THE HEPATOBILIARY SYSTEM AND

DISORDERS

ETIOPATHOGENESIS & MORPHOLOGIC

FEATURE

dr. Ni Made Mahastuti, M.Biomed, SpPA

ANATOMICAL PATHOLOGY DEPARTMENT
FK UNUD/RSUP SANGLAH DENPASAR
 LIVER DISEASE
-vunerable to metabolic, toxic, microbial,
immunologic, circulatory and neoplastic
insult.
-Major primary disease : viral Hepatitis,
NAFLD, alcoholic LD, HCC
-Secondary damages occur in : cardiac ds,
disseminated ca, extrahepatic infection
-5 general responses :
inflammation, degeneration, cell death,
fibrosis and cirrhosis
1.Hepatic Injury and Repair
 Mechanism
a.Hepatocyte and parenchymal respons
- reversible : steatosis (fat) and cholestasis (bilirubin)
- irreversible : necrosis or apoptosis
- necrosis : ischemic/hypoxic, response
to oxidative stressconfluent to bridging
necrosis
- apoptosis : viral, autoimmune hep, drug and
toxin
- regeneration : mitotic replication of normal
hepatocyte or
stem cell near canal of hering
(ductular reactions due to duct-like
morphologymarker of stem cell
mediated regeneration).
b. Scar formation and Regression
- A reaction to chronic injury, most often; but may follow
very severe acute injury
- Principal cell : hepatic stellate cell  higly fibrogenic
myofibroblast that initiated by the increased expression
of PDGRF-β
- Stimuli for stellate cell activation : chronic infl, cytokine
& chemokine from Kupffer cell, disruption ecm, toxin.
- Other cells : portal fibroblast, fibrocyte & cell from EMT
c. Inflammation and Immunity
- antigen in liverAPC (Kupffer cells and blood-
derived dendritic cells)proinflammatory
cytokinesinflammation, injury, vascular
disturbance, scarring and malignant
transformation
- Antigen-spesific and CD4+,CD8+ T cells
eradication hep B and C and also induce local
hepatocyte replication.
 Liver failure
- The most severe clinical consequence of liver ds
- 3 scenarios:
 Acute liver failure/fulminant LF,
 Chronic liver failure , causa : chronic hep B &
hep C, NAFLD, alcoholic LD
 Acute on chronic liver failure, causa : hep D
superinfection with chronic hep B
 Acute liver failure
 defined as a liver disease that produces
hepatic encephalopathy within 6 months of the
initial diagnosis (fulminant liver failure when
the encephalopathy develops within 2 weeks of
the onset of jaundice, and as subfulminant within
3 months)
 causa : acute hep B &E(Asia),
acetaminophen,drug,toxin(USA), hep A
 Morphology :
• massive hepatic necrosis
• small and shrunken of liver due to loss of
parenchym
• large zones of destruction surrounding
occasional islands of regenerating hepatocytes
• Absent of scar
 Massive liver
necrosis

Small liver with bile-stained and

congested

Residualnormal tissue

Confluent hepatocellular
necrosis
- Complication :
 Hepatic encephalopaty
 Coagulopathy
 Portal hypertension and ascites
 Hepatorenal syndrome
 Hepatopulmonary syndrome
 Chronic liver failure and cirrhosis
 diffuse transformation of the liver into
regenerative parenchymal nodule
surrounded by fibrous bands
 associated with chronic liver ds
 causa : chronic hep B & hep C, NAFLD,
alcoholic LD
 Morphology :
• regenerative parenchymal nodule
surrounded by fibrous bands
• nodular nature of the process is readily
evident both grossly and microscopically
• Ductular reaction
• Regression of fibrosis
Chronic liver
failure and
cirrhosis
- Clinical features :
 40% are asymptomatic, until the advanced stage
 Jaundice, encephalopathy, coagulopathy
 Pruritus
 Portal hypertension, portosystemic shunt,
esophagogastric varices, splenomegaly
 Hyperestrogenemia : palmar erythema, spider
angioma of skin, hypogonadism, gynecomastia (male)
 Hepatocellular carcinoma (HCC)
 Acute on chronic liver failure
 individuals after years of stable, well-
compensated,chronic disease suddenly develop
signs of acute liver failure.
 causa : hep D superinfection with chronic hep B;
emergence of resistance to medical therapy in those
with viral hepatitis; ascending bacterial cholangitis in
patients with primary sclerosing cholangitis; or
replacement of liver parenchyma by primary or
metastatic carcinoma; also systemic disorder
2.Viral Hepatitis
- systemic viral infection: EBV, CMV, HSV,
yellow fever
- hepatotrophic : HAV, HBV, HCV, HDV,
HEV
 The outcome of viral hepatitis infection are :
1. Acute Asymptomatic Infection With Recovery: identified incidentally
on the basis of elevated serum transaminases or the presence of anti-
viral antibodies.
2. Acute Symptomatic Infection With Recovery: follow some course
of ds
3. Fulminant Hepatic Failure: 2/3 by HBV, 1/3 HAV
4. Chronic Hepatitis: persist or relaps in 6 months
5. The Carrier State: chronic infected with no or subclinical evidence
6. HIV and Chronic Viral Hepatitis: coinf with HBV and HCV
Potential outcomes of HBV infection in United
State (* spontaneous clearance of HBsAg)
 Morphology of viral hepatitis
 Liver biopsy is helpful in confirming the
clinical diagnosis, excluding common
concomitant conditions (e.g., fatty liver
disease, hemochromatosis),assessing
histologic features associated with an
increased risk for malignancy,grading the
extent of hepatocyte injury and inflammation,
and staging the progression of scarring.
 Diagrammatic representation of the
morphologic features of acute & chronic hepatitis
 Acute viral hepatitis, lobular disruption,
inflammatory cells in sinusoid and hepatocyte
apoptotic
Chronic viral hepatitis (HCV) with interface
hepatitis
Portal tract with dense lymphoid infiltrate in HCV infection
GROUND GLASS HEPATOCYTE
CHRONIC HBV
3. Liver Abscesses
- developed c.: bacterial, fungal
- developing c.: parasitic (amebic,
echinococcal), protozoa, helminth
- pyogenic organisms may lead intrahepatic
abscesses and producing fever, rightupper-
quadrant pain, and tender hepatomegaly
- pathways :
ascending infection in the biliary tract,
vascular seeding (portal/arterial), direct
invasion, penetrating injury
- micros : abscess, cystic with causa
organism can be identified
- macros : solitary, multiple, mm/massive
4. Alcoholic Liver Disease & NAFL
4.1 Alcoholic liver disease
 The multiple pathologic effects of alcohol
include changes in lipid metabolism,
decreased export of lipoproteins, and cell
injury caused by reactive oxygen species
and metabolites of alcohol.
 Chronic alcohol consumption, effect :
a. Hepatic steatosis/fatty liver
moderate : microvesicular lipid droplet
chronic intake : macrovesicular lipid d.
b. Alcoholic Hepatitis
- hepatocyte swelling (ballooning) &
necrosis, Mallory bodies, neutrophilic
reaction, fibrosis
c. Alcoholic cirrhosis
- final & irreversible, 60-70%
- 3 characteristics:
• bridging fibrous septa, difus, irreversible
• parenchymal nodule of regenerating
hepatocytes (Ø<3mm/micronodule,
several cm/macronodule)
• disruption of the architecture
Figure 16-13
Alcoholic liver
disease
Fig. 16.16 Fatty liver disease associated with chronic alcohol use. A mix of
small and large fat droplets (seen as clear vacuoles) is most prominent
around the central vein and extends outward to the portal tracts. Some
fibrosis (stained blue) is present in a characteristic perisinusoidal “chicken
wire fence” pattern (Masson trichrome stain). (Courtesy of Dr. Elizabeth Brunt,
Washington University, St. Louis, Missouri.)
4.2 Nonalcoholic Fatty Liver (NAFL)
Etiopathogenesis
obesity and insulin resistance (both adipose tissue and the liver)
increase the mobilization of free fatty acids from adipose tissue and
stimulate the synthesis of fatty acids within hepatocytes.
sensitize hepatocytes to the toxic effects of inflammatory cytokines,
evidence of inflammasome activation,leading to local release of the pro-
inflammatory cytokine IL-1.
increased production of reactive oxygen species damage intracellular
component
Liver injury resulting from these various insults causes stellate cell
activation, collagen deposition, andhepatic fibrosis, which along with
ongoing hepatocyte damage
 3 types of changes :
- steatosis
- Steatohepatitis (NASH)
- Cirrhosis (10%-20%)
Natural history of NAFLD
MACROSCOPIC CIRRHOSIS
STEATOSIS HEPATIS
CIRRHOSIS HEPATIS
5. Primary carcinoma of the liver
- HCC, cholangio ca, hepatoblastoma,
angio sarcoma
- HCC : peak incidence in 20-40 yo, male>>
- Pathogenesis:
• most important underlying factor :
- HBV, HCV
- alcohol
- aflatoxin
• other risk factor : inherited disorder,
metabolic synd, NAFLD, obesitas, DM
• Mutasi oncogen & TSG (β catenin &
p53 are the most common)
5.1 HCC
• unifocal, multifocal, diffuse infiltrative
discrete mass, yellow-white, soft,
area bile, hemmorrhagic, necrotic
• histology :
- well diff (cord/small nests) – poorly diff
(multinucleate anaplastic tumor giant cell)
- globule of bile (cytoplasm, pseudocanaliculi),
acidophilic hyaline inclusion in cytoplasm,
scant stroma, vascular invasion
MACROSCOPIC HCC
Hepatocellular carcinoma
5.2 Cholangiocarcinom
• second most common
• arise from intra and extrahepatic bile duct
• risk factor : infestation of liver flukes, chronic
infl, hepatolithiasis, fibropolycystic LD, HBV,
HCV, NAFLD
• macros :
- extrahepatic : firm gray nodule >>
- intrahepatic : intrahepatal portal tract,
single massive mass
•Micros : typical mucin producing, well-
moderately diff, tubuluar/glandular, desmoplasia
CHOLANGIOCARCINOMA
II GALLBLADDER
1.Cholelithiasis (gallstones)
- type: cholesterol stones 80% & pigment st.
- pathogenesis :
- cholesterol stone :cholesterol concentration
exceed solubilizing capacity of
bile(supersaturation), nucleates into solid
cholesterol monohydrate crystal
- pigment stone : complex mixt of insoluble
calcium salt of unconjugated bilirubin w/
inorganic calcium salt
Risk factors
2. Cholecystitis
2.1 Acute cholecystitis
- pathogenesis : chemical irritation and
inflammation of gb obstruted by stone
- morphology : acute inflammatory reaction,
enlarged,tense, red, empyema, gangrenous,
90% stones +
CHRONIC CHOLECYSTITIS
2.2 Chronic cholecystitis
- morphology : chronic inflammation,
fibrosis, Rokitansky –Aschoff sinuses,
almost always stones + (>90%)
III PANCREAS
1. Pancreatitis
1.1 Acute pancreatitis
- reversible inflammatory disorder
- etiologic factors : table 17-1
most common : gallstone & alcohol
- premature enzyme activation within
acinar cell ( inappropriate trypsin activation)
autodigestion of pancreas and elicit
acute inflammatory reaction
- Morphology :
• microscopic :
- proteolytic destruction
- necrosis of blood vessels, hemorrhage
- necrosis of fat
- acute inflammatory reaction
• macroscopic : acute hemorrhage, necrotic,
softening, peritoneal : serous, turbid,
brown, suppurative
 1.2 Chronic pancreatitis
 Pathogenesis :
- ductal obstruction by concretions
- toxic metabolite
- oxidative stress
- inappropriate activation of pancreatic
enzym due to mutation of genes encoding
trypsinogen or trypsin inhibitor
- Morphology :
• microscopic : fig 17-4
fibrotic, atrophy, chronic inflammatory
cell, duct obstruction
• macroscopic : hard, dilated duct with
calcified concretion
Chronic pancreatitis
2. Carcinoma of the pancreas
- epithelial, exocrine portion
- multiple mutation in cancer- ass gene :
90% K-RAS, CDKN2A
- morphology :
• macroscopic : gritty, gray-white, hard,
mucin secretion, obstruct bile outflow
• microscopic : glandular pattern, mucin,
anaplastic cuboidal to columnar cells,
undifferentiated cell, peri or intraneural
invasion
THANK YOU