some patients, he-
patic decompensation may be precipitated by ado-
lescence or pregnancy. However, as many as 20% of
patients undergoing portoenterostomy will reach
maturity with good native liver function. Five-year
survival after liver transplantation for BA is cur-
rently 8090%, and techniques such as split-liver
grafting and living-related liver transplantation
have minimized the risk of dying on the waiting list.
The combination of Kasai portoenterostomy and
liver transplantation has transformed a disease that
was almost invariably fatal in the 1960s into one
with an overall five-year survival of about 90%.
Furthermore, long-term studies have shown a rela-
tively good quality of life in BA survivors
after portoenterostomy alone
35
and after liver
transplantation.
36
Long-term complications
In addition to the risk of progressive liver disease,
numerous other complications may occur after
portoenterostomy for BA. These include:
bacterial cholangitis;
portal hypertension;
metabolic and nutritional sequelae;
intrahepatic cysts;
hepatopulmonary syndrome;
hepatic malignancy.
Bacterial cholangitis
This is most likely to occur in the first year following
surgery and is due to infection complicating im-
paired bile flow. Approximately 40% of infants are
affected. Cholangitis typically manifests as worsen-
ing jaundice, fever and pale stools, but more subtle
effects such as poor feeding and irritability may
be dominant. Blood culture (and sometimes liver
biopsy culture) may yield a Gram-negative organ-
ism but it is important to treat suspected cases
early and empirically with broad-spectrum intrave-
nous antibiotics. The occurrence of postoperative
cholangitis in patients with established bile flow is
associated with a poorer overall outcome and a
higher likelihood of eventual liver transplantation.
Portal hypertension
Hepatic fibrosis is present at the time of porto-
enterostomy, and about two-thirds of children will
have endoscopically visible oesophageal varices by
two to three years of age, although only half of
these will ever bleed.
37,38
Endoscopic sclero-
therapy or variceal banding is an effective method
of controlling variceal bleeding, but children with
poor underlying liver function are best treated by
liver transplant.
Metabolic and nutritional sequelae
Persistent cholestasis may cause malabsorption of
fat and fat-soluble vitamins. Vitamin K-dependent
coagulopathy, rickets and fractures from vitamin D
deficiency and calcium malabsorption
39
and neuro-
logical disturbances consequent on vitamin E
deficiency are potential complications. Oral, and
sometimes parenteral, vitamin supplements are
Biliary atresia 387
needed. Malabsorption of long-chain triglycerides
and fatty acids may impair weight gain and induce
steatorrhoea. Formula feeds enriched with
medium-chain triglycerides are generally ben-
eficial but an adequate intake of essential fatty
acids must be maintained. Calorie supplementation
is often required to maintain nutrition and growth
in the presence of chronic liver disease. Abnormali-
ties of copper and zinc metabolism have also been
reported in children after portoenterostomy.
Intrahepatic cysts
Biliary cysts or lakes may develop within the livers
of long-term survivors and cause recurrent attacks
of cholangitis
40
(Fig. 2). Prolonged antibiotic treat-
ment and ursodeoxycholic acid may be helpful in
preventing further cholangitis, but unremitting in-
fection is an indication for liver transplantation.
Hepatopulmonary syndrome
Diffuse intrapulmonary shunting may occur as a
complication of chronic liver disease in children
with BA, probably as a result of vasoactive com-
pounds from the mesenteric circulation bypassing
sinusoidal inactivation. The syndrome is character-
ized by cyanosis, dyspnoea on exertion, hypoxia
and finger clubbing. It is more prevalent in children
with syndromic BA. The diagnosis is confirmed using
a combination of arterial blood gas estimations
with and without inspired oxygen, radionuclide
lung scans using macro-aggregated albumin to
quantify the degree of shunting and contrast bubble
echocardiography. This complication is progressive
but can usually be reversed by liver transplanta-
tion. Pulmonary hypertension is a rarer complica-
tion but may also develop in long-term survivors
after portoenterostomy.
Hepatic malignancy
Rarely, malignant changes (hepatocellular carci-
noma or cholangiocarcinoma) may complicate long-
standing biliary cirrhosis after portoenterostomy.
Prognostic markers
From the preceding account, it is apparent that the
Kasai procedure revolutionized the treatment of
BA, but numerous complications may still jeopard-
ize long-term outcome. Can long-term prognosis
after portoenterostomy be determined at an early
stage? Rapid resolution of jaundice and complete
normalization of biochemical liver function are
associated with a good long-term outcome but this
scenario is uncommon. Conventional biochemical
liver function tests are neither specific nor particu-
larly sensitive markers of hepatic fibrosis and func-
tional liver mass. Liver histology is the only certain
way of assessing the severity of fibrosis, but even
this is not a reliable guide to the timing of liver
transplantation. Recent research has focused on
the search for early noninvasive markers of hepatic
fibrosis in postoperative BA patients. Potential can-
didate markers, all of which have shown some cor-
relation with clinical status, include the following.
Collagen type IV and N-terminal
procollagen-III peptide (PIIIP)
Hepatic fibrosis is associated with an increased
production of various extracellular matrix compo-
nents including types III and IV collagen. Raised
levels of serum type IV collagen and PIIIP have been
observed clinically and experimentally in fibrotic
liver disease, and shown to be markers of ongoing
fibrosis.
41
Hyaluronic acid (HA)
In the liver, HA is synthesized primarily by fat-
storing Ito cells and its metabolism has recently
been elucidated. Normally, more than 90% of the
HA in circulation is taken up by HA receptors on
hepatic SEC and degraded. Provided that increased
tissue production of HA can be excluded, elevation
of serum HA is due to impaired uptake and metab-
olism of HA by hepatic SEC. Therefore, plasma HA
levels might reflect hepatic dysfunction and fibro-
sis. Kobayashi et al. (1999) have shown a positive
Figure 2 MRI image (T2) showing multiple bile lakes (arrows) in
the liver of a patient with BA after portoenterostomy.
correlation between serum HA and serum bilirubin
in patients with BA, supporting this hypothesis.
42
Endothelin
Endothelin from endothelial cells is capable of in-
ducing sustained vasoconstriction of portal veins.
High levels of serum endothelin have been observed
in patients with BA, particularly in those with portal
hypertension.
43
In contrast, no significant differ-
ence in serum nitric oxide levels between BA
patients with or without portal hypertension has
been identified.
44
-Glutathione-s-transferase (GST)
The -GST, a hepatocyte-derived enzyme found in
high concentrations within the hepatic cytosol, is a
more sensitive and specific marker for hepato-
cellular damage than serum aminotransferases. In
one study, serum -GST levels were significantly
higher in stable patients with BA complicated by
intrahepatic bile cysts.
45
Transforming growth factor-beta 1 (TGF-1)
TGF-1 is an important mediator of liver cell pro-
liferation and replication. Hepatic stellate cells
(HSC) are activated by TGF-1 and are the main
precursor cells involved in fibrogenesis. Several
studies have concluded that HSC are responsible for
increased collagen production in patients with BA
and play a key role in fibrogenesis. Kobayashi et al.
(2001) found that activated HSC displayed a
strongly positive immunoreactivity to TGF-1 in
liver biopsy specimens from patients with BA.
46
TGF-1 was strongly expressed in apparently
clinically stable patients, indicating that hepatic
fibrosis may be progressing silently in such patients.
Interferon-inducible protein-10 (IP-10)
One current hypothesis for the mechanism of
chronic liver damage implicates resident and
invasive hepatic macrophages as playing a central
role in fibrosis through the release of inflammatory
cytokines which perpetuate cellular injury and pro-
mote net collagen synthesis. The recruitment and
maintenance of macrophages are dependent on cell
adhesion molecules as well as chemo-attractants.
IP-10 is a chemokine originally isolated in re-
sponse to interferon- stimulation of monocytes,
fibroblasts and endothelial cells. IP-10 is expressed
in chronic hepatitis and its production is related to
the severity of liver dysfunction and histologic dam-
age.
47
More recently, it has been shown that serum
IP-10 levels increase in parallel with the number of
infiltrating mononuclear cells present in liver fibro-
sis. They correlate well with aminotransferase
activity, suggesting that this chemokine is released
during active inflammation and reflects ongoing
hepatic tissue damage.
48
Hepatic duplex sonography
A decreased maximum portal flow velocity and an
increased hepatic artery resistance index correlate
with measures of hepatic fibrosis and a poorer
prognosis after portoenterostomy.
49
However, in
common with the prognostic markers cited above,
it has yet to be determined whether these
parameters offer a better measure of long-term
prognosis compared with standard biochemical
liver function tests after portoenterostomy.
Conclusions
BA is a rare, complex disorder and demands expert
multidisciplinary management. Despite progressive
improvement in the results of treatment, the
condition is extremely distressing for parents and
families who not only face the anxieties of newborn
surgery with an uncertain outcome, but also the
possibility of eventual liver transplantation and
its attendant risks. Parental education and
support is essential, and charities such as the Chil-
dren's Liver Disease Foundation (http://
www.childliverdisease.org) provide invaluable
assistance to the families of affected children.
Practice points
The prognosis of BA is improved by early
detection.
BA must be excluded in any infant who has
conjugated hyperbilirubinaemia after 14 days
of age.
Infants with suspected BA should be referred
to a specialist unit for further investigation
and management.
A combination of timely expert surgery
(Kasai portoenterostomy) and liver trans-
plantation enables good long-term survival in
more than 90% of affected patients.
At least two phenotypes of BA are
recognized; the syndromic variety is
associated with other congenital anomalies
and a poorer outcome.
Biliary atresia 389
The aetiology of BA remains unknown, but
immunologic mechanisms appear to be
important in pathogenesis.
Research agenda
An improved understanding of the
pathogenesis and key mediators of hepatic
fibrosis might enable the development of
new therapeutic strategies.
The role of adjunctive therapies after porto-
enterostomy, particularly the use of
corticosteroids and other choleretic agents,
should be established by prospective
randomized controlled trials.
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Further reading
Howard, ER, Stringer, MD, Colombani, PM. Surgery of the liver,
bile ducts, and pancreas in children, 2nd ed. London: Arnold,
2002.
Biliary atresia 391
Review article
Neonatal liver tumours
Dietrich von Schweinitz
*
Paediatric Surgery, Dr. von Hauner'sches Kinderspital, Lindwurmstr. 4, D-80337 Munich, Germany
Summary Primary liver tumours are very rare during the neonatal period, but
increasing numbers of them are now diagnosed prenatally by routine ultrasound
scan. A precise diagnosis is sometimes problematic because of non-specific clinical
symptoms, misleading imaging and difficulties with histological interpretation. Benign
infantile haemangioendothelioma usually undergoes spontaneous regression, but may
be life-threatening due to congestive heart failure and/or consumptive coagulo-
pathy when treatment with resection, embolization or arterial ligation is necessary.
Malignant hepatoblastoma may occur in the newborn, and often has to be treated with
chemotherapy to achieve resectability. Symptoms are less specific and the prog-
nosis is worse than in older children. Mesenchymal hamartoma is a benign cystic
lesion that should be resected whenever possible. Rarely, germ cell tumours occur
in the neonatal liver. Benign teratomas have to be resected, while malignant
choriocarcinomas may respond to chemotherapy and can be cured in some cases.
KEYWORDS
Neonatal liver tumour;
Infantile
haemangioendothelioma;
Hepatoblastoma;
Mesenchymal
hamartoma;
Teratoma;
Choriocarcinoma
General considerations
Perhaps the first description of a neonatal liver
tumour was published in 1854 by Noeggerath of the
Obstetrical Clinic in Bonn, Germany. He reported a
huge liver carcinoma which caused obstructed
labour.
1
According to his microscopic findings, this
tumour would now be classified as a hepato-
blastoma. Since Noeggerath's findings, it has taken
more than 100 years to develop a pathological
classification of childhood liver tumours; this is now
used uniformly.
2
Liver tumours are very rare and account for
only 5% of all neoplasms in the fetus and newborn.
3
They include a variety of benign and malignant
neoplasms with a different distribution than in
older children (Table 1). The most frequent are
infantile haemangioendotheliomas, cavernous
haemangiomas, mesenchymal hamartomas, the
highly malignant hepatoblastomas and, rarely,
benign or malignant germ cell tumours. All other
entities mentioned in Table 1 have only been
reported in single cases. Thus, in the National
German Co-operative Paediatric Liver Tumour
Studies from 1989 to 2002, out of 302 liver tumours,
26 were in infants under 6 weeks of age. Of these,
17 were infantile haemangioendotheliomas or
* Tel.: +49-89-5160-3101; fax: +49-89-5160-4726
E-mail address: dietrich.vonschweinitz@kk-i.med.
uni-muenchen.de (D. von Schweinitz).
Table 1 Primary liver tumours and tumour-like lesions in
the newborn
Malignant Benign
Hepatoblastoma Infantile
haemangioendothelioma/
cavernous
Hepatocellular carcinoma
a
Mesenchymal hamartoma
Rhabdoid tumour
a
Teratoma
Yolk sac tumour
a
Adenoma
a
Choriocarcinoma
a
Focal nodular hyperplasia
a
Undifferentiated sarcoma
a
Hepatic cysts
Rhabdomyosarcoma Liver abscess
Inflammatory pseudotumour
a
Only single cases reported in the literature.
Seminars in
NEONATOLOGY
doi:10.1016/S1084-2756(03)00092-7
cavernous haemangiomas, one was a mesenchymal
hamartoma, six were hepatoblastomas and two
were germ cell tumours.
All neonatal tumours grow from immature
liver tissue. In the fourth gestational week, the
hepatic diverticulum of endoderm develops from
the foregut. It expands into the mesoderm of the
septum transversum, and differentiates into
the liver cell cords and the epithelial lining of the
bile ducts. Mesenchymal cells from the septum
transversum form fibrous tissue, haematopoietic
elements and Kupffer cells.
3
There is increasing
evidence that undifferentiated cells persist in the
liver until adulthood. It is as yet unclear from
precisely which cellular components and at what
time the various neonatal liver tumours arise.
4
With increasing use of prenatal ultrasound
screening, many tumours are detected before
birth; therefore, perinatal emergency situations
can be avoided. After birth, ultrasound is the most
convenient imaging procedure and can often give
information on the type of neoplasm encountered.
For more precise anatomical classification and
staging, however, a computed tomography (CT)
scan or, preferably, a magnetic resonance imaging
(MRI) scan is necessary. Other radiological tech-
niques such as scintigraphy and vascular contrast
imaging are sometimes indicated for tumour diag-
nosis or planning therapy.
5
Laboratory diagnostics
should include a differential blood count, liver
parameters, serology for hepatotropic viruses,
and the tumour markers alpha-fetoprotein (AFP),
beta-human chorionic gonadotrophin (beta-HCG),
lactate dehydrogenase and markers for neuro-
blastoma (catecholamine metabolites, neuron-
specific enolase). It should be noted that clinical
symptoms and laboratory tests are often non-
specific in newborns with a liver tumour, and that
imaging results can be misleading.
6,7
Furthermore,
histological differentiation can be difficult, causing
confusion between fetal hepatoblastoma and
infantile haemangioendothelioma for example, and
needle biopsies may not yield enough material for a
reliable diagnosis.
2,6
Therefore, in most cases, an
early laparotomy with an open tumour biopsy is
necessary for correct diagnosis and rapid initiation
of treatment.
Infantile haemangioendothelioma and
cavernous haemangioma
The majority of neonatal liver tumours are vascular
neoplasms. Many of these are diagnosed during the
first few weeks of life. Infantile haemangioendo-
thelioma, also termed capillary haemangioma by
some authors,
3
seems to become symptomatic
much more frequently than the cavernous type of
haemangioma in this age group. Many hepatic
vascular lesions are incidental findings during pre-
or postnatal ultrasound investigations. However,
infantile haemangioendothelioma, in particular,
can cause severe symptoms with abdominal disten-
sion and hepatomegaly, severe arteriovenous
shunting with congestive heart failure, haemo-
dynamic anaemia, thrombocytopenia and consump-
tive coagulopathy (KasabachMerrit syndrome),
rupture with intraperitoneal haemorrhage and
respiratory distress (Fig. 1a). Rarely, biliary
obstruction and jaundice can occur.
8,9
In cases with
rapid growth or in patients with multiple lesions, a
life-threatening status can develop shortly after
birth or sometimes even during the fetal period
with hydrops fetalis and intra-uterine heart failure.
In about 50% of affected newborns, there are
multiple haemangiomas on the skin and in other
organs, i.e. a haemangiomatosis syndrome.
2
Associ-
ations with omphalocele and other congenital
malformations have also been reported.
3
In gross appearance, infantile haemangioendo-
thelioma and cavernous haemangioma are like soft
sponges filled with blood. Lesions may also contain
homogeneous grey/white areas of fibrosis, calcifi-
cation or focal haemorrhage. CT and MRI scans
show these lesions as areas of reduced density.
After administration of intravenous contrast, an
enhancement from the periphery towards the
centre of the lesion is typical. Large areas of
haemorrhage, however, may imitate areas of
necrosis as in a malignant tumour (Fig. 1b). With
sonography, infantile haemangioendothelioma and
cavernous haemangioma are seen as highly vascu-
larized single or multiple tumours with a more-or-
less homogeneous pattern. The technique of colour
Doppler sonography is particularly valuable in these
cases, since the often extremely high blood flow
through the coeliac trunk and hepatic artery into
the lesion can be visualized and measured (Fig. 1c).
Accordingly, the flow through the corresponding
liver veins is also enhanced. In cases with severe
arteriovenous shunting, an abrupt decrease of the
width of the abdominal aorta directly caudal to the
branching of the coeliac trunk can be seen. Usually,
these findings are typical for infantile haemangio-
endothelioma and may function as a basis for this
diagnosis.
5
The various types of radionuclide
scans cannot deliver additional information, but
angiography may be necessary for planning treat-
ment such as arterial ligation or embolization.
The clinical symptoms and imaging findings
typical for infantile haemangioendothelioma may
404 D. von Schweinitz
also occur in the very rare congenital choriocarci-
noma of the liver, as we have encountered in one
case.
7
Therefore, caution is necessary and tumour
markers, such as AFP and beta-HCG, must be
measured in the serum. If the clinical diagnosis is
not clear, a biopsy should be taken at laparotomy,
which in an appropriate situation can be combined
with a ligation of the involved hepatic arteries.
9
An open biopsy usually establishes the diagnosis
of infantile haemangioendothelioma. However,
even here we have encountered difficulties since
the differentiation between an infantile haem-
angioendothelioma with only slightly enlarged
cavernous spaces and a fetal hepatoblastoma or a
benign hyperplastic regenerative node of the liver
can be extremely difficult.
6
Therefore, before
starting specific treatment, histology should be
reviewed by an experienced paediatric pathologist.
Usually, histology shows normal, still immature
cords of hepatic cells divided by more-or-less
vascular spaces lined by a single layer of plump,
regular endothelial cells.
2
The dimensions of
these vascular spaces determine whether they are
categorized as capillary haemangioendothelioma
or cavernous haemangioma.
3
Increased mitotic
activity is usually not apparent in these tumours. In
addition to this type 1 lesion described by Dehner
and Ishak,
10
a type 2 haemangioendothelioma with
more pleomorphic endothelial cells forming papil-
lary structures occurs rarely. These lesions, which
usually occur in older children, have a tendency to
transform into malignant angiosarcoma.
3,10
The pathogenesis of these vascular lesions is
currently unclear.
3
One would presume some
enhanced angiogenic potential in the fetal liver in
these cases, but this has not been shown to be true,
and as yet there is no solid data or measurements of
angiogenic factors in these lesions or in the
patients' blood.
11
The management of infantile haemangioendo-
theliomas and haemangiomas is controversial. Most
asymptomatic lesions can be managed expectantly,
using serial ultrasound to visualize the anticipated
spontaneous regression.
8,9
In cases with a gradual
onset of controllable symptoms, medical treatment
alone may occasionally be sufficient. This includes
Figure 1 (a) Two-week-old infant with a large infantile haemangioendothelioma resulting in cardiac failure and KasabachMerrit
syndrome. (b) Magnetic resonance scan of an infantile haemangioendothelioma in a newborn. (c) Duplex sonography of the right
hepatic artery with hugely increased blood flow, surrounding a portal vein branch into an infantile haemangioendothelioma.
Neonatal liver tumours 405
the use of digitalis and diuretics for congestive
heart failure, and the administration of blood prod-
ucts to correct anaemia and coagulopathy. This can
be accompanied by steroid therapy (prednisolone
25 mg/kg/day) in an attempt to suppress contin-
ued growth of the lesion or even encourage regres-
sion. Results are, however, often disappointing.
12
Treatment with alpha-2A-interferon (13 g/m
2
/
day) seems to be more effective, but this is
associated with potentially severe side effects.
13
In infants with a rapid onset of severe symp-
toms, more invasive measures can be life saving.
Relatively small solitary tumours are best treated
by complete resection. However, most infantile
haemangioendotheliomas are very large and extend
diffusely throughout the liver; hepatic arterial
ligation or embolization are then necessary. When
technically feasible, the latter may be favoured as
the less-invasive procedure whilst the former gives
the opportunity for an open biopsy. These measures
often stabilize the situation rapidly, but not
infrequently, new collateral feeding vessels
develop within days with the risk of recurrent prob-
lems. Despite this fact and the danger of other
complications, at least 80% of such cases have a
successful outcome after these procedures.
9
There
have been several reports of orthotopic liver trans-
plantation for massive, uncontrollable infantile
haemangioendothelioma. Apart from the young age
of the patients and the urgency of the situation,
there are major logistical problems, and the results
in the few reported cases have not been good
enough to propose orthotopic liver transplantation
as a standard procedure in the treatment of large
infantile haemangioendotheliomas.
14
There is con-
siderable optimism about the development of
potent anti-angiogenic drugs. The angiogenesis
inhibitor AGM-1470 was able to inhibit growth of
haemangioendothelioma in a mouse model.
15
There
are, however, no controlled clinical studies on such
substances, and a better understanding of patho-
genesis may be necessary before more specific
medical treatments can be developed.
Mesenchymal hamartoma
Mesenchymal hamartomas are typically diagnosed
during the first 2 years of life. Some cases are
symptomatic in the neonate, and a few cases are
detected by prenatal ultrasound scan. Many
authors suggest that mesenchymal hamartoma is
not a true neoplasm, but a developmental lesion,
which originates from the connective tissue of the
portal (ductal) plates.
3
The pathogenesis is not
clear, but abnormal blood supply to a liver lobule
3
and/or abnormal expression of fibroblast growth
factors may be relevant.
16
Mesenchymal hamartoma usually presents as a
palpable mass, most often in the right liver, in an
otherwise asymptomatic child. Typically, the lesion
contains multiple large and small cysts containing
some debris and divided by septae of variable thick-
ness (Fig. 2a). Occasionally, the cysts are so small
that the mass appears to be completely solid. The
morphologic pattern on CT, MRI and ultrasound
imaging is usually predominantly cystic. Some-
times, a high portal blood flow into the lesion can
be seen on colour Doppler sonography. Mesenchy-
mal hamartomas do not normally produce proteins
which could serve as specific markers, although
some patients have a moderately elevated serum
AFP.
17
Histologically, the multilocular cysts are lined by
endothelium or by bile duct epithelium, and are
surrounded by fibrous or myxoid tissue containing
bile ducts and multiple vessels, particularly portal
Fig. 2 (a) Gross section of a cystic mesenchymal hamartoma. (b) Histological appearance of a mesenchymal hamartoma with fibrous
tissue, multiple cysts and large portal vessels.
vein branches. The lesion is often surrounded by a
thick fibrous capsule, but can also grow into adja-
cent compressed or fibrous hepatic parenchyma
(Fig. 2b).
2,3
There is some uncertainty about the natural
history of mesenchymal hamartomas. Meyers and
Scarife
8
stated that the tumour tends to increase
in size during the first several months of life and
subsequently may either stabilize, continue to grow
or undergo regression. While complete spon-
taneous regression of mesenchymal hamartomas
has been reported,
18
instances of massive local
recurrence and later transformation to undifferen-
tiated sarcoma are well documented.
17,19,20
There-
fore, small lesions should be resected completely.
Non-resectable mesenchymal hamartomas should
be biopsied. If the mass stabilizes during the
first few months of life, it may be followed by
regular ultrasound investigation with a chance of
spontaneous regression or at least a relative reduc-
tion of size during growth of the patient. If the
lesion does not vanish completely during the first
45 years of life, we undertake resection because
of the risk of malignant transformation at a later
stage.
16
The resection is performed with the established
techniques of liver surgery, and a radical excision
should be attempted. Usually, the complication
rate is low. However, if there is a very high
portal blood flow into the lesion, its resection may
lead to venous congestion in the intestinal tract,
ischaemia, toxaemia and shock, as we encountered
in one case.
21
Hepatoblastoma
Although malignant hepatoblastoma is the most
common liver tumour of early childhood, less than
10% of cases occur during the neonatal period. In
the German national studies, six out of 194 hepato-
blastomas presented during the first 6 weeks of
life. Hepatoblastomas are significantly associated
with genetic anomalies and malformation syn-
dromes, the most important of which are
BeckwithWiedemann syndrome, trisomy 18, fam-
ilial adenomatous polyposis coli and fetal alcohol
syndrome. Extremely premature children have a
significantly increased risk of developing a hepato-
blastoma.
22
Hepatoblastoma is an embryonal neoplasm com-
posed of malignant epithelial tissue with variable
differentiation, most often with embryonal or fetal
components (Fig. 3a). Some hepatoblastomas also
contain malignant mesenchymal tissue with imma-
ture fibrous areas, spindle cells and cartilage-like
osteoid, and are then called mixed hepato-
blastoma.
2,3,22
In neonates, the relatively differen-
tiated, pure fetal histology seems to predominate
compared with older children.
23
The clinical picture of the often extensive
hepatoblastoma tumour in neonates (Fig. 3b) may
also differ in other ways to hepatoblastomas in the
typical age group of 6 months to 3 years. According
to some reports, metastases occur earlier and are
often systemic, sometimes bypassing the lungs
because of differences in the fetal circulation.
23
Neonatal hepatoblastomas do not seem to produce
such excessive amounts of AFP as those in older
children, whilst the natural blood concentrations
are still high in this period of life.
6
Hepatoblasto-
mas can be detected prenatally by abdominal
ultrasound and may cause polyhydramnios and still-
birth.
23
During labor and birth, tumour rupture with
massive haemorrhage can occur.
1,24
Due to diagnostic uncertainty, all neonatal
tumours suspected to be a hepatoblastoma should
Fig. 3 (a) Histological appearance of a hepatoblastoma with embryonal (left) and fetal (right) differentiation. (b) Large hepatob-
lastoma in a young infant involving the right liver and segment IV of the left liver.
be investigated histologically.
6,25
If a resection is
not possible, a biopsy should be taken. Chemo-
therapy containing the effective cytotoxic agents,
cisplatin and doxorubicin,
2628
should be adminis-
tered, carefully considering the dose limitations in
young infants. With this regimen, some extensive
hepatoblastomas may be reduced to an operable
size, and metastases can regress. Thus, cure can
become possible even in neonates. However, due to
their different biological behaviour, as well as the
greater risks of surgery and chemotherapy, neo-
natal hepatoblastomas are associated with a
worse overall prognosis.
3,23
In contrast to previous
reports, all six neonates registered in the German
Co-operative Trials survived tumour-free; four
after a primary tumour resection and two after
inductive chemotherapy and delayed resection.
None of these children had distant metastases.
Germ cell tumours
Primary teratomas of the liver, although very rare,
occur most often in the newborn period.
3
They are
typically cystic and contain mature or immature
elements. These tumours usually lack malignant
components. Serum AFP may be markedly elevated
in these patients.
Mesenchymal hamartoma and hepatoblastoma
are the main differential diagnoses. Diagnosis is
complicated by the fact that some hepatoblasto-
mas have teratoid features on histology.
2
The same
is true of the malignant yolk sac tumour, which has
only been described in combination with hepato-
blastoma,
3
but this might also be defined as a
hepatoblastoma with a malignant germ cell tumour
differentiation.
2
In these cases, an adequate biopsy
is important to define the different malignant and
benign tumour components. In cases of benign
teratoma, surgical excision results in cure. How-
ever, as in teratomas at other sites, it is essential
that the resection is radical, since recurrent
tumour may be highly malignant and associated
with a poor outcome.
8
The liver seems to be a favourite organ for
growth of the very rare choriocarcinoma in neo-
nates. It is not clear whether this tumour originates
in the fetus or is a metastasis from a choriocarci-
noma in the placenta of the mother. In some, but
not all, of the observed cases, a primary tumour
was found in the placenta.
29
Histologically, neo-
natal choriocarcinomas resemble those of older
patients. The clinical symptoms of choriocarcinoma
in the neonatal liver can be very similar to those of
infantile haemangioendothelioma. We encoun-
tered one case with congestive heart failure and
typical KasabachMerrit syndrome. With colour
Doppler sonography, the appearance of the tumour
was like that of an infantile haemangioendothe-
lioma with arteriovenous shunts through cavernous
vascular spaces. However, both serum AFP and
beta-HCG were markedly elevated, and a biopsy
proved the diagnosis.
7
Recent experience with single cases shows that
these tumours may respond to chemotherapy
according to the different co-operative germ cell
tumour protocols, i.e. regimens containing cis-
platin, etoposide and ifosfamide.
7,29
If regression
occurs, the tumour may become resectable. With
such a strategy, the previously very dismal prog-
nosis has improved, and tumour-free survivors,
even from metastasizing neonatal choriocarcari-
noma, have now been reported.
7,29
Conclusions
Liver tumours occur very rarely in neonates. The
most common neoplasms are benign infantile
haemangioendothelioma and, less frequently,
malignant hepatoblastoma. Other benign and
malignant tumours, such as mesenchymal hamar-
toma and germ cell tumours, can occur. Differen-
tial diagnosis of these tumours can be difficult
because of non-specific clinical symptoms, incon-
sistent expression of tumour markers, and some-
times confusingly similar histological appearances.
Treatment strategies, ranging from pure obser-
vation to chemotherapy combined with extensive
surgery, have to be tailored to the specific neo-
plasm. With the development of better therapeutic
regimens, prognosis has improved during recent
years. Intensive research is, however, essential to
gain insight into the pathogenetic mechanisms of
these different neoplasms.
Practice points
Clinical symptoms and imaging are often
non-specific in neonatal liver tumours.
Histological diagnosis is best confirmed by a
reference pathologist.
The most common entity is the benign
infantile haemangioendothelioma.
Infantile haemangioendothelioma type 1
usually regresses spontaneously.
Differential diagnosis comprises mainly
hepatoblastoma and choriocarcinoma.
Medical treatment is often disappointing.
Resection, embolization or arterial ligation
are therapeutic options in severe cases.
Diagnosis of mesenchymal hamartoma should
be confirmed histologically.
Primary or delayed complete resection is the
treatment of choice.
Differential diagnosis of neonatal
hepatoblastoma largely concerns benign
Treatment of hepatoblastoma consists of
primary resection of small tumours, or initial
chemotherapy with cisplatin and doxorubicin
followed by surgery for large lesions.
Neonatal teratoma should be resected
completely.
Choriocarcinoma may respond to
chemotherapy and thus become curable after
resection.
Research directions
The role of genetic modifications and
angiogenic factors in the pathogenesis of
The efficacy of systemic or local
anti-angiogenic substances on tumour growth
suppression.
The possible role of differentiating and
growth factors in the aetiology of
mesenchymal hamartomas.
Mechanisms of malignant transformation in
mesenchymal hamartomas.
Evaluation of the clinical and molecular
genetic conditions leading to intra-uterine
growth of hepatoblastoma.
Factors leading to the growth of
choriocarcinoma in the placenta and/or in
the fetus.
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