32. Pathology of Hepatitis Flashcards
Describe normal liver architecture.
Which hepatocytes have the best perfusion of 02 and nutrients?
- Hepatocytes: arranged in lobules and acini
- Lobule: hepatocytes in radial pattern from central vein out, bordered by portal triad.
- Hepatocytes adjacent to portal vasculature have best perfusion.
- Hepatocytes closest to Central Vein have least nutrition and O2, more susceptible to ischemic injury.
- We refer to the hepatocytes as being in Zones. Zone 1 = peri-portal (good perfusion). Zone 3 = CV (least perfusion)
Contents of the portal triad?
Portal vein
Hepatic artery
Bile duct
Acute Hepatitis: what is occuring histologically?
Acute:
Parenchyma is full of inflammatory cells, which are well-distributed. Hepatocytes show degeneration: “ballooning” degeneration which leads to apoptosis.
Inf cells are mainly lymphocytes.
Necrotic debris taken up by macrophages.
Damage stops eventually & liver can regenerate.
Chronic Hepatitis: what is occurring histologically?
Chronic:
Fewer inflammatory cells than with acute.
Some inf cells in lobules, but fewer. Some inf cells also in portal tracts –> “smoldering” inflammation.
Causes damage over years to hepatocytes at portal tract, leads to loss of hepatocytes, replacement by fibrous tissue.
Fibrous septae connect one portal tract to another, eventually sealing off lobules & forming cirrhosis/cirrhotic nodules. Slow, smoldering process.
Acute or Chronic?
Acute
- Diffuse lobular inflammation and necrosis
- Inflammatory cells = lymphocytes (SWARMING), macrophages and hyperplastic Kupffer cells
- Hydropic/ballooning degeneration and apoptosis of hepatocytes
- Regeneration of hepatocytes (which is why they look darker and smaller)
Causes of acute hepatitis?
- Hepatotropic viruses: A, B, C, D, E
- Non-hepatotropic viruses: EBV, CMV, Herpes simplex, Herpes Zoster, Adenovirus, etc
-Drug-induced
Acute or chronic? What’s at the arrow?
Acute Viral Hep
Ballooning degeneration–> apoptotic/acidophilic body (arrow) – evidence of hepatocyte injury
Acute or chronic? what’s in the circle?
Acute viral Hep
Spotty Necrosis: confluence of several damaged/necrotic hepatocytes, with inf cells scattered throughout.
See more of these in acute hep than in chronic hep.
Acute or Chronic?
What’s notable?
Acute
Severe inflammation leading to centrilobular necrosis.
Apoptotic hepatocytes, acidophilic bodies scattered throughout (red balloon-like cell), lymphocytes.
Acute or Chronic? Notable?
Acute
More severe than centrilobular necrosis: bridging necrosis. Hepatocytes damaged around CV, form bridge between CV and portal triad - or between one CV to another CV.
Acute or Chronic? Notable?
Acute. See this esp in drug-induced hepatitis.
Submassive: some remaining hepatocytes, ductal reactions in between, liver has tried to regenerate ductules. Usually first things regenerated = ductules.
Acute or Chronic? Notable?
Acute. See this esp in drug-induced hep.
Massive necrosis: see portal tract, CV, a few viable hepatocytes, but mainly this is all necrosis.
Non-hepatotropic Viral Hepatitis: what is the larger systemic picture?
What do we see on path?
How dangerous is this?
(viruses that are NOT Hep A, Hep B, Hep C: EBV, CMV, herpes simplex, adenovirus)
- Part of a systemic infection involving other organs
- “punch out” necrosis with or without viral inclusions
- In immunosuppressed patients, can be fatal
What virus? notable?
Herpes Simplex Virus
Viral inclusions (arrows)– swollen nuclei containing particulate matter.
Also “punched-out” area of necrosis.
What virus? notable?
Cytomegalovirus (CMV)
Owls-eye cell.
Both nuclear and cytoplasmic inclusions.
Drug-induced hepatitis:
what % of hepatitis is drug-induced?
what info do we need to know that it is drug-induced?
-Represents 10% of cases of apparent “hepatitis”
- More than 40% in patients above the age of 50
- Up to 25 % of cases of fulminant hepatitis
- 20-50% of cases of non-viral chronic hepatitis
-Correlation between clinical history & liver biopsy required (cannot tell only on basis of biopsy)
what are the two types of drug-induced liver injury? describe how they are different.
- Predictable/direct. Example = drugs that are known to be hepatotoxic, like acetominophen.
- Non-predictable. Drugs that have recently finished a clinical trial, then released to wider public and found to be hepatotoxic in some individuals. Features of this type of hepatotoxicity are idiosyncratic.
This pic of predictable (drug-induced) hepatotoxicity: what is notable?
Right side: eosinophilic area, necrosis
Left side: hepatocytes undergoing ballooning degeneration.
This liver will require transplant.
What’s going on here/what’s the cause?
Cholestatic drug-induced liver injury
Note presence of bile within canaliculi (brown). On biopsy of normal liver, do not see bile.
Only see it in patients with hepatitis or drug-induced injuries.
Chronic hepatitis: definition?
A clinicopathologic syndrome of different etiologies, characterized by elevation of the transaminase activities and chronic inflammation in the portal tracts, interface hepatitis, hepatocellular necrosis and lobular inflammation, and often fibrosis, for at least 6 months
Chronic Hepatitis: possible etiologies?
Autoimmune hepatitis
B virus
C virus
Drug-induced (can cause either acute or chronic hep)
Ethanol
Others: Wilson’s disease, AAT deficiency (metabolic dz)
Chronic Hepatitis: what is going on in these diagrams?
Remember in chronic hep that infllamation occurs in the portal tract.
Inflammation typically encroaches the periportal hepatocytes causing periportal necrosis (aka interface hepatitis).
Portal tract will gradually expand, eventually–> fibrous septa and bridging fibrosis.
Eventually –>cirrhosis due to all bridging fibrosis.
Right picture:
Top panel= normal
Bottom panel = cirrhosis, remodeling of vasculature. Fibrosis + incr portal pressure will occur over several years.
Acute or Chronic? What’s going on?
Chronic: portal chronic inflammation, interface hepatitis
Inf cells are centered around portal tract (within circle).
Peri-portal lymphocytes. May even see lymphoid follicle if the lymphocytes organize.
Portal tract tends to be round & well demarcated – but here you have spillover of cells into stroma due to inflamation.
Interface area: between portal stroma and hepatocytes. Inflammation here = interface hepatitis. Inf will damage adjacent hepatocytes, will be replaced by fibrosis.
Progression from portal chronic inflammation & interface hepatitis to cirrhosis (as below)
Acute or Chronic? what’s going on?
Chronic - cirrhosis.
Portal expansion (??), fibrous septa formation, forms cirrhotic nodules.
Progression from portal chronic inflammation & interface hepatitis to cirrhosis (as below)
Chronic Hep C:
What is typically seen on biopsy?
If undetected, what can result?
Biopsy may show only mild changes.
General characteristics:
- lymphoid follicles in the portal tracts
- bile duct damage
- steatosis
If undetected, can develop into cirrhosis.
What condition might this be?
What other histo findings are characteristic?
Chronic Hep C
General characteristics:
- lymphoid follicles in the portal tracts
- bile duct damage
-steatosis
Chronic Hep B:
What are classic findings on histo?
- NO steatosis
- Marked variation of hepatocytes
- “ground glass” hepatocytes
What’s this; how can you tell?
Chronic Hep B
Ground glass hepatocytes
due to accumulation of Hep B surface antigen within cell cytoplams. Nuclei are pushed aside
What’s this; how can you tell?
Chronic Hep B
Ground glass hepatocytes (special stain here)
Due to accumulation of Hep B surface antigen within cell cytoplams. Nuclei are pushed aside
Liver biopsy in chronic hepatitis:
what information can it provide?
Establishment of the diagnosis
Clues to etiology and possible superinfection or co-infection
Excluding other coexistent liver pathology (ie, obesity, steatosis)
Diagnosis of incidental lesions
Immunohistochemical assessment of viral antigens
Assessment of histological activity (grading)
Evaluation of structural changes (staging)
Monitoring therapy
What is Grading?
Assessing chronic hepatitis based on the extent of inflammation.
(interface hepatitis, lobular activity)
What is Staging?
Assessing chronic hepatitis based on the degree of fibrosis.
(portal fibrosis, fibrous septa, bridging fibrous septa, transition to cirrhosis, cirrhosis)
Is this an image for grading or staging?
Grading: extent of inflammation emanating from portal area
Is this an image for grading or staging?
Staging: extent of fibrosis.
Memory trick: with enough fibrosis you could build a stage?
What is shown in this image?
Interface hepatitis: inflammatory cells spilling over into adjacent lobules.
Part of grading of chronic hepatitis.
what is shown by these three pictures?
Degrees of liver fibrosis, used for staging of chronic hepatitis.
Left: Portal Fibrosis
Middle: Bridging Fibrosis
Right: Nodule formation (–> cirrhosis)
What is shown by these two pictures?
Left: a fragmented biopsy can indicated cirrhosis - nodules separated during slide preparation.
RIght: cirrhosis - fibrous bands encircling nodules
Autoimmune hepatitis: gender distribution?
What are serum findings?
What are biopsy findings?
Female predominance
Serum: autoantibodies, elevated IgG
Biopsy: Hepatocellular damage, severe inflammation, interface hepatitis, plasma cells, fibrous bridging/nodularity
What condition? notable features?
Autoimmune hepatitis.
Left: severe inflammation.
Right: Plasma cells predominate the inflammation (note: nuclei that are eccentrically located, basophilic cytoplasm). Plasma cells tend to cluster.
Fatty Liver Disease: How can you differentiate Alcoholic Liver Disease from Non-Alcoholic Fatty Liver Disease w biopsy?
Alcoholic Liver Dz: Steatosis, Alcoholic Hepatitis, Cirrhosis
Non-Alcoholic Fatty Liver Dz: Steatosis, Non-Alcoholic Steatohepatitis (NASH), Cirrhosis
With just a biopsy, it is very difficult to differentiate. Both may progress to cirrhosis. Need patient history.
Features of Non-Alcoholic steatohepatitis?
Any two of the following three features in Zone 3:
-Necro-inflammatory foci with mononuclear cells + neutrophils
–Ballooning degeneration of hepatocytes +/- Mallory-Denk hyalins
–Pericellular fibrosis around CV
What’s going on? What condition?
Non-alcoholic steatohepatitis.
Arrows point to Ballooning degeneration and mallory-denk bodies
What’s going on? what condition?
Non-alcoholic steatohepatitis.
arrows = mallory-denk hyalins
Cirrhosis due to steatohepatitis.
Note formation of nodules (–> cirrhosis)
Arrow? Condition?
Arrow = mallory-denk hyalin.
Condition: alcoholic hepatitis.
condition? notable?
Alcoholic hepatitis.
Don’t see central venule anymore due to severe pericellular fibrosis (blue stuff) – fibrosis is collapsing the central venule.
Condition? notable?
Alcoholic cirrhosis – micronodular
Indicates that the patient is actively drinking at time of biopsy. Cirrhosis is very fine, between hepatocytes.
Name 3 inherited metbolic disorders that cause chronic liver disease.
- Hereditary hemochromatosis
- Wilson’s Dz
- Alpha 1-antitrypsin deficiency
Clinical features of hemochromatosis?
treatment?
Clinical: Lethargy and arthralgia
Major complications:
- cirrhosis
- hepatocellular carcinoma
- diabetes
- cardiac and endocrine manifestations (due to iron depositions)
**Treatment: regular phlebotomy **
Condition? Notable?
Hemochromatosis. Can see abundant iron deposits in liver parenchyma.
Left pic: iron stains (brown pigment) in periportal area. Later in dz, there will be iron deposits diffusely throughout.
Right pic: special stain for iron (iron is blue). Can see Kupffer cells that have taken up iron.
Wilson’s Disease: Pathology on biopsy?
(Mimics fatty liver disease)
Steatosis
Ballooning degeneration of hepatocytes
Mallory-Denk hyalins
Glycogenated nuclei
Increased Cu in the hepatocytes
Fibrosis and cirrhosis or massive hepatic necrosis
Condition? notable?
Wilson’s Disease.
Arrow points to copper (orange) within hepatocytes
(has been stained for copper)
Alpha 1-Anti Trypsin Deficiency:
What will it cause in younger patients? older patients?
Histo findings?
Causes neonatal hepatitis
Causes cirrhosis in older patients
Biopsy: intracellular globules in periportal hepatocytes, which are D-PAS reactive
