Liver and Biliary Tract
Pathology
Congenital Disorders:
Extrahepatic Biliary Atresia
• Most common cause of pathologic infant jaundice;
common reason for pediatric liver transplantation
• Definition: total or partial loss of permeable bile ducts
between porta hepatis and duodenum
• Typically presents with symptoms at 1-2 months of age
• Stenotic or atretic portions of extrahepatic biliary tree
cause chronic extrahepatic large duct obstruction
• Infectious or autoimmune etiology
• Positive stains: CD56
• Molecular: 10% have mutations in Jagged 1 gene
(associated with Alagille’s syndrome)
• Marked cholestasis with intrahepatic bile duct
proliferation, fibrosis, and cirrhosis. This liver was
rock hard. The dark green color comes from
formalin acting on bile pigments in the liver from
marked cholestasis, turning bilrubin to biliverdin.
• Microscopically, extrahepatic biliary atresia
leads to this appearance in the liver, with
numerous brown-green bile plugs, bile duct
proliferation (seen at lower center), and
extensive fibrosis.
Congenital Disorders:
Polycystic liver disease
• Autosomal dominant, associated with autosomal
dominant polycystic kidney disease (71-93%)
and defect in ADPKD1 gene on #16
• Cysts don’t communication with biliary tree
• 80% occur in females
• 1-7% risk of adenocarcinoma if coexisting
Caroli’s disease; otherwise extremely rare
• Complications: infection, cholangiocarcinoma,
squamous cell carcinoma
• Gross: multiple variably sized unilocular cysts,
liver rarely is massively enlarged
• Numerous cysts appear in this liver from a
patient with dominant polycystic kidney disease
(DPKD). Less commonly the pancreas is
involved. These patients with DPKD can also
have berry aneurysms in the cerebral arteries.
von Meyenburg complex
• Also called bile duct hamartoma or
microhamartoma
• Incidental finding in 6% of adults and 1% of
children at autopsy.
• Associated with autosomal dominant polycystic
hepatorenal disease, congenital hepatic fibrosis
and Caroli’s disease
• Rarely associated with neoplastic transformation
to hyperplasia, adenoma and cholangiocarcinoma
• Positive stains: mucin (variable)
Gross: single or multiple
(20% have 4+ nodules) well
circumscribed nodules,
subcapsular, gray-white,
occasionally green; often
less than 5 mm
Micro: periportal small
clusters of modestly dilated
bile ducts, often angulated,
in fibrous stroma; may
contain intraluminal bile;
epithelial cells are bland;
usually no/minimal
inflammatory infiltrate, no
atypia
Metabolic diseases:
Alpha-1-antitrypsin deficiency
• Autosomal recessive disease, causing low serum levels of
alpha-1-antitrypsin (AAT), and leading to emphysema (80%) and
liver disease
• AAT is a small, 394 amino acid, plasma glycoprotein,
synthesized predominantly by hepatocytes, encoded by a gene
on #14
• AAT is a protease inhibitor (Pi), which inhibits neutrophilic
elastase released at sites of inflammation; also inhibits trypsin
• Although there are 75 AAT forms, PiMM (normal phenotype) is
present in 90% of population
• PiZZ: 1 per 7,000; have 10-15% of normal AAT levels, are at
high risk for clinical disease, but only 10% get clinical disease
• PiZZ: hepatic syndromes range from neonatal hepatitis (10%),
biliary atresia (intra- or extrahepatic), fibrosis, childhood
cirrhosis; 2% develop hepatocellular carcinoma
• PiMZ: intermediate plasma levels of AAT
• Pi-null: rare variant with no detectable serum AAT
• Pi-S: low serum AAT but no disease
Alpha-1-antitrypsin deficiency
• AAT deficiency variants: secretory protein does not
move from endoplasmic reticulum to GolgiDiagnosis:
serum protein electrophoresis; liver biopsy to determine
extent of histologic damage
• Treatment: liver transplantation,
• Micro: round to oval cytoplasmic eosinophilic globular
inclusions in periportal hepatocytes; rare Mallory bodies
and fatty change; also hepatocellular degeneration, giant
cell formation, cholestasis and cholangitis, portal fibrosis
and cirrhosis
• Positive stains: AAT immunostains; inclusions are
strongly PAS+ and diastase resistant
• EM: granular material in dilated endoplasmic reticulum
• The periportal red hyaline globules seen here with
periodic acid-Schiff (PAS) stain are characteristic for
alpha-1-antitrypsin (AAT) deficiency.
Cystic fibrosis
• Most common lethal genetic disease in US of whites affects 1 per 2000-4500 newborns
• 1 in 20 in US are carriers; most common mutation is
#708 of protein that regulates chloride ion transport on
Ch 7 (seen in 70% with disease)
• Mutations cause reduced chloride ion in secretions,
thicker respiratory secretions, upper respiratory
infections, late pancreatic insufficiency; also cause
defective cilia and infertility, meconium ileus (5-10%),
intussusception
• May present as neonatal cholestasis, although most
patients have no clinical evidence of liver disease
• Micro: macrovesicular steatosis, focal biliary cirrhosis
(focal findings of inspissated granular eosinophilic
material within portal bile ductules, chronic inflammatory
infiltrate in portal tract, bile duct proliferation), cirrhosis
(10% by age 25)
Hemochromatosis
• Excessive accumulation of iron, usually deposited in liver, pancreas
and heart
• Either primary or secondary
• Normal iron pool is 2-6 gm with 0.5 g in liver and 98% of that in
hepatocytes
Primary hemochromatosis
• Autosomal recessive disorder of excessive iron storage; may
exceed 50g in liver (normal 2-6 g)
• Most common single-gene disorder in whites, 80 % males
• Mutation on transferrin receptor binding protein HFE on 6p
• Common mutation (83% of primary cases) is cysteine to tyrosine at
amino acid 282 (C282Y), which inactivates the protein and causes
excess iron absorption of 3-4 mg/day vs. 1-2 mg/day normal;
• Normal HFE down regulates transferrin; loss of HFE causes up
regulation of transferrin. Excessive iron is directly toxic, due to lipid
peroxidation, stimulation of collagen, interactions of iron with DNA
Hemochromatosis
• Symptoms: after accumulation of 20 g of iron;
usually age 40+; primarily micronodular cirrhosis
diabetes mellitus and skin pigmentation; also
hemosiderin deposition in myocardium, pituitary,
adrenal, thyroid, parathyroid gland, joints, skin;
eventually cirrhosis and pancreatic fibrosis;
• High risk for hepatocellular carcinoma
• Gross: dark brown liver
• The dark brown color of the liver, as well as the pancreas
(bottom center) and lymph nodes (bottom right) on
sectioning is due to extensive iron deposition in a middleaged man with hereditary hemochromatosis
• The hepatocytes and Kupffer cells here are full
of granular brown deposits of hemosiderin from
accumulation of excess iron in the liver.
• A Prussian blue iron stain demonstrates the blue granules of
hemosiderin in hepatocytes and Kupffer cells. Note that there is
also cirrhosis. Excessive iron deposition in persons with HH can
affect many organs, but heart (congestive failure), pancreas
(diabetes mellitus), liver (cirrhosis and hepatic failure), and
joints (arthritis) are the most severely affected.
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Wilson’s Disease
(Hepatolenticular degeneration)
Autosomal recessive disorder causing accumulation of toxic levels of copper in
tissues/organs, usually liver, brain, eye
The gene for Wilson’s disease is ATP7B on Ch 13q, which encodes a
transmembrane copper-transporting ATPase which assists with copper excretion
into bile; copper accumulates within the liver causing liver injury
By age 5 years, nonceruloplasmin-bound copper causes acute or chronic liver
disease, hemolytic anemia, deposition in putamen with frank psychosis or
Parkinsonian symptoms, deposition in cornea, kidneys, bones, joints,
parathyroid gland; also increased urinary excretion of copper (which is normally
minimal)
Treatment: long-term copper chelation therapy with D-penicillamine; liver
transplantation
Micro: liver - fatty change with vacuolated nucleus (due to glycogen or water),
focal hepatocyte necrosis; an acute or chronic hepatitis;chronic hepatitis may
have Mallory bodies; cirrhosis develops
Fulminant hepatitis: liver collapse with abundant lipofuscin due to degraded
membrane fragments; remaining liver shows low-grade disease with fibrosis
brain - injury to putamen in basal ganglia
eye - Kayser-Fleischer rings (green to brown deposits of copper in Descemet’s
membrane in limbus of cornea)
• Rhodanine stain for copper
Viral Hepatitis:Acute
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Hepatotropic viruses(A,B,C,D,E and G), EBV,CMV,HSV, yellow fever,
HIV
In children: rubella, adenovirus,enterovirus
Phases: incubation, symptomatic preicteric, symptomatic icteric,
convalescence
Micro:
irregular hepatic plates due to variability in hepatocyte size and
inflammatory cells; hepatocyte necrosis
portal and lobular lymphocytic inflammation and regenerative activity;
hepatocyte death via apoptosis
ballooning degeneration or cytolysis (collapse of reticulin network where
cells have disappeared with appearance of lymphocytes or macrophages)
infiltrate is usually lymphocytes, most prominent in lobules, then spills over
into periportal hepatocytes (interface hepatitis)
in resolving phase, portal lymphocytes and plasma cells are present with
minimal lobular inflammation
Kupffer cells contain hemosiderin and lipofuscin
• Grossly, there are areas of necrosis and
collapse of liver lobules seen here as illdefined areas that are pale yellow.
• At high magnification, the hypercellularity in acute viral hepatitis is
noted to be due to infiltration of the hepatic sinusoids by an acute,
as well as chronic, inflammatory cellular infiltrate and Kupffer cell
hypertrophy and hyperplasia. The hepatic cords are also disrupted
with evidence of both hepatocyte necrosis and ongoing hepatocyte
regeneration. Regenerating hepatocytes are large, frequently
containing multiple nuclei.
• A large pink cell undergoing "ballooning degeneration" is seen
below the right arrow. At a later stage, a dying hepatocyte is seen
shrinking down to form an eosinophilic "councilman body" below the
arrow on the left.
Chronic Viral Hepatitis
• Diagnosis requires symptomatic, serologic or biochemical evidence
of continuing or relapsing hepatic disease of 6 months or more, with
histologically documented necrosis and inflammation
• Etiology (hepatitis C > hepatitis B) is the most important predictive
factor for chronic hepatitis; clinical features are not predictive
• Symptoms: spider angiomas, palmar erythema, mild
hepatosplenomegaly, hepatic tenderness, increased prothrombin
time and partial thromboplastin time, vasculitis due to immune
complex deposition (HBV, HCV), glomerulonephritis,
cryoglobulinemia (35% of HCV)
• Micro: predominantly lymphocytic portal infiltrate with less lobular
involvement than acute hepatitis; may have piecemeal necrosis and
fibrosis
• In this image of liver from a patient with chronic hepatitis
due to hepatitis B virus, a chronic inflammatory infiltrate
is seen that is limited to the portal area. It does not
extend into the adjacent lobule
Chronic hepatitis - grading /
staging
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Grade: degree of inflammation, piecemeal or bridging necrosis
Grade 0: no / minimal inflammation
Grade 1: portal inflammation or lobular inflammation without necrosis
Grade 2: mild periportal inflammation and piecemeal necrosis or focal
hepatocellular necrosis
Grade 3: moderate periportal inflammation and piecemeal necrosis or
severe focal cell damage
Grade 4: severe periportal inflammation and piecemeal necrosis or bridging
necrosis
Stage: degree of fibrosis
Stage 0: no fibrosis
Stage 1: enlarged fibrotic portal tracts
Stage 2: periportal fibrosis or portal to portal septa, without architectural
distortion
Stage 3: bridging fibrosis with architectural distortion, no obvious cirrhosis
Stage 4: cirrhosis (probable or definite)
• CMV hepatitis: hepatocytes with large, eosinophilic to
amphophilic nuclear inclusions surrounded by a clear
halo, and cytoplasmic inclusions consisting of
basophilic dots (inclusions are viral particles).
Infectious (non-viral) disorders
Aspergillus (straight septate hyphal forms with acute angle
branching)
Blastomycosis
Broad based budding organisms
Coccidiodomycosis
Small spherical endospores are present within the large sphere.
Cryptococcus
Yeast with thick gelatinous capsule
Echinococcus
Daughter cysts with germinal layer and scolices
Entamoeba histolytica
Entamoeba histolytica
• peripheral trophozoites up to 60 microns
with small eccentric nucleus and
cytoplasmic vacuoles that may contain red
blood cells; resemble histiocytes; adjacent
liver has fibrosis, chronic inflammation and
reactive hepatocytes
Alcoholic hepatitis and alcoholic
liver disease
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Alcohol related liver disease consists of hepatic steatosis (50%), alcoholic
hepatitis (20%) and cirrhosis (10
Alcoholic cirrhosis: only 10% of alcoholics develop cirrhosis
Gross: initially liver is 4-6 kg, yellow, greasy, easily fractured; later liver
becomes red with bile-stained areas; may contain visible nodules and
fibrosis
Micro:
steatosis - hepatocyte swelling and necrosis, macrovesicular fatty change
due to triglyceride in centrilobular area, Mallory’s hyaline with surrounding
neutrophils
hepatitis- hepatocyte swelling and necrosis,cholestasis, Mallory bodies,
neutrophilic reaction, fibrosis
cirrhosis –final and irreversible form of alcoholic liver disease; initially
cirrhotic liver is yellow, fatty, enlarged (> 2 kg); eventually becomes brown,
shrunken, nonfatty, < 1 kg; initial fibrous septa are delicate, regenerative
micronodules; nodules then become larger and have hobnail appearance
on hepatic surface, and bands of fibrous tissue become wider. macro- and
micronodules
• In alcoholic steatosis: lipid accumulates within the cytoplasm
of hepatocytes, creating large clear vacuoles within cells.
The nuclei in such cells are compressed to the periphery of
the cell.
• Alcoholic hepatitis:Mallory's hyaline is seen here, but
there are also neutrophils, necrosis of hepatocytes,
collagen deposition, and fatty change.
• This liver, a case of
alcoholic cirrhosis,
contains numerous, fairly
uniform, small nodules of
regenerative hepatocytes
separated by depressed
areas of fibrous scar
tissue. This morphologic
pattern is sometimes
referred to as
micronodular cirrhosis.
• In alcoholic cirrhosis, nodules of regenerating
hepatocytes consist of disordered cords of cells of
irregular thickness, many of which are two or more cell
layers thick. Note the lack of central veins in these
regenerative nodules. The nodules are surrounded by
fibrous tissue containing variable amounts of chronic
inflammatory cells and areas of bile ductular
proliferation.
Biliary Tract Disease
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Ascending cholangitis
Autoimmune cholangitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Oriental cholangiohepatitis
Secondary biliary cirrhosis
Ascending cholangitis
• Biliary tract infection (E. coli, enterococci)
with obstruction
• Micro: neutrophils within lumina of
interlobular bile ducts; large ducts may be
destroyed and replaced by scar or atretic
ducts
Primary sclerosing cholangitis
• 65% men, usually under 45 years
• Possibly autoimmune, 50-70% also have inflammatory bowel
disease (particularly ulcerative colitis, although only 4% with
ulcerative colitis have primary sclerosing cholangitis)
• Secondary sclerosing cholangitis: due to stones, prior surgery
• Symptoms: fatigue, pruritis, jaundice, right upper quadrant pain /
tenderness
• Increased risk for cholangiocarcinoma
• Xray: beading of barium column in cholangiogram due to irregular
strictures and dilations of affected bile ducts
• Treatment: liver transplant since no effective medical therapy
(associated with autoimmune liver disease in 42% and recurrence in
33%)
• Gross: periductal portal tract fibrosis, segmental stenosis of
extrahepatic and intrahepatic bile ducts
• Microscopically, this
bile duct in a case
of sclerosing
cholangitis is
surrounded by
marked collagenous
connective tissue
deposition(onionskin concentric
scar).
Primary biliary cirrhosis
• Chronic, progressive, often fatal cholestatic liver disease
with destruction of small, intrahepatic bile ducts, portal
inflammation and scarring leading to cirrhosis and liver
failure
• Possibly autoimmune; associated with Sjogren’s
syndrome, scleroderma, thyroiditis, rheumatoid arthritis,
Raynaud’s phenomenon, membranous
glomerulonephritis, systemic lupus erythematosus, celiac
disease
• Involves most proximal portion of biliary tree, the small
bile ducts and canals of Hering; larger bile ducts affected
only irregularly, 85% women, usually ages 40-60
Primary biliary cirrhosis
• IgM antimitochondrial autoantibodies in 95%
• 5% - negative antimitochondrial antibody (must have a
cholangiogram to rule out primary sclerosing cholangitis)
• M2 form of anti-mitochondrial antibody, present in 90%,
is against E2 subunit of pyruvate dehydrogenase
complex–dihydrolipoamide acetyltransferase on inner
face of inner mitochondrial membrane, causes
hypocomplementemia and formation of immune
complexes
• Antimitochondrial antibodies are most important
diagnostic marker; has coarse granular cytoplasmic
staining of distal renal tubules and parietal cells (rodent
stomach/kidney blocks) with indirect
immunofluorescence
• The cut surface is dark green, due to marked
cholestasis within the liver. Regenerative nodules of
liver parenchyma are separated by tan bands of fibrous
tissue.
• At higher magnification, it is apparent that the
chronic inflammation in the portal areas is
associated with bile duct destruction by the
inflammatory infiltrate. These are the hallmarks of
the florid duct lesions in primary biliary cirrhosis
• This immunofluorescence pattern is positive for antimitochondrial antibody (AMA) which has an association
with primary biliary cirrhosis. The tissue substrate for
this test is renal parenchyma, and the tubule cells have
lots of mitochondria, which stain bright green.