disorders of the neonatal liver and bile duct - seminars 2003.pdf

8/11/2019 Disorders of the neonatal liver and Bile Duct - Seminars 2003.pdf

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Editorial

Disorders of the Neonatal Liver and Bile Ducts

Liver and biliary tract disorders in the neonate arerelatively rare and often complex. The conse-quences of delayed diagnosis and inappropriatemanagement may be fatal. As with so much ofclinical medicine, awareness of the spectrum ofdiseases and recognition of the key clinicalfeatures of the various disorders is essential tooptimizing 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 ofSeminars in Neonatologydistills the clinical and scientific experience of aninternational group of experts in an attempt toprovide the working neonatologist (and otherhealthcare workers involved in the care of thenewborn) with a state-of-the-art review ofeach topic and a stimulating insight into recentadvances.

Sue Beath from Birmingham Children's Hospital,UK outlines current concepts of hepatic functionand physiology in the newborn, whilst the freshchallenges posed by prenatal diagnosis and molecu-lar genetics are discussed by Mark Davenport andDino 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 Hospitalfor Sick Children in Toronto, Canada. The latternicely leads on to a more detailed discussion of

biliary atresia from a combined Japanese and UKperspective. Stuart Kaufman from The Mount SinaiHospital in New York, USA brings us up to date withthe widespread and potentially hazardous problemof parenteral-nutrition-associated liver disease.Finally, there are important contributions fromPaddy McClean and Suzanne Davison in Leeds, UKon the newborn infant with liver failure, and from

Dietrich von Schweinitz in Munich on neonatalliver tumours; both are rare but extremely taxingclinical conditions.

With the constraints of space, each section is notintended to be encyclopaedic but rather, eachexpert has provided a readable account combininga useful blend of practical knowledge and analysisof current research. I would like to thank all thecontributors. I am also indebted to Sean Duggan,Managing Editor, and his assistant Ann Smiley fortheir 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: +44-1132066691E-mail address: [email protected] (M.D. Stringer).

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Hepatic function and physiology in the newbornS.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 inwhich bile secretion can be observed by 12 weeks'gestation. Full maturity takes up totwo years after birth to be achieved, and involves the normal expression of signallingpathways such as that responsible for the JAG1 genes (aberrations occur in Alagille'ssyndrome), amino acid transport and insulin growth factors. At birth, hepatocytes are

already specialized and have two surfaces: the sinusoidal side receives and absorbs amixture of oxygenated blood and nutrients from the portal vein; the other surfacedelivers bile and other products of conjugation and metabolism (including drugs) tothe canalicular network which joins up to the bile ductules. There is a rapid inductionof functions such as transamination, glutamyl transferase, synthesis of coagulationfactors, bile production and transport as soon as the umbilical supply is interrupted.

Anatomical specialization can be observed across the hepatic acinus which hasthree distinct zones. Zone 1 borders the portal tracts (also known as periportalhepatocytes) and is noted for hepatocyte regeneration, bile duct proliferation andgluconeogenesis. Zone 3 borders the central vein and is associated with detoxification(e.g. paracetamol), aerobic metabolism, glycolysis and hydrolysis and zone 2 is anarea 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 inneonates.

Stem cell research has produced many answers to the questions about liverdevelopment and regeneration, and genetic studies including studies of susceptibilitygenes may yield further insights. The possibility that fatty liver (increasingly recog-nized as non-alcoholic steatohepatitis or NASH) may have roots in the neonatal periodis 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 12months after birth. The liver differentiates fromembryonic liver progenitor cells derived from stemcells, into a mature organ containing hepatocytes,cholangiocytes and immune cells, all existing in astromal network through which approximately one-quarter of the circulating blood is pumped.1,2

This process takes place via several importantmechanisms which are only just beginning to be

understood. These include apoptosis, morphogen-esis, proliferation and polarization.35 Aberrationsof the normal sequence of embryonic and fetal

gene expression can lead to disease, e.g. the notchsignalling pathway appears to be important inAlagille's syndrome characterized by cardiac, facialand hepatic abnormalities6 (Table 1). The liver mayplay an important role in the maintenance of ahealthy feto-placental unit as intra-uterine growthrestriction is associated with reduced expression ofhepatocyte growth factors.7 External factors suchas the hormonal milieu and hypoxia influence theexpression of genes responsible for the transport ofamino acids across membranes and the production* Tel.: +44-121-333-8259; fax: +44-121-333-8251

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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 biletriangular facies

Alpha-1 antitrypsindeficiency

Mutation of gene coding for protease inhibitor on chromosome 14 Growth restriction in utero, severpresent with vitamin-K-sensitive c

Bile acid synthesisdisorders

Abnormal expression of the following enzymes:

(a) Hydroxy-steroid dehydrogenase (a) Normal GGT, low serum bile a(b) Oxosteroid reductase (b) Severe jaundice and coagulop(c) 25-Dihydroxycholanic cleavage enzymes (c) Normal GGT, elevated ALP and

Cystic fibrosis Mutation in delta 508 or other genes Jaundice, hepatomegaly, meconiustools

CriglerNajjar type 1 Various mutations in exon 15 of B-UGT1 gene coding for bilirubin

glucuronidation

Unconjugated hyperbilirubinaemi

phenobarbitone=no effectCriglerNajjar type 2 Various mutations leading to reduced affinity of the enzyme for substrate Unconjugated hyperbilirubinaemi

phenobarbitone effectiveGilbert's disease Mutation in the promoter region of the UDPGT 1 gene Unconjugated hyperbilirubinaemi

resolves after brief exposure to pDubinJohnson syndrome Autosomal recessive Conjugated bilirubin (30400 mo

pigment granules on liver biopsyPFIC type 1 Byler'sdisease

Mutation of the mixed drug reaction gene 1 (MDR-1) Normal GGT, normal cholesterol,(diarrhoeapancreatitis)

PFIC type 2 Mutation on chromosome 2 of bile salt export pump Normal GGT, no intestinal symptoPFIC type 3 Mutation in the P-glycoprotein MDR-3 gene Elevated GGT, troublesome pruritRotor syndrome Autosomal recessive Conjugated hyperbilirubinaemia,

liver and normal liver function teZellweger's Abnormal expression of peroxisome enzymes involved in side chain

modification of bile acidsAccumulation of very long-chain fforehead, profound hypotonia

PFIC, progressive familial intrahepatic cholestasis; GGT, gamma glutamyl transferase; ALP, alkaline phosphatase; MDR, multidrug-resistan


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of insulin growth factors8,9 (Table 2). An imbalancein the transport of molecules such as bilirubin andamino acids can lead to cholestasis and a giant cellhepatitis.

Fetal developmentThe liver develops from the foregut which folds intothe mesoderm. The bile ducts and hepatocytes arederived from stem cells in the endoderm, andKupffer 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 cellswhich are then committed to either hepatocyte orcholangiocyte lineage.10 The hepatocytes developin long cords into the stroma, initially as platesthree to five cells thick. At the time of birth, the

architecture of the liver is well established withportal tracts connected to the central veins byplates of hepatocytes in layers which are two cellsthick. The hepatocytes have a sinusoidal surfaceover which blood from the portal vein and hepaticartery flows, and a basolateral canalicular surfacefrom which bile is secreted.

The space between the canalicular surface ofhepatocytes communicates with biliary cells in theportal tracts via the canals of Hering which alsocontain oval cells. The oval cells are progenitor

cells which proliferate according to normal fetaldevelopment or in response to liver injury.1 Ovalcells can develop into hepatocytes or cholangi-ocytes depending on local environmental factors.2

Hepatic secretion of bile commences early ataround 12 weeks'gestation.

The main serum protein of the fetus is alpha-fetoprotein which reaches a peak concentration atthe end of the first trimester. Albumin synthesisbegins at around 16 weeks' gestation and reachesadult levels at the time of birth.

In utero, the liver acts as the main source of redcell production, and even at birth, foci of activehaematopoiesis are still present in the parenchymaof the liver. This may explain why disorders of ironmetabolism such as neonatal haemochromatosis(which have their origins in the fetus) have such adevastating effect including fulminant liver fail-

ure.11

These areas of haematopoiesis usually disap-pear within six weeks of birth being superseded bythe bone marrow. Persistence of extramedullaryhaemopoiesis is an indication of disease and maybe seen in haemolytic anaemia and neonatalhepatitis.12

Events at birth

Two major physiological events at birth affect theliver: the pressure in the lungs drops dramatically

Table 2 Environmental and other causes of neonatal jaundice

Disease Clinical features

EnvironmentalHypoxia9,28,29 Sudden rise in AST and ALT up to 20 times baseline, followed by

jaundice (conjugated hyperbilirubinaemia)Endocrine

(a) Hypothyroidism8 (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 intransporting bilirubin to canaliculus

Interuterine infection, e.g. parvovirus Intra-uterine growth restriction, hepatosplenomegaly, ascitesPostnatal infection, e.g. streptococcus28 Sudden rise in conjugated bilirubin, low platelets, coagulopathy, rise in

acute-phase proteinsParenteral nutrition (PN)32 Early rise in ALP and GGT, jaundice especially during septic episodes,

can lead to liver failure

Uncertainsusceptibility genes may be interactingwith environment

Biliary atresia Normal birth weight, 10% have situs inversus, pale stools, high GGT andALP, bilirubin rises steadily from birth

Giant cell hepatitis Growth restriction in utero, ALT and AST may be three to five timesnormal, haemolysis occasionally present, congenital infection may bedetected (especially parvovirus)

AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma glutamyl transferase; ALP, alkaline phosphatase.

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with the first few breaths; and 50% of the cardiacoutput previously going to the placenta is rapidlyre-distributed as blood flow through the umbilicusceases. Within minutes, the venous return fromvital organs such as the liver and the small bowelincreases, and the pulmonary circulation becomesas dynamic as the systemic circulation, producing a

steep rise in dissolved oxygen in arterial blood toalmost 95% saturation. In addition to these events,a more gradual change in hepatic blood flowoccurs. In the fetus, the ductus venosus connectsthe 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 withinone to two weeks of birth. Rarely, the ductus failsto close and this has been linked to the subsequentdevelopment of encephalopathy and liver tumoursin older children.

Increase in portal blood flow and bacterialcolonization

The newborn infant's first feed increases portalblood flow and exposes the intestinal tract tomicro-organisms for the first time. Within hours ofbirth, colonies of bacteria establish themselvesin the intestine and a stable microflora developsin the large bowel. Although bacterial colonizationmay be associated with necrotizing enterocolitis inpremature infants, enteric bacteria have a physio-logical role in that they produce vitamin K. It takesaround six weeks for the mass of bacteria to pro-duce sufficient vitamin K, and this is one reasonwhy haemorrhagic disease of the newborn is veryrare after this time unless a chronic cholestaticdisease is present causing malabsorption of vitaminK (e.g. alpha-1 antitrypsin deficiency13).

Induction of enzyme functions (GGT andUDPGT)

The rapid assumption of processing functions by thehepatocyte cell mass requires an induction of

enzymes such as the cytochrome P450 group andperoxisomal enzymes which were present beforebirth.14

Transferase function

It is normal to see a rise in gamma glutamyl trans-ferase (GGT) from a low baseline value of around30 IU/l up to 120150 IU/l for the first few monthsof life. A lack of increase in GGT can imply adisorder of the biliary epithelium and canalicular

aspect of the hepatocyte cell surface (e.g. progres-sive familial intrahepatic cholestasis (PFIC) types 1and 2). In a different type of bile transport disor-der, the GGT may be abnormally high as in PFICtype 3, in which one of the genes coding for thebilirubin transporter multidrug-resistant protein 3(MDR-3) is defective (Table 1). An abnormally high

GGT is also a pointer to abnormal biliary function asseen in biliary atresia. Plasma levels of alkalinephosphatase, which is concentrated in the cyto-plasm just below the bile canaliculus, are alsostrikingly elevated in biliary atresia (Table 2).

Conjugation

Conjugation develops from minimal levels to almostadult levels within two weeks of birth in mostcases. Conjugation reactions are an important stepin detoxifying by-products of metabolism and drugs,

especially relatively insoluble lipid molecules.15

Bilirubin, which is salvaged from the complex haemmolecule when worn-out red blood cells aredestroyed, is highly lipophilic and cannot easilycross cytosolic spaces inside the cell. Conjugatingthe bilirubin molecule with glucuronide is depen-dent on the function of the enzyme uridinediphosphoglucuronyl transferase (UDPGT), whichimproves the water solubility of bilirubin. Conjuga-tion also improves the efficiency of transport ofbilirubin into the canaliculus and reduces its toxicdetergent effect on the bile ducts.

A rise in unconjugated bilirubin in the first two

weeks of life (up to 50% of babies become visiblyjaundiced) may be regarded as almost physiologicalas it is usually self-limiting once the conjugationcapacity of the maturing hepatocytes catches upwith the demands of life outside the womb. How-ever, it is important to confirm that plasmabilirubin is reducing after 14 days and also to estab-lish whether the bilirubin is largely unconjugated.An elevated conjugated bilirubin can never beregarded as physiological although it may have aself-limiting cause such as septicaemia.

A delay in achieving normal levels of UDPGT isfrequently seen in preterm and septic babies

who are at risk of developing kernicterus if highlevels of unconjugated bilirubin occur. Othercauses of an elevation in unconjugated bilirubinare 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 type2 are very rare. In contrast, Gilbert's diseaseaffects up to one in 100 of the population. Fortu-nately, the defect in UDPGT expression in Gilbert'sdisease is mild and only becomes evident under

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conditions of stress, such as birth, or, in adult life,in association with prolonged fasting or a systemicillness such as influenza. Babies who are ho-mozygous for the genetic abnormality of Gilbert'sdisease are more likely to be jaundiced in the firstfew days of life than unaffected babies.16

Induction of synthetic functions

At birth, the plasma albumin concentration isusually near to adult levels (3035 g/l), but theconcentration of plasma proteins involved in coagu-lation is usually low. In parallel with the rapidinduction of enzymes involved in conjugation, thecoagulation proteins increase to adult levels within

a few days of birth. Caeruloplasmin is also low atbirth and gradually rises during the first threemonths of life. This can become grossly elevatedduring sepsis or other stresses because, likealpha-1antitrypsin, it is an acute-phase protein.12

Sinusoidal physiology and function

It is important to note that a hepatocyte functionsas if it had two surfaces: the sinusoidal surface andthe canalicular surface (Fig. 1). The sinusoidal sur-face is exposed to two sources of blood: one is richin dissolved oxygen (from the hepatic artery), and

the other is rich in glucose, amino acids, free fattyacids, 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 veindelivers approximately twice the volume of bloodas the hepatic artery, equivalent to 600 ml/min inan adult.

On the other side of a hepatocyte is the canal-icular surface. This forms a network of canaliculibounded by tight junctions, which joins up with bile

ducts in the portal tracts via the canals of Hering.Bile is actively transported by specialized transportproteins into the canaliculi and ultimately flowsunder positive pressure down the biliary tree.17

Hepatocytes act as a conduit and processor fornutrients, initially from the placenta. Within daysof birth, hepatocytes must have the capacity todeal with an enormous range of hormones, foodantigens, complex molecules and bacteria derivedfrom the intestinal tract. It is not surprising, there-fore, that environmental stress (e.g. intra-uterineinfection, respiratory distress, bacterial sepsis) and

genetic factors (abnormal transporters of bilirubin)frequently result in cholestasis and disruption ofhepatocytes, leading to a giant cell hepatitis (seeTables 1 and 2).

Maturing physiology

After the initial adaptations to circulatory changesin the newborn have taken place, the liver starts tofulfil its role in maintaining homeostasis.

Table 3 Causes of increased plasma unconjugatedbilirubin

HaemolysisTraumatic birth associated with haemorrhage and tissue

contusionNeonatal polycythaemiaCongenital hypothyroidism

SepsisHypoxiaHypoglycaemiaAutosomal-inherited disorders

CriglerNajjar types 1 and 2Gilbert's diseaseGalactosaemiaFructose intolerance

Canaliculas

Blood-filledsinusoid

Kuppfercell

Specializedendothelium

HepatocyteTightjunction

Sinusoid

Canalicularsurface

Sinusoidalsurface

Fig. 1 Arrangement of hepatocytes and the specialized sur-

faces within the sinusoidal space.

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Carbohydrate, lipid and protein metabolism

Newborn babies do not store much glycogen, andone of the first responses to a feed is a sharp rise ininsulin. This has an anabolic effect generally caus-ing glucose to enter cells for energy and for storageas glycogen and triglyceride, especially in the liver.

Newborn babies are prone to hypoglycaemia unlessthey receive frequent feeds, and it is an importantphysiological adaptation that the cells of the cen-tral nervous system can utilize ketones if glucose isnot available.

The liver plays a key role in the control of freefatty acids which may be converted to ketonesduring a fast or stored as triglyceride after a feedwhen glucose and insulin are plentiful. The lack ofketone production during a fast is indicativeof abnormal physiology as in disorders of fatoxidation, e.g. long-chain 3-hydroxyacyl dehydro-genase deficiency18 which is a cause of suddeninfant death.19 The liver is the major organ respon-sible for the clearance of lactic acid and althoughlactate may be above 5 mmol/l shortly after birth,it should normalize within 6 h. A persistentlyelevated lactate should prompt concerns aboutsepsis, adequacy of the circulation or mitochondrialdisorders.11

Amino acids are transported to the liver alongwith other nutrients via the portal vein. They arerapidly taken up by the sinusoidal hepatocyteswhere they are de-aminated, transaminated andenter the urea cycle. Alternatively, amino acids are

utilized to make nearly all of the plasma proteinsexcept immunoglobulins. Proteins normally foundin high concentrations such as albumin and coagu-lation factors are reduced in chronic liver disease.Conversely, acute-phase proteins such as alpha-1antitrypsin and fibrinogen may be raised becausethe diseased liver fails to clear them.

Bile acid formation and the enterohepaticcirculation

The elaboration of bile requires energy at severalpoints. Bile is a complex fluid derived from

cholesterol, phospholipids and haemoglobin. Thenumerous steps involved in cholesterol metab-olism, phospholipid synthesis and the conjugationof bilirubin derived from haem requires enzymeswhich 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 wasteproduct but is crucial in the activation of some ofthe intestinal lipases and in solubilizing dietaryfats. Infants who produce inadequate amounts ofbile are at risk of protein energy malnutrition sec-

ondary to malabsorption of up to half their dietaryfat and also fat-soluble vitamin deficiency (vita-mins A, D, E and K). For both these reasons, it is notsurprising that there is a physiological mechanismfor retrieving bilirubin known as the enterohepaticcirculation. It is estimated that a single molecule ofbilirubin circulates from hepatocyte to canaliculusto intestinal lumen via the common bile duct to theterminal ileum and back to the liver via the portalvein up to six times a day.12

Hepatic function by zone

The sinusoidal plates are differentiated in twoaxes: the differentiation between the sinusoidaland canalicular surfaces, and the specialization offunction longitudinally from the portal tract downto the central vein. The hepatic acinus can beseparated into three zones on the basis of proximityto the portal tracts or the central vein and specia-lization of function (Fig. 2). Zone 1 represents thearea around the portal tracts (also known as theperiportal area), zone 3 represents the area aroundthe 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

containingartery, 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.

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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 generalizationsare outlined inTable 4. Disorders of bile excretiontend to affect zone 1where the greatest concen-tration of bile exists,20 and where there is thegreatest capacity for chylomicron uptake.21 Regen-eration after hepatocyte injury begins in zone 1,and gluconeogenesis appears tobe concentrated inthe periportal hepatocytes.2224 The fact that zone3 is rich in detoxification enzymes such as glutath-ione reductase25 is important in interpreting thehistological features of paracetamol poisoning, inwhich there is a characteristic pattern of necrosisselectively affecting the hepatocytes around thecentral veins. Hypoxic events may be evident inzone 3 (haemorrhage around the central vein andapoptosis of neighbouring hepatocytes26), which isfurthest away from arterial blood and has the low-est concentration of dissolved oxygen. Glycolysisand hydrolysis have also been associated with theperivenular hepatocytes in zone 3.23,27

Clinical scenarios

Hypoxia

The neonatal liver is relatively resistant to theeffects of hypoxia, but in conditions of hypoper-fusion, such as during circulatory collapse causedby sepsis or blood loss, acute hepatocyte necrosismay be evident, especially around the centralvein.28 Over the next 210 days, an increase inplasma transaminases (alanine transaminase, as-partate transaminase) and lactate dehydrogenaseare seen which may exceed 500 IU/l,29 and a coagu-

lopathy may develop. The rise in transaminases isfollowed by a rise in conjugated bilirubin. Full

recovery is possible provided that the cause ofhypoperfusion is treated, although the improve-ment in plasma bilirubin lags behind theimprovement in transaminases and may take manyweeks to resolve.

Septic shock

Liver dysfunction commonly develops secondary tosevere sepsis in the neonate and can resolve ifappropriate antimicrobial treatment is startedpromptly. However, infection with herpes simplexvirus, 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 liverfailure in the neonate are listed in Table 5 anddiscussed in detail by McClean and Davison else-where in this issue. Ultrasound scanning of theabdomen in septicaemia may show an echo-brightliver which is considered to be due to hyperplasia ofthe reticuloendothelial system. Biliary sludge andgall stones which may obstruct the biliary tree mayalso be seen after an episode of sepsis, particularly

Table 4 Zonal specialization of hepatocyte functions

Zone Functions Marker molecule or enzymeassociated with function

Zone 1 (periportal) Bile duct proliferation20

Chylomicron uptake 125I labelled chylomicron remnant21

Hepatocyte regeneration Ki-67 antigen detection22

Gluconeogenesis23,25 PEPCK24

Insulin growth factors and binding protein IGF-1 and IGFBP-224

Zone 2 Induction of microsomal and peroxisomal enzymes P450 4A and bifunctional enzyme14

Zone 3 (perivenular) Detoxification Glucuronidation25

Induction of microsomal and peroxisomal enzymes P450 4A and bifunctional enzyme14

Aerobic metabolism Relatively more intracellular ionizedcalcium during aerobic conditions26

Insulin growth factor binding protein type 1 IGFBP-124

Glycolysis Glucose induced release of lactate23

Hydrolysis of cholesterol esters Cholesterol ester hydrolase27

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)

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with necrotizing enterocolitis where enteralstarvation 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 immatureinfants. This has brought challenges and limitationsfrom other organ systems such as the liver andgastrointestinal tract. Preterm infants are atconsiderable risk of hypoxia because of a failure toestablish a properly dynamic pulmonary circula-tion. Such infants are also vulnerable to infectionvia the intestinal tract (e.g. necrotizing enterocoli-tis) because the surface epithelium of the gut isvery permeable and the lamina propria lacksdepth.32 Bacterial translocation from the intestinevia the portal vein to the liver can cause directinfections (micro-abscesses and/or large collec-tions). The more common effects of bacterialinfection on liver function are indirect, occurring asa result of the toxicity of lipopolysaccharide, e.g.impaired cholesterol and bilirubin metabolism andtransport. The detergent properties of bile can bevery damaging, causing further disruption to thestructure and function of internal plasma mem-branes, such as the Golgi apparatus, and externalmembranes, such as the sinusoidal surface of thehepatocyte. Preterm infants are also at risk of hy-poglycaemia because of reduced stores of glycogenand adipose tissue. More importantly, gluconeogen-

esis appears to be ineffective, with energy beingdiverted to heat rather than glucose generation.

Summary

Although the blood supply and volume of the liverchange dramatically at birth, together with itsrange of required functions, a healthy baby hassufficient physiological reserve for homeostasis tobe well maintained with only a short-lived period ofmild unconjugated jaundice being apparent. Babies

who are of low birth weight, premature or stressedfor other reasons (e.g. infection, hypoxia orcongenital heart disease) may present withhypoglycaemia, acidosis and prolonged jaundice.Provided that external factors are corrected, theliver has great powers of repair and regenerationwhich are located in specific areas of the hepaticacinus and which can be enhanced with goodnutrition. The future role of malnutritionon the evolution of non-alcoholic steatohepatitis(NASH) and the place of cyto-protective agents

such as vitamin E, ursodeoxycholic acid andN-acetylcysteine are subjects of ongoing research.

Practice points

Infants with prolonged jaundice (greater

than 14 days) are at risk of developing avitamin K responsive coagulaopathy andshould receive vitamin K supplements.

Mild visible jaundice is common in babies upto 14 days after birth.

Always check that bilirubin levels arereducing from 14 days onwards.

Always measure the type of bilirubin invisibly jaundiced infants after 14 daysis itunconjugated or conjugated?

Sick infants who are jaundiced should haveurine 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 incollapsed infants.

Research agenda

There have been considerable advances instem cell research, which may ultimately

allow human organs to be produced in thelaboratory without resorting to cadavericorgan transplantation. Much of this work hasbeen performed in laboratory rats, but morerecent experiments with tissues obtainedduring neonatal surgery and from embryoresearch may yield fresh insights.

Another key area of research includescollaborative European studies on thegenetics of liver disease, and a greater focuson susceptibility genes which may contributeto the pathogenesis of rare diseases, such as

biliary atresia and idiopathic reactions todrugs. In future, a better understanding ofsusceptibility genes may allow high-riskpatients to be identified and offeredprophylactic or even pre-emptive treatment.New treatments may include the morewidespread use of cyto-protective agentssuch as vitamin E, ursodeoxycholic acid andN-acetylcysteine.33

There is increasing appreciation that thedisorder NASH occurs in childhood and may

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35. Mulhall BP, Ong JP, Younossi ZM. Non-alcoholic fatty liverdisease: an overview. J Gastroenterol Hepatol 2002;17:113643.

36. Roberts EA. Steatohepatitis in children.Best Pract Res ClinGastroenterol2002;16:74965.

37. Manton ND, Lipsett J, Moore DJ et al. Non-alcoholic steato-hepatitis in children and adolescents. Med J Aust 2000;173:4769.

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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 asinfective, anatomic/structural, metabolic, genetic, neoplastic, vascular, toxic,immune and idiopathic. Any infant who is jaundiced at 24 weeks old needs to havethe serum conjugated bilirubin measured, even if he/she looks otherwise well. Ifconjugated hyperbilirubinaemia is present, a methodical and comprehensive diag-nostic investigation should be performed. Early diagnosis is critical for the bestoutcome. In particular, palliative surgery for extrahepatic biliary atresia has thebest chance of success if performed before the infant is 8 weeks old. Definitivetreatments available for many causes of neonatal hepatitis syndrome should bestarted as soon as possible. Alternatively, liver transplantation may be life saving.Supportive care, especially with attention to nutritional needs, is important for allinfants with neonatal hepatitis syndrome. 2003 Elsevier Ltd. All rights reserved.

KEYWORDS

Neonatal hepatitissyndrome;

Conjugated

hyperbilirubinaemia;

Giant-cell hepatitis;

Neonatal liver failure;

Infant;

Metabolic liver disease

Jaundice frequently occurs in the first 3 months oflife. Most jaundiced infants have unconjugatedhyperbilirubinaemia. In contrast, infants withhepatic dysfunction have conjugated hyper-bilirubinaemia. This is one of the most importantproblems in paediatric hepatology. Many differentliver disorders can cause neonatal hepatitis syn-drome. Possible treatments and outcomes varygreatly among these disorders. It is criticallyimportant to find the cause of neonatal hepatitissyndrome as soon as possible, and in the majority of

infants, the disease is not idiopathic. Any infantwho is still jaundiced at 24 weeks of age requiresinvestigation. The first test is to determine whetherthe hyperbilirubinaemia is conjugated or not. Anyinfant with conjugated hyperbilirubinaemia has

neonatal hepatitis syndrome and requires furtherinvestigation.

Nomenclature for neonatal liver disease is notstraightforward. The simplest term neonataljaundice leads to confusion with physiologicaljaundice in the newborn. The term neonatalcholestasis is imprecise because in the first34 months of life, every infant has some degree ofneonatal cholestasis on a physiological basis. Thisphysiological cholestasis is multifactorial. Uptakeof bile acids and other organic anions by hepato-

cytes is inefficient, leading to high concentrationsof bile acids in blood; hepatocellular pathways ofbile acid conjugation and biliary secretion are alsoimmature and inefficient. The circulating bile acidpool is contracted, and ileal uptake of bile acids isunderdeveloped. Hepatic bile canalicular trans-porters are also regulated developmentally.1 Theterm neonatal hepatitis is inaccurate becausehepatic inflammation is not a feature of everycondition. The term neonatal hepatitis syndromeis preferred because it emphasizes the uniformity

* Division of Gastroenterology and Nutrition, Room 8267,Black Wing, The Hospital for Sick Children, 555 UniversityAvenue, Tronoto, Ontario M5G 1X8, Canada. Tel.:+1-416-813-7733; fax: +1-416-813-4972

E-mail address:[email protected] (E.A. Roberts).

Seminars in

NEONATOLOGY



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of the clinical presentation as well as the broadspectrum of causative disease processes.

A subset of the neonatal hepatitis syndrome is agroup 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 failurecan have an acute-pattern with extremely elevatedserum aminotransferases and normal serumalbumin, or it can have a chronic-pattern withnear-normal serum aminotransferases and lowserum albumin, consistent with a prenatal liverinjury. Since the conventional definition of acuteliver failure does not really apply to the newbornperiod, it makes sense to use the term neonatalliver failure for these disorders.2,3

As there are so many different causes of neo-natal hepatitis syndrome, it is useful to groupthem: infective, anatomic/structural, metabolic,genetic, neoplastic, vascular, toxic, immune andidiopathic (Table 1). This review will deal mainlywith entities in the infectious, metabolic, geneticand immunologic categories, as well as with idio-pathic neonatal hepatitis. Liver biopsy is oftenrequired to investigate neonatal hepatitis syn-drome adequately.4 The hallmark finding in manyneonatal liver disorders is giant-cell hepatitischaracterized by inflammation and large multi-nucleated hepatocytes in the liver parenchyma.Structural disorders causing obstruction of largebile ducts lead to typical features of duct obstruc-

tion in portal tracts and surrounding parenchyma.Typical changes of various metabolic diseases maybe evident on liver biopsy in the affected infant.

Infection

Toxoplasmosis, rubella, cytomegalovirus,herpes simplex (TORCH) infections

These congenital infections usually share clinicalsimilarities such as enlargement of the liver and

spleen, jaundice, pneumonitis, a petechial or pur-puric rash, and a tendency to prematurity or poorintra-uterine growth. Clinical presentation withneonatal liver failure is possible with any of theseagents, but it is most common with Herpes simplexinfection. Whenever possible, direct identificationof viral infection or measurement of specific IgMantibodies should be sought for rapid diagnosis;relying on conventional TORCH titres is lesspreferable. Polymerase chain reaction (PCR)-baseddiagnostic techniques can be extremely useful.

Toxoplasmosis

Congenital toxoplasmosis is rare and is usuallyassociated with maternal infection in the third tri-mester. Neonatal hepatitis is prominent. Centralnervous system involvement with chorioretinitis(with large pigmented scars), hydrocephaly or mi-

crocephaly, and intracranial calcifications usuallyoccurs, leading to convulsions, nystagmus and signsof increased intracranial pressure. In older infants,deafness may occur.

Rubella

Congenital infection with rubella virus may causenumerous abnormalities including intra-uterinegrowth retardation, anaemia/thrombocytopenia,congenital heart disease (often patent ductusarteriosus or pulmonary artery stenosis), cataracts,chorioretinitis (salt and pepper appearance),

mental retardation and sensorineural deafness.Conjugated hyperbilirubinaemia with hepato-splenomegaly usually occurs. Liver histologytypically shows giant-cell hepatitis.

Cytomegalovirus

Cytomegalovirus (CMV) is the most common causeof congenital infection, affecting 12% of new-borns, most of whom are asymptomatic. Clinicalfindings include a petechial rash, hepatospleno-megaly and jaundice in 6080%. CMV can cause

neonatal liver failure, but this is uncommon. Fetalascites is not necessarily a poor prognostic sign.CMV infection often affects the central nervoussystem, producing microcephaly, intracranialcalcification, and chorioretinitis; progressive sen-sorineural deafness may develop later in childhood.Conclusive diagnosis requires CMV to be culturedfrom the infant within the first 4 weeks of life(usually in urine).

In most children, CMV hepatitis is mild andresolves completely. Persisting neurodevelop-mental abnormalities become the main problem.A few children develop hepatic fibrosis or

non-cirrhotic portal hypertension. Intrahepaticcalcification has been reported. Rarely, cirrhosiswith chronic cholestasis eventually requires livertransplantation.

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 withneonatal hepatitis by PCR, but in only two of 26with biliary atresia, and in none of the controlspecimens.

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Table 1 Neonatal hepatitis syndrome: differential diagnosis

Diseases by category Associated with neonatal liver failure?

InfectionToxoplasmosis (congenital)Rubella (congenital)CMV (congenital)Herpes simplex (congenital) NLFacute

Syphilis (congenital)HHV-6 NLFacute (rare)Herpes zosterHepatitis B (mainly vertical) NLFacuteHepatitis C (mainly vertical) NLFacute (rare)HIV (vertical)Parvovirus 19 NLFchronicSyncytial giant cell hepatitis (?paramyxovirus)Enteric viral sepsis (echoviruses, Coxsackie viruses, adenoviruses) NLFacuteBacterial infection (extrahepatic or sepsis) NLFacuteListeriosisTuberculosis

StructuralBiliary atresia

Choledochal cystCaroli syndromeCholedocholithiasisNeonatal sclerosing cholangitisHair-like bile duct syndromeSpontaneous biliary perforationNon-syndromic duct paucityAlagille syndrome

Metabolic1-Antitrypsin deficiencyCystic fibrosisGalactosaemia NLFacute or chronicTyrosinaemia, type 1 NLFacute or chronicHereditary fructosaemia NLFchronic

Glycogen storage disease, type IVNiemannPick, type ANiemannPick, type C NLFchronicWolman diseaseGaucher diseaseProgressive familial intrahepatic cholestasis (types 1, 2, 3)North American Indian familial cholestasisAagenaes syndrome (cholestasis/lymphedema)Primary disorders of bile acid synthesis NLFchronicPeroxisomal disorders (e.g. Zellweger syndrome)Perinatal haemochromatosis NLFchronicCitrullinaemia, type IIPanhypopituitarism (septo-optic dysplasia)HypothyroidismX-linked adrenoleukodystrophy NLFchronicDubinJohnson syndrome

GeneticTrisomy 18 (biliary atresia)Cat-eye syndrome (biliary atresia)Trisomy 21 (fibrosing hepatitis with transient leukaemia) NLFchronic

NeoplasiaNeonatal leukaemia NLFacuteNeuroblastoma NLFacuteHepatoblastomaHistiocytosis XErythrophagocytic lymphohistiocytosis NLFchronic

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Herpes simplex

In the newborn, herpes simplex virus (HSV) usuallycauses a severe multisystem disorder with encepha-litis. Either type 1 or type 2 HSV is capable ofcausing severe infection, although type 2 virus shedfrom the infected cervix at birth is more frequent.Neonatal liver failure with an acute-pattern ofinjury 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 typicallyshow the virus, but herpetic skin, mouth or eyelesions may not be present. Antiviral treatmentwith acyclovir should be administered to avert theotherwise high mortality. In the child with acute-pattern neonatal liver failure, acyclovir shouldbe started immediately, even with results ofdiagnostic tests still pending.

Syphilis

Congenital syphilis causes intra-uterine growthretardation and subsequent failure to thrive,

severe anaemia and thrombocytopenia, nephroticsyndrome, periostitis, nasal discharge (snuffles),skin rash, diffuse lymphadenopathy and hepatome-galy. Central nervous system involvement occurs inup to 30% of infants. Jaundice may be presentwithin 24 h of birth or develop after treatment, andit may be severe.6 Diagnosis involves serologicaltesting, including the Venereal Disease ResearchLaboratory (VDRL) test and confirmatory testing forspecific antitreponemal antibodies. Radiographs oflong bones may show typical bony abnormalities in

the first 24 h of life and permit diagnosis while theother tests are still pending. Treatment with peni-cillin can then be started without delay. Somebabies with congenital syphilis never develop jaun-dice, but present with a typical rash on the palmsand soles or only with fever, as well as prominenthepatomegaly.

Varicella

Varicella may occur in newborn infants if maternal

infection occurs within 14 days of delivery. It tendsto be more severe in premature infants. Jaundice isa feature of severe disease, which typically involvesan extensive rash, pneumonia and multisysteminvolvement.

Hepatotropic viruses: hepatitis A, B, C

In general, infection with hepatotropic viruses inneonates does not cause jaundice unless there isacute-pattern neonatal liver failure or severehepatitis after a typical incubation period.

Hepatitis A

Hepatitis A is rare in the neonatal period. Congeni-tal infection may occur if the mother is infected12 weeks before delivery.

Hepatitis B

Vertical (mother-to-infant) hepatitis B infection isgenerally subclinical in the neonatal period;

Table 1 (continued)

Diseases by category Associated with neonatal liver failure?

ToxicTPN-associated cholestasisDrug-induced (via breast-milk or other)

Vascular

Budd

Chiari syndrome NLFacuteSevere congestive heart failureNeonatal asphyxia

ImmuneInspissated bile syndromeNeonatal lupus erythematosusNeonatal hepatitis with auto-immune haemolytic anaemia

IdiopathicLe foie vide (infantile hepatic non-regenerative disorder) NLFchronic

NLFacute, acute-pattern neonatal liver failure; NLFchronic, chronic-pattern neonatal liver failure.

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Tuberculosis

Congenital tuberculosis is rare. With the world-wide prevalence of tuberculosis rising, tuberculosisin 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 granulomasin the liver; exclusion of postnatal infection.12

Hepatomegaly is usually found in infants withtuberculosis. Jaundice occurs with severe disease.Respiratory distress, poor feeding and fever arefrequent. Mortality approaches 30%. Treatment is aquadruple antitubercular antibiotic regimen notincluding ethambutol.

Structural

Biliary atresia

Confirming or excluding biliary atresia is an import-ant diagnostic issue, because it is frequentlyresponsible for neonatal hepatitis syndrome. Earlydiagnosis is vital because surgical treatment, theKasai portoenterostomy, is less likely to be suc-cessful the later it is performed.13 (see paperby Kobayashi and Stringer.

Biliary atresia involves a progressive destruc-

tion of the extrahepatic bile ducts with scarring,obliteration and concomitant damage to small andmedium-sized intrahepatic bile ducts. Biliaryatresia is found world-wide in all racial groups, withan incidence of 1:800015 000 live births. Cur-rently, biliary atresia is often categorized into twogeneral patterns: embryonal/fetal or early andperinatal or late. The majority of infants have thelate pattern. They appear to have had a normalbiliary system, which has become involved in afibrosing inflammatory process towards the endof gestation or shortly after birth. By contrast,approximately 1020% of infants with biliary atresia

have additional congenital abnormalities includingpolysplenia, left atrial isomerism, double-sided leftlung, 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 reflectan acquired inflammatory lesion in originallynormal bile ducts. This inflammatory process isnot necessarily reversed even if bile drainage isrestored after Kasai portoenterostomy. Various

infective agents have been implicated in theaetiology of biliary atresia in humans. Early studiessuggesting that reovirus-3 infection might be theinitiating infection for idiopathic neonatal hepatitisand biliary atresia in humans were not confirmed inlater reports.16 Other studies of liver biopsies andbiliary remnants from infants with late pattern

biliary atresia have not found support for rotavirusinfection.17 CMV infection is found in a proportionof infants with biliary atresia, but CMV does notappear to be an exclusive cause of the condition. Inone report of fraternal twins with congenital CMVinfection, one had hepatitis only and the otherpresented with late pattern biliary atresia.18 Inone series of infants with biliary atresia, 25% hadCMV infection and they tended to be referred laterthan those without CMV infection.19 A more compli-cated mechanistic explanation for late patternbiliary atresia is that it occurs when an inflamma-tory insult sets off an immune-mediated process ina susceptible infant. In a murine model examiningbile duct allografts, alloreactive lymphocytesmediated a destructive process histologicallysimilar to that of biliary atresia.20 CMV remains acandidate virus for causing late presentationbiliary atresia because CMV can infect bile ductepithelial cells directly and result in increasedexpression of major histocompatibility complexclass II antigens by these cells. Infants with con-genital CMV infection and persisting conjugatedhyperbilirubinaemia should be evaluated for biliaryatresia.

Choledochal cyst

Choledochal cyst refers to a group of congenitalmalformations 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 thefetus by prenatal sonography and have been foundas early as 1516 weeks'gestation.21 The diagnosisshould be confirmed soon after birth. The majorityof these infants have conjugated hyperbilirubi-

naemia, and surgery should be performedpromptly.

Spontaneous biliary perforation

This condition may present as a severe acuteillness resembling acute peritonitis with abdominalpain and distention, jaundice and fever. It can alsopresent as neonatal hepatitis syndrome, often withabdominal distention in addition to jaundice andacholic stools. Biliary ascites is pathognomonic.

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Bacterial superinfection greatly increases mor-bidity. Surgical repair is usually curative.

Neonatal sclerosing cholangitis

Neonatal sclerosing cholangitis (NSC) was firstreported in 1987 with a few subsequent

reports.22,23 The feature which distinguishes NSCfrom childhood primary sclerosing cholangitis isthat NSC presents in early infancy with conjugatedhyperbilirubinaemia which then resolves; althoughsome children present in infancy with primarysclerosing cholangitis, they have not had earlycholestatic jaundice. After apparent spontaneousresolution of the neonatal liver disease, NSCprogresses to biliary cirrhosis with recurrence ofjaundice several years later. Liver transplantationis usually required. NSC may be a metabolic dis-ease24 or have immunological features without

persistent jaundice. In one case, non-specificauto-antibodies were detected.25

Alagille syndrome

Alagille syndrome has an important structuralfeature: paucity of small (portal) bile ducts. It is agenetic disorder with autosomal-dominant trans-mission but highly variable expression. The quotedincidence of 1:100 000 probably exaggerates itsrarity. Mutations inJAG1on chromosome 20p havebeen identified as the genetic basis for Alagille

syndrome. Its major clinical features includechronic cholestatic liver disease with decreasednumbers of small (portal) intrahepatic bile ducts,structural cardiovascular disease, skeletal abnor-malities including butterfly vertebrae, posteriorembryotoxon of the eye, and typical facies. Minorfeatures include renal abnormalities, small birthsize and/or poor growth, delayed puberty orhypogonadism, and an abnormal high-pitched cry/voice. Associated vascular abnormalities have beennoted including decreased intrahepatic portal veinradicals, coarctation of the aorta and other largevessel abnormalities, and moya-moya disease.26

Neurological abnormalities described in earlyreports probably were not part of the syndromeitself but instead due to vitamin E deficiency fromsevere chronic cholestasis. Hypothyroidism andpancreatic insufficiency have also been observedin affected children, and they are more likely toget recurrent otitis media.27 A spectrum ofbehavioural problems has been described (mentalretardation, learning difficulties or antisocialbehaviour), but many children are normal sociallyand academically.

The majority of patients with clinically import-ant Alagille syndrome have conjugated hyper-bilirubinaemia in the neonatal period.28 Cholestasismay be sufficiently severe that the stools areacholic, and hepatobiliary scanning fails to showevidence of biliary excretion.29 Liver biopsy usuallyshows reduced numbers of small bile ducts with

some giant-cell transformation and cholestasis. Thenumber of portal tracts may also be reduced. Insome infants, ongoing damage to bile ducts may befound, or bile ductular proliferation suggestive ofextrahepatic bile duct obstruction. Alagille syn-drome with a segmental atresia of the commonhepatic duct has been found in several infants.

The characteristic facies, not always evident inearly infancy, has the shape of an inverted triangleand consists of a broad forehead, deep-set eyes,mild hypertelorism, a straight nose and a smallpointed chin. The ears may be prominent. The

cardiovascular disease is usually relatively benign(peripheral pulmonary artery stenosis), but moresevere hypoplasia of the pulmonary artery branchesmay occur and other congenital heart disease hasbeen found.30 Butterfly vertebrae, due to failure ofthe anterior arches of the vertebral body to fuse,are most commonly found in the thoracic spine. Eyesigns may be very diverse;31 posterior embryotoxonis most frequent.

Alagille syndrome seems to be rather benign inmany children. The clinical features of severecholestasisjaundice, pruritus, hypercholestero-laemia with or without xanthomas, elevated serumbile acids, alkaline phosphatase and -glutamyltranspeptidase (GGT)resolve or improve duringthe first year of life. The hepatic lesion does notprogress inexorably to cirrhosis. However, youngchildren with protracted jaundice usually have apoorer prognosis, with progressive liver disease.Conservative estimates put overall mortality at 2025%, due to cardiac disease, intercurrent infectionor progressive liver disease. Liver transplantationfor severe hepatic disease is warranted andcatch-up growth may occur afterwards.32,33

JAG1 is the human homologue of the rat gene

Jagged1. It encodes a ligand of Notch 1, whichis involved in determining cell fate during differ-entiation, especially in tissues where epithelialmesenchymal interactions are important. Theseinclude many of the organs that are potentiallyabnormal in Alagille syndrome. HaploinsufficiencyofJAG1causes Alagille syndrome; mutations resultin truncated and thus inactive proteins and residualgene expression cannot compensate.34 Many muta-tions are sporadic. No clear relationship betweengenotype and phenotype has been found, although

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the Delta/Serrate/Lag-2 (DSL) domain in the JAG1protein may influence the severity of liverdisease.3537

Non-syndromic bile duct paucity

In a full-term neonate in whom Alagille syndromehas been excluded, various other disorders maycause portal ductopenia (small duct paucity). Thisnon-syndromic duct paucity may be idiopathic orassociated with other specific conditions (Table 2).Among congenital infections, CMV is most import-ant and, in such cases, CMV inclusions may be foundin bile duct epithelial cells. When idiopathic neo-natal hepatitis is clinically severe, duct paucitymay be present.

Metabolic

1-Antitrypsin deficiency

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 bindsand inactivates leukocyte elastase. More than 90variants have been reported. The deficiency statusis caused by mutations in the 1-antitrypsin geneson chromosome 14. Deficiency occurs in 1:16002000 live births in North American and Europeanpopulations, but it is much less common with otherethnic backgrounds. Only a small proportion of

individuals with 1-antitrypsin deficiency everdevelops liver disease, but 8590% of the childrenwith 1-antitrypsin deficiency who develop liverdisease present with neonatal hepatitis syndrome.In most of these infants, liver disease eventuallyresolves. Cholestasis may be severe with totallyacholic stools and a non-draining hepatobiliary

scan. Small duct paucity may be present andportends a poor prognosis. The rare infant has beenreported with both 1-antitrypsin deficiency andbiliary atresia. The 1015% who do not haveneonatal hepatitis syndrome present later with non-

jaundiced hepatomegaly. Some newborn infantspresent with potentially serious haemorrhagic com-plications associated with severe coagulopathy.

Clinical diagnosis rests upon finding low serumconcentrations of1-antitrypsin and identifying anallelic variant of1-antitrypsin. The most commondeficiency variant is Z, a slow-moving protein on

electrophoresis, with a point mutation resulting ina single amino acid substitution (lysine replacingglutamic acid at position 342). Some variants suchas MMalton and MDuarte show only subtle electro-phoretic differences from the normal M and maybe difficult to recognize. Since 1-antitrypsin is anacute-phase reactant, diagnostic low serum con-centrations may not be found due to hepaticinflammation. Determining the phenotype (PItype) by iso-electric focusing or identifying aspecific gene defect by molecular methods such asPCR is essential to the diagnosis. In individuals withthe Z- or M-variant allele, liver biopsy shows globu-lar inclusions, which are abnormal 1-antitrypsinprotein retained in the endoplasmic reticulum.These globules stain pink with periodic acidSchiff-diastase (PAS-D) stain. They are not reliably foundin liver biopsies from infants less than 3 months old.Most infants with1-antitrypsin deficiency and neo-natal hepatitis syndrome have PI type ZZ (althoughPI Z/null cannot be excluded without familystudies). Liver disease may occur with PI SZ at arelatively young age, and with PI FZ and PI MZ laterin 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, halfare entirely normal and the other half have mildlyabnormal serum aminotransferases, no jaundiceand no enlargement of liver or spleen. The rest goon to chronic liver disease with cirrhosis or die inthe first year of life. Early prognostication of indi-vidual infants with 1-antitrypsin deficiency is dif-ficult. In one study of children with neonatalhepatitis, 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

PrematurityInfection

CMVRubellaSyphilis

Hepatitis BMetabolic1-Antitrypsin deficiencyCystic fibrosisZellweger syndromeByler syndromeIvemark syndromePrune belly syndromeHypopituitarism

Genetic: chromosomal disordersTrisomy 18, 21Partial trisomy 11Monosomy X

Immune-related: grafthost diseaseSevere idiopathic neonatal hepatitisIsolated/idiopathic

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age, or the presence of bile ductular proliferation,bridging fibrosis or cirrhosis on the initial liverbiopsy presaged rapidly progressive liver disease.39

Although the severity of jaundice at presentationmay not be predictive of outcome, its durationappears to be critical. Infants in whom jaundiceresolves within a few months, usually by 6 months

old, are likely to have a good outcome, but thosewith prolonged jaundice pursue a downhill course.Liver transplantation is generally tolerated well,although attention to potential kidney diseaseassociated with 1-antitrypsin deficiency isrequired through the early postoperative period.40

The PI type of the donor effectively replaces theabnormal phenotype.

Cystic fibrosis

Abnormalities of liver function tests or on liver

biopsy are found in as many as one-third of infantswith cystic fibrosis. However, even in infants,hepatic pathology is highly variable. The spectrumof hepatic pathology includes giant-cell hepatitis,extrahepatic bile duct obstruction by inspissatedbile, massive hepatic steatosis usually without con-jugated hyperbilirubinaemia, and paucity of small(portal tract) bile ducts. Neonatal hepatitis is veryuncommon.41 Many infants who have severe liverdisease also have meconium ileus.

Galactosaemia

The incidence of galactosaemia is approximately1:50 000. 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, manychildren have normal intelligence. Some infantspresent with septicaemia. Galactosaemia canpresent as an acute or chronic type of neonatal liverfailure. A few infants never have any symptoms andare diagnosed later in childhood. The definitive

diagnostic test is measurement of erythrocytegalactose-1-phosphate uridyltransferase (GALT),which must be performed before the infant has hadany blood transfusions. Testing the urine for reduc-ing substances can be misleading, as reducingsubstances may be present in other severe neo-natal liver disease. Galactosuria may be present innormal newborns for the first few days of life, andwell into the second week in premature babies.Conversely, galactosuria may not be present inan affected infant who is too unwell to take

lactose-containing formula. Cataracts found onphysical examination require definitive assessmentby an ophthalmologist. Oil-drop cataracts arehighly typical of galactosaemia and may resolvewith treatment if the disease is diagnosed early.Treatment consists of elimination of galactose fromthe 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 tolack of fumaryl acetoacetate hydrolase (FAH),expressed mainly in the liver and kidneys.42 Theclassic clinical presentation is liver disease withrickets and aminoaciduria. However, babies withthis disorder may present with neonatal liver fail-ure in the perinatal period, with classic neonatal

hepatitis syndrome, or at a later age (between 4and 24 months) with hepatomegaly, ascites andcoagulopathy but no jaundice. Untreated heredi-tary tyrosinaemia type 1 carries a high mortality ininfancy; the proportion of patients presenting inlater childhood is comparatively small. Childrenwith hereditary tyrosinaemia type 1 who survive tomid-childhood have a very high incidence ofhepatocellular carcinoma, with a prevalenceapproaching 40% in mid-childhood. The disease isfound world-wide, but it is common in theSaguenayLac St. Jean region of Canada (1:500),Pakistan and northern Europe.

Although presentation of hereditary tyrosi-naemia type 1 as neonatal hepatitis syndromemay be less common than other presentations,hereditary tyrosinaemia type 1 has to be consideredin any infant with clinically or histologically severeneonatal hepatitis (Table 3) or neonatal liver fail-ure. Coagulopathy may be prominent, attributed inpart to dysfibrinogenaemia. Hypoglycaemia mayoccur. The liver biopsy shows parenchymal changeswith inflammation of unusual severity. Typically,the -fetoprotein level is disproportionately high

Table 3 Diseases causing histologically severe neonatalhepatitis

1-Antitrypsin deficiencyHereditary tyrosinaemia, type 1NiemannPick disease, type CSyncytial giant cell hepatitisPrimary disorders of bile acid synthesis (mainly

4

-3-oxosteroid 5-reductase deficiency)Idiopathic neonatal hepatitis

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treatment strategy is cholic acid with or withoutursodeoxycholic 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 includedtwo infants with early severe cholestasis and coagu-lopathy. Subsequent reports have included infantswith a clinical presentation resembling perinatalhaemochromatosis. Serum GGT is usually, but notinvariably, normal. Liver biopsy may reveal abnor-mal bile canaliculi in a focal, mosaic pattern. Inthis disorder, excess, potentially toxic, 4-3-oxobile acids are produced. Treatment with cholic acid(with or without ursodeoxycholic acid) appears tobe beneficial in patients without iron overload. Thehereditary disorder has to be distinguished from

acquired deficiency of the enzyme due to severeliver disease of any cause.

24,25-Dihydroxycholanoic cleavage enzymedeficiency

Infants have been described with a defect in the25-hydroxylase pathway.63 Jaundice and hepato-megaly were noted in the first week of life; serumGGT was normal but alkaline phosphatase andcholesterol were elevated, hepatobiliary scanningshowed no drainage, and pruritus developed later.

Treatment with chenodeoxycholic plus cholic acidappeared beneficial.

Other bile acid synthesis disorders

This is an evolving field. Two other inborn errors ofbile acid metabolism have recently been describedin single patients presenting with neonatal liverdisease.64,65 Neonatal hepatitis syndrome with adefect 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 bymultiple abnormalities of peroxisome function.The molecular and cell biology of these disordersis complex, involving multiple PEX genes whichencode peroxins, proteins required for peroxisomeassembly. 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 systemsbesides the liver are affected; features includeprofound hypotonia, facial dysmorphism with a highforehead and large fontanelles, developmentaldelay, seizures, bony abnormalities such as epi-physeal calcifications, and cystic malformations inthe brain and kidneys. In the first 3 months of

life, hepatic involvement may not be prominent,although some babies have persistent conjugatedhyperbilirubinaemia. Others are not jaundiced buthave hepatosplenomegaly with evidence of poorhepatic synthetic function. Hepatic fibrosis is typi-cal, and paucity of the small (portal) bile ducts maybe found. Electron microscopy reveals the absenceof peroxisomes in hepatocytes. Mitochondria mayalso appear abnormal. These infants may developcirrhosis, although extrahepatic features of thesyndrome almost always overshadow the hepaticdisease.

Perinatal haemochromatosis

This disorder is also called neonatal haemochroma-tosis or neonatal iron storage disease. It is a severeliver disease with extensive iron overload in thenewborn, suggesting fetal liver injury. It is thoughtto be extremely rare, but approximately 120 caseshave been reported. Its pathogenesis remainsuncertain. The dispute as to whether perinatalhaemochromatosis is a single liver disease or acommon clinical presentation for multiple disease

processes is justified. Some cases have a definableaetiology but pathogenesis remains unclear in asignificant proportion of patients. These appear tohave a hereditary or at least familial pattern.

Most babies present shortly after birth, althougha few have been diagnosed at 23 months ofage.6971 The affected infant has neonatal liverfailure with a classic chronic-pattern. The bio-chemical features are those of end-stage cirrhosis:near-normal serum aminotransferases, low serumconcentrations 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 fewweeks old. Ascites, including fetal ascites, may bepresent. Serum iron and transferrin are normal, butserum ferritin is usually increased to the 20003000 g/l range. The liver and certain other organs(pancreas, kidneys, adrenal glands and heartnotthe reticulo-endothelial system) show iron accumu-lation.72 Finding iron deposition in salivary glandson buccal biopsy or evidence of iron overloadon magnetic resonance imaging supports thediagnosis.

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Treatment is supportive in a well-equipped neo-natal intensive care setting; liver transplantationmay be required for survival. Recently, multipledrugs aimed at reducing oxidative stress have beenused with some success, if treatment is commencedvery early.73 This anti-oxidant cocktail includesanti-oxidants (N-acetylcysteine, selenium and

-tocopheryl polyethylene glycol succinate), ahepatocytoprotective agent (prostaglandin E1,omitted if a patent ductus arteriosus is present) anda chelator (desferrioxamine, used until the serumferritin is


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infants with biliary atresia. Stimulation programsenhance mental development of infants whorequire frequent hospitalization or for those withsyndromes associated with central nervous systeminvolvement, such as congenital CMV infection.

Practice points

Any infant jaundiced at 24 weeks of agemust be evaluated for conjugatedhyperbilirubinaemia.

Conjugated hyperbilirubinaemia in the first24 h of life strongly suggests congenitalinfection.

Structural abnormalities of the biliary treefound on prenatal ultrasound requireassessment as soon as possible after birth.

1-Antitrypsin deficiency is the most

frequent metabolic disease causing neonatalhepatitis syndrome in Caucasian infants. Conjugated hyperbilirubinaemia with

cholestasis but a normal GGT suggests PFIC(types 1 or 2) or a primary disorder of bileacid synthesis.

Chronic-pattern neonatal liver failurepresents with conjugatedhyperbilirubinaemia, unremarkable AST andALT concentrations, a low serum albumin,and a marked coagulopathy.

Research directions

The role of congenital infection in thepathogenesis of biliary atresia.

The mechanism for duct paucity in Alagillesyndrome.

The existence of other types of progressivefamilial intrahepatic cholestasis.

The mechanism of hepatic fibrosis in trisomy21 with transient myeloproliferativesyndrome/leukaemia.

The pathogenesis of perinatalhaemochromatosis.

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administration should be avoided. Fluid restrictionis also indicated for deteriorating oliguric renalimpairment, which may ultimately require dialysissupport and for control of ascites. Ascites mayrespond to optimizing serum albumin (infusing

5 ml/kg of 20% human albumin solution), and di-uretic therapy [oral spironolactone or intravenouspotassium canrenoate (1 g0.7 g spironolactone)].If causing respiratory compromise, percutaneousdrainage may be required. Ventilatory supportshould be considered early for neurological as wellas respiratory deterioration. Inotropic support

may be required, and as peripheral vasodilationmay accompany liver failure, vasoconstrictors suchas noradrenaline should be considered. Acidosis,reflecting hepatic and/or renal dysfunction, sepsisor a metabolic disorder may require bicarbonatecorrection.

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 oedemamay accompany encephalopathy; fluid overloadshould be strictly avoided.Convulsionsor deterio-

rating conscious level should prompt imaging toexclude intracerebral haemorrhage.Feeds should be withheld until galactosaemia,

tyros

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