127 - Patterns of Liver Injury 1: Pathology of Acute Hepatitis Flashcards
Definition of acute hepatitis
Elevation of serum transaminase enzymes for a period of less than 6 months duration, in a patient with no history of chronic liver disease.
Clinical features of acute hepatitis
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3
1) Malaise
2) Nausea
3) Jaundice with hepatitic profile of abnormal liver biochemistry (increased ALT).
Clinical signs of acute liver failure
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1) Encephalopathy
2) Hypoglycaemia,
3) Coagulopathy
Biopsies in hepatitis
Biopsies are not usually done unless the disease is severe,
the cause is uncertain, or there is concern for chronic liver
disease.
What can be the cause of clinical acute hepatitis?
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1) Acute hepatitis (pathological pattern)
2) Unsuspected chronic liver disease (including alcoholic liver disease)
3) Diffuse malignant infiltration of the liver (rare)
What is the pathological definition of acute hepatitis?
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1) A process with the same pathological changes in the liver as acute viral hepatitis
2) Acute hepatitis is a non-specific pattern of liver injury shared by many different causes
Causes of acute hepatitis 1 2 3 4 5
1) Acute viral hepatitis (not C - rarely acute)
2) Drug-induced liver injury
3) ‘Natural’ remedies
4) Autoimmune hepatitis
5) Ideopathic (seronegative, acute non-A, non-B hepatitis)
Hallmark features of acute hepatitis 1 2 3 4 5
1) Death of hepatocytes (apoptosis and necrosis).
2) Regeneration of hepatocytes to repopulate areas of hepatocellular death.
3) Absence of fibrosis.
4) Diffuse injury of hepatocytes
5) Resembles viral hepatitis (no neutrophil infiltrate)
Acinar zones
Division of liver lobule into three zones between portal vein and hepatic artery.
Why is the third acinar zone at particular risk of injury?
Concept of zone 3 as the “vulnerable zone” in a
range of situations (hypoxia, metabolic disorders, toxins, drugs, inflammatory conditions) because has low O2, enzymes.
Area of liver most at risk of injury
Acinar zone three
Effect on bile canaliculus of inflammation
Closes off canaliculus because heptaocyte swelling impinges on it
Mechanism of single cell death in hepatitis
Apoptosis
Mechanism of death of a group of adjacent cells in hepatitis
Necrosis
Appearance of apoptosis in acute hepatitis
Panlobular apoptosis of hepatocytes
Appearance of necrosis in acute hepatitis
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1) Appears first around central vein (zone three).
2) When necrosis is more extensive, becomes ‘bridging necrosis’. Bridges between portal vein and portal triad.
3) When very severe, multiacinar/multilobular necrosis (acute liver failure, will need a transplant)
How do hepatocytes undergo necrosis in acute hepatitis?
Undergo severe osmotic failure and burst.
You don’t see necrotic cells themselves, but the aftermath (collapse of liver reticulin framework and presence of scavenger macrophages in liver tissue)
Does coagulative necrosis arise from acute hepatitis?
No.
Gross appearance of a necrotic liver
Spots of pale (where hepatocytes are replicating).
Histological appearance of acute hepatitis 1 2 3 4 5
• Pan -lobular disarray: swollen liver cells, gaps
on liver cell plates.
• Apoptosis.
• Necrosis of variable extent depending on
severity.
• Aggregates of enlarged macrophages.
• Cholestasis.
Lobular disarray
Loss of architecture of liver from swelling of hepatocytes.
From water content, hepatocytes become pale pink (on an HE stain)
Sequelae of acute hepatitis
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- Resolution with restoration of normal structure and function.
- Massive hepatic necrosis – death or liver transplantation.
- Chronic hepatitis – HBV, autoimmune hepatitis and some drugs
Most important cause of toxic liver injury in the Western world
Deliberate overdose on paracetamol
Paracetamol toxicity
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- Intrinsic liver toxin (causes hepatocellular injury in a predictable and dose dependent fashion).
- Liver injury caused by a toxic metabolite (NAPQI) which directly injures hepatocytes and causes depletion of glutathione (a natural anti-oxidant).
- Necrosis occurs preferentially in zone 3 (this is where the enzyme CPY2E1 is located) but can be pan-acinar, multiacinar, or massive.
Why does liver necrosis occur preferentially in zone three of the liver acinus?
Because this is where the enzyme that metabolises paracetamol to a toxic metabolite (NAPQl) is preferentially expressed in zone three.
Features of paracetamol-induced liver necrosis
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1) Necrosis of hepatocytes in zone three
2) Necrosis is coagulative
3) Inflammation is minimal
Differences between paracetamol-induced liver necrosis and acute hepatitis
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1) Necrosis is in zone three with paracetamol. Hepatocellular swelling and apoptosis are pan-acinar in acute hepatitis
2) Necrosis is coagulative with paracetamol, lytic with acute hepatitis
3) Minimal inflammation with paracetamol. With acute hepatitis, inflammation present, variable severity, portal and lobular, mixed composition (lymphocytes, plasma cells, macrophages > neutrophils and eosinophils).
Physiological process that can lead to zone three necrosis
Chronic hypotension