Alcohol related liver disease

Definition
Alcoholic liver disease (ALD) is a clinical and histological spectrum of
disease which includes fatty liver (FL) at one extreme and alcoholic cirrhosis
(AC) at the other.

FL is generally benign and asymptomatic and occurs in patients who abuse

alcohol for a period of days to weeks. FL is entirely reversible with alcohol
abstinence.

Continued alcohol abuse risks more advanced disease with the

development of alcoholic hepatitis (AH) where there is inflammation of the
liver. AH can lead to formation of fibrotic tissue and cirrhosis.

Progression of alcohol related liver disease. Click on image to enlarge

Alcoholic cirrhosis occurs in only 8-20% of alcoholic patients and AH in 6-

30%.

Risk factors for progression of ALD

 Female sex
 Genetics
 Advanced age
 Induction of liver enzymes by drugs
 Co-existent viral hepatitis especially hepatitis C
Pathophysiology
The development of ALD is multifactorial. Alcohol is metabolised in the liver
by progressive enzymatic oxidation to form acetaldehyde then acetate.
Note the first oxidation of alcohol to acetaldehyde may occur via one of
three pathways:

 Alcohol dehydrogenase (ADH) most important pathway

 Cytochrome P450 E21 (CYPE21)
 Catalase

The second oxidation of acetaldehyde to acetate is via aldehyde

dehydrogenase (mainly ALDH2). In addition to the production of
acetaldehyde and acetate these oxidations involve co-enzymes such as
nicotinamide adenine dinucleotide (NAD) and result in the production of
damaging reactive oxygen species (ROS).

Alcohol metabolism by hepatocytes. Click on image to enlarge

Factor Notes
NADH There are 3 enzymes involved in the conversion of ethanol to acetaldehyde, of
which alcohol dehydrogenase (ADH) is the primary enzyme.

The conversion of ethanol to acetaldehyde by ADH requires the co-enzyme

nicotinamide adenine dinucleotide (NAD) which is converted from its oxidised form
NAD+ to its reduced form NADH during the reaction resulting in an increased
NADH:NAD+ ratio.

The NADH:NAD+ ratio controls a number of redox reactions within cells and its
increase can lead to cellular metabolic dysregulation including increased fatty acid
and triglyceride synthesis. NADH itself is metabolised by a series of oxidations
which increases the oxygen demand of hepatocytes and can lead to cellular hypoxia
 Factor Notes
if this oxygen demand is not met
Acetate Acetate may be oxidised to form CO2 or metabolized to acetyl CoA. Acetyl CoA is
a substrate for several lipids. Acetate therefore promotes cholesterol biosynthesis
and fatty liver transformation
Acetaldehyd There are several mechanisms by which acetaldehyde damages liver cells:
e

 Increased production of reactive oxygen species leading to oxidative stress

 May bind to proteins such as enzymes, microsomal proteins, and
microtubules interfering with their normal functioning. Consequences
include up regulation of cytokine production and dysfunctional collagen
deposition leading to inflammation and fibrosis.
 Acetaldehyde bound proteins may provoke an antigenic immune response
causing inflammatory damage to surrounding tissues

Genetics Several enzyme systems are involved in the metabolism of alcohol. Polymorphism's
of these systems (ALDH2, CYPE21 and cytokines TNF, IL1, IL10)
can increase hepatic damage via enhancing the pathological effects outlined above

Hepatitis C
Hepatitis C infection (HCV) and alcohol have an additive deleterious effect
on the liver. Alcohol is thought to suppress the immune response to HCV
and reduce viral clearance.

Alcohol excess and HCV both independently increase iron load in

hepatocytes. The effect is cumulative if both co-exist.

Signs & symptoms

Many patients with fatty liver will be asymptomatic with hepatomegaly on
clinical examination often the only finding. Early liver damage is often
diagnosed incidentally on routine blood tests.

Those with early liver damage who are symptomatic will often have non-
specific symptoms, such as abdominal discomfort, vomiting or anxiety. It is
not uncommon for these patients to first present to the ED following falls
or injuries sustained whilst intoxicated.

Patients with alcoholic hepatitis will typically be unwell with pyrexia and
anorexia. Liver function tests will be deranged and they may show clinical
signs of chronic liver damage.
Patients with advanced liver disease may show signs of portal hypertension
and cirrhosis. These include:

 Ascites
 Varices (rectal and oesophageal)
 Umbilical varices (caput medusae)
 Jaundice
 Cutaneous signs including spider angiomas and palmar erythema
 Encephalopathy
 Bleeding (impaired synthetic function reduces clotting factors)

Photo illustrating paraumbilical varices (caput medusae). Click on image to enlarge

Photo illustrating massive ascites. Click on image to enlarge

Screening tools for hazardous drinking

A number of screening tools exist and are in use around the UK. These
include:

 CAGE questionnaire
 FAST (Fast alcohol screening tool)
 PAT (Paddington Alcohol Test)
 AUDIT (Alcohol Use Disorders Identification Test) or AUDIT PC

AUDIT is preferred by NICE and is shown below:

 Question 0 1 2 3 4
How often do you have a drink Never Monthly 2-4 times a 2-3 times a 4 or more
containing alcohol? or less month week times a
week
How many units of alcohol do you drink 0-2 3-4 5-6 7- 9 10 or more
on a typical day when you are drinking?
How often have you had 6 or more units Never Less than Monthly Weekly Daily or
if female, or 8 if male, on a single monthly almost
occasion in the last year? daily
How often during the last year have you Never Less than Monthly Weekly Daily or
found you were not able to stop drinking monthly almost
once you had started? daily
How often during the last year have you Never Less than Monthly Weekly Daily or
failed to do what was normally expected monthly almost
from you because of your drinking? daily
How often during the last year have you Never Less than Monthly Weekly Daily or
needed an alcoholic drink in the morning monthly almost
to get yourself going after a heavy daily
drinking session?
How often during the last year have you Never Less than Monthly Weekly Daily or
had a feeling of guilt or remorse after monthly almost
drinking? daily
How often during the last year have you Never Less than Monthly Weekly
been unable to remember what happened monthly Daily or
the night before because you had been almost daily
drinking?
Have you or somebody else been injured No Yes, but not Yes,
as a result of your drinking? in the last during the
year last year
Has a relative or friend, doctor or health No Yes, but not Yes,
worker been concerned about your in the last during the
drinking or suggested that you cut it year last year
down?

Score Interpretation
0-7 indicates low-risk
8-15 indicates increasing risk
16-19 indicates higher risk
20 or more indicates possible dependence

Alcohol consumption definitions

Hazardous drinking (increasing risk drinking):

A pattern of alcohol consumption that increases someone's risk of harm.
Consumption in units per week:

 Drinking >14 units but <35 units a week for women.

 Drinking > 14 units but <50 units a week for men

Harmful drinking (high-risk drinking):

A pattern of alcohol consumption that is causing mental or physical
damage.

Consumption (units per week):

 Drinking ≥ 35 units a week or more for women.

 Drinking ≥ 50 units a week or more for men.

Investigations

 Liver function tests: especially AST:ALT ratio, gamma-

glutamyltransferase & albumin
 FBC: Low platelets and elevated MCV in ALD due to toxic effects of
alcohol on bone marrow
 PT: Prolonged in advanced ALD due to impaired synthesis of
coagulation factors
 Ultrasound +/- liver biopsy are typically organised by
gastroenterology if required.

Liver function tests

Both AST and ALT enzymes require pyridoxal-5’-phosphate (vitamin B6) to
function properly. Its absence in nutritionally-deficient heavy-drinkers has a
much larger effect on the production of ALT than that of AST, causing the
AST:ALT ratio to rise.

A normal AST:ALT ratio should be <1. In patients with alcoholic liver

disease, the AST:ALT ratio is >1 in 92% of patients, and >2 in 70%.
AST:ALT scores >2 are, therefore, strongly suggestive of alcoholic liver
disease and scores <1 more suggestive of NAFLD/NASH.

GGT is often raised but has low sensitivity and specificity. Albumin may be
low due to impaired synthetic function.

Management
Advice:

 10 minutes of advice in those found to have hazardous drinking (men

≥ 5 units/day or women ≥3 units per day) has been shown to have
benefit & reduce alcohol intake before it becomes harmful.
 Those with ALD should be advised on taking a high protein diet.

Thiamine administration:

 Thiamine should be given to all ALD patients who attend the ED.
 Thiamine should ideally be administered before a glucose load to
prevent triggering Wernicke's
 Thiamine is poorly absorbed orally in dependent alcohol drinkers so
should ideally be given parenterally.
 Multivitamins are often co-prescribed given these patient's are at
high risk of nutritional deficiency. Magnesium deficiency is common
and magnesium levels should be checked and supplemented of
appropriate.

Withdrawal:

 Patients with withdrawal symptoms may require benzodiazepines

such as chlordiazepoxide to prevent seizures and relieve symptoms

Management of complications
There are a number of complications that may arise from ALD. These
include:
  Intoxication and coma
 Encephalopathy
 Oesophageal varices & massive haemorrhage
 Ascites and liver synthetic function derangement
 Hypoglycaemia
 Coagulopathy

Management of each individual complications is beyond the scope of this

overview but the ED clinician should take an ABC approach and involve
appropriate specialities early for specialist interventions e.g. ligation of
varices.

Wernicke Korsakoff' Syndrome

Heavy alcohol use leads to vitamin B1 (thiamine) deficiency via poor
nutritional intake and impaired absorption. Severe deficiency can lead to
Wernicke's encephalopathy which is an acute neurological condition caused
by thiamine deficiency characterised by confusion, ataxia, hypothermia,
hypotension, nystagmus and vomiting.

Untreated this may progress to Korsakoff's psychosis hence the conditions

may be collectively referred to as Wernicke Korsakoff' Syndrome

Exam questions often ask about Wernicke's triad of altered mental status,
ataxic gait and ophthalmoplegia. In real life this triad is only present in
around 10% of patient's with Wernicke's.

This patient group is at risk of subdural haematoma and delirium

tremens which may present similarly to Wernicke's