Alcoholic liver disease

Alcohol is one of the most common causes

of chronic liver diseases.
Epidemiology:
Alcoholic liver disease occur when patient
drink >21U/w in female & 24U/w in male.
Most patient with liver disease have drunk
heavily > 5 years.
Average alcohol consumption to develop
cirrhosis 160g/d for an average 8ys.
Amount of alcohol in an average
drink
Beer:3.5%---------440ml/(1pint) in 2 units
9%-------------9%ml(1pint) in 4 units

Wine:10%-------------10% 125 ml in 1 unit.

Vodka: 37.5%----------25ml in one unit.

Alcopops:6%----------330ml in 2 units
 Some of the risk factors for
alcoholic liver disease
Drinking pattern.

Gender.

Genetic.

Nutrition.
 Aetiology
Alcohol is metabolized almost exclusively by
the liver.
80% of alcohol is metabolized by alcohol
dehydrogenase to Acetaldehyde.
Acetaldehyde form adducts with cellular
proteins in hepatocytes which activate
immune system leading to cell injury.
Acetaldehyde metabolized by Acetaldehyde
dehydrogenase to Acetyl Co A & acetate with
generation of NADH from NAD.
 Pathology
 Alcoholic hepatitis:
-Lipogranuloma.
-Neutrophils infiltration.
-Mallory's hyaline.
-Pericellular fibrosis.
 Macrovesicular steatosis.
 Fibrosis & Cirrhosis.
 Central hyaline sclerosis.
 Clinical features
Asymptomatic.

Abnormal liver function tests.

Cirrhosis.

The liver is often enlarged.

Stigmata of chronic liver disease.

 Fatty liver:
-Asymptomatic abnormal liver function tests.
-Normal /large liver.
Alcoholic hepatitis:
-Jaundice.
-Malnutrition.
-Hepatomegaly.
-Features of portal hypertension.
Cirrhosis:
-Stigmata of chronic liver disease.
-Large , normal or small liver.
-ascites , varices, encephalopathy.
-Hepatocellular carcinoma.
 20% of alcohol is metabolized by Mixed
Function Oxidase enzymes in the smooth
endoplasmic reticulum Cytochrom CYP2E1.

Microsomal peroxidation lead to oxygen

free radicals & mitochondrial damage.

Cytokines: These involved in the

fibrogenesis:
1-Increased endotoxines.
2-TNFalpha .from monocytes.
3-Interleukin 1,2 & 8.
Investigations:
Aim: -To establish alcohol misuse.
- Exclude alternative or coexistent
causes of chronic liver disease.
History of alcohol misuse.
Biochemical markers: Macrocytosis in the
absence of anaemia.
Increased GGT is not specific.
Unexplained rib fractures on CXR.
Jaundice suggests alcoholic hepatitis.
Determining the extent of liver damage often
required liver biopsy.
 Maddreys, score ( discriminant function DF ):

enable the clinician to assess prognosis in

alcoholic hepatitis.

DF=4.6 x increased in PT (sec.)+ bilirubin (mg/dl)

Value >32 = severe liver disease with poor prognosis
 Glasgow score:
-Age
-WBC
-Urea
-Prothrombin Time
-Bilirubin

A Score more than 9 is associated with poor

prognosis.
 Management
Cessation of alcohol consumption is
the single most important treatment.
Nutrition:
Corticosteroids: Is of value in severe
alcoholic hepatitis.
Pentoxiphylline:has weak anti-TNF
action may be beneficial in severe
alcoholic hepatitis.
Liver transplantation:
 Prognosis
Alcoholic fatty liver disease: Good&
steatosis usually disappear after 3
months of abstinence.

Alcoholic hepatitis: Worse

prognosis,1/3 die in acute phase.

Alcoholic cirrhosis: 50% only live 5ys.

Non-Alcoholic fatty Liver Disease
(NAFLD)
The most common cause of chronic liver
disease after Hepatitis B & C & alcohol.

Classification:
Simple fatty liver ( Non-alcoholic fatty
liver)
Non-alcoholic steatohepatitis (NASH)
 Epidemiology:
Incidence increased with:
 DM& metabolic syndrome.

 Drugs: eg.Tamoxifen, Amiodarone.

 Exposure to certain Petrochemicals.

 Weight reduction , Jejenal bypass surgery.

 Aetiology & Pathogenesis
Most patients with NAFLD have insulin
resistance.

2 Hits theory:
First hit lead to steatosis ( fatty liver ).
If second hit occur ( leptin is needed) to
cause hepatic fibrosis.
 Clinical features
Asymptomatic with abnormal liver
function tests.

Complications of cirrhosis.

Jaundice is only occurred when

cirrhosis is established.
 Investigations
Liver function tests:
o Increased ALT more than AST
( opposite to alcoholic liver disease )
o Increased Alkaline phosphetase in
some cases.
o Increased transaminases > twice
normal + metabolic syndrome
( Hypertriglycerideamia, HT , DM & BMI
>25) are useful predictor of NASH.
 Ultrasound:
Liver looks bright in both NAFL & NASH.

Liver biopsy:
Fat deposition is usually macrovesicular .
NASH is characterized by neutrophils
infiltration & pericellular fibrosis like alcohol
liver disease but diagnosis of NASH depend
on:
- Absence of alcohol drinking.
- Absence of jaundice.
- Presence of risk factors like obesity ,DM.
 Management
Decreased BMI & Insulin resistance.
Metformine: Improve LFTs & is first choice
for DM & NAFLD.
Thiazolidinediones : as ( Proglitazone )
improve LFTs in NAFLD & may improve
inflammation & fibrosis.
Antioxidants: As Vitamin E are not effective.
No rational to use HMG Co A reductase
Inhibitors statine in the treatment of NAFLD,
but for coexistent hyperlipidaemia.
 Prognosis
Once cirrhosis occurred survival is
similar to hepatitis induced cirrhosis.

Hepatocellular carcinoma complicate

NAFLD induce cirrhosis.
 Drugs ,Toxins & the liver
The liver is the primary site of drug
metabolism.

Liver disease may affect the capacity of

the liver to metabolize drugs .

Unexpected toxicity may occur when

patients with chronic liver disease are
given drugs in normal doses.
 Hepatotoxic drug reaction
Example of common causes of drug-induced hepatotoxicity:
-- Cholestatic:----------------- ---------------Chlorpromazine.
High dose estrogens.
-- Cholestatic hepatitis: ------------------ NSAIDs
Co-Amoxiclav
Statins
-- Acute hepatitis:------------------------- Rifampicin
INH
-- Non-alcoholic steatohepatitis: -----Amiodarone
-- Venous outflow obstruction:--------Busulfan
Azathioprine
-- Fibrosis:------------------------------------Methotrexate
Most drug reactions are acute & self limiting
& chronic liver damage is rare.

LFTs take weeks to return to normal drug

induced hepatitis & it may take months
following cholestatic hepatitis.
The diagnosis of acute drug induced
liver disease
Tabulate drug taken: prescribed ,self administered.
Establish if reported hepatotoxicity in the literature.
Relate time taken to onset of illness (4ds-8ws) usual.
Effect of stopping drugs on normalization of liver
biochemistry. Hepatitis LFTs(2Ms),Cholestatic/Mixed
LFTs(6Ms).
Exclude other causes: like viral hepatitis, biliary
disease.
Consider liver biopsy.
N.B: Challenge tests with drugs should be avoided.
 Types of liver injury
Cholestasis:
-- Estrogen in higher concentration.
-- Chlorpromazine, Flucloxacillin cause
cholestatic hepatitis.
-- Amoxiclav is the most common antibiotic
that cause abnormal LFTs ,but it may not
produce symptoms until 10-42 days after it
is stopped.
-- Anabolic steroid cause cholestatic hepatitis.
 Hepatocytes necrosis:
with high serum transaminase concentration
-- Paracetamol.
-- NSAIDs.
-- INH.
-- Allopurinol : Cause granuloma.
-- Herbal remedies.
-- Cocaine.
 Steatosis:
-- Microvesicular steatosis due to effect on
mitochondrial beta-oxidation.
-- Tetracycline.
-- Na Valproate.
-- Tamoxifen.
-- Amiodarone.
 Vascular / Sinusoidal lesions:
-- Alkylating agents: cause hepatic venous
outflow obstruction.
-- Chronic over dose of Vitamin A: Cause
portal hypertension.

Hepatic fibrosis:
-- Methotrexate :cause cirrhosis when used in
high dose over a long time.
Risk factors include: preexisting liver disease
& high alcohol intake.
 Drugs should be a voided in
cirrhosis
NSAIDs: Decrease renal bl. Flow &
Hepatorenal failure. Ulceration cause
bleeding varices.
ACE Inhibitors: decrease renal bl.flow:
Hepatorenal failure.
Codeine: Constipation: Hepatic
encephalopathy.
Narcotics: Constipation & drug
accumulation: Hepatic encephalopathy
Anxiolytics: Drug accumulation & hepatic
encephalopathy