Liver and Biliary Tract Pathology

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					Liver and Biliary Tract
      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
• 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
    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%),
• 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)
• 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

   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
• 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 middle-
  aged 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.
           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
•   Treatment: long-term copper chelation therapy with D-penicillamine; liver
•   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
•   Hepatotropic viruses(A,B,C,D,E and G), EBV,CMV,HSV, yellow fever,
•   In children: rubella, adenovirus,enterovirus
•   Phases: incubation, symptomatic preicteric, symptomatic icteric,
•   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 ill-
  defined 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
• 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 /
•   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
•   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
•   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

Broad based budding organisms

Small spherical endospores are present within the large sphere.

Yeast with thick gelatinous capsule
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
•   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
•   Micro:
•   steatosis - hepatocyte swelling and necrosis, macrovesicular fatty change
    due to triglyceride in centrilobular area, Mallory’s hyaline with surrounding
•    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
• 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
        Biliary Tract Disease
•   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
  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 /
• 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
• 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
  skin concentric
      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
• Possibly autoimmune; associated with Sjogren’s
  syndrome, scleroderma, thyroiditis, rheumatoid arthritis,
  Raynaud’s phenomenon, membranous
  glomerulonephritis, systemic lupus erythematosus, celiac
• 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
• 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
• 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
• 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 anti-
  mitochondrial 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.

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