Path 5 - Alcoholic Liver Disease

Terms in this set (50)

Alcoholism
Alcohol Abuse = repeated use despite recurrent adverse consequences.

Alcohol Dependence = alcohol abuse combined with tolerance, withdrawal, and an uncontrollable drive to drink.
Alcohol consumption and mortality- 1
Much of the evidence supporting the connection between alcohol consumption and liver disease comes from epidemiologic studies. Prohibition provided unintended evidence for this connection.
Death Rate from Cirrhosis
parallels alcohol consumption worldwide
Metabolism of Alcohol - Main Pathway
Ethanol --[Alcohol Dehydrogenase (ADH)]--> Acetaldahyde --> Acetaldehyde Dehydrogenase
CYP2E1 Pathway of Alcohol Metabolism is important because...
it affects how ppl taking in excessive amounts of alcohol process drugs
- Chronic ingestion of alcohol Causes the induction of CYP2E1 and other *Cytochrome P-459
enzymes*: can increase conversion of other compounds to toxic metabolites
Metabolism of Alcohol - 3 Pathways
Cytosolic ADH Pathway (Main)
CYP2E1 Pathway (used in excessive alcohol consumption)
Catalase (less important pathway)
ADH Pathway has what important effect?
Results in reduced NAD excess NADH
- NAD is required for fatty acid oxidation; Deficiency of this cofactor is the major cause of the accumulation of fat in liver cells
CYP2E belongs to what family?
Cytochrome P450 enzymes
Cytopchrome P450 enzymes
Liver enzymes designed to detoxify substances in the liver
- limited quantity; saturation by alcohol abuse --> unable to metabolize other toxins
Acetaldehyde is responsible
Acetaldehyde is responsible for some of the acute effects of alcohol ingestion. TOXIC.
Individuals who are unable to metabolize this compound suffer nausea, flushing and tachycardia following ingestion of alcohol (e.g. ALDH deficiency)
Alcohol --> Acetic Acid
Ethanol--> Acetaldehyde (ADH)

Acetaldehyde is metabolized to acetic acid by acetaldehyde dehydrogenase (ALDH)
ADH
Alcohol Dehydrogenase
Induction of P-450 CYP2E Pathway and the ER
The induction of in the P-450 system with excessive use including CYP2E1 is in part accomplished by hypertrophy of the smooth ER
Acetaminophen (Tylenol) in Non-Drinkers
At low doses 95% is detoxified by phase II enzymes.
Usually 5% or less is metabolised primarily by CYP2E1 to a highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQ).
NAPQ is conjugated to a non-toxic product via enzyme GSH
- NAPQ --> centrilobular hepatocyte necrosis and liver failure
NAPQ
hepatotoxin causing centrilobular hepatocyte necrosis and liver failure
Tylenol in Non-Drinkers
CYP2E is upregulated --> More Tylenol converted to NAPQ
NAPQ Overwhelms GSH
Ethanol in Liver
Activates CYP2E1
Leads to production of ROS and Acetaldehyde --> Oxidative stress and Electrophilic Stress --> Liver Injury
Nrf2
ROS and Acetaldehyde stimulate production of Nrf2 --> Stimulates Antioxidants and Anti-inflammatory enzymes
This system is overwhelmed by excessive alcohol consumption and can't keep up!
[Nrf2 is a main player in cell's defense against oxidative stress]
Ethanol in Gut
Causes inflammation --> leads to ROS and inflammatory stress --> Liver Injury x2
3 Primary Presentations of Alcoholic Liver Disease (ALD)
1.) Steatosis
2.) Cirrhosis (scarring)
3.) Hepatitis (inflammation)
= ALD
Cirrhosis and ALD both precursors to Heptatocellular Carcinoma due to frantic attempts to regenerate as the liver scars
Steatosis
- Fat accumulation in hepatocytes due to metabolic derangements (fatty liver)
- Most common morphologic abnormality
- Reversible
Interrelationships Among the Forms of
Alcoholic Liver Disease
Steatosis and alcoholic hepatitis are reversible but continued exposure or repeated attacks may lead to cirrhosis
Cirrhosis is an irreversible process with a guarded to grim prognosis
Alcoholic Liver Injury: Relationship of 3 Pathologies
Steatosis is the most common change and can develop within hours to days with heavy intake.
Alcoholic hepatitis is often associated binge drinking, and most often associated with steatosis.
- causal relationship between these entities not established
Most Common Liver Change w/ Alcohol Abuse
Steatosis (Fatty Liver)
Can develop within hours to days with heavy intake
Most Chronic Alcoholics develop this
Alcoholic hepatitis is often associated with...
binge drinking
-most often associated with steatosis
Cirrhosis
nodular fibrosis or scarring and attempted regeneration of the liver
Natural History of Ethanol-induced Liver Damage
Most chronic alcoholics develop fatty liver --> those often then develop alcoholic hepatitis --> those then develop cirrhosis --> 50% with cirrhosis who keep drinking die
Starvation in Alcoholics
Starvation --> increased mobilization of fatty acids from peripheral stores --> overwhelm the capacity of the (already overworked) liver to metabolize and export the lipids --> more fatty storage
Carbon Tetrachloride (CCl4)
...is increased in alcohol consumption and is then metabolized to CCl3+ a highly reactive free radical that causes extensive lipid peroxidation resulting in wide spread damage to ER membranes, reducing the synthesis of apoproteins.
- Protein malnutrition can also diminish apoprotein synthesis
TAGs and FA's stuck in liver
apoproteins
Transport fat from liver to blood
Hepatic steatosis: Gross Specimens
Fatty liver (hepatic steatosis) is enlarged, soft, and yellow due to fat. Greasy texture on palpation.
Liver Enlargement in Steatosis
Excess fat in cells = cells enlarge = tissues enlarge
Alcoholic steatosis is associated w/ enlargement of the liver which can be dramatic.
Enlarged liver often extends below the costal margin and can be detected clinically by palpation.
Alcoholic Steatosis on Slides
Pic
Alcoholic Hepatitis
Appears acutely and often after sustained binge
Clinical presentation can range from minimal symptoms to fulminant hepatic failure.
- Each episode associated w/ 10-20% risk of death.
~20-30% who continue alcohol consumption and have repeated episodes hepatitis go to develop cirrhosis
The major histopathologic components of Alcoholic hepatitis are:
- scattered foci of hepatocyte swelling and necrosis (inflammation!!)
- a neutrophilic reaction in and around the foci of necrosis
- formation of Mallory bodies
- Fibrosis (sometimes)
- Fatty accumulation (usually)
Mallory Bodies
Intermediate filaments of cytokeratins from cytoskeleton of the injured hepatocyte (hyaline inclusions)
eosinophilic cytoplasmic globules in liver near nucleus
3 salient features of cirrhosis
1.) fibrous bands (blue) connecting portal tracts and central veins
2.) parenchymal nodules of hepatocytes (red)
3.) disruption of the architecture of the liver
- alters blood flow through liver (note on slides that central veins and portal tracts are not evident)
Alcoholic Cirrhosis Histo Slides
The central and right hand panels are sections of liver with cirrhosis stained with a trichrome stain.
Blue = collagen in the fibrous bands
Note that Central veins and portal tracts are not evident
Regeneration vs Repair of Liver (Review)
Portal Triad and Matrix damaged = fibrosis and scarring
Mechanism of Hepatic Fibrosis
Proliferation of stellate cells (modified fibroblasts) and activation of their collagen synthesis activity causes fibrosis.
- Fibrosis causes major changes in the vascular architecture resulting in the shunting of blood from the parenchyma
- Loss of fenestrations in the of the sinusoidal endothelial cells and the deposition of dense collagen in the space of Disse further impedes the exchange of solutes between hepatocytes and the blood stream
Stellate Cell
Modified Fibroblast that resides in the space of disse in the liver that is responsible for fibrosis --> cirrhosis
Complications from Cirrhosis
Esophageal Varices (life threatening!)
Hepatic Encephalopathy
Splenomegaly
Ascites
Hemorrhoids
Hepatocellular Caricnoma
Hepatorenal and Hepatopulomonary Syndromes
Disruption of Blood Flow due to Cirrhosis
Pic
Disruption of blood flow causes backup into multiple organs; responsible for many of the complications of Cirrhosis
Esophageal Varices
Life threatening complication of cirrhosis
- occur in about 40% of patients with advanced cirrhosis
Risk to the patient = massive hematemesis (vomiting blood) associated with a 30% mortality
Hepatocellular Carcinoma
Occurs in 1-6% of patients with alcoholic cirrhosis.
These tumors are often multifocal with widely distributed nodules of varying size
The prognosis for this neoplasm is grim- the majority of patients dying
within 2 years of diagnosis.
Hepatic Encephalopathy
condition is associated with
spectrum of disturbances of consciousness.
Hepatorenal Syndrome [Cover Later]
Appearance of renal failure in the context of severe chronic liver disease
- No intrinsic morphologic or functional causes can be discerned
- Cause of this complication is not entirely clear; factors that appear to be involved include: systemic vasodilation and vasoconstriction of afferent renal arterioles
Hepatopulmonary Syndrome [Cover Later]
Triad:
- Chronic liver disease
- Hypoxemia
- Pulmonary vascular dilatation.
Possible causes include: lack uniform blood flow in the presence of stable alveolar ventilation and a "diffusion-perfusion" defect due to the rapid flow of blood in the dilated vessels.
Diseases and Conditions Resulting from Ethanol Abuse [Don't Memorize Now]
- Liver Damage (farry liver, alcoholic hepatitis, cirrhosis)
- Carcinoma of the esophagus, pharynx and oral cavity
- Pancreatitis, gastritis
- Impaired small intestinal absorption
- Degenerative brain damage (particularly in cerebellum) and peripheral neuropathy
- Muscle damage (skeletal and cardiac) and cardiomyopathy
- Fetal alcohol spectrum disorder
Alcoholism Affect on Multiple Organs (pic)
Overview, no need memorize YET
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