Fundamental Liver Pathology

Part 1

Diana Cardona, MD
June 15, 2011
 Course Objectives

• 1. Recall normal liver anatomy and histology.

• 2. Understand basic terminology/definitions.
• Apoptosis, cholestasis, limiting plate, interface hepatitis, micro- versus
macro-vesicular steatosis, steatohepatitis, balloon cell, Mallory body, lobular
hepatitis, bridging fibrosis, nodular transformation, ground glass
hepatocytes, iron accumulation, PASD resistant globules, portal tract, portal
hepatitis, jaundice
• 3. Understand the general patterns of injury, repair and
fibrosis.
• Acute versus Chronic
• Hepatocellular, Biliary, Vascular What injury occurs in each compartment?
• 4. Exposure to common liver tumors. TOMORROW
• Benign and malignant
 Normal Liver Anatomy

Adult weight:
1400-1600 g

Lobes:
Right Largest lobe
Left
Caudate
Quadrate
 Normal Liver Anatomy
Important! Dual blood supply
Blood exits through the hepatic veins and
dumps into the IVC.

Blood Supply:
Portal Vein
Hepatic Artery
- Along with the
Common Bile
Duct, they enter
through the hilum

- Branches of these
structures travel within
portal tracts
The vascular supply is important for anatomy, because
that's how surgeons decide to resect parts of the liver.
They divide up the segments of the liver:
1 = caudate
2-4 = left lobe
5-8 = right lobe
 Portal Tract
The portal tract (made of up the three structures below) is enveloped by a small amount of fibrous tissue.
The abrupt transition between the fibrous tissue and the hepatocytes is the limiting plate. This is
important histologically b/c infalmmation extending beyond that limiting plate is important to note.

Constituents:
• Bile duct
• Portal vein
• Hepatic artery

• Limiting plate
• (Interface)
 Microscopic Liver Anatomy
Two ways to look at the microscopic anatomy: lobule unit and acinar unit.

Lobule unit: central /terminal hepatic vein in center with cords

of hepatocytes radiating out, extending to the portal triads/
tracts. The blood flows from the portal tracts to hte vein. Bile
formed in the hepatocytes flows through hte canalicular
spaces back towatrds the portal tract.

Acinar unit: Look at one triangular portion of the

lobule. The acinus is broken down based on the
blood flow.
Zone 1: freshest blood, most O2-rich
Blood Zone 3: O2-poor blood, right near central vein.

central vein

Bile
BD: bile duct
Portal Tract HA: hepatic artery (dual
supply!)
PV: portal vein
 portal tracts along
periphery

blood: portal tract --> terminal hepatic

central vein vein in center

bile: hepatocytes --
> canaliculi
 Lobular Architecture

• Hepatocytes arranged
in thin plates/cords (1-2 PT
cells thick).
If you see hepatocytes in cords that are thicker than this (1-2 Zone 1
cells), you start thinking about a neoplastic process.
Bile
• Sinusoidal spaces lined
by endothelial cells and
filled with blood, Kupffer Zone 2 Blood

cells and stellate cells.

Kupffer cells - liver macrophages
Stellate cells: pluripotent stem cells of the liver

• Bile is excreted from

hepatocytes into bile Zone 3

canaliculi  canals of
Hering  bile ducts
Canals of Hering are at the limiting plate;
these dump into the bile duct.
CV
 Definitions
Portal hepatitis: Inflammation of the portal tract. Can still see Once you see spillage of the information (can't draw a
the demarcation where the inflammation ends and the hepatocytes straight line between inflammatory cells and bigger
begin. No interface activity like on the right - inflammation is hepatocytes), very irregular (projections extending
contained with the portal tract. out), extending beyond limiting plate - interface
hepatitis.

portal vein

Portal Hepatitis Interface Hepatitis

You can have both or
just portal hepatitis.
 Definitions
Injury can lead to fatty metamorphosis of the hepatocytes. Heps are forming a lot of lipids that can accumulate within the cells.

Micro - fine, small droplets. Relatively uncommon; can

Macrovesicular - large clear droplets. More common.
sometimes see some patches. Know specifically
because of how it applies to Reyes syndrome and fatty
liver of pregnancy.

Macrovesicular Microvesicular
Steatosis Steatosis
 Various forms of injury.
Definitions
Left: balloon cells and Mallory bodies are the histological hallmark of steatohepatitis.
Right: dying hepatocyte. In the liver, don't call them apoptotic bodies, call acidophil or councilman bodies.

normal hepatocyte

alloon cells: markedly

nlarged hepatocytes.
ytoskeletal elements
art clumping,
ecoming rope-y and
biquinated. Hyaline or
termediate filaments =
allory bodies.
apoptotic body. Pyknotic
nucleus (condensed
chromatin). Hyper-eosinophilic
cytoplasm. Becoming
condensed and small.

Balloon Cells with Acidophil Body

Mallory Bodies (Councilman Body)
 Cholestasis
Hepatocytes form bile. If something happens to either interrupt the excretion into the canalicular spaces or the flow of bile through
the biliary system, you'll have backup of the bile. This can occur either within the hepatocytes (L) or within the canalicular spaces
(R).

plugs of bile within

canalicular spaces

Intracellular bile accumulation

Hepatocellular cholestasis Canalicular cholestasis

 Patterns of Hepatic Injury
Dividing up injury patterns by the cell that is getting destroyed.
Can have a combination of the three occuring. If the damage is severe enough, you will have regeneration.
If the damage is chronic, you can develop fibrosis/cirrhosis of the liver.

• Hepatocyte Injury
– Cell death (i.e. Apoptosis)
– Degenerative and/or intracellular accumulations (i.e. Ballooning
degeneration and steatosis) Intracellular accumulations: fatty change, steatosis, iron accumulation
– Inflammation
• Influx of acute or chronic inflammatory cells involving the portal tracts,
interface and/or lobules
• Biliary Injury
– Cholestasis (most commonly)

• Structural versus functional

• Vascular Abnormalities Resulting in ischemia

– Which can lead to hepatocyte and/or biliary injury

• Regeneration/Fibrosis
Serum Markers for Hepatic Injury
How is the liver doing in this patient? - Liver Function Tests (LFTs) Liver functions: metabolizes drugs, creates
Any markers elevated= something injured. clotting factors, makes albumin, metabolizes
ammonia - all crucial
Hepatocyte Integrity
Hepatocellular enzymes Serum aspartate aminotransferase (AST)
Both specific for hepatocyte injury. Serum alanine aminotransferase (ALT)
Biliary
Substances secreted in bile Serum bilirubin
Normally bilirubin is excreted; if it starts
accumulating, there is something wrong with the
Total: unconjugated plus conjugated
biliary system. Direct: conjugated only
Plasma membrane enzymes Serum alkaline phosphatase
Serum γ-glutamyl transpeptidase
Can also look at membrane enzymes. Serum
alk phos isn't entirely specific.
Serum gamma-glutamyl is quite specific for the biliary system.
Hepatocyte Function
Secreted proteins (blood)
Serum albumin in injury
Look at things the
liber either Prothrombin time
produces (albumin)
or metabolizes (factors V, VII, X, prothrombin, fibrinogen) in injury
(ammonia).

Hepatocyte metabolism Serum ammonia in injury

Ammonia = bad. Too much results in psychological changes, etc.
An increase means liver isn't metabolizing it.
 Hepatocyte Injury
Various forms of hepatocyte injury:

• Infectious
– Viral Hepatitis Most common form of injury - viral hepatitis

– Others…
• Autoimmune Hepatitis
• Toxic/Drug Induced Injury
– Alcohol
• Metabolic Injury
– Non-Alcholic Fatty Liver Disease (NAFLD) Epidemic of metabolic syndrome, obesity.
This is a growing topic.

• Intracellular Depositions
– Hemochromatosis
– Alpha-1-antitrypsin
– Wilson Disease
– Metabolic disease (not addressed in this talk) Like glycogen storage disorders
- not covered today
 Viral Hepatitis

Viruses that can affect any organ/system, not specific to liver. Viruses specific to the liver.

• Non-Hepatotropic: • Hepatotropic:
– Epstein Barr Virus (EBV) ** – Hepatitis A Virus
• Sinusoidal lymphocytosis – Hepatitis B Virus
• PTLPD
– Hepatitis C Virus
– Cytomegalovirus (CMV)immunocompromised –
Seen in
Hepatitis D Virus
patients. Results in
• Post-transplant infection hepatitis.
– Hepatitis E Virus
– Herpes Simplex Virus (HSV)
• Overwhelming Fulminant,
hepatitis.
overwhelming

infection/necrosis
– Adenovirus ** Complications of EBV: in liver, can cause lobular hepatitis.
• Mainly affects children Sinusoidal spaces fill with lymphocytes.
Post-transplant lymphoproliferative disorder - essentially a
lymphoma associated with EBV. This can also occur in other
immunocompromised states (HIV, chronically treated with
methotrexate).
 Hepatotropic Viruses
Viruses with an affinity for the liver.
In general, think of hepatitis viruses as ssRNA with hte exception of HBV - dsDNA. "Hep B wants to be like its brothers and
sisters." Has reverse transcriptase, converts DNA to RNA. Uses RNA template for replication like the other hep viruses.

HAV HBV HCV HDV HEV

Agent ssRNA dsDNA ssRNA ssRNA ssRNA

Transmission •Fecal •Parenteral •Parenteral •Parenteral •Water-

•Oral •Sexual •Sexual •Sexual borne
contaminated
food
contact contact contact
•Perinatal •Needle
•Needle stick
stick
Notes:
B-D: IV drug use, sexual contact, occupational exposure
(needles).
B: perinatal (through delivery).
 Clinical Syndromes

• Acute hepatitis- asymptomatic with recovery Acute - body can clear

virus by itself (typically A,
– HAV and HBV infection during childhood sometimes B, E).

• Acute hepatitis- symptomatic with recovery

– Uncommon for HCV
• Chronic hepatitis Chronic: either relapsing/remitting or continuous - HepC, sometimes B. NOT A or E.
– Continued or relapsing disease for > 6 months
– Hallmark of HCV
• Fulminant hepatitis Fulminant: patient presents acutely, and within a few weeks
they need a liver transplant emergently.
– Progression to hepatic failure within 2 – 3 weeks
– In the US, most commonly HAV and HBV (adults)
• Carrier state
– Harbor replicating virus and can transmit the organism
Carrier: usually E. Infection, asymptomatic. Liver full of the virus, and constantly shedding.
Acute: portal, or portal + interface hepatitis. Portal tract with Chronic (at least 6 months): can still have ongoing
inflammatory cells. Extends beyond limiting plate, causing active injury (portal, interface, or lobular hepatitis) with
hepatocellular injury. Old terminology: piecemeal necrosis. scar tissue due to fibrosis within the liver. if it becomes
Lobular injury: inflammation and injury of the hepatocytes - more extensive, patient develops cirrhosis.
Councilman bodies, balloon cells, etc.
 Hepatitis A
Presents acutely. Pale stools because of liver dysfunction.
Does not form a chronic hepatitis; can rarely cause fulminant
hepatitis.

• Can present with anorexia,

nausea, and jaundice
– Occasionally subclinical
• Typically a benign, self-
limited disease.
– Rarely causes fulminant
hepatitis
• Produces an acute lobular
hepatitis +/- cholestasis
• Does not progress to
chronic hepatitis
Histologically: lobular hepatitis with lobule full of
inflammation. Can't see nice rays/cords of hepatocytes.
Councilman body
"Lobular disarray" due to injury and inflammation.
 Hepatitis B Normal
hepatocytes: very
granular
Can present acutely or subclinically. Hep B infection once
cytoplasm.
chronic is an independent risk factor for the development of
hepatocellular carcinoma.

• Often subclinical disease but

can cause an acute hepatitis
• Rarely fulminant hepatitis
• Usually resolves but can
cause chronic hepatitis (5%)
• Chronic hepatitis is associated Smudgy, very pink. Inclusions

with risk of hepatocellular

with a halo - "ground glass".
Appearance due to HBV virion
carcinoma packed in the cell.

• Can produce a “healthy”

carrier state Carrier state is unique for HBV.
• Asymptomatic but infectious
• „Ground glass‟ cytoplasmic
inclusion of virions (arrows)
Shedding disease, very infectious.
HBV core Ag HBV surface Ag
IHC imaging - cells full of HBV
 Hepatitis C
Unlike HBV which is going down due to vaccine, HCV is still a major
disease cause. Causes a much higher rate of chronic infection.

• Major cause of liver disease

worldwide
• Has a higher rate of
progression to chronic PT
hepatitis than HBV (80-85%).
• Portal, interface and lobular
hepatitis
• Progressive fibrosis - cirrhosis
• Variable steatosis
• Various subtypes exist We'll hear more on 6/15
• Multiple strains and subtypes
can exist within the same person
Can't draw a line of where the limiting plate is because
inflammation is spreading out.
Small pic: lobular hepatitis with acidophil body.
 Hepatitis D Hepatitis E
Rarest of hepatotropic viruses.
Requires HBV to survive and cause any injury.

• AKA- “delta virus” • Usually causes acute self-

• In the US, it‟s relatively limited hepatitis
uncommon • Can cause fulminant hepatitis;
• IV drug abusers • Fatal outcome particularly
associated with pregnancy
• Hemophiliacs (mortality ~ 20%)
• Requires HBsAg for • Does not progress to
encapsulation and thus chronic hepatitis
replication (infection)
• Two pathways:
• Acute co-infection (with HBV)
Immunocompromised in pregnancy. Risk of fulminant
hepatitis is higher and the women don't recover as well.

• Super-infection
Infection with another Hep virus would potentially turn
into a chronic hepatitis (HEV is the most fatal).
Pre-infected with HBV, HDV
causes super-infection.
 Other Infectious Diseases

• Bacterial
– Spirochetes
Syphilis, Borrelia.

• Fungal
– Aspergillus
Immunocompromised patients. Can also see Candidiasis.

• Parasitic
– Echinococcus
– Schistosomiasis
Cyst with multiple layers of wall. If you have
any radiographic suspicion of this, don't stick
a needle in - can develop anaphylactic
shock. Resect carefully! Echinococcus
 Autoimmune Hepatitis
Can also form chronic hepatitis.

• Chronic and progressive hepatitis of unknown etiology

– Autoimmune mediated injury
Exposure can elicit
• Several potential “triggers” – infection, drugs, herbal products a reaction.
• HLA DR3 and DR4
– ANA and Anti-smooth muscle Ab (ASMA) (Type 1) Type 1 most common -
80% of pts

• +/- anti-actin or anti-soluble liver/ liver-pancreas antigen (Type 3)

These Type 3 antibodies are often grouped under Type 1. Conflict in literature.

– Anti-liver kidney microsome-1 (ALKM-1) (Type 2 ) Type 2 is least common.

• Young to middle aged women primarily effected
– M:F 1:3; ~ 40 y/o
– Majority develop a chronic hepatitis that can progress to
cirrhosis (40%).
– Acute fulminant hepatitis can occur (40%)
Fulminant hepatitis can often lead to transplantation.
 Autoimmune Hepatitis

• Associations:
– Celiac disease, SLE, RA, Sjogren syndrome, UC, etc…
They're all associated.

• Morphology:
– Interface and lobular hepatitis with a predominant population of
plasma cells and lymphocytes.
– May present with zone 3 (perivenular) injury
– Can have overlap with PSC or PBC. PSC: Primary sclerosing cholangitis.
PBC: Primary biliary cirrhosis - both biliary
The presence of many plasma cells can help processes, also autoimmune.
differentiate autoimmune hepatitis from other types.

• Treatment:
– Immunosuppression (i.e. prednisone/ azothioprine)
– Transplantation
Progression to cirrhosis will eventually require transplantation.
 Autoimmune Hepatitis
High power: a sea of plasma cells.

Inflammation up
here in lobular
tissue too.

PT

Portal tract. Can't

clearly make out borders
(blurred by
inflammation). Portal +
interface hepatitis.
Alcohol (Toxic) Related Injury

• Excessive ethanol consumption: one of the leading causes

of liver disease
– Alcohol abuse is the 5th leading cause of death in the U.S.
– More than 14 million Americans abuse alcohol
– Rate is higher in males (11%) versus females (4%)
• “Alcohol abuse” definition varies
– 140 grams (~14 “drinks”) of alcohol per week for males
• Women are more susceptible to injury
– Interesting new data suggests that mild to moderate intake actually
protects against liver disease.
– Increased AST:ALT (≥2:1)
AST and ALT, specific for hepatocellular integrity. If elevated, hepatocellular injury. With alcohol
related injury, the ratio changes as above - this can help distinguish from other types of liver damage.
Alcohol (Toxic) Related Injury
Alcohol is absorbed unaltered. Metabolized in the liver.
3 mechanisms for conversion of EtOH, only one for metabolizing acetaldehyde. Important!
3 systems dumping acetaldehyde into 1. Rate-limiting step is conversion to acetate.

• Normal Metabolism:
ADH ALDH
– EtOH  Acetaldehyde  Acetate these can also convert EtOH to
acetaldehyde.
– Oxidizing system (CytP450, ER) and Catalase (peroxisomes)
– Acetaldehyde: nausea, reactive intermediate
– Ethanol: affects protein synthesis, membrane integrity EtOH itself is toxic.
- 50% of Asians have low ALDH.

• Net effects of excess intake:

– Metabolism diverted: NADH equivalents  fat (lipid biosynthesis - steatosis)
– Damage to protein export machinery and cellular membranes EtOH and ROS
– Clumped intermediate filaments (Mallory bodies) Ropy hyaline seen in histology
– Recruitment of inflammatory cells and activation of stellate cells
leads to the development of fibrosis Will eventually develop steatohepatitis

ADH: alcohol dehydrogenase

ALDH: acetaldehyde dehydrogenase
Alcohol (Toxic) Related Injury
Steatosis and hepatitis are reversible if you stop drinking.

10-15%

3 distinct but overlapping forms:

hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis
Alcohol (Toxic) Related Injury

Morphology Fatty liver is reversible.

– Fatty liver (microvesicular and macrovesicular steatosis)

– Alcoholic hepatitis (steatohepatitis)
• Hepatocyte swelling and necrosis
• Mallory bodies
• Neutrophilic reaction
• Fibrosis (sinusoidal fibrosis pattern)
• Alcoholic cirrhosis

Q: How long does it take the liver to heal after you stop drinking?
A: So, let's say you had a fun week, if you stop and don't totally abstain, within
a few days its totally back to normal.
Non-Alcoholic Fatty Liver Disease
Very similar histologically to alcoholic fatty liver.
No strong markers besides the clinical appearance of the patient - AST and ALT are only somewhat elevated.

• Strong association with the metabolic syndrome:

– Obesity, hyperlipidemia, hypertension and insulin resistance
– Little to no alcohol consumption
• Estimated that ~24% of the US population has NAFLD
– With the global “obesity epidemic” (affecting adults and children), it is
estimated that the prevalence of NAFLD will increase
– Can present with mild elevations in AST and ALT
• ~10-30% eventually develop cirrhosis
• Morphologic findings range from:
– Macrovesicular steatosis to steatohepatitis (NASH)
– Minimal pericellular fibrosis to cirrhosis
Same thing as seen
Steatohepatitis
with alcoholics.
Progression

Big balloon cells

Fibrosis (blue) pattern is rather unique. Fibrosis

starts surrounding individual cells that are
injured; called perisinusoidal or pericellular
fibrosis. Usually starts in zone 1 around terminal
hepatic vein and extends out from there.
 Drug Induced Injury

• The liver is the major drug metabolizing and detoxifying

organ
• Many drugs can cause liver disease through various
mechanisms:
– The drug or one of its metabolites is directly toxic to the liver.
– The drug reduces the immunologic or hormonal defense of the host.
– The drug or one of its metabolites becomes a hapten to
convert an intracellular protein into an immunogenic signal.
Examples that are important to know:
• Major hepatic drug reactions and some implicated agents
– Centrilobular necrosis: acetaminophen, halothane
– Microvesicular steatosis: tetracycline, salicylates
– Macrovesicular steatosis: ethanol, methotrexate
– Cholestasis (impaired bile formation): oral contraceptives
– Granuloma formation: sulfonamides
– Neoplasia
• Adenoma: oral contraceptives
• Thorotrast: Angiosarcoma and hepatocellular carcinoma
 Drug Induced Injury
Anisonucleosis -
variability in
nuclear size
Residual normal
portal tract and
some hepatocytes

Steatohepatitis
Dead tissue -
Tylenol toxicity

Residual central vein

Acetaminophen toxicity Methotrexate toxicity

 Normal Iron Homeostasis 1. Diferric transferrin in the
serum binds to the HFE
receptor on the hepatocyte
HFE/Transferrin
Receptor Decreased
complex serum iron
Serum Diferric
2. Binding of DT Transferrin
promotes hepcidin
release
Hepatocyte

Normally, iron is reg through a negative feedback

Promotes system.
secretion of Once this loop is dysregulated, you get problems.

Hepcidin
3. Hepcidin tells Inhibits iron
other cells absorption
(macrophages,
Serum Duodenal
dueodenal
Hepcidin
enterocytes) to start Enterocyte
storing iron 4. Iron storage
signals duodenum
to stop absorbing
Promotes iron
intracellular iron
storage Macrophage
•Adapted from 2006 Long Course at USCAP
 Hemochromatosis

• Hemochromatosis is characterized by excessive iron

accumulation in the body
– Excess iron is deposited in parenchymal organs such as
liver, pancreas, and heart
– Iron is directly toxic to the cells of these organs and
stimulates fibrosis
• Two types of hemochromatosis
– 1. Hereditary Hemochromatosis Primary. Usually due to a defective receptor.
– 2. Secondary Hemochromatosis (hemosiderosis)
• Parenteral intake (blood transfusions, i.e. sickle cell disease)
• Oral ingestion (“Bantu siderosis” or African iron overload)
Too much intake of iron can cause secondary hemochromatosis.
 Ab Normal Iron Homeostasis
Body iron stores
HFE/Transferrin
Receptor continuously
Decreased
complex increase
serum iron
Serum Diferric
Transferrin

Hepatocyte This receptor can be knocked out.

No hepcidin, no storage, no
cessation of absorption in
Promotes
No duodenum. Negative feedback
secretion of
Hepcidin
loop shut off, iron concentration
increases.
Hepcidin
Secreted Iron poor
Inhibits iron
cells
absorption
Serum Duodenal promotes
Hepcidin Enterocyte iron
absorption

Promotes
Decreased
intracellular iron
intracellular
storage
iron storage Macrophage
•Adapted from 2006 Long Course at USCAP
 Hereditary Hemochromatosis

• Autosomal recessive iron overload disorder

– Mutations in HFE gene on chromosome 6p.
• Cysteine-to-tyrosine mutation at position 282 (70%)
– Prevalent inherited genetic defect: allele frequency 6%
• Homozygosity 0.45% (1:220 persons), 11% heterozygosity (1:9
persons)
• Variable penetrance Many people have the gene but don't have disease
• Affects the liver, heart, pancreas, joint linings, endocrine
glands, and skin
– Can lead to cirrhosis, cardiomyopathy, pancreatic destruction
“bronze diabetes”, arthritis "Bronze:" iron deposits in the skin give a tanned color.
– Organ end-stage disease by fourth-to-fifth decade with heart
failure most common cause of death; increased risk of
hepatocellular carcinoma
Hereditary Hemochromatosis

Morphology
• Early changes:
– Iron deposition in periportal hepatocytes
• With disease progression: As iron accumulates:

– Iron deposition in the rest of the lobule, in bile ducts, and

Kupffer cells (macrophages)
– Fibrous septa develop and then micronodular cirrhosis
• Gold standard for diagnosis is quantitative iron analysis on
the liver biopsy Not just histology, need to check dry weight iron in the tissue.
• Treatment:
– Phlebotomy Works early on
– Transplantation Once patients are cirrhotic
Hereditary Hemochromatosis
Very dark pigmented inclusions in hepatocytes. Prussian blue stain on the right is specific for iron.
Alpha-1-Antitrypsin Deficiency
Remember emphysema?

• Autosomal recessive disorder

– Leads to low serum levels of a protease inhibitor- A1AT
• A1AT is a small glycoprotein synthesized in hepatocytes‟
endoplasmic reticulum (ER)
• Mutations result in an abnormally folded A1AT protein which
inhibits it from exiting the ER, produces cytoplasmic
accumulation and systemic deficiency
• Low serum levels permits uninhibited tissue destruction (e.g.,
pulmonary emphysema)
– Gene located on chromosome 14 (carrier rate 10%)
Alpha-1-Antitrypsin Deficiency
Various genotypes associated with the deficiency.

Genetics Serum A1AT Levels

M MM 100%
Z ZZ 10%
MZ 60%
S MS 80%
SZ 40%

Disease Associations:
• Emphysema (75%-85%)
• Hepatitis/Cirrhosis
• Panniculitis
• Anticytoplasmic neutrophilic antibody (C-ANCA) -
positive vasculitis (Wegener's granulomatosis)
Alpha-1-Antitrypsin Deficiency

• Hepatic syndromes are extremely variable ranging from

neonatal hepatitis, childhood cirrhosis and subclinical
chronic hepatitis Chronic hepatitis in adults.

• Treatment:
– Transplant (curative) You have removed the liver that can't excrete alpha-1-antitrypsin, new liver can.

Morphology
• Round/oval cytoplasmic globular inclusions in hepatocytes
– PAS-diastase (PASD) histochemical stain highlights the inclusions
• Can lead to advanced fibrosis and/or non-specific changes
• Neonatal (giant cell) hepatitis
Alpha-1-Antitrypsin Deficiency

Round cytoplasmic inclusions/

globules. PASD positive (see
upper right)

PASD

A1AT A1AT accumulating in hepatocytes

 Wilson Disease
Normal copper metabolism:
• Absorbed by the stomach/ duodenum; transported to the liver
• The liver incorporates Cu into ceruloplasmin and secretes
ceruloplasmin into the serum
• “Old” ceruloplasmin returns to the liver, is degraded, and the
copper is excreted into bile the
Willson Disease blocks the excretion of copper in the bile (at
end of this cycle)

• Wilson Disease is an autosomal recessive disorder which

creates a defective hepatocyte canalicular transporter
– ATP7B located on chromosome 13
– Cu accumulates in hepatocytes (hepatotoxic)
– Cu spills out into the circulation causing
hemolysis and pathologic changes in the
brain (deposits in basal ganglia) and eyes
(corneal deposits, “Kayser-Fleischer rings”)
K-F rings - arc of copper deposition around periphery of the iris
 Wilson Disease

• Clinical course:
– Acute hepatic failure: childhood to young adulthood
– Cirrhosis: adolescence to young adulthood
– Psychosis: adolescence to young adulthood

• Treatment:
– Chelation therapy (D-penecillamine)
Remove copper.

• Morphology
– Ranges from mild to severe :
• Cu accumulation
• Fatty change, hepatic necrosis
• With progression, cirrhosis can develop
Rhodanine stain
 Biliary Injury

• Primary Biliary Cirrhosis (PBC)

• Primary Sclerosing Cholangitis (PSC)
• Obstructive Biliary Disease (Secondary SC)
• Bile Duct Paucity (not addressed in this talk)
– Biliary Atresia
– Alagille Syndrome
– Drug related injury
• Hereditary Disorders
– Crigler-Najjar
– Gilbert Syndrome
– Dubin-Johnson
– Rotor Syndrome
– Progressive Familial Intrahepatic Cholestasis (PFIC)
 General Principles

• Hepatic bile serves 2 major functions

1. Elimination of bilirubin, cholesterol, and non-water soluble wastes
2. Bile salts promote emulsification and absorption of dietary fat in the gut
Bilirubin: breakdown product of heme

• Bile formation is a sophisticated function of hepatocytes

and is therefore is one of the most readily disrupted
Normal bile formation is one of the first things lost during hepatocellular injury

• Cholestasis = Retention of not only bilirubin but also other

solutes eliminated in bile (bile salts and cholesterol)
– Causes: a) Bile duct obstruction or b) Hepatic dysfunction
(non-obstructive) Can be due to damage to the hepatocyte itself or to the flow of bile.

• Jaundice = Yellow discoloration of skin and sclera

– Occurs when serum bilirubin levels get above 2 mg/dl [normal ~ 1.2 mg/dl]
Accumulation of bile in the system.
 •Bilirubin is derived from
the breakdown of RBCs
• Bilirubin is bound to
albumin in the serum and
transported to the liver
•In the liver is undergoes
conjugation and becomes
water-soluble and excreted
into the bile goes through
glucoronidation via UGTA1

•UGT1A1 enzyme
•Gut bacteria conjugates
Normal flora of the gut transforms the bilirubin and degrades it into
to colorless urobilinogens
urobilinogens, which gets
excreted in the feces
Once bilirubin is conjugated and secreted into
bile, it is water soluble
 Primary Biliary Cirrhosis
Autoimmune disorder. Targeted destruction of bile ducts. The presence of AMA antibodies and elevation of
LFTs is pathognomonic for this disorder. Don't have to do a biopsy.

• Chronic, progressive cholestatic liver disease caused by the

inflammatory destruction of intrahepatic bile ducts
– Autoimmune disorder- Anti-mitochondrial Ab (AMA), +/- ANA
• IgM Ab to pyruvate dehydrogenase complex- E2 subunit (PDC-E2)
found on the inner mitochondrial membrane

– Elevated Alkaline Phosphatase and γ-glutamyl transpeptidase

• Middle aged women primarily effected Like most autoimmune disorders:
middle-aged women.
– M:F
F:M 6-9:1 with a mean age 50-55

• Associations:
– Sjögren‟s syndrome, arthropathy, sicca
Remember the AMA antibodies - this is a key distinction she made between
PBC and Primary Sclerosing Cholangitis (in 3 slides)
 Primary Biliary Cirrhosis
Can be clinically silent until biliary cirrhosis develops.
Progressive, chronic disorder.

• Clinical features: Pruritis (itchiness) due to cholestasis

– Insidious, can present with pruritis, fatigue, and/or abdominal
discomfort
– Progresses over 10-20 years, ultimately developing cirrhosis

• Morphology Inflammation attacking the bile ducts spoecifically

– Portal inflammation with non-suppurative, granulomatous

destruction of medium-sized bile ducts (“Florid duct lesion”)
– Minimal to mild lobular hepatitis
– May have no cholestasis until late stages of the disease
– Cirrhosis develops in the final stage (biliary cirrhosis)
– Can overlap with autoimmune hepatitis
Lobular hepatitis is not a prominent feature; if you see a lot of this, you should start thinking about an overlap with
autoimmune hepatitis (remember: interface and lobular hepatitis).
• Treatment:
– Symptomatic (i.e. Ursodial) Potentially also immunosuppression

– Liver transplantation
Primary Biliary Cirrhosis

No obvious injury up here

Portal tract full of

Inflammation is infiltrating and
inflammation
destroying the epithelium, attacking
the bile duct

Bile duct: see high

power image on
right
Primary Sclerosing Cholangitis
The big differential: PBC from PSC.
Remember the sclerosis: choking off and fibrotically destroying the bile duct.
Because of the serial areas of sclerosis, you get the appearance below.

• Fibrotic and inflammatory

destruction of intra and extra- Strictures lead to
hepatic bile ducts beaded appearance

– Radiology- characteristic
“beading” and stricturing of
the biliary tree
– Elevated Alk Phos and GGT
LFTs aren't really going to help you

• Slight male predominance

– F:M ratio ~1:3
– Age range of 20-70 years

• Associations: Inflammatory
bowel disease (~70%)
– May occur before, during, or
after IBD onset (UC)
PSC
no AMA antibodies PBC
Normal or slightly abnormal LFTs AMA antibodies
Typically males, wide age range Elevated LFTs
Beaded appearance of bile duct Typically middle aged females
Fibrotic Inflammatory (granulomatous destruction)
Progresses to biliary cirrhosis Progresses to biliary cirrhosis
Associated with IBD, cholangiocarcinoma Associated with Sjogrens, arthropathy, etc. (autoimmune)
Primary Sclerosing Cholangitis
• Etiology and pathogenesis are largely unknown
– Autoantibodies are present in <10% of patients
Not generally considered an autoimmune disease; no autoantibodies specific for PSC

• Clinical Non-specific symptoms

– Symptoms include fatigue, pruritis

– Progressive clinical course which can lead to biliary cirrhosis
• Marked increased risk for cholangiocarcinoma Independent risk factor for bile
duct carcinoma
• Morphology:
– Concentric periductal “onion skin” fibrosis which leads to
fibrous obliteration of the duct A fibrotic process, not primarily inflammatory
– Modest lymphocytic portal infiltrate +/- copper accumulation
– Biliary cirrhosis
– Can overlap with autoimmune hepatitis Due to chronic
cholestasis

• Treatment:
– Symptomatic (Ursodiol)
– Liver Transplantation
Primary Sclerosing Cholangitis

Dense fibrosis
surrounding duct

Injured duct

Reticulin stain highlighting the dense fibrous network

Final progression: ball of fibrous

tissue where the duct once was
 Obstructive Biliary Disease

• Prolonged obstruction of the extrahepatic biliary tree (large

duct obstruction) can result in profound liver damage
– Most common cause is extrahepatic cholelithiasis . Gallstones
• Initial manifestations may include cholestasis, jaundice,
and/or abdominal pain
– Initial morphologic changes are reversible If the patient passes the stone.
– Over time: inflammation, bile duct and hepatocellular
damage, fibrosis and secondary biliary cirrhosis develop
• Subtotal obstruction may promote bacterial infection
of the biliary tree (Ascending cholangitis)
Large Duct Obstruction with
Ascending Cholangitis

Neutrophils in
lumen of bile duct.
Neutrophils come
up from hte gut, up
through the bile
duct, affecting the
liver
 Hereditary Disorders
Hereditary disorders involving the biliary system.

Defects in Bilirubin
Disorder Inheritance Metabolism Liver Pathology Clinical Course
UNCONJUGATED HYPERBILIRUBINEMIA
Crigler-Najjar AR Absent UGT1A1 activity None Fatal in neonatal period
Enzyme used to
syndrome type I Don't biopsy Buildup of unconjugated bilirubin
conjugate bilirubin
Crigler-Najjar AD with Decreased UGT1A1 None Generally mild, occasional
syndrome type II variable activity kernicterus
penetrance
Gilbert syndrome AR Decreased UGT1A1 None Innocuous (fluctuating)
activity
CONJUGATED HYPERBILIRUBINEMIA
Dubin-Johnson AR Impaired biliary Pigmented Innocuous
syndrome excretion of bilirubin cytoplasmic
The only one that glucuronides due to globules;
shows pathology! mutation in canalicular ?epinephrine
If you get a slide, multidrug resistance metabolites
it's this one. protein 2 (MRP2) Not bile
Rotor syndrome AR Decreased hepatic None Innocuous
uptake and storage?
Decreased biliary
excretion?
Dubin-Johnson syndrome

Intracellular
pigmented
accumulations
Normal
These are core
biopsies of liver; DJS
look green/brown -
obvious color change

DJS

DJS