Alcoho1l Talk

The Treatment of Alcohol Withdrawal and Alcoholic

Hepatitis

Dr R J Warner

SpR to Dr Summerton

The extent of the problem 1

• >300,000 people in the UK have ETOH related problems

• 5% of males vs. 2% of females report ETOH related problems

• mortality/morbidity is 2-3X general population

The extent of the problem 2

• 30-40% of A&E attendees have ETOH concentrations >legal driving limit

• 20% of male medical admissions are alcohol related

• 1 in 5 “healthy males” attending well-man clinics have biochemical evidence of abuse

• average consumption has increased from 5.2litres in 1950 to 8.5litres in 1991

The extent of the problem 3

The average GP with 2000 patients will have

• 100 heavy drinkers

• 40 problem drinkers

• 10 physically dependant

Percentage of adults with excess alcohol consumption

0

5

10

15

20

25

30

35

40

45

18-24 25-44 45-64 65+ total

malefemale

Symptoms of withdrawal within 12 hours

• agitation

• nausea

• sweating

• misperception

• tremor

Symptoms of withdrawal within 48 hours

Alcoholic fits ( also known as “rum fits”)

• common in alcoholics

• occasionally in single binge drinkers

• subsequent EEG in normal

Alcohol withdrawal after 24 hours- Delirium Tremens

Symptoms• disorientation• agitation• tremor• visual hallucinations

Signs• sweating• tachycardia• tachypnoea• pyrexia• dehydration

Differential Diagnosis for the Alcoholic Patient

• trauma

• metabolic

• toxicology

• infection

• psychiatric

Management of alcohol withdrawal

• General alcohol withdrawal

• Alcoholic seizures

• DTs

• Alcoholic hepatitis

General alcohol withdrawal

• vitamins

• chlordiazepoxide

• fluid balance

• antibiotics if appropriate

• nutrition

• education

Alcoholic Seizures

• ABCDEFG

• iv diazemuls

• consider phenytoin

• oral benzodiazepines

• exclude other causes of seizures

• without an epileptogenic focus there is no role for long term anticonvulsants

DTs

• as for general alcohol withdrawal but more aggressive, especially electrolyte imbalance

• consider iv lorazepam

• avoid haloperidol

• avoid heminevrin

• involve family

Alcoholic Hepatitis• Withdrawal of ETOH often appears to exacerbate

the LFTs• several mechanisms involved, but attention is now

focused on the immune system levels of IgA, ANA, anti ds DNA IL-1, IL-6, IL-8• B & T lymphocytes found in portal/periportal

areas• TNF can induce apoptosis of hepatocytes

Mortality for alcoholic hepatitis

• Overall 30 day mortality ~ 15%

• if severe ~ 50%

• if mild ~ < 5%

• 1 year mortality ~ 40%

Treatment of alcoholic hepatitis 1

Standard treatment

• stop alcohol!

• Vitamins - pabrinex & thiamine

• ? Vitamin K

Treatment of alcoholic hepatitis 2

Treat complications

• fits

• withdrawal

• DTs

• GI bleeding

• encephalopathy

Treatment of alcoholic hepatitis 3

Failed treatments• anabolic steroids (Mendenhall 1993)

oxandrolone had no benefit• propylthiouracil basal metabolic rate of

liver - no benefit in 2 large randomised studies

• parvolex/vitamin E/amlodipine all tried with no benefit

Treatment of alcoholic hepatitis 4

Successful treatments

• transplant

• insulin/glucagon

• nutrition

• corticosteroids

• infliximab

The debate about corticosteroids 1

• >50 studies published over 30 years

• no benefit for mild alcoholic hepatitis

• suppress inflammatory & immune mediated hepatic destruction

• anti-anabolic effects suppress regeneration & may slow healing

risk of complications

The debate about corticosteroids 2

• 3 large meta-analyses favour steroids

• 1 large meta-analysis does not

• overall benefit is for severe disease +/- encephalopathy

• severe alcoholic hepatitis defined by Maddrey’s discriminate factor (DF) >32 (Maddrey et al 1978)

Maddrey’s formula

4.6 x (prothrombin time - control in seconds)

+bilirubin (micromols/litre) /17

The debate about corticosteroids 3

• Ramond et al 1992

• 61 patients with severe disease

• 32 had 40mg prednisolone for 28/7

• 29 had placebo

• 16/29 died by 2 months

• 4/32 died by 2 months

Use of steroids with infliximab 1

• Spahr et al J Hep 2002• first human study (pilot) • 20 patients with severe AH• 11 received prednisolone 40mg &

infliximab 5mg/kg iv• 9 received prednisolone 40mg & placebo• histology, IL-6 & IL-8 were measured @

days 0 & 10

Maddrey’s score

0

5

10

15

20

25

30

35

40

45

day 0 day 10 day 28

placeboinfliximab

Serum bilirubin

0

20

40

60

80

100

120

140

day 0 day 10 day 28

placeboinfliximab

Interleukins

0

50

100

150

200

250

300

350

IL-6 day 0 IL-6 day 10 IL-8 day 0 IL-8 day10

placeboinfliximab

Conclusions from the study

• Infliximab was well tolerated

• significant improvement in Maddrey’s score

• favourable changes in IL levels

• hopefully larger studies will now take place

The last slide!

• Without treatment prognosis for AH is poor

• Many treatment strategies have been tried

• Prednisolone & nutrition are indicated

• Infliximab may have a role