Far Eastern University – Nicanor Reyes Medical Foundation
Pathology B – Liver and Biliary Tree
Mirian Viterbo M.D.
Liver and Bile Ducts
 Normal adult liver weighs 1,400 to 1,600 grams.
 It has dual blood supply:
 Portal Vein supplies 60-70% of the blood flow.
 Hepatic Artery supplies 30-40% of the blood flow.
 The blood supply enters the liver via porta hepatis and travel
within parallel tracts, ramifying through 17-20 branches.
 Hepatic microarchitecture is based on the lobular model.
 The liver is divided into 1-2mm diameter lobules that are
oriented around the terminal tributaries of the hepatic vein
(central vein), with portal tracts at the lobule’s periphery.
 Often drawn as hexagon in shape:
 Those near the periphery of the terminal branch of the
hepatic vein (central vein) are called centrilobular.
 Those near the portal tract are called periportal.
 Division of the parenchyma into zones is a useful concept since
certain types of hepatic injury tend to preferentially affect zones.
 Between trabecular plates of hepatocytes are vascular sinusoids
where blood traverses and exits via the terminal hepatic vein.
 The sinusoids are lined by fenestrated endothelial cells.
 Beneath the endothelial cells is the space of Disse, into which
protrude abundant hepatic microvilli.
 Kupffer cells are attached in the luminal face of the endothelium
 Hepatic Stellate Cells are found in the space of Disse, they are
fat-containing myofibroblastic cells.
 Between hepatocytes are bile canaliculi which are channels that
drain into the canals of Herring that connect to bile ductules in
the periportal region which ultimately empties into the terminal
bile duct.
General Features of Liver Disease
 The liver is vulnerable to a wide variety of metabolic, toxic,
microbial, circulatory, and neoplastic insults.
 Major diseases of the liver are:
 Viral Hepatitis
 Non-alcoholic Fatty Liver Disease (NAFLD)
 Alcoholic Liver Disease
 Hepatocellular Carcinoma (HCC)
 Can occur secondary to some most common diseases such as
heart failure, cancer, and extrahepatic infections.
 More often hepatic damage is secondary.
 With exception of acute liver failure, liver disease is insidious.
 May heal without clinical detection.
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MECHANISM OF INJURY AND REPAIR
Hepatocyte and Parenchymal Responses
 Hepatocytes can undergo number of degenerative but
potentially reversible changes such as steatosis (ballooning
degeneration) and cholestasis (feathery degeneration)
 Hepatocyte Necrosis results from cellular swelling due to
defective osmotic regulation at cell membrane leads to rupture.
 Before rupture, membrane blebs form, carrying off cytoplasmic
contents into the extracellular compartment.
 Macrophages cluster at sites of injury and mark the sites of
hepatic injury, this form is the predominant mode of death in
ischemic/hypoxic injury and significant part of oxidative stress.
 Hepatocyte Apoptosis is an active form of programmed cell
death resulting in hepatocyte shrinkage, nuclear chromatin
condensation (pyknosis), fragmentation (karyorrhexis), and
cellular fragmentation into acidophilic apoptotic bodies.
 When there is widespread parenchymal loss, there is often
evidence of confluent necrosis; a severe, zonal loss of
hepatocytes may be seen in toxic, ischemic injuries, severe viral
or autoimmune hepatitis.
 May begin as a zone of hepatocyte dropout around the
central vein, resulting space is filled by cellular debris,
macrophages, and remnants of the reticulum meshwork.
 In bridging necrosis, this zone may link central veins to portal
tracts, or bridge adjacent portal tracts.
 Regeneration occurs primarily by mitotic replication of
hepatocytes adjacent to the lost ones.
 Hepatocytes are almost stem cell-like in their ability to continue
to replicate even in the setting of years of chronic injury and thus
stem cell replenishment is usually NOT a significant part of repair
Scar Formation and Regression
 Principal cell in scar deposition is the hepatic stellate cell.
 In its quiescent form it is a lipid (Vit. A) storing cell.
 In several acute and chronic injuries, the cells are activated
and converted into highly fibrogenic myofibroblasts.
 Myofibroblasts express platelet-derived growth factor receptors.
 Kupffer cells release cytokines that modulate gene expression in
stellate cells particularly TGF-β, MMP-2, and TIMP-1.
 Myofibroblasts are contractile and stimulated by endothelin-1.
 Stellate cell activation may originate from:
 Chronic Inflammation with production of cytokines (TNF).
 Cytokine and chemokine production by Kupffer cells
 Response to disruption of the ECM
 Direct simulation of the stellate cells from toxins
 Zones of parenchymal loss transform into dense fibrous septa
through a combination of the collapse of underlying reticulin and
activated stellate cells.
 Eventually these septa encircle surviving hepatocytes in late
chronic disease give rise to diffuse scarring termed cirrhosis.
 If the chronic injury is interrupted, the stellate cell activation
stops and the scars condense and thin out then can be reversed
Inflammation and Immunity
 Antigens in the liver are taken up by APC such as Kupffer cells
and blood-derived dendritic cells.
 TLRs detect host molecules and foreign invaders that lead to
production of pro-inflammatory cytokines.
LIVER FAILURE
 The most severe consequence of liver disease is liver failure.
 May be result of sudden, massive destruction: acute liver failure
or more often, a chronic liver failure which follows upon years
or decades of insidious, progressive liver injury
 80-90% of hepatic functional capacity must be lost before
hepatic failure ensues.
 Transplantation offers the best hope for survival, mortality rate
without transplant is about 80%.
Acute Liver Failure
 Defined as an acute liver illness associated with encephalopathy
and coagulopathy that occurs within 26 weeks of the initial liver
injury, in the absence of pre-existing liver disease.
 Has been referred as fulminant liver failure.
 Caused by massive hepatic necrosis, most often induced by
drugs or toxins.
 Mechanism may be direct toxic damage (e.g. acetaminophen) or
more often variable combination of toxicity and immune-
mediated hepatocyte destruction (hepatitis viral infection).
Morphology
 Massive hepatic necrosis with broad regions of parenchymal
loss surrounding islands of regenerating hepatocytes,
 Prominence of scars depends on the nature and duration.
 Toxic injuries usually take place within hours to days, too
brief to allow scar formation or regeneration.
 Acute Viral infections may cause failure over weeks or
months, regeneration is often demonstrable.
 There may be diffuse poisoning of he liver cells without obvious
cell death and parenchymal collapse such as diffuse
microvesicular steatosis related to fatty liver of pregnancy.
 In states of immunodeficiency, non-hepatic viruses such as HSV,
CMV, and adenovirus can cause fulminant liver failure.
Clinical Course
 Manifests first with nausea, vomiting, and jaundice, followed by
life-threatening encephalopathy and coagulation defects.
 Serum liver transaminases are markedly elevated.
 Liver is initially enlarged due to swelling and edema, as it the
parenchyma is destroyed it shrinks dramatically.
 Decline of serum transaminases are not a sign of improvement
but rather an indication that there are few viable hepatocyte left
 This suspicion is confirmed if there is worsening jaundice,
coagulopathy, and encephalopathy.
 Alterations of bile formation and flow become evident as a
yellow discoloration of the skin (jaundice) and sclera (icterus)
due to retention of bilirubin.
 Hepatic encephalopathy ranges from subtle behavioral
abnormalities to marked confusion and stupor to coma & death.
 Asterixis, a particular sign, is a non-rhythmic, rapid
extension-flexion movement of head and extremities.
 Elevated ammonia levels in the blood and CND correlate with
impaired neuronal function and cerebral edema.
 Easy bruisability is the earliest sign of coagulopathy.
 Portal hypertension develops when there is diminished flow to
the portal venous system which can occurs because of
obstruction at the prehepatic, intrahepatic, or posthepatic levels.
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 Hepatorenal Syndrome – sodium retention, impaired free water
excretion, & decreased renal perfusion and glomerular filtration.
 Onset begins with from in urine output and rising BUN and
creatinine levels.
Chronic Liver Failure and Cirrhosis
 Leading cause include chronic Hepa B and C, non-alcoholic fatty
liver disease, and alcoholic liver disease.
 Most often associated with cirrhosis.
 Not all cirrhosis leads to chronic liver injury and not all liver
injury is cirrhotic.
 The Child-Pugh classification of cirrhosis distinguishes:
 Class A - well-compensated cirrhosis.
 Class B – partially decompensated
 Class C – decompensated
Morphology
 Cirrhosis is a condition marked by disffuse transformation of the
entire liver into regenerative parenchymal nodules surrounded
by fibrous bands and variable degrees of vascular shunting
(usually portosystemic).
 Narrow, densely compacted fibrous septa separated by large
islands of hepatic parenchyma have less portal hypertension.
 Broad bands of dense scar, often with dilated lymphatic spaces,
with less intervening parenchyma are likely to be progressing to
portal hypertension and to end-stage disease.
 In chronic liver disease, ductular reactions increase with
advancing stage and are usually most prominent in cirrhosis.
 Role of liver stem cells in parenchymal regeneration
increases as the preexisting hepatocytes undergo replicative
senescence after year sof high turnover.
 Ductular reactions may incite scarring in chronic liver disease
and may have negative effect on progressive liver disease.
 Regression of fibrosis, although uncommon, may occur.
Clinical Features
 40% are asymptomatic until the most advanced stage.
 Present with non-specific manifestations such as anorexia,
weight loss, and weakness.
 Ultimate cause of death, whether cirrhotic or not, include those
seen in acute liver failure and additional frim outcomes such as
development of HCC.
 Hepatic encephalopathy, esophageal varices and bacterial
infections are often terminal events.
 Pruritus can occur in the setting of chronic jaundice.
 Impaired estrogen metabolism and hyperestrogenemia in males
can give rise to palmar erythema and spider angiomas of skin.
 In men, it can result to hypogonadism and gynecomastia.
 Hypogonadism can occur in females due to disruption of the
hypothalamic-pituitary axis function.
Portal Hypertension
 Increased resistance may develop in variety of circumstances.
 Can be divided into prehepatic, intrahepatic, and posthepatic.
 The dominant intrahepatic cause is cirrhosis, accounting for
most cases of portal hypertension.
 Increased resistance to portal flow is due to contraction of
vascular smooth muscle and myofibroblasts, and the disruption
of blood flow by scarring and formation of nodules.
 Main pre-hepatic cause is obstructive thrombosis, narrowing of
the portal vein before it ramifies within the liver.
 Main post-hepatic causes are severe RSHF, constrictive
pericarditis, and hepatic vein outflow obstruction.
 Increase in portal venous blood flow resulting from a
hyperdynamic circulation cause by arterial vasodilation in
splanchnic circulation.
 Nitric Oxide has emerged as the most significant one.
Consequences of Portal Hypertension
1. Ascites
2. Formation of Portosystemic venous shunts
3. Congestive Splenomegaly
4. Hepatic Encephalopathy
Ascites
 Accumulation of excess fluid in the peritoneal cavity
 Becomes clinically detectable when at least 500ml have
accumulated, fluid is generally serous, less than 3mg/dl protein
and serum to ascites albumin gradient of greater than 1.1 g/dl.
 Long-standing ascites, seepage of peritoneal fluid via trans-
diaphragmatic lymphatics may produce hydrothorax more often
on the right side.
 Pathogenesis of ascites involve the flowing mechanisms:
 Sinusoidal Hypertension, altering Starling’s forces and
driving fluid in the space of Disse, from where it is removed
by hepatic lymphatics, promoted by hypoalbuminemia.
 Percolation of hepatic lymph into the peritoneal cavity,
lymph may approach 20 L/day exceeding thoracic duct
capacity, hepatic lymph is rich in protein and low in lipids.
 Splanchnic vasodilation and hyperdynamic circulation
Portosystemic Shunts
 Flow is reversed from portal to systemic circulation by dilation of
collateral vessels and development of new vessels due to rise in
portal system pressure.
 Venous bypasses develop wherever the systemic and portal
circulation shares common capillary beds.
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 Principal sites are veins around the rectum (hemorrhoids),
esopahogastric junction (varices), retroperitoneum and the
falciform ligament of the liver.
 40% cause massive hematemesis and death.
 Abdominal wall collaterals appear as dilated subcutaneous veins
extending from umbilicus toward rib margins (caput medusa).
Splenomegaly
 Massive splenomegaly may secondarily induce hypersplenism
manifests as thrombocytopenia or even pancytopenia.
Two additional syndromes can occur in chronic liver failure:
Hepatopulmonary Syndrome
 Seen in 30% of patients, where they develop intrapulmonary
vascular dilations of capillaries up to 100µm in size.
 The blood flows rapidly through the vessels giving inadequate
time for oxygen diffusion and leading to ventilation-perfusion
mismatch and right-to-left shunting manifesting as hypoxia.
Portopulmonary Hypertension
 Pulmonary arterial hypertension.
 Depends on concomitant portal hypertension and excessive
pulmonary vasoconstriction and vascular remodeling.
Acute-on-Chronic Liver Failure
 Stable but well-compensated advanced chronic liver diseases,
suddenly develop signs of acute liver failure.
 There is often established cirrhosis with extensive vascular shunt
 Large volumes of liver parenchyma have a borderline vascular
supply leaving them vulnerable to lethal insults.
 Ex: Patients with chronic Hepa B infection who becomes
superinfected w/ Hepa D may undergo sudden decompensation
Infectious Disorders
VIRAL HEPATITIS
 Hepatitis can refer to:
 Hepatotrophic viruses (Hepatitis A – E)
 Histologic patterns of hepatitis injury both acute and chronic
 Hepatocellular injury caused by systemic viruses such as EBV,
CMV, Yellow Fever virus.
Hepatitis A Virus (HAV)
 HAV is usually benign, self-limited disease.
 Incubation period is 2-6 weeks.
 Does NOT cause chronic hepatitis or carrier state.
 Uncommonly causes acute hepatic failure, fatality rate
associated with HAV is only about 0.1-3.0%
 HAV is a small, non-enveloped, positive strand RNA, Picornavirus
that occupies its own genus, Hepatovirus with icosahedral capsid
 HAV is spread by ingestion of contaminated water and foods and
is shed in the stool for 2-3 weeks.
 HAV can also be detected in serum and saliva.
 Because HAV viremia is transient, blood-borne transmission
of HAV occurs rarely.
 Specific IgM antibody against HAV appears with the onset of
symptoms, constituting a reliable marker of acute infection.
 Fecal shedding ends as IgM titers rises.
 IgM response declines in a few months followed by IgG elevation
 Acute infection with Resolution

Hepatitis B Virus (HBV)

 HBV can produce:
1. Acute Hepatitis followed by recovery and clearance
2. Non-progressive chronic hepatitis Progression to Chronic Infection
3. Progressive chronic disease ending in cirrhosis
4. Acute hepatic failure with massive liver necrosis
5. Asymptomatic, healthy carrier state
 Prevalence is >8% in Africa, Asia, and Western Pacific, 2-7% in
Southern and Eastern Europe, and <2% in Western Europe,
North America, and Australia.
 Mode of transmission can occur based on the geographic region:
 In high prevalence, 90% occurs during childbirth.
 In intermediate prevalence, horizontal transmission is the
dominant mode of transmission.
 In low prevalence, it occurs in unprotected sex and
intravenous drug abuse (sharing needles).
 HBV has a prolonged incubation period, 2-26 weeks.
 Occasionally, mutated strains arise that do not produce HBeAg
 HBV remains in the blood until and during active episodes of
but are replication competent and express HBcAg.
acute and chronic hepatitis.
 The host immune response to the virus is the main determinant
 65% who acquire HBV are asymptomatic & do not have jaundice
of outcome to infection.
 25% have non-specific constitutional symptoms.
 Innate immune mechanisms protect the host during the
 Chronic disease occurs in 5-10% of infected individuals.
initial phase of the infection.
 Fulminant hepatitis is rare, 0.1-0.5% of acutely infected patients
 Strong response by virus-specific CD4+ and CD8+ IFN-γ
 HBV virion is a spherical double-layered Dane particle that has an
producing cells is associated with resolution of infection.
outer surface envelope of protein, lipid, and carbohydrate
 Hepatocyte injury is caused by CD8+ cytotoxic T cells.
enclosing an electron dense hexagonal core.
 Age at the time of infection is the best predictor of chronicity
 The double stranded genome encodes for:
 The younger the age, the higher the chance of chronicity
 Nucleocapsid core protein (Hepa B core antigen, HBcAg).
 HBV can be prevented by vaccination and screening of donors.
 Envelope glycoproteins (Hepa B surface antigen, HBsAg).
 Polymerase (Pol) that exhibits both DNA polymerase and
Hepatitis C Virus (HCV)
reverse transcriptase activity.
 Most common chronic blood-borne infection.
 HBx protein which is necessary for virus replication, acts as
 Chronic HCV is based on the presence of HCV RNA in the serum.
transcriptional transactivator of both viral and host genes.
 Major route of infection is perinatal.
 The course of the disease can be tracked using serum markers:
 Member of Flaviviridae family, a small enveloped, single-sranded
 HBsAg appears before the onset of symptoms, peaks during
RNA virus with a 9kb genome that codes for a single polyprotein.
over disease, and often declines to undetected in 12 weeks.
 Because of low fidelity of the HCV RNA Polymerase, it is
 Anti-HBs does not rise until the acute disease is over,
inherently unstable, providing many genotypes.
concomitant with the disappearance of HBsAg.
 HCV exists within any individual as closely related genetic
 In some cases, Anti-HBs does not appear after several
variants known as quasispecies.
months before HBsAg disappearance, detection can be done
 The genomic instability and antigenic variability have hampered
via IgM anti-HBc antibody.
efforts to develop an HCV Vaccine.
 HBeAg, HBV-DNA, and DNA polymerase appear in serum
 The E2 protein of the envelope is the target of many
soon after HBsAg, and all signify active viral replication.
vaccines, but at the same time is the most variable region.
 Persistence of HBeAg is an indicator of continued viral
 Elevated titers of Anti HCV IgG occurring after an active infection
replication, infectivity, and progression to chronic hepatitis.
do NOT confer effective immunity.
 IgM Anti-HBC antibody becomes detectable in serum shortly
 A feature of HCV therefore is repeated bouts of hepatic damage,
before the onset of symptoms, concurrent with onset of
which result from reactivation of infection or mutated strain.
elevated serum aminotransferases.

Page 4 of 21
Acute infection with Resolution Hepatitis E Virus (HEV)
 Enterically transmitted water-borne infection that occurs
primarily in young to middle aged adults.
 HEV is a zoonotic disease with animal reservoirs such as monkeys
 Characteristic feature of HEV infection is high mortality rate
among pregnant women.
 HEV is self-imiting, not associated with chronic liver disease.
 An unenveloped, positive stranded RNA virus in the Hepevirus.
 Virions are shed in stool during the acute illness.
 Before the onset of illness, HEV RNA and HEV Virions are
detected by PCR in stool and serum
 Onset of rising aminotransferases, clinical illness, and elevated
IGM anti-HEV titers are virtually simultaneous.
Progression to chronic infection
Clinicopathologic Syndromes of Viral Hepatitis
 Several clinical syndromes may develop following exposure:
1. Acute asymptomatic infection with recovery (serologic evidence)
2. Acute symptomatic hepatitis with recovery, anicteric or icteric.
3. Chronic hepatitis, with or without cirrhosis.
4. Acute liver failure with massive to submassive hepatic necrosis
 HAV and HEV do not cause chronic hepatitis, and only a small
number of HBV develop chronic hepatitis.
 HCV is notorious for chronic infection.
 Fulminant hepatitis is seen primarily with HAV, HBV, & HDV.
 HEV can cause fulminant hepatitis in women.
 Serologic and molecular studies are essential for diagnosis,
 Incubation period ranges from 4-26 weeks, mean of 9 weeks.
 85% have asymptomatic acute infection.
Acute Asymptomatic Infection with Recovery
 HCV RNA is detectable in blood for 1-3 weeks, coincidental with
 Identified only incidentally, on the basis of minimally elevated
rise of serum transaminases.
serum transaminases or presence of antibodies.
 Persistent infection and chronic hepatitis are the hallmarks of
 HAV and HBV infections are frequently subclinical.
HCV infection, despite the generally asymptomatic nature.
 A clinical feature of HCV is that the serum aminotransferases are
Acute Symptomatic Infection with Recovery
persistently elevated; their level wax and wane but almost never
 More or less the same regardless with the virus, can be divided
become normal.
into 4 phases:
 A feature unique to HCV is the association with metabolic
1. Incubation Period
syndrome, in particular HCV genotype 3.
2. Symptomatic Pre-icteric phase
 HCV can give rise to insulin resistance and non-alcoholic FLD.
3. Symptomatic Icteric phase
 HCV is curable, combination of pegylated IFN-α and ribavirin. 4. Convalescence

Hepatitis D Virus (HDV) Acute Liver Failure

 Also called the delta agent, a unique RNA virus that is dependent  Hepatitis A and E are the most common, globally.
for its lifecycle on HBV infection.
 HBV is more common in Asian and Mediterranean.
 Can arise as:
 No specific histologic findings which are indicative of the virus.
 Co-infection – occurs following exposure to serum containing
 Treatment is supportive, transplantation for non-recovering px.
HDV and HBV, the HBV must be established first to provide
the HBsAg necessary for development of complete HDV.
Chronic Hepatitis
 Superinfection – occurs when a chronic carrier of HBV is
 Symptomatic, Biochemical, or Serologic evidence of continuing
exposed to new inoculum of HDV, this results in disease 30-
or relapsing hepatic disease for more than 6 months.
50 days later presenting either as severe acute hepatitis or as
 Etiology is most important determinant.
an exacerbation of preexisting HBV infection.
 Clinical features are extremely variable.
 A double-shelled particle, external coat antigen of HBsAg
 Most common finding is fatigue, less common are malaise, loss
surrounds an internal polypeptide assembly, designated delta
of appetite, and mild jaundice.
antigen (HDAg), the only protein produced by the virus.
 HDV RNA is detectable in the blood and liver just before and in
the early days of acute symptomatic disease.
 IgM anti-HDV antibody is the most reliable indicator although its
appearance is late and short-lived.

Page 5 of 21
Carrier State
 Carrier is an individual who harbors and can transmit an
organism but has no manifesting symptoms.
 Can be defined as:
 Someone who carry one of the viruses but have no liver dse.
 Someone who have non-progressive liver damage but free of
symptoms or disability
HIV and Chronic Viral Hepatitis
 Co-infection became a more clinical problem since transmission
mode and high risk patient population are the same.
 In AIDS patients, liver disease is the second most common cause
of death.
 HIV exacerbates severity of disease caused by HBV and HCV.
Morphology
 Morphologic changes in chronic and acute viral hepatitis are
shared among hepatotrophic viruses and can be mimicked by
drug or autoimmune hepatitis.
Acute Viral Hepatitis
 Grossly, liver involved by mild acute hepatitis appear normal or
slightly mottled, in massive necrosis, it may shrink greatly.
 Both acute and chronic evoke mononuclear infiltrates.
 Most parenchymal injury is scattered throughout the hepatic
lobule as spotty necrosis or lobular hepatitis.
 In hepatic necrosis, cytoplasm appears empty with only
scattered wisps of cytoplasm remnant.
 Eventually there is rupture of cell membranes leading to dropout
of hepatocytes, leaving collapsed sinusoidal collagen mucin
framework behind.
 Confluent necrosis is seen around the central veins, there maybe
cellular debris, collapsed reticulin fibers, congestion, and
hemorrhage.
 There is central-portal bridging necrosis followed by
parenchymal collapse.
 Some patients rapidly develop posthepatic cirrhosis.
Page 6 of 21
Chronic Viral Hepatitis
 Defining histologic feature is mononuclear portal infiltration.
 There is often interface hepatitis as well, distinguished by its
location at the interface between the hepatocellular
parenchyma and portal stroma.
 Hallmark of progressive damage is scarring.
 At first only portal tracts exhibit fibrosis, with time, fibrous septa
extend between the portal tracts.
 In parallel with increased scarring, there is also increase ductular
reaction reflecting stem cell activation.
 Continued scarring and nodule formation leads to cirrhosis
 Clinical diagnosis requires liver biopsy in chronic hepatitis.
 In chronic Hepa B, ground-glass hepatocytes or cells with ER
swollen by HBsAg is diagnostic hallmark confirmed by IHC stains.
 In chronic Hepa C, commonly shows lymphoid aggregates or fully
formed lymphoid follicles. Genotype 3 shows fatty change, and
can also cause bile duct injury.
BACTERIAL, PARASITIC, AND HELMINTHIC INFECTIONS
 Several bacteria can infect the liver directly:
 S. aureus – Toxic shock syndrome
 S. typhi – Typhoid fever
 T. pallidum – Secondary or Tertiary syphilis.
 Bacteria may also proliferate in the biliary tree especially when
outflow is compromised, composed of gut flora, acute
inflammatory within the intrahepatic biliary tree called
ascending cholangitis.
 Fungi (Histoplasmosis) and mycobacteria can also infect liver in
disseminated diseases.
 Parasitic and helminthic infections include:
 Malaria
 Schistosomia
 Strongyloides
 Crytosporidium
 Leishmania
 Opistorchis
 Hydatid Cysts are usually cause by Echinococcus infections, often
have calcifications in the cyst walls.
 Cystic liver degeneration can be caused by amoebas.
Autoimmune Hepatitis
 A chronic progressive hepatitis with all the features of
autoimmune diseases in general.
 Genetic predisposition (Strong HLA associations)
 Presence of autoantibodies
 Therapeutic response to immunosuppression
Clinicopathologic Features
 There is female predominance.
 Autoimmune hepatitis is classified into types 1 and 2 based on
patterns of circulating antibodies.
 Type 1 is more common in middle-aged to older individuals,
characterized by presence of Anti-nuclear (ANA), anti-smooth
muscle (ASMA), anti-soluble liver antigen/liver-pancreas antigen
(anti-SLA/LP) and less commonly anti-mitochondrial (AMA).
 Type 2 seen in children and teenagers, main serologic marker are
anti-liver kidney microsome-1 (anti-LKM-1) directed against
CYP2D6, and anti-liver cytosol-1 (ACL-1).
Morphology
 In autoimmune hepatitis, there is an early phase of severe
parenchymal destruction followed by rapid scarring.
 Features:
 Severe necroinflammatory activity, extensive interface
hepatitis or foci of confluent or parenchymal collapse.
 Plasma cell predominance.
 Hepatocyte rosettes in areas of marked activity
 Clinical evolution correlates with a limited number of patterns:
 Very severe injury with widespread confluent necrosis but
little scarring. Often seen as symptomatic acute hepatitis and
represents first sign of disease.
 A mix of marked inflammation and degree of scarring, seen
in early or later stage disease.
 Burned-out cirrhosis, with little necroinflammatory activity,
preceded by years of subclinical disease.
Drug- and Toxin-induced Liver Injury
 As the major drug metabolizing and detoxifying organ, liver is
subject to injury from an enormous array of therapeutic and
environmental agents.
 Injury may result from direct toxicity, when liver converts a
xenobiotic to an active toxin.
 Diagnosis may be made on the basis of a temporal association of
liver damage with drug or toxin exposure.
 Exposure to a toxin should always be included in the differential
diagnosis of any form of liver disease.
Page 7 of 21
 Alcohol produces more toxic liver than any other agent.
 May be classified as predictable (intrinsic) or unpredictable
(idiosyncratic).
 Predictable reactions affect all in a dose-dependent manner.
 Unpredictable reactions depend on idiosyncrasies of the host
 Classic predictable hepatotoxin is acetaminophen, most
common cause of acute liver failure in US.
 Toxic agent is a metabolite produced by CYP-450 in acinus
zone 3 hepatocytes.
 As zone 3 cells die, zone 2 cells take over, severe overdoses,
the zone injury extends to the periportal hepatocytes.
 Example of drugs that can cause idiosyncratic reaction:
 Chlorpromazine, cause cholestasis in patients who are slow
metabolizers, it is converted to an innocuous by product.
 Halothane can cause fatal immune-mediated hepatitis in
patients exposed to this anesthetic drug.
Alcoholic Liver Disease
 Excessive ethanol consumption is the leading cause of liver injury
th
 Ranks 8 globally as the highest risk factor for death.
 Three distinctive, overlapping forms of alcoholic liver injury:
1. Hepatocellular steatosis or fatty change.
2. Alcoholic hepatitis (Steatohepatitis)
3. Steatofibrosis
Morphology
 All changes begin in acinus zone 3 and extend outwards.
Hepatic Steatosis
 Lipid droplets accumulate in hepatocytes begins as small
droplets that coalesce into large droplets which distend the
hepatocyte and push the nucleus aside.
 Grossly large (4-6kg), soft, yellow and greasy
Alcoholic / Steatohepatitis
 Hepatocyte swelling and necrosis – ballooning due to fat and
water accumulation, as well as proteins.
 Mallory-Denk bodies – usually present as clumped, amorphous,
eosinophilic material in ballooned hepatocytes, made up of
tangled skeins of intermediate filaments such as keratins 8 & 18.
Characteristic but not diagnostic, also present in non-alcoholic
liver disease such as Wilson dse and chronic biliary tract dse.
 Neutrophilic Reaction – permeates hepaticlobule and
accumulates around degenerating hepatocytes.
Alcoholic Steatofibrosis
 Often accompanied by prominent activation of sinusoidal
stellate cells and portal fibroblasts giving rise to fibrosis.
 Begins with sclerosis of central veins.
 Accumulates in th space of Disse of centrilobular region
spreading outward in a chicken wire fence patern.
 These wbes of scar eventually link to portal tracts and then begin
to condense in the central-portal fibrous septa.
 When alcohol use continues, the continual subdivision of
established nodules by new webs of scarring leads to classic
micronodular or Laennec Cirrhosis.
Pathogenesis  Lab findings reflect hepatic dysfunction with elevated serum
aminotransferases, hyperbilirubinemia, and variable elevation of
alkaline phosphatase, hypoproteinemia, and anemia.
 In end-stage alcoholic the proximate cause of death are:
 Hepatic Coma
 Massive GI hemorrhage
 Intercurrent infection
 Hepatorenal syndrome
 Hepatocellular carcinoma

Metabolic Liver Disease

 Most common is non-alcoholic fatty liver disease.

Non-alcoholic Fatty Liver Disease (NAFLD)

 Represents a spectrum of disorders that have in common the
 Short-term ingestion of as much as 80g of alcohol (6 beers) over
presence of hepatic steatosis in individuals who do not consume
one to several days generally produces mild, reversible steatosis.
alcohol or do so in small amount (<20g/week)
 Daily intake of 80g or more ethanol generates significant risk.
 The terms non-alcoholic steatohepatitis (NASH) is often used to
 Only 10% - 15% develop cirrhosis.
denote overt clinical features of liver injury.
 Factors:
 Hallmark of NAFLD is associated with metabolic syndrome.
 Gender – women are more susceptible to hepatic injury,
difference may be related to alcohol pharmacokinetics, and
estrogen-dependent response to gut-derived endotoxin.
 Ethnic and Genetic – cirrhosis rates are higher for African
 American drinkers. Genetic polymorphisms in detoxifying
enzymes may play significant role, ALDH*2, a variant of
ALDH, has low activity in Asians. Individuals with
homozygous ALDH*2 are unable to oxidize acetaldehyde and
do not tolerate alcohol (upper body flushing).
 Co-morbid conditions – iron overload and infections with
HCV and HBV synergize with alcohol.
 Hepatocellular Steatosis results to:
 Increased NADH+ H shunts normal substrates away from
catabolism and toward lipid synthesis, decreasing NADH.
 Impaired assembly and secretion of lipoproteins.
 Increased peripheral catabolism of fat, increased FFA.
 Acetaldehyde induces lipid peroxidation and protein-adduct Pathogenesis
formation disrupting cytoskeletal and membrane function.  Two hit model for NAFLD:
 CYP-450 produces reactive oxygen species.  Insulin resistance give rise to hepatic steatosis.
 Decreased glutathione levels, sensitizes liver to oxidative injury.  Hepatocellular oxidative injury resulting in liver cell necrosis
 Release of bacterial endotoxin from the gut into the portal and the inflammatory reactions to it.
circulation induces inflammatory response, due to activation of  Hepatic steatosis arises from overabundance of calorie rich food,
NF-kB and release of TNF, IL-6, and TGF-α. diminished exercise, and genetic/epigenetic mechanism.
 Alcohol stimulates release of endothelin causes vasoconstriction  High fructose corn syrup, an inexpensive sweetener also appears
and contraction of activated myofibroblastic stellate cells leading to promote insulin resistance.
to decrease in hepatic sinusoidal perfusion (portal hypetension).  Visceral adipose tissue not only increases but also becomes
dysfunctional with reduced production of the lipid hormone
Clinical Features adiponectin & increased production of inflammatory cytokines
 Hepatomegaly, mild elevation of serum bilirubin and alkaline  These changes in turn promote hepatocyte apoptosis.
phosphatase levels.  Fat laden cells are highly sensitive to lipid peroxidation products
 Alcohol withdrawal and adequate diet is sufficient. generated by oxidative stress.
 Tends to appear acutely, following heavy drinking.  Diminished autophagy also contributes to mitochondrial injury
 Non-specific symptoms of malaise, anorexia, weight loss, upper and formation of Mallory-Denk bodies.
abdominal discomfort and tender hepatomegaly.  Kupffer cells production of TNF-α and TGF-β stimulate stellate
 AST tends to be higher than ALT (2:1 ratio) compared to other cells leading to scar tissue deposition.
liver diseases where ALT is usually higher than AST.  Levels of hedgehog pathway activity correlates with stage of
 Alcoholic cirrhosis manifestations are same with other forms. fibrosis in NAFLD.

Page 8 of 21
Morphology  Features of severe iron overload:
 Pathologic steatosis is defined as involving more than 5% of  Fully developed case exhibit:
hepatocytes.  Micronodular Cirrhosis in all patients
 Droplets of fat, predominantly triglycerides, accumulate within  Diabetes mellitus in 75-80%
the hepatocytes.  Abnormal skin pigmentation in 75-80%
 At the most clinically benign end, there is no appreaciable  Hereditary accumulation is lifelong, symptoms usually first
th th
inflammation, death or scarring. appear in the 4 -5 decades in life in men, and later in
 NASH almost completely overlaps in its histologic feature with women balanced by menstrual bleeding.
alcoholic hepatitis.
 In NASH, mononuclear infiltrates may be more prominent.
 Mallory-Denk bodies are less prominent.
 Cirrhosis may develop and is often subclinical.
 Greater than 90% of previously described cryptogenic cirrhosis is
not thought to represent such burned-out NAFLD.
 Pediatric NAFLD differs significantly, shows more diffuse
steatosis, portal rather than central fibrosis, and portal and
parenchymal mononuclear infiltration.

Clinical Features

Pathogenesis
 Since there is no regulated iron excretion of the body, total body
content is tightly regulated by intestinal absorption.
 Net iron accumulation of 0.5-1gm/year.
 Disease manifests itself typically after 20g accumulated.
 Mechanism of injury include:
1. Lipid peroxidation via iron-catalyzed free radical reaction
2. Stimulation of collagen formation by activation of stellate cells
3. Interaction of ROS and Iron with DNA (predisposition to HCC).
 Simple steatosis are generally asymptomatic.
 Presentation is often related to other signs and symptoms of
metabolic syndrome, particularly the insulin resistance.
 Imaging studies may reveal fat accumulation in the liver.
 Biopsy is the most reliable diagnostic tool for NAFLD and NASH.
 Serum AST and ALT are elevated.
 General symptoms – hepatomegaly, right-sided abdominal pain.
 Goal of treating is to reverse steatosis and prevent cirrhosis.
 NASH also increases the risk of HCC.

Hemochromatosis
 Main regulation of iron absorption is the protein hepcidin,
 Caused by excessive iron absorption, most of which is deposited
encoded by HAMP gene secreted by the liver.
in parenchymal organs such as liver and pancreas.
 Hepcidin is originally named because of bactericidal activities
 Followed by heart, joints, and endocrine organs.
 Transcription is increased by inflammation and iron.
 Hereditary Hemochromatosis – inherited.
 Decreased by iron deficiency, hypoxia, and ineffective
 When accumulation occurs secondary to other causes such as
erythropoiesis.
transfusion it is Secondary Hemochromatosis.
 Hepcidin binds to the cellular iron efflux channel ferroportin
 Total iron body pool is from 2-6g, about 0.5g is stored in the liver
causing internalization and proteolysis, thereby inhibiting
 In most severe forms of hemochromatosis, it may exceed 50g,
release of iron from intestinal cells.
more than 1/3 accumulates in the liver.
 Hepcidin lowers plasma iron levels, deficiency = overload

Page 9 of 21
 Decreased hepcidin synthesis caused by mutations in hepcidin,
HJV, TFR2, and HFE, adult form of hemochromatosis is almost
always caused by HFE mutations.
 HLE gene is located on the short arm of chromosome 6 at 6p21.3
 Most common mutation is cys-to-tyr substitution at AA 282.
 Male predominance.
Morphology
1. Deposition of hemosiderin in the following organs in decreasing
severity: Liver, pancreas, myocardium, pituitary gland, adrenal
gland, thyroid and parathyroid, joints, and skin.
2. Cirrhosis
3. Pancreatic Fibrosis
 In the liver, iron becomes evident first as golden-yellow
hemosiderin granules in the cytoplasm of periportal hepatocytes
 Increased iron load, there is progressive involvement of the rest
of the lobule, along with bile duct epithelium and kupffer cells.
 Iron is a direct hepatotoxin and inflammation is absent.
 Fibrous septa develop slowly, leading ultimately to a small,
shrunken liver with micronodular pattern of cirrhosis.
 Liver parenchyma is often dark brown to nearly black.
 Quantitative assessment of tissue iron content is no longer
necessary due to available genetic testing.
 Normally, 1000µg of iron per gram dry weight of liver
 In hemochromatosis, 10,000µg of iron per gram dry weight.
 Pancreas become intensely pigmented, has diffuse interstitial
fibrosis, may exhibit some parenchymal atrophy.
 Heart is often enlarged and has hemosiderin granules.
 Pigmentation is associated in hemosiderin deposition in dermal
macrophages, characteristic slate-gray color of the skin.
 Acute synovitis may develop due to deposition of hemosiderin in
the synovial joint linings.
 Excessive deposition of calcium pyrophosphate damages the
cartilage, producing pseudogout.
 Testes may be small and atrophic, secondary to degenerating
hypothalamic-pituitary axis.
Clinical Features
 Principal manifestation include hepatomegaly, abdominal pain,
abnormal skin pigmentation, deranged glucose homeostasis or
diabetes mellitus due to pancreatic cell destruction, cardiac
dysfunction (arrhythmia, cardiomyopathy), and atypical arthritis.
 In some patients, presenting complaint is hypogonadism.
 Often in males, rarely evident before 40.
 Death may result from cirrhosis or cardiac disease.
 A significant cause of death is hepatocellular carcinoma.
 Treatment of iron overload does not fully remove cancer risk
because of DNA alterations that occurred prior to treatment.
 Screening of family members of probands is important.
 Neonatal Hemochromatosis is a disease of unknown origin
manifested as severe liver disease and extrahepatic hemosiderin
deposition, it is NOT an inherited disease.
 Most common cause of secondary hemochromatosis are
disorders associated with ineffective erythropoiesis (thalassemia,
myelodysplastic syndrome).
Page 10 of 21
Wilson Disease
 An autosomal recessive disorder caused by mutations of the
ATP7B gene, resulting in impaired copper excretion into the bile
and failure to incorporate copper into ceruloplasmin.
 Marked by accumulation of toxic levels of copper, principally in
the liver, bran, and eyes.
 Estimated total body copper is only 50-150mg.
Pathogenesis
 Mutations in the ATP7B gene located on chromosome 13, it
encodes a transmembrane copper-transporting ATPase,
expressed on hepatocyte canalicular membrane.
 Majority of patients are compound heterozygotes with different
mutations of the ATP7B allele.
 Deficiency in the ATP7B protein causes a decrease in copper
transport into bile, impairs its incorporation to ceruloplasmin,
and inhibits ceruloplasmin in the blood.
 Copper causes injury by 3 mechanisms:
 Promoting formation of free radicals by Fenton Reaction.
 Binding to sulfhydryl groups of cellular proteins.
 Displacing other metals rom hepatic metalloenzymes
 Sudden onset of severe systemic illness is triggered by spillage of
non-ceruloplasmin bound copper from the liver into the
circulation causing hemolysis.
Morphology
 Liver often bears the brunt of injury but it may also present as a
neurologic disorder.
 Steatosis may be mild to moderate with focal hepatocyte
necrosis.
 Fulminant hepatitis can mimic acute viral hepatitis.
 Chronic hepatitis exhibits moderate to severe inflammation and
necrosis, admixed with fatty change and features of
steatohepatitis (w/ Mallory-Denk bodies).
 Special stain can demonstrate excess copper:
 Rhodamine for free copper
 Orcein for copper-associated proteins
 Toxic injury to the brain primarily affects the basal ganglia
particularly the putamen, which shows atrophy and cavitation.
 Kayser-Fleischer Rings, a green to brown deposition of copper in
descemet membrane of the limbus of the cornea may develop.
Clinical Features
 Age and onset is variable, average is 11.4 years.
 Neurologic involvement presents as movement disorders or rigid
dystonia, may be confused with Parkinsonism.
 May also have psychiatric symptoms.
 Hemolytic anemia may occur due to toxicity of Cu to RBC.
 Biochemical diagnosis of Wilson disease is based on:
 A decrease in serum ceruloplasmin
 An increase in hepatic content (most accurate and sensitive)
 Increased urinary excretion of copper (most specific)
 Serum copper levels are of no diagnostic value.
 Demonstration of Kayser-Fleischer rings further favors diagnosis.
 Long copper chelation therapy (with D-penicillamine) or zinc-
based therapy (blocks gut uptake of Cu).
α1-Antitrypsin Deficieny (α1AT) BILIRUBIN AND BILE FORMATION
 α1AT is an autosomal recessive disorder of protein folding
marked by very low levels of circulating α1-Antitrypsin.
 Major function of the protein is inhibition of proteases,
particularly neutrophil elastase, cathepsin G, and proteinase 3,
which are normally released by neutrophils at sites of inflamm.
 α1AT leads to development of pulmonary emphysema because
activity of destructive proteases is not inhibited.
 It also causes liver disease as a consequence of hepatocellular
accumulation of misfolded protein.
 Cutaneous necrotizing panniculitis occurs in minor subset of px.
 The gene located on chromosome 14 is very polymorphic and at
least α1AT forms have been identified.
 General notation is Pi for protease inhibitor, and an alphabetic
letter for the position in the electrophoresis gel denote the
genotype of the individual.
 PiMM occurs in 90% - wild type.
 PiS – moderate reduction of serum concentration.
 Pi-null – no detectable serum α1AT  Intracellular heme oxygenase converts heme to biliverdin which
is immediately reduced to bilirubin by biliverdin reductase.
 Most clinically significant mutation is PiZ, homozygotes for the
PiZZ protein have circulating α1AT levels only 10% of the normal.  Bilirubin is conjugated with albumin necessary for liver uptake; it
is then processed and conjugated with 1-2 molecules of
Pathogenesis glucuronic acid to make it water soluble, and non-toxic, which is
then excreted in the bile.
 Deficiency variants show a selective defect in migration of
protein from ER to Golgi body, particularly characteristic of PiZ  Most bilirubin glucoronides are deconjugated in the gut lumen
polypeptide resulting from AA substitution of Glu342 to Lys342. by bacteria and degraded to colorless urobilinogens excreted in
the feces or reabsorbed.
 Mutant polypeptide (α1AT-Z) is abnormally folded creating ER
stress and triggering unfolded protein response.
Pathophysiology of Jaundice
 All individuals with PiZZ genotype accumulate α1AT-Z in the ER
but only 10-15% develop overt clinical liver disease.

Morphology
 Characterized by presence of round-to-oval cytoplasmic globular
inclusions in hepatocytes, acidophilic in H&E stains.
 Strongly PAS positive and diastase resistant.
 Periportal hepatocytes contain the mutant proteins involving
progressively more central hepatocytes.
 Number of globule containing cells do not correlate with severity

Clinical Features
 Neonatal hepatitis with cholestatic jaundice in 10-20%.
 Presenting symptoms may be related o hepatitis, cirrhosis, or
pulmonary disease in adolescents.
 Disease remain silent until cirrhosis appears in mid- to late-life
 Treatment for hepatic dse is transplantation.
 Avoid smoking since it accelerates emphysema in α1AT-def.
 Both unconjugated and conjugated may accumulate.
Cholestatic Diseases  Unconjugated is virtually insoluble in water, exists in tight
 Hepatic bile serves 2 functions: complexes with serum albumin, cannot be excreted in the urine.
 Emulsification of dietary fat  Small fraction may diffuse into tissues, particularly in the brain
 Elimination of bilirubin, excess cholesterol, xenobiotics and produce toxic injury (kernicterus).
 Tissue deposition of bile becomes clinically evident as yellow  Unbound fraction may increase in severe hemolytic disease.
discoloration of the skin (jaundice) and sclera (icterus) due to  Conjugated bilirubin is water soluble and non-toxic, its weak
retention of bilirubin, and as cholestasis, when there is systemic association with albumin makes it easy to be excreted in urine.
retention of not only bilirubin but also other solutes within bile.  Two conditions are associated with specific defects in
 Jaundice occurs when there’s bilirubin overproduction, hepatitis, hepatocellular bilirubin metabolism: Neonatal Jaundice and
or obstruction of flow of bile, which can disturb the equilibrium Hereditary hyperbilirubinemia.
between clearance and production.
Page 11 of 21
Neonatal Jaundice
 Hepatic machinery does not fully mature until 2 weeks of age,
thus almost every new born develop transient and mild
unconjugated hyperbilirubinemia (Physiologic Jaundice).
 Exacerbated by breastfeeding.
 Sustained jaundice is normal.
Hereditary Hyperbilirubinemia
 Multiple genetic mutations.
 UGT1A1, a product of its gene located in chromosome 2q37, a
member of family of enzymes that catalyze glucoronidation.
 Mutations cause hereditary unconjugated hyperbilirubinemia:
 Crigler-Najjar Syndrome
 Type 1 – absent UGT1A1
 Type 2 – decreased UGT1A1 activity
 Gilbert Syndrome - decreased UGT1A1 activity
 Conjugated hyperbilirubinemia syndromes (both recessive):
 Dubin-Johnson Syndrome – impaired biliary excretion due to
mutations in canalicular multidrug resistance protein (MRP2)
 Rotor Syndrome – Decreased uptake, storage, excretion (?).
Cholestasis
 Caused by impaired bile formation and bile flow that give rise to
accumulation of bile pigment in the hepatic parenchyma.
 Caused by extrahepatic or intrahepatic obstruction of channels,
or defects in hepatocyte bile excretion.
 May present as jaundice, pruritus, skin xanthoma, or symptoms
related to intestinal malabsorption of fat-soluble vitamins.
 Lab finding is elevated serum alkaline phosphatase and γ-
glutamyl transpeptidase, enzymes present on the apical
membrane of hepatocytes and bile duct epithelium.
Morphology
 Common to both obstructive and non-obstructive is
accumulation of bile within the hepatic parenchyma.
 Elongated green-brown plugs are seen in dilated canaliculi.
 Ruptured canaliculi lead to extravasation of bile, quickly
phagocytosed by kupffer cells.
 Droplets accumulate within hepatocytes, takes on a fine, foamy
appearance so called feathery degeneration.
Large Bile Duct Obstruction
 Most common cause is extrahepatic cholelithiasis (gallstones)
followed by malignancies of the biliary tree or head of pancreas,
and strictures from previous surgical procedures.
 Obstructive conditions include biliary atresia, cystic fibrosis,
choledochal cysts, & syndromes w/ insufficient intrahepatic duct
Page 12 of 21
 Reversible with correction of the obstruction.
 Prolonged obstruction can lead to biliary cirrhosis.
 Subtotal or intermittent obstruction may promote ascending
cholangitis, enteric organisms can infect the biliary tree.
 Usually present with fever, chills, abdominal pain, and jaundice.
 Most severe form is suppurative cholangitis, in which purulent
bile fills and distends the bile ducts.
 Extrahepatic biliary obstruction is often amenable by surgery,
but cholestasis due to diseases of the biliary tree or secretory
failure is not benefited by surgery.
Morphology
 Acute biliary obstruction causes distention of the upstream bile
ducts, often becomes dilated.
 Bile ductules proliferate at the portal-parenchymal interface,
accompanied by stromal edema and neutrophilic infiltrates.
 Histologic hallmark of ascending cholangitis is the influx of
periductular neutrophils into the bile duct epithelium & lumen.
 If left untreated, secondary inflammation resulting from chronic
biliary obstruction & ductular reaction lead to periportal fibrosis
 Hepatic scarring and nodule formation generates secondary or
obstructive biliary cirrhosis.
 Cholestatic features may be seen.
 Formation of bile infarcts from detergent effects of bile.
Cholestasis of Sepsis
 Sepsis may affect the liver b:
 Direct effects of intrahepatic infection (abscess formation)
 Ischemia relating to hypotension due to sepsis
 Response to circulating microbial products.
 The last one leads to cholestasis of sepsis, particularly when
infection is due to gram-negative organisms.
 Most common form is canalicular cholestasis, with bile plugs
predominantly within centrilobular canaliculi, associated with
activated Kupffer cells and mild portal inflammation, but
necrosis is mild and absent.
 Ductular cholestasis is more ominous finding, dilated canals of
Hering & bile ductules at interface become dilated with plugs.
Primary Hepatolithiasis
 Hepatholithiasis is a disorder of intrahepatic gallsone formation
that leads to repeated bouts of ascending cholangitis,
progressive inflammatory destruction of hepatic parenchyma,
and predisposes to biliary neoplasia.
 Previously called recurrent pyogenic cholangitis focusing on its
most common clinical findings, and oriental cholangitis based on
its ethnic predilection.
Morphology
 Pigmented calcium bilirubinate stones in distended intrahepatic
bile ducts.
 The ducts show chronic inflammation, mural fibrosis, and
peribiliary gland hyperplasia, all in the absence of extrahepatic
duct obstruction.
 Biliary dysplasia may be seen and evolve to invasive
cholangiocarcinoma.
Clinical Features
 Repeated episodes of cholangitis due to secondary infections of
the involved ducts, marked by fever and abdominal pain.
 Parenchymal collapse and scarring due to repeated inflammation
 Sometimes present with mass-like lesion mistaken for tumor
 Increases risk of cholangiocarcinoma.
Neonatal Cholestasis
 Prolonged conjugated hyperbilirubinemia in neonates.
 Major causes are:
 Cholangiopathies, primarily biliary atresia
 Disorders that cause conjugated hyperbilirubinemia referred
to as neonatal hepatitis
 Idiopathic neonatal hepatitis constitutes only 10-15% of cases.
Differentiation of biliary atresia from non-obstructive neonatal cholestasis is
very important, since the surgical treatment for biliary atresia (Kasai
procedure) may adversely affect the course of a child with other disorders.
 Variability in the anatomy of the atresia
 Common duct (Type 1)
 Right/Left Hepatic Bile Ducts (Type II).
Clinical Course
 Present with neonatal cholestasis but exhibit normal birth
weight and postnatal weight gain.
 Slight female preponderance.
 Initially normal stools change to acholic stools
 Serum bilirubin values usually range from 6-12 mg/dL, with only
moderately elevated aminotransferase and alkaline phosphatase
 Without surgery, death usually occurs within 2 years of birth.
Autoimmune Cholangiopathies
 Two main autoimmune disorders of intrahepatic bile ducts:
 Primary Biliary Cirrhosis (PBC)
 Primary Sclerosing Cholangitis (PSC)

Morphology
 Lobular disarray with focal liver cell apoptosis and necrosis.
 Panlobular giant-cell transformation.
 Prominent hepatocellular and canalicular cholestasis.
 Mild mononuclear infiltrates in portal areas.
 Reactive changes in kupffer cells.
 Extramedullary hematopoiesis.
 May blend with ductular pattern of injury, with ductural reaction
and fibrosis of portal tracts.

Biliary Atresia
 Complete or partial obstruction of the lumen of the extrahepatic
biliary tree within the first 3 months of life.
 Represents 1/3 of neonatal cholestasis.

Pathogenesis
 Two major forms are recognized based on the presumed timing
of luminal obstruction.
 Fetal form – 20% of cases, commonly associated with
anomalies resulting from ineffective establishment of
laterality of thoracic and abdominal organs (situs inversus,
malrotation, ruptured IVC, polysplenia, CHD), presumed
cause is aberrant intrauterine development of biliary tree.
 Perinatal form – more common, normally developed biliary
tree is destroyed following birth, etiology is unknown but
strongly associated with viral (reovirus, rotavirus, CMV) and
autoimmune destruction.
Morphology
 Salient feature is inflammation and fibrosing stricture of the
hepatic or common bile duct.
 Some progress into the intrahepatic ducts leading to progressive
destruction of the intrahepatic biliary tree.
 On biopsy, florid structures are evident in 2/3 of cases.
 The remaining have inflammatory destruction of intrahepatic
duct paucity, w/out ductular reactions, edema, and neutrophils.
 If remained unrecognized or uncorrected, cirrhosis develops
within 3-6 months of birth.
Primary Biliary Cirrhosis (PBC)
 An autoimmune disease characterized by non-suppurative,
inflammatory destruction of small and medium sized
intrahepatic bile ducts.
 Large ducts and extrahepatic ducts are not involved.
 Most are diagnosed in the early stages when cirrhosis is distant.
 Not all end-stage PBC is fully cirrhotic.
 Primarily a disease of middle-aged women, 9:1 predominance.
 Peak incidence in 50 years of age (30-70 y/o)
Pathogenesis
 Anti-mitochondrial antibodies (AMA) are the most characteristic
lab finding in PBC, they recognize E2 component of pyruvate
dehydrogenase complex.
 PDC-E2 specific T cells are also present.
 Aberrant expression of MHC class II molecules on biled duct
epithelial cells, accumulation of autoreactive T cells around bile
ducts, and antibodies against other components (nuclear pore
protein, and centromeric proteins).

Page 13 of 21
Morphology
 Interlobular bile ducts are actively destroyed by
lymphoplasmacytic inflammation with or without granuloma –
florid duct lesion.
 Ductular reactions follow duct injury, and these in turn
participate in the development of portal-portal septal fibrosis.
 Increasingly widespread duct loss, slowly leading to cirrhosis,
and in the end stage, to profound cholestasis.
 Bile accumulation is NOT centrilobular, it is periportal/periseptal.
 Associated with feathery degeneration and ballooned, bile-
stained hepatocyte, often with prominent Mallory-Denk bodies.
 Some patients develop portal hypertension; there is widespread
nodularity without scar tissue a feature called nodular
regenerative hyperplasia.
 Marked hepatomegaly.
Clinical Course
 Most are diagnosed when asymptomatic with elevated serum
alkaline phosphatase and γ-glutamyltransferase.
 Hypercholesterolemia is common.
 AMA are present.
 Disease is confirmed by liver biopsy, which is considered
diagnostic if a florid duct lesion is present.
 Onset is insidious, present with fatigue and pruritus.
 Untreated patients may follow one of 2 pathways to end-stage
 One in which hyperbilirubinemia predominates
 Another with prominent portal hypertension
 Treatment with oral ursodeoxycholic acid slows progression.
 Progression present with skin hyperpigmentation, xanthelmas,
steatorrhea, Vit.-D malabsorption related osteomalacia.
 May also have extrahepatic manifestations of autoimmunity
such as Sjogren syndrome, Scleroderma, thyroiditis, RA, Raynaud
phenomenon, and celiac disease.
Primary Sclerosing Cholangitis (PSC)
 PSC is characterized by inflammation and obliterative fibrosis of
intrahepatic and extrahepatic bile ducts with dilation of
preserved segments.
 Characteristic beading on radiographs, attributable to irregular,
biliary strictures, and dilations.
 IBD, particularly ulcerative colitis, coexists in 70% of cases.
Pathogenesis
 First degree relatives have increased risk suggesting genetics.
 T-cells in the periductal stroma, presence of circulating
autoantibodies, association with HLA-B8 and other MHC
antigens, link to ulcerative colitis support immunologic process.
 Atypical Perinuclear Anti-neutrophil cytoplasmic antibodies
(pANCA) targeting envelope protein are found in 65% of cases.
Morphology
 Differ between the large ducts (intra and extrahepatic) and
smaller intrahepatic ducts.
 Large duct inflammation is similar to that seen in ulcerative
colitis: acute, neutrophilic infiltration of the epithelium,
superimposed on a chronic inflammatory background.
 Inflamed areas develop strictures because edema and
inflammation narrows the lumen due to subsequent scarring.
Page 14 of 21
 Smaller ducts have little inflammation, and shows a striking
circumferential ‘onion skin’ fibrosis around an increasingly
atrophic duct lumen.
 Eventually leads to obliteration by a tombstone scar.
 Diagnosis depends on radiologic imaging of extrahepatic and
larger intrahepatic ducts.
 As it progresses, it becomes markedly cholestatic, culminating in
biliary cirrhosis.
Clinical Features
 Asymptomatic patients may come into attention because of
persistent elevation of serum alkaline phosphatase, particularly
in patients with ulcerative colitis.
 Progressive fatigue, pruritus, and jaundice may develop.
 Acute bouts of ascending cholangitis may also signal PSC.
 Chronic pancreatitis and chronic cholecystitis from involvement
of pancreatic duct and gallbladder may be seen.
Structural Anomalies of the Biliary Tree
Choledochal Cysts
 Congenital dilations of the common bile duct.
 Present in children before age 10 as jaundice or recurrent
abdominal pain, symptoms that are typical of biliary colic.
 Occur in conjunction with cystic dilation of the intrahepatic
biliary tree (Caroli disease) in some cases.
 Female-to-male ratio is 3:1 to 4:1.
 Take the form of segmental or cylindric dilation of the common
duct, diverticular of the extrahepatic ducts, or choledochoceles.
 Predispose to stone formation, stenosis, and stricture,
pancreatitis, and obstructive biliary complications.
Fibropolycystic Disease
 Heterogeneous group of lesions in which the primary
abnormalities are congenital malformations of the biliary tree.
 May be found incidentally.
 Most severe form manifest as hepatosplenomegaly or portal
hypertension in the absence of hepatic dysfunction.
 Three sets of pathologic findings:
 Von Meyenburg Complexes – small bile duct hamartomas.
 Single or multiple, intrahepatic or extrahepatic biliary cysts,
if present alone may be associated with ascending
cholangitis, if present with congenital hepatic fibrosis, it is
termed as Caroli syndrome.
 Congenital Hepatic Fibrosis – portal tracts are enlarged by
irregular, broad bands of collagenous tissue, forming septa
that divide the liver into irregular islands.
 All are related to abnormal development of the biliary tree
representing ductal plate malformations associated with
persistence of periportal ductal plates from fetal development.
 Often occurs with autosomal recessive polycystic renal disease.
Circulatory Disorders
IMPAIRED BLOOD FLOW INTO THE LIVER
Hepatic Artery Compromise
 Liver infarcts are rare due to its dual blood supply.
 Thrombosis or compression of an intrahepatic branch of the
hepatic artery may result in a localized infarct that is either pale
and anemic or hemorrhagic if there is suffusion with portal blood
 Retrograde flow through accessory vessels, when couple with
portal venous supply, is usually sufficient to sustain the liver.
 Exception is hepatic artery thrombosis in a transplanted liver,
which generally leads to infarction of the major ducts of the
biliary tree, since their blood supply is entirely arterial.
Portal Vein Obstruction and Thrombosis
 Blockage of the extrahepatic portal vein may be insidious and
well tolerated or may be lethal, most fall somewhere in between
 Typically produces abdominal pain, and other manifestations of
portal hypertension, principally esophageal varices, which are
prone to rupture.
 Ascites is not common because the block is presinusoidal.
Extrahepatic Portal Vein Obstruction
 May be idiopathic or arise from:
 Subclinical occlusion of portal vein from neonatal umbilical
sepsis or umbilical vein catheterization.
 Intraabdominal sepsis.
 Inherited or acquired hypercoagulable state.
 Trauma, surgery
 Pancreatitis and pancreatic cancer that initiate splenic vein
thrombosis which propagates into the portal vein.
 Invasion by HCC
 Cirrhosis
Intrahepatic portal vein radicle obstruction
 Can be due to acute thrombosis.
 Results in sharply demarcated areas of red-blue discoloration
called infarct of Zahn.
 No infarct, no necrosis, only severe atrophy and marked stasis.
Small Portal Vein branch diseases
 Genetically distinct conditions characterized by non-cirrhotic
portal hypertension with portal fibrosis and obliteration.
 Most common cause is obstruction by schistosomiasis.
 Eggs of the parasite lodge in and obstruct smallest branches.
Page 15 of 21
IMPAIRED BLOOD FLOW THROUGH THE LIVER
 Most common intrahepatic cause of flow obstruction is cirrhosis.
 Physical sinusoidal occlusion occurs in a small group of diseases:
 Sickle Cell Disease
 Disseminated Intravascular Coagulation
 Eclampsia
 Diffuse Intrasinusoidal Metastatic tumor
 Obstruction of may lead to massive necrosis and acute failure.
 Peliosis Hepatitis a peculiar form of sinusoidal dilation that
occurs in any condition in which hepatic blood efflux Is impeded.
 Liver contains blood-filled cystic spaces.
 Pathogenesis is unknown, related to Bartonella in AIDS px
 Also seen in cancer, tuberculosis, post-transplant
HEPATIC VENOUS OUTFLOW OBSTRUCTION
Hepatic Vein Thrombosis
 Obstruction of two or more major hepatic veins produces liver
enlargement, pain, and ascites, known as Budd-Chiari syndrome.
 Obstruction of a single vein is clinically silent.
 Damage is consequence of increased intrahepatic pressure.
Morphology
 Liver is swollen and red-purple and has a tense capsule.
 Differential areas of hemorrhagic collapse alternating with areas
of preserved or regenerating parenchyma.
 Microscopically reveals centrilobular congestion and necrosis.
 Centrilobular fibrosis develops in instances in which the
thrombosis is more slowly developing.
 Major veins may contain totally occlusive fresh thrombi, subtotal
occlusion or organized adherent thrombi in chronic cases.
 Mortality is high, prompt surgical creation of a portosystemic
shunt permits reverse flow and improve prognosis.
Sinusoidal Obstruction Syndrome
 Originally described in Jamaican drinkers of pyrrolizidine
alkaloid-containing bush tea and names veno-occlusive disease.
 Occurs in 2 settings:
 Following allogeneic hematopoietic stem cell transplantation
within the first 3 weeks.
 In cancer patients receiving chemotherapy.
Pathogenesis
 Obstruction arises from toxic injury to sinusoidal endothelium.
 Sloughed endothelium obstructs the sinusoidal flow.
 Erythrocytes enter into the space of Disse followed by necrosis
of perivenular hepatocytes and downstream accumulation of
cellular debris in the terminal hepatic vein.
Morphology
 Obliteration of the terminal hepatic venules by subendothelial
swelling and collagen deposition.
 In acute disease, there is centrilobular congestion, hepatocellular
necrosis, and accumulation of hemosiderin-laden macrophages.
 As it progresses, obliteration is easily identified with special
stains for connective tissues.
 Histology is the gold standard for diagnosis, but frequently made
on the clinical grounds (tender hepatomegaly, ascites, weight
gain, and jaundice).

PASSIVE CONGESTION AND CENTRILOBULAR NECROSIS
 Represents a morphologic continuum.
 Components of both left and right-sided failure can contribute to
the injury variably in different clinical settings.
Morphology
 Right-sided decompensation leads to passive congestion of the
liver, it is slightly enlarged, tense, and cyanotic with round edges.
 Microscopically there is congestion of centrilobular sinusoids.
 With time, centrilobular hepatocytes become atrophic, resulting
to markedly attenuated liver cell plates.
 Left-sided cardiac failure or shock may lead to hepatic
hypoperfusion and hypoxia causing ischemic coagulative
necrosis in the central region.
 Parenchymal damage may be sufficient to induce mild to
moderate jaundice.
 Combination of hypoperfusion and retrograde congestion acts to
cause centrilobular hemorrhagic necrosis.
 Liver takes a mottled appearance, known as nutmeg liver.
 Microscopically, there is a sharp demarcation of viable periportal
and necrotic or atrophic pericentral hepatocytes.
 Uncommonly, with sustained severe congestive heart failure,
cardiac sclerosis develops with centrilobular fibrosis.
Hepatic Complications of Organ or HSC Transplant
GVHD AND LIVER GRAFT REJECTION
Morphology
 In acute GVHD, occurs 10-50 days after HSC transplant, donor
lymphocytes attack the epithelial cells of the liver.
 This results to hepatitis with necrosis of hepatocytes and bile
duct epithelial cells, and inflammation of parenchyma of the
portal tracts.
 In chronic GVHD, more than 100 days after transplant, there is
portal tract inflammation, selective bile duct destruction, and
eventual fibrosis.
 Cholestasis may be observed in both.
 In transplanted liver, acute rejection is characterized by
infiltration of mixed portal inflammatory infiltrate associated
with bile duct injury.
 In chronic rejection, obliterative arteriopathy of small and large
arteries lead to ischemic changes, results to vanishing bile duct
syndrome which requires retransplantation.
Hepatic Disease Associated with Pregnancy
 May occur in women with chronic liver disease who become
pregnant or develop during pregnancy in women who were not
affected by liver disease.
 Most common cause of jaundice is viral hepatitis.
 HEV infection runs a more severe course in pregnant women.
PREECLAMPSIA AND ECLAMPSIA
 Preeclampsia affects 3-5% of pregnancies characterized by
maternal hypertension, proteinuria, peripheral edema, and
coagulation abnormalities.
 When hyperreflexia and convulsions occur it is called eclampsia
Page 16 of 21
 Subclinical hepatic disease may be the primary manifestations as
part of syndrome of Hemolysis, Elevated Liver enzymes, and Low
platelets (HELLP syndrome).
Morphology
 Periportal sinusoids contain fibrin deposits associated with
hemorrhage into the space of Disse, leading to periportal
hepatocellular coagulative necrosis.
 Blood under pressure may coalesce and expand to form a
hepatic hematoma, dissection of blood under Glisson capsule
may lead to hepatic rupture in eclampsia.
 Modest to severe elevation of serum aminotransferase.
 Hepatic dysfunction results to coagulopathy.
ACUTE FATTY LIVER OF PREGNANCY
 Acute fatty liver presents with a spectrum of disorders ranging
from subclinical or modest hepatic dysfunction (elevated
aminotransferase) to hepatic failure, com, and death.
rd
 Usually in 3 trimester.
 Symptoms are directly attributable to incipient hepatic failure,
including bleeding, nausea, and vomiting, jaundice and coma.
 Pathogenesis is unknown but mitochondrial dysfunction has
been implicated.
Morphology
 Diagnosis rests on biopsy, identification of the characteristic
diffuse microvesicular steatosis of hepatocytes.
 In severe cases there may be lobular disarray with hepatocyte
dropout, reticulin collapse, and portal tract inflammation.
INTRAHEPATIC CHOLESTASIS OF PREGNANCY
rd
 Onset of pruritus in the 3 rimester followed by darkening of
urine and occasionally light stools and jaundice.
 Serum bilirubin, mostly conjugated, rarely exceeds 5mg/dl.
 Alkaline phosphatase may be slightly elevated.
 Altered hormonal state of pregnancy seems to combine with
biliary defects in secretion of bile salts or sulfated progesterone
metabolites to engender cholestasis.
 Benign condition.
Nodules and Tumors
 Hepatic masses may generate epigastric fullness and discomfort
or may be detected by routine PE or radiographic studies
 Nodular hyperplasia and true neoplasms
NODULAR HYPERPLASIAS
 Solitary or multiple hyperplastic hepatocellular nodules that
develop in non-cirrhotic liver
 Two types: focal nodular and nodular regenerative hyperplasia
 Both types due to either focal or diffuse alterations in hepatic
blood supply by obliteration of portal vein radicles and
compensatory augmentation of arterial supply
Morphology:
Focal Nodular Hyperplasia
 Well-demarcated but poorly encapsulated nodule
 Spontaneous mass lesion in a normal liver
 Frequently in young to middle aged adults
 Lesion is lighter than the surrounding liver, sometimes yellow
indicating steatosis
 Central gray-white, depressed stellate scar from which fibrous
septa radiate to the periphery
 Central scar contains large vessels (usually arterial) with
fibromuscular hyperplasia and an eccentric or concentric
narrowing of the lumen
 The parenchyma between septa comprises of normal
hepatocytes separated by thickened sinusoidal plates
 Vascular lesion (congenital or acquired) is the initiating insult
 Hypoperfused areas become the septa, hyperperfused regions
undergo hyperplasia
Nodular Regenerative Hyperplasia
 Denotes a liver entirely transformed into nodules w/o fibrosis
 Plump hepatocytes surrounded by rims of atrophic hepatocytes
 can lead to the development of portal hypertension
 Associated with conditions affecting intrahepatic blood flow
(e.g. solid organ transplantation, hematopoetic stem cell
transplantation, vasculitis), HIV infected persons and
rheumatologic diseases (e.g. SLE)
 Asymptomatic and is usually found in autopsies
BENIGN NEOPLASMS
Cavernous Hemangiomas
 The most common benign liver tumors
 Appear as discrete red-blue, soft nodules, <2cm in diameter
located beneath the capsule
 The tumor consists of vascular channels in a bed of connective
fibrous tissue
 Might be mistaken as metastatic tumor
Hepatocellular Adenomas
 Benign neoplasms developing from hepatocytes
 Rupture may lead to intraabdominal bleeding that is a surgical
emergency
 Oral contraceptives and anabolic steroids are associated with
development
 Has three types with different relative risk of malignant
transformation
Pathogenesis:
HNF1-α Inactivated hepatocellular adenomas
 90% have somatic inactivating mutations of HNF1-α, 10% have
germline mutations
 Heterozygous germline mutations are responsible for autosomal
dominant MODY-3 (maturity onset diabetes of the young, type
3)
 Mostly found in women, associated with oral contraceptive pills
β-Catenin Activated Hepatocellular Adenomas
 Activating mutations of β-catenin are associated with neoplasia
and malignancy in other organs
 High risk of malignant transformation and should be resected
even if asymptomatic
 Associated with OCP and anabolic steroid use, found in men and
women
Page 17 of 21
Inflammatory Hepatocellular Adenomas
 Found in both men and women and associated with non-
alcoholic fatty liver disease
 Small but definitive risk for malignancy and should be resected
 Activating mutations in gp13, a co-receptor of IL-16 and part of
the JAK-STAT signaling pathway
 10% also have concomitant β-catenin activating mutations
Morphology:
HNF1-α Inactivated hepatocellular adenomas
 Fatty and devoid of cellular or architectural atypia
 Almost no risk of malignant transformation
 Liver fatty acid binding protein (LFABP) is absent in these
tumors due to inactivating mutation of HNF1-α (diagnostic of the
mutation)
β-Catenin Activated Hepatocellular Adenomas
 High degree of cytologic or architectural dysplasia with overt
areas of hepatocellular CA
 Immunostain shows nuclear translocation indicative of its
activated state (diagnostic)
 Glutamine synthetases (norm. in perivenular hepatocytes) is
diffusely (+)
 Molecular analysis is necessary
Inflammatory Hepatocellular Adenomas
 Characteristically has additional areas of fibrotic stroma,
mononuclear inflammation, ductular reactions, dilated
sinusoids and telangiectatic vessels
 May overexpress acute phase reactions (e.g. C-reactive protein,
serum amyloid A)
MALIGNANT TUMORS
 Can be primary or metastatic (more common is metastatic)
 Most primary liver CA arise from hepatocytes and are termed
hepatocellular CA (HCC)
 Much less are CA of the bile ducts (cholangiocarcinomas)
Primary tumors are usually solitary. Metastatic tumors are multiple.
Hepatoblastoma
 Most common liver tumor of early childhood, rarely occurs over
the age of 3 years
 Two variants:
 Epithelial type – small polygonal fetal cells or smaller
embryonal cells forming acini, tubules, or papillary
structures that recapitulate liver development
 Mixed epithelial and parenchymal type – contains foci of
mesenchymal differentiation with primitive mesenchyme,
osteoid, cartilage or striated muscle
 Frequent activation of WNT signaling pathway involving
mutations in APC gene
 FAP patients frequently develop hepatoblastomas
 Sporadic cases involve β-catenin activation
 Chromosomal abnormalities are common, FOXG1 is highly
expressed
 May be associated with Beckwith-Wiedemann Syndrome
 Tx: Surgical resection and chemotherapy
Hepatocellular Carcinoma (HCC)  HCC may appear grossly as:
 Erroneously known as Hepatoma, accounts for 5.4%  Unifocal, usually large mass
 More than 85% of cases occur in countries with high rates of  Multifocal, widely distributed nodules of variable size
chronic HBV infection  Diffusely infiltrative cancer
 Incidence is increasing, owing to hepatitis C epidemic  Liver is enlarged
 May occur with or without cirrhosis  Lesion may be pale compared to surrounding liver
th
 Male > Female with 3:1 or 8:1 ratio, and is the 5 leading cause  White when there is abundant stroma, yellow fatty change
of death in males predominates and green if bile is abundant
 Intrahepatic metastases: vascular invasion or direct extension
Pathogenesis:  Metastases are small, satellite tumor around the large, primary
 Chronic liver disease are the most common setting for mass
emergence of HCC  Hematogenous route > lymph node metastasis
 Most important underlying factors in hepatocarcinogenesis are  Fibrolamellar CA – 5% of HCC, presents as a large, hard scirrhous
viral infections (HBV, HCV) and toxic injuries (alfatoxin, alcohol) tumor with fibrous bands coursing through it
 Metabolic disease such as hereditary hemochromatosis and
α1AT deficiency, metabolic syndrome increase the risk of HCC Clinical Features
 Activation of β-catenin (unrelated to HBV) and inactivation of  Related to underlying cirrhosis or chronic hepatitis
p53 (strongly assoc. with alfatoxin) are the two most common  Ill-defined upper abdominal pain, malaise, fatigue, weight loss,
early mutational events hepatomegaly, abdominal mass or fullness
 Mutations in the IL-6/HNF4-α signaling axis may also lead to HCC  Jaundice, fever, GI or esophageal variceal bleeding are
but is still undetermined inconstant
 Elevated levels of serum α-fetoprotein are found in 50% with
Precursor Lesions of HCC advanced HCC
 In chronic liver disease, there are cellular dysplasias called large  Most valuable detection method: ultrasound and CT/MRI with
cell change and small cell change vascular/contrast studies
 Small cell change is a direct marker for premalignancy  Death occurs from:
 Large cell change is at least a marker of increased risk of HCC in  Cachexia
the liver as a whole, but in Hep B may also be directly  GI or esophageal variceal bleeding
premalignant  Liver failure with hepatic coma
 Dysplastic nodules have different appearance as the  Rupture of the tumor with fatal hemorrhage
surrounding cirrhotic nodules in size and vascular supply
(increasingly arterial) Cholangiocarcinoma (CCA)
 Low grade dysplastic nodules may or may not undergo  Second most common primary malignant tumor of the liver after
transformation to higher grade lesions, higher risk for HCC HCC
 High grade dysplastic nodules most important primary pathway  Malignancy of the biliary tree, arising from bile ducts within and
for emergence of HCC in viral hepatitis and alcoholic liver disease outside of the liver
 In countries with infestation of liver flukes: CCA > HCC
Morphology  Risk factors for CCA cause chronic inflammation and cholestasis
 Large Cell Change  Infestation by liver flukes
 Scattered hepatocytes near portal tracts or septa that are  Chronic inflammatory disease of the large bile ducts (e.g.
larger than the normal with large, often multiple, primary sclerosing cholangitis, hepatolithiasis and
moderately pleomorphic nuclei fibropolycystic liver disease)
 N:C ratio is normal  Hep B and C, and non-alcoholic fatty liver disease
 Small Cell Change  Most often sporadic
 High N:C ration and mild nuclear hyperchromasia and/or  Extrahepatic forms include :
pleomorphism
 Perihilar tumors (Klastskin tumors) located at the junction
 Hepatocytes form tiny expansile nodules within a single of the hepatic ducts (60%)
parenchymal lobule
 Distal tumors arising in the common bile duct (20-30%)
 Low-grade dysplastic nodules
 Intrahepatic form (10%)
 Devoid of cytologic or architectural atypia
 Premalignant lesions:
 Clonal and probably neoplastic
 Intraepithelial neoplasias (most important): Bi1IN03 –
 No change in blood supply incurs the highest risk for malignancy
 High-grade dysplastic nodules  Mucinous cystic neoplasms
 Have cytologic or architectural change (e.g. small cell  Papillary biliary neoplasia
change, pseudoglands, trabecular thickening)
 Subnodule within a larger nodule
 Portal tracts are fewer, arteries predominates

Page 18 of 21
Morphology:
 Extrahepatic CCA are generally small lesions at the time of
diagnosis
 Most are firm, gray nodules within the bile duct wall, some are
diffuse infiltrative lesions, others are papillary, polypoid
 Intrahepatic CCA occurs in noncirrhotic liver
 Regardless of site, CCAs are typical adenoCAs
 Often produce mucin
 Well to moderately differentiated with clearly defined
glandular/tubular structures lined by malignant epithelial
cells
 Marked desmoplasia
 Lymphovascular and perineural invasion are common
Cholelithiasis (Gallstones)
 Vast majority of gallstones are silent and most individuals remain
free of biliary pain or complications for decades
 General classes:
 Cholesterol stones – contains 50% of crystalline cholesterol
monohydrate
 Pigment stones – predominantly bilirubin calcium salts
Prevalence and Risk Factors:
 Pigment gallstones are predominant in non-western populations
and arise primarily in the setting of bacterial infections of the
biliary tree and parasitic infections

Other Primary Hepatic Malignant Tumors

 Combined HCC and CCA suggesting an origin of multipotent
stem cell
 Mucinous cystic neoplasms
 Intraductal papillary biliary neoplasia
 Angiosarcoma has associations with vinyl chloride, arsenic or
thorotrast
 Epithelioid hemangioendothelioma
 Hepatic lymphomas is associated with Hep B, C and HIV and PBC
 Diffuse large B-cell lymphomas – most common
 MALT lymphomas
 Hepatosplenic delta-gamma T cell lymphoma – most
 Age and Sex: predominantly affects middle to older age
common in y.a. males, has a predilection for hepatic and
 Higher in female in any region or ethnicity
splenic sinusoids as well as the marrow
 Hypersecretion of biliary cholesterol play the major role
in both age and gender difference
METASTASIS
 Metabolic syndrome and obesity
 Metastatic tumor is more common than primary malignancy  Environmental Factors:
 Most common primary sources are: colon, breast, lung and  Estrogen exposure increases expression of hepatic
pancreas but may come from anywhere in the body lipoprotein receptors and stimulates hepatic HMG-CoA
 May appear as multiple nodes (common) or solitary and can be reductase activity, enhancing uptake and biosynthesis
resected  Excess biliary secretion of cholesterol
 Cause hepatomegaly and serves as the only telltale clinical sign  Obesity & rapid weight loss also increase secretion
 Jaundice and liver enzyme elevations may also appear.  Acquired disorders:
 Gallbladder stasis (hormonal or neurogenic) – fosters an
Gallbladder environment favorable for gallstone formation
 The organ is not essential for biliary function, since humans do  Hereditary Factors:
not suffer from indigestion or malabsorption of fat after  ATP-binding cassette (ABC) transporters – encodes for
cholecystectomy hepatocyte proteins that transports biliary lipids,
 More than 95% is attributed to cholelithiasis associated with stone formation
 Mutation in ABCG8 gene is associated with increased risk
Congenital Anomalies for cholesterol gallstones
 Gallbladder may be congenitally absent, or duplicated with
Pathogenesis
conjoined or independent cystic ducts
Cholesterol Stones:
 Bilobed gallbladder – created by a longitudinal or transverse
 When cholesterol concentrations exceed the solubilizing
septum
capacity of bile (supersaturation), cholesterol can no longer
 Aberrant locations (5-10%) – most commonly partial or
remain dispersed and nucleates into solid cholesterol
complete embedding in the liver substance
monohydrate crystals
 A folded fundus is the most common anomaly creating a
 Conditions that contribute to stone formation:
Phrygian cap appearance.
 Supersaturation of bile with cholesterol
 Agenesis of all or any portion of the hepatic or common bile
 Hypomotility of the gallbladder
ducts and hypoplastic narrowing of the biliary channels (true
 Accelerated cholesterol crystal nucleation
biliary atresia)
 Choledochal cysts may be an isolated finding or associated with  Hypersecretion of mucus, trapping nucleated crystals
leading to accretion of more cholesterol
other extrahepatic biliary tree cyst or fibropolycystic disease

Page 19 of 21
Pigment Stones:
 Disorders associated with elevated levels of unconjugated
bilirubin in bile (e.g. chronic hemolytic anemia, severe ileal
dysfunction or bypass, bacterial contamination) increases the
risk of stone formation
 Unconjugated bilirubin increases when infection leads to the
release of microbial β-glucuronidases
 Escherichia coli, Ascaris lumbricoides and Clonorchis sinensis
increases likelihood of formation
Morphology
Cholesterol Stones:
 Exclusively in the gallbladder and 50-100% pure cholesterol
 Pure are pale yellow, round to ovoid and have finely granular,
hard external surface, on transection, reveals glistening radiating
crystalline palisade
 Increasing proportions of calcium carbonate, phosphates and
bilirubin makes the color gray-white or black and may be
lamellated
 Multiple stones, range up to several centimetres in diameters,
surfaces may be rounded or faceted
 A very large stone may fill the fundus
 Stones composed largely of cholesterol are radioluscent; calcium
carbonate make stones radiopaque
Pigment Stones:
 Black stones are seen in sterile gallbladder bile
 Contain oxidized polymers of of calcium salts of
unconjugated bilirubin, calcium carbonate, calcium
phosphate, mucin glycoprotein and some cholesterol
monohydrate crystals
 Rarely greater than 1.5 cm in diameter, invariable present
in great number and quite friable, contours are speculated
and molded
 50-75% are radiopaque due to calcium salts
 Brown stones are seen in infected large bile ducts
 Contain similar compounds along with cholesterol and
calcium salts of palmitate and stearate
 Tend to be laminated and soft with soap like or greasy
consistency
 Radioluscent
 Mucin glycoproteins constitute scaffolding and interparticle
cement of ALL TYPES of stones
Clinical Features:
 70-80% are asymptomatic with a conversion rate of 4% per year
 Biliary colic is the most prominent among symptoms following a
fatty meal forcing the stone against the gall bladder outlet
leading to increased pressure in the bladder
 Pain is localized to the RUQ or epigastrium and may radiate to
the right shoulder or back
 Inflammation of the gallbladder (cholecystitis)
 Severe complications: empyema, perforation, fistulas,
cholangitis, obstructive cholestasis and pancreatitis
 The larger the calculi, the less likely to cause obstruction of the
cystic or common ducts, very small or gravel stones are the
culprit
 Larger stones may erode directly into and adjacent loop of small
bowel, generating intestinal obstruction (gallstone ileus or
Bouveret syndrome)
 Associated with increased risk of gallbladder carcinoma
Page 20 of 21
Cholecystitis
 May be acute, chronic or acute superimposed on chronic
 Almost always occur with gallstones
 One of the most common indications for abdominal surgery
ACUTE CHOLECYSTITIS
 Precipitated in 90% of cases by obstruction of the beck or cystic
duct by a stone
 Primary complication of gallstones and most common reason for
emergency cholecystectomy
 Cholecystitis without gallstones (acalculous cholecystitis) may
occur in severely ill patients
Pathogenesis:
 Acute calculous cholecystitis results from chemical irritation and
inflammation of a gallbladder obstructed by stones
 Glycoprotein mucus layer is disrupted exposing mucosal
epithelium to direct detergent action of bile salts
 Prostaglandins contribute to mucosal and mural inflammation
 Distention and increased intraluminal pressure compromise
blood flow to mucosa
 Acute acalculous cholecystitis (without stone involvement) is
due to ischemia
 Involvement of cystic artery
 Inflammation and edema of the wall compromising blood
flow
 Gallbladder stasis
 Accumulation of microcrystal of cholesterol (biliary
sludge), viscous bile and gallbladder mucus causing cystic
duct obstruction in the absence of stone
 Risk factors for acalculous cholecystitis:
 Sepsis with hypotension and MOF
 Immunosuppression
 Major trauma or burns
 Diabetes mellitus
 Infections
Morphology:
 Acute cholecystitis – enlarged and tense gallbladder, bright red
or blotchy, violaceous to green-black discoloration, imparted by
subserosal hemorrhages
 Serosal covering is covered with fibrinous exudate or may
be fibrinopurulent
 Calculous cholecystitis – obstructing stone is present in the neck
or cystic duct of the bladder
 Present of one or more stone with a cloudy or turbid bile
with large amounts if fibrin, pus and hemorrhage
 If exudate is virtually pus, it is referred to as gallbladder
empyema, wall is thickened, edematous and hyperemic
 In severe cases, gangrenous cholecystitis occur, where the
gallbladder transforms to a green-black necrotic organs with
small to large perforations
 Inflammation is predominantly neutrophilic
 Acute emphysematous cholecystitis – presence of gas forming
organisms (e.g. Clostridia, coliforms)
Clinical Features
 Progressive RUQ or epigastric pain that lasts for >6 hours
 Mild fever, anorexia, tachycardia, sweating, nausea & vomiting
 Free of jaundice except when (+) obstruction
 Mild to moderate leukocytosis may be accompanied by mild
elevations in serum alkaline phosphatase values
 Acute calculous cholecystitis may appear with remarkable
suddenness and constitute an acute surgical emergency or may
resolve without intervention
 Acute acalculous cholecystitis tend to be more insidious, they are
obscured by the underlying conditions precipitating the attacks
 Oncoprotein ERBB2 (Her-2/neu) is overexpressed in a third to
2/3 of cases and can be targeted with small molecular inhibitors
of monoclonal antibodies
 Mutations of chromatin remodeling genes such as PBRM1 and
MLL3 is also seen

CHRONIC CHOLECYSTITIS Morphology:

 A sequel to repeated bouts of mild to severe acute cholecystitis
or develops in the apparent absence of antecedent attacks
 Supersaturation of bile predisposes to both chronic
inflammation and stone formation
 E. coli and enterococci can be cultured from bile in 1/3 of cases
 Obstruction of gallbladder outflow is not a requisite
Morphology:
 Serosa is usually smooth and glistening but may be dulled by
subserosal fibrosis
 Dense fibrous adhesion may remain as sequelae of pre-existing
acute inflammation
 Wall is variable thickened has opaque gray-white appearance
 Scattered lymphocytes, plasma cells and macrophages in the
mucosa and subserosal fibrous tissue in mild cases
 Marked subepithelial and subserosal fibrosis with mononuclear
cell infiltration in advanced cases
 Outpouching through the RA sinus may be prominent
 Porcelain gallbladder – due to extensive dystrophic calcification
within the gallbladder wall, increase incidence of cancer
 Xanthogranulomatous cholecystitis – massively thickened wall
and is shrunken, nodular and inflamed with necrosis and
hemorrhage triggered by rupture or RA sinus
 Hydrops of the Gallbladder – atrophic, chronically obstructed,
dilated gallbladder and contain only clear secretions
 Two patterns:
 Infiltrating – more common and usually appears as a
poorly defined area of diffuse mural thickening and
induration. Can cause fistulas. Scirrhous and very firm
consistency
 Exophytic – grows into the lumen as irregular, cauliflower
mass, and invades underlying wall
 Most CA are adenocarcinomas
 May be papillary (well to moderately differentiated) to
infiltrative (poorly to undifferentiated)
 5% are squamous cell CA with adenosquamous differentiation
 Minority are carcinoid or a variety of mesenchymal features
(carcinosarcoma)
 Papillary tumors have better prognosis
 Peritoneum, GIT and lungs are common sites of seeding
Clinical Features:
 Preoperative diagnosis of CA of the gallbladder is the exception
rather than the rule
 Symptoms are insidious and indistinguishable with cholelithiasis:
abdominal pain, jaundince, anorexia, nausea and vomiting
 Surgical resection along with adjacent liver is the only effective
treatment along with chemotherapy

Clinical Features:
 Characterized by recurrent attacks of steady epigastric or RUQ
pain with accompanying nausea, vomiting and intolerance of
fatty foods

Complications of Acute and Chronic Cholecystitis

 Bacterial superinfection with cholangitis or sepsis
 Gallbladder perforation and local abscess formation
 Gallbladder rupture with diffuse peritonitis
 Biliary enteric fistula with drainage to adjacent organs
 Aggravation of pre-existing medical illness with cardiac,
pulmonary, renal or liver decompensation
 Porcelain gallbladder, increasing risk for cancer

Carcinoma
 Carcinoma of the gallbladder is the most common malignancy of
the extrahepatic biliary tract
 Twice as common in women than in men

Pathogenesis:
 The most important risk factor for gallbladder cancer (besides
gender and ethnicity) is gallstones
 Chronic bacterial or parasitic infections have been implicated as
risk factors
 Chronic inflammation ties gallstones or infections with cancer
 Harbor recurrent molecular alterations that might be actionable
“Ñuhor līr gūrēnna.”
targets of therapy
(I will take what’s mine)

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