Seminars in Neonatology (2003) 8, 357374

Seminars in NEONATOLOGY
www.elsevierhealth.com/journals/siny

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

KEYWORDS
Neonatal hepatitis syndrome; Conjugated hyperbilirubinaemia; Giant-cell hepatitis; Neonatal liver failure; Infant; Metabolic liver disease

Summary Conjugated hyperbilirubinaemia in an infant indicates neonatal liver disease. 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 diagnostic 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. 2003 Elsevier Ltd. All rights reserved.

Jaundice frequently occurs in the first 3 months of life. Most jaundiced infants have unconjugated hyperbilirubinaemia. In contrast, infants with hepatic dysfunction have conjugated hyperbilirubinaemia. This is one of the most important problems in paediatric hepatology. Many different liver disorders can cause neonatal hepatitis syndrome. 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

* 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).

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 hepatocytes 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 transporters 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

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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 failure 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 neonatal 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 idiopathic neonatal hepatitis. Liver biopsy is often required to investigate neonatal hepatitis syndrome adequately.4 The hallmark finding in many neonatal liver disorders is giant-cell hepatitis characterized by inflammation and large multinucleated hepatocytes in the liver parenchyma. Structural disorders causing obstruction of large bile ducts lead to typical features of duct obstruction in portal tracts and surrounding parenchyma. Typical changes of various metabolic diseases may be evident on liver biopsy in the affected infant.

Toxoplasmosis Congenital toxoplasmosis is rare and is usually associated with maternal infection in the third trimester. Neonatal hepatitis is prominent. Central nervous system involvement with chorioretinitis (with large pigmented scars), hydrocephaly or microcephaly, 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 hepatosplenomegaly usually occurs. Liver histology typically shows giant-cell hepatitis. Cytomegalovirus Cytomegalovirus (CMV) is the most common cause of congenital infection, affecting 12% of newborns, most of whom are asymptomatic. Clinical findings include a petechial rash, hepatosplenomegaly 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 sensorineural 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 neurodevelopmental 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 neonatal 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.

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 purpuric 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.

Neonatal hepatitis syndrome

Table 1 Neonatal hepatitis syndrome: differential diagnosis Associated with neonatal liver failure?

359

Diseases by category Infection Toxoplasmosis (congenital) Rubella (congenital) CMV (congenital) Herpes simplex (congenital) Syphilis (congenital) HHV-6 Herpes zoster Hepatitis B (mainly vertical) Hepatitis C (mainly vertical) HIV (vertical) Parvovirus 19 Syncytial giant cell hepatitis (?paramyxovirus) Enteric viral sepsis (echoviruses, Coxsackie viruses, adenoviruses) Bacterial infection (extrahepatic or sepsis) 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 Tyrosinaemia, type 1 Hereditary fructosaemia Glycogen storage disease, type IV NiemannPick, type A NiemannPick, type C 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 Peroxisomal disorders (e.g. Zellweger syndrome) Perinatal haemochromatosis Citrullinaemia, type II Panhypopituitarism (septo-optic dysplasia) Hypothyroidism X-linked adrenoleukodystrophy DubinJohnson syndrome Genetic Trisomy 18 (biliary atresia) Cat-eye syndrome (biliary atresia) Trisomy 21 (fibrosing hepatitis with transient leukaemia) Neoplasia Neonatal leukaemia Neuroblastoma Hepatoblastoma Histiocytosis X Erythrophagocytic lymphohistiocytosis

NLFacute NLFacute (rare) NLFacute NLFacute (rare) NLFchronic NLFacute NLFacute

NLFacute or chronic NLFacute or chronic NLFchronic

NLFchronic

NLFchronic NLFchronic

NLFchronic

NLFchronic

NLFacute NLFacute

NLFchronic

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Table 1 (continued)

E.A. Roberts

Diseases by category Toxic TPN-associated cholestasis Drug-induced (via breast-milk or other) Vascular BuddChiari syndrome 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)

Associated with neonatal liver failure?

NLFacute

NLFchronic

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

Herpes simplex In the newborn, herpes simplex virus (HSV) usually causes a severe multisystem disorder with encephalitis. 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 necrosis with viral inclusions in intact hepatocytes; however, profound coagulopathy may preclude biopsy. 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 acutepattern neonatal liver failure, acyclovir should be started immediately, even with results of diagnostic tests still pending.

the first 24 h of life and permit diagnosis while the other tests are still pending. Treatment with penicillin can then be started without delay. Some babies with congenital syphilis never develop jaundice, 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. Congenital 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;

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 hepatomegaly. 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

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prompt administration of both hepatitis B immunoglobulin 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, presentation with jaundice and hepatitis occurs later, at approximately 6 months of age.8

Parvovirus B19 infection

Congenital parvovirus B19 infection may cause profound anaemia leading to hydrops and fetal death. It is a cause of chronic-pattern neonatal liver failure, resembling perinatal haemochromatosis.9 The affected infant may have dermal erythropoiesis (blueberry muffin rash), anaemia and perinatal distress in addition to conjugated hyperbilirubinaemia, 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.

acute-pattern neonatal liver failure may be the prominent feature. Most infants with enteric viral sepsis are less than 5 weeks old at presentation; 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 serotype 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 conjunction 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 septicaemia 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.

Human herpesvirus-6 infection

Human herpesvirus-6 (HHV-6) causes exanthem subitum, a common but usually benign febrile illness 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.

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, diffuse areas of focal necrosis. These micro-abscesses contain numerous Gram-positive bacilli. Pneumonia is usually present. A history of maternal illness is common.

Enteric viral sepsis (echovirus, Coxsackie viruses, adenoviruses)

Enteroviruses can cause systemic viral infection in the newborn period. Severe hepatitis causing

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E.A. Roberts

Tuberculosis
Congenital tuberculosis is rare. With the worldwide prevalence of tuberculosis rising, tuberculosis in infants may occur somewhat more frequently. Practical criteria for diagnosing congenital tuberculosis are a proven tuberculous infection in the newborn baby and at least one of the following: lesions in the first week of life; tuberculous infection 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 important 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 successful the later it is performed.13 (see paper by Kobayashi and Stringer. Biliary atresia involves a progressive destruction 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. Currently, 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 malrotation, 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 complicated mechanistic explanation for late pattern biliary atresia is that it occurs when an inflammatory 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 congenital 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 common 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 hyperbilirubinaemia, 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.

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Bacterial superinfection greatly increases morbidity. 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 disease24 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 transmission 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 abnormalities 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 important Alagille syndrome have conjugated hyperbilirubinaemia 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 syndrome 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, hypercholesterolaemia 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 differentiation, 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 mutations are sporadic. No clear relationship between genotype and phenotype has been found, although

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Table 2 Causes of non-syndromic paucity of bile ducts (ductopenia) in infants Prematurity Infection CMV Rubella Syphilis Hepatitis B Metabolic 1-Antitrypsin deficiency 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

E.A. Roberts

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 important and, in such cases, CMV inclusions may be found in bile duct epithelial cells. When idiopathic neonatal hepatitis is clinically severe, duct paucity may be present.

Metabolic
1-Antitrypsin

deficiency

This is the most common inherited cause of neonatal 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 nonjaundiced hepatomegaly. Some newborn infants present with potentially serious haemorrhagic complications 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 MMalton and MDuarte show only subtle electrophoretic differences from the normal M and may be difficult to recognize. Since 1-antitrypsin is an acute-phase reactant, diagnostic low serum concentrations 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 globular inclusions, which are abnormal 1-antitrypsin protein retained in the endoplasmic reticulum. These globules stain pink with periodic acidSchiffdiastase (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 neonatal 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 individual infants with 1-antitrypsin deficiency is difficult. In one study of children with neonatal hepatitis, persisting elevation of serum aminotransferases and serum GGT through 612 months of

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Table 3 Diseases causing histologically severe neonatal hepatitis
1-Antitrypsin deficiency 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

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 deficiency is associated with 1-antitrypsin 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 conjugated 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.

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 complications, mainly neurodevelopmental problems, may develop later despite good dietary control.

Hereditary tyrosinaemia, type 1

Hereditary tyrosinaemia type 1 is an autosomalrecessive 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 failure 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 hereditary 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 tyrosinaemia 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 failure. 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

Galactosaemia
The incidence of galactosaemia is approximately 1:50 000. Clinical features are extremely variable in the neonatal period and include vomiting, diarrhoea, jaundice, poor weight gain and malnutrition. 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 reducing substances can be misleading, as reducing substances may be present in other severe neonatal 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

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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 methionine. Succinylacetone can be detected in the urine in virtually all patients. Treatment with 2-(2-nitro4-trifluoromethyl-benzoyl)-1,3-cyclohexanedione (NTBC: an inhibitor of 4-hydroxyphenylpyruvatedioxygenase), in addition to a low-tyrosine phenylalanine diet, has revolutionized the management of this disease and extended survival dramatically,43 although a long-term risk of hepatocellular carcinoma persists.

Hereditary fructosemia
Hereditary fructose intolerance is an autosomalrecessive 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, leading 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 pathognomonic changes in hepatocyte cytoplasm (socalled 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.

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 hyperbilirubinaemia, often with prominent splenomegaly. The infants appear neurologically normal, although subsequent motor and speech development may lag.48 Fetal ascites may occur. Liver biopsy shows a histologically severe neonatal hepatitis, with pericellular fibrosis and pseudoacinar formation; features suggesting that extrahepatic 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 propria, 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 hyperbilirubinaemia 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 deficiencies, 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 chenodeoxycholic 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 transplant, 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

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 childhood in most, but not all, cases. The gene product of NPC1 appears to mediate trafficking of sterols

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P-type ATPase (ATP8B1) involved in aminophospholipid 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 cholestasis51 and for benign recurrent intrahepatic 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 ATPbinding 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 transformation of hepatocytes, fibrosis and ductular proliferation 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 translocator 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.

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 supplementation. 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-C27-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 histologically 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-C27-steroid dehydrogenase/isomerase deficiency have normal serum GGT and low serum total bile acid concentrations, but no pruritus. They produce excessive amounts of C24-bile acids with a 3 -hydroxy-5 structure. The currently preferred

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 prominent, 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; hepatosplenomegaly, pruritus, facial telangiectasia and,

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treatment strategy is cholic acid with or without ursodeoxycholic acid. 4-3-Oxosteroid 5 -reductase deficiency 4-3-Oxosteroid 5 -reductase is an important cytosolic enzyme in the bile acid synthetic pathway. The original description of this disorder included two infants with early severe cholestasis and coagulopathy. Subsequent reports have included infants with a clinical presentation resembling perinatal haemochromatosis. Serum GGT is usually, but not invariably, normal. Liver biopsy may reveal abnormal 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 hepatomegaly 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

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 epiphyseal 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 typical, 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 haemochromatosis 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 biochemical 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 conjugated hyperbilirubinaemia. Jaundice may be somewhat 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 accumulation.72 Finding iron deposition in salivary glands on buccal biopsy or evidence of iron overload on magnetic resonance imaging supports the diagnosis.

Zellweger syndrome
Zellweger syndrome is the prototype of the peroxisomal 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 associated with mutations in PEX1 and PEX6.6668 Zellweger syndrome is rare, occurring in 1:100 000,

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Treatment is supportive in a well-equipped neonatal 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 E1, 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 incidental hepatocellular carcinoma has been reported in three infants. Certain clinical patterns associated with perinatal haemochromatosis are unusually severe: a renal tubular disorder74 or 4-3oxosteroid-5 -reductase deficiency.

Genetic
Trisomy 18
Trisomy 18 is associated with growth retardation, skeletal abnormalities and complex congenital heart disease. In a series of 10 infants with cytogenetically confirmed trisomy 18, giant-cell hepatitis 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 disease has been reported with Down's syndrome. Some patients had severe hepatic fibrosis associated 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

Citrullinaemia, type II
Although jaundice is rare with the classic form of citrullinaemia (type I, argininosuccinate synthetase deficiency), infants with neonatal hepatitis syndrome 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.

Immune
Inspissated bile syndrome
The inspissated bile syndrome is the term traditionally used for conjugated hyperbilirubinaemia complicating severe jaundice associated with haemolysis, usually due to Rhesus factor or ABO incompatibility or erythrocyte abnormalities. Intrahepatic 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.

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 localization.80,81 Neonatal hepatitis syndrome has been reported rarely in DubinJohnson syndrome.82 Diagnosis is hampered by the difficulty in recognizing 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.

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 manifestation; a discoid lupus erythematosus rash may be

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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 obstruction, with acholic stools and a non-draining hepatobiliary scan. One infant with severe liver disease resembled perinatal haemochromatosis. Transient unexplained isolated conjugated hyperbilirubinaemia in the perinatal period and later presentation 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 Sjo gren's syndrome, the diagnosis should be suspected. 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 immunofluorescence.88 The risk of neonatal lupus erythematosus 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 supplementation 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 assessment 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 functionally 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 disease 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 intervention 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

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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 neonatal 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 relatively 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 neonatal period with jaundice. A more difficult problem 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 breastfeeding at that point. A breast-feeding device to provide supplementary formula at the nipple may be useful. In biliary atresia, resting energy expenditure runs approximately 30% higher than in normal infants of the same age and sex;90 an aggressive approach to feeding is required, including nasogastric 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 fatsoluble 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 supplementation after 2 months of age or earlier if the baby was born preterm. Vitamin E attached to polyethylene glycol 1000 through a succinate linkage ( -tocopheryl polyethylene glycol succinate or TPGS) has been shown to have the best bioavailability in severe cholestasis, since its absorption depends on simple passive absorption of the polyethylene glycol. Since vitamin E absorption is exquisitely dependent on luminal bile acids, any jaundiced infant with deficiency of another fatsoluble vitamin should be assumed to require extra vitamin E. Coagulation should be monitored closely in all infants with cholestasis. Infants with a coagulopathy (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 interaction and play during waking hours. It is often difficult to treat. Local measures such as nonperfumed skin creams and colloidal oatmeal bath preparations may help. If there is some bile flow, as in Alagille syndrome, cholestyramine or ursodeoxycholic 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

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3. Jackson R, Roberts EA. Identification of neonatal liver failure and perinatal hemochromatosis in Canada. Paediatr Child Health 2001;6:24850. 4. Lichtman S, Guzman C, Moore DL et al. Morbidity after percutaneous liver biopsy. Arch Dis Child 1987;62:9014. 5. Chang MH, Huang HH, Huang ES et al. Polymerase chain reaction to detect human cytomegalovirus in livers of infants with neonatal hepatitis. Gastroenterology 1992; 103:10225. 6. Wolf MJ, Beunen G, Casaer P et al. Extreme hyperbilirubinaemia in Zimbabwean neonates: neurodevelopmental outcome at 4 months. Eur J Pediatr 1997;156: 8037. 7. Roberts EA, Yeung L. Maternalinfant transmission of hepatitis C virus infection. Hepatology 2002;36:S10613. 8. Persaud D, Bangaru B, Greco MA et al. Cholestatic hepatitis in children infected with the human immunodeficiency virus. Pediatr Infect Dis J 1993;12:4928. 9. Silver MM, Hellmann J, Zielenska M et al. Anemia, blueberry-muffin rash, and hepatomegaly in a newborn infant. J Pediatr 1996;128:57986. 10. Gillam GL, Stokes KB, McLellan J et al. Fulminant hepatic failure with intractable ascites due to an echovirus 11 infection successfully managed with a peritoneo-venous (LeVeen) shunt. J Pediatr Gastroenterol Nutr 1986;5: 47680. 11. Garcia FJ, Nager AL. Jaundice as an early diagnostic sign of urinary tract infection in infancy. Pediatrics 2002; 109:84651. 12. Cantwell MF, Shehab ZM, Costello AM et al. Brief report: congenital tuberculosis. N Engl J Med 1994;330:10514. 13. Chardot C, Carton M, Spire-Bendelac N et al. Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology 1999;30: 60611. 14. Karrer FM, Hall RJ, Lilly JR. Biliary atresia and the polysplenia syndrome. J Pediatr Surg 1991;26:5247. 15. Vasquez J, Lopez Gutierrez JC, Gamez M et al. Biliary atresia and the polysplenia syndrome: its impact on final outcome. J Pediatr Surg 1995;30:4857. 16. Steele MI, Marshall CM, Lloyd RE et al. Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology 1995;21:697702. 17. Bobo L, Ojeh C, Chiu D et al. Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia. Pediatr Res 1997;41:22934. 18. Hart MH, Kaufman SS, Vanderhoof JA et al. Neonatal hepatitis and extrahepatic biliary atresia associated with cytomegalovirus infection in twins. Am J Dis Child 1991; 145:3025. 19. Tarr PI, Haas JE, Christie DL. Biliary atresia, cytomegalovirus, and age at referral. Pediatrics 1996;97:82831. 20. Schreiber RA, Kleinman RE, Barksdale EM et al. Rejection of murine congenic bile ducts: a model for immune mediated bile duct disease. Gastroenterology 1992;102:92430. 21. Stringer MD, Dhawan A, Davenport M et al. Choledochal cysts: lessons from a 20 year experience. Arch Dis Child 1995;73:52831. 22. Amedee-Manesme O, Bernard O, Brunelle F et al. Sclerosing cholangitis with neonatal onset. J Pediatr 1987;111:2259. 23. Mulberg AE, Arora S, Grand RJ et al. Expanding the spectrum of neonatal cholestatic liver disease. Hepatology 1992; 16:192A.

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.

References
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