ALCOHOLIC LIVER DISEASES.
LIVER
Liver is Shaped like a wedge with its base to the right, the liver lies
in the right and left upper quadrants (mainly on the right side)
inferior to the diaphragm which separates it from the pleura, lungs,
pericardium and heart.
Liver is the Largest
solid organ in the body it Performs over 500 chemical processes,Produces
over 160 different proteins,Makes clotting factors for the blood,Stores
& releases sugar as glycogen,Metabolizes, detoxifies, synthesizes,The
role of the liver — the largest internal organ is complex and varied.
FUNCTIONS
OF LIVER INCLUDES
Liver
perform many functions at all.Hundreds of functions are performed by the
liver ranging from:- - Metabolism
- Detoxification from our blood,
- Fighting off infection,
- Controlling blood sugar levels,
- Manufacture hormones and proteins
- Synthesis function
ALCOHOLIC
LIVER DISEASE
What is Alcoholic Liver Disease?
As the name implies, alcoholic liver disease is liver injury
attributed to alcohol abuse. The majority of Americans manage to drink alcohol
without serious consequences. Research suggests, however, that liver disease
may begin to develop after a "threshold" dose of alcohol has been
consumed—generally assumed to be four drinks a day (four 12 ounces beers, four
glasses of wine, or four ounces of hard liquor) for men, and one half that
quantity for women. Nearly everyone who consumes this amount or more will have
some evidence of liver injury, although less than 50% will develop serious
liver disease.
Symptoms of alcoholic liver
The range of clinical features of alcoholic liver disease
varies, from asymptomatic to end-stage liver disease with portal hypertension,
jaundice and encephalopathy Patients may
present with nonspecific digestive tract symptoms such as nausea, dry retching,
diarrhea, anorexia, and abdominal pain—but often they wait until severe liver
decompensation forms before consulting a physician. Patients may also seek
medical attention as a result of the consequences of alcoholism, which may
include accidents, violent behavior, depression, tremors, poor work
performance, or social disruptions.
Fatty liver is usually asymptomatic. On evaluation
hepatomegaly is present in 70% of patients and there may be mild abnormalities
in transaminases.Patients with alcoholic hepatitis may also be asymptomatic.
Hospitalized patients usually have jaundice and hepatomegaly and may exhibit
ascites, encephalopathy,and fever depending on the severity of their disease.
Signs and symptoms of
alcohol-related liver disease.
Most patients with alcohol-induced cirrhosis have
hepatomegaly and/or splenomegaly. Clinical presentation is similar to other
forms of end-stage liver disease but
may be accompanied by concurrent alcoholic hepatitis. Spider
angiomata are frequently found in this patient population, along with palmar
erythema, enlargement of parotid and lacrimal glands, testicular atrophy,
ascites, venous collaterals, jaundice and encephalopathy.
Stages of alcoholic
liver disease
Alcoholic liver disease is defined by three stages of liver
damage following chronic heavy alcohol consumption: fatty liver, alcoholic
hepatitis, and fibrosis/cirrhosisHowever, the assumption that alcoholic liver
disease always progresses linearly from alcoholic fatty liver, to alcoholic
hepatitis and ultimately to cirrhosis is not correct.
histologically
detectable liver damage often overlap—and some cases of alcoholic liver disease
never progress, regardless of the patient’s continued ethanol abuse.Fatty
liver, or steatosis, is an abnormal accumulation of fat in the parenchymal
cells of the liver and can occur within hours of significant alcohol intake. In
the majority of patients (90%) it is associated with palpable liver
enlargement. Fat deposits accumulate predominantly in the central and mid-zonal
areas of the liver (zones 3 and2) and may be macrovesicular (large droplets) or
microvesicular (small droplets). Other conditions, such as nonalcoholic fatty
liver disease, drug toxicity and fatty liver of pregnancy may cause steatosis
that is indistinguishable from alcoholic fatty liver. Fatty liver is a
completely reversible lesion, assuming the patient abstains from alcohol.
One-third of chronic heavy alcohol
users develop alcoholic hepatitis and most will have no symptoms. The prognosis
is variable and depends on the severity of disease. Classic signs of alcoholic
hepatitis include fatty changes, necrosis of liver cells, Mallory bodies and
perivenular inflammatory infiltrates (especially neutrophils). Mallory bodies,
eosinophilic collections of intermediate filaments found in the cytoplasm, are
detected in most patients with alcoholic hepatitis but also occur with other
liver diseases.
Fibrosis (or scar formation) first
begins in the pericentral zone and then progresses if injury continues. If
fibrosis is found on biopsy, it predicts a progression to cirrhosis or
end-stage liver disease. Alcoholic cirrhosis is of the micronodular type. The
normal lobular architecture is obscured and central veins are difficult to
locate.
The amount of fat is variable and
alcoholic hepatitis may or may not be present. Continuing necrosis and fibrosis
results in the progression from a micro- to a macronodular pattern. This
progression is accompanied by a reduction in steatosis in end-stage liver
disease. Cirrhosis is not reversible.
Alcoholic Liver Disease: Causes
Introduction
Although alcohol ingestion is required to develop alcoholic
liver disease, not everyone who consumes the "threshold dose" of alcohol
will develop the disease.Amazingly, nearly 50% of individuals who ingest large
amounts of ethanol are spared serious injury. In addition to the amount and duration
of alcohol use, several other factors have been linked to an increased risk for
the development of liver disease. These include genetics, gender, viral liver
disease, nutrition, and exposure to other hepatotoxins.
Genetics
Polymorphisms exist in the enzymes ADH, CYP2E1, and ALDH.
Differences in ADH and ALDH certainly contribute to the negative association
with ethanol dependence in some Asian populations. HLA phenotypes, a genetic
predisposition toward alcoholism and female gender may also contribute to
overall risk.
Viral Liver Disease
Concurrent viral hepatitis increases the incidence of liver
injury in alcoholics. Studies have shown that alcoholics co-infected with hepatitis
C virus (HCV), (but not necessarily hepatitis B virus), develop liver injury at
a younger age and with a lower cumulative dose of alcohol than those not
infected with HCV. These patients also have a much higher chance of developing
cirrhosis and hepatocellular cancer compared to alcoholics without hepatitis C Hepatitis B
virion; C, Hepatitic C virion.
Nutrition
Initial hypotheses suggested that alcoholic liver disease
was a result of alcohol intake in the face of poor nutrition. Today, however,
it is understood that while malnutrition may worsen the severity of disease and
obesity may increase the risk of developing disease, alcoholic liver disease
does indeed occur in well-nourished individuals. Nutrition probably plays a
role in hepatotoxicity. Current research suggests that patients with diets
deficient in essential nutrients are more susceptible to the development of
liver damage. Alcohol ingestion promotes the absorption of iron from the
intestine, increasing hepatic iron stores. Iron acts as an electron donor, accelerating
the generation of unstable free oxygen radicals. In addition to contributing to
membrane injury, this may also exacerbate inflammatory response.
Hepatotoxin Exposure
In general, two insults are worse than one. Just as viral
hepatitis increases the risk to develop alcohol related liver injury, other
hepatotoxins may act synergistically or additively with alcohol. This is
especially true with acetaminophen and vitamin A overdose.
Pathogenesis
Several factors have been proposed to explain the
pathogenesis of alcoholic liver injury. These include:
·
Variations in alcohol metabolism
·
Centrilobular hypoxia
·
Inflammatory cell infiltration and activation
·
Antigenic adduct formation
·
Variations in alcohol metabolism
Alcohol must be metabolized in order for liver injury to occur,
and there are several pathways that contribute to its metabolism.
The major pathway occurs in the liver and begins by breaking
ethanol into acetaldehyde via the enzyme alcohol dehydrogenase (ADH) . This in
turn is broken down to acetate by the enzyme acetaldehyde dehydrogenase (ALDH).
There is considerable genetic variability in both of these enzymes, which may
account for differences in blood alcohol levels but does not predict
susceptibility to liver disease. Asians typically have efficient ADH but
deficient ALDH. This allows acetaldehyde to build up causing flushing,
tachycardia, hypotension and, usually, an aversion to alcohol.
When alcohol concentration overwhelms the ADH pathway, it is
typically oxidized by the microsomal ethanol oxidizing system (MEOS) and
catalase. Generally, these pathways are more likely to generate injurious
byproducts. Cytochrome P-450 2E1 (CYP2E1), a critical enzyme in MEOS, is
up-regulated with chronic alcohol ingestion. Polymorphisms of CYP2E1 also exist
and may correlate with differences in susceptibility to hepatocellular (liver)
damage. In addition, CYP2E1 is responsible for metabolizing other drugs such as
acetaminophen. This may help explain an alcoholic's increased risk to
Tylenol®-induced liver injury even at recommended doses.
Centrilobular hypoxia
Liver injury is most prominent in the zonal region
surrounding the central vein. This area is furthest from oxygenated blood and
has the highest concentration of
CYP2E1, suggesting that oxygen debt contributes to injury
Inflammatory cell infiltration and
activation
Pro inflammatory cytokines and inflammatory cells are often
found in the blood and liver of patients with alcoholic hepatitis. Although several
cytokines are present in patients with alcohol related liver injury, studies
have concentrated on interleukin-8 (IL-8) and tumor necrosis factor-alpha
(TNF-alpha) as both correlate inversely with prognosis. These mediators may
contribute to injury by promoting leukocyte adherence and activation. Kupffer cells
(macrophages in the liver) may also be an important source of injury as they
produce inflammatory and fibrogenic cytokines after being activated by alcohol.
Chronic alcohol ingestion ultimately increases intestinal permeability,
allowing endotoxins into the portal blood (Figure 4). This may exaggerate the
release of cytokines and oxygen radicals from alcohol-primed Kupffer cells.
Antigenic adduct formation
Ethanol is metabolized to acetaldehyde and can also result
in the formation of hydroxyethyl radicals. These radicals bind to hepatocellular
proteins altering the proteins (forming adducts that are antigenic) and
provoking an immune response. The contribution of autoimmunity in alcoholic
liver injury is not clear. Antibodies to these adducts are found in serum from
alcoholic patients. Animal studies have shown that guinea pigs immunized with
acetaldehyde-protein adducts develop hepatic injury and fibrosis after ethanol
ingestion. Other studies suggest that these adducts are not always located in
areas that are accessible to the production of an immune response (e.g.,
retained within the hepatocyte).
Alcoholic
Liver Disease: Diagnosis
History
A history of
habitual ethanol consumption is key in suggesting alcohol as the cause of liver
disease. The type of beverage most often consumed, be it beer, wine, or
distilled spirits
does not influence the likelihood of ethanol-induced hepatotoxicity. Alcohol
intake at two or more drinks a day should raise suspicion as patients may
underestimate their
intake or have concomitant hepatic insults.
Biochemical
Tests
Blood tests are
useful in the evaluation of disorders of the liver and biliary system. There
are several laboratory abnormalities characteristic of alcoholic liver disease.
However, these
abnormalities do not necessarily correlate with disease severity.
Aminotransferases
Aminotransferase
abnormalities are common in alcoholic liver disease. A disproportionate
increase of serum aspartate aminotransferase, AST (SGOT) compared to
alanine
aminotransferase, ALT (SGPT) is highly suggestive of alcoholic liver injury—
especially if the ratio of AST:ALT is greater than 2.0. Aminotransferase levels
are
generally lower
than 300 IU/L, and other etiologies for liver disease should be considered if
the enzymes concentrations are higher than this.
Gamma
glutamyl transpeptidase
Gamma glutamyl
transpeptidase (GGTP) is a membrane-associated enzyme involved in the uptake of
amino acids. Increased serum activity of GGTP is often found
in chronic alcohol
users—in fact, over 70% of alcoholic individuals have elevated GGTP activity.
Unfortunately, several other medications also increase GGTP and
therefore this
value must only be considered in combination with other laboratory and clinical
information.
Hematologic
and electrolyte abnormalities
Mean corpuscular
volume (MCV), serum uric acid levels and serum electrolytes are all affected by
chronic alcohol consumption. In addition, although symptoms may
be nonspecific,
increased serum uric acid, hypokalemia, hypomagnesemia and acidosis are
indicators that alcohol may play a significant role in liver disease. Alcohol
related bone marrow
toxicity and/or splenic sequestration might contribute to macrocytosis
(increased MCV) and thrombocytopenia. Leukocytosis is frequent in
individuals with
alcoholic hepatitis and may correlate with disease severity.
Prothrombin
time (PT)
This blood test is
not of great diagnostic value in the detection of mild hepatocellular
dysfunction. A mild increase may more accurately reflect poor nutrition
(vitamin K
deficiency) than
liver disease. However, when combined with bilirubin to generate a discriminant
function (Discriminant function = 4.6 [PT (seconds) - control] bilirubin
(mg/dL). A value
greater than 32 is associated with high mortality), PT may predict the severity
of liver disease in hospitalized alcoholics with hepatitis and ultimately
help guide therapy
(see therapy).
Liver
Biopsy
Alcoholic hepatitis
may require a biopsy for definitive diagnosis (Figure 11). In the absence of a
liver biopsy, however, a diagnosis can be made on a history of
chronic, current,
heavy alcohol consumption, clinical and biochemical data and the exclusion of
other etiologies such as viral hepatitis. Noninvasive tests such as
ultrasonography and
serologies complement a thorough history and physical examination. Histology is
the most sensitive measure of disease stage and is a useful
prognostic
indicator of disease course. It is currently the only reliable method to
estimate the degree of a patient’s fibrosis. Fatty liver changes alone are not
as
serious as
perivenular sclerosis (a precursor of cirrhosis). Biopsy can also confirm the diagnosis
of cirrhosis.
Ultrasound
Ultrasound is
noninvasive, easy to perform and has no known accompanying risks. It is often
used as a screening tool in patients with hepatic dysfunction. Abdominal
ultrasound,
however, is not able to detect minimal changes in the liver or to distinguish
fibrotic changes and therefore cannot predict those patients at risk to develop
cirrhosis.
Computed
Tomography
CT scanning is useful in the diagnosis
of cirrhosis, portal hypertension and liver masses.
In other way we can sy that Alcoholic liver disease
is a term that encompasses the liver manifestations of:-
·
alcohol overconsumption,
·
including fatty liver, alcoholic
hepatitis, and
·
chronic hepatitis with liver fibrosis or
cirrhosis
- Alcoholic liver It is the major cause of liver disease in Western countries.
- Of all chronic heavy drinkers, only 15–20% develop hepatitis or cirrhosis, which can occur concomitantly or in succession.
- The mechanism behind this is not completely understood.
- 80% of alcohol passes through the liver to be detoxified.
- Chronic consumption of alcohol results in the secretion of pro-inflammatory:-
- cytokines
- TNF-alpha
- Interleukin 6
- Interleukin 8
- lipid peroxidation
- acetaldehyde toxicity.
- These factors cause inflammation, apoptosis and eventually fibrosis of liver cells.
- Why this occurs in only a few individuals is still unclear.
- Additionally, the liver has tremendous capacity to regenerate and even when 75% of hepatocytes are dead, it continues to function as normal.
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