Alcohol-Related Liver Disease Prognosis

ALCOHOL IN THE ICU:
A HEPATOLOGISTS VIEW OF ALCOHOL-
RELATED LIVER DISEASE (ARLD)
Dr Simon Hazeldine
Gastroenterologist and Hepatologist
Fiona Stanley Hospital
December 2015

The burden of alcohol
• 3.8% global mortality
• 4.6% disability-adjusted life-years (DALYS) lost due to
premature death.
• Australian alcohol consumption

NCEPOD- National Confidential Enquiry into
Patient Outcome and Death (UK, 2013)
2454 cases over 6 months identified
385 reviewed

NCEPOD – ArLD report
• Average age of death 59 and falling.
• 8500 alcohol-related deaths in the UK in 2011

Main points from NCEPOD
• 71% patients that died due to ArLD had an admission to
hospital within the 2 years prior to their death and 46%
within 3-months!
• Patients outcomes were considerably better if cared for by
a specialist.
• Simple things were missed.
• Lack of escalation to higher levels of care and referral to
specialists.
• Missed opportunities for the alcohol services to intervene.

NCEPOD recommendations
• ALL patients presenting to hospital should be screened for
alcohol misuse.
• ALL patients presenting to acute services with a hx of
harmful drinking should be referred to alcohol services
• EACH hospital should have a 7-day alcohol specialist
nurse service, psych liaison and brief interventions /
access to services within 24 hours.
• Integrated Alcohol Care Team
• ALL patients with decompensated liver disease should be
seen by a specialist within 72 hours.
• Close liaison between medical and critical care teams

FSH alcohol in the ICU audit
• Over a 3-month period those patients ‘at risk’ of alcohol
excess including: liver related illnesses, pancreatitis,
seizures, overdoses, GI bleed etc.
• 20% had an admission within the last 3 months and 41%
within the last 2 years.
• Only 80% patients had an alcohol history at all during the
entire admission.
• Of those patients that were documented to drink alcohol
to excess only 12% were referred to the alcohol services.

ICU perspective: What do you want to
know about a patient with ArLD?
• Name, age etc
• Stage of liver disease and complications
• Indication for admission to ICU
• Comorbidities
• Detailed alcohol history
• Likelihood of abstinence
• Prognosis
• Are they on the liver transplant list?

• Threshold can be as low
as 25g ethanol / day
• Binge drinking –
M ≥5 SD in 2 hours
F ≥4 SD in 2 hours
• Consuming 60g alcohol / day

An approach to ArLD
•Bleeding
•Renal impairment and electrolyte abnormalities
•Ascites
•Infection
•Nutrition and Neoplasm
•Encephalopathy
•Social issues

Comorbidities
• Cardiomyopathy
• Mental illness and poly-drug use / addiction
• Pancreatic insufficiency
• Diabetes
• Malnutrition
• Ischaemic heart disease
• Malignancy
• Central and peripheral neuropathy
• Myopathy

Detailed alcohol history: why is this
important?
• Screening tools used are the AUDIT-C, CAGE or ASSIST screening
tool.
• Identify those at risk of
• Complications of liver disease
• Alcohol withdrawal
• Referral to the liver service
• Opportunity to intervene and change drinking behaviour through
referral to alcohol services
• Early identification and intervention in the setting of hazardous
drinking is successful and cost effective in reducing consumption in
primary care (1) and ED (2).
• Up to 65% of patients with early liver disease stopped drinking at
harmful levels simply as a result of being informed of the diagnosis (1)
1. Kaner et al. The Cochrane library. Apr 2007
2. Gornal J. Alcohol and Public health. Under the influence. BMJ 2014

A common first presentation - Alcoholic
hepatitis
• Clinical syndrome
• Recent onset of jaundice +/- decompensation in patients with
recent alcohol misuse +/- tender liver +/- systemic inflammatory
response syndrome
• Lab results
• AST & ALT 1-6 ULN, high Bil & INR, low Alb, moderate CRP (20-
40)

Alcohol-related liver disease management
• Abstinence
• Management of alcohol withdrawal
• Nutritional
• Screen and treat (and repeat)
• Extrahepatic complications (varices)
• Infection
• Renal failure (creatinine increase by 50%)

Alcoholic Hepatitis - Treatment
• Corticosteroids
• Meta-anaylsis in 2011 showed that in severe ASH, corticosteroids
improve survival when compared to placebo (28 day mortality 20%
vs 34%) (1). Can be used in patients with infection if controlled
beforehand.
• Pentoxifylline
• evidence is dwindling
• N-acetylcysteine –
• only improves 1m survival in combination with steroids. Rarely
used (2).
• 1. Mathurin et al Gut 2011
• 2 E Nguyen-Khac et al. NEJM 20

Steroids Or Pentoxifylline for Alcoholic
Hepatitis (STOPAH) trial
• Group A : placebo / placebo Group B : placebo /
prednisolone Group C : pentoxifylline / placebo Group D
: pentoxifylline / prednisolone
• Primary end-point = death at day 28
• Secondary end-point = death or liver transplant at day 90
and 1 year
• Prednisolone 40mg od and or pentoxifylline 400mg tds for
1 month
Stopah trial. NEJM. 2015

STOPAH trial- Results
• Over 3 years, 5234 patients were screened and 1103
patients underwent randomisation.
• 1053 were available for the primary end-point.
• All patients were followed for 12 months or until death.
• The 4 groups were well matched in regards to their
baseline characteristics and lab results.

STOPAH - Results
Died % Lost to f/u % Withdrawn %
28 days 16 1 2
90 days 29 5 3
1 year 56 (died / liver
transplant)
8 4

STOPAH – Factors associated with 28
day mortality

STOPAH – Main points
• The use of steroids did not significantly reduce mortality at
28 days (although there was a trend) and made no
difference at 90 days and 1 year
• In secondary analysis – adjustments made for baseline
determinants of prognosis did reveal a significant
improvement in prognosis with steroids but only short
term (28 days).
• Pentoxifylline added no benefit
• Abstinence (self-reported) rates at 1 year were …………

STOPAH – Main points
• The use of steroids did not significantly reduce mortality at
28 days (although there was a trend) and made no
difference at 90 days and 1 year
• In secondary analysis – adjustments made for baseline
determinants of prognosis did reveal a significant
improvement in prognosis with steroids but only short
term (28 days).
• Pentoxifylline added no benefit
• Abstinence (self-reported) rates at 1 year were
37%!

Alcohol-related liver disease management
• Abstinence
• Management of alcohol withdrawal
• Nutritional
• Screen and treat (and repeat)
• Extrahepatic complications (varices)
• Infection
• Renal failure (creatinine increase by 50%)
• Encephalopathy!!

Prognostic indicators of ArLD in the ICU
• MELD score: creatinine, bilirubin, INR
• Designed initially to improve organ allocation but is more widely
used.
• Studies have failed to demonstrate that other clinical
manifestations of liver decompensation, such as variceal
haemorrhage, HE, new onset ascites or SBP were independent
predictors of survival over and above the MELD score.
• Predicts 3 month mortality
Score Mortality
40 71.3%
30-39 52.6%
20-29 19.6%
10-19 6.0%
<9 1.9% Kamath PS et al. Hepatology. 2001
Kim WR. N Engl J Med. 2008

Prognostic indicators of ArLD in the ICU
• SOFA score: BP/Pressors, plts, bilirubin, GCS, creatinine,
PaO2/FiO2 ratio, mechanical ventilation
• Objective score to organ dysfunction over time, used in
clinical trials
• Not useful in deciding need for admission or predicting
outcome.
Moreno R. Intensive Care Med. 1999

Prognostic factors of ArLD
0
10
20
30
40
50
60
70
80
Alc r fatty
liver
disease
Alc r
hepatitis
(no
cirrhosis)
Alc r
cirrhosis
Alc r Hep
and
cirrhosis
% survival at 48 months
% survival at 48 months
• Alc. fatty liver disease – patients died of other causes not liver related
• Alc. r. hepatitis – ascites, ALT, gms of alcohol consumed, continued intake,
clinical disease severity.
• Alc. r. cirrhosis – INR, histology severity score. ?MELD
• Alc. r. hepatitis + cirrhosis – age, gms of alcohol consumed, AST:ALT ratio, histology,
clinical disease severity
Chedid A. Am J Gastro. 1991

Prognostic factors in ArLD – cirrhotic
patients
0
10
20
30
40
50
60
70
80
90
% survival at 1 year
% survival at 5 years
Jepsen P. Hepatology. 2010

Alcoholic Hepatitis – Prognostic indicators
Altamirano et al. J. Clin. Gastro 2012

Outcomes of decompensated liver
disease
• 165 consecutive patients were followed after there 1st
episode of decompensation alcohol related cirrhosis
(without HCC) and followed up until death.
• Median survival was 61 months.
Long-term Clinical Course of Decompensated Alcoholic
Cirrhosis: A Prospective Study of 165 Patients.
Alvarez, Marco et al. Journal of Clinical Gastroenterology.
45(10):906-911, 2011.

© 2011 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
45(10):906-911, 2011.
TABLE 1. Significant Factors
Correlating With Survival
Prognostic indicators

NCEPOD
• Lack of escalation of care

Outcomes of patients with cirrhosis in the
ICU
• Admission to ICU is associated with improved survival
during the first 3 days of deterioration compared to ward
care (1).
1. Truog R et al. Crit Care Med 200
ICU mortality % Hospital
mortality %
Patients without
cirrhosis
Patients with
cirrhosis (2-4)

ICU
care (1).
mortality %
Patients without
cirrhosis
20
Patients with
cirrhosis (2-4)

ICU
care (1).
mortality %
Patients without
cirrhosis
20 30
Patients with
cirrhosis (2-4)

ICU
care (1).
mortality %
Patients without
cirrhosis
20 30
Patients with
cirrhosis
37
(2-4)

ICU
care (1).
1. Truog R et al. Crit Care Med 2006.
2. Aggarwal A et al. Chest 2001.
3. Olson J et al Hepatology 2011.
4. Harrison et al. Crit Care. 2004.
mortality %
Patients without
cirrhosis
20 30
Patients with
cirrhosis
37 49
(2-4)

ICU
• Mortality is closely related to the number of organs
requiring support.
• MELD and SOFA are strongly associated to 28 day and 1
year mortality in a retrospective cohort study (1). This
study also showed that, as in other studies, improvement
in MELD and SOFA scores at 48 hrs after admission to
ICU predicts improved 28 day and 1 year mortality.
• MELD appears to be more accurate in predicting survival
confirming that liver dysfunction is the main factor in
predicting survival (1).
1. Boone M et al. J Critical Care. 2014

Fig. 2. Hospital mortality in the 246 patients with
cirrhosis admitted to the ICU and who required
mechanical ventilation according to the degree of Acute
on Chronic Liver Failure (ACLF) at admission as
defined by the CLIF-SOFA score.
Eric Levesque et al. J of Hepatol 2014
Fig. 3. Cumulative one-year survival of the 246
patients with liver cirrhosis admitted to the ICU and
who required mechanical ventilation.
Cirrhotic patients requiring ventilation

ICU
• In a study from Kings Hospital, London
• 660 cirrhotic patients admitted to ICU from 2000-2007
• Alcohol 47%, and variceal bleed 37% were the most
common causes for admission
• Invasive ventilation was required in 74% of cases,
vasopressors in 49% and 50% required RRT.
• 50% survived their ICU admission and 34% survived
hospital.
• Patients admitted with variceal bleeding and organ
dysfunction to ICU have a significantly better outcome
than other groups.
Shawcross D. J Hepatol 2012

ICU
• This study showed that patients with alcohol-related liver
disease do not have poorer outcomes or higher hospital
costs than those with cirrhosis from other etiologies (1).
• Just as Wildman and colleagues have shown for patients
with chronic obstructive pulmonary disease and asthma
admitted to ICU in the UK (2).
1. Shawcross D. J Hepatol 2012
2. Wildman M. BMJ. 2007

Outcomes of ‘alcoholics’ in the ICU
• Some studies show that alcohol dependence is
associated with increased rates of sepsis, organ failure
and hospital mortality amongst ICU patients (1).
• Christensen et al. studied 16,848 patients of whom 1229
(7.3%) were deemed to be alcoholic as determined by
ICD 10 codes, past discharge summaries and drug history
(2).
• They divided this group up into those with and without
complications of their alcoholism!
• Compared the 30 mortality of ‘non-alcoholics’ to
‘alcoholics’
Obrien JM. Crit Care Med 2007
Christensen S. Crit Care. 2012

Cumulative mortality curves (percent) for non-alcoholic and alcoholic ICU patients, Aarhus University Hospital Collaboration, 2001-2007.
30-d mortality
%
Adjusted
MRR
3-yr mortality
%
Adjusted
MMR
Non alcoholic
patients
19.7 1.0 40.9 1.0
Alc with
complications
33.6 1.64 64.5 1.67
Alc. Without
complications
15.9 1.04 36.2 1.16
Christensen S. Crit Care. 2012

The effects of abstinence
• The most important intervention is abstinence as it is an
important risk factor for disease progression (1).
• Outcomes improve with abstinence
• Histological improvement
• Decreased rates of progression to cirrhosis
• Reduction in portal pressure
• Decreased rates of variceal rebleeding
• Reduction in hospital admissions
• Improved survival
• Abstinence is more likely in those patients that receive
treatment for dependence or alcohol abuse both
pharmacological and psychosocial.
1. Chedid A. Am J Gastro. 1991

The effect of abstinence on mortality
45(10):906-911, 2011.
FIGURE 1 .
Actuarial probability of
survival in relation o abstinence.

Rates of abstinence relapse
• After an episode of severe alcoholic hepatitis
37% are abstinent at 1 year (1).
• After first diagnosis of decompensated liver
disease 60% remained abstinent at 10 years (2)
• Post liver transplantation reports vary from 10-
50% of “any use” (3,4). 10% of patients resume
heavy drinking after 1 year (5)
1. STOPAH Trial
2. Alverez. Journal Clinical Gastro. 2011
3. Mackie J et al. Liver transpl. 2001
4. Tome S. et al. J Hepatol. 2002
5. Tang et al Gut 1998

A common question from ICU
• Is this patient on the transplant list?

Liver Transplantation for ArLD
• Benefit is restricted to patients with advanced
decompensation (Child’s Pugh score 11-15)(1,2)
• 6-month ‘rule’
• Allow some patients to recover obviating the need
• Helps identify subset of patients likely to maintain abstinence after
liver transplant.
1. Poynard, T. et al. J Hepatol 1999
2. Vanlemmens C. et al. Ann Intern Med 2009

• Early liver transplantation
• Steroid non-responders
• First liver disease event
• Non response by Lille score ≥0.45 or worsening of liver
function by day 7.
• Patients selected on the basis of:
• absolute consensus of paramedical and medical staff
• no co-morbidities
• social integration
• supportive family members
• psychiatric evaluation and addictive profile
Mathurin NEJM 2011

Liver transplant for alcohol related
hepatitis
• By definition the patient is still consuming alcohol
• In the setting of Alc. Hep, if the patient has shown no
improvement by 3 months of medical management,
including abstinence the chance of spontaneous recovery
in patients with ASH and cirrhosis are poor.
• A study has shown an unequivicol improvement of
survival in patients who received early transplant.
Mathurin NEJM 2011

0
25 %
50 %
75 %
100 %
0 50 100 150 180
74.7±9.8%
35±10.7%
p=0.005
Liver Transplantation for Severe Alcoholic Hepatitis
Transplanted
Non-transplanted
Days
Mathurin, NEJM 2011
Liver transplantation for severe alcohol-
related hepatitis

Alcohol in the ICU - Conclusion
• The stage of liver disease and likelihood of abstinence are
strong prognostic factors in predicting outcomes.
• Our main role, in patients with alcohol related liver
disease, is to give their liver the chance to recover by
treating the reversible problems and making sure they are
supported to maximise rates of long-term abstinence.
• Prevention is better than cure. Identification of patients
drinking hazardous amounts of alcohol will make the
biggest impact in the mortality figures.

Alcohol-Related Liver Disease Prognosis

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