Liver biopsy interpretation

LIVER BIOPSY
INTERPRETATION
Dr. MAITHILI KULKARNI
Guide
Dr. J. K. KUDRIMOTI
Dr. M. V. JADHAV

NON INVASIVE CLINICAL EVALUATION
• Detailed history of hepatotoxins ,
source of infection
• Physical examination
• Battery of appropriate lab tests of
liver function & integrity
• Serologic tests for infectious agents
& autoimmunity
• Radiological studies

Four methods :-
Percutaneous needle biopsy
(transcut. Intercostal route),
Usg & CT guided Bx
Laparoscopy,
Laparotomy,
Transvenous route
(Transjugular / transfemoral)

• The choice of one technique over
another is based on availability,
personal preference, and the
clinical situation.
Choice Of Technique

THREE TYPES OF NEEDLES :
 Vim-Silverman’s needle,
 Menghini’s aspiration biopsy needle,
 ‘Tru-cut’ biopsy needle (modified Vim-
Silverman’s)
• Biopsy Gun / Biopter
(modified Tru-cut needle)

INDICATIONS FOR LIVER BIOPSY
 Diagnosis, grading, and staging of alcoholic liver
disease, nonalcoholic steatohepatitis, or autoimmune
hepatitis
 Grading and staging of chronic hepatitis C or chronic
hepatitis B
 Diagnosis of hemochromatosis in index patient and
relatives, with quantitative estimation of iron levels
 Diagnosis of Wilson’s disease, with quantitative
estimation of copper levels
 Evaluation of the cholestatic liver diseases primary
biliary cirrhosis and primary sclerosing cholangitis

 Evaluation of abnormal results of biochemical tests of the
liver in association with a serologic workup that is negative
or inconclusive
 Evaluation of the efficacy or the adverse effects of
treatment regimens (e.g. methotrexate therapy for
psoriasis)
 Diagnosis of a liver mass
 Evaluation of the status of the liver after transplantation or
of the donor liver before transplantation
 Evaluation of fever of unknown origin, with a culture of
tissue
INDICATIONS FOR LIVER BIOPSY Continued …..

Contraindications to liver biopsy include the
following:
• Increased prothrombin time, international
normalized ratio (INR) greater than 1.6
• Thrombocytopenia, platelet count less than 60,000
• Ascites (transjugular route preferred)
• Difficult body habitus (transjugular route
preferred)
• Suspected hemangioma
• Suspected echinococcal infection
• Uncooperative patient

Complications of percutaneous liver biopsy
 Pain
– Pleuritic, Peritoneal, Diaphragmatic
 Hemorrhage
– Intraperitoneal,
– Intrahepatic and/or sub capsular
– Hemobilia
 Bile peritonitis
 Bacteremia
 Sepsis and abscess formation
 Pneumothorax and/or pleural effusion
 Hemothorax
 Arteriovenous fistula
 Subcutaneous emphysema
 Anesthetic reaction
 Needle break
 Biopsy of other organs :-
– Lung, Gallbladder, Kidney, Colon

Interpretation of liver biopsy starts with
gross examination of biopsy specimen
Hand lens can be used
• Cylinders of even color & thickness which
not fragment easily- normal liver
• Cirrhosis- Fragmented, irregular in
caliber, obviously nodular
• Nodular, no fibrous septa – NRH
• steatosis - Yellow color, greasy sensation
, float in fixative

Limitations
 Sampling error – focal lesions (cysts ,
tumors ) can not be entirely excluded
 Misdiagnosis – inadequate sample
 Operative biopsies – hemorrhages ,
PMN infiltration
 Artifacts –due to rough handling , poor
fixation

Adequacy Of Sample
• In general, a sample of
• 1.5 cm in length
• 1.2-2 mm in diameter and
• contains at least 3 portal triads is
considered adequate. This represents
approximately 1/50,000th of the adult
liver.
• Adequacy depends on the disease process
concerned.
• In HCC, adequate if malignant cells are seen,
amyloidosis, storage disorder

Gross Examination
 Hand lens can be used
 Fragmented, irregular in caliber, obviously
nodular – Cirrhosis
 Nodular, no fibrous septa – NRH
 Yellow colour, greasy – float in fixative –
steatosis
 Rusty brown – genetic hemochromatosis
 Slate gray - malaria,
 Brown-Black - Dubin Johnson syndrome
 Black – protoporphyria
 Light tan to white foci – lymphoma
carcinoma

Gross cont
 Rusty brown –genetic
hemochromatosis
 Slate gray- malaria
 Black or dark brown- Dubin Johnson
syndrome
 Black – protoporphyria
 Deep red - cong
 Light tan to white foci – lymphoma
carcinoma

Processing Of specimen
Excessive manipulation should be avoided
USE OF FIXATIVE –
FOR LIGHT MICROSCOPY-
1. Routinely - 10 % neutral formalin 3 hrs at room temp
2. For metabolic diseases which contain water soluble stored
material –
• Cystinosis GSD– alcohol
• Mucopolysaccharidosis – Lindsays dioxane picrate
3. Frozen section – demonstration of lipids ,
immunohistochemisry
FOR ELECTRON MICROSCOPY – minute pieces put into
appropriate fixative like glutaraldehyde
Uses – inborn error of metabolism, tumor of doubtful
histogenesis, viral infection

SECTIONS TO BE TAKEN
• 3 to 5 micron sections –consecutive
sections
• For special stains- Depending on clinical
suspicion, no. of sections are taken
• Serial or step sections – granulomas or
tumor deposits ,parasitic egg,larva, Serial
biopsies following liver transplant.

MICROSCOPY
STAINS USED
1. H & E stain
2. Special stains
H & E Stain
• All fragments should be examined
• Look for –architecture (Special stain is required)
• Locating terminal hepatic venules – moving in
direction of portal areas
• Look at- portal tracts, Hepatocytes, Bile canaliculi,
Sinusoids & their contents, Kupffer cells
Abnormal deposits in spaces of Disse–amyloid,
collagen

Normal portal tract and central vein

Special stains
• Reticulin – structural changes , outlining areas of focal or
zonal necrosis,
• MT-
• Pericellular fibrosis
• New collagen formation
• Changes involving blood vessel
• Elastin – For recent collapse/fibrosis
• Orcein – elastic tissue, hepatitis B surface Ag, Cu
associated protein
• PAS – complex CHO, glycogen (benign & malignant
hepatocellular tumors)
• D-PAS – to remove glycogen, 1 antitrypsin –DPAS
positive
• PAS – amyloid, starch, amoebae, pathogenic fungi,
basement membrane of acinar ducts
• PTAH – fibrin in (DIC & Eclampsia)

• Gomori methanamine silver – fungi
• Prussian Blue :- Iron
• Rhodanine :- Cu( ICC, Chronic cholestasis,
wilson)
• PTAH -> Fibrin
• Van Gieson -stains Bile green
• Congo red - Amyloid
• AFB -> TB bacilli, schistosoma egg, hooklets in
scolices of echinococcal cyst
Special stains continued…..

 Warthin starry - Spirochetes, Leptospira,
cat scratch bacilli
 Geimsa -> Hematopoietic cells
 Frozen – Oil red O -> Neutral Lipid
 Bakers acid hematin with pyridine
reaction -> Neimannpick

Liver, Wilson disease - High power
This special stain (rhodanine stain) highlights the
accumulation of copper in the hepatocytes of patients
with Wilson disease.

Low power :
 Quality of biopsy (size, staining),
 Overall architecture,
 Presence / absence of normal structures,
 Pattern of injury,
 Fibrosis and nodularity,
 Gross area of necrosis or congestion

Medium & High power :
 Portal tracts :
 Presence of normal structures (Bile duct, vein, artery),
 Inflammation (Type, intensity, relation with normal
structures),
 Fibrosis, edema,
 Bile duct changes (inflammation, proliferation,
necrosis, cholestasis, loss),
 Arterial / venous changes (inflammation, thrombosis)

 Lobule :
Inflammation (type, intensity,
location/zonality),
Necrosis (type, intensity, location/zonality),
Status of cell plates (regeneration, atrophy),
 Status of sinusoids (dilated, congested)
 Other changes : Amyloid deposition,
Fibrosis,

 Central vein :
 Size, shape (round / compressed),
 Inflammation,
 Fibrosis

Degeneration :
 Ballooning
 Feathery,
 Fatty (Steatosis),

• Hydropic change / Oncosis): increased cell
volume with pale staining granular
cytoplasm
• seen in damage from toxic, ischemic or
immunological insult, e.g. Ac Hep., Alc.
Hep.

•.swollen hepatocytes with thread-like
reticular yellowish brown cytoplasm
• seen in Cholestasis

HYALINE DEGENERATION – Mallory's
hyaline represents aggregates of
intermediate filaments- alcoholic hepatitis ,
non alcoholic steatohepatitis , HCC, ICC,
Wilson Ds,

Type of deposition
Acinar distribution
Possible complications
 Macrovesicular-
alcohol, obesity, DM,
TPN, PEM
 Microvesicular-
AFLP, Reyes, Tn,
jamiakan vomiting
sickness
 Mixed
 Focal

Type of fat
Acinar distribution
Possible complications
 Periportal- TPN,
AIDS, Kwashiorkar
 Centrilobular- Alc,
obesity, DM
 Diffuse

Type of fat
Acinar distribution
Possible complications  Steatohepatitis
 Portal fibrosis
 Cirrhosis

 Alcoholic liver disease
(ALD),
 Obesity,
 diabetes mellitus,
 Kwashiorkor,
 Drugs,
 Ethanol,
 Methotrexate
 Chr. HCV,
 Metabolic diseases

 Acute fatty liver of
pregnancy
 Reye’s syndrome
 Drugs
 Tetracyclins,
 Valproate toxicity
 Salicylates,
 TPN
 Cholesterol storage
diseases
 Toxic shock syndrome

Apoptosis :
 Acidophil / Councilman bodies
•hepatocyte
shrinkage,
• increased
eosinophilia
•and nuclear
pyknosis
•Acute Viral
hepatitis, AIH

Necrosis :
 Spotty / Focal,
 Confluent /
Bridging
 Submassive,
 Massive,
 Zonal,

Zones Causes
Zone 1
• Eclampsia,
• HAV,
• Infectious mononucleosis,
• Phosphorous poisoning
Zone 2 • Yellow fever
Zone 3
• Shock,
• CCF, CCL4
• Chloroform poisoning

Liver Cell Necrosis
1. Focal necrosis- Non specific reaction to disease
elsewhere in body, spotty-same lesion with
Gap in liver cell plates- Liver cell dropout &
inflammatory reaction.- acute hepatitis
2. Haphazardly distributed areas of necrosis- Disseminated
herpes virus, micobacteria.
3. Tumor Necrosis- Reticulin pattern
4. Bridging necrosis- Bridging of THV to PT- acute viral
hepatitis (No elastic fibers)
5. Piecemeal Necrosis: Destruction of liver cells at an
interface between portal tract & parenchyma with
lymphoplasmacytic infiltrate- chronic hepatitis

Diffuse confluent necrosis:
With inflammation : Viral hep, Drug induced
hep
Without : Shock, LVF

Inflammation :
Hepatitis,
Interface hepatitis,
 Lymphocytic (Classic),
 Biliary (Lympho + Poly)

Hemosiderin Golden brown refractile, PB positive
 In hepatocytes – genetic hemochomatosis
 In kupffer cells – hemolytic anemia ,viral hepatitis ,
Parenteral iron , blood transfusion , impaired release
of iron – chronic infl , malignancy
Lipofuscin – granular, near cytoplasmic membrane
Bile:- Homogeneously stained- green/yellow or orange,
bile plugs in small ductuels, hall staining
Hemozoin pigment:- Malarial pigment in kupffer cells,
finely granular, dark brown or black.

Hemosiderin- golden brown, PB +
Lipofuschin- Yellow brown
DJ pigment- Dark brown & black
Bile pigment

Regeneration :-
Disorganization
of structure
Mitoses,
Multinucleation,
Thickening of
hepatocyte cords,

Fibrosis :-
Bridging
Cirrhosis

Non neoplastic lesions :
 Infections : Hepatitis,
 Cirrhosis,
 Cholestatic liver dis,
 Metabolic disorders,
 Liver transplant,
 Granuloma
 Liver in systemic condn
,
Tumours & D/Ds :
 Focal nodular hyperplasia,
 Hepatocellular Adenoma,
 Hepatoblastoma
 Hepatocellular carcinoma,
 Bile duct adenoma
 Cholangiocarcinoma

Acute,
Chronic,
Autoimmune,
Steatohepatitis

INFECTIVE :
 Viral,
 Bacterial,
 Parasitic,
 Fungal,
DRUG INDUCED,
AUTOIMMUNE

EBV- mild hepatitis during the acute phase;
CMV - particularly in the newborn or
immunosuppressed patient
yellow fever- which has been a major and serious
cause of hepatitis in tropical countries.
Infrequently, in children and immunosuppressed
patients, the liver is affected in the course of rubella,
adenovirus, herpesvirus, or enterovirus infections.
Hepatotropic viruses cause overlapping patterns of
disease. Each hepatotropic virus and the disease
conditions it causes will be introduced before a
general discussion of hepatitis.

Ballooning
degeneration
(Hydropic change)
Acidophil /
Councilman
bodies
Interface hepatitis

Focal necrosis (Spotty
necrosis) with collapse
& mild lymphocytic
infiltran
Same (focal collapse)
area on Reticulin
stain

Lobular disarray,
Portal tract infiltrate of lymphocytes &
plasma cells with some neutrophils &
eosinophils,
Lobular infiltration of mixed infiltrate,
‘Ceroid macrophages’,
Cholestasis (Cholestatic hepatitis),
Ductular reaction,

Severe necrotizing
hepatitis, with
 ‘Confluent necrosis’,
(usually centrilobular)
 Bridging necrosis

Cause Histological Findings Other Features
HAV
Mild portal + lobular PL infiltrate,
Cholestasis
Serological markers,
Self limiting
HBV
Prominent centrilobular bollooning
degeneration
Serological markers
HCV
Prominent portal lymphoid follicles,
Bile duct damage
Rarely acute,
Serological markers
CMV /
HSV /
EBV
Confluent necrosis with minimal
infiltrate, Typical viral inclusions
Drugs
Mixed infiltrate, Prominent eosinophils,
Granulomas, Mixed steatosis
History of hepatotoxic
drug ingestion, Resolves
after discontinuation
AIH
Abundant plasma cells, periportal areas
of collapse, bridging necrosis
Serum markers for Ab,
ed  Globulins

Non neoplastic lesions :
 Infections : Hepatitis,
 Cirrhosis,
 Cholestatic liver dis,
 Metabolic disorders,
 Liver transplant,
 Liver in systemic condn
,
Tumours & D/Ds :
 Focal nodular hyperplasia,
 Hepatocellular Adenoma,
 Hepatoblastoma
 Hepatocellular carcinoma,
 Bile duct adenoma
 Cholangiocarcinoma

• Chronic hepatitis
•HBV
•HCV•HBV+HDV
•AIH
•Wilson’s Disease•PBC
•PSC
•A1AT
•Hemochromatosis
•Drugs
•Cryptogenic
•NASH
•ALD

Hepatocellular necrosis (spotty/confluent)
Portal / periportal inflammation
Fibrosis
Cirrhosis

Type Special Features
HBV Ground glass hepatocytes
HCV
Portal lymphoid aggregates,
Steatosis, Bile duct injury
AIH
Plasma cell portal infiltrate,
Severe damage with
rossettes & giant cell formn
Drugs Any possible change

GRADE INFLAMMATION NECROSIS
0 None None
1 Portal or lobular None
2 Mild interface Focal
3 Moderate interface Confluent
4 Severe interface Bridging

STAGE FIBROSIS
0 No firosis
1 Enlarged portal tracts
2 Periportal / P-P septa
3 Bridging fibrosis
4 Cirrhosis

• Usually +nt as chr hepatitis, predominantly affecting
females, viral serological markers must be negative,
• IgG and Gamma globulin levels are raised (> 1.5
times),
• High titre of ANA, AsmAb and Anti-LKM, Anti-
mitochondrial Ab absent,
• Correct diagnosis is imp. because pt. may benefit
from immunosuppressive therapy,
• High necro-inflammatory pathology, bridging
confluent necrosis, marked interface hepatitis,
hepatic liver cell rossettes,
• Plasma cells, usually in clusters – prominent
feature,
• Lymphoid aggregates and follicles – may +nt (<
HCV

Steatosis,
Mallory bodies
Neutrophilic infiltrate
(Satellitosis)
Perivenular/ pericellular
fibrosis
Alcoholic cirrhosis

Disruption of architecture,
Regenerating nodules,
Bridging fibrous septae

Establish diagnosis
Possible aetiology
To detect HCC

GROSS :
Fragmented,
Rounded, smooth
MICRO (Retic stain):
Thick cell plates,
Condensed reticulin
fibres surrounding
nodules

Congenital Hepatic Fibrosis Parenchyma does
not show e/o destruction or regeneration
Disease
Diffuse
Involvement
Septa Nodule
Cirrhosis + + +
Nodular regenerative
Hyperplasia
+ - +
Focal Nodular
Hyperplasia
- + +

Primary Sclerosing Cholangitis
Primary Biliary cirrhosis,
Sec. Biliary Cirrhosis

• CANALICULAR – dilated bile canaliculi bet
hepatocytes
• CYTOPLASM OF HEPATOCYTES &
KUPFFER CELLS
• DUCTULAR CHOLESTASIS – sepsis , ductal
plate malformation
• Acute – canalicular (perivenular )
•Chronic – periportal hepatocytes

Four stages :
Florid duct
lesion,
Ductular
proliferation,
Scarring ,
Cirrhosis,

• AI dis with unknown etiology selectively affecting the small
IHBD,
• Initial lesions may be called ‘chronic non-suppurative
destructive cholangitis’,
• Middle aged women (peak 40-60 yrs),
• Presents with intense pruritus d/t cholestatic jaundice, ass with
antimitochondrial Ab (95%), granulomas (40-70%),
• Progressive destruction of intrahepatic biliary tree by
lymphoplasmacellular infiltrate,
• Biopsy needle may fail to sample duct lesions owing to their
focal distribution,
•

Causes –
 Cholelithiasis,
Stricture
 Malignancies of BT, ca of head of pancrease
Histology –
 Coarse fibrous septae divides the liver into irregular
jigsaw pattern pseudolobules
 FS contais small & large bile ducts with inspissated
bile
Extensive ductular proliferation
 Hepatocytes showe xtensive feathery deg, with bile
lakes,
 PMN infiltrate around bile ducts

EHBA
Cystic fibrosis
Choledochal cyst

Aetiology Histological Features
Extrahepatic
biliary
atresia
Proliferation of bile
ductules in portal tracts;
portal fibrosis; ductular
cholestasis
Neonatal
hepatitis
Portal & lobular
mononuclear cell
inflammation; Giant
cells; acidophil bodies

• Variety of disorders causing conjugated
hyperbilirubinemia are called Neonatal
hepatitis.
• Infants present with jaundice, dark urine
acholic stools n hepatomegaly
• Biopsy critical role in distinguish between
above two conditions,

 Primary
• Hemochromatosi
ss  Secondary

 Wilson’s disease,
 Indian childhood cirrhosis

In alpha1-antitrypsin (AAT) deficiency, alpha1-antitrypsin
accumulates in the cytoplasm of hepatocytes. Due to an inherited
metabolic defect, the protein is not secreted and thus accumulates
in hepatocytes. This is apparent as eosinophilic globular material in
the cytoplasm of hepatocytes in a PAS-with-diastase-stained
section.

Focal nodular hyperplasia,
Adenoma,
HCC,
 Typical,
 Fibrolamellar,
Hepatoblastoma,
Cholangiocarcinoma

Liver Cell Adenoma :
– More or less normal reticulin pattern is
detected throughout which is rarely
seen even in well differentiated HCC.
– Absence of fibrous tracts & bile ducts –
differentiate from focal nodular
hyperplasia
– Absence of large amount of oedematous
mesenchyme- from hamartoma

 Hepatocellular Carcinoma:
– Trabecular Misshapen upto many cells thick,
sinusoidal stroma
– Deficiency of reticulinIn low grade Ca
Differentiate from adenoma or dysplastic
nodule.
– Quality of stroma separating cords of tumour
cells in HCC Empty or blood containing
vessels where as in bile duct carcinoma
Fibrous connective tissue.
– Sinusoidal pattern and / or bile production 
HCC
– Glandular pattern and/or mucous secretion 
CHOLANGIO CARCINOMA

Liver, hepatocellular carcinoma - Medium
power
This biopsy specimen shows irregular trabeculae or cords of malignant
hepatocytes with enlarged nuclei that contain nucleoli, consistent
with a well-differentiated hepatocellular carcinoma.

Liver, cholangiocarcinoma - Low power
Malignant glands are noted within dense, fibrotic tissue
(desmoplastic response) in this case of cholangiocarcinoma
of the liver. Normal hepatic parenchyma is present in the
upper right of the image.

Portal Tracts
Points to be noted:
1. Adequacy of biopsy- At least 3 portal tracts
2. Contains hepatic artery, bile duct (of same
size in the center), portal vein branch.
3. Number of bile ducts equal hepatic artery
branches-look for ductopenia & ductal
proliferation.
4. Inflammation
5. Limiting plate

INFLAMMATION CONFINED TO PORTAL TRACT
 Canalicular cholestasis, spotty necrosis, stain for
elastic fibers :Acute hepatitis
– P,L,E,N – hepatitis A
– L,P – hepatitis B, D, C
– N,L – hepatitis E
 Partial or complete loss of small & medium sized
bile ducts ,lymphocytes , neutrophils
,granulomas  Chronic biliary tract disease
 Wilsons disease –biochemical , clinical
 PAS positive globulesAAT deficiency
 Dense , more homogeneous , total or near total
involvement of portal tractLymphoma – NHL

A Liver-Biopsy Specimen from a 32-Year-Old Man Presumed to Have
Acute Hepatitis. The specimen shows a portal mononuclear infiltrate
with prominent plasma cells (arrow in Panel A) and lobular
inflammation with apoptotic hepatocytes (arrow in Panel B), findings
consistent with the presence of autoimmune hepatitis (hematoxylin
and eosin, ¬100).
A B

Inflammation Confined To Portal Tract
Portal Inflammation, lesions of bile duct
in portal tract, periportal injury
(piecemeal necrosis- destruction of
limiting plates), degeneration &
necrosis of hepatocytes, fibrosis
(periportal or bridging)  Chronic
Hepatitis
1. Grading Degree of activity
2. Staging Degree of fibrosis

Portal tract showing stellate "maple leaf" pattern of
chronic active hepatitis with extensive piecemeal
necrosis and loss of limiting plates

Margin of portal tract showing inflammation
(predominantly lymphocytes) and piecemeal necrosis

Hepatic Artery
 Systemic arterial diseases- SLE, giant cell
arteritis
 Systemic HTN- Thickened & hyaline
 Amyloidosis- Thickening of arterial wall,
congo red with polarized microscope
Infarct- arteritis, aneurysm, thrombosis,
embolism

Loss of bile ducts (ratio of BD HA <1)
 Fibrous obliteration of ducts , dense portal fibrosis with
little inflammation PRIMARY SCLEROSING
CHOLANGITIS
 Four Stages showing-
1. Florid duct lesion , portal hepatitis,
2. ductular proliferation & periportal hepatitis,
3. scarring, bridging necrosis ; septal fibrosis
4. cirrhosis
(granulomatous cholangitis ,chronic inflammation of portal
tract )  PRIMARY BILIARY CIRRHOSIS
 Idiopathic
 GVHD
 Sarcoidosis
 Rejection of liver graft

Liver, primary sclerosing cholangitis -
High power
Concentric periductular fibrosis around bile ducts, leading
eventually to destruction and stricture of affected bile
ducts, is seen in primary sclerosing cholangitis. In between
the areas of stricture, bile ducts become ectatic and
inflamed. The liver in primary sclerosing cholangitis
eventually becomes cirrhotic.

Liver, primary biliary cirrhosis - Low
power
In this biopsy specimen of liver from a patient with primary
biliary cirrhosis, the portal areas contain a chronic
inflammatory infiltrate, consisting of lymphocytes,
macrophages, plasma cells, and eosinophils.

Liver, primary biliary cirrhosis - Medium
power
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.

Liver, primary biliary cirrhosis - Low
power
As liver damage progresses in patients with primary biliary
cirrhosis, fibrous bridges form between portal areas. The
end stage of the process is the development of biliary
cirrhosis.

Bile Duct Proliferation –
– Ductular proliferation – chronic liver
disease (new duct formation )
– Elongation & tortuosity of preexisting
interlobular ducts – obstruction to large
bile ducts

PORTAL VEIN
 Thrombosis – disorders of coagulation ,
cirrhosis , liver transplantation , invasion
by HCC
septic thrombi
 Non cirrhotic portal fibrosis – portal vein
branches are thickened , narrowed
 Pipe stem fibrosis – schistosoma granuloma
around parasitic ova

HEPATIC VEINS
 Veno occlusive diseases – terminal hepatic
venule , & intercalated veins occluded by
fibrous tissue
 Obstrution to large veins – ( budd chiari
syndrome ) – perivenular sinusoids are
dilated , hemorrhages & necrosis in zone3

SINUSOIDS
 Dilatation & congestion –
– CCF
– Oral contraceptives
– Venous outflow obstruction , tumor , granuloma
– Sickle cell disease – Sickled RBCS
 Neutrophilic infiltration – sepsis
 Lymphocytes – mononucleosis , TSS
 Fibrin thrombi – DIC , ( PTAH)
 Peliosis – blood filled spaces , incomplete
endothelial lining
 Neoplasia – mets , leukemia , systemic
mastocytosis
 Parasites – malaria , microfilaria
 Obliteration of sinusoids- GSD type 1

KUPFFER CELLS
 Hypertrophy-
1. Malaria- Hemozoin pigment, in acute
malaria-parasites, RBCs, iron
2. Leishmaniasis- LD bodies
 Swollen foamy & DPAS positive neimann
pick
 Enlarged, moderate DPAS positive-
Gauchers diseases

Aetiology Favoured Site Special Features
Sarcoidosis Portal/Periportal Clustering, Hyalinization,
Inclusion in giant cells
Tuberculosis None Necrosis
PBC Portal
Near damaged bile duct,
acinar granuloma
uncommon
Drugs None
Eosinophills, Other lesions
often presents (Hepatitis,
fat, cholestasis)
Mineral Oil
Portal,
perrivenous Oil Vacuoles
Cue fever None Fibrin-ring granuloma
HEPATIC GRANULOMA

CAUSES OF CHRONIC HEPATITIS
Agent Morphologic Clues
Hepatitis B Ground-glass hepatocytes
Hepatitis C Fat
Bile duct injury
Portal Lymphoid aggregates
Talc (IV drug abuse)
Autoimmune
Hepatitis
Severe hepatocellular injury;
Rosettes,
giant cell transformation, many
plasma cells
Drugs None

Liver, chronic viral hepatitis (hepatitis C
virus) - Low power
This image of liver is from a patient with chronic hepatitis C virus
infection. Portal inflammatory infiltrates in chronic hepatitis C viral
infections frequently contain lymphoid aggregates or lymphoid
follicles. Steatosis is also present in HCV infections, in contrast to HBV
infection.

Grading Activity In Chronic Hepatitis
Grade Piecemeal
Necrosis
Parenchymal
Injury a
Activity
Mild
Found only after
diligent search >5 per 10 X field
Both are
Mild
Moderate
Majority of portal
areas have
atleast some,
but most have
<50% of
circumference 5-20 per 10 X field
Either is
moderat
e
Marked
>50% of
circumference
of the majority
of the portal
areas >20 per 10 X field
Either is
marked.
a--> Apoptotic bodies, ballooned cells, inflamatory cell
aggregates.

Liver, chronic viral hepatitis (hepatitis
B virus) - Medium power
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.

Liver, chronic viral hepatitis (hepatitis B
virus) - Medium power
This image is from another patient who has chronic viral hepatitis. In this patient,
there is a chronic inflammatory infiltrate in the portal areas of the liver that
extends beyond the portal area into the adjacent lobule, where it encircles
hepatocytes, many of which are undergoing degeneration and necrosis. This is
the morphologic correlate of progressive active liver damage that is present in
some patients with chronic viral hepatitis.

Change Score
No Fibrosis 0
Fibrous expansion of some portal areas, with or
without short fibrous septa 1
Fibrous expansion of most portal areas, with or
without short fibrous septa 2
Fibrous expansion of most portal areas, with
occassional portal to portal (P-P) bridging 3
Fibrous expansion of portal areas, with marked
bridging ( portal-portal (P-P) as well as portal-
central (P-C)) 4
Marked bridging (P-P and/or P-C) with occassional
nodules (incomplete cirrhosis) 5
Cirrhosis, probable or definite 6
Histological Activity Index Staging

CIRRHOSIS
 Establish diagnosis
 Assess cause as far as possible
 To detect HCC
Microscopic clues 
1. Fragmented biopsy, fragments have rounded edges
2. Alteration in the spatial relationship between portal
vessels & central veins
3. Cell plates- > one cell in thickness , compressed
sinusoids are invisible
4. Complete loss of acinar structure
5. Reticulin stain – irregular pattern ,thin strips of
connective tissue investing margins of fragments
6. Liver cell dysplasia

Differential Diagnosis Of Cirrhosis
 Budd chiari – portal tracts remain largely
uninvolved
 SBC – fibrosis is portal in distribution
 AAT deficiency – PAS , immunostain
 Wilsons disease , PBC – Cu stain
 Biliary cirrhosis – absence of bile ducts
 Hemochromatosis – iron stain
 Post necrotic – immunostain for hepatitis
B Sag

Liver-Biopsy Specimens from a 45-Year-Old Woman with Chronic
Hepatitis C Virus Infection, in Whom There Was No Clinical
Suspicion of Cirrhosis.
Panel B shows a dense portal infiltrate with the formation of
lymphoid aggregates (hematoxylin and eosin, ¬66). Panel A
shows bridging fibrosis with architectural distortion and early
cirrhosis (Masson trichrome, ¬10).
A B

Congenital Hepatic Fibrosis Parenchyma does
not show e/o destruction or regeneration
Disease
Diffuse
Involvement Septa Nodule
Cirrhosis + + +
Nodular regenerative
Hyperplasia + - +
Focal Nodular
Hyperplasia - + +
D/D OF CIRRHOSIS

Liver Biopsy In Transplantation
 Graft rejection-
Hyper acute- hemorrhagic infarct
Cellular rejection – acute ,triad of
portal inflammation , bile duct & hepatocyte
damage , endotheliitis
Ductopenic ( chronic rejection ) –
- progressive loss of bile ducts
- obliterative arteriopathy of small & med
sized vessels l/d widespresd ischemic
damage to hepatocytes

Liver in GVHD
Acute - 10-50 days after BMT
- Donar Lym attack hepatocytes &
bile duct epithelial cells causes injury &
necrosis
- Inflammation in PT & lobules
Chronic- >100 days after
- severe PT inflammation
- BD destruction
- Fibrosis

Graft Dysfunction
 Infections –CMV (intranuclear &
cytoplasmic inclusions ), EBV ( portal tract
& sinusoids – atypical lymphocytes &
immunoblasts )
 Vascular thrombosis
 Drug toxicity - cyclosporine A (
cholestasis) , azathioprin – (sinusoidal
congestion& zone3 necrosis )
 Recurrent viral hepatitis & PBC
 Post transplant lymphoproliferative
disease

Liver, transplant rejection - Medium
power
Rejection of this transplanted liver is manifest in this image as an
inflammatory portal infiltrate with bile ductular destruction. The
morphologic evidence of bile ductular damage includes a disordered
appearance of bile duct epithelial cells, lack of a visible bile duct
lumen, and inflammatory cell infiltrates in the bile duct walls.

Liver, transplant rejection - Medium power
Endothelialitis of the central vein is present in this image of
the transplanted liver undergoing rejection. This is
manifest as an inflammatory infiltrate surrounding and
infiltrating the central vein wall.

 Assessement of viral serologies
 Microbial culture
 Review of drug therapy
 Radiological demonstration of
patency of biliary tree & vessels

Rejection Rec. HBV Rec. HCV Bile Duct
Obstruction
Cholestasis Yes
Portal inflammation
Mixed Yes
L, P Yes Yes
Neutrophils Yes
Bile Duct Damage Yes Yes
Endotheliitis Yes
Zone-3 necrosis If chronic
Sinusoidal infla. ++
Acidophilic Bodies + ++

Childhood Liver Diseases
• Is acinar structure normal for age ?,see
for fibrosis ,nodularity,cirrhosis early in
evaluation
• Are cholestasis & giant cells present ?
– cholestasis – in portal tract-biliary
tract obstruction , portal tract &
parenchyma- hepatitis
• Hepatitis – giant multinucleated
hepatocytes , liver cell degeneration ,
mononuclear cell infiltration in acini &
portal tract
• Are interlobular ducts normal -

Proliferation of bile ducts
Paucity of bile ducts
Malformation of bile ducts
 Does specimen contain iron or Cu –
neonatal hemochromatosis , ICC ( Cu
toxicity) , Wilson's disease
 Study by DPAS – AAT deficiency
 Are storage cells present – metabolic
diseases

Metabolic Diseases
 Hepatocytes – glycogenosis , AAT def
 Macrophages – Gauchers disease
 Both –Niemann pick , cholesterol ester
storage
PAS stain –
Electron microscopy –
Frozen – biochemical & histochemical
studies

 Type 1 GSD – swollen pale staining hepatocytes
, centrally placed nuclei , mallory bodies ,
uniform mosaic pattern
 AAT defi – periportal hepatocytes show PAS
positive DR globules
 Gauchers – enlarged kupffer cells & portal
macrophages,
 Neimann pick – hepatocytes & macrophages are
swollen ,foamy

Aetiology Histological Features
Extrahepatic biliary
atresia
Proferation of bile ductules in portal
tracts; portal fibrosis; ductular
cholestasis
Paucity of intrahepatic
bile ducts
Loss of intelobular bile ducts (bile
duct; hepatic artery ratio <1)
Neonatal hepatitis
Lobular disaaray ,
cholestasis,Portal & acinar
mononuclear cell inflammation;
acidphil bodies, giant cells , EMH
Metabolic disorders
Fat; fibrosis or cirrhosis; storage
product in liver cells or Kupffer
cells
Proliferation of bile ductules, portal
Liver Biopsy interpretation in Neonatal Cholestasis

CHOLESTASIS
A—
• CANALICULAR – dilated bile canaliculi bet
hepatocytes
• CYTOPLASM OF HEPATOCYTES &
KUPFFER CELLS
• DUCTULAR CHOLESTASIS – sepsis , ductal
plate malformation
B-
Acute – canalicular (perivenular )
Chronic – periportal hepatocytes

Intrahepatic Extrahepatic
Causes
Pure cholestasis-D-J-
S,Rotor S
Gallstones,Ca Head
pancreas,Inflammatory,stricture
s,Tumors of bile duct.
Acquired cholestasis-Viral
hepatitisAlcohlic
Hep,Drug
induce,PBC,PSC,
Degree Mild More marked
Biopsy HPE
findings
Dilated bile canaliculi,bile
plugs,feathery,degene
ration of
hepatocytes,proliferati
on of bile ductules
initially followed by
destruction and
periportal fibrosis
Dilated bile ducts,rupture->Bile
Lakes->toxic to HEP->Focal
necrosis,ascending cholangitis
proliferation of bile ductules

Biopsy In AIDS
 Abnormal LFTs
 AFB & silver stains- mycobacteria & fungus
 Gram stains or warthin starry stain
 Portion of biopsy should be sent for culture
 Opportunistic infection & infestations:
 Histiocytes-striated appearance  Mycobacterium
avium intracellular
 Mycobacterium Tuberculosis
AIDS Cholangoipathy
 Lymphomas Nodular masses or portal tract
infiltration

• Ac Fatty liver of pregnancy (Microvesic), IH
Cholestasis,
• Eclampia :- Fibrin deposits in periportal
sinusoids with haemorrhages in space of
Disse,
• Amyloidosis :- in hep art branches, along
sinusoids in space of Disse, Light chains of
Kappa type

Fibrotest- Actitest
The Fibrotest-Actitest™ is a six-parameter
scoring system that allows quantification of
liver fibrosis and inflammation.
This test has been validated by several
studies in hepatitis B and C viruses and
alcoholic liver disease, with a high
correlation between the liver biopsy.
Six parameters evaluated are total bilirubin,
GGT, alpha-2 macroglobulin, haptoglobin, ,
and ALT, apolipoprotein-A1.

 Fibroscan(Transient Elastography)
 Transient elastography is an ultrasound-based, non-
invasive method, which measures the liver stiffness by
means of a FibroScan® device (EchoSens, Paris,
France).
 By using an ultrasound transducer probe mounted on
the axis of a vibrator, the transmission of low-
frequency vibrations from the right intercostal space
creates an elastic shear wave that propagates into the
liver. A pulse-echo ultrasound acquisition is then used
to detect the velocity of wave propagation.
 This velocity is proportional to the tissue stiffness,
with faster wave progression occurring through stiffer
material. Measurement of liver stiffness is then
performed and measured in kPa.
 The stiffer the liver, the more severe the hepatic
fibrosis (scarring).

Liver biopsy interpretation

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Liver biopsy interpretation