Liver Biliary System and Gallbladder

IDIOPATHIC NEONATAL HEPATITIS

outcome in two thirds of cases ●● Mild inflammation, mild fibrosis ●● Cholestasis in hepatocytes/canaliculi ●● Diagnosis of exclusion

EXTRAHEPATIC BILIARY ATRESIA (EHBA)

●● Conjugated hyperbilirubinemia in neonate/young infant

●● Sclerotic-inflammatory process resulting in obstruction of part/entire extrahepatic biliary tree

●● Most frequent indication for liver transplant in children

●● Etiology unknown; hypothesis-viral/toxic/ immune/malformative

●● Treatment: Biliary drainage (Kasai portoenterostomy) crucial before 60 days of age

inflammation ●● Bile duct/ductular proliferation, bile stasis

in bile ducts, bridging fibrosis/cirrhosis ●● CBD (common bile duct) shows fibrosis and

pinpoint lumina ●● Depleted epithelial lining, epithelial nests

in duct walls ●● Gallbladder may be diminutive/fibrosed

SYNDROMIC BILE DUCT PAUCITY: ALAGILLE SYNDROME

●● NOTCH2 mutations identified in small subset of patients

portal tract is = 0.5 (normal BD/PT ratio = 0.9-2.0)

●● Characteristic facial features: Triangular face, prominent forehead, deep-set eyes, hypertelorism

●● Cardiac murmur, ocular posterior embryotoxon, and butterfly vertebrae

●● Clinical features due to liver disease: Neonatal jaundice in most, persistent jaundice, hepatosplenomegaly, increased serum bilirubin, portal hypertension, hepatic failure

and presence of proliferating cholangioles at periphery of liver lobules (CK7+ve)

●● Paucity of ducts, cholestasis, bile plugs, giant cells, micronodular cirrhosis

age ●● Remote risk of hepatocellular carcinoma

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (PFIC)

●● Severe genetic cholestatic abnormalities of earlier life

mation, canalicular/cytoplasmic cholestasis, central lobular fibrosis

PFIC-1 (ATP8B1): Byler disease

pholipids ●● Normal or low GGT, elevated bile acids ●● Diarrhea, asthma, pancreatitis, hearing

impairment

PFIC-II-(ABCB 11)

noma

intrahepatic cholestasis of pregnancy

BENIGN RECURRENT NONPROGRESSIVE CHOLESTASIS IN BRIC

BILE ACID SYNTHESIS DEFECTS

acids ●● Enzyme defects on sterol nucleus (early in

life): 3β-Hydroxy δ − C27 steroid dehydrogenase, Δ 4-3-oxosteroid 5β-reductase

non-specific hepatitis ●● Mass spectrometric analysis of urine bile

acids

FAMILIAL CHOLESTASIS: NORTH AMERICAN INDIAN CIRRHOSIS

●● High GGT transient neonatal jaundice progressing to biliary cirrhosis

fold protein)

tion pneumonia) ●● Ciliated foregut cyst: Subcapsular, lined by

pseudostratified ciliated epithelium, portal hypertension, and abdominal pain

CHOLEDOCHAL CYST OF BILE DUCT

●● Clinical triad of pain/jaundice/right upper quadrant mass

●● Segmental cystic dilatation of intra-/extrahepatic bile ducts

tive tissue cyst wall, chronic inflammation, no residual smooth muscle

CAROLI DISEASE

●● Multiple segmental cystic/saccular dilatations of large intrahepatic bile ducts (continuity with biliary tree)

●● Occasional familial cases (no gene identified)

giocarcinoma

CONGENITAL HEPATIC FIBROSIS (CHF)

tric arrangement of bile ducts ●● Expanded/fibrotic portal region ●● Portal hypertension, esophageal varices

for Cu estimation ●● Histology indicates a possible metabolic dis-

order = steatosis, steatohepatitis, storage cells ●● Immunohistochemistry, EM = confirm the

diagnosis ●● Early diagnosis crucial = treatable condi-

tion/family counseling/sibling assessment

DISORDERS OF CARBOHYDRATE METABOLISM

Glycogen storage disease

●● Metabolic disorders with specific enzyme defects, accumulation of normal/abnormal glycogen within cells

●● Type I (von Gierke disease): Hepatocytes distended by glycogen, obliteration of sinusoids, mosaic pattern/glycogenated nuclei

mic distension by glycogen, uniform mosaic pattern

of fibrillary material, glycogen/tubules ●❑ Hepatocytes with pale hyaline inclu-

sions surrounded by indistinct halos resembling Lafora bodies

extracted

Galactosemia

transferase ●● Located on GALT gene ●● Impaired conversion of galactose into glucose ●● Canalicular/hepatocellular cholestasis,

pseudo acinar formation, steatosis, bile duct proliferation, fibrosis/cirrhosis

●● Similar histology in tyrosinemia and fructosemia

Tyrosinemia

hepatopathies ●● If chronic, micronodular cirrhosis ●● Long-term risk for HCC ●● Liver transplantation recommended soon

after diagnosis

Fructosemia

LYSOSOMAL DISORDERS

Gaucher disease

tension ●● Gaucher cells in liver with striated cyto-

plasm (like wrinkled tissue paper)

●● EM: Membrane-bound inclusions, twisted tubules in Kupffer cells

Niemann pick disease

cells/hepatocytes ●● EM: Myelin figures in Kupffer cells/

hepa tocytes

Wolman and CESD

Wolman disease

●● Generalized accumulation of foam cells, calcification of adrenal glands, fatal in early life

CESD

Mucopolysaccharidosis

and Kupffer cells ●● Stored material positive with colloidal iron ●● EM: Cholesterol clefts and fibrosis

Mucolipidosis (I cell disease, sialidosis, pseudo-Hurler disease)

culent material

Oligosaccharidosis

●● Deficiency of sialidase, mannosidase, fucosidase

granular material

Metachromatic leukodystrophy

macrophages, hepatocytes, and Kupffer cells

●● Gallbladder has thick mucosa, fine cobblestone/papillary surface

●● Papillary fronds lined by columnar epithelial cells, amphophilic cytoplasm

●● EM: Lysosomal inclusions with closely packed herringbone appearance

Farber (lipogranulomatosis)

inclusions

Gangliosidosis

A deficiency ●● Sandhoff disease (GM2) = hexosaminidase

A and B deficiency ●● Zebra bodies; concentric membrane-bound

lysosomal inclusions

Fabry disease

sions with lamellar/concentric patterns

BILE ACID METABOLISM DISORDERS

chronic hepatitis in older children ●● Treatment is bile acid substitution

PEROXISOMAL DISORDERS

Zellweger syndrome (cerebrohepatorenal syndrome)

abnormalities, psychomotor defects, renal cortical cysts, liver abnormalities

●● Mutation of genes involved in peroxisome biosynthesis

●● Absence of peroxisomes in hepatic/renal tubular cells

IRON STORAGE DISEASE

increased body iron

Primary (hemochromatosis)

●● Gene mutations (HFE gene on chromosome 6)

●● Disordered regulation of iron absorption by intestines

●● Cirrhosis of liver, diabetes (iron deposition in pancreas), congestive cardiomyopathy (iron deposition in myocardium), hypermelanosis of skin

●● High risk of HCC, prevented by early treatment (phlebotomy)

●● Iron deposited in hepatocytes, biliary cells, and Kupffer cells

Secondary overload (hemosiderosis)

●● Transfusion induced (children with hemoglobin disorders)

Neonatal iron storage disease

cells ●● Metabolic error, high recurrence rate in

subsequent pregnancies ●● Iron deposits in minor salivary glands = oral

mucosa biopsy for diagnosis

WILSON DISEASE

●● Gene (ATP7B) encodes ATPase-dependent copper transporter

ration into ceruloplasmin ●● Serum ceruloplasmin decreases, serum Cu

variable

early ●● Hepatocytes with ballooning, decreased

cytoplasmic eosinophilia, glycogenated nuclei, apoptotic bodies, finely granular cytoplasm, hepatocyte necrosis/ultimately cirrhosis

●● Rhodamine/orcein biochemical stains highlight copper in periportal hepatocytes

●● EM: Lysosomal copper deposits in hepatocytes

FATTY ACIDS OXIDATION DEFECTS

Carnitine deficiency

●● Recurrent episodes of Reye-syndrome-like illness and similar hepatic histology

Acyl-CoA-dehydrogenase deficiency

●● Glutaric aciduria, acidosis, non-ketotic hypoglycemia, multiple congenital malformations, panlobular steatosis, and portal fibrosis

PORPHYRIAS

●● Disorders of porphyrin and heme biosynthesis

UREA CYCLE DISORDERS

(Xp21.1), citrullinemia ●● Non-specific morphological changes

●● Associated with several metabolic/nutritional disorders

●● Childhood obesity and type II diabetes; non-alcoholic fatty liver disease (NAFLD).