LIVER PATHOLOGY

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CHAPTER 10 LIVER PATHOLOGY

Overall approach to the pediatric liver biopsy
Handling of the liver biopsy specimen

Prolonged neonatal cholestasis

Introduction
Extrahepatic biliary atresia
Cholededochal cyst
Neonatal hepatitis
Alpha-1-antitrypsin deficiency
Cystic fibrosis
Progressive familial intrahepatic cholestasis (PFIC)
Bile acid synthesis defects
Lymphedema–cholestasis syndrome
Arthrogryposis–renal dysfunction–cholestasis syndrome
Galactosemia
Tyrosinemia
Hereditary fructose intolerance
niemann–pick disease type c
Mitochondrial cytopathies
Alpers’ syndrome (progressive infantile poliodystrophy)
Peroxisomal disorders
Paucity of intrahepatic bile ducts
Primary sclerosing cholangitis
Sepsis and total parenteral nutrition-associated liver disease
North american indian childhood cirrhosis (NAIC)
Neonatal iron overload

Investigation of hepatomegaly

Introduction
Clinical features
Glycogen storage diseases

Pediatric steatosis (the fatty liver)

Introduction
Non-alcoholic steatohepatitis (NASH)
Reye’s syndrome
Fatty acid oxidation defects
Lysosomal storage diseases

Portal hypertension

Introduction
Budd–chiari syndrome (hepatic venous outflow obstruction)

Intrahepatic bile duct dilations

Introduction
Congenital hepatic fibrosis (CHF)
Caroli’s disease

Liver infiltration

Langerhans cell histiocytosis
Familial hemophagocytic lymphohistiocytosis

Chronic liver disease

Introduction
Viral hepatitis
Hepatitis c
Wilson’s disease
Autoimmune liver disease

Acute liver failure in children
Pediatric liver tumors and tumor-like lesions

Focal nodular hyperplasia
Liver cell adenoma
Nodular regenerative hyperplasia (NRH)
Hepatocellular carcinoma (HCC)
Hepatoblastoma
Mesenchymal hamartoma of the liver
Infantile hemangioendothelioma of the liver
Undifferentiated embryonal sarcoma of the liver

Pathology of pediatric liver transplantation

Indications for liver transplantation in children
Hyperacute rejection
Acute rejection
Late acute rejection (LAR)
Chronic graft rejection
Post transplant infections
Recurrence of disease in transplant
Liver disease post bone marrow transplantation

OVERALL APPROACH TO THE PEDIATRIC LIVER BIOPSY

• Significant progress has been made in recent years in the assessment of liver dysfunction by the application of non-invasive radiological and biochemical tests and procedures

image the small but definite risk of post-biopsy complications has led to a fall in liver biopsy rate

– greatest impact in the field of inherited metabolic disease where the diagnosis may be made by other means

• Liver biopsy remains an important diagnostic procedure in the following clinical situations:

image prolonged cholestatic jaundice in infancy
image hepatomegaly/hepatosplenomegaly

– with or without other clinical features
– liver tumors
– chronic liver disease

· including transplanted livers

HANDLING OF THE LIVER BIOPSY SPECIMEN

• Detailed clinicopathological correlation is essential in order to obtain maximum information from the liver biopsy

image discussions should take place before the biopsy is submitted

• Biopsy processing and handling is generally similar to adult liver biopsies but may require additional / different testing

image eg metabolic disease

• The biopsy should be received fresh in the laboratory

image aliquot for histopathological assessment
image aliquot for freezing
image aliquot for electron microscopy

• Routine stains include:

image H&E
image PAS

– with and without diastase

image HVG
image Orcein

• Immunostaining for low molecular weight cytokeratins

image identification of bile ducts

PROLONGED NEONATAL CHOLESTASIS

INTRODUCTION

• Any infant noted to be jaundiced at 2 weeks of age should be evaluated for cholestasis

image measurement of total and direct serum bilirubin
image ultrasound examination

– principal investigation in the differentiation of extra-hepatic biliary atresia from other causes of neonatal conjugated hyperbilirubinemia

• The main differential diagnoses are:

image inspissated bile syndrome

– associated with:

· severe hemolytic anemia
· bacterial infection
· viral infections

image choledochal cyst / malformation
image extrahepatic biliary atresia
image inherited disease

– alpha-1-antitrypsin deficiency
– galactosemia
– cystic fibrosis

image paucity of interlobular bile ducts
image progressive familial intrahepatic cholestasis (PFIC)
image bile acid synthesis defects
image autoimmune primary sclerosing cholangitis
image lymphedema-cholestasis syndrome

– Aagenaes syndrome

image arthrogryposis renal dysfunction cholestatic (ARC) syndrome

• Many of these diagnoses can be made or suspected on the basis of diagnostic imaging, biochemical, microbiological, virological and genetic investigations

image liver biopsy remains the main diagnostic test for extrahepatic biliary atresia

• Striking iron overload may be a non-specific feature in a liver biopsy from a neonate with liver failure
• In infants who have been treated in neonatal intensive care units, jaundice due to episodes of sepsis and prolonged total parenteral nutrition may render interpretation of the diagnostic changes in a liver biopsy difficult
• Assessment of the liver biopsy in all of these disorders requires detailed evaluation of portal tracts

image recommended that an adequate biopsy contains >5 portal tracts.

– in practice, this is not always the case:

· if <5 portal tracts in the biopsy the pathologist should consider adding a caveat to the report

EXTRAHEPATIC BILIARY ATRESIA

Epidemiology

• 30–50% of prolonged neonatal cholestatic jaundice
• incidence of 1 : 10,000 live births
• Most frequent indication for liver transplantation in children
• Accurate prelaparotomy diagnosis can be made by liver biopsy in 90%
• Early diagnosis is essential as long-term results for portoenterostomy are closely correlated with timing of the procedure

image portoenterostomy best performed by 100 days of life

Genetics

• Biliary atresia does not appear to be a simple inherited disorder

image genetic factors likely to be important

– particularly in the embryonic or fetal form

Clinical features

• Two forms:

image Common

– >70% of cases
– infants are well at birth

· passing normally pigmented stool

– cholestastic jaundice develops between 2 and 8 weeks of age

image Embryonic or fetal form

– infants are cholestatic at birth
– more likely to be associated with other congenital abnormalities

· visceral heterotaxy ± pulmonary ciliary dyskinesia
· polysplenia syndrome
· vascular anomalies
· Turner’s syndrome
· trisomies 18 and 21
· small bowel atresia
· isolated cardiac, renal and urinary tract anomalies

Histopathological features (Figs 10.1–10.3)

• Cholestasis
• Bile plugging in cholangioles and interlobular bile ducts

image characteristic diagnostic feature

• Periportal ‘neoductular proliferation’

image ductular metaplasia of periportal hepatocytes

• Progressive fibrosis of ‘biliary’ type

image deposition of loose fibrous tissue between hepatocytes at the limiting plate leading to its irregularity

– progressive

· may be minimal in early biopsies

• Hyperplasia of the hepatic artery is a frequent concomitant feature
• Giant cell transformation of hepatocytes

image 15%

• Acute and chronic inflammation in portal and periportal areas
• Disappearance of interlobular bile ducts
image

Fig 10.1 Photomicrograph of a portal tract in extrahepatic biliary atresia demonstrating ductular proliferation, hyperplastic prominent thick-walled vessels and absent bile ducts together with cholangiolar bile plugs.

image

Fig 10.2 Photomicrograph of liver parenchyma demonstrating cholestasis and a small cholangiolar bile plug.

image

Fig 10.3 Photomicrograph of the edge of a liver biopsy demonstrating biliary fibrosis and proliferated small bile ducts.

Differential diagnoses and pitfalls

• Similar morphological appearances can be seen in alpha-1-antitrypsin (A1AT) deficiency

image serum alpha-1-antitrypsin concentration should always be measured before surgery is undertaken
image note that the characteristic PAS-positive globules of A1AT do not appear before the age of 4 months

• Inspissated cholangiolar bile plugs and paucity of interlobular bile ducts are most useful features in early biopsies

image fibrosis may not yet be marked

• Immunostaining for low molecular weight cytokeratins enhances recognition of ductular proliferation
• Ductular proliferation may also occur in total parenteral nutrition

image more focal

• Ductular proliferation is not a feature of Alagille syndrome

CHOLEDEDOCHAL CYST

• Congenital abnormality of the extrahepatic bile duct system
• 2% of infants with prolonged cholestasis

Epidemiology

• Two-thirds present before the age of 10 years

image remainder are diagnosed in adult life

– some cases up to sixth decade

• 80% are female

Clinical features

• Infants

image cholestatic jaundice
image higher incidence of associated atresia or stenosis of the biliary tree with congenital hepatic fibrosis and portal hypertension

• Older children

image features of ascending cholangitis

• Overall 3% risk of carcinoma arising in cystic dilatations of the bile duct

image <1% in first decade
image 7% in second decade
image 15% in later decades

• Preoperative diagnosis usually with ultrasound examination, cholangiography and isotope scanning
• Treatment of choice is excision of the gallbladder and dilated common bile duct and hepaticoenterostomy

Histopathological features

• Liver biopsy (Mishra et al 2007):

image in the infant

– similar features to extrahepatic biliary atresia

· intrahepatic ducts dilated

image in older children

– features of bile duct obstruction

image may be associated congenital hepatic fibrosis
• Cyst wall:

image thickened

– inflammation and fibrosis

image bile-stained
image usually no epithelial lining

– islands of columnar epithelium may be preserved
– in older patients there may be intestinal metaplasia

NEONATAL HEPATITIS

• The main histological differential diagnosis of prolonged neonatal cholestasis is neonatal hepatitis

Epidemiology

• No known etiology in >50% of neonatal hepatitis
• Recognized causes include:

image viral and other infections
image Coombs positive hemolytic anemia
image alpha-1-antitrypsin deficiency
image galactosemia
image hereditary fructose intolerance
image cystic fibrosis
image progressive familial intrahepatic cholestasis
image bile acid synthesis defects
image Niemann–Pick type C disease
image mitochondrial cytopathies
image peroxisomal disorders
image familial
image fetal thrombotic vasculopathy

– under-recognized association with perinatal liver disease
– may be associated with abnormal liver perfusion
– may recur, especially when a genetic thrombophilia is present (Ernst et al 2007)

Clinical features

• Prognosis in idiopathic neonatal hepatitis is usually good

image ‘transient neonatal cholestasis’

• Mean onset of jaundice is 7 days

image mean resolution at 3.5 months

• Hepatomegaly and liver function tests return to normal by 1 year of age
• Treatment is supportive

Histopathological features (Figs 10.4, 10.5)

• Varying degrees of cholestasis
• Giant cell transformation of hepatocytes

image due to fusion of rosette-forming hepatocytes

– often more marked in perivenular areas

• Ballooning degeneration
• Extramedullary hematopoiesis
• Intralobular and portal inflammation
• Acidophil bodies
image

Fig 10.4 Photomicrograph of liver biopsy demonstrating intralobular and portal inflammation and giant cell transformation of hepatocytes.

image

Fig 10.5 Photomicrograph of same case as illustrated in Fig 10.4 demonstrating multinucleated giant hepatocytes.

Differential diagnosis and pitfalls

• Features suggestive of an underlying metabolic disorder in a biopsy showing neonatal hepatitis are (Jevon & Dimmick 1998, Ishak 2002):

image excessive portal and lobular lymphocytic inflammation
image periportal and intralobular fibrosis
image focal cholangiolar proliferation
image paucity of bile ducts
image fatty change

– various combinations of histological features may help in distinguishing diagnoses

• Electron microscopy may show some specific features in the following:

image bile acid synthesis defects
image Niemann–Pick disease type C
image mitochondrial cytopathies
image peroxisomal disorders

– many of these disorders are associated with rapid progression to cirrhosis

ALPHA-1-ANTITRYPSIN DEFICIENCY

Epidemiology

• PiZ allele found in 1–2% of Northern European Caucasians

image highest in Scandinavian populations
image virtually absent in black and Oriental populations

• In North America homozygosity for the Z allele occurs in between 1 in 2000 and 1 in 6000 births

Genetics

• Alpha-1-antrypsin gene

image chromosome 14q31-32.3
image phenotypic expression is co-dominant
image protein resulting from expression of the Z allele accumulates in the rough endoplasmic reticulum

– may result in hepatic, lung or renal damage

Clinical features

• Up to 10% of infants with alpha-1-antitrypsin deficiency develop neonatal cholestasis

image usually resolves by 6 months of age without therapy

Histopathological features (Figs 10.6, 10.7)

• There are three distinct patterns of liver damage seen in neonatal liver disease associated with alpha-1-antitrypsin deficiency:

image indistinguishable from extrahepatic biliary atresia
image paucity of intrahepatic bile ducts
image neonatal cirrhosis

– rare

• PAS+ globules may be present, similar to adults

image note: PAS+ globules do not appear before the age of 4 months

image

Fig 10.6 Photomicrograph of liver biopsy demonstrating periportal accumulation of PAS-positive granules in alpha-1-antitrypsin deficiency in a 1-year-old child.

image

Fig 10.7 Photomicrograph of liver biopsy demonstrating immunopositive periportal alpha-1-antitrypsin granules in the same biopsy as shown in Fig 10.6.

CYSTIC FIBROSIS

Epidemiology

• 1 in 2500 births in Europe

Genetics

• Autosomal recessive

image CFTR gene 7q31.2

– protein is expressed at the apical membranes of branching hepatic bile ducts and gallbladder

image most common mutation is delta F508

– neonatal screening using serum immunoreactive trypsin and mutational analysis on Guthrie spots now in use in some countries

Clinical features

• Primarily involves the lung and the pancreas
• Up to 40% of patients develop neonatal cholestasis

Histopathological features (Figs 10.8, 10.9)

• Focal biliary fibrosis
• Cholangiolar proliferation
• Periportal fibrosis
• Dilated cholangioles
• Cholangiolar lumen contains pink to light orange concretions

image PAS positive and diastase resistant

• Macrovesicular fatty change
• Chronic inflammatory cells may be present in portal tracts
image

Fig 10.8 Photomicrograph of liver biopsy demonstrating portal fibrosis and cholangiolar proliferation in cystic fibrosis.

image

Fig 10.9 Photomicrograph of liver biopsy demonstrating dilated cholangioles containing amorphous material in cystic fibrosis.

Differential diagnosis and diagnostic pitfalls

• In infants less than 3 months of age

image may only be periportal fibrosis without cholangiolar proliferation and inspissated secretions

• In congenital hepatic fibrosis dilated ductular structures may also contain a small amount of pink to light orange material

image appears different to dense inspissated secretions of CF

• Cystic fibrosis may rarely present as non-alcoholic fatty liver disease (NAFLD; Roberts et al 2002)

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (PFIC)

• Group of rare autosomally inherited disorders of transport of conjugated bile acids into the bile canaliculus
• Severity depends on the subtype and mutation

Epidemiology

• Originally described in an Amish family

image now recognized worldwide

Genetics

• Divided into types 1, 2 and 3

image probably also other forms
image all are autosomal recessive

• PFIC1

image formerly known as Byler disease
image mutations in the ATP8B1 or FIC-1 gene chromosome 18q21-22

– codes for an ATP-ase expressed in bile duct cells and canalicular membrane

image severe progressive cholestatic disease in the Amish community
image mutations in this gene also result in benign recurrent intrahepatic cholestasis (BRIC)

• PFIC2

image mutations in the bile salt export protein (BSEP) gene ABCB11 chromosome 2q24
image codes for a protein expressed on the canaliculus

• PFIC3

image mutations in the multidrug resistance (MDR 3) gene ABCB4 chromosome 7q21
image codes for a p-glycoprotein that translocates phosphatidyl choline across the canalicular membrane.

Clinical features

• Severe pruritus
• Conjugated hyperbilirubinemia
• Low or normal levels of gamma glutamyl transpeptidase in types 1 and 2
• Serum bile acid concentrations are usually high

image decreased bile acids have also been reported in some cases

• PFIC 3 carries a high risk for hepatocellular carcinoma in young children (Knisely et al 2006)

Histopathological features (Figs 10.10–10.12)

• Variable features including:

image minimal changes of bland cholestasis
image mild bile duct proliferation
image progressive portal–portal fibrosis
image cirrhosis

• Giant cell hepatitis

image associated with PFIC2

image

Fig 10.10 Photomicrograph of liver biopsy demonstrating bridging fibrosis in PFIC2.

image

Fig 10.11 Photomicrograph of liver biopsy demonstrating ductular proliferation in PFIC2.

image

Fig 10.12 Electron photomicrograph demonstrating amorphous bile in PFIC2.

Immunohistochemical staining

• Commercial antibodies are available to BSEP and MDR3

image BSEP expression absent on canalicular epithelial cells in PFIC2
image MDR3 expression absent from bile duct epithelium in PFIC3

Electron microscopy

• Characteristic structural alterations in bile

image PFIC 1

– coarsely granular bile

image PFIC2

– amorphous or finely filamentous bile

Differential diagnosis and pitfalls

• The main clinical differential diagnosis is with inherited bile acid synthesis defects

image also cause neonatal cholestasis with normal levels of gamma glutamyl transpeptidase
image diagnosis is made biochemically
image liver biopsy in bile acid synthesis defects shows giant cell hepatitis

BILE ACID SYNTHESIS DEFECTS

Epidemiology

• Rare
• Three enzyme deficiencies are described:

image delta 4-3 oxosteroid 5-beta-reductase deficiency
image 3-beta-hydroxy delta 5-C 27 steroid dehydrogenase deficiency
image oxysterol 7 alpha hydroxylase deficiency

Genetics

• Autosomal recessive

Clinical features

• Neonatal cholestasis
• Normal gamma glutamyl transpeptidase
• Elevated bile acids in the urine
• Diagnosis is by mass spectrometry of bile acids in urine or bile

Histopathological features (Fig 10.13)

• Neonatal hepatitis
• Prominent cholestasis
• Giant cell transformation
• Extramedullary hematopoiesis
• Bridging fibrosis
image

Fig 10.13 Photomicrograph of liver biopsy demonstrating a non-specific neonatal hepatitis-like picture in 5-beta-reductase deficiency.

Electron microscopy

• Non-uniform mosaic of normal and abnormal canaliculi

image often in adjacent hepatocytes
image some show diverticula and convoluted junctional complexes

– often enclosing pockets of dense granular material

· presumed bile residue

Differential diagnosis and pitfalls

• Clinical differential diagnosis is with progressive familial intrahepatic cholestasis

LYMPHEDEMA–CHOLESTASIS SYNDROME

(Aagenaes syndrome; Drivdal et al 2006)

• Hereditary intrahepatic cholestasis with lymphedema
• Hypothesis that cholestasis is due to abnormal lymphatic function

Genetics

• >75% of cases are Norwegian

image most from a few communities in the south-western part of Norway

• Autosomal recessive

image a locus, LCS1, mapped to chromosome 15q in a Norwegian kindred

– second LCS locus may exist

• Another pedigree has been described which suggests autosomal dominant inheritance

Clinical features

• Cholestasis

image present prior to or shortly after birth

– usually improves considerably during the first two years of life
– periods of recurrent cholestasis occur later

• Lymphedema

image sometimes present at birth
image usually develops during childhood

• Prognosis for the liver disease is good

image cirrhosis has developed in about 15%

Histopathological features

• Non-specific

image cholestasis

ARTHROGRYPOSIS–RENAL DYSFUNCTION–CHOLESTASIS SYNDROME

(ARC; Bull et al 2006)

Genetics

• Mutation of the class C vacuolar protein sorting gene VPS33B

image product acts in intracellular trafficking of vesicles to the hepatocyte apical membrane

• Phenotypes associated with VPS33B mutation may include incomplete ARC

Clinical features

• Arthrogryposis, renal tubular acidosis and conjugated hyperbilirubinemia
• All have severe cholestasis

image serum gamma glutamyltransferase values are normal

• In some there are associated features:

image ichthyosis
image central nervous system malformation
image sensorineural deafness
image platelet abnormalities

Histopathological features

• Giant cell hepatitis
• May show paucity of interlobular bile ducts

GALACTOSEMIA

• Inherited defect in galactose-1-phosphate uridyl transferase (classical type)

Genetics

• Autosomal recessive

image mutations in the galactose-1-phosphate uridyl transferase (GALT) gene located on chromosome 9q13

Clinical features

• Failure to thrive, vomiting and diarrhea
• Predisposition to overwhelming E. coli septicemia
• Hemolytic anemia
• Jaundice
• Long-term neurodevelopmental complications:

image ataxia
image dyspraxic speech
image developmental delay

• Diagnosis made by demonstrating a deficiency of galactose-1-phosphate uridyl transferase in blood

Histopathological features (Fig 10.14)

• Marked steatosis
• Marked periportal cholangiolar proliferation
• Cholangiolar bile plugs
• Marked pseudoglandular transformation of liver plates
• Extramedullary hematopoiesis
• Hemosiderosis
• Long-term fibrosis

image leading to micronodular cirrhosis

• Adenomas may develop

image macroregenerative nodules on the background of cirrhosis

image

Fig 10.14 Photomicrograph of liver biopsy demonstrating marked steatosis, fibrosis and cholangiolar proliferation in galactosemia.

Differential diagnosis

• Histological features are very similar to tyrosinemia and hereditary fructose intolerance

TYROSINEMIA

• Inherited defect in fumarylacetoacetate hydrolase (type I)

Genetics

• Autosomal recessive

image mutation in the fumaryl acetoacetate hydrolase (FAH) gene chromosome 15q22-25
image particularly common in the Canadian province of Quebec

Clinical features

• Vomiting
• Diarrhea
• Failure to thrive
• Abdominal distension
• Anemia
• Bleeding
• Rickets
• Hepatosplenomegaly
• High succinylacetone level in the urine is diagnostic

Histopathological features (Figs 10.15, 10.16)

• Fatty change
• Cholestasis
• Pseudoacinar transformation of liver cell plates
• Pericellular and periportal fibrosis
• Hemosiderosis
• Extramedullary hematopoiesis
• Regenerative nodules
image

Fig 10.15 Photomicrograph of liver biopsy demonstrating steatosis, pseudoacinar transformation and extramedullary hematopoiesis in tyrosinemia.

image

Fig 10.16 Photomicrograph of liver biopsy demonstrating hemosiderosis in tyrosinemia (Perl’s stain).

Differential diagnosis

• Histological features are very similar to those seen in galactosemia

image periportal cholangiolar proliferation is less striking in tyrosinemia than in galactosemia

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