Fatty Liver Disease
Lecture 21, 22
By Dr Mohammad Manzoor Mashwani BKMC Mardan
The five Ayat (Ayas) of the Quran that most directly address the
consumption of alcohol are as follows:
• 1. They ask thee concerning wine and gambling. Say: "In them is
great sin, and some profit, for men; but the sin is greater than
the profit." (Al-Baqara; 2:219)
• 2. And from the fruit of the date palm and the vine, ye get out
wholesome drink and food: behold, in this also is a sign for those
who are wise. (An-Nahl; 16:67)
• 3. O ye who believe! Approach not prayers with a mind befogged,
until ye can understand all that ye say…. (An-Nisa; 4:43)
• 4. O ye who believe! Intoxicants and gambling, (dedication of)
stones, and (divination by) arrows, are an abomination, Of
Satan’s handiwork: Eschew such (abomination) that ye may
prosper. (Al Maeda; 5:90)
• 5. Satan’s plan is (but) to excite enmity and hatred between you,
with intoxicants and gambling, and hinder you from the
remembrance of God, and from prayer: Will ye not then refrain?
One gram of alcohol gives 7 calories.
But alcohol cannot be stored in the body and
must undergo obligatory oxidation, chiefly in
the liver. Thus, these empty calories make no
contribution to nutrition other than to give
Moderate amounts of alcohol (one drink per day) have been
reported to increase serum levels of high-density lipoproteins
(HDLs) and inhibit platelet aggregation, thus protecting
against coronary heart disease.
Excessive alcohol (ethanol) consumption is
the leading cause of liver disease in
most Western countries.
Excessive ethanol consumption causes more than 60% of chronic liver disease in Western
countries and accounts for 40% to 50% of deaths due to cirrhosis.
Forms of alcoholic liver disease
(1)Hepatic steatosis (fatty liver disease)
(2) Alcoholic hepatitis
There are three sequential stages in alcoholic liver Disease:
I. Fatty Liver /Steatosis
• Fatty liver is the collection of excessive
amounts of triglycerides and other fats
inside liver cells.
The break down of fats in the liver can be disrupted
1.Hepatic Steatosis (Fatty Liver).
After even moderate intake of
alcohol, microvesicular lipid droplets
accumulate in hepatocytes.
1.Hepatic Steatosis (Fatty Liver).
After even moderate intake of alcohol,
microvesicular lipid droplets accumulate
Alcoholic cirrhosis. A, The characteristic diffuse nodularity of the surface reflects the
processes of nodular regeneration and scarring. The greenish tint of some nodules is
due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the
lower edge of the right lobe (lower left).
Alcoholic cirrhosis. The characteristic diffuse nodularity of the surface is induced by the underlying fibrous scarring. The
average nodule size is 3 mm in this close-up view. The greenish tint is caused by
With chronic intake of alcohol, lipid
that compress and displace the hepatocyte
nucleus to the periphery of the cell.
Fatty liver disease. Macrovesicular steatosis is most prominent around the central
vein and extends outward to the portal tracts with increasing severity. The
intracytoplasmic fat is seen as clear vacuoles. Some fibrosis (stained blue) is present in a
characteristic perisinusoidal“ chicken wire fence” pattern. (Masson trichrome stain.)
The normal adult liver weighs 1400 -1600 gm
Macroscopically, the fatty liver of chronic
alcoholism is a large(as heavy as 4 to 6
kg), soft organ that is yellow and greasy.
The fatty change is completely reversible if there is
abstention from further intake of alcohol.
Morphology 2. Alcoholic Hepatitis (Alcoholic Steatohepatitis).
Alcoholic hepatitis is characterized by:
1. Hepatocyte swelling and necrosis
2. Mallory bodies:
Mallory bodies are visible as eosinophilic cytoplasmic clumps in hepatocytes.
3. Neutrophilic reaction
Large, poorly defined accumulations of eosinophilic
material in the cytoplasm of damaged hepatic cells
in certain forms of cirrhosis especially those due to
• Synonym(s): alcoholic hyalin, alcoholic hyaline
Mallory body, Mallory-Denk body, and Mallory's
A, Alcoholic hepatitis with clustered inflammatory cells marking the
site of a necrotic hepatocyte. A Mallory-Denk body is present in
another hepatocyte (arrow).
B, Steatohepatitis with many ballooned hepatocytes (arrowheads) containing prominent Mallory-Denk
bodies; clusters of inflammatory cells are also seen; inset shows immunostaining for keratins 8 and 18
(brown), with most hepatocytes, including those with fat vacuoles, showing normal cytoplasmic
staining, but in the ballooned cell (dotted line), the keratins are collapsed into the Mallory-Denk
body, leaving the cytoplasm “empty.”
Mallory body with the characteristic twisted-rope appearance (centre of image - within a
ballooning hepatocyte). H&E stain
B, The microscopic view shows nodules of varying sizes entrapped in blue-staining
fibrous tissue. The liver capsule is at the top (Masson trichrome).
3. ALCOHOLIC CIRRHOSIS.
Alcoholic cirrhosis is the most common form of lesion, constituting 60-70% of all
cases of cirrhosis. Several terms have been used for this type of cirrhosis such as
Laennec’s cirrhosis, portal cirrhosis, hobnail cirrhosis, nutritional cirrhosis, diffuse
cirrhosis and micronodular cirrhosis.
Grossly, alcoholic cirrhosis classically begins as micronodular cirrhosis (nodules less
than 3 mm diameter), the liver being large, fatty and weighing usually above
2 kg .Eventually over a span of years, the liver shrinks to less than 1 kg in weight,
becomes non-fatty, having macronodular cirrhosis (nodules larger than 3 mm
in diameter), resembling post-necrotic cirrhosis. The nodules of the liver due to their
fat content are tawny yellow, on the basis of which Laennec in 1818 introduced
the term cirrhosis first of all (from Greek kirrhos = tawny).
The surface of liver in alcoholic cirrhosis is studded
with diffuse nodules which vary little in size,
producing hobnail liver (because of the resemblance of
the surface with the sole of an old-fashioned shoe having
short nails with heavy heads). On cut section,
spheroidal or angula nodules of fibrous septa are
Microscopically, alcoholic cirrhosis is a progressive alcoholic
liver disease. Its features include the following
i) Nodular pattern: Normal lobular architecture is effaced in
which central veins are hard to find and is replaced with
ii) Fibrous septa: The fibrous septa that divide the hepatic
parenchyma into nodules are initially delicate and extend
from central vein to portal regions, or portal tract to
portal tract, or both. As the fibrous scarring increases with
time, the fibrous septa become dense and more
iii) Hepatic parenchyma: The hepatocytes in the islands of
surviving parenchyma undergo slow proliferation
Alcoholic liver disease. The interrelationships among hepatic steatosis,
hepatitis, and cirrhosis are shown, depicting key morphologic features.
Risk Factors for Alcoholic Liver Disease
• 1. Drinking pattern
• 2.Gender- women
• 3. Malnutrition
• 4. Infections
• 5.Genetic factors
• 6. Hepatitis C infection
Why all alcoholics do not
develop cirrhosis but only 10-15%?
Only10% to 15%
Ethanol after ingestion and absorption from the small
bowel circulates through the liver where about 90% of it is
oxidised to acetate by a two-step enzymatic process
involving two enzymes: alcohol dehydrogenase (ADH)
present in the cytosol, and acetaldehyde dehydrogenase
(ALDH) in the mitochondria of hepatocytes. The remaining
10%of ethanol is oxidised elsewhere in the body.
First step: Ethanol is catabolized to acetaldehyde in the
liver by the following three pathways, one major and
i) In the cytosol, by the major rate-limiting pathway
of alcohol dehydrogenase (ADH).
ii) In the smooth endoplasmic reticulum, via
microsomal P-450 oxidases (also called microsomal ethanol
oxidising system, MEOS), where only part of ethanol is metabolised.
iii) In the peroxisomes, minor pathway via catalase
such as H2O2.
Acetaldehyde is toxic and may cause membrane damage and cell necrosis.
Second step: The second step occurs in the mitochondria
where acetaldehyde is converted to acetate with ALDH
acting as a co-enzyme.
Most of the acetate on leaving the liver is finally oxidised to
carbon dioxide and water, or converted by the citric acid
cycle to other compounds including fatty acids.
Simultaneously, the same cofactor, NAD, is reduced to NADH
resulting in increased NADH: NAD redox ratio which is the
basic biochemical alteration occurring during ethanol
metabolism. A close estimate of NADH:NAD ratio is
measured by the ratio of its oxidised and reduced
metabolites in the form of lactate-pyruvate ratio and β-
hydroxy butyrate-acetoacetate ratio.
I. Major Pathway
II. Minor Pathway
III. Minor Pathway
STEP I STEP II
CMI- cell mediated immunity
Marked increase in the
redox ratio in the hepatocytes
results in increased redox ratio
of lactate-pyruvate, leading to
lactic acidosis. This altered
redox potential has been
implicated in a number of
metabolic consequences such
as in fatty liver, collagen
formation occurrence of gout,
impaired gluconeogenesis and
altered steroid metabolism.
ethanol oxidising system,
• Short-term ingestion of as much as 80 gm of
alcohol over one to several days generally
produces mild, reversible hepatic steatosis.
• Daily intake of 80 gm or more of ethanol
generates significant risk for severe hepatic
injury, and daily ingestion of 160 gm or more for 10
to 20 years is associated more consistently with
•Only10% to 15% of alcoholics, develop
• Thus, other factors must also influence
the development and severity of alcoholic liver
Hepatocellular steatosis results from
(1) shunting of normal substrates away from
catabolism and toward lipid biosynthesis
(2) impaired assembly and secretion of
(3) increased peripheral catabolism of fat.
A concentration of 80 mg/dL in the blood constitutes the legal
definition of drunk driving in most states.
Drowsiness occurs at 200 mg/dL, stupor at 300 mg/dL, and coma, with
possible respiratory arrest, at higher levels. The rate of metabolism
affects the blood alcohol level.
Persons with chronic alcoholism can tolerate levels as high as 700
mg/dL, due in part to accelerated ethanol metabolism caused by a
5- to 10-fold increase in induction of the hepatic cytochrome P-450
• 1. Direct hepatotoxicity by ethanol.
• 2. Hepatotoxicity by ethanol metabolites.
• 3. Oxidative stress
• 4. Immunological Mechanism
• 5. Inflammation
• 6. Fibrogenesis
• 7. Increased redox ratio
• 8. Retention of Liver cell water & proteins
• 9. Hypoxia
• 10. Increased liver fat
Effects of Alcoholism
Alcohol consumption in moderation and socially acceptable
limits is practiced mainly for its mood-altering effects. Heavy
alcohol consumption in unhabituated person is likely to cause
acute ill-effects on different organs.
• 1. Liver
• 2. Pancreas
• 3. GIT
• 4. CNS
• 5. CVS
• 6. Endocrine system
• 8. Immune System
• 9. Cancer
Chronic alcoholism is defined as the
regular imbibing of an amount of
ethyl alcohol (ethanol) that is
sufficient to harm an individual
socially, psychologically or
• 1.Hepatic steatosis (fatty liver):
• with mild elevation of serum bilirubin and alkaline
• Severe hepatic dysfunction is unusual.
Alcohol withdrawal and the provision of an adequate dietare sufficient treatment.
2. Alcoholic hepatitis
tends to appear acutely, usually following a bout of
3. Weight loss,
4. Upper abdominal discomfort,
5. Tender hepatomegaly,
An acute cholestatic syndrome may appear, resembling large bile duct obstruction.
• The outlook is unpredictable; each bout of
hepatitis incurs about a 10% to 20% risk of death.
• With repeated bouts, cirrhosis appears in about
one third of patients within a few years.
• Alcoholic hepatitis also may be superimposed on
• With proper nutrition and total cessation of
alcohol consumption, the alcoholic hepatitis may
• However, in some patients, the hepatitis
persists, despite abstinence, and progresses to
• In some instances, liver biopsy may be
indicated, since in about 10% to 20% of cases of
presumed alcoholic cirrhosis, another disease
process is found.
Cirrhosis typically develops after 10 to 15 years of
drinking or more, but only occurs in a small (10-15%)
proportion of chronic alcoholics; alcoholic cirrhosis has the
same morphologic and clinical features as cirrhosis caused by viral hepatitis.
Cirrhosis may be clinically silent, discovered only at autopsy or
when stress such as infection or trauma tips the balance
toward hepatic insufficiency.
• Five-year survival approaches 90% in abstainers
who are free of jaundice, ascites, or hematemesis;
• it drops to 50% to 60% in those who continue
In the end-stage alcoholic the proximate causes of death are
(1) hepatic coma,
(2) massive gastrointestinal hemorrhage,
(3) intercurrent infection
(4) hepatorenal syndrome
(5) hepatocellular carcinoma
Advantages of Alcohol
Moderate amounts of alcohol (one drink per day) have been
reported to increase serum levels of high-density
lipoproteins (HDLs) and inhibit platelet aggregation, thus
protecting against coronary heart disease.
One gram of alcohol gives 7calories.
Ethanol is a substantial source of energy