alcoholic liver disease strategies for seamless care

Alcoholic Liver Disease –

Strategies for Seamless Care

or

An Clinical Approach to the

Jaundiced Alcoholic Patient

Dr Ewan Forrest

Glasgow Royal Infirmary

Liver Disease for the General Physician Royal College of Physicians July 2017

Increasing Burden of Alcoholic Liver Disease

• >60% increase in discharges with alcoholic

liver disease 2000/1 to 2009/10.

• 222% increase in alcohol-related deaths 1980

to 2010.

The start of another medical receiving ward

round.....

• 35 year old woman

– history of alcohol excess; flu-like symptoms for 5 days

– increasingly unwell; yellow eyes

• Bilirubin 126; AST 3241; ALT 1194; ALP 234; PTr 3.9

• Jaundiced; no ascites evident

• What is this likely to be?

A. Alcoholic Hepatitis

B. Acute Liver Injury

C. Portal Vein Thrombosis

D. Decompensated Alcoholic Cirrhosis

E. Ascending Cholangitis

Biochemical Patterns of Alcoholic

Liver Disease

• Raised AST : ALT ratio (De

Ritis Ratio)

• AST not >500 (ALT usually

<300)

De Ritis Ratio Decision Limit

Condition <1.0 1.0 to <1.5 1.5 to <2.0 ≥ 2.0

Healthy Women (up to 1.7)

Children Neonate Men (up to 1.3)

Acute Viral Hepatitis Resolving Worsening Fulminant

Alcoholic Liver Disease Resolving Alcohol Abuse Acute Hepatitis

Chronic Liver Disease Stable Fibrosis risk Other Causes

Muscle Disease Chronic Resolving Acute

The Jaundiced Alcoholic: Scenario 1

• Acute Liver Injury

– In context of either no background fibrotic

liver disease or established cirrhosis

– Atypical biochemistry; clinical context

– Possible Causes

• Drug induced: even ‘therapeutic’

paracetamol

• Acute viral infection (HAV; HBV; HEV)

• Ischaemic/ Hypoxic hepatitis

• Co-incident primary liver disease: AIH

Another ward round in an alternate universe..... • 35 year old woman

– >80g alcohol per day; abdominal and ankle swelling

– increasingly unwell for 6 months; yellow eyes for 4 months

• Bilirubin 105; AST 93; ALT 32; ALP 234; PT 22 seconds (PTr

1.9); Urea 6.5; WCC 3.4

• Jaundiced; drowsy; moderate abdominal distension; hepatic

flap present.



B. Acute Liver Failure

C. Acute Portal Vein Thrombosis




• Chronic Decompensation of Chronic Disease

– In context of established cirrhosis

– Typical biochemistry; SIRS not florid

– Clinical Context

• Progressive deterioration over weeks/ months

• Jaundice evident >2 months

• Ascites and encephalopathy often predominant

– Represents progressive disease with continued

drinking but may herald development of

hepatoma

In the next bed, just arrived..... • 35 year old woman

– >80g alcohol per day; flu-like symptoms for 5 days

– increasingly unwell; yellow eyes for 2 weeks

• Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds (PTr

2.4); Urea 6.5; WCC 17.4

• Jaundiced; pyrexial; drowsy; abdominal distension

• Abdominal US showed large ascites and hepato-splenomegaly.

• What should we do next?

A. Percutaneous liver biopsy

B. MRCP

C. Transjugular liver biopsy

D. CT Head

E. Diagnostic Ascitic Aspiration

• Ascitic Fluid Analysis

– SBP diagnosed in 20% cirrhotics admitted to

hospital, and 2-3% attending for outpatient

paracentesis

– >250 neutrophils/cm3 (>500 WBC/ cm3) and

suggest spontaneous bacterial peritonitis (SBP)

– Samples to be sent in ‘blood’ culture bottles

– Early antibiotics (see local guidelines) and

Albumin (20% HAS: 1.5g/kg Day 1; 1g/kg Day 3

for high risk patients: Bilirubin >68 and/or

Urea>11)

Sepsis in Alcoholic Liver Disease


• Acute Decompensation of Chronic Disease

– Precipitant: often GI bleeding/ Sepsis/ Portal

Vein Thrombosis

– Typical biochemistry; SIRS usually evident

– Clinical Context

• Can be difficult to differentiate from Alcoholic

Hepatitis (and may co-exist)

– Full sepsis screen: blood cultures; urinalysis and

culture; diagnostic ascitic tap; CXR

– Low threshold for antibiotics (but be wary of

gentamicin)

BSG/BASL Clinical Bundle for Decompensated

Liver Disease: the First 24 hours

Stuart McPherson et al. Frontline Gastroenterology

Curiously an hour later there arrives...... • 35 year old woman

• Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds

(PTr 2.4); Urea 6.5; WCC 17.4

• Jaundiced; pyrexial; drowsy; moderate abdominal distension

• Abdominal US showed moderate ascites and hepato-

splenomegaly.

• Sepsis screen negative



B. Acute Liver Failure

C. Portal Vein Thrombosis




• ‘Clinically relevant’ Alcoholic Hepatitis

– Essential Features

• excess alcohol within 8 weeks

• < 2 month onset of Bilirubin > 80mol/l

• Exclusion/ treatment of sepsis

• AST < 500 (AST: ALT ratio >1.5)

– Characteristic Features

• hepatomegaly fever leucocytosis hepatic bruit

NIAAA 2016: Probable Alcoholic Hepatitis Inclusion Criteria •Onset of jaundice within prior 8 weeks •Ongoing consumption of > 40 (female) or 60 (males) g alcohol/day for ≥6 months with <60 days of abstinence before the onset of jaundice •Aspartate aminotransferase > 50, aspartate aminotransferase/alanine aminotransferase > 1.5, and both values < 400 IU/L •Serum bilirubin (total) > 3.0 mg/dL (50µmol/l) •Liver biopsy confirmation in patients with confounding factors

Back to our patient...... • 35 year old woman

• Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds

(PTr 2.4); Urea 6.5; WCC 17.4

• Jaundiced; pyrexial; drowsy; moderate abdominal

distension

• Abdominal US showed moderate ascites and hepato-

splenomegaly.

• What is her short-term (28 day)prognosis?

A. Excellent (>95% survival)

B. Reasonable (~80% survival)

C. Moderate (~60% survival)

D. Poor (~50% survival)

E. Terrible (<40% survival)

We Need to Talk About Maddrey.......

• DF: the usual means of identifying ‘severe’ alcoholic hepatitis

DF = 4.6 (PTPATIENT – PTCONTROL) + Serum Bilirubin (mol/l) / 17

• BUT

– Concerns regarding accuracy (50%)

– Wide variation in the measurement of prothrombin time

• Kulkarni et al, 2004

– 89 patients

– C-statistic: 0.666

DF

GAHS

0 20 40 60 80 100

100-Specificity

100

80

60

40

20

0

Se

nsitiv

ity

AUC:

GAHS = 0.783(0.736 – 0.825)

DF = 0.721(0.671 – 0.767)

(p=0.014)

The Glasgow Alcoholic Hepatitis Score

DF

GAHS

Day 28 Outcome (Accuracy)

Day 84 Outcome (Accuracy)

GAHS</≥9 81% 75% Day 1

Data

DF</≥32 49% 53%

GAHS</≥9 81% 78% Day 6-9

Data

DF</≥32 52% 57%

Score Given

1 2 3

Age < 50 50 -

WCC (109/l) < 15 15 -

Urea (mmol/l) < 5 5 -

PT ratio/ INR < 1.5 1.5 – 2.0 > 2.0

Bilirubin (mol/l) < 125 125 - 250 > 250

AUC:

GAHS = 0.783 (0.736 – 0.825)

DF = 0.721 (0.671 – 0.767)

(p=0.014)

Alternatives to GAHS:

– MELD=3.8 x loge(bilirubin, mg/dl)+ 11.2 x loge(INR)+ 9.6 x loge(creatinine,mg/dl)

– ABIC=(age*0.1)+(bilirubin*0.08)+(creatinine*0.3)+(INR*0.8) <6.71 100% survival 6.71 – 9.0 70% survival >9.0 22% survival

– Lille Score: R = 3.19 - (0.101*age in years) + (0.147*albumin day 0 in g/L) +

(0.0165*evolution in bilirubin level in M) - (0.206*renal insufficiency)#- (0.0065*bilirubin day 0 in M) - (0.0096*INR)

# creatinine>115M

Score = EXP(-R) / [1+EXP(-R)]

Back to our patient...... • 35 year old woman

• Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds (PTr

2.4); Urea 6.5; WCC 17.4; Alb 26

• Jaundiced; pyrexial; drowsy; moderate abdominal distension

• US showed moderate ascites and hepato-splenomegaly.

• Sepsis screen negative

• What treatment should be considered?

A. Terlipressin and Albumin infusions

B. Pentoxifylline orally

C. Prednisolone orally

D. Rifaximin

E. Broad spectrum antibiotics

STeroids Or Pentoxifylline for

Alcoholic Hepatitis

• Pentoxifylline 400mg tds; Prednisolone 40mg: each for 4

weeks

• Primary End-point: 28 Day mortality

Pentoxifylline

No Yes Total

Prednisolone

No 16.7%

(45/269)

19.4%

(50/258)

18.0%

(95/527)

Yes 14.3%

(38/266)

13.5%

(35/260)

13.9%

(73/526)

Total 15.5%

(83/535)

16.4%

(85/518)

16.0%

(168/1053)

OR = 0.72 (0.52 - 1.01) p = 0.056

OR = 1.02 (0.77 - 1.35) p = 0.875

OR = 1.01 (0.76 - 1.35) p = 0.937

OR = 1.07 (0.77 - 1.49) p = 0.686

OR = 0.97 (0.73 - 1.28) p = 0.807

OR = 0.99 (0.74 - 1.33) p = 0.972

Prednisolone vs No Prednislone Pentoxifylline vs No Pentoxifylline

STOPAH: Mortality

Determinants of 28 Day Outcome

Multivariate and Meta- Analysis

Multivariate Analysis

Variable Odds ratio (95% CI) p-value

Prednisolone vs no prednisolone 0.609 (0.409 – 0.090) 0.015

Prothrombin ratio 1.381 (1.129 – 1.691) 0.002

Bilirubin 1.002 (1.001 – 1.003) 0.003

Age 1.050 (1.029 – 1.071) <0.001

White Blood Cells 1.030 (1.002 – 1.060) 0.037

Urea 1.065 (1.015 – 1.118) 0.037

Creatinine 1.564 (1.048 – 2.332) 0.028

Hepatic Encephalopathy 3.073 (2.050 – 4.605) <0.001

Risks of Prednisolone in Alcoholic

Hepatitis: Infection

• Infection developed in 13% of those who received

prednisolone (cf 7%; p=0.002)

• Vergis et al, 2017: for patients who present with infection

– If not receiving prednisolone,

continuation of antibiotics does not

impact upon mortality

– If receiving prednisolone concurrent

antibiotic therapy significantly

reduces mortality

Placebo/

Placebo

(n=272)

Pred/

Placebo

(n=274)

Placebo/

PTX

(n=273)

Pred/

PTX

(n=273)

Total

(n=1092)

Infections and infestations 27 (20%) 44 (24%) 16 (11%) 30 (19%) 117 (19%)

Lung infection 11 (8%) 20 (11%) 6 (4%) 18 (11%) 55 (9%)

Corticosteroid Responsiveness:

baseline disease severity

*p<0.05 cf no treatment

#p<0.005 cf no treatment

Corticosteroid ‘Responsiveness’:

Day 7 Progress

• Mathurin et al, 2003

– 238 patients: DF32,

biopsy-proven AH.

– ECBL response.

• Louvet et al, 2007

– 320 patients: DF 32,

biopsy-proven; 118 in

validation set.

– ‘Lille model’

Intensive Enteral Nutrition in Alcoholic

Hepatitis

• Moreno et al 2016

– ‘Conventional nutrition’ or intensive EN: 14 days NG tube

– 48.5% premature NG tube removal: 3 cases of aspiration

– No increased risk of upper GI bleeding

– 6 month mortality: 44.4% with EN; 52.1% without (p=0.406)

– Improved survival if ≥1692kcal/day or ≥21.5kcal/kg/day

irrespective of treatment group

EASL

Guidelines

2012

GAHS

?

Just then in the next bed......

• Patient with known alcohol related cirrhosis

• Admitted 36 hours earlier with jaundice

• Increasing confusion with agitation

• Now shouting and threatening staff and other patients

• How should her agitation be managed?

A. Regular Diazepam

B. Symptom-triggered Diazepam

C. Symptom-triggered Lorazepam

D. Intravenous Chlormethiazole

E. 5-10mg Haloperidol

Confusion and Agitation in the Jaundiced

Alcoholic: a Broad Differential • Withdrawal State

– Alcohol; benzodiazepine; (SSRI)

• Wernicke’s Encephalopathy

– Undernourished; dextrose load; low Mg

• Hepatic Encephalopathy

– Acute; Chronic (porto-systemic)

• Brain Injury

– Traumatic: subdural (history of falls); chronic ARBD

• Seizure Disorder

– Post-ictal: unwitnessed seizure; Non-convulsive Status

• Delerium/ Metabolic

– Hyponatraemia; Possible sepsis

• Intoxication

– Prolonged effect (unknown street drugs); illicit use

• (Psychiatric)

Alcohol Withdrawal in the Liver Patient

• NICE Clinical Guidelines 100, 2010:

“In older adults and people with compromised liver function, long-acting agents are known to accumulate. In the absence of clinical evidence supporting one agent over another, the GDG agreed on consensus that a shorter-acting agent (e.g. oxazepam or lorazepam) could be offered to the elderly or if there was evidence of encephalopathy.”

• Consider Symptom Triggered Treatment (STT) rather than Fixed Dose Treatment (FDT):

– Lorazepam 1-2mg

• Haloperidol for severe agitation (note QT interval)

• Anaesthetic involvement in extreme cases

BSG 2016

Tremor

0) No tremor

1) On movement

2) At rest

Sweating

0) No sweat visible

1) Moist

2) Drenching

sweats

Hallucination

0) Not present

1) Dissuadable

2) Not dissuadable

Orientation

0) Orientated

1) Vague, detached

2) Disorientated,

no contact

Agitation

0) Calm

1) Anxious

2) Panicky

Score: (Do not use scoring tool if

patient intoxicated; must be at least 8

hours since last drink.)

0: Repeat Score in 2 hours

(Discontinue after scoring on 4

consecutive occasions, except if less

than 48hrs after last drink)

1 – 3: Give 10mg Diazepam:

Repeat Score in 2 hours

4 – 8: Give 20mg Diazepam:

Repeat Score in 1 hour

9 - 10: Give 20mg Diazepam :

Repeat Score in 1 hour;

discuss with medical staff

Glasgow Modified Alcohol Withdrawal Score

(GMAWS)

• Derived from Foy

et al, 2006 and

Swift et al, 2010.

• Preferred by

nursing staff in

acute medical

units compared

with CIWA-Ar

(McPherson et al,

2012).

Importance of abstinence... 1 year mortality

Alcohol Consumption at Day 90 n Odds

ratio 95% CI

p-

value

Not reduced (still drinking as much or

more than when presented) vs Abstinent 478 2.99 1.47 - 6.05 <0.001

Reduced drinking but above safety limits

vs Abstinent 478 2.28 1.07 - 4.86 0.032

Reduced drinking to below safety limits

vs Abstinent 478 2.17 1.07 - 4.39 0.031

Pharmacotherapy Options in ALD

• Little evidence with significant alcohol-related liver injury.

• Acamprosate has the best safety profile.

– No hepatic metabolism and no reported hepatotoxicity.

– Acamprosate does not adversely affect neuropsychiatric status in patients with Child's Grade A and B cirrhosis.

• Naltrexone not associated with hepatotoxicity

• Disulfiram related to hepatotoxicity: 28% mortality

• Baclofen: Addolorata et al, 2007

– alcoholic cirrhosis; Baclofen 10mg tds for 12 weeks

– 71% abstinent (cf 29%): OR 6.3 (2.4, 16.1), p=0.0001

– excluded people with diabetes, encephalopathy, psychiatric comorbidity and comorbid drug misuse

The Jaundiced Alcoholic: an approach

• Is it Alcohol?

– Look for other precipitants; atypical biochemical pattern

• Is it chronic decompensation or a more acute change?

– >2 month history; relative lack of SIRS; typical biochemistry

• If acute, is there sepsis or other trigger?

– Full sepsis screen; Abdo US; early treatment

• If acute and no sepsis, likely alcoholic hepatitis

– Assess severity: Prednisolone 40mg for 4 weeks if GAHS>8

and improvement after 7 days; continue antibiotics if sepsis

• For ALL patients:

– Address general nutrition and specific deficits (Folate; B1; Mg)

– Manage AWS safely

– Engage with alcohol services

alcoholic liver disease strategies for seamless care

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