Alcoholic liver disease

1. Alcoholic Liver Disease
• Three distinctive, overlapping forms
of alcoholic liver injury:
–Hepatocellular steatosis or fatty
change
–Alcoholic hepatitis(steatohepatitis)
–Steatofibrosis
• Cirrhosis develops in only a small
fraction of chronic alcoholics

2. Morphology
• Changes begin in acinus zone 3 and
extend outward toward portal tracts
with increasing severity of injury

3. Hepatic Steatosis
(Fatty Liver)
• Intake of alcohol  lipid droplets
accumulate in hepatocytes
• Increases with amount and chronicity
of alcohol intake
• Begins as small droplets
(microvesicular)  coalesce into
large droplets(macrovesicular)

5. • Macroscopically  liver is large (4 to
6 kg), soft, yellow and greasy.
• Fatty change is completely reversible
if there is abstention from further
intake of alcohol

6. Alcoholic Hepatitis
(Steatohepatitis)
• Characterized by:
1. Hepatocyte swelling and
necrosis:
Single or scattered foci of cells
undergo swelling (ballooning) and
necrosis
Swelling results from accumulation
of fat and water, & proteins that
are normally exported.

8. 2. Mallory-Denk bodies:
 Present as clumped, amorphous,
eosinophilic material in ballooned
hepatocytes
 Made up of tangled skeins of
intermediate filaments keratins 8
and 18 in complex with other
proteins such as ubiquitin

10.  Characteristic but not specific
feature of alcoholic liver disease,
also present in non-alcoholic fatty
liver disease and in periportal
distributions in Wilson disease and in
chronic biliary tract diseases.

11. 3. Neutrophilic reaction:
 Neutrophils permeate hepatic
lobule and accumulate around
degenerating hepatocytes, having
Mallory-Denk bodies
 may be admixed with mononuclear
cells

12. Alcoholic steatofibrosis
• Activation of sinusoidal stellate cells
and portal fibroblasts, giving rise to
fibrosis
• Begins with sclerosis of central veins
• Perisinusoidal scar then accumulates
in space of Disse of centrilobular
region, spreading outward, encircling
individual or small clusters of
hepatocytes in chicken wire fence
pattern

14. • Webs of scar eventually link to portal
tracts and then begin to condense
into central-portal fibrous septa.
• With developing nodularity, cirrhosis
becomes established
• Micronodular or Laennec cirrhosis
 end-stage alcoholic liver disease

15. Pathogenesis
• Daily intake of >/=80 gm of ethanol
generates risk for severe hepatic
injury and ingestion of >/=160 gm
for 10 to 20 years is associated more
consistently with severe injury
• Only 10% to 15% of alcoholics
develop cirrhosis

16. • Other factors also influence
development and severity of alcoholic
liver disease. These include:
–Gender: Women more susceptible
to hepatic injury than men
–Related to alcohol pharmacokinetics
and metabolism, and estrogen-
dependent response to gut-derived
endotoxin (LPS) in liver

17. • Ethnic and genetic differences: In
US, cirrhosis rates are higher for
African American drinkers than for
white Americans drinker.
• Genetic polymorphisms in detoxifying
enzymes and some cytokine
promoters may play significant roles

18. • Comorbid conditions: Iron
overload and infections with
HCV and HBV synergize with alcohol

19. • Hepatocellular steatosis results from:
1. Increased lipid biosynthesis
resulting from increased generation
of reduced nicotinamide adenine
dinucleotide (NADH) by enzymes of
alcohol metabolism, alcohol
dehydrogenase and acetaldehyde
dehydrogenase

20. 2. Impaired assembly and secretion of
lipoproteins
3. Increased peripheral catabolism of
fat, releasing free fatty acids into
circulation.

21. Cause of alcoholic hepatitis
• Acetaldehyde induces lipid peroxidation
and acetaldehydeprotein adduct
formation, disrupting cytoskeletal and
membrane function.
• Cytochrome P-450 metabolism
produces reactive oxygen species that
react with cellular proteins, damage
membranes, and alter hepatocellular
function

22. • Alcohol impairs hepatic metabolism
of methionine decreases
glutathione levels  sensitizing liver
to oxidative injury.
• Induction of cytochrome P-450
enzymes enhances conversion of
other drugs (acetaminophen) to toxic
metabolites.

23. • Alcohol causes release of bacterial
endotoxin from gut into portal
circulation, inducing inflammatory
responses in liver

24. • Alcohol stimulates release of
endothelins from sinusoidal
endothelial cells, causing
vasoconstriction and contraction of
activated myofibroblastic stellate
cells, leading to decrease in hepatic
sinusoidal perfusion

25. Clinical Features
• Hepatic steatosis  hepatomegaly,
with mild elevation of serum bilirubin
and alkaline phosphatase levels
• Alcoholic hepatitis  range from
minimal to those that mimic acute
liver failure
• Nonspecific symptoms malaise,
anorexia, weight loss, upper
abdominal discomfort, and tender
hepatomegaly

26. Laboratory findings
• Hyperbilirubinemia
• Elevated serum aminotransferases
and alkaline phosphatase
• Neutrophilic leukocytosis
• Serum AST:ALT levels - 2:1

27. Complications
• Hepatic coma
• Massive gastrointestinal hemorrhage
• Intercurrent infection
• Hepatorenal syndrome
• Hepatocellular carcinoma