LIVER PATHOLOGY

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

Related posts:

  1. METABOLIC DISEASE PATHOLOGY
  2. BONE PATHOLOGY
  3. DERMATOPATHOLOGY
  4. RENAL PATHOLOGY

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Jun 18, 2016 | Posted by in PEDIATRICS | Comments Off on LIVER PATHOLOGY

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