Liver and biliary tract

disease

Dr. Ciise
 2. ALCOHOLIC LIVER
DISEASE

• Alcohol is one of the most common

causes of chronic liver disease
worldwide, with consumption
continuing to increase in many
countries .
• Patients with alcoholic liver disease
(ALD) may also have risk factors for
other liver diseases (e.g. coexisting
NAFLD or chronic viral hepatitis
infection), and these may interact to
increase disease severity.
• In the UK, a unit of alcohol contains 8 g
of ethanol (Box 23.51).
• A threshold of 14 units/week in
women and 21 units/week in men is
generally considered safe.
• The risk threshold for developing ALD
is variable but begins at 30 g/day of
ethanol.
• However, there is no clear linear
relationship between dose and liver
damage.
• For many, consumption of more than 80
g/day, for more than 5 years, is required
to confer significant risk of advanced liver
disease.
 Some of the risk factors for ALD are:

A. Drinking pattern. ALD and alcohol

dependence are not synonymous; many
of those who develop ALD are not
alcohol-dependent and most dependent
drinkers have normal liver function.
B. Gender.
•The incidence of alcoholic liver disease is
increasing in women, who have higher
blood ethanol levels than men after
consuming the same amount of alcohol.
•This may be related to the reduced volume
of distribution of alcohol.
C.Genetics.
•Alcoholism is more concordant in
monozygotic than dizygotic twins.
•Whilst polymorphisms in the genes
involved in alcohol metabolism, such as
aldehyde dehydrogenase, may alter
drinking behaviour, they have not been
linked to ALD
• Recently, the patatin-lik phospholipase
domain-containing 3 (PNPLA3) gene, also
known as adiponutrin, has been
implicated in the pathogenesis of both
ALD and NAFLD .
 D .Nutrition

• Obesity increases the incidence of liver-

related mortality by over fivefold in heavy
drinkers.
• Ethanol itself produces 7 kcal/g (29.3
kJ/g) and many alcoholic drinks also
contain sugar, which further increases the
calorific value and may contribute to
weight gain.
• Excess alcohol consumption is frequently
associated with nutritional deficiencies
that contribute to morbidity.
 Pathophysiology

• Alcohol reaches peak blood concentrations

after about 20 minutes, although this may be
influenced by stomach contents.
• It is metabolised almost exclusively by the
liver via one of two pathways (Fig. 23.28).
• Approximately 80% of alcohol is metabolised
to acetaldehyde by the mitochondrial
enzyme, alcohol dehydrogenase (ADH).
• Acetaldehyde is then metabolized to acetyl-
CoA and acetate by aldehyde dehydrogenase.
• This generates NADH from NAD
(nicotinamide adenine dinucleotide),
which changes the redox potential of the
cell.
• Acetaldehyde forms adducts with cellular
proteins in hepatocytes that activate the
immune system, contributing to cell
injury.
• The remaining 20% of alcohol is
metabolised by the microsomal ethanol-
oxidising system (MEOS) pathway.
• Cytochrome CYP2E1 is an enzyme that
oxidises ethanol to acetate. It
• It is induced by alcohol, and during
metabolism of ethanol it releases oxygen
free radicals, leading to lipid peroxidation
and mitochondrial damage.
• The CYP2E1 enzyme also metabolises
acetaminophen, and hence chronic
alcoholics are more susceptible to
hepatotoxicity from low doses of
paracetamol.
• All of these cytokines have been
implicated in the pathogenesis of liver
fibrosis (see Fig. 23.4, p. 925).
• The pathological features of alcoholic liver
disease are shown in Box 23.52.
• In about 80% of patients with severe
alcoholic hepatitis, cirrhosis will coexist at
presentation.
• Iron deposition is common and does not
necessarily indicate haemochromatosis
• Figure 23.30 (p. 960) shows the
histological features of alcoholic liver
disease, which are identical to those of
non-alcoholic steatohepatitis.
 Clinical features

• ALD has a wide clinical spectrum ranging

from mild abnormalities of LFTs on
biochemical testing to advanced cirrhosis.
• The liver is often enlarged in ALD, even in
the presence of cirrhosis.
• Stigmata of chronic liver disease, such as
palmar erythema, are more common in
alcoholic cirrhosis than in cirrhosis of
other aetiologies.
• Alcohol misuse may also cause damage of
other organs and this should be
specifically looked for (see Box 10.35, p.
253).
 types of ALD
• Three types of ALD are recognized (Box
23.53) but these overlap considerably, as
do the pathological changes seen in the
liver.
 Alcoholic fatty liver disease

• Alcoholic fatty liver disease (AFLD)

usually presents with elevated
transaminases in the absence of
hepatomegaly.
• It has a good prognosis and steatosis
usually disappears after 3 months of
abstinence
 Alcoholic hepatitis

• This presents with jaundice and

hepatomegaly; complications of portal
hypertension may also be present.
• It has a significantly worse prognosis than
AFLD.
• About onethird of patients die in the acute
episode, particularly those with hepatic
encephalopathy or a prolonged PT
• Cirrhosis often coexists; if not present, it is
the likely outcome if drinking continues.
• Patients with acute alcoholic hepatitis
often deteriorate during the first 1–3
weeks in hospital.
• Even if they abstain, it may take up to 6
months for jaundice to resolve.
• In patients presenting with jaundice who
subsequently abstain, the 3- and 5-year
survival is 70%.
• In contrast, those who continue to drink
have 3- and 5-year survival rates of 60%
and 34% respectively.
 Alcoholic cirrhosis

• Alcoholic cirrhosis often presents with a

serious complication, such as variceal
haemorrhage or ascites, and only half of
such patients will survive 5 years from
presentation.
• However, most who survive the initial
illness and who become abstinent will
survive beyond 5 years
 Investigations

• Investigations aim to establish

– alcohol misuse,
– to exclude alternative or additional coexistent
causes of liver disease and
– to assess the severity of liver damage.
• The clinical history from patient,
– alcohol misuse duration
– and severity.
• Biological markers, particularly
macrocytosis in the absence of anaemia,
may suggest and support a history of
alcohol misuse.
• A raised GGT is not specific for alcohol
misuse and may also be elevated in the
presence of other conditions, including
NAFLD
• The level may not therefore return to
normal with abstinence if chronic liver
disease is present, and GGT should not be
relied on as an indicator of ongoing
alcohol consumption .
• The presence of jaundice may suggest
alcoholic hepatitis.
• Determining the extent of liver damage
often requires a liver biopsy .
• In alcoholic hepatitis, PT and bilirubin are
used to calculate a ‘discriminant function’
(DF), also known as the Maddrey score,
which enables the clinician to assess
prognosis (PT = prothrombin time; serum
bilirubin in μmol/L is divided by 17 to
convert to mg/dL):
• DF Increase in PT (= [4.6 ¥ sec)]+Bilirubin
(mg/dL)
• A value over 32 implies severe liver
disease with a poor prognosis and is used
to guide treatment decision.
• A second scoring system, the Glasgow
score, uses the age, white cell count and
renal function, in addition to PT and
bilirubin, to assess prognosis with a cutoff
of 9 (Box 23.54).
 Management

• Cessation of alcohol consumption is the

single most important treatment and
prognostic factor.
• Life-long abstinence is the best advice.
General health and life expectancy are
improved when this occurs, irrespective of
the stage of liver disease
• Abstinence is even effective at preventing
progression, hepatic decompensation and
• death once cirrhosis is present.
• Treatment of alcohol dependency is
discussed on page 253.
• In the acute presentation of ALD it is
important to identify and anticipate
alcohol withdrawal and Wernicke’s
encephalopathy, which need treating in
parallel with the liver disease and any
complications of cirrhosis.
 Nutrition

• Good nutrition is very important, and

enteral feeding via a fine-bore nasogastric
tube may be needed in severely ill
patients.
 Corticosteroids

• These are of value in patients with severe

alcoholic hepatitis (Maddrey’s
discriminative score > 32) and increase
survival (Box 23.55).
• A similar improvement in 28-day survival
from 52% to 78% is seen when steroids are
given to those with a Glasgow score of
more than 9.
• Sepsis is the main side-effect of steroids,
and
• existing sepsis and variceal haemorrhage
are the maincontraindications to their use.
If the bilirubin has not
• fallen 7 days after starting steroids, the
drugs are unlikely
• to reduce mortality and should be stopped
 Pentoxifylline

• Pentoxifylline, which has a weak anti-TNF

action, may be beneficial in severe
alcoholic hepatitis. It reduces the
incidence of hepatorenal failure and its
use is not complicated by sepsis (Box
23.56)
• It is not known whether corticosteroids,
pentoxifylline or a combination is superior
in the treatment of alcoholic hepatitis.
 Liver transplantation

• The role of liver transplantation in the

management of ALD remains
controversial. In many centres, ALD is a
common indication for liver
transplantation.
• The challenge is to identify patients with
an unacceptable risk of returning to
harmful alcohol consumption.
• Many programmes require a 6-month
period of abstinence from alcohol before a
patient is considered for transplantation.
• Although this relates poorly to the
incidence of alcohol relapse after
transplantation, liver function may
improve to the extent that transplantation
is no longer necessary
• The outcome of transplantation for ALD is
good and, if the patient remains abstinent,
there is no risk of disease recurrence.
Transplantation for alcoholic hepatitis has
a poorer outcome and is seldom
performed.