150. Liver Histo + Basic Path

Question 1

What are the two different models for architecture of the liver?

What makes up the portal triad?
What is normal appearance of liver under reticulin and Trichrome Stains?

Answer 1

Lobular Model
Centrilobular - around CV
Periportal - near portal triad

Acinar Model
Zone 1: near portal triad, O2 rich
Zone 2
Zone 3: near CV, risk for ischemia, enzymatic activity

Portal Triad: PV (largest), HA (muscular), BD (cuboidal cell layer)
Reticulin: shows fibrosis
Trichrome: shows fibrosis (blue)
Normal fibrosis around portal tracts - collagen-rich

Question 2

What are the 5 key mechanisms/signs of injury/repair in liver?

Answer 2

1. Hepatocyte Degeneration (reversible): ballooning due to substance accumulation (fat - steatosis; bile - cholestasis)
2. Necrosis/Apoptosis: groups of ghost cells around CV (zone 3, coagulative necrosis) vs. individual mummified hepatocyte (apoptosis)
3. Inflammation: chronic, autoimmune or med-induced
4. Fibrosis: Stellate cells (in b/w sinusoids and hepatocytes), activated due to injury/inflammation - cause deposition of scar matrix and activation of kupffer cells = fibrosis
5. Regeneration and Fibrosis: scar/fibrosis commonly in Zone 3, regeneration (scars - fibrous septa - dissolve), becomes irreversible fibrosis if chronic and ongoing
   Portal/Pericellular fibrosis = bridging fibrosis = regeneration nodule formation

Question 3

Acute Liver Failure

• key signs
• fulminant vs. subfulminant
• mechanism
• causes
• histo

Answer 3

sign: hepatic encephalopathy
fulminant (<2wks), subfulminant (<3mo)
Mechanism: massive hepatocyte necrosis
cause: drugs (50% ACETAMINOPHEN), toxins (amanita phalloides, CCl4), viruses (HAV, HBV), Autoimmune hepatitis
Histo:
Acetaminophen Overdose: ONLY centrilobular necrosis (zone 3 responsible for enzymatic metabolism)
Other: necrosis - pink w/o visible nuclei

Question 4

Chronic Liver Disease

• types
• mechanisms
• causes
• path: Trichrome stain, gross

Answer 4

Types: chronic hepatitis (continuous injury) vs repeated injuries over time
Mechanisms: fibrosis = cirrhosis = liver failure
Cause: AFLD, NASH = NAFLD, viruses (HBV, HCV), autoimmune hepatitis, biliary disease, genetic metabolic disease

Trichrome: normal (collagen in portal tract) = portal fibrosis (extends to nearby hepatocytes) = pericellular fibrosis = bridging fibrosis (blue bands) with regenerating pink nodules

Gross: multiple nodules, not smooth outer surface

Question 5

What is hepatic dysfx without overt necrosis? What are two causes?

Answer 5

Liver tissue viable but hepatocytes unable to perform metabolic fx
Cause: tetracycline toxicity, acute fatty liver of pregnancy

Question 6

Fatty Liver Disease

• progression stages
• RF for AFLD and NAFLD
• why does fat develop in liver
• what is the two-hit hypothesis for NAFLD

Answer 6

1. Steatosis: fat accumulation in hepatocytes
2. Steatohepatitis: inflammation and steatosis
3. Fibrosis (progressive) = cirrhosis
4. Liver failure or HCC due to ongoing cirrhosis

AFLD: alcohol use (>20g/day)
NAFLD: (<20g/day), Obesity/Metabolic Syndrome, Diabetes

Fatty Liver: liver is checkpoint for fat when adipocytes overwhelmed, ectopic TG storage causing steatosis, in metabolic syndrome - excess energy - increased FA uptake by liver, increased FA synthesis, increased TG synthesis all cause fatty liver

1. fat accumulation (steatosis)
2. oxidative stress to hepatocytes = steatohepatitis

Question 7

Histo for different stages of fatty liver disease

include key features of alcoholic liver disease

Answer 7

1. Steatosis
   Macrovesicular (nuclei periphery) and microvesicular (central nuclei) fat globules/vesicles in hepatocytes
2. Steatohepatitis
   Lipogranulomas (inflammatory cell aggregations
   Ballooned hepatocytes
   Lipoapoptosis: hepatocyte death due to exposure of non-adipose tissue (liver) to excess of LCFAs
   Pericellular + Perivenular Fibrosis (surrounding individual cells or central vein)
3. Fibrosis/Cirrhosis: bridging fibrosis with regeneration nodules
4. HCC/Cirrhosis: micronodularity with fat accumulation

Alcoholic Steatohepatitis: Mallory Bodies!

Question 8

Alcoholic Fatty Liver Disease

• types of EtOH consumption
• how does alcohol cause hepatotoxicity?
• what zone does steatosis start in for AFLD?

Answer 8

Binge: too much too fast (5+ drinks in 2 hrs, 1x/wk)
Steady: too much too often (4-5 drinks/day)

95% EtOH oxidized to acetaldehyde then acetate
Alcohol Dehydrogenase (ADH): converts EtOH to acetaldehyde
Aldehydedehydrogenase (ALDH2): converts acetaldehyde to acetate (producing NADH from NAD+)

High NADH/NAD+ ratio favors FA/TG synthesis = Fatty Liver

Hepatotoxic effects: high lipid peroxidation, binds plasma membranes, interferes with mito etc, inhibits nuclear repair, interferes with microtubule fx, increases collagen synthesis (stellate cell activation)

AFLD steatosis begins in Zone 3 and extends toward portal area