Non Neoplastic Liver

SURGICAL PATHOLOGY
Liver: Non-neoplastic
Conditions
August 17, 2010
VIRAL HEPATITIS
ACUTE HEPATITIS
Definition
Acute infection by hepatotropic viruses A, B, C, D. The
necrosis can be spotty, bridging or submassive.
Clinical features
• Severe and very severe necrotizing hepatitis:
o uncommon
o clinically fulminant hepatitis with:
 acute liver failure
 coma
Pathogenesis
Acute Viral Hepatitis B Fig. 1: Acute viral hepatitis B. Centrilobular area of liver
• Liver cell damage apparently caused by T cell- lobule, characterized by liver cell pleomorphism
mediated and humoral mechanisms1 (including ballooning of hepatocytes), some canalicular
bilirubin stasis, focal liver cell loss, and mononuclear
• Thought to be an ‘elimination type’ of disease: (mainly lymphocytic) inflammatory infiltration. (H&E)
o i.e. virus eradication ensures self-limited
course2  increased cell volume
 pale-staining, granular cytoplasm:
Histopathology  i.e. hydropic change
• Appearance due to different hepatitis viruses may be o probably precursor stages of lytic necrosis
similar or cell dropout
• Varying severity: • Other hepatocytes:
o mild o show:
o moderate:  shrinkage
o severe  increased eosinophilia
o fatal  nuclear pyknosis
• Lesions involve: o most represent cells in process of
o lobular parenchyma apoptosis3,4
o portal tracts o may appear as:
 condensed shrunken cell
Typical Acute Viral Hepatitis  clusters of cell fragments:
• Spotty necrosis  may contain pyknotic
nuclear material
• Panlobular
o often described as:
• Changes may predominate in:
o centrilobular region in hepatitis B and C  acidophil bodies
o periportal zone in hepatitis A  Councilman bodies (incorrect term)
o may be:
• Hepatocellular alterations variable
• Some parenchymal cells:
 naked
o show:  in close proximity to mononuclear
inflammatory cells (Fig. 2)
 ballooning (Fig. 1)
SURG PATH – Non-neoplastic
Page 2 of 54
o phagocytose cell debris from dying
hepatocytes:
 results in intracellular accumulation
of clumps of golden brown, lipid-
rich ‘ceroid’ pigment:
 best revealed in PAS–
diastase stains
 these ‘ceroid macrophages’ are:
 small and scattered as
single cells in earlier
stages
 larger and form clusters
that predominate in
centrilobular and midzonal
areas later
 found migrated into portal
Fig. 2: Detail of lobular parenchyma in mild acute viral connective tissue in still
hepatitis C. Eosinophil condensation of hepatocellular later stages
cytoplasm (Mallory body-like) and rounded eosinophil
fragments of apoptotic hepatocyte, with a few adjacent  may stain for iron in acute
mononuclear inflammatory cells. (H&E) viral hepatitis
 inside phagocytosing macrophages Acute Viral Hepatitis

• Mild steatosis: • Lobular parenchymal lesions predominate
o minority of cases • Portal tracts:
• Several hepatocytes may appear in mitosis o mononuclear cell infiltration:
• Syncytial, multinucleated, giant hepatocytes:  composed of:
o typical of neonatal hepatitis  lymphocytes
o sometimes in adults  plasma cells
o without diagnostic significance for specific  neutrophils
etiology
 eosinophils
• Loss of normal regular liver cell plate pattern:
o i.e. lobular disarray  pigment-laden
macrophages:
o diagnostically helpful
 especially in later
o due to combination of: stages
 heterogeneous appearance of  usually within portal connective
parenchymal cells: tissue, with preservation of limiting
 ballooning plate
 shrinkage  sometimes spills out into adjacent
 apoptosis parenchyma:
 cell dropout  blurs outline of portal tract
 regeneration of surviving  resembles piecemeal
hepatocytes necrosis or interface
hepatitis characteristic of
• Some microscopic bilirubin stasis: chronic hepatitis
o common
o reflects variable degree of cholestasis
Acute Hepatitis
• Inflammatory cells infiltrate altered parenchyma:
• Increase in ductular profiles at portal–parenchymal
o predominance of mononuclear and interface:
lymphocytic cell types o so-called ductular reaction
o most lymphocytes are activated memory T o very mild in classical acute lobular hepatitis
cells5
o also plasma cells from early stage6 o better revealed by cytokeratin 7
immunostains
o small clusters of lymphocytes represent: o extent increases with severity of necrotizing
 foci of cytotoxic lymphocyte- parenchymal lesions
mediated target cell attack
• May be:
 described as: o lymphocytic infiltration between and inside
 focal inflammation bile duct lining cells
 focal necrosis o some bile duct epithelial damage:
 spotty necrosis o especially in viral hepatitis C7
Later Stages Of Acute, Self-Limited Hepatitis
• Kupffer cells:
o enlarge • Most parenchymal and portal changes gradually
disappear
o become more prominent
• Residual changes:
Page 3 of 54
o such as:
 mild infiltration in some portal
tracts
 some focal inflammation in lobules
 a few remaining macrophages
 anisokaryosis too prominent for
patient's age
o may persist for several months
Minimal Acute Hepatitis

• Limited damage and inflammation
• Slight liver cell ballooning
• Some apoptotic bodies
• No bilirubin stasis
• Mild lymphocytic infiltrate
• Scant numbers of macrophages Fig. 3: Severe necrotizing acute viral hepatitis B. Overview of
liver lobule; mild to moderate mononuclear cell infiltration in
• Minimal infiltration in only part of portal areas portal tracts (lower left, top, and lower right). Bridging portal–
central confluent lytic necrosis, realizing a ‘star-shaped’ area
Severe Acute Hepatitis of necrosis with a centrilobular vein at its center and
peripheral points reaching portal tracts. Inflammatory cells
• Acute hepatitis with bridging necrosis
are scattered throughout the lobule. (H&E)
• Death of larger groups of hepatocytes )
• More extensive parenchymal damage: o even higher degree of severity;
o usually lytic necrosis of hepatocytes  lytic necrosis of all acinar zones:
affecting contiguous parenchymal
territories:
 i.e. panlobular and
multilobular necrosis
 i.e. confluent necrosis
 predominantly in microcirculatory
Necrotic Bridges
periphery
• Patterns of necrosis best explained according to
• Change in appearance over time:
acinar concept of liver architecture:8 o if new:
o with increasing severity, confluent necrosis  reveal lobular areas where
wipes out parenchyma of periphery of parenchyma has disappeared,
acinar zone 3: without or little collapse of reticulin
framework
 results in centrilobular confluent
necrosis  necrotizing areas infiltrated by:
o a higher degree involves entire acinar zone  mononuclear cells
3:  some small ceroid
 results in dropout of parenchyma macrophages
between portal tracts and central o later stages:
veins:
 collapse of reticulin fibers
 i.e. bridging hepatic
 proliferation of mesenchymal cells
necrosis:
 used to have a
 collagen deposition
broader  possibly:
meaning9,10  bulging of regenerating
 here definition is: remaining parenchyma
 acinar  larger numbers of ceroid
zone 3 macrophages
necrosis, o older necrotic bridges:
or  heal with fibrous scars:
 portal–  result in portal–central
central bridging fibrosis
bridging
o severely necrotizing hepatitis:
necrosis
(Fig. 3)  more severe periportal ductular
reaction
 areas of surviving parenchyma:
 changes of classical
lobular hepatitis but:
 usually more
marked:
 focal
necrosis
Page 4 of 54
 bilirubin Acute Viral Hepatitis
stasis • Histology:
o similar for acute viral hepatitis A, B, C, D,
Acute Hepatitis With Panlobular And Multilobular and E
Necrosis o may be confused by:
• Submassive liver necrosis  coinfection with more than one
• Severe and very severe necrotizing hepatitis virus
• Parenchyma:  concomitant liver disease, e.g.:
o lytic confluent necrosis:  hepatitis of alcoholic type
 throughout entire liver lobule:  primary sclerosing
cholangitis
 i.e. panlobular necrosis
 affects several adjacent lobules:
Acute Viral Hepatitis A14–17
 i.e. multilobular necrosis:
• May be:
 if survive results
o dominant centrilobular bilirubin stasis
in alternating:
o little liver cell damage and inflammation
 collapse
and • May cause cholestatic hepatitis:
fibrous o particularly in adults
scarring o may be some bile duct damage20
of
necrotic • Sometimes hepatitic changes show periportal
zones predominance, with dense, plasma cell-rich portal
infiltrates:

nodular o periportal parenchymal necrosis with
regener
interruptions of canals of Hering may
ation of
contribute to the cholestatic features16
survivin
g • Also other patterns of hepatitis
parench • Rarely:
ymal o severely necrotizing hepatitis with
territorie multilobular necrosis
s
o extensive confluent necrosis usually • May be fibrin ring granulomas21,22
distributed heterogeneously throughout • Requires serologic analysis:
liver: o occasionally prolonged and polyphasic
 needle biopsies may not be clinical course with two or more relapses of
representative rise in transaminase values23
• Ductular reaction:
o more prominent in multilobular necrosis Acute Viral Hepatitis B
o represents attempt at regeneration by liver • When fully developed:
progenitor cells o little or no hepatitis B surface antigen
o corresponds to ‘atypical’ ductular reaction: (HBsAg)
 i.e. epithelial proliferation o hepatitis B core antigen (HBcAg)
comprises: demonstrated immunohistochemically
Acute Viral Hepatitis B
 bile ductular cells
• Similar to other forms of hepatitis14,15,24,25
 transitional cells with
phenotype intermediate • Centrilobular predominance of liver cell damage and
between cholangiocytes inflammation
and hepatocytes11,12 • Lymphocytes may lie:
o if severe necrosis or sepsis: o in close contact with hepatocytes:
 some ductules may contain  i.e. peripolesis
inspissated bilirubin-stained o inside hepatocytes:
concrements:13
 i.e. emperipolesis
 should not be mistaken as
sign of biliary obstruction • Ground glass hepatocytes:
o not seen
o presence indicates chronicity
Special Stains and Immunohistochemistry • Intravenous drug abuse recognized by presence of
Acute Viral Hepatitis A14–17 birefringent spicules of talc in portal tracts26,27
Immunohistochemistry:
viral antigen in cytoplasm of:
• Controversial about whether chronic course can be
predicted on findings in liver biopsy during acute
hepatocytes
stage:
Kupffer cells18
Viral RNA located by in situ hybridization19 o no single lesion has predictive value in early
infection
o later biopsies (> 2 months) may yield
Diagnosis unfavorable prognostic information:
Page 5 of 54
 in form of periportal interface o Wilson's disease
hepatitis28 • Often impossible to pinpoint etiology on histologic
 possibly also confluent lytic grounds because all or most parenchymal cells
(bridging) necrosis disappear through lytic necrosis
 definitely when viral antigens
(HBsAg, HBcAg) can be Minimal Acute Hepatitis
demonstrated in tissue • Poorly diagnostic picture:
o resembles nonspecific reactive hepatitis:
Acute Viral Hepatitis C  mild hepatitic changes in liver with
• Essentially features previously described for non-A, extrahepatic inflammatory disease
non-B hepatitis, i.e.:21,29–31 (e.g. pneumonia)
o liver cell swelling
o apoptosis Differential Diagnosis
- Drug Induced Toxic Liver Injury
o cholestasis - Steatohepatitis
o lymphocytic intralobular infiltration
o bile duct damage Acute Viral Hepatitis A14–17
o portal lymphoid aggregates and lymphoid • May be mistaken for other causes of cholestasis:
follicles: o e.g. drug-induced cholestasis
 most characteristic features of
chronic hepatitis C Acute Hepatitis With Marked Cholestasis
• Lymphocytic infiltration: • Differentiated from obstructive forms of cholestasis
o may be prominent in sinusoids (‘Indian file’ by typical necroinflammatory lobular lesions in acute
appearance) in absence of noticeable hepatitis
parenchymal damage:
Drug-induced Hepatitis
 resembling Epstein–Barr virus
hepatitis: • May be indistinguishable histologically from viral
hepatitis:
 i.e. mononucleosis-like
picture • Features suggestive of drug-induced lesion:
o sharply delineated centrolobular necrosis
• Steatosis:
o fairly common24 o abundant eosinophils
o granulomas
• Fulminant hepatitis with multilobular necrosis rare in
developed countries • Absence of these features does not exclude drug
hepatitis
• Immunohistochemistry in situ hybridization for HCV
RNA:32
Autoimmune Hepatitis
o overall results lack specificity
• Can have acute onset histologically similar to viral
hepatitis
Acute Viral Hepatitis D
• Three settings: Acute Hepatitis Of Alcoholic Type
o simultaneous acute hepatitis D infection and • Recognized by:
acute type B hepatitis o conspicuous steatosis
o acute hepatitis D superimposed on chronic o Mallory bodies
hepatitis B o neutrophil satellitosis
o chronic hepatitis D infection superimposed o pericellular (‘chicken-wire’) fibrosis
on chronic hepatitis B33
• Histology similar to other forms of hepatitis, but Acute vs Chronic Hepatitis
tends to be more severe: • Histologic differentiation between acute and chronic
o cannot be reliably distinguished from hepatitis difficult
hepatitis B or C34–36 • To make diagnosis consider:
• Immunohistochemistry for HDV antigens in tissue o global histologic picture:
reliable for documenting infection34,36,37
 differentiation generally based on:
• Microvesicular change in hepatocytes:
 predominance of:
o in parts of South America and Africa38
 portal and
o i.e. spongiocytic change or morula cell periportal
degeneration changes and
o attributed to accumulation of small lipid fibrosis in chronic
droplets in damaged hepatocytes hepatitis
 lobular lesions in
Severe Necrotizing Hepatitis acute hepatitis
• Causes: o clinical data
o hepatitis viruses • Fibrous bridges in chronic hepatitis recognized by
o autoimmune hepatitis gradual deposition of elastic fibers:
o adverse drug reactions o i.e. positive elastica stains:
o toxic liver cell necrosis o bridges in acute hepatitis stain negative
Page 6 of 54
CHRONIC VIRAL HEPATITIS

Definition Spotty Necrosis
Chronic inflammation of the liver. Common causes include • An older term
hepatitis B, hepatitis C, autoimmune and cryptogenic. • Loosely applied to:
o apoptosis
o genuine necrosis of single hepatocytes
Pathogenesis
Multiple Etiologies • More appropriate term would be focal
Viral necroinflammation:
• HBV o recognizable as:
• HDV  small cluster of mononuclear cells:
• HCV1  lymphocytes
• Combined infections:  possibly histiocytes
o B+D  may be adjacent identifiable
o B+C apoptotic body or bodies
o C+HIV • Looks the same as in acute hepatitis (Fig. 1)
o C+HGV
Nonhepatitis Viral Causes

• Cytomegalovirus
• Epstein–Barr virus
• Herpes virus
• Adenovirus
Other
• Autoimmune2
• Drug-induced3,4 Fig. 1: Acute viral hepatitis B. Centrilobular area of
liver lobule, characterized by liver cell pleomorphism
(including ballooning of hepatocytes), some
Chronic Viral Hepatitis B
canalicular bilirubin stasis, focal liver cell loss, and
• Successive phases of viral replication, elimination, mononuclear (mainly lymphocytic) inflammatory
and integration, associated successively with: infiltration. (H&E)
o lesser, higher, and again decreasing
degrees of necroinflammatory disease Confluent Lytic Necrosis
activity5,6 • More severe disease14
o implies successive occurrence of CPH and • Dropout of contiguous groups of hepatocytes with
CAH variants in individual patients denudation of reticulin framework
• Extent may range from focal and zonal over
Chronic Hepatitis C ‘bridging’ confluent necrosis (Fig. 2)
• Hepatocellular damage mainly immune mediated7
Factors Associated With Fibrosis

• Strength of association varies
• Include:
o male gender
o advanced age
o excessive alcohol use
o duration of infection
o HIV coinfection8–10
o nonalcoholic steatohepatitis11
o porphyria cutanea tarda12 Fig. 2: Bridging confluent lytic necrosis in severe
chronic viral hepatitis B. Inflamed portal tract
‘bridged’ through area of necrosis with centrilobular
area (lower left). The upper right part corresponds to
Histopathology
an area of extensive lytic necrosis in phase of
Elementary Lesions
postnecrotic collapse of the reticulin framework and
• Comprise: early fibrosis. (H&E) to more extensive panlobular
o spotty necrosis and multilobular
o confluent lytic necrosis
o portal inflammation • Often small, glandlike clusters of surviving
o interface hepatitis hepatocytes – hepatitic rosettes – within inflamed
tissue (Fig. 3):
o fibrosis
o cirrhosis13
Page 7 of 54
 mesenchyme (portal tract or
septum)
 parenchyma
• Periportal18
• Corresponds to extension of lymphocytic portal
infiltrate beyond limits of portal tract
• Associated with cell death (cell by cell or ‘piecemeal’)
of hepatocytes
• Surviving hepatocytes trapped within inflammatory
infiltrate
• Neoangiogenesis
Fig. 3: Severe chronic viral hepatitis B. Area of • Fibrosis
multilobular lytic necrosis in phase of postnecrotic • May be:
collapse and early fibrosis, with several small islands o mild:
of surviving hepatocytes, appearing swollen and
pale, and sometimes arranged in tubular fashion  one or a few foci around portal
(‘hepatitic-type liver cell rosettes’). (H&E) perimeter without noticeable
fibrous extension
o usually surrounded by connective tissue o severe:
o presumably attempts at regeneration from  wedge-shaped extension of
surviving hepatocytes necroinflammatory lesion
 obvious fibrosis deep into lobule
Portal Inflammation • Causes enlargement of portal tracts with irregular
• May be: outlines
o mild
o moderate Fibrosis
o dense • Progressive in more active variants
• Composed of: • Intralobular fibrosis:
o mononuclear cells: o apparently due to continuous ongoing
lobular necroinflammatory damage19
 mainly lymphocytes
o variable numbers of plasma cells • Septal fibrosis:
o other mononuclear cells: o may be:
 histiocytes  periportal:
 immature lymphocytes  presumably result of
interface hepatitis
• May be:
o lymphoid aggregates
 portal–portal:
o true lymphoid follicles  presumably result of
interface hepatitis
 portal–central septa:
Interface Hepatitis
 apparently result of
• Originally termed ‘piecemeal necrosis’ (Fig. 4) portal–central (bridging)
confluent necrosis
Cirrhosis
• Result of:
o ongoing necroinflammation
o progressive fibrosis
o parenchymal regeneration
• Necroinflammatory changes may:
o subside:
 i.e. inactive cirrhosis
Fig. 4: Marked interface hepatitis (‘piecemeal o continue unabated:
necrosis’) in chronic viral hepatitis B. Note inflamed
portal tract (upper right) and wedgelike extension of
 i.e. active cirrhosis
necroinflammation (towards lower left) and irregular
interface between portal periphery and adjacent Chronic Viral Hepatitis B
parenchyma all around the necroinflammatory area. • Viral antigens may be recognizable by light
microscopy, creating helpful diagnostic markers such
• Interface hepatitis preferred terminology because: as:
o mode of liver cell death is apoptosis, not o ground glass hepatocytes
necrosis15–17 o sanded nuclei
o lesion is at interface between:
Ground Glass Hepatocytes20
Page 8 of 54
• Parenchymal liver cells with:  occurs in other
o finely granular and more pale appearance of liver diseases26–
part or all cytoplasm – ‘ground glass’ area: 32
 often separated from cell
membrane by clear halo – an Sanded Nuclei
artefact (Fig. 5) • Larger central part of nucleus:
o finely granular
o pale eosinophilic:33
 due to massive accumulation of
HbcAg
 not easily recognized
 specific immunohistochemistry
helpful in identifying HBcAg
Findings During Course Of Disease

• Vary
Early Viral Replication And Immune Tolerance Phase

• Minimal hepatocellular damage and inflammation
• HbcAg37 and HbeAg in:38
o nucleus
Fig. 5: Chronic viral hepatitis B,
o cytoplasm
high magnification. Ground glass o liver cell membranes (Fig. 6)
hepatocytes, characterized by
more pale, eosinophilic, and
homogeneous cytoplasm than
surrounding normal (more
granular) hepatocytes. Note
(artefactual) cleft between ‘ground
glass’ cytoplasm and
hepatocellular cell membrane. The
first nucleated hepatocyte in the
left lower corner reveals a less
pronounced ‘ground glass’
appearance (corresponding to less
extensive endoplasmic reticulum
hyperplasia and less massive
Fig. 6: Chronic viral hepatitis B; viral
accumulation of HBsAg). (H&E)
replicative phase. Hepatitis B core antigen
is localized in hepatocellular nuclei and, in
 due to marked hypertrophy of several hepatocytes; also in the cytoplasm
smooth endoplasmic reticulum: and cell membrane. (Immunoperoxidase
 displaces cytoplasmic stain for HBcAg)
organelles to periphery of
cell • HbsAg in:
 contains excess o cytoplasm of some scattered hepatocytes
filamentous structures of o membrane of numerous parenchymal cells:
HBsAg in cisternae:21,22
 honeycomb-like pattern (Fig. 7)
 HBsAg
relationship
confirmed by
special stains,
such as:
 Shikata'
s orcein
stain23
 Victoria
blue24
 aldehyd
e
fuchsin2
5
 specific
antibody
 not entirely specific:
Page 9 of 54
 ground
glass
cells, or
 staining
in
peripher
y of
parench
ymal
cells
(Fig. 8
Fig. 7: Chronic viral hepatitis B: viral replicative phase.
Hepatitis B surface antigen is localized in variable quantity in
the cytoplasm and in the cell membrane of several
hepatocytes. Note only mild lymphocytic infiltrate in portal
tract and lobule. (Immunoperoxidase stain for HBsAg)
Viral Elimination Phase

• Low viral replication
• Immune clearance of hepatocytes
• Seroconversion from HBeAg to HBe antibody
• Disappearance of HBV DNA from serum
• More necroinflammatory lesions:
o including confluent lytic necrosis in more
severe cases42
• HBcAg in:
o nucleus
o cytoplasm
o liver cell membranes
• HBeAg in:
o nucleus
o cytoplasm43
• HbsAg:
o weak positivity in cytoplasm of some
hepatocytes with membranous staining
pattern:34,35,41
 mild inflammation may persist for
some time after loss of HBsAg in
serum44
• After acute exacerbations45 cirrhotic changes in
≈40% of patients:34 Fig. 8: Chronic viral hepatitis B: viral nonreplicative
o if cirrhosis does not supervene liver may (integration) phase. Hepatitis B surface antigen is localized in
recover with only minimal histologic considerable quantity in the cytoplasm of a contiguous group
abnormalities46 (‘clone’) of hepatocytes. Note relatively mild lymphocytic
infiltrate in portal tract and lobule. The more intensely
• Sometimes ongoing inflammatory activity and staining cells appear as ‘ground glass hepatocytes’ on H&E
interface hepatitis: staining. (Immunoperoxidase stain for HBsAg)
o due to persistence of a special mutant of
HBV with deficient HBeAg synthesis47,48
• HBcAg usually absent
o immunostaining reveals cytoplasmic
HbcAg49 • No active replication of HBV
• More aggressive forms of disease41 and cirrhosis46
more likely if:
Phase Of Viral Integration
o persistent HBcAg in liver
• Occurs when some virus-replicating hepatocytes
apparently escape immune elimination:
o higher level of HBV viremia
o leads to: • May be:
 persistence of viral infection
o normal architecture
o variable degrees of fibrosis
 integration of viral DNA into host
genome: o cirrhosis:
 HBsAg is continuously  progresses slowly over 20–30 years
produced by these cells50  eventually decompensation and
 patient becomes HBsAg other complications
carrier  initially micronodular
 HBsAg accumulates in  later more macronodular34
clusters of hepatocytes:  may be complicating hepatocellular
 appears as: carcinoma:
Page 10 of 54
• Healthy HBsAg carriers: o reactivation after immunosuppressive
o no cirrhosis therapy71
o risk for hepatocellular carcinoma o relapse after interferon therapy
• May be precancerous lesions in precirrhotic and

o portal infiltrate rich in lymphocytes:
cirrhotic stages:  often lymphoid aggregates (Fig. 9)
o large cell dysplasia
o small cell dysplasia
o macroregenerative nodules
Chronic Viral Hepatitis B + D

• Compared with uncomplicated chronic hepatitis B
chronic hepatitis D tends to be:
o more severe, with:
 higher activity
 risk of progression51,52
• Occasionally:
o rapid progression to cirrhosis with active
HBV replication
• More commonly:
o slow disease evolution
o evolves into cirrhosis over many years53,54
• HDV:
o selectively suppresses HBcAg and HBeAg, Fig. 9: Chronic viral hepatitis C.
Low-power view of two joined
but not HbsAg55
portal tracts with dense
o depends on low-grade HBV multiplication mononuclear cell infiltration,
and release56 forming a lymphoid aggregate and
• Immunohistochemically, HDAg found: a lymph follicle. The portal–
o mainly in liver cell nuclei:57 parenchymal interface is irregular
(moderate degree of interface
 may show sanded appearance58 hepatitis). A few scattered
due to excess HDAg macrovesicular steatosis vacuoles
o in cytoplasm and membranes of are visible in the lobular
hepatocytes59 parenchyma. (H&E)
• Double immunostaining for HBV and HDV antigens:
o often separate expression of HDAg versus  even follicles:
HBsAg or HbcAg  particularly prominent
o may be coexpression60 germinal centers72–79
 not specific for hepatitis C
Chronic Viral Hepatitis C  also in:
• 170 million people with chronic infection  hepatitis B72,77
worldwide61,62
 autoimmune
• Usually silent onset hepatitis72
• High rate of viral persistence  primary biliary
• Potential worsening chronic liver disease: cirrhosis
o chronic hepatitis • Lesions of interlobular bile ducts (Fig. 10):
o cirrhosis
o occasionally hepatocellular carcinoma61
• Retrospective studies tend to overestimate
progression to cirrhosis and cancer
• Prospective and cohort studies:
o indicate lower rate of progression
o suggest spontaneous viral clearance may be
higher than thought
o severe, life-threatening, progressive liver
disease in perhaps 30% of those chronically
infected
• Characteristic histopathology:63–66
Fig. 10: Chronic viral hepatitis C. Detail of portal tract showing
o initially often mild with little parenchymal a lymph follicle containing an irregular and damaged bile duct
damage:67,68 near its center. Note the epithelial irregularity and intramural
o mainly focal inflammation and lymphocytic infiltrate. (H&E)
hepatocellular apoptosis69
o spontaneous exacerbations70 o in 15 to 91% of biopsies:65,72
Page 11 of 54
 i.e. poor consensus on definition of • Increased hepatic iron:
bile duct lesion o even in absence of blood transfusion or
o most frequently observed lesion: alcohol abuse94
 infiltration of lymphocytes between o iron overload impairs response to interferon
cholangiocytes therapy:95
 bile duct lining cells show variable  liver biopsy assessment should
degrees of: include comment about presence
 vacuolation or absence of excess iron in
hepatocytes96
 stratification
• Similar histopathology in children:97
 crowding o perhaps faster development of fibrosis98
o most pronounced bile duct lesion:80
• Different genotypes of HCV may influence
 swelling and polystratification of histopathology, such as:
bile duct lining cells o degree of steatosis
 infiltration by lymphocytes and o rate of bile duct lesions
larger mononuclear cells
o disease activity99,100
 preservation of basement
membrane81 • Increased inflammatory activity, especially interface
hepatitis:101
 differentiate from lesion in primary o if clinical manifestations of autoimmunity
biliary cirrhosis
• Lobular lesions:
Premalignant Lesions In Chronic Viral Hepatitis B and C
o may comprise striking number of acidophil
bodies (apoptosis) • Strong association between hepatocellular carcinoma
and:
• Mild to moderate steatosis (Fig. 11):
o chronic hepatitis B102
o chronic hepatitis C103
• Main presumed or proven premalignant lesions in
chronic hepatitis type B and C:
o liver cell dysplasia:
 large and small cell types:104
 dysplastic foci:

groups of (large-
cell or small-cell)
dysplastic
hepatocytes
<1mm
Fig. 11: Chronic viral hepatitis C: moderately dense portal diameter105
infiltrate, focus of interface hepatitis; marked macro- and o macroregenerative nodules (adenomatous
mediovesicular steatosis; occasional apoptotic body (middle hyperplasia)106
left). (H&E)
Large Cell Dysplasia107
o usually macrovesicular
o in 1 to 72%65,72 of biopsies
• Hepatocytes:
o enlarged
o appears to be mainly viral effect,82
o nuclei:
especially of HCV genotype 383
• Periportal hepatocytes:  irregularly shaped
o may contain coarse clumps of eosinophilic  hyperchromatic
cytoplasm:  prominent nucleoli
 Mallory body-like77,84 o nucleocytoplasmic ratio:
• Lymphocytic infiltration in lobules:  normal or slightly increased108
o may form rows along sinusoids (Indian files): • Mainly HBV and HCV infection109
 resembles hepatic mononucleosis • Not direct forerunners of malignant carcinoma cells
• Venous lesions: • An independent risk factor for development of
o resemble endotheliitis in cellular liver hepatocellular carcinoma110
allograft rejection85
• Epithelioid granulomas: Small Cell Dysplasia
o in 5% of cases86–88 • Hepatocytes:
o apparently transient89 o smaller than in large cell dysplasia
o has been correlated with interferon-α o cytoplasm:
therapy90
 basophilic
o associated with good91 and bad response92 o nucleus:
o exclude other causes of granulomas87
 moderately increased size
• Some bile duct loss in late (cirrhotic) stage:93 o nucleocytoplasmic ratio:104
o differentiate from primary biliary cirrhosis
Page 12 of 54
 increased
• May be a better precancerous candidate than large
cell dysplasia111
Macroregenerative Nodule
• Previously termed adenomatous hyperplasia
• Unusually large regenerative nodule ≥0.8cm
diameter
• In cirrhosis and other chronic liver disease:
o particularly macronodular cirrhosis112,113
• Dysplastic nodules: Fig. 12: Chronic viral hepatitis C. Viral
o >1mm antigen (HCV-E2), appearing as positive
o considered to be more advanced precursor cytoplasmic granules, is localized in virtually
every periportal hepatocyte in this case.
lesions105
(Immunoperoxidase ‘Envision’ technique,
o low or high grade, with varying degrees of: using antibody IGH222 – Innogenetics,
 liver cell dysplasia Ghent, Belgium119)
 increased cellularity
 loss of cohesiveness • No accurate noninvasive markers of disease activity
 pseudoacini and fibrosis
 focal loss of reticulin fibers113,114 • Liver biopsy:122,123
o exclude other liver pathology
o establish stage
Histopathology of chronic hepatitis
• Suggestive features:101,115 Autoimmune Hepatitis
o necroinflammatory activity tends to be high • Several types:
in untreated patients o different patterns of autoantibodies124
o common features: • May benefit from immunosuppressive therapy
 bridging confluent necrosis
 marked interface hepatitis Drug-induced Chronic Hepatitis
 hepatitic liver cell rosettes116 • Always consider when etiology obscure
• May be multinucleated giant hepatocytes:117,118
o also in other types of hepatitis116 Cryptogenic Chronic Hepatitis
• Inflammatory infiltrate: • No characteristic features pointing to a particular
o mainly lymphocytes etiology
o prominent plasma cells: • Disease activity often mild125
 often clusters72
o may be lymphoid aggregates and follicles: Combined Pathology
Combined Infection With HBV and HCV
 less than in viral hepatitis C
• May be overlap syndrome with features of biliary
• Increases severity of histologic liver lesions126
disease: • Triple infection with HBV, HDV, and HCV:
o confounded by finding of bile duct lesions in o severe disease in acute superinfection stage
genuine autoimmune hepatitis119 o course:
 relatively benign
Diagnosis
 slowly progressive
Chronic Viral Hepatitis C  usually dominated by HCV127,128
• HCV RNA detection in frozen liver tissue sections by
in situ hybridization: Superinfection Of Chronic Hepatitis B with HDV
o lacks specificity120 • Usually severe activity with extensive interface
• Immunocytochemical demonstration of viral antigens hepatitis33,43
in cytoplasm of hepatocytes:
o few antibodies give reproducible and HIV Infection
clinically useful results in paraffin-
embedded material • Results in reactivation of hepatitis B:
o antibody IGH222 (Innogenetics, Ghent, o higher levels of HBV replication
Belgium) may be more promising (Fig. 12) o no increase in necroinflammation
o more immunocytochemically demonstrable
HBcAg and HBeAg129
• With chronic hepatitis C:
o higher necroinflammatory activity
o cirrhosis more frequent130
Page 13 of 54
 consider clinical and
HGV Virus Infection serologic data
• No apparent effect on chronic hepatitis C131,132  grade of disease activity
 stage of disease progression (Table
1)
TTV Infection
• Reported not to affect course of chronic hepatitis B Table 1.
or C and response to interferon-α therapy133 Classification of chronic hepatitis
Multiple Hepatitis Virus Infection Diagnosis of chronic hepatitis

Etiology
• Quite common Grade of disease activity
• Cannot be reliably recognized histologically134 Stage of disease progression
• Immunocytochemical stains for viral antigens
helpful135
Differential Diagnosis
- Drug Induced Toxic and Liver Injury
Hemochromatosis136 - Acute Hepatitis
• May be foci of hepatocellular hemosiderosis in
chronic viral hepatitis C and B • Distinction should be made between:
o true ‘lymphocytic piecemeal necrosis’ as in
Classification chronic hepatitis
Original Classification o ‘biliary piecemeal necrosis’ of chronic biliary
• Simple classification of chronic hepatitis, based on disease:
histology proposed in 1968:137  irregular outline of enlarging portal
o immunosuppression was standard tract due to ductular reaction with
treatment reserved for the more ‘active’ associated:
forms  neutrophil infiltration
o distinguished between:
 cholate stasis of periportal
 milder form with low level hepatocytes143
necroinflammatory activity:
• Wilson's disease:
 chronic persistent o may resemble chronic hepatitis clinically
hepatitis (CPH) and histologically144,145
 more severe variants with more • Alpha-1-antitrypsin deficiency146
severe necroinflammatory lesions:
• Piecemeal necrosis also observed in chronic biliary
 chronic aggressive or diseases such as:
active hepatitis (CAH)
o primary biliary cirrhosis
o widely accepted
o primary sclerosing cholangitis
o used worldwide for nearly 40 years
o emphasized that CPH and CAH were: Without Interface Hepatitis
 variations in degree of disease • Resolving acute hepatitis
activity
• Nonspecific inflammation
 not distinct disease entities
• Primary biliary cirrhosis
• Lymphoma
Revised Classification
• Because more efficient treatment for viral types of With Lobular Lesions
chronic hepatitis32,138–140 • Distinguish from acute hepatitis
• In 1994, two proposals:141,142 • Orcein staining helps identify older collapse
o restrict term ‘chronic hepatitis’ to original • Ground glass hepatocytes testify to chronicity in
meaning: hepatitis B
 i.e. clinical and pathologic • Bilirubin stasis much more frequent in acute hepatitis
syndrome:
 with several causes With Interface Hepatitis
 characterized by varying • Primary biliary cirrhosis
degrees of hepatocellular • Primary sclerosing cholangitis
necrosis and inflammation
• Wilson's disease
 still defined (as in 1968) as a
continuing disease without • Alpha-1-antitrypsin deficiency
improvement for at least 6 • Lymphoma
months141 • Alertness, special stains, and coordination with
o also determine: clinical information essential for correct diagnosis
 etiology:
 cannot be based on Staging/grading
histology alone Grade of Disease Activity
• Clinical symptoms
Page 14 of 54
• Aminotransferase levels  as a tool in clinical therapeutic
• Histopathology of liver biopsy: trials153
o main components: • Choose most suitable system for:
 portal inflammation o grading173
o staging174
 interface hepatitis
o use:
 intralobular damage and
inflammation  clinical practice
 confluent necrosis  investigative work166
o several systems: • Define criteria for each score as strictly as
 daily practice: possible156,172
 an adequate report • Scoring carried out by at least two observers152

consists of accurate • Control intra- and interobserver variation:167
estimate of various o accurate meta-analysis not possible172
lesions, described as:
 minimal Other systems
 mild • A mathematical scoring system:
 moderate o based on fractal geometry for quantifying
irregular pattern of liver fibrosis175
 severe
• Morphometry173 and image-analysis
 for specific purposes, such as quantification:177–179
comparison of pre- and post-
o appear more sensitive than
treatment biopsy specimens and
for evaluation of therapeutic trials: semiquantitative scoring in detecting
smaller changes in degree of fibrosis
 semiquantitative scoring
systems • Restricted to specialized centers
• Best used in combination with semiquantitative
Stage Of Disease Progression histologic evaluation systems178
• Evolutionary stage has significant prognostic and
therapeutic implications142 Management
• Histologic evaluation based on:
o extent of fibrosis • Immunosuppressive treatment reduces severity of
necroinflammation and fibrosis180
o development of cirrhosis
• Connective tissue stains are essential for staging CIRRHOSIS
Definition
• Can be expressed in classical descriptions:
Diffuse hepatic fibrosis and replacement of normal hepatic
o appropriate method for daily reporting of architecture by parenchymal nodules separated by fibrous
biopsies tissue. The end stage of a variety of chronic liver disorders.
• For specific purposes, semiquantitative scoring
systems
Clinical Features
Semiquantitative Scoring
• End stage of many chronic liver diseases
• Several systems proposed as applied in other areas
of diagnostic histopathology147–162
• Histological Activity Index (HAI or Knodell index) Histopathology
o published 1981158 • Diffuse hepatic fibrosis:
o most widely used o replacement of normal lobular architecture
• Simple scoring system proposed by Scheuer:162 by parenchymal nodules separated by
o easily applicable and reproducible154 fibrous tissue1
• Modified HAI: • Portal–central septa linking portal tracts and central
veins:
o extension of Knodell system, with
modifications156
o important component
o validated for intra- and interobserver • Histologically best appreciated on reticulin stain2
variability163 • Variable hepatocellular features of individual nodules
• Chronic hepatitis C system proposed by French such as:
METAVIR Cooperative Study Group:150,151 o steatosis
o widely applied, especially for o siderosis
staging164,165 o ground glass hepatocytes
• Different scoring systems have different strengths Morphologic Classification
and weaknesses150,166–172 • Based on size of nodules1
• Histologic scoring:
o reserve for special purposes:
 comparing pre- and post-treatment
biopsies of a single patient
 as a research method for studying
course of disease
Page 15 of 54
o micronodular: • Nodularity and septa may be readily evident in
micronodular cirrhosis
• More subtle criteria for macronodular cirrhosis
including:
o fragmentation of biopsy specimen:
 especially with slender tissue
cylinders provided by thin
aspiration type needles
o thin layers of connective tissue adhering to
rounded edges of nodular biopsy fragments
o abnormal orientation of reticulin fibers due
to different rates of parenchymal growth in
different areas
o portal tracts and central veins:
 nearly all nodules <3mm diameter
(Fig. 1)  abnormal spacing
  excess numbers of draining veins
in relation to number of portal
 tracts
o presence of minute and poorly formed
portal tracts (‘mini-portal tracts’)
o hepatocellular features of regeneration:
 double-cell plates over widespread
areas
 different appearance of
hepatocytes in adjacent areas
 liver cell dysplasia:
 large cell
 small cell
Fig. 1: Detail from micronodular cirrhosis. Incomplete Septal Cirrhosis

(Reticulin silver impregnation) • Most difficult type to recognize (Fig. 3)
o macronodular:
 nearly all nodules >3mm diameter
(Fig. 2)
Fig. 3: Detail from ‘incomplete septal type’ cirrhosis.

Can be considered a macronodular variety of
cirrhosis with large multilobular nodules, thin,
incomplete septa, and little inflammatory activity.
(Sirius red stain)
• Characterized by:
o vague nodularity
Fig. 2: Detail from macronodular o slender septa:
cirrhosis. Note larger nodules, thin,
fibrous septa, and irregular  some end blindly
orientation of liver cell plates. o mini-portal tracts
(Reticulin silver impregnation) o excess efferent veins
o sinusoidal dilatation
o mixed micro-macronodular:
• Parenchymal hyperplasia with compression of
o ≈ equal numbers of nodules > and <3mm reticulin fibers in adjacent areas
diameter
• Absent or minimal:
o inflammation
Needle Biopsy Specimens o necrosis3
Micronodular and Macronodular Cirrhosis
• Nodular size determines ease with which diagnosis
can be made Histologic Activity
• Should be noted
Page 16 of 54
• May reflect ongoing disease even in cirrhotic stage o but micronodular cirrhosis may convert into
• Activity consists of: macronodular type8
o various forms of liver cell damage and
inflammation seen in precirrhotic stage e.g.: Pattern of Nodules And Fibrosis
 interface hepatitis in posthepatitic • Biliary cirrhosis:
cirrhosis o garland-shaped nodules
 steatohepatitis in cirrhotic o progressive nature reflected in a clear halo
alcoholics and NASH in nodular periphery due to:
• Inactive cirrhosis characterized by;  edema
o (near) absence of necroinflammatory lesions  cholate stasis
o sharp delineation between paucicellular  ductular reaction
septa and nodules
• Cardiac-type cirrhosis or cardiac sclerosis:
o nodules centered by normal-looking portal
Complications tracts
• In hypoperfusion: o due to chronic venous outflow obstruction
o nodular infarction: leading to central–central fibrous septa9
 i.e. coagulation necrosis of entire • Ductopenia:
nodules or their centers4 o indicates vanishing bile duct disease:
• In nonbiliary cirrhosis:  most frequently:
o severe bilirubin stasis:  in adults:
 often seen in decompensation  primary biliary
phase2 cirrhosis
• Hepatocellular carcinoma:  primary
o common in cirrhotic liver sclerosing
o putative precancerous markers and stages: cholangitis
 macroregenerative nodules  in children and young
adults:
 dysplastic foci and nodules
 other ductopenia
 large cell and small cell liver cell
syndromes
dysplasia5
o ductular reaction (cholangiolitis) reflects
active, ongoing biliary disease
Diagnosis • Hepatic venous lesions such as occlusion, narrowing,
Incomplete Septal Cirrhosis or recanalization:
• Diagnosis easier in surgical than needle specimens o may suggest venous outflow block as cause
o also occur in other types of cirrhosis10
• Borderline between cirrhosis and various forms of
noncirrhotic portal hypertension6,7 • May be steatohepatitis in:
o cirrhotic alcohol abusers (ASH)
Ease With Which Cirrhosis Is Diagnosed o teetotal patients (NASH):
• Depends on:  may be no etiologic markers
o type of specimen: (cryptogenic cirrhosis) in NASH11
 surgical • Features of activity (necroinflammation) as in
precirrhotic chronic hepatitis:
 needle o indicate posthepatitic cirrhosis
o type of needle used:
• Ground glass hepatocytes and demonstration of
 aspiration type HBsAg, HBcAg, HBeAg or HbxAg:
 Tru-cut o help in recognizing HBV infection
 Transjugular • Lymphoid aggregates and lymph follicles:
o quality of applied reticulin stains o suggest HCV infection
• Sometimes histopathologist can only hint at • Numerous plasma cells:
possibility of cirrhosis o suggest autoimmune hepatitis
• Complicating factors are:
o dynamic nature of process
Etiologies Identified On Finding Intracellular Deposits
o may take months or years to develop:
• Severe parenchymal siderosis:
 cirrhosis may be: o in genetic hemochromatosis12
 developing
• Deposits of copper (rhodanine stain) and
 incipient metallothionein (orcein stain):
 fully developed o in cirrhosis of different etiologies:
 advanced  perinodular copper suggests biliary
disease
Etiologic Diagnosis  positive staining of entire nodules
• Size of nodules has some use in defining etiology: in Wilson's disease, though other
nodules may be negative
Page 17 of 54
 abundant copper deposition in • Reproducible in experimental animals
Indian childhood cirrhosis13 • Examples:
 copper and copper-binding protein o acetaminophen (paracetamol) overdose
sometimes detected in cirrhosis of
any etiology14
• Not main problem in therapeutic practice
• Eosinophilic, PAS positive, and diastase resistant

hepatocellular inclusions: Unpredictable Reactions
o alpha-1-antitrypsin deficiency • Compared with predictable reactions:
o best recognized by specific o of more concern2
immunostaining15 o more frequent
• Only small fraction of population exposed
- Focal Nodular Hyperplasia • No clear dose relationship
- Nodular Transformation • Latent period:
- Liver Cell Carcinoma o may be quite long:
Other nodular and fibrotic conditions of liver:
 weeks/months
• nodular regenerative hyperplasia

• Not reproducible in experimental animals
• congenital hepatic fibrosis

• Conclusive proof of responsibility of particular drug
or combination of drugs often impossible to obtain
• focal nodular hyperplasia (Table 1):
• Inadvertent re-challenge may provide strong
circumstantial evidence, even years after first
Table 1. episode3
Differential diagnosis of cirrhosis
Disease Diffuse Sep Nodul Bile Duct Damage And Ductopenia

involvement of ta es • Cholestasis usually prolonged:
the liver o may be months–years4
Cirrhosis + + +
Nodular + – +
Pathogenesis
regenerative
hyperplasia • Liver is main site of biotransformation of endo- and
Focal nodular – + + xenobiotics
hyperplasia
Predictable Reactions
o may resemble ductopenic biliary cirrhosis

• Due to intrinsic hepatotoxicity of molecule
DRUG INDUCED AND TOXIC LIVER INJURY Unpredictable Reactions

• May be based on:
o genetically determined differences in drug
metabolism:
 i.e. metabolic idiosyncrasy
o immunological reactions to neoantigens
formed by interaction between drug
metabolite and tissue or cell membrane
component:
 i.e. immuno-allergic
idiosyncrasy2,5
Elementary Lesions
Zonal Distributions
Definition
Liver injury due to medications or other toxic agents. Can
• Due to predominance of microsomal
biotransformation enzymes in centrilobular zone
resemble any liver process; clinical correlation essential in
diagnosis.
Hepatocytes in Centrilobular Area
• Ground glass appearance:
Clinical Features o due to hypertrophy of smooth endoplasmic
• >600 potentially hepatotoxic drugs identified1 reticulum with associated enzyme induction
o causes include:
Predictable Reactions  phenobarbital
• Dose dependent  rifampin (rifampicin)
• All exposed individuals  dioxin6
• Latent period: o reflects adaptation rather than injury
o relatively short • Increased accumulation of lipofuscin:
o variable
Page 18 of 54
o induced by prolonged intake of drugs such o most hepatotoxic drugs e.g.:
as:  chloroform
 phenacetin o acetaminophen
 aminopyrine (aminophenazone)  hepatic poisons e.g.:
 chlorpromazine  the mushroom Amanita
 Cascara Sagrada7 phalloides
 anticonvulsant therapy8  carbon tetrachloride
Periportal Hepatocytes Periportal Necrosis

• Ground glass inclusions: • Produced by other chemicals e.g.:
o induced by alcohol aversion drugs o ferrous sulfate
(cyanamide)9 o yellow form of inorganic phosphorus
Steatosis Hepatocellular Tumors

• Frequently occurring effect of xenobiotics • Best known causative agents:
• Macrovesicular steatosis: o oral contraceptives:
o causes:  may be responsible for
 carbon tetrachloride development of benign liver cell
adenoma
 methotrexate
 debated whether induce
 ethanol10 hepatocellular carcinoma –risk low
• Microvesicular steatosis: o anabolic–androgenic steroids:
o apparently due to inhibition of mitochondrial  may induce:
fatty acid β-oxidation and mitochondrial
dysfunction11  adenomas
o causes:  peliosis
 alcohol
o thorium dioxide:19
 intravenous tetracycline  Thorotrast – used as a radiologic

contrast medium between 1920s
 amiodarone and mid 1950s
 valproate  has caused:
 acetyl salicylate in children (Reye's  hepatocellular carcinoma
syndrome)12,13
 angiosarcoma
 several antiviral nucleoside analogs
(e.g. fialuridine)14  cholangiocarcinoma19
Bi- And Multinucleated Hepatocytes

Phospholipidosis
• Causes:
• Increased number of binucleated hepatocytes:
o Coralgil (4,4-diethylamino-ethoxy-hexestrol)
o cause:
o perhexiline maleate  sulindac
o amiodarone15 • Multinucleated hepatocytes:
o cause:
Cholestasis  some instances of acute and
chronic drug-induced hepatitis (e.g.
• Simple drug-induced cholestasis: clometacin)20
o causes include:
 anabolic and contraceptive Hepatic Granulomas
steroids:
• ≈60 drugs incriminated including:21
o mechanisms:
o sulfonamides
 multiple and complex16 o methyldopa
• Most drugs causing cholestasis or cholestatic o phenylbutazone
hepatitis are substrates for transporting polypeptides
on canalicular membrane17 • Fibrin ring granuloma:
o hypersensitivity to allopurinol22,23
Hepatocellular Death • Mineral oil granulomas:
o may be related to:
• Caused by cytokines and their cognate receptors18
• Induced by:
 absorption and deposition of
mineral oil:
o toxic drug metabolites
o immunoallergic hypersensitivity reactions  taken as laxative
 ingested as food additive
or food contaminant from
Hepatocellular Necrosis food packaging24,25
Centrilobular Necrosis
 liver steatosis26
• Produced by larger doses of:
Page 19 of 54
o isoniazid
Periportal Sinusoidal Dilatation o halothane
• Related to oral contraceptive use o indomethacin
• May be associated with inflammatory disease27
Drug-induced Chronic Hepatitis
Peliosis Hepatis • In a small number of patients after prolonged or
• Has been associated with: repeated exposure to some drugs
o anabolic– androgenic steroids • Incriminated drugs include:
o contraceptive steroids o
o azathioprine28  nitrofurantoin32
 phenytoin33
Angiosarcoma
• Has been ascribed to: Drug-induced Steatohepatitis
o inorganic arsenicals • Causes:
o Thorotrast o amiodarone34
o anabolic–androgenic steroids o parenteral nutrition35
o oral contraceptives
o vinyl chloride
o radium therapy27 Histopathology
• Variety of:
Hepatic Stellate Cell Hyperplasia o structural and functional changes in all
cellular components
• Observed in:
o composite patterns
o hypervitaminosis A29
o methotrexate therapy30
Elementary Lesions
Zonal Distributions
Bile Duct Damage And Ductopenia
• Hepatocytes in centrilobular area:
• Causes: o ground glass appearance
o chlorpromazine o increased accumulation of lipofuscin:
o haloperidol
 differentiate from pigment
o ajmaline
accumulation in Dubin–Johnson
o glycyrrhizin syndrome
o amoxicillin • Periportal hepatocytes:
o floxacillin (flucloxacillin)31 o ground glass inclusions:
 resemble those in viral hepatitis B,
Vascular Lesions Lafora's disease and glycogenosis
• Thrombosis of hepatic veins and portal vein type IV
branches: o can be immunostained using a monoclonal
o rare complication of contraceptive steroids antibody against Lafora bodies (KM279) with
specificity for polyglucosan36
• Veno-occlusive disease or nonthrombotic narrowing
of central vein lumina by loose connective tissue:
o causes: Steatosis
 pyrrolizidine alkaloids • Hepatocellular fat accumulation
 radiation • Macrovesicular steatosis
 antineoplastic agents • Microvesicular steatosis:
 conditioning for bone marrow o fine-droplet fatty change
transplantation27 o may be associated clinical manifestations of
• Phlebosclerosis of portal vein branches: severe liver injury in absence of overt
hepatocellular necrosis
o causes:
 long-term use of inorganic
arsenicals (Fowler's solution) Phospholipidosis
 Thorotrast • Phospholipid accumulation resulting in:
 vinyl chloride
o foamy cytoplasmic vacuoles
o enlargement of hepatocytes and Kupffer
 vitamin A
cells
 azathioprine
• Electron microscopy:
 methotrexate27 o lamellated myeloid bodies (fingerprints) in
enlarged lysosomes
Composite Patterns
Drug-induced Acute Hepatitis
Cholestasis
• An immuno-allergic idiosyncratic type reaction
• Simple drug-induced cholestasis:
• Numerous drug causes including:
Page 20 of 54
o bland bilirubin stasis Hepatic Stellate Cell (Ito Cell) Hyperplasia
• Increased number of hepatic stellate cells with
prominent lipid vacuoles per unit volume of liver
Hepatocellular Death
tissue
• If dose of drug or poison:
• May be associated pericellular and septal fibrosis
o sufficient:
 necrosis usually fatal and massive Vascular Lesions
o smaller:
• May affect all intrahepatic blood vessels
 apoptosis of liver cells
• Phlebosclerosis of portal vein branches:
 with time, may result in fibrosis o if thrombosis, may lead to nodular
and cirrhosis37 regenerative hyperplasia25
• Arteritis:
Hepatocellular Necrosis
o may affect intrahepatic branches of hepatic
• May be: artery, resulting in:
o variable appearance:
 multifocal hemorrhagic necrosis
 coagulative or lytic  exceptionally rupture of liver27
o variable topography:
 centrilobular Composite Patterns
 periportal • Histopathology combines several elementary lesions
o variable extent: in varying proportions
 focal
 zonal Drug-induced Acute Hepatitis
 bridging • Histopathology virtually indistinguishable from acute
 lobular viral hepatitis
 multilobular • Combines:
o hepatocellular damage and death:
Centrilobular Necrosis  variable degree
• Associated: o portal and parenchymal inflammation:
o ballooning and steatosis in adjacent non-  variable extent
necrotic parenchymal cells
o no or little inflammatory infiltration38 Drug-induced Chronic Hepatitis
• Elementary lesions of chronic hepatitis in various
Kupffer Cells stages, including cirrhosis
• Involved in: • No specific histologic lesions
o storage of foreign materials
o granuloma development Drug-induced Steatohepatitis
• Resembles acute hepatitis of alcoholic type
Materials Stored In Kupffer Cells
• Include: Drug-induced Cholestatic Hepatitis
o talc and cellulose:
• Lesions of acute hepatitis with moderate or marked
 in drug addicts bilirubin stasis
o silica and anthracotic pigment: • May be prominent eosinophils in inflammatory
 in coal miners, infiltrate
o polyvinyl pyrrolidone and hydroxyethyl
starch:39 Drug-induced Granulomatous Hepatitis
 from infusion of plasma expanders • Combines features of:
o silicone: o usually mild hepatitis
 from prosthetic heart valve devices o noncaseating granulomas
o Thorotrast40 • If bilirubin stasis and infiltration of eosinophils,
virtually diagnostic for drug-induced liver disease42
Hepatic Granulomas
• Variants include:
Special Stains and Immunohistochemistry
o fibrin ring granuloma22,23 Drug-induced Chronic Hepatitis
o mineral oil granuloma:
• Autoantibodies may cause confusion with
 composed of lipophages autoimmune hepatitis43
 in portal tracts and near central
veins
• Gold identified in lipophages and granulomas when Diagnosis
gold therapy used for rheumatoid arthritis41 • Recognition difficult because:44
Page 21 of 54
o may mimic any naturally occurring liver  high degree of suspicion in
disease absence of viral markers
o occurs with compounds from all classes of  close cooperation from clinician
drugs2,45,46 and patient
o may not be clinical signs of a
hypersensitivity reaction
Drug-induced Granulomatous Hepatitis
o drug histories often not reliable
• Virtually diagnostic for drug-induced liver disease if:
o often impossible to pinpoint causative agent
o bilirubin stasis
if on multiple drug therapy
o same drug may cause different patterns of o infiltration of eosinophils
liver damage in different patients47
o hepatotoxicity may not yet have been
- Chronic Hepatitis
reported for a particular drug, even after a - Acute Hepatitis
long time on the market - Cholestasis
o liver damaging effect may be accentuated - Steatohepatitis
by concomitant administration of other - Granuloma
pharmacologic agents
• Specific sources of information include: Bile Duct Damage And Ductopenia
o Books1,48 • Differential diagnosis includes most vanishing bile
o Reviews49–53 duct diseases
• Always maintain high degree of suspicion:54 Drug-induced Cholestatic Hepatitis
o especially:
• Differentiation from bile duct obstruction relies on
 in elderly absence or low expression of typical obstructive
 if on histopathology: features such as:
 resembles viral hepatitis: o portal edema
 with
o neutrophil-associated ductular proliferation
disproportionatel • Severe liver cell damage and marked inflammation
y severe are more suggestive of:
parenchymal o viral hepatitis
necrosis in o viral-like drug-induced acute hepatitis
relation to clinical
condition STEATOSIS AND STEATOHEPATITIS
 associated: STEATOSIS
 steatosis Definition
Accumulation of triglycerides in the hepatocytic cytoplasm,
 granulo usually indicating reversible liver damage. Divided into
mas macrosteatosis and microsteatosis, the latter being seen in
 infiltrati life-threatening conditions such as Reye's syndrome.
on by
eosinop
hils Clinical Features
 bile duct • Common
damage
55 • Hepatomegaly
 centrilobular necrosis • May be elevated serum:
sharply delineated from o aminotransferases
non-necrotic parenchyma, o alkaline phosphatase
especially if: o γ-glutamyl transpeptidase
 associated
steatosis
Microvesicular Steatosis
 only mild or
• Potentially life threatening
minimal
inflammation • Frequently disturbed liver function and coma1
 numerous ceroid • Effects on other tissues
macrophages55 • If survival, no long-term effects on liver
 parenchymal giant cell
hepatitis in adult Reye's Syndrome
 hepatocyte necrosis with • Mainly young children
veno-occlusive disease56
• Presentation:
o acute mild viral illness followed by:
Drug-induced Chronic Hepatitis
• Diagnosis:
 vomiting
o important:  lethargy
 may be cured by withdrawal of  coma

drug o fatal in about one-third of patients
o relies on:
Page 22 of 54
Patterns and Distribution

Pathogenesis
• Two patterns:
• Complex: o macrovesicular steatosis:
o alterations at many points in lipid
metabolism  most common
o lead to accumulation of neutral fat within o microvesicular steatosis
hepatocytes2,3 • Both patterns may be in same biopsy specimen:
• Manifestation of reversible cell injury4 o suggests that large droplets form through
coalescence of small lipid vacuoles
• Nonspecific
• Variety of causes:
o minor amount: Macrovesicular Steatosis
 uncertain significance
• Large droplet fatty change (Fig. 1)
 more frequent in elderly5

o more extensive:
 variety of primary hepatic diseases
 several systemic conditions
• Impaired of β-oxidation of lipids
• Multiple causes include:
o acute fatty liver of pregnancy
o Reye's syndrome:
 may be:
 attributable to salicylate
use6
 sometimes related to
inherited metabolic
disorder of mitochondrial
β-oxidation:7 Fig. 1: Hepatic steatosis in patient with alcohol
abuse. The picture shows a mixture of
 many patients have macrovesicular and microvesicular steatosis and a
defects in fatty acid lipogranuloma (upper right corner). (H&E)
oxidation
 form of primary mitochondrial • Single large vacuole:
hepatopathy8,9 o distends hepatocyte
o displaces nucleus to one side
Causes • If uncomplicated used to be regarded as benign and
• Therapeutic drugs including: potentially fully reversible:
o salicylates: o this notion has been challenged14,15
 Reye's syndrome • Variable zonal distribution and although exceptions:
o sodium valproate o most often centrilobular, e.g. in:
o intravenous high dose tetracycline10  alcoholic liver disease
• Ethanol:  obesity
o small proportion of patients:  diabetes
 alcoholic foamy degeneration o may become panlobular when more severe
• Fulminant hepatitis D: o when in periportal zones more common in:
o in Amazon basin11  cachexia and protein–energy
• Multiple hornet stings12 malnutrition (kwashiorkor)
• Inborn errors of mitochondrial fatty acid β-oxidation  AIDS
• Inherited urea cycle disorders13  after total parenteral nutrition
 phosphorus poisoning
 steroid therapy
Histopathology
• Accumulation of triglycerides in cytoplasm of Severity
hepatocytes:
o variable degree: • Mild:
o less than one-third parenchyma involved
 may be:
• Moderate:
 occasional fat droplets
o one-third to two-thirds parenchyma involved
 diffuse deposition
involving most
• Severe:
parenchymal cells o more than two-thirds parenchyma involved
Page 23 of 54
o tissue postfixed in osmium tetroxide17
• Small droplet fatty change (see Figs 1 and 2)
Diagnosis
• Not possible to define etiology on pattern of lipid
distribution in individual case:
o identification of cause requires close
clinicopathologic correlation
• Important information in report:
o severity
o a mixed pattern of macro- and
microvesicular steatosis:
 may be of prognostic importance in
alcoholic liver disease18
Fig. 2: Acute fatty liver of pregnancy. Detail of

lobular parenchyma characterized by microvesicular Other investigations
steatosis and a small number of lymphocytes. (H&E) Focal Steatosis
• Identified by modern imaging techniques
• Often more difficult to recognize than macrovesicular • May be other coincident liver pathology
steatosis • Multifocal steatosis resembling metastatic liver
• Demonstration may require histochemistry disease radiologically described in AIDS
Reye's Syndrome
• Panlobular steatosis: Differential Diagnosis
o smaller droplets in centrilobular areas - Drug Induced Toxic and Liver Injury
- Steatohepatitis
o somewhat larger fat vacuoles in periportal - Chronic Hepatitis
regions
• May be necrosis of periportal hepatocytes Lipogranuloma
• Serial sections may be required to identify central fat
Lipogranuloma globule and differentiate from other forms of
granuloma19
• Focal response to rupture of lipid-laden hepatocytes
• Fat-laden macrophages within portal tracts:
• Contains:
o must be distinguished from mineral oil
o macrophages
granulomas in which:
o occasional lymphocytes
 vacuoles are larger and more
o eosinophils irregular
o sometimes giant cells (see Fig. 1)  generally more fibrosis
• May be:
o abundant: STEATOHEPATITIS
 especially in alcohol-induced Definition
Steatosis, necroinflammation and fibrosis of liver. Can be
steatosis
alcoholic or non-alcoholic.
o confluent
o fat-laden macrophages within portal
tracts16 Pathogenesis
• Lead to focal fibrosis without great clinical • Fatty liver of alcoholic or nonalcoholic etiology:
significance
o can coincide with or lead to:
 necroinflammation
Focal Steatosis
 fibrosis1
• Sometimes an isolated finding
• Steatosis may be a direct cause of more advanced
• Usually under liver capsule pathology2
• Two-hit hypothesis for development:
Special Stains and Immunohistochemistry o first hit:
• In routinely fixed tissue:  steatosis
o cytoplasmic vacuoles because lipid o second hit:
dissolved during processing  presence of other factor(s) such as
• Very small droplet steatosis may be difficult to oxidative stress3
recognize • Lipid peroxidation:
• Histochemical staining helpful: o one mechanism linking steatosis to
o lipid demonstrated in: necroinflammation and fibrosis
 frozen sections using:
o causes oxidative stress of the cell
 oil red O  interindividual differences in
magnitude explain individual
 Sudan black susceptibility i.e.:3,4
Page 24 of 54
 in chronic alcoholics: microvesicular steatosis with
canalicular bilirubin stasis:
 alcoholic
steatohepatitis  i.e. alcoholic foamy
(ASH) degeneration16
 people who do not
o strong correlation between degree (without
steatohepatitis) and number of activated
consume alcohol:
hepatic stellate cells17 stimulated by
 nonalcoholic ethanol metabolites in absence of
steatohepatitis necroinflammation18
(NASH)
• Fibrosis:
• Oxidizable fat within liver is enough to trigger lipid o constant feature:
peroxidation5
o different patterns
o identification requires collagen stains
NASH
• Causes include:
Most Essential Features
o jejunoileal bypass surgery Liver Cell Injury
o gastroplasty • Ballooned hepatocytes:
o other causes of rapid profound weight loss o may contain Mallory bodies:19–22
in obese subjects i.e. perinuclear inclusions (Fig. 1)
o total parenteral nutrition that are:
o drugs:
 amiodarone
 perhexiline maleate
 estrogens and estrogen receptor
ligands
 methotrexate
o occupational hepatotoxicity:
 as at a petrochemical plant in
Brazil6
o copper toxicity
o disorders with extreme insulin resistance
• Usually:
o etiopathogenesis appears multifactorial:
 i.e. obesity, type 2 diabetes, and
hypertriglyceridemia7
o can be regarded as hepatic consequence of:
 metabolic syndrome
 cardiovascular dysmetabolic
syndrome
 syndrome X8
• May be relationship with cryptogenic cirrhosis
through shared risk factors of obesity and diabetes9
Histopathology
ASH
Early Stages
Fig. 1: Acute alcoholic hepatitis (ASH). Detail of
• Predominantly centrilobular zones
centrilobular parenchyma, characterized by
• Usually all lobules pericellular fibrosis, steatosis, hydropic swelling
• Constellation of changes: of several hepatocytes containing Mallory
o not all present in individual case bodies, and neutrophils swarming around
hydropic parenchymal cells (satellitosis). (H&E)
o variation without correlation with clinical
and biochemical data in:
 homogeneous
 severity
 eosinophilic
 extent of lobular involvement
 variable size and shape
• Steatosis:
o common  complex structures
composed of:
o usually macrovesicular:
 aggregated
 worse prognosis if mixed macro- hyperphosphoryl
and microvesicular pattern15 ated cytokeratin
 even worse prognosis if almost polypeptides:
panlobular, predominantly  includin
g
Page 25 of 54
cytokera
tins 7, Less Essential Features
18, and
19 • Giant mitochondria:
 ubiquitin
o round, oval, or cigar-shaped inclusions:
 heat shock  variable size
proteins  eosinophilic
 tan proteins  PAS–diastase negative
 easily discernible in o better visualized with:
routinely stained sections  chromotrope–aniline blue (CAB)
in florid cases stain
 may be small and difficult  immunohistochemistry27
to identify in mild disease: o not specific for alcohol-induced liver
 immunostaining disease28
of cytokeratins or • Veno-occlusive lesions:
ubiquitin helpful
• Ductular metaplasia29
• Liver cell death by:
o necrosis
o apoptosis23 Later Stages
• Fibrosis extends to lobular periphery
Inflammatory Infiltrates • Necrotic bridges and fibrous septa link central veins
with portal tracts:
• Predominantly neutrophil polymorphs:
o often surround and even invade
o obscure lobular topography
hepatocytes containing Mallory bodies: o together with parenchymal regeneration,
lead to cirrhosis30
 i.e. satellitosis
• A semiquantitative scoring system suitable for
alcoholic fibrosis published31
Pericellular (or Perisinusoidal) Fibrosis24
• Cirrhosis of alcoholic origin:
• So-called ‘chicken-wire fibrosis’ (Fig. 2)
o micronodular
o ongoing superimposed steatohepatitis:
 worsens prognosis32
 suggests etiology
ASH vs NASH
• No qualitative histologic differences33–35
• When large groups of patients compared:
o alcoholics tend to develop more severe
Fig. 2: Acute alcoholic hepatitis (ASH). Detail of disease
centrilobular zone, showing fibrous obliteration of the o NASH usually associated with:
centrolobular vein (veno-occlusive lesions; center)  more:
and marked pericellular (‘chicken-wire’) fibrosis.
(Sirius red stain)
 fat
 nuclear glycogen
• Ensheathes pillars of hepatocytes25  less:
• Possibly:  hepatocellular damage
o perivenular fibrosis:  inflammation
 lumen of central veins may be  fibrosis
narrowed or occluded by  Mallory bodies
subendothelial fibrosis14
o phlebosclerosis
• In a minority: Diagnosis
o centrilobular confluent areas with ASH
parenchyma replaced by: • Alcoholic etiology suspected (but not proved) by:
 fibrosis o micronodular pattern
 central–central bridging fibrosis: o dense fibrosis blurring nodular edges
 originally described as o steatosis
sclerosing hyaline o central vein occlusions
necrosis26 • Liver biopsy quite useful for diagnosis36
• May be:
o macrophages NASH
o lymphocytes • Need for consensus to establish diagnosis regarding:
o apoptotic bodies from dying hepatocytes o minimal histologic criteria:
o some bilirubin stasis
Page 26 of 54
 histologic criteria proposed37
include patterns of injury similar to
features of alcoholic injury Management
 not agreed upon by all ASH
investigators38–42 • On stopping alcohol:
o maximum amount of alcohol intake43 o parenchymal regeneration improves
• Subclassification proposed to include o nodules increase in size
etiopathogenesis: o all features of alcoholic etiology disappear
o primary NASH:
CHOLESTASIS AND BILIARY DISEASES
 related to obesity and insulin
CHOLESTASIS
resistance
Definition
o secondary NASH: Bile accumulation in the liver. Could be mechanical or
 post bypass surgery functional.
 drugs
 toxins37
Clinical Features
• Term nonalcoholic fatty liver disease (NAFLD)
• May be acute or chronic
proposed to incorporate spectrum of steatotic
syndromes not induced by alcohol41 • Acute:
• Not all lesions of alcoholic liver disease in NASH o usually:
• Not all lesions of NASH in alcoholic liver disease33  complete
• A system for grading and staging histologic lesions in  due to either:
NASH published  total functional exocrine
secretory failure of
Differential Diagnosis hepatocytes e.g.:
- Drug Induced Toxic and Liver Injury  drug-induced
- Chronic Hepatitis cholestasis
- Steatosis
 complete obstruction of
ASH extrahepatic bile ducts
Viral Hepatitis e.g.:
• May be suspected clinically, but liver histopathology  impacted
different gallstone
• Chronic:
Chronic Venous Congestion
o indicates longer duration cholestatic
condition (weeks, months, years)
• May be confusion if incomplete picture of ASH, with o may be:
only perivenular and pericellular centrilobular fibrosis
 complete e.g.:
Diseases Unrelated To Alcohol

 chronic total extrahepatic
bile duct obstruction by
• Mallory bodies, neutrophils, and fibrosis are part of carcinoma of pancreas or
histopathology of diseases unrelated to alcohol such
as:
 variably incomplete e.g.:
o chronic cholestasis:  primary biliary cirrhosis
 easy to differentiate due to primary sclerosing
periportal predominance of cholangitis).
changes o if incomplete may remain anicteric for long
o Wilson's disease: periods
 always consider, especially in
younger patients
Pathogenesis
• Arrest or marked reduction in bile secretion and bile
Hypervitaminosis A flow due to:
• May cause pericellular fibrosis progressing to o functional secretory disturbances of hepatic
cirrhosis45 parenchymal cells1
o obstruction at any level in excretory
Hepatocellular Siderosis pathways of bile, from canaliculi to papilla of
Vater2
• In some alcoholics
• May be confused with genetic hemochromatosis:
Intrahepatic Cholestasis
o may be solved by:
• Cause:
 quantitative tissue iron
o primary focus inside liver:
determination
 calculation of hepatic iron index46
 diseases of:
 parenchymal cells
NASH
 intrahepatic bile ducts
• Identical histopathology
Page 27 of 54
 sometimes both
parenchymal cells and
intrahepatic bile ducts1
Extrahepatic Cholestasis
• Cause:
o bile excretory block in larger ducts:
 outside liver along extrahepatic
bile ducts e.g.:
 gallstones
 bile duct tumors
Fig. 1: Marked bilirubin stasis in hepatocytes,
 bile duct strictures canaliculi, and Kupffer cells in neonate with
 in larger hilar intrahepatic ducts extrahepatic bile duct atresia. (H&E)
o starts in centrilobular zone

Combined Intra- And Extrahepatic Cholestasis
o pigment granules in parenchymal cells:
• Involves both:
o intrahepatic segments of biliary tree  hepatocellular bilirubin stasis
o extrahepatic segments of biliary tree o inspissated bilirubin-stained bile plugs in
dilated intercellular canaliculi:
• Examples:
 canalicular bilirubin stasis
o extrahepatic bile duct atresia in neonates
o primary sclerosing cholangitis in adults and • Hypertrophic Kupffer cells:
children
o phagocytose debris resulting from
hepatocellular damage and death due to
• Block in bile secretion: retention of detergent bile acids, i.e.:
o may be:  dying parenchymal cells
 complete:  liberated canalicular bile plugs
 total arrest of bile secretion o Kupffer cell bilirubin stasis indicates at least
 retention of: several days' duration3
bile salts • Edema of portal tract connective tissue:
bilirubin o especially if extrahepatic obstructive origin
 functional or obstructive o results in:
 incomplete  some rounding of portal contours
 usually incomplete or partial  incipient ‘ductular reaction’
obstruction of:
intrahepatic bile ducts: Chronic Complete Cholestasis
 mostly due to destructive • Parenchymal changes appear with time
diseases of intrahepatic bile superimposed on early bilirubin stasis
ducts (vanishing bile duct • Bilirubin stasis:
diseases) such as: o gradually extends toward periportal
primary biliary cirrhosis parenchyma
primary sclerosing cholangitis • Lymphocytic inflammatory infiltrate:
extrahepatic bile ducts: o restricted to area with bilirubin stasis
 incomplete obstruction o mild
(narrowing or strictures) of o in most forms lasting for weeks
segments of larger bile ducts o apparently secondary to cholestatic
 retention of: changes
bile salts (but not bilirubin)
Chronic Incomplete Cholestasis
• Bilirubin stasis not a feature:
Histopathology o except if:
Acute Complete Cholestasis
• Changes in:
 terminal decompensating phase
o lobular parenchyma  superimposed pathologic changes:
o portal tracts  e.g. drug-induced liver
Bilirubin accumulation in liver lobule (Fig. 1): damage
Histopathologic Diagnosis of Chronic Cholestasis

• Applies to both complete and incomplete chronic
cholestasis
• Parenchymal, portal, and periportal alterations as
outlined below
Page 28 of 54
Parenchymal Changes
• Include:
o cholate stasis
o cholestatic liver cell rosettes
o feathery degeneration
o xanthomatous cells
o bile infarcts Fig. 3: Cholate stasis in periphery of cirrhotic nodule in patient
with stage 4 primary biliary cirrhosis. Lysosomal copper–
Cholate Stasis metallothionein complexes appear as red-stained granules in
the copper-specific rhodanine stain.
• Periportal hepatocyte lesion:
o thought to be due to membrane-damaging  orcein
effect of retained bile acids4 (metallothionein)
• Hepatocytes: (Fig. 4
o swollen (Fig. 2)
Fig. 2: Cholate stasis in periphery of

parenchymal nodule in cirrhotic liver of
patient with end stage primary sclerosing
cholangitis. The hepatocytes near the
fibrous septum (lower part) show hydropic
swelling, clumping of the cytoplasm, and
Mallory bodies. (H&E)
o pale
o coarsely granular:
 contain granules of lysosomal
copper, complexed with copper-
binding protein (metallothionein):
 stainable with:
 rhodanine
(copper) (Fig. 3)
Fig. 4: Cholate stasis in periportal parenchyma in patient with

primary sclerosing cholangitis. The picture shows orcein-
positive granules in periportal hepatocytes, representing
lysosomal localization of copper binding protein
(metallothionein). (Orcein stain)
)
o with time:
 contain Mallory bodies
o very late stages:
 may be bilirubin inclusions
Cholestatic Liver Cell Rosettes

• Useful diagnostic feature5
• Tubular rearrangement of liver cell plates that are
normally one cell thick
• Glandular or tubular structures:
o lined by four or more hepatocytes:
 may show feathery degeneration
o central lumen:
 may:
Page 29 of 54
 vary greatly in diameter • Lesions consist of necrotic hepatocytes:
(Fig. 5) o mostly paraportal
o possibly bilirubin impregnation of central
necrotic area
o gradually replaced by organizing
mesenchymal tissue
o finally result in fibrous scars
Two Further Characteristic Changes In Neonatal

Cholestatic Liver Diseases
Parenchymal Multinucleated Giant Cells
• Due to syncytial fusion of several mononucleated
hepatocytes
• Variable:
o number of nuclei
o location
• Often contain pigment granules corresponding to:
o bilirubin
o lipofuscin
o hemosiderin
• May:
o appear necrotic
o surrounded by neutrophil polymorphs6
Extramedullary Hematopoiesis
• Foci comprising clusters of:
o erythrocyte precursor cells
o myeloid precursor cells
o megakaryocytes
Fig. 5: Cholestatic liver cell rosettes. Liver biopsy of patient
with primary sclerosing cholangitis. The involved hepatocytes • Common
appear in tubular arrangement. (H&E)
Periportal And Architectural Changes
 appear empty • Comprise:
 be filled with eosinophilic o ductular reaction
or bilirubin-stained o ductular reabsorption
material in variable
degrees of inspissation
o periductular fibrosis
o biliary fibrosis
Feathery Degeneration o final stage of biliary cirrhosis
• Hydropic swelling of:
o single cells Ductular Reaction
o groups of parenchymal cells • Increased number of ductular profiles in periphery of
portal tract:
• May be some bilirubin impregnation of remaining o gradually extend into periportal
visible cytoplasm in chronic complete cholestasis
parenchyma toward neighboring portal
tracts in periphery of liver lobule
Xanthomatous Cells o accompanied by:
• Feature of longstanding incomplete and complete  edema
cholestasis
 neutrophil infiltration (Fig. 6)
• Lipid-laden histiocytes with foamy cytoplasm:
o accumulate in:
 parenchyma
 portal tracts
o single or in clusters
o represent tissular expression of
hyperlipidemia that accompanies chronic
cholestasis
Bile Infarcts
• So-called Charcot–Gombault infarcts
• Late parenchymal lesion in severe cholestasis of long
duration Fig. 6: Ductular reaction in chronic cholestasis. Liver biopsy
from patient with primary sclerosing cholangitis. The picture
• Mainly in large duct obstruction
shows a mildly inflamed portal tract (upper part) with (at 8
Page 30 of 54
o'clock) a focus of ‘ductular reaction’ composed of bile  reveals a phenotypic switch to a
ductules, edematous stroma, and some neutrophil infiltration. biliary type of intermediate
(H&E) filament cytoskeleton in periportal
hepatocytes (Fig. 7)
• If obstruction of extrahepatic bile ducts:
o mainly due to increased bile pressure8,9
o involves elongation of pre-existing bile
ductules9
o has been described as ‘marginal bile duct
proliferation’10
• In other cholestatic diseases, not necessarily
obstructive:
o proinflammatory cytokines may be
predominant triggers11,12
o cholangiocytes lining ductules may show
signs of reabsorption:
 reflected in vacuolization of
cytoplasm
 accumulation of bilirubin and
lipofuscin
• Biliary piecemeal necrosis describes:13
o irregular portal–parenchymal interface due
to:
 wedge-shaped periportal extension
 accompanying inflammation into
periportal parenchyma
 possibly features of cholate stasis
Periductular Fibrosis
• Accompanies ductular reaction
Biliary Fibrosis
• Progressive ductular reaction with periductular
fibrosis eventually results in fibrous linkage of
adjacent portal tracts:
o i.e. portal–portal septal fibrosis
o potentially reversible14 because basic
angioarchitectural pattern of liver
preserved15
Fig. 7: Primary biliary cirrhosis. Detail of portal tract and
Biliary Cirrhosis surrounding parenchyma. This cytokeratin 7 immunostain
highlights an increase in the number of ductular structures at
• Final stage in disturbance of lobular architecture
the portal tract periphery; expression of cytokeratin 7 in
• Characterized – like any cirrhosis – by: periportal hepatocytes (early stage of cholate stasis), and a
o additional portal–central fibrous septa few scattered, small cytokeratin 7 positive cells at some
o nodular parenchymal regeneration distance from the portal tract (presumed hepatic progenitor
cells). (Immunostain for cytokeratin 7)
• Ongoing cholestasis:
o characterized by:
• With time:
 persistence of ductular reaction o cytokeratin 7 expression extends with
 edema decreasing gradient from limiting plate
 periductular inflammation toward center of the lobule over a distance
of several cells16
 fibrosis
o together with lesions of cholate stasis in
nodular periphery creates at low Cholestatic Liver Cell Rosettes
magnification impression of clear halo • Some or all lining hepatocytes may
between cirrhotic nodules and fibrous septa: o express bile duct-type cytokeratin i.e.:
 indicates actively progressing  cytokeratin 7
disease in its cirrhotic stage
 tissue polypeptide antigen (TPA):
 indicates partial shift
Special Stains and Immunohistochemistry toward bile duct cell
Cholate Stasis phenotype (Fig. 8)
• Earliest stages:
o may be revealed by immunostaining for
cytokeratin 7:
Page 31 of 54
Absent Ductular Reaction

• Chronic states of cholestasis sometimes lack obvious
ductular reaction e.g. may be absent in:
o Alagille's syndrome
o some cases of:
 primary sclerosing cholangitis
 chronic liver allograft rejection
- Paucity of Interlobular Bile Ducts
- Neonatal Giant Cell Hepatitis
- Primary Sclerosing Cholangitis
- Primary Biliary Cirrhosis
- Drug Induced and Toxic Liver Injury
Bilirubin Stasis
• Dark brown to black deposits (in hepatocytes,
canaliculi, Kupffer cells, and ductules) in
erythropoietic protoporphyria:
o easily identified by polarized light:
 protoporphyrin deposits have a red
to yellow birefringence with a
Maltese cross configuration in
coarser (ductular) deposits (Figs 9
and 10)
Fig. 8: Cholestatic liver cell rosettes. Immunostaining for

cytokeratin 7 reveals cholestatic liver cell rosettes to better
advantage. Normal hepatocytes do not express cytokeratin 7,
whereas cells in cholestatic rosettes express this intermediate
filament to variable extent.
 should not be
misinterpreted as
expression of
hepatocellular
regeneration
Fig. 9: Erythropoietic
protoporphyria. Dark brownish-
black deposits of protoporphyrin in
Diagnosis
hepatocytes, canaliculi, Kupffer
• If incomplete and anicteric: cells, and ductules. (H&E)
o no microscopically visible accumulation of
bilirubin in liver tissue sections
o underscores usefulness of distinguishing
between:
 bilirubin stasis
 cholate stasis
 either separately or in
combination may
constitute picture of
histologic cholestasis19
• Basic differences between chronic complete and
incomplete cholestasis are:
o absence of bilirubin stasis in incomplete Fig. 10: Erythropoietic
category protoporphyria. The deposits are
o occasionally more pronounced expression of birefringent, and show a Maltese
lesions in complete variety cross picture of red birefringence
in the larger deposits. (Polarized
light)
Giant Cell Transformation Of Parenchymal Cells
• Occurs in a variety of conditions Extramedullary Hematopoiesis
• Appear to be more specific for age than disease: • Not a reliable criterion for differentiation between
o nonspecific reaction of infant's hepatocytes various cholestatic diseases such as biliary atresia
to various types of injury: and neonatal hepatitis
o occasionally in adults
Biliary Fibrosis
Page 32 of 54
• Distinguish from true biliary cirrhosis
Staging/grading
Staging In Chronic Cholestatic Liver Diseases
• Based on periportal and architectural changes
• Stage 1:
o portal
• Stage 2:
o periportal
• Stage 3:
o septal
Fig. 1: Extrahepatic bile duct
• Stage 4: atresia (EHBDA). Detail of a portal
o Cirrhotic tract in liver biopsy from neonate
with EHBDA, showing mild
Vanishing Bie Duct Diseases inflammatory infiltrate, and a bile
Extrahepatic Bile Duct Atresia duct with irregular outline and
Definition epithelial damage: vacuolization in
Congenital disorder where there is progressive some cholangiocytes, apoptosis in
necroinflammatory destruction of intrahepatic and others, and some inflammatory
extrahepatic bile ducts. cells inside the basement
membrane. (H&E)
Clinical Features
• May start: • Thickening of basement membrane
o in utero • Progressive atrophy and disappearance of ducts4
o in perinatal period • Histopathology of obliterated extrahepatic ducts:
o various stages of:
Pathogenesis
• Etiology unknown
 nonspecific inflammation
• Probably heterogeneous and represents common

 epithelial desquamation and
necrosis
phenotype of several underlying disorders1,2
 ulceration
Histopathology  fibrosis5,6
• Involves both extrahepatic and intrahepatic ducts: Early Severe Variant
o originally maximal involvement of part or all • In >25%7–9 of cases interlobular bile ducts appear in
extrahepatic duct system early embryologic shape:
• Panbiliary o so-called ‘ductal plate malformation’ (Fig. 2)
• Progressive necroinflammatory destruction of bile
ducts
• During first 3–4 weeks:
o mostly nonspecific bilirubin stasis
o some parenchymal giant cells
o foci of extramedullary hematopoiesis
• Gradual development:
o portal edema
o ductular reaction:
 considered most reliable, though
not pathognomonic criterion in
diagnosing extrahepatic Fig. 2: Extrahepatic bile duct atresia
obstruction in liver specimens3 (EHBDA), early severe type in stage of
• Ductules often contain inspissated bile concrements advanced fibrosis. The picture shows part of
a large, fibrous portal area, with
• Later stages:
recognizable hepatic artery branches,
o periportal fibrosis barely visible or no portal vein branches,
o finally resulting in secondary biliary cirrhosis and bile duct structures in ductal plate
• Intrahepatic ducts: configuration (ductal plate malformation).
o irregularity of lining cholangiocytes, which The lining cholangiocytes show involutional
changes: flattening, shrinkage, and nuclear
feature:
pyknosis. (H&E)
 vacuolization
 nuclear pyknosis o suggests antenatal start associated with
 atrophy arrest of remodeling of embryonic ductal
plates10
 infiltration by inflammatory cells
(Fig. 1) • Histology reveals advanced fibrosis, even at 4 weeks
of age
Diagnosis
Page 33 of 54
• Liver biopsy cornerstone in diagnosis o destruction of ducts generally starts after 3
months of age
o early changes do not allow prediction of
Differential Diagnosis future development of fibrosis2
- Drug Induced and Toxic Liver Injury • Nonsyndromic PILBD:
- Inborn Errors of Metabolism
o may be:
 isolated hepatic abnormality
• Other causes of obstruction: (idiopathic)
o mainly choledochal cyst in this neonatal  one component of more complex
period: systemic process with or without
o degenerative lesions of intrahepatic ducts known cause
• Neonatal giant cell hepatitis:

 associated with:
o no or much less ductular reaction  alpha-1-antitrypsin
deficiency
o more intralobular than perilobular fibrosis
 rubella
• Chronic liver injury by parenteral nutrition
 trisomy 21
• Several inborn errors of metabolism
 Turner's syndrome
Management  Byler's disease
• Hepatic portoenterostomy or Kasai operation with  other conditions
resection of obliterated extrahepatic ducts o most frequent diagnosis for conjugated
• Correlation between number and size of patent ducts hyperbilirubinemia in first month of life3
in porta hepatis at portoenterostomy and success of o destruction of interlobular ducts starts early
procedure controversial:11,12 (before 3 months) and progression usually
o some assess bile duct luminal size in frozen faster than in syndromic PILBD2,3
sections of proximal resection margin during
a Kasai procedure Histopathology
o some consider total diameter of all prehilar • Nonspecific, inflammatory destruction of interlobular
structures important, with total diameter ducts, resulting in progressive ductopenia
>400μm indicating favorable prognosis for • Changes:
adequate bile drainage
o mainly of chronic incomplete cholestasis
Paucity of Interlobular Bile Ducts and neonatal cholestasis

• Immunostains for cytokeratin 7 (or 19) or tissue
polypeptide antigen (TPA):
o for better visualization of interlobular
ducts:4
 especially in very young children5
Diagnosis
• Requires sufficiently large biopsy specimen and
quantitative evaluation of interlobular ducts:
o needle biopsy may suffice if contains at
least five portal tracts3
o 70–80% of branches of hepatic artery
normally accompanied by duct of
Definition approximately similar size near center of
Congenital disorder where there is destruction and loss of portal tract
small interlobular bile ducts. Divided into syndromic  ‘widowed artery’ signals missing
(Alagille's) and non-syndromic forms associated with alpha-1- duct6
antitrypsin deficiency, rubella, Turner's syndrome, trisomy 21
and others. • Ratio of number of interlobular ducts to number of
portal tracts:
Clinical Features o 0.9–1.8 in normal children and adults7
• Subdivided according to associated clinical features o in PILBD:
into syndromic and nonsyndromic PILBD  originally defined as <0.5
• Syndromic PILBD:  now also defined as a reduced bile
o Alagille's syndrome or arteriohepatic duct to portal tract ratio >0.5:
dysplasia  especially when ducts with
o abnormal facies degenerative changes8
o vertebral, cardiac, ocular, and renal  in premature infants <0.9 may be
abnormalities: normal:9
 according to presence or absence,  due to incomplete bile
result in a complete or incomplete duct development at birth
syndrome1
Page 34 of 54
- Extrahepatic Bile Duct Atresia site of an adjacent epithelioid granuloma.
- Drug Inuced Toxic and Liver Injury (H&E)
- Alpha 1 Antitrypsin Deficiency  mainly lymphocytes:
Primary Biliary Cirrhosis  sometimes aggregated in
Definition lymphoid follicle with
Autoimmune disorder in middle-age females where there is germinal center
chronic non-suppurative destruction of bile ducts resulting in  may be:
cirrhosis. Antimitochondrial antibody to M2 component of  abundant plasma cells
pyruvate dehydrogenase is found in 90% of the cases.
 quite prominent
Clinical Features eosinophils
• Nearly 10× more frequent in females than males  neutrophils
• Usually insidious onset starting with pruritus  single or small clusters of
epithelioid cells:
Pathogenesis  sometimes
• Considered to be autoimmune: epithelioid
granulomas close
o often other autoimmune disorders to or surrounding
o proof strong, but only indirect and bile duct
circumstantial1
• Smaller ducts:
Gross Pathology o may be surrounded by edema or fibrosis:
• Basic lesion:
o presumably result of more distal obstruction
o chronic, nonsuppurative, destructive • May be parenchymal changes:
cholangitis: o lobular infiltration by scattered lymphocytes
 possibly ending in cirrhosis2 o nodular regenerative hyperplasia:4
Histopathology  together with narrowing of portal
Early Stage vein branches,5 may explain
• Involves ducts 40–80μm diameter: development of portal
o i.e. segmental and larger interlobular ducts hypertension before development
of fibrosis and cirrhosis
o size may be difficult to estimate because
some enlarge apparently through:
o lesions of chronic cholestasis absent or
minimal
 damage to basement membrane
 reactive hyperplasia of lining Histologic Progression
epithelium3 • Most cases within 2 years:
• Lesions: o 20% remain histologically stable
o focal in liver o sustained regression in 2%6
o segmental within duct system • Extension beyond limits of portal tract
• Affected duct segments: • Increasing:
o epithelial swelling or eosinophil o fibrosis
condensation o disturbance of lobular architecture
o possibly stratification
o infiltration by lymphocytes and plasma cells • Appears to be driven by:
o periportal and architectural changes of
o damage of basement membrane may lead chronic cholestasis
to rupture
inflammatory cells accumulate beside or
o lymphocytic interface hepatitis (piecemeal
around duct (Fig. 1): necrosis):7,8
intralobular ‘invading’ lymphocytes
play role in development of septal
fibrosis9 (Fig. 2)
Fig. 1: Granulomatous cholangitis in primary

biliary cirrhosis (PBC). Detail from a portal
tract with dense lymphoplasmacytic
infiltrate and lymphoid aggregate (left). The Fig. 2: Primary biliary cirrhosis,
interlobular bile duct (center) shows a focal stage 3. The picture shows portal–
rupture of its cholangiocytic lining, at the portal septal fibrosis (septal stage
3), portal inflammation with
Page 35 of 54
lymphoid aggregate, absence of • A florid bile duct lesion in PBC can be categorized as:
interlobular bile duct (ductopenia), o lymphocytic
and cholate stasis in periportal and
periseptal parenchyma. (H&E) o pleomorphic
o granulomatous cholangitis (see Fig. 1):
 may be variable degree of  most diagnostic feature
intralobular necroinflammation10
• May be liver cell dysplasia of large and small cell Differential Diagnosis
type11 - Nodular Regeneration
- Chronic Hepatitis
• Progressive ductopenia - Drug Induced and Toxic Liver Injury
- Primary Scelrosing Cholangitis
Advanced Cases
• Portal lymphoid aggregates mark site of disappeared • Chronic hepatitis, especially viral hepatitis C:
bile ducts (see Fig. 2) o in viral hepatitis C, affected duct segment
• Cholestatic and hepatitic features result in shows:
progressive fibrosis with:
 vacuolization and stratification of
o portal–portal septum formation cholangiocytes
o additional portal–central septa9
 preservation of basement
• Resulting cirrhosis: membrane16
o biliary type when cholestatic features  no cholestatic features
predominate
• Drug-induced bile duct damage:
o more macronodular type when
o usually ducts of smaller caliber than in PBC
predominance of hepatitic features
o may be any combination of two patterns o clinical history comprises episode of
jaundice17
• Hepatitic-type lesions appear most important for
progression of fibrosis12
• Conditions characterized by bile duct damage and
granulomas:
Special Stains and Immunohistochemistry o fascioliasis
• Antimitochondrial antibodies:
o sarcoidosis:
o in >90% of patients1  may be difficult because may lead
o most specific against M2 component of to:
pyruvate dehydrogenase complex  ductopenia
• Aberrant expression of cytokeratin 7 in hepatocytes  chronic cholestatic liver
(Fig. 3) may be marker for: disease
 final diagnosis requires
consideration of clinical context
and laboratory data
• Immune cholangitis18 or autoimmune
cholangiopathy:19
o clinically, biochemically, and histologically
similar to PBC, but antimitochondrial
antibodies negative
o represents antimitochondrial antibody-
negative PBC:20
 but reactivity to recombinant
mitochondrial antigens by
immunoblotting in about 75% of
Fig. 3: Primary biliary cirrhosis. Detail of portal tract
such patients21
and surrounding parenchyma. This cytokeratin 7
immunostain highlights an increase in the number of • Autoimmune hepatitis–PBC overlap syndrome:22
ductular structures at the portal tract periphery; o rare
expression of cytokeratin 7 in periportal hepatocytes o clinical, biological, and histologic features of
(early stage of cholate stasis), and a few scattered, PBC and autoimmune hepatitis,
small cytokeratin 7 positive cells at some distance simultaneously or sequentially
from the portal tract (presumed hepatic progenitor o higher degrees of ‘hepatitic component’ of
cells). (Immunostain for cytokeratin 7)
PBC, which responds to corticosteroid
therapy23
o degree of cholestasis
o progression13 Staging/grading
• Several systems proposed for staging2,24–26
Diagnosis
• Most popular applicable to any vanishing bile duct
• Liver biopsy: disease:24
o important in diagnosis and staging14 o distinguishes four stages:
o characteristic bile duct lesions not always
seen:
 stage 1:
 due to sampling variability

 portal
 prevents firm histologic diagnosis

 stage 2:
Page 36 of 54
 periportal fibrosis) around the interlobular bile duct
(center). (H&E)
 stage 3:
 septal fibrosis  with degeneration and atrophy of
 stage 4: epithelial lining:
 cirrhosis  results in disappearance
• Staging in small needle biopsy specimens valuable if of duct and eventual
interpreted with caution: replacement by a fibrous
o considerable variability in degree of fibrosis scar
in different parts of liver  loss of ducts
more frequent in
Primary Scelrosing Cholangitis smaller portal
Definition tracts
Disorder of the biliary tract in which there is inflammation and  sometimes scars
sclerosis of usually the medium and large ducts. About 6% of unusually
cases have small duct involvement only. Associated with prominent and
inflammatory bowel disease. resemble keloid
scars6,7
Clinical Features
 in <40% of biopsy
• One of most common adult chronic cholestatic liver specimens5
diseases
 more often medium-sized
• 75% cases are male tracts8
• Average age at diagnosis 40 years:  not pathognomonic – also
o sometimes children1 in other types of biliary
• Typically associated with inflammatory bowel disease disease
(70%)2–4  not present in every stage
of disease
Gross Pathology • If longlasting and more severe disease:
• Inflammation, strictures, and saccular dilatations in o portal fibrosis more marked
biliary system o fibrous septa
• Any part of biliary tree o biliary cirrhosis
Histopathology
• More progressive disease:
o moderate to severe lymphocytic type of
• Changes depend on:
interface hepatitis9
o stage of disease
• Less severe disease:
o site of biopsy:
o only mild and insignificant lesions over
several years10
Portal Tracts
• Proximal to strictures: • Increased risk of developing cholangiocarcinoma:11
o only features of obstruction and cholangitis o strong association with dysplasia of bile
duct epithelium12
• Affected by primary disease:
o pleomorphic and fibrous–obliterative Parenchymal Changes
cholangitis5 • Less striking than portal changes
• Key lesion: • Correspond to features of chronic cholestasis
o onion skin-type periductal fibrosis (Fig. 1):
• May be nodular regenerative hyperplasia before
precirrhotic stage

• PAS–diastase staining:
o thickening of basement membrane around
damaged ducts (Fig. 2), or
Fig. 1: Primary sclerosing cholangitis. Detail

of portal tract with moderately dense
inflammatory infiltrate (mainly lymphocytes,
some eosinophils) and concentric,
lamellated, periductal fibrosis (‘onion skin’
Page 37 of 54
• Most common liver disease in children:
o seen in 11% of infants
• Usually resolves without therapy by 6 months of age
• In ≤10%:
o pruritus
o cirrhosis
• Poor prognosis if persistent hyperbilirubinemia
beyond 1 year of age1,2
Alpha-1 Antitrypsin Deficiency In Adults3
Fig. 2: Primary sclerosing cholangitis.

• Usually presents with pulmonary emphysema4
Overview of portal tract and periportal • Liver disease:
parenchyma. This portal tract shows only o incidence increases with age5
mild inflammation; two interlobular bile • Increased prevalence of hepatitis B and C viral
ducts show clear-cut thickening of their infection:
basement membrane, a helpful diagnostic
feature. (PAS–diastase stain)
o may contribute to hepatic complications6–8
• Increased risk for:
o wrinkled empty basement membranes13 o hepatocellular carcinoma in adult
homozygous PiZ with or without
Diagnosis cirrhosis9,10
• Usually combined large and small duct PSC o chronic liver disease in middle-aged or old
adults with heterozygous PiZ11
• Small duct PSC corresponds to involvement of only
microscopically identifiable (septal and interlobular)
Pathogenesis
ducts:
o previously indicated by now obsolete term • An endoplasmic reticulum storage disease:
pericholangitis14 o molecular abnormality of alpha-1-
antitrypsin:
Other investigations  hinders transfer through
• Cholangiography endoplasmic reticulum:
 results in:
 retention in
endoplasmic
- Large Duct Obstruction
reticulum
- Primary Biliary Cirrhosis
 deficiency in
plasma12
• Chronic hepatitis:
o lacks: • Alpha-1-antitrypsin:
o serum glycoprotein
 periductal fibrosis
o protease inhibitor (Pi)
 ductopenia
o >70 allelic variants13
 cholestatic features. o usual phenotype PiM
• PBC: o most common deficiency alleles:
o may be difficult to differentiate in later
stages
 PiZ:
o epithelioid granulomas:  amino acid lysine
substitution for glutamic
 also in about 4% of PSC cases, but acid at position 34214
not as part of granulomatous
cholangitis15  PiS
o florid portal inflammation with or without
Histopathology
lymph follicle formation favors PBC
• Globular inclusions:
• Overlap autoimmune hepatitis and PSC described16–
o in endoplasmic reticulum of periportal
18
hepatocytes15
• Other vanishing bile duct diseases o eosinophilic
CHILDHOOD DISORDERS AND DISORDERS OF o PAS–diastase positive
METABOLISM o 1–10μm diameter (Fig. 1)
ALPHA-1 ANTITRYPSIN DEFICIENCY
Definition
Genetic endoplasmic storage disease where there is mutation
in the serum glycoprotein and protease inhibitor AIAT. The
mutated protein (homozygous SERPINA1 Z being the most
common) becomes deposited in the ER of hepatocytes,
resulting in its deficiency in the serum and associated
pulmonary emphysema.
Clinical Features
Neonatal Cholestasis
Page 38 of 54
DISORDERS OF COPPER AND IRON METABOLISM
WILSON’S DISEASE
Definition
Rare autosomal recessive disorder where there is tissue injury
from increased copper deposition in the liver, brain, cornea
and kidneys. The mutation is localized to chromosome 13q14-
21.
Clinical Features
• Rare
• Autosomal recessive:
o gene mutation on chromosome 13q14–211
Fig. 1: Alpha-1-antitrypsin deficiency. Detail
of periportal parenchyma, showing PAS-
• After 5 years of age may present with:2
positive inclusions of varying size in the o acute hepatitis
majority of periportal hepatocytes. (PAS– o fulminant hepatitis
diastase stain) o chronic hepatitis
o cirrhosis
o difficult to detect in infants <3 months of
age Pathogenesis
Neonatal Cholestasis
• Tissue injury due to copper overload in:
o liver
• Parenchymal giant cells
o other organs:
• Ductular reaction
 brain
• Fibrosis
 cornea
• Paucity of interlobular bile ducts:16
o in up to 10% of cases  kidneys
Histopathology
Alpha-1 Antitrypsin Deficiency In Adults3
• Histologic abnormalities precede clinical appearance
• Liver disease:
o varying degrees of fibrosis • Early stage:
o cirrhosis o steatosis
o sometimes lipogranulomas3
Special Stains and Immunohistochemistry • Periportal hepatocytes:
• Immunostaining with polyclonal anti-alpha-1- o may be:
antitrypsin  strikingly abundant lipofuscin
• Specific monoclonal antibody:  glycogen vacuoles in nuclei4
o allows identification of PiZ gene products17 • Kupffer cells:
• Large areas of lobular hepatic parenchyma may be o may be laden with iron:
immunopositive for alpha-1-antitrypsin in PiMZ
individuals  due to frequent acute hemolytic
crises
Differential Diagnosis • Progressive fibrosis with fine septa extending from
- Neonatal Giant Cell Hepatitis portal tracts
- Paucity of Interlobular Bile Ducts • Sometimes portal tracts infiltrated with mononuclear
inflammatory cells:
• Immunoreactive globules in several liver diseases:19 o indistinguishable from chronic hepatitis due
o alpha-1-antitrypsin phenotyping in plasma to other causes4–6
by immunodiffusion or electrophoresis • Untreated, progresses to cirrhosis
needed for final diagnosis
• Helpful diagnostic clues:
Neonatal Cholestasis o steatosis
• May resemble extrahepatic bile duct atresia: o ballooned hepatocytes
o need to screen for alpha-1 antitrypsin o glycogenated nuclei
deficiency before a Kasai procedure o moderate to marked copper deposition
o Mallory bodies in periportal hepatocytes
Genetics o lymphocytic portal and interface
• Alpha-1-antitrypsin: inflammation
o >70 allelic variants13 o possibly occlusive venous lesions4
o usual phenotype PiM • If fulminant hepatic failure:
o most common deficiency alleles: o extensive parenchymal necrosis
 PiZ: o collapse of the reticulin framework
 amino acid lysine o nodular parenchymal regeneration
substitution for glutamic o development of a cirrhotic pattern7
acid at position 34214
• Electron microscopy:
 PiS o characteristic mitochondrial and lysosomal
changes8
Page 39 of 54
Special Stains and Immunohistochemistry • Copper and metallothionein may accumulate in other
• Cytochemical staining for copper and copper-binding diseases e.g.:
protein: o cholestasis
o may be useful in establishing diagnosis (Fig. o Indian childhood cirrhosis
1)
• Neonatal liver usually contains high levels of
copper13
Genetics
• Autosomal recessive:
o gene mutation on chromosome 13q14–211
Management
• Penicillamine or zinc acetate:
o may arrest disease
o prevent development in siblings
IRON OVERLOAD
Fig. 1: Wilson's disease, cirrhotic stage. This Definition
rhodanine stain reveals accumulation of Deposition of iron in the liver secondary to chronic anemia,
copper (red granules) in varying degree, blood transfusion, chronic renal failure and porphyria cutanea
most pronounced in a nodular cluster of tarda.
hepatocytes (left). (Rhodanine stain)
Clinical Features
• Timm's silver stain: • Demonstrable iron in tissues
o appears most sensitive technique10 • Causes:
• Stains may be negative in some stages of the o genetic hemochromatosis
disease o chronic anemia including thalassemia:
Diagnosis  often termed secondary
hemochromatosis
• Quantitative determination of hepatic copper:
o neonatal iron overload:
o may be necessary for final diagnosis
o can be performed on routinely processed  rare
paraffin-embedded tissue11 o blood transfusion
• Great variety of possible lesions:
o hemolysis
o creates problems for histopathologist o chronic renal failure
o consider in differential diagnosis of o porphyria cutanea tarda
hepatocellular disease at all ages, but o ingestion of excessive amounts of iron e.g.
especially if young due to:1
• Young and asymptomatic:  self-medication with iron
o hepatic copper levels high, but difficult to compounds
demonstrate histochemically due to diffuse  use of iron containers by South
distribution in hepatocyte cytoplasm African blacks for brewing
• Older and signs of disease: traditional beers
o copper metal diffusely distributed and
Pathogenesis
intralysosomal
• Neonatal iron overload:
• Advanced disease:
o etiology unknown
o all copper confined to lysosomes:12
o no relationship with genetic
 more easily recognized granular hemochromatosis
pattern o putative environmental agents suspected to
• Cirrhotic stage: interact with one or more factors intrinsic to
o parenchymal nodules may vary strikingly in developing fetal liver2
copper content (see Fig. 1)
Histopathology
Other investigations Iron Distribution
• Liver biopsy: • Varies according to cause
o useful for: • Exogenous siderosis loads Kupffer cells first (Fig. 1)
 diagnosis
 monitoring
- Steatohepatitis
- Cirrhosis
- Cholestasis
- Chronic Hepatitis
Page 40 of 54
o correspond to ferritin and hemosiderin
packed together within siderosomes (iron-
laden lysosomes)7
• Evaluation requires attention to:
o extent (grade or amount) of stainable iron:
 semiquantitative assessment of
stored tissue iron achieved in
different ways:
 simplest system grades
from 1 (minimal) to 4
(massive deposits)
Fig. 1: Secondary siderosis. Hemosiderin (blue) is  grades 2 and 3 indicate
located exclusively in Kupffer cells, sparing the intermediate amounts
hepatocytes. (Perls' iron stain) o distribution in different cell types of portal
tract and lobule
• Always most pronounced in periportal hepatocytes
• Predominantly parenchymal in: Other investigations
o hemochromatosis • Chemical determination of tissue iron:
o neonatal iron overload: o performed on:
 marked hepatocellular necrosis  liver tissue separated from
specimen taken for histology
 parenchymal giant cell
transformation  block deparaffinized after
histopathologic study:
 siderosis
 ensures tissular
 fibrosis
composition of sample
 parenchymal nodule development3 known8
• In thalassemia and other forms of chronic anemia: • Hepatic iron index (HII):9
o both hepatocytes and Kupffer cells store o chemically measured hepatic iron
iron: concentration (μmol/g dry weight)/patient's
 Kupffer cell and macrophage age in years
siderosis is present from early o enables distinction of genetic
stages hemochromatosis (HII ≥1.9) from
o associated fibrosis and cirrhosis heterozygous individuals and patients with
o in contrast with genetic hemochromatosis, siderosis from other causes
often more portal and lobular lymphocytic • Chemically measured HII correlates well with
infiltration, due to transfusion-related viral histological hepatic iron index (HHII) (dividing by the
hepatitis C4 age in years)10
• Dense Perls-positive granules in endothelial cells in • Microscopic evaluation:
various liver diseases, including: o may allow blocked tissue to be preserved
o acute hepatitis o can be used to quantitate when chemical
o alcoholic liver disease: iron determination is not possible
 some hepatic siderosis common in • Computerized image analysis:
cirrhosis o correlates well with classical assays
 most alcoholics with marked o additional technique
hepatic iron overload also have
genetic hemochromatosis5 Differential Diagnosis
• Porphyria cutanea tarda: - Cirrhosis
o often siderosis in periportal hepatocytes: - Hemochromatosis
 usually mild6 • Genetic hemochromatosis

• Ingestion of excessive amounts of iron:1
o combined reticuloendothelial and HEMOCHROMATOSIS
hepatocellular siderosis Definition
Autosomal recessive disorder of iron metabolism most
Special Stains and Immunohistochemistry common in Northern Europeans where there is increased iron
Perls' Stain Using Acid Ferrocyanide deposition in liver, heart, pancreas and gonads. The most
common mutation is missense (C282Y) of the HFE gene on
• Best demonstrates siderosis chromosome 6p.
• Gives Prussian blue reaction with ferric compounds:
o ferritin Clinical Features
o hemosiderin • Autosomal recessive:
• Ferritin dispersed in hyaloplasm: o heterozygosity rarely associated with liver
o gives diffuse bluish tint to the cell's damage due to iron alone1
cytoplasm • Most common inherited disorder in white
• Intense blue granules: Caucasians2
• Risk of hepatocellular carcinoma:
o incidence ≈15%:
Page 41 of 54
 predominantly in males • Fibrosis with:
o not prevented by removal of iron3 o expansion of portal tracts:
 carry iron-laden macrophages
Pathogenesis o small fibrous spurs conferring spiked
• In Northern Europe: contour to portal tracts
o >90% of cases homozygous for missense o some increase in ductular profiles:
mutation (C282Y) in HFE gene on short arm
of chromosome 6:
 usually without marked
inflammation
o mutation leads to dysregulation of o accumulation of granules of stainable iron
intracellular iron homeostasis in
by cholangiocytes of:
enterocytes:
 results in inappropriately high iron
 ductules
absorption  interlobular ducts
o role of a second mutation (H63D) in HFE o some reports of foci of eosinophilic or lytic
gene unclear:4 hepatocellular necrosis of iron-laden
hepatocytes:
 C282Y mutation alone leads to mild
hepatic siderosis, with exception of  often close association with
H63D/C282Y compound clusters of macrophages:
heterozygotes5  so-called sidero-necrosis6
o progressive increase in proportion of iron
Histopathology outside hepatocytes versus hepatocellular
• Progressive iron accumulation in: iron
o liver • Periportal fibrosis proceeds:
o heart o slender periportal septa:
o pancreas  join portal tracts
o other organs  progressively envelope lobules to
• Rate of accumulation varies: produce pattern characteristic for
o even within same family hemochromatosis of combination
of:7
If Young  discrete parenchymal
• Stainable iron in periportal hepatocytes: nodules
o positivity in males generally greater than in  partially preserved lobules
females of same age • Further advancement:
o first abnormality o results in diffuse micronodular pattern with
portal-based septal fibrosis:
With Advancing Age
 resembles secondary biliary
• Progressive deposition of hemosiderin toward cirrhosis
centrilobular area:
o usually maintains decreasing portal–central • Excessive alcohol consumption:
gradient
o induces shift of hemosiderin from
parenchymal to:
• Some Kupffer cells and occasional portal
macrophage may become iron positive:  Kupffer cells
o overwhelmed by almost exclusive  macrophages in fibrous septa7
parenchymal storage • In later stages of heavy iron overload:
• Hepatocellular iron appears as pericanalicular o occasional small areas:
granules representing lysosomal storage (Fig. 1)  without or with little parenchymal
siderosis and only some Kupffer
cell iron load
 most often seen in established
cirrhosis
 represent preneoplastic lesion8
After Therapeutic Phlebotomies

• Steady disappearance of stainable iron:
o pattern reverse of accumulation:
 periportal hepatocytes remain
Perls' positive longer:
 iron removal unmasks
Fig. 1: Parenchymal siderosis in genetic brown lipofuscin-
hemochromatosis. Detail of lobular parenchyma resembling pigment in
showing marked parenchymal siderosis in typical hepatocytes and portal
lysosomal (pericanalicular) localization. There was a mesenchyme
decreasing portal–central gradient in lobular
siderosis (not shown). (Perls' iron stain)
o portal collagen most resistant to iron
removal
With Progressing Siderosis
Page 42 of 54
Perls' Stain Using Acid Ferrocyanide blood vessels, and connective tissue, generating a
• Best demonstrates siderosis score between 0 and 60:13
• Gives Prussian blue reaction with ferric compounds:
o together with HHII14 helpful in assessment
of genetic hemochromatosis
o ferritin
o hemosiderin • Microscopic evaluation:
o may allow blocked tissue to be preserved
• Ferritin dispersed in hyaloplasm:
o can be used to quantitate when chemical
o gives diffuse bluish tint to the cell's
iron determination is not possible
cytoplasm
• Computerized image analysis:
• Intense blue granules:
o correlates well with classical assays
o correspond to ferritin and hemosiderin
o additional technique
packed together within siderosomes (iron-
laden lysosomes)9
• Evaluation requires attention to: - Iron Overload
o extent (grade or amount) of stainable iron: - Cirrhosis
 semiquantitative assessment of
stored tissue iron achieved in Genetics
different ways: • In Northern Europe:
 simplest system grades o >90% of cases homozygous for missense
from 1 (minimal) to 4 mutation (C282Y) in HFE gene on short arm
(massive deposits) of chromosome 6:
 grades 2 and 3 indicate o mutation leads to dysregulation of
intermediate amounts intracellular iron homeostasis in
o distribution in different cell types of portal enterocytes:
tract and lobule  results in inappropriately high iron
absorption
Diagnosis o role of second mutation (H63D) in HFE gene
• Important: unclear4
o cirrhosis can be prevented by appropriate  C282Y mutation alone leads to mild
treatment of patient and homozygous hepatic siderosis, with exception of
relatives, with return of life expectancy to H63D/C282Y compound
normal3 heterozygotes5
• Usually based on clinical, biochemical, genetic, and
histopathologic data Management
• Genetic diagnosis a reality:16 • Therapeutic phlebotomies
o but phenotypic diagnosis remains
NODULAR HYPERPLASIA
important17
• Unexplained small amounts of iron in hepatocytes
should always raise suspicion of early stage:
o calculation of (H)HII and further serum
biochemistry may help establish diagnosis
Other investigations
• Chemical determination of tissue iron:
o performed on:
 liver tissue separated from
specimen taken for histology
 block deparaffinized after
histopathologic study:
 ensures tissular
composition of sample
known10 Definition
• Hepatic iron index (HII):11 Non-cirrhotic non-neoplastic nodular transformation of the
o chemically measured hepatic iron liver parenchyma. It consists of nodular regenerative
concentration (μmol/g dry weight)/patient's hyperplasia thought to be caused by portal venous
age in years thrombosis, the closely related partial nodular transformation
o enables distinction of genetic which is limited to the perihilar region near the porta hepatis,
and focal nodular hyperplasia due to arterial hyperplasia with
hemochromatosis (HII ≥1.9) from
nodular parenchymal hyperplasia and cholestasis.
heterozygous individuals and patients with
siderosis from other causes
Clinical Features
• Chemically measured HII correlates well with
histological hepatic iron index (HHII) (dividing by the
• Accompanies limited number of disorders, such as:
age in years)12 o congestive heart failure
• Also grading system for estimation of iron in o Felty's syndrome
hepatocytes, mesenchymal cells, cholangiocytes, o lymphoproliferative disorders
Page 43 of 54
o drug-induced reactions, usually associated • May be aberrant ‘paraportal shunt’ vessels of
with portal hypertension noncirrhotic portal hypertension (portal
• May be: phlebosclerosis):4
o part of early noncirrhotic stages of primary o in portal hypertension
biliary cirrhosis1 o without portal hyperpressure (or possibly
o in liver containing metastatic or primary subclinical stage)
liver tumor2 • Nodularity better revealed on reticulin stain5
• Sometimes:
o portal hypertension Diagnosis
o elevated: • Histopathologic diagnosis:
o easier on surgical specimens
 alkaline phosphatase
o possible on needle biopsies
 γ-glutamyl transpeptidase
LIVER DISEASE IN PREGNANCY
Pathogenesis
ACUTE FATTY LIVER OF PREGNANCY
• Basic lesion postulated to be portal venous Definition
thrombosis, resulting in: Rare but serious metabolic disorder affecting primigravidae
o parenchymal atrophy and multipara women in the last weeks of gestation
o compensatory hyperplasia3 characterized by fatty replacement of liver. Believed to be
caused by a fatty acid transport and mitochondrial oxidation
• Arterial lesions, particularly age-associated disorder of the fetus.
arteriosclerosis, may contribute3
Clinical Features
Gross Pathology
• Rare
• Non-neoplastic nodules not delimited by fibrous
septa3 • Most serious pregnancy-associated disease
• Develops in last weeks of gestation
Histopathology • Both primigravidae and multipara
• Nodules of hyperplastic hepatocytes: • Unexplained jaundice in late pregnancy
o in plates > one cell thick
• Usually does not recur in subsequent pregnancies1
o adjacent parenchymal cells (usually
centrilobular areas): Pathogenesis
 compressed: • Fatty acid transport and mitochondrial oxidation
 sometimes with (FATMO) disorder of fetus2
perisinusoidal fibrosis
 atrophic Gross Pathology
o portal tracts: • Yellow
 generally in center • Frequently small due to substantial loss of
o interface with other nodules: parenchyma
 not defined by fibrous septa: Histopathology

 differentiates lesion from • Microvesicular steatosis:
cirrhosis (Table 1) o most characteristic feature
o usually involves entire liver lobule
Table 1.
Differential diagnosis of nodular regenerative o sometimes spares narrow periportal rim of
hyperplasia hepatocytes (Fig. 1)
Disease Diffuse Sep Nodul

involvement of ta es
the liver
Cirrhosis + + +
Nodular + – +
regenerative
hyperplasia
Focal nodular – + +
hyperplasia
• Generally:
o no or minimal inflammation Fig. 1: Acute fatty liver of pregnancy. Detail
of lobular parenchyma characterized by
o no liver cell damage microvesicular steatosis and a small
• Vascular changes: number of lymphocytes. (H&E)
o may be subtle and inconspicuous in needle
biopsies • Fibrin thrombi:
o occasionally in hepatic sinusoids
• Sometimes:
Page 44 of 54
o cholestasis • Hypertension induced or aggravated by pregnancy
o hepatocellular necrosis • Association with:
o extramedullary hematopoiesis o proteinuria
o giant mitochondria3,4 o peripheral edema
Diagnosis
• Occasional coagulation abnormalities
• In routinely stained sections:

• May be convulsions and coma2
o hepatocytes containing very fine fat • If severe:
droplets <1μm diameter: o hepatocellular dysfunction with elevated:
 may not be recognized as steatotic  serum transaminases
 may appear as ballooned  alkaline phosphatase
hepatocytes: o may lead to:
 mimic hydropic swelling of  liver failure
liver cells in acute viral  two rare often fatal complications:
hepatitis:
 liver rupture preceded by
 may cause subcapsular hematoma
problems of
diagnosis in the  infarction of liver3
10–20% of cases
with a Gross Pathology
lymphoplasmacyt • Diffuse, fine or blotchy hemorrhages over capsule
ic infiltrate and and on cut surface2,3
acidophil • Intravascular coagulation due to endothelial injury
bodies3,5 and disruption
• Histochemical fat stains on frozen section:4
o make diagnosis clear Histopathology
• Fibrin thrombi in:
Differential Diagnosis o portal vessels
- Toxemia of Pregnancy
o periportal sinusoids
- Steatohepatitis • Hemorrhage
- Acute Hepatitis • Hepatocellular necrosis
Management Special Stains and Immunohistochemistry

• Termination of pregnancy • Fibrin identified by:
• Supportive care for hepatic encephalopathy and o phosphotungstic acid–hematoxylin (PTAH)
extrahepatic complications staining
o immunohistochemistry
Prognosis
• Has improved dramatically over past couple of Differential Diagnosis
decades - Drug Induced and Toxic Liver Injury
- Acute Fatty Liver of Pregnancy
TOXEMIA OF PREGNANCY
LIVER INVOLVEMENT IN OTHER ORGAN SYSTEMS AND
SYSTEMIC DISEASES
GRANULOMAS
Definition
Granulomas are seen in 3-15% of liver biopsies. Some causes
include sarcoidosis, primary biliary cirrhosis, infections such
as Q-fever, tuberculosis and fungi.
Clinical Features
Epithelioid Granulomas
Definition
Complication of
• In 3–15% of liver biopsies1,2
Sarcoidosis
pregnancy
characterized by hypertension with proteinuria, peripheral • Incidence in established sarcoid 21–79%
edema and coagulation abnormalities (pre-eclampsia) and • If clinical evidence of hepatic disease:
convulsions and coma (eclampsia). HELLP syndrome o granulomatous inflammation in 100% of
(hemolysis, elevated liver enzymes and low platelet count) biopsies3
can also occur in pre-eclamptic women.
Clinical Features
Pathogenesis
• 5% of pregnancies: Epithelioid Granulomas
o incidence increased in:
• Diverse etiologies4
 primigravidae
• Cause unknown in up to 50% of cases5
 acute fatty liver of pregnancy1 Fibrin-ring Granulomas
• Generally during third trimester
Page 45 of 54
• Occur in:
o Q fever
o allopurinol hypersensitivity
o cytomegalovirus infection
o Epstein–Barr virus infection
o leishmaniasis
o toxoplasmosis
o hepatitis A
o Hodgkin's lymphoma
o giant cell arteritis
o systemic lupus Fig. 1: Q fever. Detail of lobular parenchyma
• May be nonspecific reaction to liver injury6 with some steatosis and two fibrin ring
granulomas. The granuloma is composed of
a central fat vacuole, a layer of histiocytes
Lipogranuloma and lymphocytes, a fibrin ring, and
• Focal response to rupture of lipid-laden hepatocytes additional accumulation of inflammatory
cells. (H&E)
Histopathology Lipogranuloma
Epithelioid Granulomas • Focal lesion
Sarcoidosis • May be:
• Three broad categories of abnormalities besides o abundant:
granulomatous inflammation:3
o cholestatic (58%)  especially in alcohol-induced
steatosis
o necroinflammatory (41%) o confluent
o vascular (20%)
• Contains:
• Histologic mimics of several other disorders, o macrophages
including:
o occasional lymphocytes
o primary biliary cirrhosis
o eosinophils
o primary sclerosing cholangitis
o sometimes giant cells (Fig. 2)
o drug-induced liver disease
o bile duct obstruction
o viral hepatitis
• Hepatic fibrosis (in 21%), including 6% with cirrhosis:
o sometimes progressive liver disease
• Epithelioid granulomas:
o may be differing ages
o typically:
 greatest frequency in portal and
periportal areas, often in clusters
 heal with fibrosis:
 so often in same biopsy
Fig. 2: Hepatic steatosis in patient with
varying numbers and
alcohol abuse. The picture shows a mixture
degrees of:
of macrovesicular and microvesicular
 epithelioid cells steatosis and a lipogranuloma (upper right
 inflammation corner). (H&E)
 giant cells
 scarring Epithelioid Granulomas
o sometimes masses of granulomas and • Stains for microorganisms:
fibrosis (sarcoidoma): o Ziehl–Neelsen
 raise clinical suspicion of o silver methenamine for fungi
neoplasm3
Fibrin-ring Granulomas
o immunostaining
• Distinctive ring pattern • Polarizing microscopy for inclusions
• Fibrin deposited circumferentially within or at margin • X-ray microanalysis e.g. for:

o gold
• Composed of:
o epithelioid cells o barium
o giant cells o silicon4
o neutrophils
o central fat vacuole (Fig. 1) Diagnosis
• Careful histologic evaluation of:
Page 46 of 54
o granulomas  chronic cholestasis9,10
o associated changes e.g.:  may coexist11
 hepatitis • Sometimes predominantly portal hypertension:12
 bilirubin stasis o due to portal granulomas and fibrosis13
 bile duct damage o final diagnosis cannot be made from liver
• Step sections: biopsy alone due to multiplicity of
o often helpful mimicking granulomatous diseases
o essential when suspected but not in initial
sections
• Special techniques may be helpful4
AMYLOIDOSIS AND LIGHT CHAIN DEPOSITION DISEASE

Etiologic Diagnosis Definition
• Made with clinical context in mind Perisinusoidal and portal deposition of homogeneous material
(amyloid and lambda and kappa light chains) in the liver.
Four Groups4
Clinical Features
• See cause on microscopic examination e.g.: Amyloidosis
o ova of schistosoma • Systemic amyloidosis:
o demonstrable mycobacteria after o commonly involves liver
appropriate staining
o rarely clinically evident hepatic disease
• Know cause or diagnosis: Light Chain Deposition Disease
o requires knowledge of clinical data e.g. • Exceptionally:
 primary biliary cirrhosis if: o coexists with amyloid
 granulomas and lymphoid o intrahepatic cholestasis1
infiltrates adjacent to
injured bile ducts in Histopathology
middle-aged female with: Amyloidosis
 pruritus • Amyloid:
 raised serum o homogeneous eosinophilic extracellular
alkaline material (Fig. 1)
phosphatase
 antimitochondrial
antibodies4
• Suspect diagnosis e.g.:
o granulomas with many eosinophils suggest:
 drug-induced lesions, or
 parasitosis.
• Cause unknown:
o largest group
o consider tuberculosis
Fibrin-ring Granulomas Fig. 1: Amyloidosis. Detail of lobular

• May require serial sections7 parenchyma with massive amyloid
deposition in the space of Disse and
corresponding marked atrophy of liver cell
Lipogranuloma plates. (H&E)
• May require serial sections to:
o identify central fat globule o Amyloid deposition:
o differentiate from other forms of granuloma o usually:
 in hepatic artery branches
 along sinusoids in space of Disse:
- Cholestasis leads to:
- Lymphoma atrophy of liver cell plates
narrowing of sinusoids:
Sarcoidosis occasionally results in:
• Primary biliary cirrhosis: intrahepatic cholestasis
o differentiation can be difficult to because: portal hypertension2,3
 both may lead to: o much more rarely globular deposits4
 portal granulomas
Light Chain Deposition Disease
 bile duct injury and
• Hepatic involvement:
destruction
 ductopenia
Page 47 of 54
o homogeneous perisinusoidal and portal • Regresses spontaneously over several weeks1
depositions: Humoral Rejection
 resemble amyloid • Rare
o usually renal symptoms • Within first few hours after transplantation

• Results in coagulative and hemorrhagic necrosis in a
few days
Amyloidosis
Acute Rejection
• Amyloid:
• Most common form of rejection
o apple green birefringence after positive
Congo red staining • Mean incidence ≈50%2
• Generally within first 3 weeks after transplantation:
Light Chain Deposition Disease o median onset 7–10 days3
• Light chain deposits: o late presentations usually related to
o no green birefringence after Congo red decreased immunosuppression4
staining Chronic Rejection
• Immunohistochemical staining for kappa and lambda • History of acute cellular rejection
light chains: • Progressive cholestasis
o permits identification
o usually kappa (Fig. 2) Other Complications Following Transplantation
Bile Duct Stricture
• At site of anastomosis or elsewhere
Hepatic Artery Thrombosis
• Alone or in combination with portal vein thrombosis
• More common in children
• Results in infarction
Infections
• Common
Drug-induced Injury
• Several drugs in immunosuppressive therapeutic
regimen capable of causing hepatic damage
Fig. 2: Light chain deposition disease. Detail • May be difficult to incriminate a specific drug due to
of lobular parenchyma with kappa chain numerous confounding features
deposition in the space of Disse. Recurrent Disease
(Immunostain for kappa light chain) • Risk highest if:
o neoplastic
o chronic viral hepatitis
Diagnosis
HCV Recurrence
Amyloidosis
• Primary myeloma-associated (AL) amyloidosis vs
• Severe progressive cholestatic syndrome:
reactive (AA) amyloidosis: o incidence 2–10%
o cannot be reliably distinguished by Primary Biliary Cirrhosis
topographic distribution pattern of deposits • Antimitochondrial antibodies:
o AL amyloid: o persist
 Congo red positive if potassium o do not correlate with disease recurrence
permanganate treatment before Neoplastic Disease
Congo red staining5 • Malignancies after liver transplantation comprise:
 positive in light chain o hepatocellular carcinoma:
immunostains  recurrent5 or de novo6,7
 mainly in recipients transplanted
- Cirrhosis for chronic viral hepatitis B and C
- Alpha 1 Antitrypsin Deficiency o post-transplant lymphoproliferative disease
 mostly nodal and extranodal B-cell
LIVER PATHOLOGY IN ORGAN TRANSPLANTATION lymphoma
LIVER TRANSPLANT
Definition
Hepatic pathology associated with transplantation includes Pathogenesis
preservation injury, hyperacute, acute and chronic allograft Diseases Affecting Grafted Liver8
rejection. Diseases such as hepatitis B, C, PBC, PSC,
autoimmune hepatitis and tumors can also recur in the • Diseases affecting nontransplanted livers
allograft. • Preservation (ischemia/reperfusion) injury
• Allograft rejection
• Complications e.g.:
Clinical Features
Preservation injury
o surgical mishap
o hepatic artery thrombosis
• Appears early:
o first 2 weeks post transplant o portal vein thrombosis
Page 48 of 54
o bile duct problems such as: o may attenuate HBV recurrence post
 dehiscence transplantation20
HCV Recurrence
 leaks
• Severe progressive cholestatic syndrome:
 necrosis
o apparently due to direct viral cytopathic
 strictures effect by high viral load21,22
 concrement formation Neoplastic Disease
 infection • Post-transplant lymphoproliferative disease:
• Drug reactions o complication of immunosuppressive
treatment
• Opportunistic infections
• Recurrent disease
• Post-transplant lymphoproliferative disorder Histopathology
Preservation injury Identification of underlying donor liver disease at
• Nonimmunologic graft damage resulting from: allograft procurement
o harvesting • Frozen section
o ischemic preservation Contraindications To Use As Allograft
o transportation • Marked macrovesicular steatosis:23,24
o reperfusion9 o risk of primary graft dysfunction25
Allograft Rejection o semiquantitative parenchymal involvement:
• Caused by immunologic reaction of host2,10–13  absent
• May be:  mild (<30%)
o humoral:  moderate (30–60%)
o acute:  marked (>60%):24,25
o chronic (ductopenic)14,15 • Primary or metastatic malignant tumor
Humoral Rejection Preservation injury
• Rare • Surgical necroses:
• Preformed or subsequently formed antibodies: o quite common
o to an ABO blood group-incompatible o often observed in any surgical specimen26
donor16 o clusters of neutrophils and scattered
o react with graft vasculature acidophil bodies (Fig. 1)
o cause endothelial damage and thrombosis
Acute Rejection
• Cell-mediated immune reaction directed at:
o bile duct epithelium
o endothelium of portal and centrilobular
veins15
Chronic Rejection
• Immunologic injury that:
o usually evolves from severe or persistent
acute cellular rejection
o results in potentially irreversible damage to:
 bile ducts
 arteries
Fig. 1: Surgical necroses consist of focal
 terminal hepatic veins necrosis of hepatocytes and accumulation
 surrounding parenchyma14,17 of clusters of neutrophil polymorphs.
Originally described in specimens taken at
the end of abdominal surgical interventions,
Other Complications Following Transplantation they are now also recognized as a marker of
Infections ‘preservation damage’ in donor livers after
• Consequence of immunosuppressive therapy revascularization during liver
• Wide range of bacterial, viral, fungal, and protozoal transplantation. (H&E)
pathogens including:
o cytomegalovirus and Epstein–Barr virus • Functional cholestasis:
infections o bilirubin stasis in:
o sepsis due to Gram-negative bacilli  hepatocytes
Recurrent Disease
Recurrent Hepatitis B
 canaliculi27
o distinguish from cholestasis associated with:
• Fibrosing cholestatic hepatitis:18
o associated with high viral load  acute rejection
o occurs in other types of immunodeficiency  drug toxicity
states19  hepatitis
• Co-infection by hepatitis B and D virus as primary  bile duct obstruction
disease:  sepsis
Page 49 of 54
• Hepatocellular ballooning: o areas of cell stratification or occasional
o diffuse or centrilobular28,29 dropout
o by itself, does not carry a bad prognosis29 o irregularities in duct outlines
o possibly associated with bilirubin stasis Endotheliitis
• Portal or central veins
• Centrilobular hepatocyte necrosis:
o a more severe preservation injury • Supraendothelial and subendothelial lymphocytes
o due to hypoperfusion • Endothelial damage
o a differential diagnostic problem because • Lifting off of endothelium from underlying layers
confluent necrosis in: • Indicative of severe cellular rejection of:
 vascular complications o centrilobular veins
 drug-induced injury o necrosis of centrilobular hepatocytes
 as poor prognostic sign in acute • Periportal extension of portal inflammatory
and chronic allograft rejection30 infiltrate33
Acute Rejection (Fig. 2) A Less Frequent Form Of Cellular Rejection
• Endothelial predominance:
o isolated central venulitis in adult and
pediatric liver allograft recipients34,35
o may result in:
 perivenular fibrosis
 a veno-occlusive syndrome36
Grading Systems
• Several proposed:2
o to predict unfavorable clinical outcomes
o consensus document33
• Additional features less consistently present:
o bilirubin stasis
o some lobular inflammatory mononuclear
Fig. 2: Acute (cellular) rejection of liver allograft. Detail of
infiltrate
portal tract showing dense mixed infiltrate (including
lymphocytes, more immature lymphoid type cells, and o if severe rejection:
eosinophils), mild endotheliitis (from center to lower right), centrilobular confluent
and bile duct involvement (center left and center bottom). parenchymal necrosis
(H&E) (Courtesy of Prof. T Roskams, Leuven) Chronic Rejection (Fig. 3)
• Triad of:
o portal infiltration
o bile duct damage:
o usually endotheliitis
Portal Infiltration
• Mixture of inflammatory cells:
o small lymphocytes predominate
o larger lymphoid type cells
o immunoblasts
o macrophages
o plasma cells
o neutrophils
o eosinophils:
 sometimes abundant and a helpful Fig. 3: Chronic ‘ductopenic’ rejection of liver allograft. Portal
diagnostic feature31 tract without bile duct and very sparse lymphocytic
o typically expands portal tract infiltration. (H&E)
o may be focal and unevenly distributed
o occasionally:
• Minimal diagnostic criteria:
o bile duct atrophy/pyknosis:
 extends beyond limits of portal
tract  affects majority of bile ducts
 leads to portal–portal bridging  with or without bile duct loss
necrosis32 o convincing foam cell obliterative
Bile Duct Damage arteriopathy, or
• Bile ducts infiltrated by: o bile duct loss of >50% of portal tracts
o lymphocytes • Arteries with pathognomonic changes:
o lymphoid-type cells (lymphocytic o predominate in hilar region
cholangitis) o rarely in needle biopsy specimens
• Bile duct epithelial damage reflected in: • Considerable significance placed on damage and loss
o anisonucleosis of small bile ducts
o cytoplasmic vacuolization • Changes mainly affect:
Page 50 of 54
o portal tracts:  rapidly progressive graft
 loss of small bile ducts dysfunction
small branches of hepatic artery  characterized by:
o centrilobular areas  perisinusoidal bands of
Early Bile Duct Changes fibrosis around plates of
• Uneven nuclear spacing ductular-type epithelium
• Nuclear:
 prominent bilirubin stasis
o enlargement  ground glass hepatocytes
o hyperchromasia  hepatocellular ballooning
with cell loss
• Interrupted epithelial lining of ducts
Early Arterial Lesions  mild mixed inflammatory
reaction18
• Accumulation of subintimal, medial, and adventitial
HCV Recurrence
foamy macrophages
Late Bile Duct And Arterial Damage • As defined by histologic injury almost universal
• Mainly evaluated by extent of loss: • Sometimes severe graft injury resulting in graft
o bile duct loss when <80% of portal tracts loss20,41,42
Primary Biliary Cirrhosis
contain bile ducts
o arterial loss when <77% of portal tracts • Liver biopsy:
contain hepatic artery branches17 o gold standard for diagnosis of recurrence:43
Early lesions In Centrilobular Area  most helpful features:
• Subendothelial and perivenular mononuclear  florid bile duct lesions
inflammation of centrilobular vein
 epithelioid granulomas
• Centrilobular hepatocyte dropout
 granulomatous
• Pigment-laden macrophages cholangitis also
• Mild perivenular fibrosis observed in
‘Transitional Hepatitis’ chronic viral
hepatitis C44
• Sometimes difficult to distinguish from viral hepatitis
• May occur during evolution to late stages37
 less helpful features that may
occur in chronic hepatitis C and
Late Chronic Rejection
allograft rejection:
• Severe (bridging) perivenular fibrosis
 portal lymphoid
• At least focal central–central or central–portal aggregates
bridging
 ductopenia
• Occasional obliteration of terminal hepatic venules
 other useful features:
 ductular reaction
Other complications following transplantation
Bile Duct Strictures  progressive cholate stasis
(including copper
• Histologic features of any biliary obstruction deposition)
Drug-induced Injury
 suggested early marker:
• Azathioprine:
o associated with: plasma cells in portal
infiltrate45
 sinusoidal congestion Primary Sclerosing Cholangitis46
 centrilobular necrosis38 • Requires well-defined cholangiographic and
• Ciclosporin: histologic criteria42
o may cause: • Features resemble those of complications of
 canalicular bilirubin stasis transplant procedure
 hepatocyte ballooning
• Based on clinical, biochemical, serologic, and
 vacuolization of bile duct epithelial histologic criteria:43
cells39 o portal and periportal inflammation (interface
Recurrent Disease
hepatitis) containing plasma cells47
• Some have histopathologic features that overlap with
those in:
o rejection Diagnosis
o post-transplant biliary stricture • Percutaneous liver biopsies:
Recurrent Hepatitis B o obtained when symptoms of deterioration of
• May cause: liver function
o acute and chronic hepatitis • Protocol biopsies:
o cirrhosis o biopsies obtained on planned schedule
o minimal histologic changes (carrier state) irrespective of liver chemistry48,49
o in a minority of cases, fibrosing cholestatic • Fine needle aspiration biopsy:
hepatitis:18 o may be adequate in experienced hands50
 occurs early (before 150 days)40 • Several pathologic conditions may coexist in liver
allograft such as:
Page 51 of 54
o drug toxicity Chronic GVHD
o viral hepatitis • Usually preceded by acute GVHD
o disease recurrence • May be de novo:
o rejection o ≈25% of cases
Preservation injury • >3 months after bone marrow transplantation
• Time zero biopsies:
o for evaluation Pathogenesis
o obtained at transplantation directly after • Complication of bone marrow transplantation1,2
revascularization of graft51
Chronic Rejection Histopathology
Acute Hepatic GVHD
• Diagnosis based on combination of clinical,
radiological, laboratory, and histopathologic findings • Cholestasis
• Defining features not uniformly present: • Bile duct damage:
o bile duct loss can occur without arteriopathy o affected ducts:
o arteriopathy can occur without bile duct loss  irregular profile
o severe (bridging) centrilobular fibrosis may  epithelial atypia with:
be present without significant bile duct loss  nuclear pleomorphism
or obliterative arteriopathy
o may be late features of one component (e.g.  cytoplasmic vacuolation
bile duct loss) and early features of another  cell necrosis
component (e.g. perivenular necrosis)17 o may be duct destruction
• Working formulation for histopathologic staging and o lymphocytic infiltration of duct epithelium
reporting of chronic liver allograft rejection proposed: o mild portal inflammation
o early chronic rejection: • Early biopsies (<35 days):
 if no more than one of the target o less bile duct damage
structures shows late changes o marked hepatocellular apoptosis3
o late chronic rejection:
• Other lesions:
 at least two or more target o endotheliitis
structures show late changes
o siderosis
Differential Diagnosis o veno-occlusive disease4
- Cholestasis Chronic GVHD
- Chronic Hepatitis • Similar to acute GVHD, but more severe
- Acute Hepatitis
• Dense portal infiltration:
Chronic Rejection
o sometimes:
• Other causes of ductal injury and loss including:  periportal extension
o biliary tract obstruction  interface hepatitis
o hepatic artery thrombosis17 • Lobular changes include:
HCV Recurrence o bilirubin stasis
• Differentiation from cellular rejection may require: o apoptotic bodies
o sequential biopsies • When advanced:
o grading of lesions to document progressive o ductopenia5
appearance of hepatitis C features o cholate stasis
o progressive periportal fibrosis
GRAFT VERSUS HOST DISEASE
o cirrhosis
- Acute Hepatitis
- Drug Induced and Toxic Liver Disease
- Cholestasis
Acute Hepatic GVHD

• Picture in early biopsies (<35 days) easily confused
with viral hepatitis C
ECHINOCOCCUS CYST (Hydatid Cyst)

Definition
Infection of the liver by the larval or cystic stage of
echinococcus tapeworms. The most common is E. granulosus,
Definition but the most aggressive is E. multilocularis.
Liver damage as a complication of bone marrow
transplantation. Divided into acute and chronic forms. Clinical Features
Echinococcus granulosus
Clinical Features
Acute Hepatic GVHD • Most frequent cause of echinococcus cysts:
• <90 days after bone marrow transplantation
Page 52 of 54
• Commonly communication with biliary tract and o may be surrounding pericyst layer of either:
superimposed infection1  granulation tissue
• May rupture:  fibrous capsule:
o into peritoneal cavity and result in:  calcification signifies cyst
 fatal anaphylactic reaction is dead
 formation of innumerable small • Adjacent liver parenchyma:
granulomas grossly resembling o often:
peritoneal tuberculosis:
 pressure atrophy
 fragments of germinal
membrane or scolices in
 portal infiltrate:
center points indicate  eosinophils may be
diagnosis prominent
o inside gallbladder • Viable cyst:
o through diaphragm into pleural space and o filled with colorless fluid:
lung contains:
Echinococcus multilocularis
daughter cysts
• Compared with E. granulosus:
brood capsules with scolices:
o less common
o more aggressive clinical disease scolices easily identified:
 after macerating portion of
Pathogenesis germinal layer in saline
• Result of hydatid disease caused by larval or cystic characte
stage of Echinococcus tapeworms ristic hooklets 20–40μm long
Echinococcus granulosus • Sometimes daughter cysts outside chitinous layer:
• Adults in dogs and jackals in all continents2 o i.e. extracapsular or satellite cysts5
• Ingested eggs hatch into larval oncospheres, which Echinococcus multilocularis
enter liver by portal vein • Irregular cysts:
o may be surrounding:
Gross Pathology
Echinococcus granulosus  granulomatous reaction containing
neutrophils and eosinophils
• Hepatic cyst (Fig. 1):
 rim of:
 necrosis
 fibrosis
 focal calcification6
• Laminated membrane:
o clearly visualized by PAS stain
o often fragmented
• No:
o nucleated germinal membrane
o protoscolices
- Liver Abscess
- Metastatic Tumors
- Mucous Cystadenoma
Fig. 1: Echinococcosis of the liver. ABSCESS
o one or more in 75% of infected individuals

o slow growth
o typically spherical
o may be >30cm diameter
o usually right lobe
o may be multiple, involving all lobes3,4
Echinococcus multilocularis
• Multilocular, necrotic, cystic cavities:
o contain thick pasty material
o not surrounded by a fibrous wall
Histopathology Definition
Echinococcus granulosus Hepatic abscesses are due to the following in descending
• Cyst wall: order: biliary obstruction and infection, systemic bacteremia,
o outer chitinous (or fibrous laminar) layer direct extension from contiguous infection, trauma and
o inner germinal layer pylephlebitis. Tuberculous and anaerobic infections have been
Page 53 of 54
increasing while amebic and culture negative cases have
been decreasing.
Clinical Features
• Mortality rate 10–20%1,2
• In US usually:
o older adults, or
o HIV-infected or other immunocompromised
young individuals
Amebic Abscess
• Usually adult3,4
Fig. 2: Amebic abscesses occupying most of
Pathogenesis the right lobe of the liver. Three distinct
• In past usually: lobules are seen. (Courtesy of Dr RA Cooke,
o amebic, or Brisbane, Australia; from Cooke RA, Stewart
o secondary to pylephlebitis B: Colour Atlas of Anatomical Pathology.
Edinburgh, Churchill Livingstone, 2004).
• Today in US:
o usually due to enteric bacteria • Greater tendency for multicentricity if
o increasing number of tuberculous immunocompromised
‘abscesses’5,6 in immunocompromised
• Necrotic center:
• Predisposing factors, in descending order of o usually contains odorless, pasty, chocolate
frequency: brown fluid
o biliary tract obstruction/infection
• May be:
o systemic bacteremia o extension and perforation into:
o direct extension from contiguous infection
o penetrating or nonpenetrating trauma  pleuropulmonary structures
o pylephlebitis7,8  subphrenic space
• Specific causes:
 peritoneal cavity
o secondary bacterial infection of metastatic  less commonly:
tumor nodules  pericardial sac
o inflammatory bowel disease9  bile ducts
o pancreatitis10  kidney
o chemotherapy11  mediastinum
o dental disease12  chest wall
Gross Pathology  abdominal wall
• Size varies (Fig. 1)  flank16
Histopathology
Amebic Abscess
• Mainly necrotic material
• Few if any neutrophils
• Surrounding layer of:
o fibrin
o macrophages
o lymphocytes
o few fibroblasts
• Wall thinner than that of bacterial liver abscess
• Usually clusters of amebae:
Fig. 1: Large liver abscess surrounded by a thick
fibrous wall.
o extensive search may be necessary
• May be:
• May be multiple: o superinfection by bacteria
o ≈50% of pyogenic abscesses
Other investigations
o ≈25% of amebic abscesses13
• Anaerobic culture10
• Communication between abscess and intrahepatic
biliary system slightly <50% of cases14 • Diagnostic imaging:
o ultrasonography
Amebic Abscess o CT
• Usually: o MRI
o single o angiography
o right sided o useful in:
o close to liver dome15 (Fig. 2)  identifying hepatic abscesses
 distinction from necrotic tumors
Page 54 of 54
- Acute Hepatitis
- Metastatic Tumors
Management
• Includes:
o antibiotics:
 rarely effective if sole treatment
o aspiration:
 rarely effective if sole treatment
o drainage
o excision

Non Neoplastic Liver

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Non Neoplastic Liver

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SURGICAL PATHOLOGY

 inside phagocytosing macrophages Acute Viral Hepatitis

Minimal Acute Hepatitis

CHRONIC VIRAL HEPATITIS

Nonhepatitis Viral Causes

Factors Associated With Fibrosis

Findings During Course Of Disease

Early Viral Replication And Immune Tolerance Phase

Viral Elimination Phase

• May be precancerous lesions in precirrhotic and

Chronic Viral Hepatitis B + D

Multiple Hepatitis Virus Infection Diagnosis of chronic hepatitis

 an adequate report • Scoring carried out by at least two observers152

Fig. 1: Detail from micronodular cirrhosis. Incomplete Septal Cirrhosis

Fig. 3: Detail from ‘incomplete septal type’ cirrhosis.

• Eosinophilic, PAS positive, and diastase resistant

• nodular regenerative hyperplasia

• congenital hepatic fibrosis

Disease Diffuse Sep Nodul Bile Duct Damage And Ductopenia

o may resemble ductopenic biliary cirrhosis

DRUG INDUCED AND TOXIC LIVER INJURY Unpredictable Reactions

Periportal Hepatocytes Periportal Necrosis

Steatosis Hepatocellular Tumors

 intravenous tetracycline  Thorotrast – used as a radiologic

Bi- And Multinucleated Hepatocytes

 may be cured by withdrawal of  coma

Patterns and Distribution

 more frequent in elderly5

Fig. 2: Acute fatty liver of pregnancy. Detail of

Diseases Unrelated To Alcohol

o starts in centrilobular zone

Histopathologic Diagnosis of Chronic Cholestasis

Fig. 2: Cholate stasis in periphery of

Fig. 4: Cholate stasis in periportal parenchyma in patient with

Cholestatic Liver Cell Rosettes

Two Further Characteristic Changes In Neonatal

Absent Ductular Reaction

Fig. 8: Cholestatic liver cell rosettes. Immunostaining for

• Probably heterogeneous and represents common

• Neonatal giant cell hepatitis:

Special Stains and Immunohistochemistry

Fig. 1: Granulomatous cholangitis in primary

 due to sampling variability

 prevents firm histologic diagnosis

Special Stains and Immunohistochemistry

Fig. 1: Primary sclerosing cholangitis. Detail

Alpha-1 Antitrypsin Deficiency In Adults3

Fig. 2: Primary sclerosing cholangitis.

 usually mild6 • Genetic hemochromatosis

After Therapeutic Phlebotomies

 not defined by fibrous septa: Histopathology

Disease Diffuse Sep Nodul

• In routinely stained sections:

Management Special Stains and Immunohistochemistry

• Fibrin deposited circumferentially within or at margin • X-ray microanalysis e.g. for:

AMYLOIDOSIS AND LIGHT CHAIN DEPOSITION DISEASE

Fibrin-ring Granulomas Fig. 1: Amyloidosis. Detail of lobular

Special Stains and Immunohistochemistry

Acute Hepatic GVHD

ECHINOCOCCUS CYST (Hydatid Cyst)

Fig. 1: Echinococcosis of the liver. ABSCESS

o one or more in 75% of infected individuals

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