PATHOLOGY OF THE LIVER & BILIARY TRACT

Dr. Linda Tamesis

11/24/14
INTRODUCTION
The liver is a vital organ.
silent- can be damaged even w/o
signs/ symptoms (insiduous; discovered
late)
Incidence of liver disease is rising.
LIVER CANCER
Local statistics
3rd most common cancer for
men, 6th for women
Most: death within a year of diagnosis
<5% expected 5-year survival rate
without treatment
35% expected 5-year survival rate if
diagnosed early & treated aggressively
WHO DATA OF LIVER DISEASE (Ph) April 2011
Liver disease death in the philippines: 7,232
per 100,000 or 1.72% of total deaths
Age adjusted death rate is 12.25 per 100,000
of population
# 70 rank in the world
Liver disease 14th cause of death in the
philippines
CLINICAL MANIFESTATIONS OF LIVER DISEASE
50% asymptomatic
If with symptoms, very non-specific
Fatigue
Excessive tiredness
PATTERNS OF HEPATIC INJURY
Degeneration
Intracellular accumulation
Necrosis and apoptosis
Inflammation
Regeneration
Fibrosis

LIVER FAILURE

May be sudden, massive (fulminant) OR

insidious
80% to 90% functional capacity destroyed
Liver transplantation only hope
80% mortality without transplant

THREE CATEGORIES:
-Acute Liver Failure,
-Chronic Liver Disease
-Hepatic Dysfunction Without Overt Necrosis.

1. Acute Massive Necrosis

-Liver illness with encephalopathy within 6 mos.
FULMINANT LF - Encephalopathy w/in 2 wks of onset
of jaundice
SUB-FULMINANT LF - Encephalopathy w/in 3 mos of
onset of jaundice
-Caused by drugs or toxins
2. Chronic Disease
HEPATITIS/CIRRHOSIS - Most common
route to hepatic failure
3. Dysfunction Without Necrosis
Hepatocytes are viable but UNABLE to
perform normal metabolic functions
tetracycline toxicity
acute fatty liver of pregnancy
CLINICAL FEATURES
1. Jaundice/Icterus
2. Hypoalbuminemia
3. Hyperammonemia
Fetor hepaticus - is a characteristic body odor
that is variously described as musty or sweet
and sour. It is related to the formation of
mercaptans.
4. Hyperestrogenemia
Palmar erythema
Spider angiomas
Male hypogonadism
Gynecomastia - Impaired estrogen
metabolism
and
consequent
hyperestrogenemia are the putative
causes of palmar erythema ( a reflection
of local vasodilatation) and spider
angiomas of the skin.
Is a putative cause of
Palmar erythema local vasodilation
Spider angioma - central, pulsating, dilated
arteriole from which small vessels radiate.
COMPLICATIONS OF LIVER DISEASE
Coagulopathy
Multiple organ failure
Hepatic encephalopathy
Hepatorenal syndrome
Hepatopulmonary syndrome
Hepatorenal Syndrome
Appearance of renal failure in patients with severe
chronic liver disease

STEPHEN DAVE M. CHUA (2D)

No intrinsic morphologic or functional causes for

renal failure
Onset heralded by a drop in urine output, with
rising bun & creatinine
Precipitating stress factors: infection, GIT
hemorrhage, and major surgical procedure
Poor prognosis
Median survival
2 weeks - 6 months

Hepatopulmonary Syndrome

Chronic liver disease

Hypoxemia
Intrapulmonary vascular dilations (IVPD)
Most patients respond to oxygen therapy, although liver
transplantation is the only curative treatment.

LIVER CIRRHOSIS
Cirrhosis is the 12th most common cause of death in the
u.s., accounting for most liver-related deaths. The chief
worldwide causes of cirrhosis are alcohol abuse, viral
hepatitis, & non-alcoholic steatohepatitis (nash). Other
etiologies include biliary disease and iron overload.
Bridging fibrous septae
parenchymal nodules
Disruption of liver architecture

PATHOGENESIS
Death of hepatocytes
ECM deposition
Vascular reorganization
Deposition of type I and III collagen in
space of Disse
Activation of stellate cells and Kupffer
cells
In the normal liver, interstitial collagens (types i and iii)
are concentrated in portal tracts and around central
veins, and thin strands of type iv collagen are present in
the space of disse.
Injury-fibrosis-regeneration
In cirrhosis, types i and iii collagen are deposited in the
space of disse, creating fibrotic septal tracts. The
vascular architecture of the liver is disrupted by the
parenchymal damage and scarring, with the formation of
new vascular channels in the fibrotic septa.
ETIOLOGY
Alcoholic liver disease
Viral hepatitis
Biliary diseases
Primary hemochromatosis
Wilsons disease
A antitrypsinase defic.
Cryptogenic
CLINICAL FEATURES
40% asymptomatic
Anorexia, weight loss, weakness, osteoporosis
Causes of death:
Progressive liver failure
Complication of portal hypertension
Hepatocellular carcinoma
PORTAL HPN
INCREASED RESISTANCE TO PORTAL BLOOD
FLOW AT THE LEVEL OF THE SINUSOIDS
Due to contraction of vascular smooth
muscle cells and myofibroblasts and
disruption of blood flow because of
scarring and formation of parenchymal
nodules
INCREASE IN PORTAL VENOUS BLOOD FLOW
RESULTING
FROM
A
HYPERDYNAMIC
CIRCULATION
Caused by arterial vasodilation,
primarily in splanchnic circulation

STEPHEN DAVE M. CHUA (2D)

A. PREHEPATIC
Obstructive thrombosis,
Narrowing of the portal vein before it
ramifies within the liver
Massive splenomegaly with increased
splenic vein blood flow
B. POSTHEPATIC
Severe right-sided heart failure
Constrictive pericarditis
Hepatic vein outflow obstruction
C. INTRAHEPATIC
Cirrhosis
CLINICAL CONSEQUENCES OF PORTAL HYPERTENSION
Ascites
Formation of portosystemic venous shunts
Congestive splenomegaly
Hepatic encephalopathy
ASCITES
Ascites is the accumulation of excess fluid in the
peritoneal cavity.
Most often cause is cirrhosis.
Clinically detectable - 500 ml
Serous, < 3 gm/dl of protein
Serum to ascites albumin gradient of >/=1.1
gm/dl.
PATHOGENESIS
sinusoidal HPN
percolation of hepatic lymph into the peritoneal
cavity
splanchnic vasodilation and hyperdynamic
circulation
FORMATION OF PORTOSYSTEMIC VENOUS SHUNTS
ESOPHAGOGASTRIC VARICES
Appear in 40% of pts with cirrhosis
Causes hematemesis
CAPUT MEDUSAE
Abdominal wall collaterals appear as dilated
subcutaneous veins extending from the
umbilicus toward the rib margins called caput
medusae & constitute an impt clinical hallmark
of portal hypertension.
CONGESTIVE SPLENOMEGALY
The degree of splenic enlargement varies widely
and may reach as much as 1 kg, but it is not
necessarily correlated with other features of
portal hpn. The massive splenomegaly may

secondarily induce hematologic abnormalities

attributable to hypersplenism, such as
thrombocytopenia or even pancytopenia.
HEPATIC ENCEPHALOPATHY
-Disturbances in consciousness
-disorder of neurotransmission in the cns &
neuromuscular system
-elevated ammonia levels in the blood & cns
Impair neuronal function
Promote generalized edema
Astrocyte swelling
JAUNDICE
-occurs when equilibrium between bilirubin production
and clearance is disturbed by
Excessive extrahepatic production of bilirubin
Reduced hepatocyte uptake
Impaired conjugation
Decreased hepatocellular excretion
Impaired bile flow
Common Causes Of Jaundice (2-2.5mg/dl)
Bilirubin overproduction
Hepatitis
Obstruction to the flow of bile
PREHEPATIC CAUSES (hemolysis B1)
Malaria
Defects in hgb structure
Autoimmune disorders
G6pd
Spherocytosis
Drugs
INTRAHEPATIC CAUSES (B1)
Drug-induced liver dse
Acetaminophen
Penicillin
Oral contraceptives
Steroids
Drugs cholestatic jaundice
Liver disease
Liver cancer
Hepatitis
Cirrhosis
Criggler-najjar syndrome b1
Gilberts syndrome b1
Paracetamol overdose

STEPHEN DAVE M. CHUA (2D)

POSTHEPATIC CAUSES (B2)

Pancreatitis
Pancreatic cancer
Gallstones in bile ducts
Gallbladder cancer
Bile duct stricture
Cholangitis
Parasites
Pregnancy
Congenital malformation, newborn jaundice
HEREDITARY HYPERBILIRUBINEMIA B1
Crigler-Najjar 1
AR, No UGT1A1, liver normal, lethal
Crigler-Najjar 2
AD, Some UGT1A1, not lethal, helped by
phenobarbital
Gilbert
AR, Fluctuating levels of B1,
HEREDITARY HYPERBILIRUBINEMIA B2
Dubin Johnson
AD, transport problem, pigmented liver,
non lethal
Rotor
AR, uptake/excretion problem, non
lethal
CHOLESTASIS
Etiology: impaired bile formation and blood flow
(intra/extra)
Accumulation of bile in hepatic parenchyma
Jaundice, pruritus, xanthoma, inc ALP, Dec Vit
ADK

hepatocyte bile secretion. Patients may have

jaundice, pruritus, skin xanthomas (focal
accumulation of cholesterol), or symptoms
related to intestinal malabsorption, including
nutritional deficiencies of the fat-soluble
vitamins a, d, or k. A characteristic lab finding is
elevated serum alk phosphatase & gamma
glutamyl transferase.
MICROSCOPIC
Feathery or foamy degeneration
Accumulation of bile pigments
Bile lakes, bile plugs

*BYLER DISEASE PFIC 1

AR, intrahepatic cholestasis
impairment of bile salt excretion
Mutation of ATP8B1 gene

INFECTIOUS DISORDERS

VIRAL FOREMOST HEPATIC INFECTION

Miliary tuberculosis
Malaria
Staphylococcal bacteremia
Salmonellosis
Candida
Amebiasis
VIRAL HEPATITIS
Infectious Mononucleosis (EBV)
CMV in newborn or immunosuppressed
Yellow fever virus
Hepatitis A, B, C, D, E, G

It can be caused by extrahepatic or intrahepatic

obstruction of bile channels, or by defects in
STEPHEN DAVE M. CHUA (2D)

HEPATITIS B
HBV can produce - Acute hepatitis, Non
progressive chronic hepatitis, Progressive
chronic disease, cirrhosis, fulminant hepatitis,
asymptomatic carrier state
Present in all body fluids except stool
Prolonged viremia
Vertical transmission results in carrier state
ds DNA Hepadnavirus
HEPATITIS B VIRUS
SEROLOGY
HBsAg-before onset of symptoms
HBeAg- active viral replication
HBcAb- with elevation of transaminases
HBeAb-disease is on the wane
HBsAb- acute disease over, immunity
Carrier state- (+) HBsAg > 6 months
HEPATITIS C
Transfusion hepatitis
Progresses to chronic disease and cirrhosis
Ss RNA Flavivirus
IgG anti HCV does not confer immunity
Episodic elevations of transaminases
HEPATITIS D VIRUS
Delta agent
ssRNA defective virus
Causes hepatitis only with Hep B
Coinfection
o (IgM HDV & HBcAb) - fulminant
Superinfection
o (IgM HDV & HBsAg) cirrhosis
HEPATITIS E
Water-borne, enterically transmitted
Self limiting except in pregnant women
SsRNA
CLINICOPATHOLOGIC SYNDROMES OF VIRAL HEPATITIS
HEPATITIS A
Infectious hepatitis, ingestion
Benign, self-limiting,
ssRNA Picornnavirus
viremia is transient
SEROLOGY
IgM-onset of symptoms
IgG-rises after a few months
persists for years

1. ACUTE ASYMPTOMATIC INFECTION WITH RECOVERY:

serologic evidence only
2. ACUTE SYMPTOMATIC INFECTION WITH RECOVERY
Incubation period -infectivity
Symptomatic preicteric phase - malaise
Symptomatic icteric phase
Convalescence
3. CHRONIC HEPATITIS
- continuing hepatic disease for more than 6 months
4. THE CARRIER STATE
- harbors and can transmit an organism, but has no
manifestations of symptoms.

STEPHEN DAVE M. CHUA (2D)

MORPHOLOGIC FEATURES OF ACUTE AND CHRONIC

HEPATITIS

Bridging necrosis (and fibrosis) is shown only for chronic

hepatitis but may also occur in acute hepatitis.
Acute viral hepatitis showing disruption of lobular
architecture, inflammatory cells in the sinusoids, and
hepatocyte apoptosis. On the right is chronic viral
hepatitis due to hcv, showing portal tract expansion with
inflammatory cells and fibrous tissue and interface
hepatitis with spillover of inflammation into the adjacent
parenchyma. A lymphoid aggregate is present.
ACUTE VIRAL HEPATITIS

-Ballooning degeneration, cholestasis, drop-out

necrosis, councilman bodies, Kupffer cell hyperplasia
CHRONIC VIRAL HEPATITIS

BACTERIAL, PARASITIC, AND HELMINTHIC INFECTIONS

BACTERIAL ETIOLOGY
S. aureus, S. typhi, & T. pallidum
Bacterial GUT flora in ascending
cholangitis
PARASITIC AND HELMINTHIC
Malaria,
schistosomiasis,
strongyloidiasis,
cryptosporidiosis,
leishmaniasis, echinococcosis, liver
flukes
LIVER ABSCESS
Amoebic, pyogenic
Solitary or multiple; echinococcal or amebic
Spread thru
portal vein,
arterial supply,
direct extension
penetrating trauma
ascending infection
Rx: surgical drainage/antibiotics
MR: 30% to 90%
80% survive with early dx
AUTOIMMUNE HEPATITIS
A chronic and progressive hepatitis of unknown
etiology
Salient features
Female predominance (78%)
Absence of viral serologic markers
Elevated serum IgG & gamma-globulin
levels
High serum titers of autoantibodies
Types based on the patterns of circulating antibodies:
Type I- associated with HLA DR-3
ANA, SMA, AAA, anti-SLA/LP antibodies
Type II
ALKM-1, ACL-1

Lymphocyte and plasma cell infiltrates are

prominent
May progress to cirrhosis without clinical
diagnosis
Untreated, 40% die within 6 months, cirrhosis in
at least 40% of survivors

-bridging necrosis and interface hepatitis,

STEPHEN DAVE M. CHUA (2D)

DRUG & TOXIN INDUCED LIVER DISEASE

Predictable Drug Reactions:
Acetaminophen- leading cause of drug-induced
acute liver failure
Amanita phalloides toxin, CCl4
A. REYE SYNDROME
potentially fatal mitochondrial dysfunction of
liver, brain, exceedingly rare
microvesicular steatosis (fatty change) and
encephalopathy
Develops 3-5 days after a viral infection
Vomiting, irritability and hepatomegaly usually
seen in young children
B. ALCOHOLIC LIVER DISEASE
Excessive consumption of alcohol is the leading
cause of liver disease in most western countries
Forms of alcoholic liver disease
Hepatic steatosis
Alcoholic hepatitis
Cirrhosis
ALCOHOLIC STEATOSIS
Micro-macro steatosis
Starting centrilobular

the cluster of inflammatory cell marks the site of a

necrotic hepatocyte. Eosinophilic mallory bodies are
seen in hepatocytes, which are surrounded by fibrous
tissue.
PATHOGENESIS:
Up to 80 grams - mild, reversible hepatic change
80 grams or more -significant risk of severe hepatic injury
160 grams or more daily for 10 to 20 yrs -consistently
severe injury
*only 10% to 15% of alcoholics develop cirrhosis
FACTORS FOR DEVELOPMENT AND SEVERITY OF
ALCOHOLIC LIVER DISEASE
Gender. Women seem to be more susceptible.
Estrogen increases gut permeability to endotoxins,
prediposing to increased production of proinflammatory cytokines and chemokines
Ethnic differences. Cirrhosis rates are higher for
african americans
Genetic factors
Co-morbid conditions: Iron overload, HCV, and HBV
DETRIMENTAL EFFECTS OF ALCOHOL &
BYPRODUCTS ON HEPATOCELLULAR FUNCTIONS:
1. Excess NADH + H+ promotes lipid synthesis
2. Impaired assembly & secretion of lipoproteins
3. Increased peripheral fat catabolism

ALCOHOLIC HEPATITIS
Ballooning degeneration
Mallory bodies
Neutrophilic reaction
Perivenular fibrosis

ITS

Alcohol can become sources of calories in diet,

displacing other nutrients and leading to malnutrition
and vitamin deficiency
Alcohol causes release of bacterial endotoxin in GUT
inducing inflammatory responses in the liver
Acetaldehyde- induces lipid peroxidation disrupts
cytoskeletal and membrane function

CAUSE OF DEATH:
1. hepatic coma
2. massive GIT hemorrhage
3. intercurrent infection
4. hepatorenal syndrome
5. hepatocellular carcinoma (1% - 6%)

STEPHEN DAVE M. CHUA (2D)

METABOLIC LIVER DISEASES

1. Nonalcoholic Fatty Liver Disease and Steatohepatitis
2. Hemochromatosis
3. Wilson Disease
4. Alpha-1-AT Deficiency
5. Neonatal Cholestasis
1. NONALCOHOLIC FATTY LIVER DISEASE
Most common cause of chronic liver disease in
U.S.
MOST COMMON CAUSE OF CRYPTOGENIC
CIRRHOSIS
10% to 30% eventually develop cirrhosis
Individuals who do not consume alcohol or in
those with very small quantities
Men & women equally affected
Strong association with obesity, dyslipidemia,
hyperinsulinemia & insulin resistance, and type
2 diabetes
Increased AST and ALT
Morphology:
Steatosis
Steatohepatitis
Cirrhosis
2. HEMOCHROMATOSIS
Excessive accumulation of body iron especially in
parenchymal organs, e.g., liver and pancreas
Results from genetic defect causing excessive
absorption (hemochromatosis) or parenteral
administration of iron, (hemosiderosis) e.g.,
transfusion
Total iron >50 gm (NV: 2 to 6 gm)
Adult form of primary hemochromatosis is
almost always caused by mutations of HFE gene
at chr 6p21.3
MECHANISMS OF DIRECT TISSUE TOXICITY OF
EXCESSIVE IRON:
1. lipid peroxidation via iron-catalyzed free radicals
2. stimulate collagen formation
3. reactive O2 & iron interacting with DNA causing lethal
injury or predisposition to HCC
MORPHOLOGY
1. hemosiderin deposition in liver, pancreas,
myocardium, pituitary, adrenal, thyroid and
parathyroid glands, joints, and skin
2. Cirrhosis

3. Pancreatic fibrosis
Inflammation absent; liver enlarged, tense,
chocolate brown, later micronodular cirrhosis
CLINICAL FEATURES
Males, rarely evident before 40 yrs
Hepatomegaly,
abdominal
pain,
skin
pigmentation, deranged glucose homeostasis or
frank diabetes, cardiac dysfunctions, and
atypical arthritis, hypogonadism
CLASSIC TRIAD: pigment cirrhosis with
hepatomegaly, skin pigmentation & DM
CAUSES OF DEATH: cirrhosis, cardiac, HCC
DIAGNOSIS AND TREATMENT
Very high serum iron and ferritin, exclude
secondary causes, liver biopsy
Screening of family members
Diagnosed in the subclinical, precirrhotic stage:
regular phlebotomy with normal life expectancy
3. WILSON DISEASE

Autosomal recessive, mutation of ATP7B gene

Impaired excretion of copper into bile and failure
to incorporate copper into ceruloplasmin
marked by accumulation of toxic levels of copper
in many tissues or organs, principally liver, brain
and eye.

PATHOGENESIS
Morphology
LIVER: fatty change, vacuolated nuclei ;
acute/chronic
hepatitis;
massive
necrosis
atrophy/cavitation, BRAIN
Kayser-Fleischer rings, limbus of
CORNEA
CLINICAL FEATURES
Extremely variable at age onset
Most common presentation: acute or chronic
liver disease
Neuropsychiatric Sx, e.g., behavioral changes to
frank psychosis, Parkinson dse-like
Dx: decreased serum ceruloplasmin, increased in
hepatic Cu content, and increase in urinary
excretion of Cu; demo of Kayser-Fleischer rings

STEPHEN DAVE M. CHUA (2D)

4. ALPHA-1-AT DEFICIENCY
Autosomal Recessive
marked by abnormally low serum levels of A1AT
protease inhibitor (Pi)
Inhibits proteases, elastase, cathepsin G, and
proteinase 3
Gene located in chromosome 14
PiMM, 90% genotype, normal A1AT
Pi-null, no detectable serum A1AT, rare
PiZZ, 10% normal A1ATclinical disease
PATHOGENESIS
Mutant polypeptide (A1AT-Z) is abnormally
folded and polymerizes retention in the ER of
hepatocytes
A1AT not hepatotoxic
10% PiZZ develop clinical disease due to lag in ER
protein degradation pathway intense
autophagocytic response autophagocytosis of
mitochondria
MORPHOLOGY
PAS (+), diastase-resistant, round to oval
cytoplasmic globular inclusions
Neonatal hepatitis with cholestatic jaundice in
10% to 20% neonates with deficiency
Hepatitis or cirrhosis, adolescence
CLINICAL FEATURES
Remain silent until cirrhosis appears in middle to
later life
PULMONARY EMPHYSEMA
HCC in 2% to 3% of PiZZ
Rx: liver transplant; avoidance of cigarette
smoking

5. NEONATAL CHOLESTASIS
Prolonged conjugated hyperbilirubinemia in the
neonates
CHOLANGIOPATHIES (atresia #1)
jaundice, dark urine, light or acholic stools,
hepatomegaly, hypoprothrombinemia
Dx: liver biopsy

MORPHOLOGY

lobular disarray with focal necrosis

panlobular giant cell transformation with rosette
formation
cholestasis
mild portal mononuclear infiltrates
reactive Kupffer cells
extramedullary hematopoiesis

INTRAHEPATIC BILIARY TRACT DISEASE

Intrahepatic bile ducts are frequently damaged as
part of more general liver diseases as in drug toxicity,
viral hepatitis, liver transplantation, and graftversus-host
disease
after
bone
marrow
transplantation.
1. Primary Biliary Cirrhosis- destruction of intrahepatic
BT
2. Secondary Biliary Cirrhosis- uncorrected obstruction
of extrahepatic BT
3. Primary Sclerosing Cholangitis- BOTH extra and intra
4. Anomalies of the Biliary Tree
PRIMARY BILIARY CIRRHOSIS
Nonsuppurative, granulomatous destruction of
intrahepatic bile ducts
Middle aged women,
S/S
pruritis, hepatomegaly, xanthomas,
steatorrhea, osteomalacia, Autoantibodies
(AMA M2), Systemic abnormalities
Micro-intense
lymphocytic
infiltration,
granulomas, Bile duct destruction, destruction of
adjacent hepatocytes Piecemeal destruction
STEPHEN DAVE M. CHUA (2D)

SECONDARY BILIARY CIRRHOSIS

Extrahepatic obstruction results in liver damage
Causes: Common bile duct obstruction, Biliary
atresia, Pancreatic ca, Strictures
Bile stasis-periportal fibrosis
bacterial infection with coliforms
ascending cholangitis
bile stasis and neutrophils
PRIMARY SCLEROSING CHOLANGITIS
Inflammation, obliteration and segmental
dilatation of the intrahepatic and extrahepatic
bile ducts
S/S fatigue, pruritis, jaundice, beading on x-ray,
70% with chronic ulcerative colitis
micro- concentric periductal fibrosis, onion skin
fibrosis, cord like scars

HEPATIC CIRCULATORY DISORDERS

HEPATIC DISEASE ASSOCIATED WITH PREGNANCY
Viral hepatitis (hav, hbv, hcv, and even hbv + hdv)
is the most common cause of jaundice in
pregnancy. Hev infection runs a more severe
course in pregnant patients.
1. PREECLAMPSIA AND ECLAMPSIA
2. ACUTE FATTY LIVER OF PREGNANCY
3. INTRAHEPATIC CHOLESTASIS OF PREGNANCY
HEPATIC COMPLICATIONS OF ORGAN OR BONE
MARROW TRANSPLANTATION
1. Drug Toxicity After Bone Marrow Transplantation
2. Graft-versus-Host Disease and Liver Rejection
3. Nonimmunologic Damage to Liver Allografts

HEPATIC VEIN THROMBOSIS

BUDD-CHIARI SYNDROME
Hepatomegaly, weight gain, ascites and
abdominal pain
Seen in: polycythemia vera, pregnancy,
postpartum, oral contraceptives, PNH, intraabdominal Ca. (30% idiopathic)
acute form with high mortality
liver swollen with tense capsule
congestion and necrosis-cardiac sclerosis

*LIVER TOXICITY
Syndrome of liver dysfunction following cytotoxic
therapy prior to bone marrow transplant
Weight gain, tender hepatomegaly, edema,
ascites, hyperbilirubinemia, & fall in urinary
sodium excretion
Centrilobular
necrosis
&
inflammation
culminating in veno-occlusive disease
Nodular regenerative hyperplasia in wks to
months
May die from septicemia, pneumonia, bleeding,
&/or multiorgan failure

STEPHEN DAVE M. CHUA (2D)

10

LIVER TRANSPLANT REJECTION

ACUTE REJECTION
mixed cellular infiltrates into portal tracts, bile
duct and hepatocyte injury and endothelitis
CHRONIC REJECTION
severe obliterative arteritis of small and larger
arterial vessels
ischemic necrosis + progressive bile duct
occlusion loss of graft

NODULES AND TUMORS

1. NODULAR HYPERPLASIAS
Focal nodular hyperplasia
Nodular regenerative hyperplasia
2. BENIGN NEOPLASMS
Cavernous hemangioma
Liver cell adenoma
3. MALIGNANT TUMORS
Hemangioblastoma
Hepatocellular CA
Angiosarcoma
Cholangiocarcinoma
NODULAR HYPERPLASIAS (Not mentioned)
BENIGN NEOPLASMS
a. CAVERNOUS HEMANGIOMA
most common benign tumor
discrete red-blue, soft nodules, <2 cm, beneath
capsule
Significance: mistaken for metastatic tumors and
NOT for blind percutaneous biopsy
b. LIVER CELL ADENOMA
benign neoplasms developing from hepatocytes
are called hepatic adenomas or liver cell
adenomas.
Grossly, it is pale, yellow-tan, frequently bilestained nodules, found anywhere in the hepatic
substance but often beneath the capsule. They
are usually well demarcated and solitary.
young, oral contraceptive users
Significance:
1. mistaken for HCC, if intrahepatic
2. subcapsular adenomas may rupture during
pregnancy
3. may transform into HCC

MALIGNANT TUMORS
Can be primary or secondary
PRIMARY LIVER CA
uncommon in N. America and W. Europe (0.5% to
2%)
20% to 40% other countries
HEPATOCELLULAR CA : arise from hepatocytes
CHOLANGIOCARCINOMA: from bile ducts
HEPATOBLASTOMA: young childhood
ANGIOSARCOMA: PVC, arsenic, thorotrast
1. HEPATOCELLULAR CARCINOMA (HCC)
Third most frequent cause of cancer death
Male predominance, 2.4:1
FOUR MAJOR ETIOLOGIC FACTORS ASSOCIATED
Chronic viral infection (HBV, HCV)
Chronic alcoholism
Non alcoholic steatohepatitis (NASH)
Food contaminants (aflatoxin)
PATHOGENESIS
Other conditions
TYROSINEMIA
40% develop HCC despite adequate
dietary control
Cirrhosis important but not requisite for HCC
CLINICAL FEATURES
Masked by those related to cirrhosis of chronic
hepatitis
Ill-defined upper abdominal pain, malaise,
fatigue, weight loss, abdominal mass or fullness
Jaundice, fever, GIT or esophageal bleed
DIAGNOSIS
INCREASED AFP
USG
Hepatic angiography
CT, & MRI
biopsy
DEATH FROM: cachexia, GIT or esophageal
variceal bleeding, liver failure with hepatic coma,
& tumor rupture
2. CHOLANGIOCARCINOMA
Malignancy of the biliary tree, arising from bile
ducts within and outside of the liver
Risk conditions: primary sclerosing cholangitis,
congenital fibropolycystic diseases of biliary

STEPHEN DAVE M. CHUA (2D)

11

system, previous exposure to thorotrast &

previous infection by liver fluke, O. sinensis
Morphology: adenocarcinomas
Mixed variants with HCC & cholangiocarcinoma
may occur
Hematogenous metastasis to lungs, bones
(mainly vertebra), adrenals, brain, etc present on
autopsy in 50% of cases
Detected late in its course
Median time from diagnosis to death: 6 months
3. HEPATOBLASTOMA
MOST COMMON LIVER TUMOR OF YOUNG
CHILDHOOD
1 to 2 in 1 million births
Fatal within a few years if not treated
Two variants
a. Epithelial type
b. Mixed epithelial and mesenchymal
type
Maybe associated with
o Familial Adenomatous Polyposis syndrome
o Beckwith Wiedemann syndrome
Treatment
o chemotherapy and complete surgical
resection
Therapy raising 5-year survival rate to 80%

THE BILIARY TRACT

1. Congenital Anomalies
2. Disorders of the Gallbladder
3. Disorders of the Extrahepatic Bile Ducts
4. Tumors
5. Iatrogenic Injury to the Biliary Tree

CONGENITAL ANOMALIES

Congenitally absent
Duplication
Aberrant locations
Folded fundus phrygian cup
Agenesis of hepatic or CBD
Hypoplastic narrowing of biliary channels

DISORDERS OF THE GALLBLADDER

1. CHOLELITHIASIS (GALLSTONES)
2. CHOLECYSTITIS ACUTE/CHRONIC
1. CHOLELITHIASIS. Risk Factors for Gallstones

FIBROLAMELLAR CARCINOMA

Young males and females

Patients do not have underlying chronic liver
disease
Unknown etiology
METASTATIC TUMORS
More common than primary liver CA
Breast, lung, & colon, pancreas
Any site, leukemias and lymphomas
Hepatomegaly + nodularity of free edge
Central necrosis and umbilication

cholesterol & pigmented gallstones

CLINICAL FEATURES
80% are silent
90%- cholesterol stones; the rest are pigment
stones composed of bilirubin calcium salts
excruciating colicky or constant biliary pain
COMPLICATIONS: empyema, perforation, fistula,
cholangitis, and obstructive cholestasis or
pancreatitis, intestinal obstruction, risk for
cholangiocarcinoma
STEPHEN DAVE M. CHUA (2D)

12

2. CHOLECYSTITIS
Acute, chronic or acute superimposed on chronic
Almost always in association with gallstones
Most common indications for abdominal surgery
ACUTE CALCULOUS CHOLECYSTITIS
o chemical irritation and inflammation of
obstructed gallbladder
o 90% precipitated by obstn of the neck
or cystic duct
ACUTE ACALCULOUS CHOLECYSTITIS
o ischemia
o Contributing factors: pigment load;
gallbladder stasis; accumulation of
microcrystals of cholesterol, viscous bile,
and mucus; inflammation and edema;
bacterial contamination
o severely ill patients without gallstones
Postoperative state after major
nonbiliary surgery
Severe trauma/burns, MOF,
prolonged
IV
hyperalimentation, postpartum
state
ACUTE CHOLECYSTITIS:
CLINICAL FEATURES
ACUTE: progressive RUQ or epigastric pain
Mild fever, anorexia, tachycardia, sweating N &
V, no jaundice
Mild-moderate leukocytosis, ALP
ACUTE CALCULOUS CHOLECYSTITIS may appear
with remarkable suddeness ACUTE SURGICAL
EMERGENCY
ACUTE ACALCULOUS CHOLECYSTITIS: needs high
index of suspicion; may be fatal; HIGH
INCIDENCE OF GANGRENE AND PERFORATION
CHRONIC CHOLECYSTITIS
Sequel to repeated bouts of mild to severe acute
cholecystitis
>90% associated with cholelithiasis
Morphology: mononuclear cells, fibrosis,
prominent RA sinus
Porcelain gallbladder
Xanthogranulomatous cholecystitis
Hydrops of gallbladder
Complications:
bacterial
superinfection,
perforation & abscess, rupture, fistula,
aggravation of pre-existing medical problems

DISORDERS OF THE EXTRAHEPATIC BILE

DUCTS
1. CHOLEDOCHOLITHIASIS

presence of stones within the bile ducts of

biliary tree
As opposed to cholelithiasis (stones in the
gallbladder). In asia, there is a much higher
incidence of primary stone formation within the
biliary tree. The stones are usually pigmented &
associated with biliary tract infections.
Choledocholithiasis may be asymptomatic or
may cause symptoms from pancreatitis,
obstruction, cholangitis, hepatic abscess,
secondary biliary cirrhosis, & acute calculous
cholecystitis.
asymptomatic or
cause symptoms from
Obstruction
Pancreatitis
Cholangitis
Hepatic abscess
2o biliary cirrhosis
Acute calculous cholecystitis

2. ASCENDING CHOLANGITIS
CHOLANGITIS: bacterial infection of bile ducts
ASCENDING CHOLANGITIS: intrahepatic ducts
3. SUPPURATIVE CHOLANGITIS
Is the most severe form of cholangitis in which
purulent bile fills and distends bile ducts. Sepsis
dominate the picture.
4. BILIARY ATRESIA
Complete or partial obstruction of the lumen of
the extrahepatic biliary tree within the 1st 3
months of life.
STEPHEN DAVE M. CHUA (2D)

13

 Progressive inflammation & fibrosis of

intrahepatic & extrahepatic bile ducts
MOST FREQUENT CAUSE OF DEATH FROM
LIVER DISEASE IN EARLY CHILDHOOD
50% to 60% liver transplant
Forms: fetal or perinatal(more common)
5. CHOLEDOCHAL CYSTS
Congenital dilations of the common bile
duct, presenting most often in children before
the age of 10. Approximately 20% become
symptomatic only in adulthood. The female-tomale ratio is 3:1 to 4:1. These uncommon cysts
of the common bile duct, diverticuli of the
extrahepatic ducts, or choledochoceles, which
are cystic lesions that protrude into the
duodenal lumen. Choledochal cysts predispose
to stone formation, stenosis & stricture,
pancreatitis, & obstructive biliary complications
within the liver. In the older patient, the risk of
bile duct carcinoma is elevated.
6. GALLBLADDER ADENOMA
Adenomas are benign epithelial tumors,
representing localized neoplastic growth of the
lining epithelium. Adenomas are classified as
tubular, papillary, and tubulopapillary.
7. INFLAMMATORY POLYPS - Sessile mucosal
projections
8. ADENOMYOSIS OF THE GALLBLADDER
hyperplasia of muscle layer, containing
intramural hyperplastic glands

gallbladders containing stones or infectious

agents develop cancer as a result of irritative
trauma and chronic inflammation. Carcinogenic
derivatives of bile acids are believed to play a
role. Most carcinomas of the gallbladder are
adenocarcinomas. Some are papillary, & are
well to moderately differentiated; others are
infiltrative and poorly differentiated to
undifferentiated. About 5% are squamous cell
carcinomas
or
have
adenosquamous
differentiation. A minority may show carcinoid
or carcinosarcoma. Papillary tumors have a
better prognosis than other tumors.
a. Infiltrating Carcinoma Of The Gallbladder
The infiltrating pattern is more common
& usually appears as a poorly defined area of
diffuse thickening & induration of the
gallbladder wall. Deep ulceration can cause
direct penetration of the gallbladder wall or
fistula formation to adjacent viscera into which
the neoplasm has grown. These tumors are
scirrhous & have a very firm consistency.
b. Exophytic Carcinoma Of The Gallbladder
The exophytic pattern grows into the
lumen as irregular, caulifower mass but at the
same time invades the underlyiing wall. The
luminal portion may be necrotic, hemorrhagic, &
ulcerated.
The most common sites of
involvement are the fundus & the neck; about
20% involve the lateral walls.
METASTASES OF GALLBLADDER CARCINOMA

9. CARCINOMA OF THE GALLBLADDER - most

common malignancy of the extrahepatic biliary
duct. Most frequently it occurs in the 7th decade
of life. The most important risk factor is
gallstones (cholelithiasis).
Presumably,

By the time these neoplasms are discovered, most

have invaded the liver centrifugally, & may have
extended to the cystic duct & adjacent bile ducts &
STEPHEN DAVE M. CHUA (2D)

14

portal-hepatic lymph nodes. The peritoneum, git, &

lungs are common sites of seeding. Preoperative
diagnosis of gallbladder carcinoma is the exception
rather than the rule, occuring in fewer than 20% of
patients.
Presenting symptoms are insiduous:
abdominal pain, jaundice, anorexia, nausea, & vomiting.

LABORATORY TESTS
Prothrombin time
Gamma-glutamyl transferase (ggt)
Alkaline phosphatase (alp)
Transaminase (alt, ast)
Albumin
Alpha-1 antitrypsin

The liver is vulnerable to a wide variety of metabolic,

toxic, microbial, circulatory, & neoplastic insults. The
major primary diseases of the liver are viral hepatitis,
alcoholic liver disease, nonalcoholic fatty liver disease
(nafld), and hepatocellular carcinoma (hcc). Hepatic
damage also occurs secondary to some of the most
common diseases in humans, such as cardiac
decompensation, disseminated cancer, and extrahepatic
infections.
HISTORY TAKING AND PHYSICAL EXAMINATION
Age
Gender
Drug intake
Alcohol beverage drinker
Street foods
Fatty foods
Body weight
Liver span
Living conditions
Drugs of abuse
Sexual practice
With sex worker
Unprotected
Blood transfusion

GOOD LUCK!
My FIRST and LAST time to transcribe.
So hello
Jacob, Grace, Hannah, Evita, Dyan, CJ,
and Tricia.
Chammy, Jessica, Camille, and James!
And also, hi Rea!

STEPHEN DAVE M. CHUA (2D)

15