Liver Pathology Class 1 2010

LIVER PATHOLOGY
CLASS 1
DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 1

Gross view:

Residing at the crossroads between the
digestive tract and the rest of the body, the
liver has the enormous task of maintaining
the body's metabolic homeostasis.

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR
DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, 4
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CANTLIE’S LINE

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Microscopic anatomy:

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Hepatic Parenchyma-1
Parenchyma – cribiform anastomosing sheets or

"plates" of hepatocytes.
There is a radial orientation of the hepatocyte cords

around the terminal hepatic vein.
Limiting plate.
Hepatocytes exhibit variation in size,
Nuclei may vary in size, number, and ploidy,

particularly with advancing age. Uninucleate

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Hepatic Parenchyma-2
Sinusoids. Hepatocytes are bathed on 2

sides by well-mixed portal venous and
hepatic arterial blood.
Space of Disse,
Kupffer cells .
Perisinusoidal stellate cells.

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Liver Cell plates

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Liver- Functions
1. Metabolic functions.
2. Synthetic functions.
3. Catabolic functions.
4. Storage functions.
5. Excretory functions.

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Metabolic functions
Control of synthesis and utilization of

carbohydrates, lipids and proteins.
The liver is the central organ of
glucose homeostasis,
maintaining blood glucose levels by

glycogenolysis and gluconeogenesis.

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Synthetic functions

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Catabolic functions
Endogenous substances, including
Hormones
Serum proteins to maintain a balance

production = elimination.
Exogenous substances - principal site for the

detoxification of foreign compounds
(xenobiotics).

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Storage functions
The liver is an important storage site for
●
Glycogen,
●
Triglycerides,
●
Iron, copper,
●
Lipid-soluble vitamins.

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Excretory functions
The principal excretory product of the liver is bile,

an aqueous mixture of
•
conjugated bilirubin,
•
bile acids, phospholipids,
•
cholesterol
•
electrolytes.
Bile is also vital for fat absorption.

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Liver function tests:
No single test is sufficient.
Battery of tests are always employed.
4 utilities:
1. Detect the presence of liver disease.
2. Distinguish among different types of liver disorders.
3. Measure the extent of known liver damage.
4. Follow up of response to treatment.

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Limitations:
1. Can be normal in patients with sever liver

disease – NASH, early stages of Chr. Liver
diseases.
2. Abnormal in diseases that does not affect liver.
3. Rarely suggestive of a specific diagnosis, only

could suggest a Hepatocellular / Cholestatic
disorder.

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Hepatocyte integrity Biliary excretory function

Cytosolic hepatocellular Substances normally
enzymes secreted in bile
••Serum aspartate ••Serum bilirubin

aminotransferase (AST) - OT ••Total
••Serum alanine ••Direct: conjugated only
aminotransferase (ALT) - PT ••Delta: linked to albumin
••Serum lactate dehydrogenase ••Urine bilirubin
(LDH) * ••Serum bile acids

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Plasma membrane Hepatocyte function Hepatocyte
enzymes Proteins secreted metabolism
(from damage to bile into the blood
canaliculus)
••Serum alkaline ••Serum albumin ••Serum ammonia

phosphatase ••Prothrombin time ••Aminopyrine breath
••Serum γ−γλυταµψλ (factors V, VII, X, test (hepatic
τρανσπεπτιδασε prothrombin, demethylation)
(ΓΓΤ) fibrinogen) ••Galactose elimination
••Σερυµ 5∋−
νυχλεοτιδασε

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EFFECTS OF INJURY ON THE LIVER TISSUE
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Pathology:
Vulnerable to a wide variety of insults.
May be Primary but more commonly Secondary in humans.
General features pertaining to liver diseases:
● General morphologic patterns of hepatic injury.
● Syndromes:
1. Jaundice & Cholestasis.
2. Hepatic failure &
3. Cirrhosis.

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General morphologic patterns of hepatic i
njury:
Degeneration & intracellular accumulations.
Necrosis and apoptosis.
Inflammation.
Regeneration.
Fibrosis.

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Degeneration & intracellular accumulatio
ns:
1. Ballooning degeneration.
• Hydropic or cloudy degeneration.
• Markedly swollen hepatocytes due to water influx.
2. Foamy degeneration.
• Result of injury due to cholestasis.
• Ballooning with cytoplasmic clumps.
• Retention of biliary material.

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ns:
3. Fatty degeneration – Steatosis.
Microvesicular Macrovesicular
No displacement of Nucleus is displaced

nucleus
Tetracycline toxicity Alcoholism
Reye’s syndrome Diabetes mellitus
Acute fatty liver of Kwashiorkor disease

pregnancy
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ns:
4. Other substances accumulated in liver.
•
Iron pigments.
•
Copper.
•
Enzyme – α1 antitrypsin.

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Necrosis & Apoptosis:
1. Single cell.
•. Apoptosis:
● Toxins / Immune mediated injury.
● Hepatocyte – shrunken, nucleus is pyknotic &

eosinophillic.
● Councilman bodies.

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2. Group of cells:
•. Coagulative necrosis:
•. Lytic necrosis:

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2. Group of cells.
•. Focal – irregular area of necrosis.
•. Zonal – certain zones of lobule.
● Centrilobular – alcoholism, drugs/ toxins.
● Midlobular / perilobular – acute fatty liver of

pregnancy.
•. Piecemeal – at the periphery near the portal tract.
● Chronic hepatitis.

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2. Group of cells.
•.
Extensive:
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Bridging.
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Submassive – entire lobule.
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Massive – entire liver parenchyma +
hepatic failure.

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Inflammation:
Site:
●
Portal.
●
Interface.
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Lobular.
●
Both.

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Inflammation:
Type of inflammatory cell:
●
Neutrophillic – alcohol, bile stasis, pyogenic
infection.
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Lymphocytic – viral infn.
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Plasma cells – autoimmune.
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Eosinophils – parasitic infn.

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Inflammation:
Granulomatous:
● TB / Leprosy / Syphilis / Sarcoidosis.

● Others :
1. Chronic hepatitis C.
2. PBC.
3. Foreign body.
4. Drugs.

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Regeneration:
Signs:
●
Binucleation.
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Mitosis.
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Basophillia.
Pattern - depends upon the reticulum network.
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If intact – completely normal.
●
If destroyed – regenerative nodules.

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Fibrosis:
Irreversible change.
Portal / Periportal – Schistosomiasis.
Septal – extension of portal fibrosis to the

lobule.
Perivenular.
Bridging fibrosis.
Cirrhosis.
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Ductular reaction:
Proliferation of intrahepatic biliary ductules

& canals of Hering in biliary diseases.
Associated with fibrosis and inflammation.

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CLINICAL SYNDROMES:

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JAUNDICE & CHOLESTASIS:

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Bilirubin metabolism:

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End product of heme degradation.
70 – 90% - senescent RBCs.
Heme [Heme oxygenase] Biliverdin
[Biliverdin reductase] Bilirubin.
Transported in plasma bound to albumin.

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Transfer from blood to bile – 4 distinct but

related steps:
1. Hepatocellular uptake.
2. Intracellular binding.
3. Conjugation.
4. Biliary excretion.

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1. Hepatocellular uptake.
Carrier-mediated uptake – carrier not specified yet.
2. Intracellular binding.
Binding as a nonsubstrate ligand to several of the

glutathion-S-transferases.

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3. Conjugation.
Bilirubin + Glucoronic acid [Bilirubin UDP

glucoronosyl transferase] Bilirubin
mono/di – glucoronide.
4. Biliary excretion.
Mono / diglucoronides are excreted into the

canaliculi mediated by MRP2, ATP
dependant .
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CB [intestinal bacteria in gut] colorless UBG.
UBG major part undergoes enterohepatic circulation.
A small part not taken up by liver reaches the

systemic circulation & is cleared by the kidneys.
UCB is normally not excreted into bile, except –
1. Neonates,
2. Sever unconjugated hyperbilirubinemia.
This UCB is partly reabsorbed.

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Jaundice & Cholestasis:
Bile has 2 functions:
Dietary fat absorption.
Excretion – bilirubin, excess cholesterol &

xenobiotics.
Jaundice – yellow discoloration of tissues due to

retention of bilirubin pigment.
Cholestasis – retention of bilirubin + all other

solutes.
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CAUSES OFJAUNDICE:
PREDOMINANTLY UNCONJUGATED HYPERBILIRUBINEMIA:
1. Excess production.
2. Reduced hepatic uptake.
3. Impaired conjugation.
PREDOMINANTLY CONJUGATED HYPERBILIRUBINEMIA:
4. Decreased hepatic excretion.
5. Impaired bile flow.

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UNCONJUGATED HYPERBILIRUBINEMIA
:
Excess production:
1. Hemolytic anemias.
2. Ineffective erythropoiesis syndromes.
3. Reabsorption from internal hemorrhage.
Reduced uptake:
4. Drug interference with membrane carrier systems.
5. Gilbert syndrome – some cases.

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UNCONJUGATED HYPERBILIRUBINEMIA
:
Impaired conjugation:
1. Neonatal jaundice.
2. Breast milk jaundice.
3. Genetic deficiency of bilirubin UGT activity.
4. Diffuse hepatocellular disease.

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CONJUGATED HYPERBILIRUBINEMIA:
Decreased hepatic excretion:
1. Deficiency in canalicular membrane transporters:
2. Dubin – Johnson syndrome.
3. Rotor syndrome.
4. Drug-induced canalicular membrane dysfunction.
5. Hepatocellular damage or toxicity.
Impaired intra- / extra-hepatic bile flow.:

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HEREDITARY HYPERBILIRUBINEMIAS:

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HEREDITARY HYPERBILIRUBINEMIAS:

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CHOLESTASIS:

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CHOLESTASIS:
Causes:
1. Hepatocellular dysfunction.
2. Intra- / extra-hepatic biliary obstruction.
Clinical manifestation:
3. Jaundice.
4. Pruritus.
5. Malabsorption & deficiency of vitamins A, D, E & K.

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CHOLESTASIS:
PATHOLOGY:
1. Accumulation of bile pigments in
2. Hepatocytes – foamy degeneration,
3. Canaliculi – canalicular plugging,
4. Kupffer cells.
5. Bile lake formation.
6. Bile duct proliferation.
7. Portal tract edema.
8. Neutrophillic infiltration.
9. Portal tract fibrosis – Cirrhosis.

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CHOLESTASIS:

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CHOLESTASIS:

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CHOLESTASIS:

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CHOLESTASIS:

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CHOLESTASIS:

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HEPATIC FAILURE

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HEPATIC FAILURE:
Most sever clinical consequence of liver disease.
Sudden & massive destruction.
End point of progressive liver damage
● Insidious destruction of hepatocytes,
● Repetitive discrete waves of parenchymal damage.
80 – 90% functional capacity must be lost.

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HEPATIC FAILURE:
Precipitating factors that decompensate liver are
● GI bleeding.
● Systemic infn.
● Electrolyte disturbance.
● Sever stress.
Prognosis – grave – 70 – 90% mortality.
Liver transplantation is only hope, rarely conservative.

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MORPHOLOGIC ALTERATIONS THAT CA
USE HF:
3 categories:
Chronic liver disease – MC route.
Massive hepatic necrosis.
Hepatic dysfunction without overt
necrosis.

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ETIOLOGIC AGENTS:
A. Viral:
Hepatotropic – HAV, HBV ± HDV, HEV.
Nonhepatotropic – HSV, CMV, EBV, HVZ, ADENOVIRUS.
B. Drugs & toxins:
Dose-dependant: Acetaminophen, CCl4, Yellow phosphorus, Amanita phalloides, Bacillus cereus toxin, Sulfonamides, Tetracycline,
Herbal remedies.
Idiosyncratic: INH, Rifampicin, Valproic acid, NSAIDs.
C. Vascular:
Right HF, Budd-Chiari syndrome, Veno-occlusive disease, Shock liver, Heat stroke.
D. Metabolic:
Acute fatty liver of pregnancy, Wilson’s disease, Reye’s syndrome, Galactosemia.
E. Chronic liver diseases :
Chronic hepatitis, ALD.
F. Miscellaneous:
A. Liver metastasis, Lymphoma, AI hepatitis.
G. Indeterminate: Primary graft non-function in liver transplanted patients.

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CLINICAL FEATURES:
Jaundice.
Hypoalbuminemia – edema.
Hyperammonemia.
Fetor hepaticus.
Palmar erythema.
Spider angioma.
Hypogonadism & gynaecomastia – males.
Coagulopathy.

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COMPLICATIONS:
1. Hepatic encephalopathy.
2. Hepatopulmonary syndrome.
3. Hepatorenal syndrome.

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HEPATIC ENCEPHALOPATHY:

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DEFINITION:
Portosystemic encephalopathy.
HE is a neuropsychiatric syndrome that

encompasses multiple manifestations
resulting from liver failure & / or
portosystemic shunting &
are potentially reversible with correction

of the underlying cause.
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CLASSIFICATION:

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PATHOGENESIS:
Specific cause – unknown.
Most important factors are
Sever hepatocellular dysfunction & / or
Intra-/extra-hepatic portosystemic shunting of blood by

passing the liver.
Various toxic substances absorbed from the intestine are

not detoxified by the liver.
Metabolic abnormalities in the CNS.

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Pathogenesis of Hepatic Encephalopathy
BRAIN
Porta systemic
shunts
LIVER
Toxic N2 metabolites
DEPARTMENT OF PATHOLOGY, MKCGFrom
MEDICAL Intestines
COLLEGE, BRAHMAPUR
PATHOGENESIS:
Neurotoxins commonly implicated:
Ammonia.
Mercaptans.
GABA.
Manganese.

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PATHOGENESIS:
Mechanism Hypothesis
Accumulation of toxins (ammonia, Impaired neural function through
mercaptans) cytotoxicity, cell swelling, and
depletion of glutamate
Enhanced GABAergic Neuronal inhibition through
neurotransmission stimulation of the GABA receptor
complex in postsynaptic membranes
Accumulation of false Increase in the ratio of plasma
neurotransmitters aromatic amino acids to branched-
chain amino acids results in an
increase in brain levels of aromatic
amino acid precursors of false
neurotransmitters

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PATHOGENESIS:
Precipitating factors:
Gastrointestinal bleeding.
Increased dietary protein.
Electrolyte disturbances – Hypokalemic

alkalosis.
Barbiturates, Benzodiazepines.

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Clinical Stages of Hepatic Encephalopathy
CLINICAL STAGES:
Impairment

Intellectual Function Neuromuscular Function
Clinical Stage
Normal examination Subtle changes on
Subclinical findings, but work or driving psychometric or number
may be impaired connection tests
Impaired attention, Tremor, incoordination,
Stage 1 irritability, depression, or apraxia
personality change
Drowsiness, behavioral Asterixis, slowed or slurred
Stage 2 changes, poor memory and speech, ataxia
computation, sleep disorders
Confusion and Hypoactive reflexes,
Stage 3 disorientation, somnolence, nystagmus, clonus, and
amnesia muscular rigidity
Stupor and coma Dilated pupils and
decerebrate posturing;
oculocephalic (“doll's eye”)
Stage 4
reflex; absence of response
to stimuli in advanced
stages

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DIAGNOSIS:
1. Acute / chronic hepatocellular disease &/or
extensive portosystemic shunts.
2. Disturbances of awareness & mentation,

forgetfulness & confusion stupor
coma.
3. Neurologic signs: Asterixis, rigidity, hyperreflexia,

plantar extensor & seizures.
4. Charcteristic symmetric, high-voltage, triphasic

slow-wave pattern on the EEG.
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HEPATOPULMONARY SYNDROME:

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1. Hypoxemia, platypnea & orthodeoxia.
2. Due to right-to-left intrapulmonary shunts

through dilatations in intrapulmonary
vessels.
3. Mechanism of shunt formation – unclear.

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HEPATORENAL SYNDROME:

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1. Serious complication.
2. Functional renal failure.
3. Characterized by
worsening azotemia with avid sodium
retention & oliguria,
Absence of identifiable specific cause of renal
dysfunction.
4. Exact basis – not known, possibly altered
renal hemodynamics.
5. No histopathological abnormality.
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CIRRHOSIS:

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CIRRHOSIS
Term was 1st coined by Laennec in 1826.
Many definitions but common theme is injury, repair,

scarring and regeneration.
NOT a localized process; involves entire liver.
Primary histologic features:
1. Marked fibrosis
2. Destruction of vascular & biliary elements
3. Regeneration
4. Nodule formation
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Definition:
Diffuse, chronic, progressive, end stage disorder of liver
characterised by;
1. Complete loss of normal architecture,
2. Extensive fibrosis with,
3. Regenerating parenchymal nodules.
Additional features:
1. Necrosis ±.
2. Inflammation – variable degree.
3. Proliferating bile ducts.

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Definition:
Focal injury with scarring does not constitute
cirrhosis.
Not also diffuse nodular transformation without
fibrosis.
Nodularity is part of the diagnosis and reflects the
balance between regenerative activity and
constrictive scarring.
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Definition:
Vascular architecture is reorganized - with the formation
of abnormal interconnections between vascular inflow and
hepatic vein outflow channels -blood partially bypasses
the functional hepatocyte mass.
Fibrosis is the key feature of progressive damage to the

liver.
Once cirrhosis has developed, reversal is thought to be

rare.

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Normal Liver

Cirrhosis

Normal Liver Histology
CV
PT

Cirrhosis
Fibrosis
Regenerating Nodule

Etiology of Cirrhosis
Alcoholic liver disease 60-70%
Viral hepatitis 10%
Biliary disease 5-10%
Primary hemochromatosis 5%
Cryptogenic cirrhosis 10-15%
Wilson’s, 1AT def rare

● Storage diseases.
● Diffusely infiltrative cancer.
● Veno-occlusive disease
● Autommune
● Drugs and toxins
● Metabolic diseases

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Classification of Cirrhosis:
Morphologic classification:
– Micronodular.
– Macronodular.
– Mixed.

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Micronodular Cirrhosis
Nodules are <3 mm in diameter.
Relatively uniform in size.
Distributed throughout the liver.
Rarely contain portal tracts or efferent veins.
Liver is of uniform size or mildly enlarged.
Reflect relatively early disease.
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Micronodular cirrhosis

Micronodular cirrhosis:

Macronodular & Mixed Cirrhosis
Nodules are >3 mm in diameter and vary
considerably in size.
Usually contain portal tracts and efferent veins.
Liver is usually normal or reduced in size.
Mixed pattern if both type of nodules are present in

equal proportions.
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Macronodular Cirrhosis

Pathogenesis:
• Alcohol, virus, drugs, toxins etc..
Primary event is injury to hepatocellular elements:
Necrosis of hepatocytes.
Collapse of reticulin network.
Activation of Kupffer cells.
Release of cytokines & proinflammatory substances -

initiates inflammatory response.

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Pathogenesis:
Cytokines are produced by
Chronic inflammatory cells – TNF α, TGF β & IL1.
Endogeneous cells – Kupffer cells, endothelial cells etc – PDGF,

TNF, ET1 & MCP 1.
Stimulate HSC – myofibroblastic property.
Collagen production & deposition – fibrous scars.
Surviving hepatocytes proliferate to form spherical nodules.

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Pathogenesis:
Primary cell responsible for fibrosis is

stellate cell.
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Pathogenesis:
Normal liver
Interstitial collagen i.e. type I & III are concentrated

in portal tracts and around central veins with
occasional bundles in the space of Disse.
Hepatocytes are supported by delicate strands of

type IV collagen (reticulin).

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Pathogenesis:
In cirrhosis
type I & III collagen is deposited in the lobule – delicate to broad

septal tracts.
New vascular channels in the septa connect branches of portal vein /

hepatic artery to central vein – PORTOSYSTEMIC SHUNTING.
Continued deposition of collagen in the space of Disse – loss of

fenestrations – impairment of exchange of substances between blood
& hepatocytes.

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Clinical Features:

Clinical Features
Hepatocellular failure.
Malnutrition, low albumin & clotting factors -

bleeding.
Hepatic encephalopathy.
Portal hypertension.
Ascites, Porta systemic shunts, varices,

splenomegaly.

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Lab findings:
Hyperbilirubinemia±.
ALP – raised.
AST & ALT – raised. [AST/ALT > 2 suggest alcoholic cirrhosis.]
Sr albumin – decreased.
Sr globulin – raised.
Blood ammonia – increased.
Glucose intolerance – endogeneous insulin resistance.

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Lab findings:
Electrolyte imbalance.
Anemia
GI blood loss.
Folic acid & B12 deficiency.
Hypersplenism.
PT – prolonged.

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Liver Biopsy – Cirrhosis

Liver Biopsy – Cirrhosis:

Complications:
Portal hypertension.
Congestive splenomegaly.
Bleeding varices.
Ascites, SBP.
Coagulopathy.
Hepatocellular failure.
Hepatic encephalopathy / hepatic coma.
Hepatocellular carcinoma.

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Portal Hypertension
Portal Hypertension (PH)
Portal vein pressure, normal range - 5 to 8

mm Hg.
PH if
PVP > 10 mm of Hg.
Portal vein - Hepatic vein pressure gradient
greater than 5 mm Hg (>12 clinically
significant).
Represents an increase of the hydrostatic
pressure within the portal vein or its
tributaries.
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Portal Hypertension (PH)
Portal vein pressure, normal range - 5 to 8

mm Hg.
PH if
PVP > 10 mm of Hg.
Portal vein - Hepatic vein pressure gradient
greater than 5 mm Hg (>12 clinically
significant).
Represents an increase of the hydrostatic
pressure within the portal vein or its
tributaries.
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Pathophysiology of PH
Portal tract NO valves.

Resistance at any level between right side
heart & splanchnic vessels cause – PH.
In relation to sinusoids resistance can occur at
3 levels:
●
Presinusoidal.
●
Sinusoidal.
●
Postsinusoidal.
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1. Presinusoidal:
Outside the liver – PV thrombosis.
Within the liver – proximal to sinusoids
with normal parenchyma –
Schistosomiasis.
2. Sinusoidal: CIRRHOSIS.
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3. Postsinusoidal: at the level of

Hepatic veins – Budd Chiari syndrome.
IVC.
Within the liver – Veno-occlusive disease.
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Causes of PH
1. Cirrhosis – MC.
2. Portal vein obstruction:
3. Idiopathic – PCV, ET, Def of Pr C, Pr S / AT III.
4. Infection, Pancreatitis, Abd trauma.
5. Budd – Chiari syndrome.

6. Hepatic veno-occlusive disease.
7. Non-cirrhotic portal fibrosis.
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Clinical features of PH
Due to Porto-systemic shunting.

Variceal bleeding.
Splenomegally with hypersplenism.
Ascites.
Hepatic encephalopathy.
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Ascites
Definition:
Accumulation of excess fluid within the

peritoneal cavity.
Common causes:
Cirrhosis.
Congestive heart failure.
Nephrotic syndrome.
Diffuse carcinomatosis.
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Pathogenesis in Cirrhosis:
PH – raised hydrostatic pressure in the splanchnic bed.
Hypoalbuminemia – decreased plasma oncotic pressure.
Weeping of hepatic lymph from surface of liver – distortion &
obstruction of sinusoids & lymphatics.
Renal retention of Na+ & H2O – secondary
hyperaldosteronism.
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Ascitis in Cirrhosis

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INFECTIOUS DISEASES OF LIVER

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HEPATITIS
Ancient Greek hepar or hepato, - liver, and
suffix -itis, meaning "inflammation".
Hepatitis implies injury to the liver
characterized by the presence of inflammatory
cells in the tissue of the organ.

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Infectious Disorders
Among inflammatory disorders, infections are
by far the most frequent.
Toxins, certain drugs, heavy alcohol use,

autoimmune diseases, etc are the other causes.
Invariably blood-borne infections
systemic or
local abdominal.

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Infectious agents can be grouped to
Viral
Bacterial – Salmonellosis, Staphylococcal

bacterimia, Milliary tuberculosis.
Fungal – Candida.
Protozoal – Malaria, Amebiasis & Hydatid cyst.

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Viral Hepatitis

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2 groups
Systemic viral diseases:
EBV – Infectious mononucleosis,
CMV – in newborn & immunosuppressed patients,
Yellow fever virus,
Rare causes – Rubella, Adenovirus, Herpes virus,

Enterovirus.

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137
Hepatotropic viruses:
Group of viruses having affinity for liver.
“Viral hepatitis”
Overlapping pattern of disease.
HAV, HBV, HCV, HDV, HEV & HGV.

138
138
Viral Hepatitis - Historical Perspec
tive
“Infectious” A Enterically
E
transmitted
Viral NANB
hepatitis
Parenterally
“Serum” B D C transmitted
F, G,
? other
139
139
HAV HBV HCV HDV HEV
ssRNA, ssRNA,
dsDNA, ssRNA, ssRNA,
Agent Icosahedral Unenvelop
Enveloped Enveloped Enveloped
capsid ed
Parenteral, Parenteral, Parenteral,
Transmissi Waterborn
Fecal-oral Close Close Close
on e
contact contact contact
Incubation 4 – 26 2 – 26
2 – 6 weeks 4 – 7 weeks 2 – 8 weeks
period weeks weeks
0.1 – 1.0% 0.2 – 1.0%
1 – 10% in
of blood of blood
drug
Carrier donors in donors in
None addicts & Unknown
state USA & USA &
hemophilia
Western Western
cs
world world
<50%
5 – 10% of coinfection
Chronic
None acute >50% , 80% upon None
hepatitis
infections superinfect
ion
No Unknown140
140
Hepatitis A Virus

141
141
A benign, self-limited disease.
Infectious hepatitis.
Does not cause chronic hepatitis or a carrier state and
rarely causes fulminant hepatitis
HAV is a small, nonenveloped, single-stranded RNA

picornavirus that occupies its own genus, Hepatovirus.

142
142
Second level
●
Third level
●
Fourth level
●
Fifth level

143
143
Shed in the stool for 2 to 3 weeks before and 1
week after the onset of jaundice.
Close personal contact with an infected individual or

fecal-oral contamination – developing countries.
By the consumption of raw or steamed shellfish –

Western world.
HAV viremia is transient.

144
144
Immunopathogenesis:
Does not have any cytopathic effect.
Host immune response is the cause for
the necroinflammatory lesion seen.
Activated T cell secrete γ-INF that promote
the representation of HLA-Ⅰantigen on the
liver cells,CTL may kill the target cell

145
145
146
Serologic Diagnosis:
IgM anti-HAV - at the onset of symptoms - a reliable
marker of acute infection.
Fecal shedding of the virus ends as the IgM titre rises.
IgM titre declines in a few months and is followed by the

appearance of IgG anti-HAV.
IgG anti-HAV – provides life long protective immunity

against all strains of HAV.
Hence, the HAV vaccine is effective.

147
147
Hepatitis B Virus

148
148
A partially double stranded DNA virus.
Genus – Hepadnaviridae.
Australia antigen .
Serum hepatitis.
Hardy virus can withstand extreme

temperature & humidity.
A serious form of hepatitis which may proceed

to chronic
DEPARTMENT state
OF PATHOLOGY, and
MKCG MEDICAL possibly
COLLEGE, BRAHMAPUR cirrhosis and
149
149
HBV remains in blood during the
last stages of the incubation period and
active episodes of acute and chronic

hepatitis.
Present in all physiologic and pathologic

body fluids, with the exception of stool.

150
150
Modes of spread:
In endemic region: Vertical transmission.
In low prevalent region: Horizontal

transmission: a. Blood & blood products, b.
Needle stick injuries in health care workers, c.
Intravenous drug abuse & d. Sexual contact.

151
151
The genome of HBV is a partially double-
stranded circular DNA molecule of 3200
nucleotides that encodes:

152
152
1. HBcAg - Hepatitis B core antigen
2. HBeAg - hepatitis B "e" antigen
3. HBeAg is secreted into blood and is

essential for the establishment
of persistent infection.

153
153
3. HBsAg - Hepatitis B surface antigen.
4. A DNA polymerase with reverse
transcriptase activity.
5. HBV-X protein, which acts as a
transcriptional transactivator for
many viral and host genes.

154
154
The virus has 2 phases:
Proliferative, in which the virus replicates
with presence of antigens.
Integrative, in which antibodies are found

155
155
Immunopathogenesis:
HBcAg, HBsAg, HBeAg are expressed on the
infected liver cells along with the HLA- I
receptor which are recognized by CTL leads to
the cytolysis of liver cells.
Helper T cells are activated - stimulate B cells

to release anti-HBs and clear HBV.
The expression of HBcAg on the liver cells may

cause cytopathy.
156
156
Immunopathogenesis:
Excess production & accumulation of HBsAg within
liver cells lead to ground-glass change of liver
cells.
Ag-Ab complexes are precipitated on the wall of

blood vessels and glomerular basement
membranes causing GN.
Chronicity of hepatitis B is related to immune

tolerance, immune suppression and genetic
factors.
157
157
Spectrum of disease manifestation:

158
158
Serologic diagnosis of Hepatitis B:

159
159
Hepatitis C Virus

160
160
HCV - Sources of Infection
Injecting drug use 60%

Sexual 15%
Transfusion 10%
(before screening)
Other* 5%
Unknown 10%
*Nosocomial;
Source: Centers for Disease Control and Prevention Health-care work;
Perinatal
161
ssRNA virus – Flaviviridae, 6 genotypes.
Long incubation period similar to HBV.
One of the major causes of chronic liver disease.
Contaminated blood transfusion & Intravenous

drug abuse - common mode of transmission.
Sexual & vertical transmission – low.
Persistent infection is the hallmark of HCV

infection – 80 – 85% of subclinical or asymptomatic
infections.

162
162
Immunopathogenesis:
Cause of failure in large proportion of patients
to permanently eradicate the virus is unclear.
Similar to the HBV, several arms of the
immune system are essential for orchestrating
the viral clearance.

163
163
Self limited disease:
Multispecific vigorous intrahepatic CD4 & CTL response is seen.
CD4 cells induce production of IFN γ & maturation of CTL.
CTL’s – cytolytic & noncytolytic activities.
Cytolytic response – Acute hepatitis.
Nonimmunologic gene like genes associated with lipid

metabolism have a role in viral clearance.

164
164
Chronic cases:
The HCV specific CTL response targets both
infected & noninfected hepatocytes through the
release of proapoptotic Fas ligand & TNF α.
Also antigen nonspecifc T cells are recruited.

165
165
Spectrum of disease manifestation:

166
166
Serologic diagnosis of Hepatitis C:

167
167
Hepatitis D Virus

168
168
Delta agent – incomplete virus.
Replication defective, can cause infection only

when HBs Ag is avilable.
Infection occurs in 2 settings:
1. Co-infection
2. Super-infection

169
169
Fate is different in both:
Coinfection – complete recovery.
Superinfection – progression to chronic liver

disease with increased severity.

170
170
Second level
●
Third level
●
Fourth level
●
Fifth level

171
171
Second level
●
Third level
●
Fourth level
●
Fifth level

172
172
Hepatitis E Virus

173
173
ss RNA unenveloped virus – Calcivirus.
Similar to HAV in many aspects.
Fulminant hepatic failure in pregnant
women.

174
174
175
Commonly Encountered Serologic Patterns of
Hepatitis B Infection
HBsAg Anti-HBs Anti-HBc HBeAg Anti-Hbe Interpretation
+ - IgM + - Acute HBV infection,
high infectivity
+ - IgG + - Chronic HBV infection,

high infectivity
Late-acute or chronic
+ - IgG - + HBV infection, low
infectivity
- - IgM +/- +/- Acute HBV infection

window period
1. Low-level HBsAg
- - IgG - +/- carrier
2. Recent past infection
- + IgG - +/- Recovery from HBV

infection
1. Immunization with
HBsAg (after
- + - - -
vaccination)
2. Remote past
infection (?)
176
Clinical Features and Outcomes
of Viral Hepatitis:

177
177
1. Asymptomatic acute infection.
2. Acute hepatitis: Anicteric or Icteric.
3. Chronic hepatitis + / - cirrhosis.
4. Chronic carrier state: asymptomatic without
apparent disease.
5. Fulminant hepatitis: submassive to massive
hepatic necrosis with acute liver failure.

178
Asymptomatic Infection :
•
Identified only incidentally on the basis of:
•
Investigation of minimally elevated serum
aminotransferases or
•
By the presence of antiviral antibodies.
179
Acute Viral Hepatitis :
•
Any one of the hepatotropic viruses can cause.
•
Acute hepatitis, whatever the agent, can be divided
into four phases:
•
An incubation period,
• A symptomatic preicteric phase (Prodromal phase).
• A symptomatic icteric phase (with jaundice and scleral

icterus), and
• Convalescence.
180
ACUTE VIRAL HEPATITIS CLINICAL FEATURES
Prodromal Symptoms:
systemic and quite variable.
constitutional symptoms: anorexia, nausea, vomiting,

fatigue, malaise, arthralgia, myalgia, headache,
photophobia, pharyngitis, cough, coryza.
precedes jaundice 1-2 weeks.
181
Acutehep-diffuse
Clinical Jaundice:
constitutional prodromal symptoms usually diminish
mild weight loss  2.5-5 kg in some
enlarged, tender liver + RUQ pain and discomfort
cholestatic feature infrequently  extrahepatic biliary obstruction
spider angiomas.
183
Recovery Phase:
constitutional symptoms disappear.
some liver enlargement and biochemical abnormalities evident.
duration variable: 2-12 weeks.
Complete biochemical and clinical recovery expected:
1-2 months: Hepatitis A and E
3-4 months: 3/4 uncomplicated cases of Hepatitis B
and C.
184
ACUTE VIRAL HEPATITIS LABORATORY FEATU
RES
Serum Aminotransferases: AST, ALT
variable  during prodrome
precedes rise in bilirubin
acute level does NOT correlate well with degree of liver cell damage.
peak levels: 400 4,000 IU.
185
RES
Jaundice: (+) serum bilirubin > 2.5 mg/dl.
The jaundice is caused predominantly by conjugated

hyperbilirubinemia - dark-colored urine.
• With hepatocellular damage and consequent defect in bilirubin

conjugation, unconjugated hyperbilirubinemia can also occur.
• The stools may become light colored due to cholestasis, and the
retention of bile salts may cause distressing pruritus.
186
RES
Neutropenia
transient followed by lymphocytosis
Lymphopenia
Atypical lymphocytes
Prothrombin time - if   worse prognosis
Hypoglycemia
Normal or mild  alkaline PO4tase
Mild  gamma globulin.
187
Pathology - Acute Hepatitis :
Gross: Enlarged, reddened liver; greenish if cholestatic.
Microscopic:
Hepatocyte injury: swelling (ballooning degeneration).
Cholestasis: canalicular bile plugs.
Mild fatty change – HCV.
Hepatocyte necrosis: isolated cells or clusters.
● Cytolysis or apoptosis
● If severe: bridging necrosis
● Lobular disarray: loss of normal architecture
188
Pathology - Acute Hepatitis :
Regenerative changes: hepatocyte proliferation
Kupffer cell proliferation with phagocytosed debris in

cytoplasm.
Influx of mononuclear cells into sinusoids
Portal tracts inflammation: predominantly mononuclear
Inflammatory spillover into adjacent parenchyma, with

hepatocyte necrosis.
189
Chronic Hepatitis :
•
Represents a group of liver disorders of
•
varying causes and severity,
•
hepatic inflammation and necrosis continue for
more than 6 months,
•
evidenced by symptomatic, biochemical, or serologic
markers &
•
histological documentation of inflammation and necrosis.
190
Chronic Hepatitis :
•
MC cause - the hepatitis viruses.
•
Many other causes:
– chronic alcoholism,
– drugs (isoniazid, α-methyldopa, methotrexate),
– autoimmunity ,
– Wilson disease and
– α1-antitrypsin deficiency.
191
Chronic Hepatitis :
●
Progression to chronic progressive hepatitis and
end stage liver disease is determined by:
• Etiologic agent
• And not by the clinical features or the histologic

pattern at the time of diagnosis.
●
Example: HCV is notorious for causing a chronic
hepatitis evolving to cirrhosis in a significant
percentage of patients regardless of histologic
features at the time of initial evaluation.
192
Chronic Hepatitis :
Classification by cause:
1. Chronic Viral hepatitis caused by Hepatitis B,
B + D, C.
2. Autoimmune hepatitis.
3. Drug-associated chronic hepatitis.
4. Cryptogenic chronic hepatitis = unknown cause.

193
Chronic Hepatitis :
Classification by cause:
1. Chronic Viral hepatitis caused by Hepatitis B,
B + D, C.
2. Autoimmune hepatitis.
3. Drug-associated chronic hepatitis.
4. Cryptogenic chronic hepatitis = unknown cause.

194
Chronic Hepatitis :
Classification by grade: based upon examination of
liver biopsy – HISTOLOGICAL ACTIVITY INDEX:
a. Necrosis - periportal necrosis/ piecemeal

necrosis / interface hepatitis / bridging necrosis.
b. Intralobular necrosis.
c. Degree of portal inflammation.
d. Fibrosis.
195
Chronic Hepatitis :
Classification by stage:
reflects level of progression of disease.
based on degree of fibrosis
●
0 = no fibrosis.
●
1 = mild fibrosis.
●
2 = moderate fibrosis.
●
3 = severe fibrosis, including bridging fibrosis.
●
4 = cirrhosis.
196
Histologic Staging
Stage 0 Stage 1 Stage 2

No Fibrosis Portal Fibrosis Few septa
Stage 3 Stage 4
Numerous septa Cirrhosis

197
Chronic Hepatitis :
●
Laboratory studies:
●
Hyperbilirubinemia, and mild elevations in
alkaline phosphatase levels.
●
Prolongation of the prothrombin time.
●
Hypergammaglobulinemia,
●
Cryoglobulinemia is found in as many as 50%
of individuals with hepatitis C.
●
Viral markers.
198
Pathology - Chronic Hepatitis :
Changes shared with acute hepatitis:
Hepatocyte injury, necrosis, apoptosis, and regeneration
Sinusoidal cell reactive changes
Portal tracts
Inflammation:
● Confined to portal tracts, or
● Spillover into adjacent parenchyma, with necrosis of hepatocytes ("interface

hepatitis"), or
● Bridging inflammation and necrosis
Fibrosis:
● Portal or Portal and periportal deposition or bridging fibrous septa.
199
Pathology - Chronic Hepatitis :
Cirrhosis: the End-Stage Outcome
HBV: ground-glass hepatocytes (accumulation of HBsAg)
HCV: bile duct epithelial cell proliferation, lymphoid aggregate
formation
200
groundglass hepatocyte1
chr hep lymphoid aggregate
Chronic Hepatitis :
●
The clinical course is highly variable.
• Spontaneous remission.
• Indolent disease without progression.
• Rapid progressive disease and develop cirrhosis

within a few years.
●
The major causes of death:
• Hepatic failure & encephalopathy,
• Massive hematemesis from esophageal varices,
• Hepatocellular carcinoma.
203
The Carrier State :
●
A "carrier" is an individual without manifest
symptoms who harbors and therefore can
transmit an organism – RESERVOIR OF
INFECTION.
●
With hepatotropic viruses, carriers are:
• Those who harbor one of the viruses but are

suffering little or no adverse effects, and
• Those who have nonprogressive liver damage but

are essentially free of symptoms or disability.
204
The Carrier State :
●
Vertical transmission of HBV - produces a
carrier state 90% to 95% of the time.
●
In contrast, only 1% to 10% of HBV infections
acquired in adulthood yield a carrier state.
●
Individuals with impaired immunity are
particularly likely to become carriers.
●
HCV carrier state - 0.2% to 0.6% of the
general US population.
205
Fulminant Hepatitis :
●
Acute liver failure, resulting from massive
hepatic necrosis - very small proportion of
patients with acute hepatitis A, B, or E.
●
Subacute hepatic necrosis - both massive
necrosis and regenerative hyperplasia.
●
As discussed later, drugs and chemicals can
also cause massive hepatic necrosis
206

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LIVER PATHOLOGY

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 1

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 2

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 3

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, 5

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, 8

Parenchyma – cribiform anastomosing sheets or

There is a radial orientation of the hepatocyte cords

Hepatocytes exhibit variation in size,

Nuclei may vary in size, number, and ploidy,

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 12

Sinusoids. Hepatocytes are bathed on 2

Perisinusoidal stellate cells.

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 13

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, 15

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 17

Control of synthesis and utilization of

The liver is the central organ of

maintaining blood glucose levels by

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 18

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 19

Endogenous substances, including

Serum proteins to maintain a balance

Exogenous substances - principal site for the

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 20

The liver is an important storage site for

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 21

The principal excretory product of the liver is bile,

Bile is also vital for fat absorption.

Battery of tests are always employed.

1. Detect the presence of liver disease.

2. Distinguish among different types of liver disorders.

3. Measure the extent of known liver damage.

4. Follow up of response to treatment.

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 23

1. Can be normal in patients with sever liver

2. Abnormal in diseases that does not affect liver.

3. Rarely suggestive of a specific diagnosis, only

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 24

Hepatocyte integrity Biliary excretory function

••Serum aspartate ••Serum bilirubin

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 25

••Serum alkaline ••Serum albumin ••Serum ammonia

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 26

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 27

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, 28

Vulnerable to a wide variety of insults.

May be Primary but more commonly Secondary in humans.

General features pertaining to liver diseases:

● General morphologic patterns of hepatic injury.

1. Jaundice & Cholestasis.

2. Hepatic failure &

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 29

Necrosis and apoptosis.

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 30

• Hydropic or cloudy degeneration.

• Markedly swollen hepatocytes due to water influx.

• Result of injury due to cholestasis.

• Ballooning with cytoplasmic clumps.

• Retention of biliary material.

DEPARTMENT OF PATHOLOGY, MKCG MEDICAL COLLEGE, BRAHMAPUR 31

No displacement of Nucleus is displaced

Reye’s syndrome Diabetes mellitus