Pathology of the liver, biliary

tract and pancreas

THE LIVER
 Introduction
• One of the vital
organs of the body,
responsible for
multiple chemical
reactions the body
needs to survive
 Introduction
Functions Examples
Carbohydrate metabolism Gluconeogenesis, glycogen synthesis and
breakdown
Fat metabolism Fatty acid synthesis, cholesterol synthesis
and excretion, lipoprotein synthesis,
ketogenesis, bile acid synthesis, 25-OH of
vitamin D

Protein metabolism Synthesis of plasma proteins, urea synthesis

Hormone metabolism Both steroid and poly peptide hormones

Drugs and foreign compounds Metabolism and excretion
Storage Glycogen, vitamin A, B12 , iron, folic acid
Metabolism and excretion of
bilirubin
 Introduction
• Has a dual blood supply- the portal vein
and hepatic artery
• Within the liver, the branches of the portal
veins, hepatic arteries and bile ducts travel
in parallel portal tracts
 Introduction
• In the micro-
architecture, the liver
is divided into
hexagonal lobules
oriented around the
terminal hepatic veins
with the portal tracts
at the periphery of the
lobule
• Kupffer cells and bile
canaliculi are also
present
 Introduction
• The liver is vulnerable to a wide variety of
metabolic, toxic, microbial, circulatory and
neoplastic diseases
• Hepatic damage may also occur due to cardiac
disease, disseminated cancer and extra-hepatic
infections
• It has a great functional reserve but with
progression of diffuse disease or disruption of bile
flow, the consequences of deranged liver function
become life threatening
• Liver disease tends to be insidious except in cases
of fulminant hepatic failure
 Laboratory evaluation of liver disease
• Hepatocyte integrity
• Serum aspartate aminotransferase (AST)
• Serum alanine aminotransferase (ALT)
• Serum lactate dehydrogenase (LDH)
• Substances normally secreted by the liver
• Serum bilirubin (total and direct), urine bilirubin
• Plasma membrane enzymes from damage to bile canaliculus-
• Serum alkaline phosphatase
• Serum γ glutamyl transpeptidase
• Serum 5’ nucleotidase
• Hepatocyte function
o Proteins secreted into blood
o Serum albumin
o Prothrombin time (clotting factors I,II, V, VII, X)
o Metabolic functions
 Hepatic syndromes
• Occur as a consequence of many different
diseases
• The hepatic syndromes include:
• Hepatic failure
• Cirrhosis
• Portal hypertension
• Disturbances of bilirubin metabolism causing
jaundice and cholestasis
 Hepatic failure
• Is the most severe consequence of liver
disease
• May be due to sudden and massive hepatic
destruction (fulminant hepatic failure) or
more often may be the end stage of
progressive chronic damage to the liver
• 80%- 90% of the hepatic functional
capacity must be lost before hepatic failure
occurs
 Hepatic failure
• Classified into:
1. Acute liver failure
• Acute liver illness associated with
encephalopathy within 6 months after the
initial diagnosis
• It is caused by massive hepatic necrosis most
often induced by drugs or toxins
• Acetaminophen, antimycobacterial, halothane,
antidepressants (monoamine oxidase inhibitors),
carbon tetrachloride, mushroom poisoning,
hepatitis A & B virus, autoimmune hepatitis
• It may also be idiopathic
 Hepatic failure
• Classified into:
2. Chronic liver disease- due to persistent
chronic hepatitis
3. Hepatic dysfunction without overt necrosis-
tetracycline toxicity and acute fatty liver of
pregnancy
 Hepatic failure
Clinical features
• Jaundice
• Hypoalbuminemia- peripheral edema
• Hyperammonemia- cerebral dysfunction
• Fetor hepaticus- musty body odor
• Impaired estrogen metabolism- palmar erythema,
spider angiomas, and in males hypogonadism and
gynecomastia
• With hepatic failure- patients are susceptible to
multi-organ failure- cerebral, respiratory, renal
failure, coagulopathy which may cause GI bleeding
 Cirrhosis

• Consists of:
• Bridging fibrous septa –
fibrous bands linking portal
tracts with one another and
terminal hepatic veins
• Parenchymal nodules-
hepatocytes encircled by
fibrosis, may be small or large
• Disruption of the architecture
of the entire liver- diffuse
liver involvement
 Cirrhosis
Causes
• Alcohol abuse
• Viral hepatitis
• Non- alcoholic steatohepatitis
• Biliary disease
• Iron overload
 Cirrhosis
Clinical features
• May be asymptomatic until late
• Non-specific symptoms- anorexia, weight loss,
weakness
• In advanced disease- symptoms and signs of
hepatic failure
• Mechanism of death in most cirrhotic patients
• Progressive liver failure
• A complication related to portal hypertension
• Development of hepatocellular carcinoma
 Portal hypertension
• Increased resistance to portal blood flow
• Classified into pre-hepatic, intra-hepatic
and post-hepatic causes
• Pre-hepatic:
• Obstructive thrombosis
• Narrowing of the portal vein before it divides
in the liver
• Massive splenomegaly with increased splenic
blood flow
 Portal hypertension
• Intra-hepatic causes
• Cirrhosis
• Schistosomiasis
• Massive fatty change
• Diffuse fibrosing granulomatous disease e.g.
sarcoidosis
• Post hepatic causes
• Severe right sided heart failure
• Constrictive pericarditis
• Hepatic vein outflow obstruction
 Portal hypertension
Clinical features
• Ascites- accumulation of
fluid in the peritoneal cavity
• Formation of porto-systemic
shunts
• Esophageal varices and
hemorrhoids
• Peri-umbilical (caput
medusae)
• Congestive splenomegaly
• Hepatic encephalopathy
 Jaundice and cholestasis
• Bile is composed of a mixture of bile salts,
bilirubin, cholesterol and other wastes
• Bile is produced by the liver
• Is useful for
• Emulsification of dietary fat
• Elimination of bilirubin, excess cholesterol,
xenobiotics and other waste products that are
insufficiently water soluble to be excreted in
the urine
 Jaundice and cholestasis
• Bilirubin can be:
• Unconjugated-
• Insoluble in water
• Bound to albumin
• May diffuse in tissues (especially the brain in infants
leading to kernicterus)
• Cannot be excreted in urine
• Conjugated (bilirubin glucoronides) -
• Water soluble
• Non-toxic
• Loosely bound to albumin
• Can be excreted in urine
 Jaundice and cholestasis
• Jaundice- yellow
discoloration of
the skin and
sclera due to
retention of
bilirubin
• Cholestasis-
systemic retention
of bilirubin and
other solutes
eliminated in bile
 Jaundice and cholestasis
• Jaundice occurs when the equilibrium between
bilirubin production and clearance is disturbed by:
• Excessive extra hepatic production of bilirubin-
hemolytic anemia and ineffective erythropoieisis
• Reduced hepatocyte uptake- drug interference with
membrane carrier systems, Gilbert syndrome
• Impaired conjugation- genetic disorders (Criggler
Najjar syndrome), diffuse hepatocellular disease,
physiological jaundice (newborn)
• Decreased hepatocellular excretion- deficiency of
membrane transporters
• Impaired bile flow- cholestasis
 Liver infections
Viral hepatitis
• Hepatic infections caused by a group of viruses known
as a hepatotropic virus (hepatitis viruses A, B, C, D and
E) that have a particular affinity for the liver
• Hepatitis D occurs as a co-infection with hepatitis B
virus
• Chronic liver disease occurs with infection by hepatitis
B & C viruses and are transmitted by parenteral, sexual
routes
• Hepatitis A & E are transmitted by the fecal-oral route
and do not cause chronic liver disease
 Liver infections
Viral hepatitis
• HIV infection exacerbates the severity of liver
disease caused by HBV or HCV
• Morphology of viral hepatitis
• Acute hepatitis
• Chronic hepatitis
• Deposition of fibrous tissue- hallmark of chronic
liver damage
• Continued loss of hepatocytes and fibrosis -
cirrhosis
 Liver infections
• Liver abscesses caused by echinococcal and amebic
infections
• Bacteria that can infect the liver directly include
Staphylococcus aureus, Salmonella typhi, T.
pallidum
• Pyogenic abscesses reach the liver by the
• Portal vein
• Arterial supply
• Ascending infection in the biliary tract
• Direct invasion of the liver from a nearby source
• Penetrating injury
 Liver infections
• Liver abscess may be solitary or multiple
• Associated with fever, right upper quadrant
pain, tender hepatomegaly
• Antibiotic therapy may control smaller
lesions but surgical drainage is required for
larger lesions
• Mortality rate ranges between 30-90% due
to delayed diagnosis and co-existent disease
 Metabolic liver disease
• Liver disease attributable to disorders of
metabolism, either acquired or inherited
• Examples:
• Non- alcoholic fatty liver disease
• Hemochromatosis
• Wilson’s disease
• Neonatal hepatitis
• α1-antitrypsin deficiency
 Metabolic liver disease
Non-alcoholic fatty liver disease
• Steatosis (fatty liver)
• Patients do not consume or alcohol or use very
small quantities
• Common in patients with obesity
• May manifest with or without inflammation
• With inflammation – non-alcoholic
steatohepatitis (NASH) there is hepatocyte
injury which may progress to cirrhosis in a few
patients
 Metabolic liver disease
Hemochromatosis
• Excessive accumulation of body iron, most of it
deposited in organs such as the liver, pancreas,
joints, heart, endocrine glands
• It is due to a genetic disorder causing excessive
iron absorption
• May develop cirrhosis, diabetes and skin
pigmentation
• Hemosiderosis (secondary hemochromatosis)
usually occurs due to parenteral administration
of iron
 Metabolic liver disease
Wilson disease
• Genetic disorder- impaired copper excretion
in bile and failure to incorporate copper into
ceruloplasmin
• Accumulation of toxic levels of copper in the
liver, brain and eye
• May present with a wide range of hepatic
disease- steatosis, acute hepatitis, chronic
hepatitis, cirrhosis and massive liver necrosis
Hepatocellular carcinoma (HCC)
• Mot common primary hepatic malignancy
• Most cases occur in developing countries
with high rates of chronic HBV infection
• More common in males
• Major etiological factors
• Chronic viral infections (HBV, HCV)
• Chronic alcoholism
• Non-alcoholic steatohepatitis
• Food contaminants (primarily aflatoxins)
Hepatocellular carcinoma (HCC)
Pathogenesis
• Precise mechanisms of carcinogenesis is
unknown
• Repeated cycles of cell death and regeneration
may cause accumulation of mutations due
damage of DNA repair mechanisms
• Universal vaccination against HBV in
endemic areas has been shown to reduce the
incidence
Hepatocellular carcinoma (HCC)
Morphology
• Gross
• Unifocal, multifocal or
diffusely infiltrative. All 3
patterns may cause liver
enlargement
• Tends to be paler and may
take on a greenish hue
Hepatocellular carcinoma (HCC)
• Have a strong propensity for invasion of
vascular structures- can tract through the
portal vein- inferior vena cava and right
side of the heart

Microscopy
• Ranges from well differentiated to highly
anaplastic undifferentiated lesions
Hepatocellular carcinoma (HCC)
Clinical features
• Ill-defined upper abdominal pain
• Malaise
• Fatigue
• Weight loss
• Abdominal mass or fullness
• Rarely jaundice, fever, GIT or esophageal
variceal bleeding
Hepatocellular carcinoma (HCC)
Causes of death in HCC
• Cachexia
• GIT or esophageal variceal bleeding
• Liver failure with hepatic coma
• Rupture of the tumor with fatal
hemorrhage
 Cholangiocarcinoma
• Second most common malignancy after
HCC
• Malignancy of the biliary tree arising from
bile ducts within and outside the liver
• Risk factors
• Primary sclerosing cholangitis
• HCV infection
• Chronic infection with liver fluke
(Opisthorchis sinensis)
 Metastatic tumors
• More common that primary tumors
• Most common sources colon, breast, lung
and pancreas (any cancer may spread to
the liver)
• Multiple nodular metastases that may
cause striking hepatomegaly or may be a
single nodule
THE
BILIARY
TRACT
 Cholelithiasis (gallstones)
• Majority are asymptomatic
• There are 2 main types- cholesterol and
pigment stones
• Cholesterol stones-females sex hormones,
pregnancy, obesity, rapid weight
reduction, gall bladder stasis
• Pigment stones- chronic hemolytic
syndromes, biliary infections, GIT
disorders
 Cholelithiasis (gallstones)
Clinical features Complications
• Most patients are • Cholecystitis
asymptomatic • Empyema
• Biliary pain- • Perforation
excruciating and • Fistulas
constant or colicky
• Cholangitis
(inflammation of the
biliary tree)
• Obstructive
cholestasis
• Pancreatitis
 Acute cholecystitis
• Primary complication of gallstones (90%)
or may be found in severely ill patients
(10%)
• Clinical features
• Right upper quadrant or epigastric pain
• Mild fever, anorexia, tachycardia, sweating,
nausea and vomiting
 Chronic cholecystitis
• May be due to repeated bouts of
mild to severe acute cholecystitis or
may be associated with cholelithiasis
• Clinical features are similar to those
of acute cholecystitis
• Morphology
• Features of chronic inflammation
• Rarely may develop dystrophic
calcification leading to formation of a
porcelain gallbladder- thought to have
an increased incidence of development
of cancer
THE PANCREAS
Introduction
 Introduction
Architecture
• Complex lobulated organ with
distinct exocrine and
endocrine parts
• The exocrine portion produces
digestive juices (1.2 -1.5L) and
constitutes 80-85% of the
organ
• The endocrine portion is
composed of clusters of cells –
Islets of Langerhans producing
various hormones and
constitutes 1-2% of the organ
 Congenital anomalies
• Agenesis
• Pancreatic divisum- failure of fusion of the
fetal dorsal and ventral duct system
• Annular pancreas- band like ring of
normal pancreas that completely encircles
the duodenum
• Ectopic pancreas- stomach, small intestine
 Acute Pancreatitis
• Reversible pancreatic parenchymal injury
associated with inflammation
 Acute pancreatitis -Etiology
Metabolic Mechanical
• Alcoholism • Gallstones
• Trauma
• Hyperlipoproteinaemia
• Iatrogenic injury
• Hypercalcemia
• Drugs e.g. azathioprine Vascular
• Shock
Genetic • Atheroembolism
• Mutations in the • Vasculitis
cationic trypsinogen and
trypsin inhibitor genes Infections
• Mumps
 Acute Pancreatitis- Morphology
• Ranges from trivial
inflammation and edema to
severe extensive necrosis and
hemorrhage
• Red black hemorrhage
interspersed with foci of yellow
white , chalky fat necrosis
• Foci of fat necrosis may also be
found in extra-pancreatic
collections of fats e.g. omentum,
mesentery, subcutaneous fat
Acute Pancreatitis- Morphology
• The most severe form is hemorrhagic pancreatitis
• The pancreas shows extensive parenchymal
necrosis accompanied by dramatic hemorrhage
within the pancreas
Acute Pancreatitis- Clinical Features
• Abdominal pain –constant, intense, often
referred to the upper back and
occasionally to the left shoulder
• Severity of the pain varies from mild and
uncomfortable to severe and
incapacitating
• Anorexia, nausea and vomiting
• Full blown acute pancreatitis is a medical
emergency- “Acute abdomen”
 Chronic Pancreatitis
• Inflammation of the pancreas with
irreversible destruction of exocrine
parenchyma, fibrosis and in the late
stages, the destruction of endocrine
parenchyma
 Chronic Pancreatitis- Etiology
• Most common cause is alcohol abuse
• Other causes include:
– Long standing obstruction of the pancreatic
duct (often with dilation of the duct)-
pseudocysts, calculi, trauma, neoplasms or
pancreatic divisum
– Tropical pancreatitis
– Hereditary pancreatitis
– Cystic fibrosis
 Chronic Pancreatitis- Pathogenesis
• Not well understood
• Repeated episodes of acute pancreatitis
• Proposed that recurrent acute pancreatitis
results in fibrosis, duct distortion and
altered pancreatic secretions
• Proposed events include
– Duct obstruction by concretions
– Toxic effects on acinar cells e.g. alcohol
– Oxidative stress
 Chronic Pancreatitis- Morphology
Macroscopic appearance
• Hard gland (parenchymal fibrosis and calcified
concretions) with extremely dilated ducts
Chronic Pancreatitis- Clinical features
• Repeated attacks of moderately severe abdominal
pain, recurrent attacks of mild pain or persistent
abdominal and back pain
• May be silent until pancreatic insufficiency and
diabetes develop
• Recurrent attacks of jaundice or vague attacks of
indigestion
• Attacks may be precipitated by alcohol abuse,
overeating or use of opiates
• Weight loss
• Edema
 Pancreatic carcinoma
• Infiltrating ductal adenocarcinoma
• Worldwide- 4th leading cause of cancer
deaths in the US
• Precursor lesions-Pancreatic intra-epithelial
neoplasias (PanINs)
• Primarily a disease of the elderly, between
the ages of 60- 80 yrs
• More common in blacks than whites
• More common in Ashkenazi Jews
 Pancreatic carcinoma- Etiology
• Cigarette smoking- doubles the risk
• Consumption of a diet rich in fats
• Chronic pancreatitis
• Diabetes mellitus
• Inherited predispositions
Pancreatic carcinoma- Morphology
• Approximately 60% arise in the head of the
pancreas, 15% body, 5% tail and 20 % diffuse
organ involvement
• Hard, stellate, gray-white, poorly defined
masses
 Pancreatic carcinoma- Morphology
• Often grow along nerves and invade the
retro peritoneum
• They may directly invade the spleen,
adrenals, vertebral column, transverse
colon and stomach
• Surrounding lymph nodes are also
involved (peripancreatic, gastric,
mesenteric, omental, portahepatic)
• Distant metastasis occurs to liver, lungs
and bones
Pancreatic carcinoma- Clinical features

• Silent until invasion or obstruction of adjacent

structures
• Pain- mid- epigastric with radiation to the back
• Obstructive jaundice- painless
• Weight loss, anorexia, generalized malaise,
weakness
• Migratory thrombophlebitis- Trousseau sign
(10%)
• Onset of diabetes within the previous year
Pancreatic carcinoma- Clinical features

• Pruritus
• Advanced disease
• Ascites
• Hepatomegaly from liver metastasis
• Splenomegaly from portal vein obstruction
• Lymph node metastasis- paraumbilical, cervical nodes
• Note: Fewer than 20% are resectable at the time
of diagnosis