• Cholestasis: conjugated bilirubin ≥25 micromol/L and/or ≥20% of total bilirubin
• Acute liver failure with raised transaminase and coagulopathy unresponsive to vitamin K

• Not all liver dysfunction in preterm babies is caused by parenteral nutrition. Extra-hepatic biliary atresia does occur and must be diagnosed and managed in a timely fashion

• Pale or acholic stools
• Dark urine
• Prolonged jaundice (defined as visible jaundice at day 14 in term and day 21 in preterm babies)
• Bleeding, including intraventricular haemorrhage from vitamin K deficiency
• Green jaundice on any day of life
• Acute collapse with liver failure
• Hypoglycaemia

First line investigations

• Complete the following as soon as possible:
  • FBC and film
  • coagulation screen
  • blood gas – glucose and lactate
  • transaminases, including ALT, AST, bilirubin (total and conjugated), albumin, gamma GT, and alkaline phosphatase, LDH, AFP, ferritin
  • albumin
  • galactosaemia and tyrosinaemia screen
  • alpha-1 antitrypsin concentration and phenotype
  • serum cortisol, T4 and TSH
  • stool in opaque pot for consultant review
  • urine for MC&S
  • abdominal ultrasound scan, after 4 hr fast if possible, to include liver and gallbladder examination
  • if clinical suspicion high toxoplasma serology, CMV IgM or urine PCR for CMV, syphilis serology, viral culture from swabs of any vesicles for herpes simplex, hepatitis E serology 
  • if metabolic disorder suspected, plasma lactate, plasma and urine amino acids, and urine organic acids, ammonia
  • discuss with biochemistry before sampling (transport may need to be arranged)

• Follow advice of liver team
• Standard aggressive protocol used to investigate term babies is inappropriate in preterm babies due to:
  
  • insufficient blood volume for blanket testing
  • poor temperature control when attending for isotope scans
  • limited size increases risk of liver biopsy
• Transfer to specialist centre often not possible owing to need for ongoing respiratory support and neonatal nursing care
• Preterm babies with diagnoses requiring surgery (e.g. Kasai procedure for biliary atresia) need to be around 2 kg before surgery performed but liver team should be informed in advance of baby reaching this weight
• Early isotope scanning not widely available and of limited value, many babies can be investigated without this procedure – follow advice of liver team 
• Assessment of stool colour can determine which babies with cholestasis require urgent further investigation, as shown below:

Investigations for ongoing liver dysfunction

• If indicated by results of first line investigations or progressive dysfunction and on advice of liver team: 
  • ophthalmic review (other than for retinopathy of prematurity)
  • micro-array for dysmorphism
  • karyotype
  • very long chain fatty acids for neurological abnormality
  • urinary bile salts
  • other congenital infections screen
  • isotope scan, liver biopsy or bone marrow aspirate

• Surgical correction, if appropriate (e.g. Kasai, choledochal cyst), usually when around 2 kg, discuss individual cases with liver unit team

Nutrition

• Seek nutritional review and ongoing nutritional advice from neonatal/liver dietitian 
• If baby acutely unwell stop all enteral feeds until galactosaemia excluded. Otherwise, continue mother’s own breast milk, as available, +/- breast milk fortifier or preterm or term formula (as appropriate) while baby achieves adequate growth velocity

Babies with faltering growth

Concentrated Aptamil® Pepti Junior (16%)

• Add 4 level scoops Aptamil® Pepti Junior to 100 mL of cooled, boiled water and mix well
• Store in fridge until use, discard unused feed after 12 hr 
• Per 100 mL: 79 kcal, 2.16 g protein, 1 mmol sodium
• If conjugated bilirubin >50 and baby not receiving parenteral lipid >10 mL/kg/day start fat soluble vitamins in doses below:
  • vitamin K: 300 micrograms/kg oral (IV if acute liver failure) daily: monitor PT and APTT
  • vitamin A: 1000 units/kg (rounded to nearest 1000 units) 
  • ergocalciferol 400–800 units/kg/day
  • vitamin E: alpha-tocopherol 10 mg/kg/day 
• DO NOT give ABIDEC or Dalavit alongside fat soluble vitamins A, D, E, K

Ursodeoxycholic acid

• 10 mg/kg twice daily

Parenteral nutrition

• Wherever possible, feed enterally, as even small amounts have trophic effects on gut, reduce bacterial colonisation and promote bile flow
• Bolus feeds promote bile flow more readily than continuous feeds, but the latter may be better absorbed
• Refer to neonatal/paediatric or network dietitian for advice in babies who fail to make enteral progress
• If direct bilirubin >50 micromol/L, consider switching to SMOF lipid 
• Discontinue PN as soon as possible in all preterm babies with cholestasis

Specific treatments

• Babies with cystic fibrosis, galactosaemia, tyrosinaemia type 1, hypopituitarism, hypothyroidism or bile acid disorders require additional targeted management and life-long follow-up shared by local teams and appropriate specialists

• For babies with persistent cholestasis, arrange outpatient follow-up with liver team after discharge from NNU
• If liver dysfunction has resolved, no follow-up with liver team necessary
• For all others with a specific diagnosis, follow-up will be directed by liver team, appropriate specialists and local consultant
• Long-term hepatic outcome for multifactorial preterm or neonatal hepatitis is excellent, majority resolve within first year