FATTY LIVER (2) Prepared by

Darien Liew Daojuin

ALCOHOLIC LIVER DISEASE 14 May 2017
DEFINITION
ALD presents as a broad spectrum of disorders, ranging from simple
fatty liver to more severe forms of liver injury, including alcoholic
hepatitis (AH), cirrhosis, and superimposed hepatocellular carcinoma
(HCC)
Alcoholic hepatitis is a syndrome of progressive inflammatory liver
injury associated with long-term heavy intake of ethanol.
OVERVIEW
Facts:
90%-100% of heavy drinkers develop fatty liver (i.e., hepatic steatosis)
Among those, 10% to 35% develop alcoholic hepatitis
Only 8% to 20% of chronic alcoholics develop cirrhosis.
Steatosis, alcoholic hepatitis, and fibrosis may develop independently, so
they do not necessarily represent a continuum of changes.
Hepatocellular carcinoma arises in 10% to 20% of patients with alcoholic
cirrhosis.
METABOLISM OF ETHANOL
Most of the alcohol in the blood is metabolized to acetaldehyde in the
liver by three enzyme systems: alcohol dehydrogenase, cytochrome P-
450 isoenzymes, and catalase.
The main enzyme involved is alcohol dehydrogenase, located in the
cytosol of hepatocytes. At high blood alcohol levels, however, the MEOS
has an important role. It involves cytochrome P-450 enzymes,
particularly the CYP2E1 isoform, located in the smooth ER.
Induction of P-450 enzymes by alcohol explains the increased
susceptibility of alcoholics to other compounds metabolized by the same
enzyme system, e.g. drugs (acetaminophen, cocaine), anesthetics,
carcinogens, and industrial solvents.
METABOLISM OF ETHANOL
When alcohol is present in the blood at high concentrations, it
competes with other CYP2E1 substrates and may delay the catabolism
of other drugs, thereby potentiating their effects.
Catalase is responsible for only about 5% of alcohol metabolism.
Acetaldehyde produced by these systems is in turn converted by
acetaldehyde dehydrogenase to acetate, which is utilized in the
mitochondrial respiratory chain.

Note: The induction of cytochrome P450 by chronic alcohol use leads

to augmented transformation of other drugs to toxic metabolites. This
effect can accelerate the metabolism of acetaminophen into highly
toxic metabolites and increase the risk of liver injury.
ETIOLOGY AND RISK FACTORS
Genetic, environmental, nutritional, metabolic, and immunologic
factors, as well as cytokines and viral disease have been invoked.
PATHOGENESIS
1. Genetic Factors
The genetic factor that most clearly affects susceptibility is male or female sex. For a
given level of ethanol intake, women are more susceptible than men to developing
alcoholic liver disease
Patatin-like phosphoipase domain-containing 3 (PNPLA3) gene, also known as
adiponutrin, has been implicated in both ALD and NAFLD.

2. Ethanol Metabolism
Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.
Induces lipid peroxidation and adduct formation disrupts cytoskeleton and
membrane function

3. Generation of Free Radicals

ROS produced from the MEOS pathway and neutrophils damages the membrane and
protein.
Acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic
defense against free radicals. Other antioxidant defenses, including selenium, zinc,
and vitamin E, are often reduced in individuals with alcoholism.
4. Steatosis
Oxidation of ethanol requires conversion of NAD to the reduced form NADH.
NAD is required for the oxidation of fat, its depletion inhibits fatty acid
oxidation, thus causing accumulation of fat within the hepatocytes (steatosis). A
higher NADH concentration induces fatty acid synthesis while a decreased
NAD level results in decreased fatty acid oxidation.
Some of the excess NADH may be reoxidized in the conversion of pyruvate to
lactate.
Accumulation of fat in hepatocytes may occur within days of alcohol ingestion;
with abstinence from alcohol, the normal redox state is restored, the lipid is
mobilized, and steatosis resolves.
Although steatosis has generally been considered a benign and reversible
condition, rupture of lipid-laden hepatocytes may lead to focal inflammation,
granuloma formation, and fibrosis, and it may contribute to progressive liver
injury.
Non-oxidative metabolism of ethanol may lead to the formation of fatty acid
ethyl esters, which may also be implicated in the pathogenesis of alcohol-
induced liver damage.
5. Acetaldehyde Adducts
Effects of Adducts:
impairment of the mitochondrial beta-oxidation of fatty acids,
formation of oxygen-derived free radicals, and
depletion of mitochondrial glutathione.
In addition, acetaldehyde may bind covalently with several hepatic
macromolecules, such as amines and thiols, in cell membranes, enzymes, and
microtubules to form acetaldehyde adducts. This binding may trigger an
immune response through the formation of neoantigens, impair the function
of intracellular transport through precipitation of intermediate filaments and
other cytoskeletal elements, and stimulate hepatic stellate cells to produce
collagen.
The levels of acetaldehyde in the liver represent a balance between its rate
of formation (determined by the alcohol load and activities of the 3
alcohol-dehydrogenating enzymes) and its rate of degradation by ALDH.
ALDH is downregulated by long-term ethanol abuse, with resultant
acetaldehyde accumulation.
6. Immune System
Active alcoholic hepatitis often persists for months after cessation of drinking. In
fact, its severity may worsen during the first few weeks of abstinence. This
observation suggests that an immunologic mechanism may be responsible for
perpetuation of the injury.
The levels of serum immunoglobulins, especially the immunoglobulin A (IgA) class,
are increased in persons with alcoholic hepatitis. Antibodies directed against
acetaldehyde-modified cytoskeletal proteins can be demonstrated in some
individuals. Autoantibodies, including antinuclear and antisingle-stranded or
antidouble-stranded DNA antibodies, have also been detected in some patients
with alcoholic liver disease.
B and T lymphocytes are noted in the portal and periportal areas, and natural
killer lymphocytes are noted around hyalin-containing hepatocytes. Patients have
decreased peripheral lymphocyte counts with an associated increase in the ratio
of helper cells to suppressor cells, signifying that lymphocytes are involved in a
cell-mediated inflammatory process.
Lymphocyte activation upon exposure to liver extracts has been demonstrated in
patients with alcoholic hepatitis. Immunosuppressive therapy with glucocorticoids
appears to improve survival and accelerate recovery in patients with severe
alcoholic hepatitis.
7. Cytokines
It is thought that pro-inflammatory cytokines may also be involved in inducing
hepatic damage in alcoholic hepatitis, since endotoxin is released into the blood
because of increased gut permeability, leading to release of tumour necrosis factor
alpha (TNF-), interleukin (IL)-1, IL-2, IL-6 and IL-8 from immune cells. All of these
cytokines have been implicated in the pathogenesis of liver fibrosis
PATHOLOGICAL FEATURES
PATHOLOGICAL FEATURES
Alcoholic fatty liver is an early and reversible consequence of
excessive alcohol consumption. Fatty liver develops in every individual
who consumes more than 80 g of alcohol per day. (Robbins)
 CLINICAL FEATURES
Most patients presents with malaise, anorexia, weight loss, upper abdominal
discomfort, tender hepatomegaly and fever.

Pathological Features Clinical Features

Hepatic Steatosis Hepatic steatosis may cause hepatomegaly, with mild
elevation of serum bilirubin and ALP levels.
Alcoholic Hepatitis Jaundice, hepatomegaly
Deteriorates during the first 1-3 weeks in hospital
Alcoholic Cirrhosis Complications of portal hypertension: Variceal
hemorrhage, ascites and encephalopathy
Investigation
The response to steroid therapy can also
be evaluated by the Lille score (>0.45
indicates poor response to steroids, which
can therefore be stopped) and the
Glasgow score. A Glasgow score>9
indicates steroids are necessary because
at >9 the 28-day mortality is 75%, while
at <9 it is 50%. The MELD score is also
used, but does not indicate which patients
need steroid therapy.
END STAGE ALCOHOLIC LIVER DISEASE
The immediate cause of death for patients with ESALD:
Hepatic failure
Massive GI hemorrhage
Intercurrent infection
Hepatorenal syndrome
Hepatocellular carcinoma (3%-6% of cases)
REFERENCES
1. Davidsons Principles and Practice of Medicine, 22nd Edition
2. Robbins Basic Pathology, 9th Edition
3. http://emedicine.medscape.com/article/175472-overview#a1
4. http://emedicine.medscape.com/article/170539-overview
5. Harrisons Principles of Internal Medicine, 19th Edition
6. Kumar and Clarks Clinical Medicine 8th Edition