Semin Neonatol 2002; 7:153165 doi:10.1053/siny.2002.0103, available online at http://www.idealibrary.

com on

Neonatal cholestasis
P. J. McKiernan

Liver Unit, Childrens Hospital NHS Trust, Birmingham B4 6NH, UK

Neonatal cholestasis must always be considered in a newborn who is jaundiced for more than 1421 days and a measurement of the serum total and conjugated bilirubin in these infants is mandatory. Conjugated hyperbilirubinaemia, dark urine and pale stools are pathognomic of the neonatal hepatitis syndrome which should be investigated urgently. The neonatal hepatitis syndrome has many causes and should be investigated using a structured protocol. The most important condition in the differential diagnosis is biliary atresia and affected infants require a Kasai portoenterostomy performed by an experienced surgeon, ideally before the infant is 60 days old. A modied evaluation schedule should be used for preterm infants who have required neonatal intensive care. Genetic causes of the neonatal hepatitis syndrome are increasingly recognized and early diagnosis facilitates genetic counselling and, in some situations, specic treatment. The management of cholestasis is largely supportive, consisting of aggressive nutritional support with particular attention to fat-soluble vitamin status. The use of ursodeoxycholic acid is associated with improvement in biochemical measures of cholestasis and may improve the natural history of cholestasis in some circumstances. Outcome is dependent on aetiology. In idiopathic neonatal hepatitis more than 90% make a complete biochemical and d clinical recovery.  2002 Elsevier Science Ltd. All rights reserved.

Prolonged neonatal jaundice is dened as jaundice lasting more than 1421 days. The immediate priority is to differentiate between the pathological neonatal cholestasis or unconjugated hyperbilirubinaemia which is usually benign. This article will concentrate on the investigation and general management of neonatal cholestasis with specic discussion of the most important causes. Neonatal hepatitis syndrome is dened as a state in the newborn period where, as a result of decreased bile ow, there is an accumulation of substances in the liver, blood and extrahepatic tissues which would normally be excreted in bile. Strictly speaking this implies elevated serum bile acids, but in practice it is usually dened by the presence of conjugated hyperbilirubinaemia.
Correspondence to: Dr P. J. McKiernan, BSc, MRCP, FRCPCH, Consultant Paediatrician, Liver Unit, Childrens Hospital NHS Trust, Birmingham B4 6NH, UK. Tel.: +44 121 3338254; Fax: +44 121 3338251; E-mail: Pat.Mckiernan@bhamchildrens.wmids.nhs.uk

Incidence
The population incidence of the neonatal hepatitis syndrome is approximately 1:2500 live births. The largest diagnostic groups are idiopathic neonatal cholestasis, biliary atresia and the multifactorial cholestasis seen in premature infants and those requiring neonatal surgery [1].

Pathophysiology
Bile production depends on an active process involving the transport of bile acids and other osmotic compounds across a concentration gradient into the bile canaliculus. This osmotic concentration in turn induces the passive movement of water into the canaliculus. Active transporters are localized at the hepatic basolateral membrane (for
2002 Elsevier Science Ltd. All rights reserved.

10842756/02/$-see front matter

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uptake from sinusoidal blood) and at the canalicular membrane (for biliary excretion) [2]. The major transporters at the basolateral membrane are the Na + taurocholate cotransporting polypeptide (NTCP) and organic anion transporting proteins (OATP). NTCP accounts for 80% of hepatocyte uptake of conjugated bile acids and is structurally related to the intestinal bile acid transporter expressed in the ileum. OATP are multispecic transporters which mediate uptake of unconjugated bile acids and a wide range of organic anions, steroids and drugs. Bile secretion at the canalicular membrane is mediated by the bile salt export pump (BSEP). Other important canalicular transporters include multidrug resistant proteins MRP2 (also known as cMOAT, canalicular multispecic organic anion transporter) and MDR3 which transport conjugated bilirubin and phospholipids into bile respectively. The role of these transporters in cholestatic disease processes is being increasingly recognized. Genetic defects in different transporters are recognized as the cause of a wide range of familial childhood cholestatic diseases, e.g. mutations in the gene for BSEP cause progressive familial intrahepatic cholestasis (PFIC) type 2. More surprisingly, perhaps, is the recognition of the importance of mutations in transporters causing adult onset diseases such as intrahepatic cholestasis of pregnancy (associated in some cases with mutations in the gene for MDR3) [3]. Expression of these transporters responds to liver disease and sepsis in a complex manner which acts to protect the hepatocyte from the cytotoxic effects of raised bile acid levels. NTCP and OATP expression are markedly decreased, so that bile acids and other anions are not taken up into the hepatocyte. At the canalicular level BSEP and hence bile acid excretion are relatively preserved while MRP2 expression is down regulated, which probably explains why jaundice is sometimes an early sign of sepsis. Bile ow is low in the foetus and newborn as a result of a combination of immature bile acid synthetic and transport processes. Animal studies have shown that the ntcp and bsep are present prenatally but at birth in concentrations that are well short of adult levels. The dynamics of the development process for human hepatocyte transporters have not yet been quantied, but plasma bile acids do not fall into the normal adult range until 6 months of age.

The consequences of cholestasis include bile acid retention and decreased bile production. Bile acid retention is manifest as jaundice, hyercholesterolaemia and pruritis. Decreased delivery of bile to the intestine results in malabsorption of dietary long chain fat and fat-soluble vitamins.

Presentation
This is usually with prolonged jaundice. Newborn infants have pale urine and a history of persistently yellow urine conrms the presence of conjugated hyperbilirubinaemia. The presence of pale stools is very sensitive for liver disease and even as an isolated nding should prompt immediate investigation. Acholic or white stools imply complete cholestasis with a consequently worse prognosis. An alternative presentation is with bleeding due to vitamin K deciency. This may be as bruising, even raising suspicion of non-accidental injury, or with a devastating intracranial bleed. Seizures may result from hypocalcaemia secondary to vitamin D deciency or rarely due to hypoglycaemia. The latter strongly suggests metabolic liver disease or hypopituitarism. Examination reveals hepatomegaly in most and splenomegaly in 50% of cases. Other helpful diagnostic clinical features may include stigmata of syndromic disorders, facial dysmorphic features, evidence of congenital heart disease and manifestations of intra-uterine infection such as growth retardation or thrombocytopenia. Cutaneous cavernous haemangiomata may be associated with intrahepatic haemangiomata.

Investigations
The most important step is to consider the diagnosis in what may be a well-looking infant. If doubt remains, or if any jaundice persists for more than 3 weeks, total and conjugated bilirubin should be measured urgently. An elevated level of conjugated bilirubin must be explained. The potential causes of neonatal cholestasis are summarized in Table 1. With such a wide differential diagnosis it is essential to have a structured approach to investigation (Fig. 1). The rst priority is to recognize conditions or complications requiring immediate treatment. These are summarized in Table 2. Once

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Table 1. Causes of neonatal cholestasis Bile duct abnormalities Biliary atresia Choledochal cyst Caroli disease Inspissated secretion Gall-stones Spontaneous perforation of bile ducts Neonatal sclerosing cholangitis Infections Systemic Septisaemia Urinary tract infection Hepatitic TORCH Echo, Adeno, Coxsackie-virus Human Herpes virus-6, Varicella-zoster HIV, Hepatitis B Inherited and metabolic disorders 1-Antitrypsin deciency Alagilles syndrome Galactosaemia Cystic brosis NeimannPick type C Progressive familial intrahepatic cholestasis Gauchers disease Wolmans disease Tyrosinaemia Zellwegers syndrome Carbohydrate decient glycoprotein syndrome DubinJohnson syndromedeciency in MRP2 (cMOAT) Rotor syndrome Bile acid synthetic disorders Aagenaes syndrome Endocrine disorders Hypopituitarism Hypothyroidism Hypoadrenalism Chromosomal disorders Trisomy 21, 13, 18 Turner syndrome Toxic Parenteral nutrition Chloral hydrate Foetal alcohol syndrome Vascular disorders BuddChiari syndrome Perinatal asphyxia Multiple haemangiomata Congestive heart failure Miscellaneous Familial haemophagocytic lymphohisticytosis ARC syndrome (Arthrogryposis, renal tubular dysfunction and cholestasis)

these have been excluded, the most important differential diagnosis is biliary atresia. Here it is crucial that investigations are carried out in a timely fashion so that affected children can undergo surgery as quickly as possible; while conditions which may mimic biliary atresia, for whom surgery may be harmful are excluded. It should take no longer than 1 week to complete these investigations. Subsequent third line investigations can be reserved for specic clinical circumstances or where no other aetiology has been recognized (Table 3). In some cases, particularly those referred early, a nal diagnosis may not be apparent at this stage. If doubt remains about the possibility of biliary atresia it may be necessary to reassess the situation, and if necessary repeat some of the investigations, before the age of 60 days. This schemata is appropriate for term infants only. In preterm infants the same principles of investigation apply, but surgical causes of cholestasis such as biliary atresia are very unlikely, so a different schedule of investigation is indicated (see below).

Biochemical investigations
An elevated level of conjugated bilirubin implies impairment of biliary excretion and requires evaluation. The transaminases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are normally intracellular, and raised levels are sensitive markers of hepatic inammation. However they have little individual diagnostic or prognostic value. Alkaline phosphatase is found in liver, bone and kidney. Raised levels are suggestive of biliary obstruction, but persistently high levels often suggest metabolic bone disease. Gamma-glutamyl transpeptidase (GGT) is concentrated in bile ductular epithelium. Normal ranges are age related, but elevated levels are a very sensitive marker of biliary obstruction or inammation and normal levels make biliary atresia highly unlikely. Normal levels of GGT in the presence of cholestasis implies a failure of bile excretion at canalicular level, so that detergent bile acids do not come into contact with biliary epithelium. This may occur where there are genetic bile duct transport abnormalities or where there is incipient liver failure.

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Figure 1. Flow chart for the investigation of the neonatal cholestasis in term infants. Abbreviations. T4, thyroxine, TSH, Thyroid stimulating hormone; IRT, Immunoreactive trypsin, TORCH, serology for toxoplasmosis, rubella, cytomegalovirus and herpes simplex; HBS, hepatabiliary scan; A1ATD, alpha-1-antitrypsin deciency, CF, Cystic brosis; ERC, Endoscopic retrograde cholangiography.

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Table 2. Immediate investigations in infant with prolonged jaundice Blood count Blood and urine culture Prothrombin time* Plasma urea, electrolytes and glucose Bilirubin total and unconjugated Urinalysis for reducing substances If acutely unwell plasma ammonia, glucose, lactate, acid-base, urinary pH and ketones, chest X-ray. Freeze plasma and urine for future analysis
*If abnormal, to have immediate parenteral vitamin K 1 mg. If not corrected by 6 h later this implies liver failure which should be immediately discussed with a specialized liver unit.

Hepatobiliary scanning (HBS) This is carried out using technetium labelled iminodiacetic derivatives. Best resolution is achieved if there is at least 3 days pre-treatment with phenobarbitone (5 mg/kd/d). Serial images are taken for up to 24 h or until gut activity is visualized. The major benet of HBS is the 100% sensitivity for biliary atresia, with conrmed gut excretion at any time excluding the diagnosis. Delayed excretion does not appear to have any prognostic implications. The specicity of a non-excreting scan for biliary atresia is only 60% and where an acholic stool has been seen by an experienced observer HBS adds little information. Given this poor specicity and in view of the timescale needed to organize the scan some units have abandoned HBS altogether in neonatal cholestasis. However HBS still has a role where the liver biopsy is ambiguous, and in the evaluation of preterm infants. Endoscopic retrograde cholangiography (ERC) In theory this is an attractive method to conrm suspected biliary atresia and is highly specic. In addition the procedure can be used therapeutically where cholestasis is caused by bile duct stones. However it is highly technically demanding, and even in experienced hands will only be feasible in a proportion of neonates. As a result ERC has only a minor role in the evaluation of neonatal cholestasis in most centres. Liver biopsy This is the single most informative investigation in neonatal cholestasis, with >90% diagnostic accuracy for biliary atresia in experienced hands. The diagnostic appearances of biliary atresia include bile duct proliferation, bile plugging and portal brosis, whereas in idiopathic neonatal hepatitis lobular disarray and giant cell transformation are characteristic. In addition to conventional histology a wide range of complemetary techniques are used, as appropriate, to improve diagnostic yield. These include immunostaining, histochemistry, electron microscopy and biochemical assay. With an integrated approach, liver biopsy can be diagnostic for

Radiological investigations
Chest X-ray This is indicated to assess the presence of cardiovascular and situs anomalies, which may be associated with biliary atresia, and to detect skeletal abnormalities characteristic of Alagilles syndrome.

Abdominal ultrasound Ideally this should be carried out after a 4 h fast. A small or absent gall bladder, particularly if the wall is irregular, is suggestive of biliary atresia. Conversely a normal gall bladder makes this diagnosis unlikely. However this nding is of limited accuracy and cannot be solely relied on to exclude biliary atresia [4]. Bile duct dilation is not a feature of biliary atresia. Ultrasound is a very sensitive method for recognizing other surgical causes of neonatal cholestasis, such as a choledochal cyst or to appreciate the structural abnormalities of the biliary atresia-splenic malformation syndrome. An ultrasound is mandatory prior to carrying out a liver biopsy in neonatal cholestasis as the ndings may demonstrate a need for surgical exploration irrespective of biopsy ndings. Some centres have reported that the triangular cord sign (an echogenic area in the porta hepatis) is highly specic for biliary atresia [5]. However other centres have only noted this sign in a small proportion of childen with subsequently proven biliary atresia.

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Table 3. Third-line investigations in neonatal hepatitis syndrome Circumstance Idiopatic neonatal hepatitis If elevated amino acids Signicant splenomegaly Neurological abnormality Dysmorphic features Investigations Transferrin electrophoresis, urinary bile salts Alfafetoprotein, porphobilinogen synthase and urinary succinylacetone Bone marrow aspirate Plasma very long chain fatty acids, specic white cell enzymes Karyotype

other specic conditions such as -1 antitrypsin deciency and some types of storage diseases. In addition, non specic ndings such as microvesicular steatosis are important pointers towards metabolic liver disease.

Specic disorders
Biliary atresia This is the most important differential diagnosis in the neonatal hepatitis syndrome and is the commonest cause for children requiring liver transplantation. The pace of the investigation of neonatal hepatitis syndrome is driven by the need for biliary atresia to be recognized and treated before the age of 60 days. In biliary atresia all or part of the extra hepatic biliary ducts are obliterated leading to complete biliary obstruction. In approximately 5% of cases the gall bladder and common bile duct are patent. It is aetiologically heterogeneous. Up to 25% of cases have features of the biliary atresia splenic malformation syndrome, which includes abnormalities of the portal vein and inferior vena cava, situs inversus and poly- or asplenia. The disorder occurs world-wide and has an incidence in the British Isles of 1:16 000 live births [6]. Children are usually born after a normal pregnancy and show normal early growth. In a small proportion pigment may be reported as having been seen in the stools within the rst week of life but beyond this all children have acholic stools. Hepatomegaly is invariable.
Investigations

bladder with an irregular wall. A normal gall bladder does not however exclude biliary atresia. Liver biopsy is essential, classically showing bile duct proliferation and bile plugs with expansion of portal tracts. However the liver biopsy will be ambiguous in up to 10% of cases. Radio-isotope hepatobiliary scanning has 100% sensitivity for biliary atresia but only 60% specicity. This probably adds little where stools are acholic but is useful where there is an ambiguity about the liver biopsy ndings or when the stools have not been visualized. The importance of the remaining investigations are to exclude conditions which may mimic biliary atresia in order to avoid an inappropriate laparotomy. It is mandatory that -1-antitrypsin deciency is excluded before a laparotomy is undertaken.
Management

Biochemical ndings show cholestasis with elevated GT. Coagulation is normal unless vitamin K malabsorption is present. Ultrasound after a 4-h fast usually shows an absent or small gall

The diagnosis is conrmed at laparotomy with direct cholangiography where appropriate. The denitive treatment is the Kasai portoenterostomy, in which the atretic extrahepatic tissue is removed and a Roux-en-Y jejunal loop anastamosed to the hepatic hilum. For surgery to be effective there must be some patent bile ductules at the level of the resection in the porta hepatis. Successful surgery is judged by appearance of bile in the stool and subsequently by clearance of jaundice. Factors predicting the success of surgery include the anatomical ndings, the size of bile ductules in the porta hepatis, age at surgery and the experience of the surgeon. With increased awareness of the importance of early referral in neonatal cholestasis, the only one of these factors that can be modied is the experience of the surgical centre. In a recent prospective study of biliary atresia in the British Isles, the only factor predictive of success was the caseload of the centre where sugery was undertaken [6]. Survival without liver

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transplantation was twice as likely in centres managing >5 cases yearly compared to those centres managing <5 yearly. As a result, surgery for biliary atresia in England and Wales has been concentrated in three centres. The relationship between age at surgery and successful Kasai is non-linear. Age at surgery makes little difference until after a threshold of 6080 days, and beyond this point the likelihood of success falls with time [7]. In general all children should undergo a Kasai portoenterostomy irrespective of age, unless there is evidence of decompensation at the time of diagnosis. If the Kasai is unsuccessful in clearing jaundice, almost all children will require liver transplantation before three years of age. In experienced hands, with timely surgery the Kasai should be successful, with long-term survival, in up to 70% of cases. In the British study referred to previously, where Kasai portoenterostomy was successful, 74% of children were alive with their native liver after 7 years. The great majority of these children have chronic liver disease, but this may remain compensated for many years. Standard management for cholestasis should be used and include supplementary antibiotics and fat soluble vitamins for at least the rst year of life. Post-operative complications
Ascending cholangitis

infancy but they are the second commonest surgical cause of neonatal cholestasis. Presentation is usually similar to biliary atresia, but may be suspected by the sudden onset of cholestasis or of cholangitis. An abdominal mass may be palpable. Diagnosis is usually easily established by abdominal ultrasound, and further preoperative investigations are rarely necessary. Treatment is by surgical resection of the abnormal bile ducts in combination with drainage of the proximal biliary tree into a jejunal Roux loop. Long-term outlook is excellent and normal liver function is to be expected. Later development of choledocholithiasis and pancreatitis are rare complications. Idiopathic neonatal hepatitis In 2530% of cases no specic aetiology for the neonatal hepatitis syndrome is found. These infants are more likely to have been the product of an abnormal pregnancy with frequent prematurity, intrauterine growth retardation and other abnormalities. The onset of cholestasis may be later than seen in biliary atresia and acholic stools are less common. Liver biopsy classically shows lobular disarray and giant cell transformation with relatively normal portal tracts. Prognosis is good with >90% showing clinical and biochemical resolution by age 1 year, with little risk for chronic liver disease. Adverse prognostic features include, acholic stools, biliary features on liver biopsy, rm hepatomegaly and a positive family history. There is an empirical 1% recurrence in subsequent siblings. Multifactorial cholestasis in premature infants Cholestasis is common in very low birth weight infants where the normal immaturity of biliary excretion is exaggerated. In addition they are exposed to further cholestatic insults which may include hypoxia, interrupted enteral feeds, the use of parenteral nutrition, drug toxicity and sepsis. In preterm infants the risk of biliary atresia is very low and a modied schedule of investigation is appropriate (Fig. 2). Initial investigation should focus on excluding metabolic disorders and other factors contributing to cholestasis. HBS and liver

This occurs in at least 50% of cases and presents with fever, abnormalities of liver function tests recurrence of jaundice. Blood culture is only positive in 20% of cases. Suspected cases should be treated aggressively with broad spectrum intravenous antibiotics.
Portal hypertension

More than 50% of children develop oesophageal varices, and 40% will bleed from these before 3 years of age [8]. Once variceal bleeding occurs it may be associated with a rapid deterioration in liver function and should prompt an assessment of the need for liver transplantation. Choledochal cyst These are congenital anomalies which can occur in any part of the biliary tree. Only 25% present in

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Figure 2. Flow chart for the investigation of the neonatal cholestasis in preterm infants. Abbreviations. T4, thyroxine, TSH, Thyroid stimulating hormone; IRT, Immunoreactive trypsin, TORCH, serology for toxoplasmosis, rubella, cytomegalovirus and herpes simplex; HBS, hepatobiliary scan; A1ATD, alpha-1-antitrypsin deciency, CF, Cystic brosis; USS, abdominal ultrasound; UDCA, ursodeoxycholic acid.

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biopsy should be deferred until corrected age is more than term and weight is >2 kg unless there is biliary dilation. Liver biopsy should only be undertaken where stools are acholic or a non-excreting HBS is found or where cholestasis persists beyond a corrected age of 3 months
Management

UDCA should be used in all but the mildest form of cholestasis until jaundice has resolved. Infants on parenteral nutrition should receive at least some enteral feed as this has trophic gut effects, reduces the risk of bacterial translocation and promotes bile ow. Parenteral nutrition should be discontinued as soon as possible, and while this is being achieved the regimen should be monitored to ensure that sufficient calories for growth are provided without overfeeding, and early cycling is used. Where parenteral nutrition must be continued despite cholestasis there may be a role for intermittent cholecystokinin. Prognosis is excellent so long as parenteral nutrition can be discontinued. Inspissated bile syndrome and choledocholithiasis In some infants with multifactorial cholestasis there may be an obstructive component, and rarely bile duct obstruction may occur in otherwise well infants. The distinction from multifactorial cholestasis is usually recognized by ultrasound which demonstrates the presence of stones or sludge in the biliary tree outside the gall baldder, often accompanied by proximal bile duct dilation. Finding acholic stools or a non-excreting HBS implies complete biliary obstruction. Initial management is with ursodeoxycholic acid (UDCA). If stools remain acholic, or if bile duct obstruction persists intervention will be indicated. This is usually by biliary lavage, either percutaneously or surgically. Occasionally it may be possible to remove isolated stones endoscopically. Eventual prognosis for liver function is excellent. Alpha-1-antitrypsin deciency This is the commonest inherited cause of neonatal hepatitis. -1-antitrypsin is the most abundant circulating proteinase inhibitor and acts to protect tissues by inhibiting destructive proteases. 95%

of the Northern European population are homozygous for the M allele and 23% carry the Z mutation.1:23000 are homozygous for ZZ deciency which is associated with neonatal liver disease and adult emphysema. Despite all carrying the same mutation only 15% of newborns with ZZ -1-antitrypsin deciency present clinically. The mutation changes the structure of the -1-antitrypsin molecule, interfering with its passage through the golgi apparatus resulting in less efficient hepatic excretion. The mechanism of liver disease is unclear but is related to the accumulation of the mutant -1-antitrypsin which can polymerize in vivo [9]. The development of disease in individual patients probably represents a complex balance between environmental factors which increase -1-antitrypsin production, genetic factors which regulate degradation of mutant -1antitrypsin and physical factors (such as fever) which promote polymerization.
Clinical features

This may present very similarly to biliary atresia. However children with -1-antitryspin deciency are more likely to have intrauterine growth retardation, and vitamin K responsive coagulopathy. Diagnosis is made by documenting low plasma levels and demonstrating the phenotype by isoelectric focussing.
Management

There is no specic management for -1antitrypsin deciency. The goal of treatment is to maintain growth with aggressive nutritional support. Outcome is related to the severity of the neonatal liver disease. There are four broad outcome categories. Five to 10% of children have acholic stools and behave very similarly to untreated biliary atresia, dying or requiring liver transplantation within a year. In 2030% cholestasis resolves but there is evidence of cirrhosis or progressive liver disease and children usually die or require liver transplantation within the rst 10 years of life. More than 50% of children have compensated disease; half of these become clinically and biochemically normal and half have persistent biochemical and mild clinical liver disease. By the age of 10, 40% of children will have died or required liver transplantation but 50% of children will be clinically normal. There is no increase in primary

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respiratory disease in the rst two decades of life. Advice about the importance of not smoking is essential [10].
Genetics

The condition is autosomal recessive but even within families the concordance of the severity of liver disease is approximately 70%, making prenatal counselling difficult. Progressive familial intrahepatic cholestasis (PFIC) These are a group of genetic disorders showing progressive intrahepatic cholestasis. The prototype of these disorders is Bylers disease which was originally described in the descendants of Jacob Byler, an Amish American. Since then similar phenotypes were recognized in other racial groups. Our understanding of these disorders has been transformed by the characterization of the underlying genetic defect in various hepatic transporters and all have autosomal recessive inheritance [11]. PFIC-1 This is the original Byler disease. It is caused by mutations in the FIC1 gene and appears to be an allelic disorder with benign recurrent intrahepatic cholestasis. The function of the FIC1 protein is unknown, but it is expressed in hepatocyte canalicular membranes, but also at high levels in gut, kidney and pancreas [12]. Presentation is with cholestasis in the rst months of life which may be episodic. Diarrhoea, fat-soluble vitamin deciency and recurrent pancreatitis are characteristic. Pruritis may be disabling after infancy. Serum GGT and cholesterol are normal implying failure of bile acid excretion at canalicular level. Liver biopsy shows a relatively bland cholestasis with bile duct paucity. Electron microscopy (EM) shows canalicular bile with a characteristic granular appearance.
Management

success in some centres. These results have not been seen consistently in all centres, and whether this represents regional differences in technique or reects a differing response in some genotypes is unclear. Liver transplantation is the only treatment when hepatic decompensation occurs, but may be complicated by troublesome diarrhoea post-operatively. Cirrhosis develops by the end of the rst decade and liver transplantation is usually required during the second decade. PFIC-2 Here the defect is in the canalicular bile acid transporter, BSEP [13]. The clinical and biochemical presentation is similar to PFIC-1, but without pancreatitis. Liver biopsy shows a more inammatory picture than in PFIC-1 and EM shows more amorphous bile. Treatment is similar to PFIC-1, but the prognosis is worse, with most requiring transplantation in the rst decade of life. Liver transplantation is curative in PFIC-2 as BSEP is only expressed in the liver. PFIC-3 In this distinct disorder the primary defect is in MDR3, which is a canalicular phospholipid transporter. Bile acid excretion continues, but cholangiocytes are unprotected from their detergent effect with resulting inammation and damage. Clinical presentation may be similar to PFIC-1, but is variable and may be delayed until adult life. There may be a history of maternal cholestasis of pregnancy. Investigation reveals cholestasis and high GGT. Bile analysis shows high bile acid/phospholipid ratio. Liver biopsy shows biliary features which can mimic bilary atresia, but the extrahepatic bilary tree is patent. Treatment is similar to other types, and prognosis is variable and in individual cases difficult to predict. Not all familial cholestatic disorders are included in these described PFIC subtypes. In addition it appears that other recognized entities have a clear genetic basis which has not yet been explained e.g. neonatal sclerosing cholangitis. These suggest that it is very likely that more transporter defects will be elucidated in the near future.

Standard medical management for cholestasis should be used. Surgical methods to decrease bile acid levels including partial external biliary diversion or ileal exclusion have been used with

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Bile acid synthetic disorders Bile acids are synthesized in the liver from cholesterol in a complex multistep process. The process is controlled by feedback of primary bile acids, cholic and chenodeoxycholic acid at the rate limiting step in the pathway. Where a defect in one of these steps occurs there are two consequences, rstly deciency of primary bile acids (and hence bile ow) and secondly accumulation of intermediate metabolites proximal to the block. These metabolites are usually hepatotoxic and their production continues unchecked due to the lack of feedback from primary bile acids. Presentation is similar to PFIC types with cholestasis, low GGT and fat soluble vitamin deciency. Liver biopsy usually shows an inammatory neonatal hepatitis picture. Diagnosis is made by urine fast atom bombardment spectroscopy where the abnormal excretion of bile acid precursors is demonstrated. Treatment is with cholic acid substitution. Prognosis is excellent as long as treatment is started prior to establishment of cirrhosis. Alagilles syndrome This syndrome of bile duct hypoplasia was rst described in France in the late 1960s and in Britain in the early 1970s. The incidence of this disorder is approximately 1:100 000 and has been found in all ethnic groups. The genetic basis of this disorder, which is autosomal dominant with variable penetrance, has recently been discovered. Alagilles syndrome is caused by mutations in the Jagged 1 gene which is a ligand for the notch intracellular signalling pathway. A large number of individual mutations have been described and approximately 50% of cases represent new mutations. Even within families there is great heterogeneity in clinical manifestations suggesting that factors other than the Jagged mutation are important in pathogenesis [14].
Clinical features

(iv) cardiac abnormalities; most commonly peripheral pulmonary artery stenosis but also including pulmonary valve stenosis, Fallots tetralogy, aortic stenosis and ventricular septal defects (v) ocular abnormalities including posterior embryotoxin and optic nerve drusen. Other common ndings are renal abnormalities, developmental delay, growth retardation which starts prenatally, and pancreatic insufficiency. Children usually present with neonatal cholestasis, the characteristic facies may not be easy to recognize in the newborn period. Great difficulty can occur in the differentiation from biliary atresia, particularly where the liver biopsy initially shows bile duct proliferation. The kasai procedue should be avoided as it does not improve outcome and may worsen it.
Management

This consists of aggressive nutritional and fatsoluble vitamin support. A major disabling feature for many children is pruritus. Pancreatic supplementation may be necessary.
Prognosis

Current studies suggest that the prognosis is worse than originally felt. For children presenting with neonatal cholestasis very few will show resolution of symptoms within childhood. As many as 50% will die or require liver transplantation before age 10 [15]. Liver transplantation may be indicated prior to the development of endstage liver disease as a result of severe impairment of quality of life from pruritus. Liver disease is the major cause of mortality but other contributing factors include complex congenital heart disease and intracranial bleeding. Patients with Alagilles syndrome appear highly susceptible to raised intracranial pressure, which may be a further factor contributing to a high incidence of silent visual loss.
Medical management of cholestasis

There are ve major features: (i) chronic cholestasis (ii) characteristic facies with broad forehead, recessed eyes and a small chin (iii) vertebral anomalies including buttery vertebra, curved phalanges and short ulna

There is no unequivocal evidence that any medical treatment alters the natural history of cholestasis, as opposed to the consequences of cholestasis, especially pruritis.
Ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) is a naturally occurring hydrophilic bile acid that was initially used in

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Table 4. Causes of the neonatal hepatitis syndrome which require specic treatment Condition Hypopituitarism Galactosaemia Fructosaemia Tyrosinaemia type 1 Bile acid synthetic disorders Autoimmune haemolytic anaemia with giant cell hepatitis Treatment Hydrocortisone, thyroxine growth hormone Galactose free diet Fructose free diet (2 (2 nitro-triuoromethylbenzoyl)-1,3-cyclohexenedione) NTBC Cholic acid chenodeoxycholic acid UDCA Immune suppression

the dissolution of gallstones and was observed to have benecial effects on many forms of cholestasis. The mode of action of UDCA is not completely understood but appears to have two components: (a) substitution in the bile acid pool for more hydrophobic bile acids and (b) stimulation of bile ow. UDCA has been shown to improve biochemical parameters, symptom control and slow progression of hepatic brosis in progressive familial intrahepatic cholestasis. In other neonatal cholestatic syndromes, UDCA has shown a consistent tendency for improvement in biochemical measures of cholestasis and in pruritis. My personal practice is to use UDCA as the rst line treatment for pruritis due to cholestasis, where cholestasis persists beyond 6 weeks, in parenteral nutrition associated cholestasis and in biliary atresia. The initial dose is 20 mg/kg/d in divided doses. The only common side effect is diarrhoea which usually responds to dose reduction. UDCA can be discontinued when cholestasis has resolved.
Rifampicin

but its use is limited by behavioural side effects. The recommended dosage is 35 mg/kg/d.
Cholestyramine

This acts by binding intestinal bile acids and cholesterol, thus preventing reabsorption and promoting bile acid synthesis from cholesterol. Unfortunately it is impalatable and also binds fat-soluble vitamins and other drugs. Other side effects include metabolic acidosis and constipation. It may be useful in resistant pruritis and severe hypercholesterolaemia.
Specic treatments

There are an increasing number of disorders for which specic treatment options are available. Although individually rare this makes selective screening for these disorders more important. Table 4 summarizes these disorders and their specic treatment.
Nutritional management of cholestatic infants

The mechanism of action in cholestasis is unclear, but it is known to inhibit hepatocyte bile acid uptake and induce microsomal enzymes It is indicated in the management of pruritis, but liver function should be monitored due to potential hepatotoxcicity. The recommended dose is 310 mg/kg/d.
Phenobarbitone

This has a choleretic action and induces hepatic microsomal enzymes. It has a modest effect on biochemical measures of cholestasis and pruritis,

This requires a high calorie diet containing 120 150% of the Estimated Average Requirement with an increased percentage of fat as medium chain triglyceride (MCT). It is reasonable to start with a proprietary milk such as Pregestimil or Pepti-Junior which contain 4050% of fat as MCT. Additional calorie and mineral supplements will be necessary in premature infants. In all but the mildest cases the exibility of a modular feed, in which the individual components, overall calorie density and osmolality can be manipulated, outweigh the complexity of this regime. Most infants with liver disease are initially hyperphagic and supplemental enteral

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nutrition is usually only required in those with progressive liver disease or prematurity.
Fat soluble vitamins

Large doses of oral fat soluble vitamins are needed. It is best to use individual preparations of each vitamin as this gives complete exibility for dose adjustment. Personal practice is to start with the following daily doses, vitamin K 12 mg, vitamin E 100 mg, Alphacalcidol 3050 ng/kg and vitamin A 25005000 IU. Subsequent dose adjustment should be based on blood vitamin levels or biological response. Fat soluble vitamins should be continued for at least 3 months after the resolution of jaundice as there is a delay before normal bile ow is established. References
1 Roberts EA. The Jaundiced baby. In: Kelly DA (ed.) Diseases of the Liver and Biliary System in Children, 1st edn. Oxford: Blackwell, 1999; 1145. 2 Arrese M, Ananthananarayanan M, Suchy FJ. Hepatobiliary transport: molecular mechanisms of development and cholestasis. Pediatr Res 1998; 44: 141147. 3 Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deciency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120: 14481458. 4 Farrant P, Meire HB, Mieli-Vergani G. Ultrasound features of the gall bladder in infants presenting with conjugated hyperbilirubinaemia. Br J Radiol 2000; 73: 11541158.

5 Kotb MA, Kotb A, Sheba MF, et al. Evaluation of the triangular cord sign in the diagnosis of biliary atresia. Pediatrics 2001; 108: 416420. 6 McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 2000; 355: 2529. 7 Davenport M, Kerkar N, Mieli-Vergani G, Mowat AP, Howard ER. Biliary atresia: the Kings College Hospital experience (19741995). J Pediatr Surg 1997; 32: 479 485. 8 Miga D, Sokol RJ, Mackenzie T, Narkewicz MR, Smith D, Karrer FM. Survival after rst esophageal variceal hemorrhage in patients with biliary atresia. J Pediatr 2001; 139: 291296. 9 Perlmutter DH. Alpha-1-antitrypsin deciency. Semin Liver Dis 1998; 18: 217225. 10 Francavilla R, Castellaneta SP, Hadzic N, et al. Prognosis of alpha-1-antitrypsin deciency-related liver disease in the era of paediatric liver transplantation. J Hepatol 2000; 32: 986992. 11 Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin Liver Dis 2000; 4: 753763. 12 Jacquemin E, Hadchouel M. Genetic basis of progressive familial intrahepatic cholestasis. J Hepatol 1999; 31: 377 381. 13 Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deciency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999; 117: 13701379. 14 Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999; 29: 822829. 15 Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001; 49: 431 435.