Liver Pathology

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Liver Pathology

• Aaron Auerbach
• AFIP

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Copies of all my lectures can be found at
www.afip.org/consultation/hemepath
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Liver biopsies

• 75 liver biopsies are for non neoplastic
  conditions.
• For BOARDS, know reactive diseases of the liver

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Job of the Hepatologist

• Confirm diagnosis
• Ascertain etiology
• Grade activity Grade
• Grade fibrosis Stage

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cholestatic
cholate stasis
AMA
PBC
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Key to liver path, location, location, location

• Central veins
• Parenchyma
• Portal areas

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Pattern 1 Hepatitis
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Types of Hepatitis

A
B
C
D
E
Source
feces
blood/
blood/
blood/
feces
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
mucosal
mucosal
mucosal
Chronic
no
yes
yes
yes
no
infection
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A E fecal oral

A
B
C
D
E
Source
feces
blood/
blood/
blood/
feces
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
mucosal
mucosal
mucosal
Chronic
no
yes
yes
yes
no
infection
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A E, no chronic infxn

A
B
C
D
E
Source
feces
blood/
blood/
blood/
feces
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
mucosal
mucosal
mucosal
Chronic
no
yes
yes
yes
no
infection
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B, C, Dblood

A
B
C
D
E
Source
feces
blood/
blood/
blood/
feces
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
mucosal
mucosal
mucosal
Chronic
no
yes
yes
yes
no
infection
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B, C, D-Chronic infxn

A
B
C
D
E
Source
feces
blood/
blood/
blood/
feces
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
mucosal
mucosal
mucosal
Chronic
no
yes
yes
yes
no
infection
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Ab.c.d.efef
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Geographic Distribution of HAV Infection
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
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aB.c.d.efef
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Question on most board exams!

• What serologic markers are positive in people who
  have been vaccinated for Hep B?
• HbsAg
• Anti HbsAg
• HbcAG
• Anti Hbc

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Answer Anti Hbs
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Features of Hepatitis

• 1. Portal-based portal inflammation
• 2. Interface hepatitis piecemeal necrosis
• 3. Focal necrosis apoptosis acidophil bodies
• Foci of lobular inflammation necrosis of
  single
• hepatocytes

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Portal inflammation and interface hepatitis
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Focal necrosis
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HbsAg
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HbcAg
Nuclear and cytoplasmic
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ab.C.d.efef
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Chronic Hepatitis C, an epidemic
HAV
HBV
HCV
HDV
Acute infections
(x 1000)/year
125-200
140-320
35-180
6-13
Fulminant
deaths/year
100
150
?
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Chronic
0
1-1.25
3.5
infections
million
million
70,000
Chronic liver disease
deaths/year
0
5,000
8-10,000
1,000
Range based on estimated annual incidence,
1984-1994.
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HbC for boards fat and lymphoid aggregates
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Archaic terminology-to be abandoned (except on
boards)
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What does this liver have?
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Autoimmune hepatitis

• Most frequent in females, bimodal age
  distribution
• Assoc with hyperglobulinemia
• Assoc w ANA, ASma, ant LKM1
• Only chronic hepatitis that responds to
  corticosteroid

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Autoimmune hepatitis-Histology

• Severe hepatitis w bridging necrosis and
  multi-acinar collapse or cirrhosis
• Lots of plasma cells and eos

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The International Autoimmune Hepatitis Group
Grading system

• Parameter Score Parameter Score
• Female sex 2 Alcohol intake
• Alk Phos/AST ratio lt 25 gm/day 2
• lt1.5 2 gt60 gm/day -2
• 1.5-3.0 0 Other autoantibody 2
• gt3.0 -2 HLA DR3 or DR4 1
• Serum globulins or IgG Liver histology
• gt2 3 Interface hepatitis 3
• 1.0-1.5 2 plasma cells 1
• ANA, SMA or LKM1 rosetting of liver
  cells 1
• gt180 3 None of the above -5
• 180 2 biliary changes -3
• 140 1 Other diagnosis -3
• lt140 0 Response to therapy
• AMA positive -4 Complete 2
• Hepatitis viral markers Relapse 3
• Positive -3
• Negative 3 Interpretation
• Drug history Pretreatment Positive -4
  definite AIH gt15

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Pattern 2cholestasis

• Cholestasis occurs when there is defective
  excretion of bile from the liver. In some liver
  diseases, it is the primary injury while in many
  others, cholestasis is secondary to some other
  injury

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Cholestasis

• bile pigment
• Cholate stasis (pseudoxanthomatous change or
  feathery degeneration)
• Bile duct injury and loss
• Ductular (cholangiolar) proliferation
  (non-specific)
• Copper accumulation
• Cholestatic Mallory bodies, zone I

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Copper stains
Victoria blue Rhodanine
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Primary Biliary Cirrhosis (PBC)

• Females, 40 60 years old, assoc w HLA DR,
• Autoimmune diseases (thyroid, SS, RA,
  scleroderma)
• 80-95 AMA positive
• Cholestasis
• Bile duct injury
• Granulomas

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Primary Sclerosing Cholangitis (PSC)

• Males gt Females, 25 60 year old
• 75 assoc with UC
• Immune attack on large bile ducts
• fibrous obliteration of bile ducts
• periductal fibrosis, ductopenia
• ? cholangiocarcinoma

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Cholangiocarcinoma in PSC

• 10 incidence
• As high as 30 40 autopsy, 10 30 liver
  explants
• 1/3 diagnosed within 2 years of established PSC
• Annual incidence 1

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PBC vs. PSC
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Pattern 3 steatohepatitis--the epidemic
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Steatohepatitis

• Macrovesicular
• Alcohol
• Diabetes
• Drugs
• Obesity
• Deficient diet (TPN)

• Microvesicular
• Pregnancy (AFLD)
• Reyes syndrome
• Drugs/Toxins
• Valproic acid
• Mushrooms
• Tetracycline

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Steatohepatitis

• Macrovesicular
• Alcohol
• Diabetes
• Drugs
• Obesity
• Deficient diet (TPN)

• Microvesicular
• Pregnancy (AFLD)
• Reyes syndrome
• Drugs/Toxins
• Valproic acid
• Mushrooms
• Tetracycline

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Alcohol-Related Hepatitis

• Big three criteria
• Steatosis
• Mallory bodies
• Zone 3 (perivenular/pericentral) fibrosis
• Other helpful features
• Inflammation of portal areas
• Ballooning degeneration of hepatocytes

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Ubiquitin or p62
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NASH Clinical Features
Study n Age F Obese
DM ?Chol Sxs ?Fibr
Ludwig Itoh Diehl Lee Powell Bacon Baldridge
Values shown in percent ()
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Drugs can cause any type of liver disease, but
for the board know

• Acetaminophen causes hepatocellular necrosis with
  inflammation

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Infectious, Non-Viral

• Bacterial
• Brucellosis, salmonella (S. typhi)
• Mycobacterial
• M. tuberculosis, MAIC
• Fungal
• Coccidiomycosis
• Parasitic
• Amebiasis
• Hydatid disease

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Rickettsial Q fever (Coxiella burnetti)
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Echinococcus
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Potpouri of other reactive liver diseases
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a1-antitrypsin deficiency

• Cholestatic changes and hepatitic changes
• Pulmonary emphysema
• Autosomal recessive
• Chromosome 14
• PiSZ, PiSS, PiMZ
• Mmmm, Mmmmm Good
• PiZZ most common, worst prognosis
• Periportal PAS/D positive inclusions

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pas
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Board type question, What is your diagnosis?
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Dubin-Johnson syndrome
AR Conjugated hyperbilirubinemia Only one with
liver pathology
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Hemochromatosis, shows up on every board

• - 85 due to C282Y and/or H63D mutations
• - C282Y cysteine to tyrosine substitution at
• amino acid position 282
• - H63D histidine to aspartate at position 63
• - C282Y, highest iron overload
• - H63D, lowest iron overload
• - Compound heterozygotes, C282Y H63D
  intermediate

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? Serum iron,? Serum ferritin

• Hepatic Iron Index

Mcg Fe/gm dry weight Micromoles/gm 56
Micromoles/gm Hepatic Iron Index Age (Years)
Fe can be measured in formalin-fixed paraffin
embedded tissue
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Genetic Hemochromatosis

• Hepatic Iron Index
• Normal lt1
• Alcoholic cirrhosis lt2
• Heterozygous lt2
• Hemochromatosis gt2
• 15 of HFE patients will have index lt1.9 Some
  chronic anemia patients will be gt1.9

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Morphology

• Periportal Fe (zone 1gt2gt3)
• Advanced disease Fe in ducts

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Look at the next 3 slides and give me your
diagnosis?
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What is your diagnosis?
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Wilsons disease

• AR
• copper metabolism (Chr 13)
• Liver brain
• Inability to secrete copper, not increased
  absorption
• Low serum cerruloplasmin

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Look at the next 3 slides and give me your
diagnosis?
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TUMORS FOR DUMMIES
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HCC mimics normal liver cells
Trabeculae-cord like pattern Pseudoglands
single layer of tumor cells, dilated bile
canaliculi Bile Mallory bodies, intermediate
filaments, ubiquitin, p62 Hyaline bodies,
alpha-1-antitrypsin.
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Immuno
Hepatocyte (Dako) positive in tumor cells
rule out other carcinomas Polyclonal CEA
canalicular
pattern CD34 vascular pattern Alpha
fetoprotein or CK 8/18 usually CK
7 50 positive AFIP study CK 20 25
positive

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Cytokeratin 20
Auerbach, A. Ishak KG and Goodman ZD Cytokeratin
Expression of Hepatocellular Carcinoma. USCAP
2004.
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Cytokeratin 7
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Incidence of Hepatocellular Carcinoma
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Malignant Liver TumorsPrimary Site
LACUSC Medical Center and USC liver autopsies
1918-1982, 11005 autopsies
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Malignant Liver Tumors in CirrhosisPrimary Site
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Alpha fetoprotein
AFP is not elevated in all patients with
HCC. AFP can be elevated in other dz, i.e.
hepatitis AFP immunostain is negative in 50 of
HCC
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Hepatic adenoma

• Young females, OCPs, steroids, DM
• Solitary, well-circumscribed

Morphology Resemble hepatocytes, one to two cells
thick cords Clear cell changeglycogen. No portal
triads. Naked arteries or veins. Rare
mitosis Preserved reticulin pattern No CD34
capillarization (focal)
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Free-floating vessels
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Miss Idaho
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Focal nodular hyperplasia

• Young females, no assoc OCPs, asymptomatic
• Solitary, central scar

Morphology Vascular lesion, arteries in fibrous
stroma Divides liver into nodules-focal
cirrhosis Cholestasis, ductures, copper, cholate
stasis .
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Geekier than pathologists
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Fibrolamellar hepatocellular CA

• Bob Peeterseosinophilic carcinoma with lamellar
  fibrosis
• Differs from other HCC

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Lamellar fibrosis
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No sinusoids, nests Tumor cells larger than
HCC, Inc cytoplasm, oncocytic, mitochondria,
50 cytoplasmic pale bodies
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FLC HCC Age 23 61 Sex M F MF
41 Cirrhosis 4 80 AFP no yes HBV no
yes Site LgtR RgtL Survival 43mos 6.5mos
Cure 32 2 Better off transplanted
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Cholangiocarcinoma
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Stroma, most important feature. Stroma in CC,
versus sinusoids in HCC.
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Can you tell the difference between
cholangiocarcinoma and adenocarcinoma on
histology?
NO!!! Look the same Immunohistochemistry doesnt
distinguish
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Incidence and risk factors
Clonorchis sinensis, China/Korea O. viverrini,
Thailand Calcium bilirubinate stones. Fibrocysti
c disease, Carolis disease, solitary
cysts. Primary sclerosing cholangitis,
ulcerative colitis, EBV, Thorotrast
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Intrahepatic Cholangiocarcinoma
of Malignant Hepatic Tumors
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What is your diagnosis of the next slide?
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Epithelioid Hemangioendothelioma

• Also in lung (IVBAT) and soft tissue
• Epithelioid cells
• Dendritic cells, vacuoles with red cells
• Occlude vessels
• CD34, Factor VIII positive

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