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Neonatal Liver Biopsy
Dr Claire Bowen
Consultant Paediatric Pathologist
Topics Covered
• Neonatal jaundice• Indications for biopsy• Handling of biopsy in the laboratory• Histological assessment of the liver biopsy• Patterns of liver disease with examples
– Biliary atresia– A1AT– Cystic fibrosis– Neonatal hepatitis– Metabolic
Neonatal Jaundice• Common
– 60% term and 80% of preterm babies develop jaundice in first week of life
– 10% breast fed babies still jaundice at 1 month• Usually harmless
– High concentrations of conjugated hyperbilirubinaemia can cause permanent brain damage (kernicterus)
• Prolonged jaundice can be a sign of underling serious liver disease (conjugated bilirubinaemia >25 umol/L)
• Early recognition and prompt treatment essential– Phototherapy– Kasai portoenterostomy– Metabolic screening– Transplant
Indications
Biopsy indicated• Conjugated
hyperbilirubinaemia– Jaundice persisting
beyond 2 weeks (3 weeks in preterm babies)
– Dark urine– Pale stools
• Total parenteral nutrition in the context of intestinal failure
• Assessment of rejection post-transplant
• Tumour
Biopsy not indicated• Unconjugated
hyperbilirubinaemia – Physiological– Sepsis– Haemolysis
• Liver failure– Coagulopathic– Limited contribution to
aetiology– Usually see explanted
liver
Handling
• Procedure risk - general anaesthetic, bleeding
• Need maximum amount of information from biopsy
• Light microscopy
• Snap frozen tissue for metabolic cases
• Electron microscopy for storage disorders
• Dry tissue for copper
H&E• Number and size of tissue cores• Portal tracts
– Number– Presence/absence of bile ducts– Bile duct proliferation– Inflammation– Fibrosis
• Parenchyma– Giant cell transformation– Rosetting of hepatocytes– Haematopoiesis– Storage cells
• Central veins– Vascular flow abnormalites– Inflammation in rejection
Special stains
• Connective tissue stains to assess fibrosis– EVG – mature fibrosis/pericellular fibrosis
– Reticulin – cell plates, acute collapse
– Trichrome – tends to overestimate fibrosis
• Orcein - Copper associated protein and Hep B
• Perls to assess iron
• PAS/DPAS – glycogen, storage cells and Alpha-1-Antitrypsin globules
Van Gieson
Reticulin
Orcein
Perls
DPAS
Histological patterns
1) Biliary Features
• Fibrosis– Fibrous portal tract expansion– Bridging fibrosis– Lobular pattern of cirrhosis
• Ductular proliferation• Ductular bile plugging• Periportal copper-associated protein• Variable giant cell change• Haematopoiesis
Differential diagnosis
• Extrahepatic biliary atresia
• Alpha-1-antitrypsin (mimic)
• Total parenteral nutrition
• Cystic fibrosis – eosinophilic secretions in bile duct and fatty change
Biliary Atresia
• Rare - 1 in 17000 in UK• Presents in first few weeks• 50 cases a year with normal antenatal scans• 20% other anomalies (cardiac, polysplenia)• Lumen of biliary tree obliterated with
obstruction to bile flow• Progressive liver damage – cirrhosis• 5 categories of postulated aetiology –>
Inflammatory, Developmental, Vascular, Environmental and Viral
Alpha-1 Antitrypsin
• Defective A1AT protein• Defective production of A1AT leading to
decreased A1AT activity in the blood and lungs• Deposition of excessive abnormal A1AT protein in
liver cells. • Mimics – Can see biliary pattern or giant cell
pattern• PAS positive globules within hepatocytes – not
identified in first 3 months• Immuno for A1AT
Cystic Fibrosis
• Liver disease 5% in CF patients
• Fibrosis
• Cholestatsis
• Fatty change
• Biliary features
• Mucin in bile ducts characteristic but not always seen
2) Neonatal / giant cell hepatitis
• Largely normal portal tracts• Hepatocyte disarray and collapse• Florid giant cell change• Rosetting of hepatocytes• Cholestasis• Extramedullary haematopoiesis• May see storage cells• Not usually fibrotic
Differential diagnosis
• Idiopathic with spontaneous recovery• Infection• Metabolic• Storage• A1AT
3) Paucity of bile ducts
• Bile duct proper lacking
• Need at least 10 portal tracts (1 in 10 miss bile duct normally)
• Abberent periportal cytokeratin 7 expression– Normally stains biliary epithelium– Stains periportal hepatocytes where there is
duct loss
Differential diagnosis
• Syndromic– Alagilles syndrome
• Non-syndromic– CMV infection– A1AT– Cystic fibrosis– Chronic rejection
Alagille syndrome
• Characteristic facial features – triangular face• Heart problems• Bile ducts seen in early biopsies• Progressive bile duct loss/absence• Fibrosis• Abberant Cytokeratin 7 staining in periportal
hepatocytes
Early features
Late Features
4) Bland cholestasis
• Canalicular cholestasis
• No ductular reaction or bile plugging
• Minimal parenchymal changes
• +/- Fibrosis
Pitfalls in children
• Copper-associated protein present in babies up to 3 months (periportal)
• Small amounts of periportal iron present at birth
• Fat not generally seen, metabolic conditions should be considered
• Hepatocyte plates 2 cells thick until 5/6 years
• Erythropoiesis stops approx. 36 weeks gestation
Neonatal Haemochromatosis• Severe form of iron
overload• Starts to accumulate in
utero - can cause fetal death
• Liver failure• Massive necrosis –
collapse• Iron +++• Usually diagnosed on lip
biopsy – iron storage in salivary glands
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