10/13/2010
Alcohol and the Liver
Dr Vikrant Sibartie
MRCP(Ireland), CSCST
Gastroenterologist
Apollo Bramwell Hospital
1
10/13/2010
Case presentation
36 yearyear-old man
z Several previous admissions with alcoholalcoholrelated presentations
z Drinks
Di k 1b
bottle
ttl rhum/day
rhum
h /day
/d
z 2002: Delirium Tremens
z 2003: Seizures
z Jul 2007: Alcoholic hepatitis
z Nov 2007: Alcoholic hepatitis
z
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Admission 2009
Jaundice
z Confusion
Confusion-- encephalopathic
z Ascites
z Hypotensive
Hypotensive,, BP=90/54
z Pyrexial
z
z
Admitted to HDU
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Labs
z
z
z
z
z
z
z
z
z
z
N 118
Na
K 2.9
Urea 3.3
Creat 64
AST 85
ALT 58
GGT 570
Bili 375
Alk Phos 142
Albumin 24
Hb 10.1
10 1
Plt 148
WCC 13
INR 1.6
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Ascitic WCC=500/mm3, 90% neutrophils
z IV Tazobactam/
Tazobactam/Piperacillin
z IV Albumin
z
Worsening renal function
z Urea=19.3
z Creatinine
Creatinine=453
=453 (Day 15)
z Oliguric despite being on IV Albumin and
Terlipressin
z
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Ongoing sepsis despite broadbroad-spectrum
antibiotics
z INR=2.1
z Worsening
W
i encephalopathy
h l
th d
despite
it
Lactulose (NG tube)
tube)-- becomes comatose
z Ascites
Ascites++
++
z
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z
z
z
Consensus after consultation with family,
Anaesthesia and Renal medicine:
Prognosis overall poor and dialysis would not
g
alter prognosis.
Patient dies after 25 days
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Case 2
DL, 43 yearyear-old female
z Drinks 80 units/week
z Jaundice
z Abdo pains
z Nausea
z Hepatomegaly
z
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10/13/2010
Day 1
z INR=1.3
z Bili
Bili=116
=116
z Aphos
Aphos=219
=219
z AST=217
z Alb=38
z GGT=142
z mDF
mDF=11
=11
z
Day 8
INR=1.5
Bili=
Bili= 332
mDF=43
mDF=43
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Started on Pentoxifylline 400 mg TDS
z NG feeding
z Overall condition improves
z Bili
Bili=190,
=190, INR=1.3 at discharge
z
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Background
z
z
Alcoholism and ALD
rife in developed
societies, including
Mauritius.
Little wonder, as Man
has been brewing and
distilling alcohol since
the Stone Age!
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Epidemiology
Globally, 4% of the burden of disease and
3.2% of all deaths attributable to alcohol
(WHO)
z Encompass injury
injury, violence,
violence
disease(ALD), social problems and highhighrisk behaviour.
z Alcohol is a factor in 25% of A&E
attendances in large Irish city hospitals.
z
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WHO Collaborative Study on Alcohol and Injuries
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WHO Collaborative Study on Alcohol and Injuries
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WHO Collaborative Study on Alcohol and Injuries
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Mauritius
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Heavy episodic drinkers ( 5 drinks or more
per week in one sitting)
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Cause of death Mauritius
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Cases treated as inin-patients Brown Sequard hospital 2008
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Natural history of ALD
Alcohol
Normal liver
Al h li Fatty
Alcoholic
F tt Li
Liver (90-100%)
(90 100%)
Alcoholic Steatohepatitis (10-35%)
Diet Genetics
Obesity
Female gender
Hep C Haemochromatosis
Alcoholic Cirrhosis (8-20%)
HCC (1-2% p.a)
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Alcoholic steatosis
z
z
z
z
z
O
Occurs
invariably
i
i bl if alcohol
l h l consumption>80
ti
80 g/day
/d
Present in 80% of heavy drinkers
Hepatocyte cytoplasm occupied by triglyceride
LFTs often normal
Reversible with abstinence
May progress to cirrhosis
z
22% with alcoholic fatty liver developed cirrhosis after median 13 years
Dam--Larsen et al. Scand J Gastroenterol 2005
Dam
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Alcoholic Fatty Liver - Histology
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Alcoholic Cirrhosis
RR=13 for males drinking 60 g daily. For
females: 40 g daily.
z Survival in decompensated cirrhotics is
65% at one year and 35
35--50% at 5 years
years.
z Clinical presentation usually due to
complications.
z
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Alcoholic Cirrhosis - Histology
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Alcoholic Cirrhosis – Clinical Features
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Acute Alcoholic Hepatitis
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Acute Alcoholic Hepatitis
z
S d
Syndrome
characterised
h
t i d by
b pathological
th l i l and
d
clinical features:
z
Jaundice
Anorexia/ Weight loss
Vomiting/ Fever
Ascites
Encephalopathy
Gastrointestinal haemorrhage
Hypoglycaemia
Renal failure
z
z
z
z
z
z
z
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Often deteriorate after stopping alcohol
z 70 units per week
z Women more susceptible
z
z
40 - 50% mortality
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Laboratory Findings
z
z
z
z
Elevated bilirubin
Prolonged prothrombin time
Hypoalbuminaemia
Modest elevation of transaminases
z
z
z
z
z
AST/ ALT ratio > 2
Thrombocytopaenia
Neutrophilia
Low urea
Hyponatraemia
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Pathophysiology
z
Oxidative stress
z
z
z
Neutrophil infiltration and activation
z
z
z
z
z
Characteristic of alcoholic hepatitis
IL--8
IL
Inflammatory cell infiltration and activation
z
z
Reactive oxygen species
Induction of CYP2E1CYP2E1- generates oxidants
COX-2
COXThromboxanes
Cytokines- TNF
CytokinesBacterial translocation (Gram negatives)
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Histology
Liver cell necrosis
z Mallory bodies
z Perivenular neutrophil infiltration
z Steatosis
z Fibrosis/Cirrhosis
z
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Alcoholic Hepatitis
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Prognosis
Morbidity
zSepsis/SBP
zMalnutrition
zHepatorenal syndrome
z 70% cirrhotic at presentation
z 40 - 50% mortality
z
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Genetics of ALD
z
Genes predisposing to alcohol abuse:
ADH3,
ADH
3, ALDH1A1
ALDH1A1ӿ
ӿ2
z
Genes protective against alcohol abuse:
abuse:
ADH1B,ADH1C, ALDH2
z
Genes involved in generation of oxidant stress:
CYP2E1, TNF
TNF--α,SOD2,MAT1A,GST,Nrf
,SOD2,MAT1A,GST,Nrf--1
z
Cytokine genes and receptors:
receptors:
IL--10,TNFIL
10,TNF-α,TNFRs
z
Genes encoding endotoxin receptors
receptors::
CD14,NOD2,TLR4
Fibrosis genes:
genes:
CTGF,adiponectin,leptin,MMP,TIMP,collagens,DDX5
z
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Management
z
z
z
z
z
z
Supervised by gastroenterologist
Abstinence
Alcohol withdrawal
Nutrition
Medications
Other Rx
z
z
z
Ascites
Encephalopathy
Renal failure
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Nutrition
z
Enteral route preferred (No benefit with
parenteral route)
z
z
z
z
2000 - 2500kcal daily
1 0 - 1.5g
1.0
1 5 protein/kg
t i /k b
bodyweight
d
i ht
Thiamine/ Multivitamins/ Minerals
In practice
z
z
z
U early
Use
l
Safe
May need nasogastric tube
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Corticosteroids
S
Severe
alcoholic
l h li h
hepatitis
titi
z DF > 32
z C/ I
z
z Bleeding
z Sepsis
Reduce short term mortality
z No influence on progression to cirrhosis
z Prednisolone preferred
preferred-- 40 mg for 1 month
z
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Pentoxifylline in ASH
z
P ti t with
Patients
ith severe ASH
28-day mortality
(DF>32)
z
z
50
Double-blind,placeboDoubleblind,placebo-controlled
Tx with 400 mg TDS for 28 days
45
40
p=0.037
35
z
z
z
RESULTS
Improved survival with PTX,
mainly due to reduced hepatohepatorenal syndrome
Reduced TNF
TNF--α
Effect exceeds expected benefit
from steroids
30
%
z
25
20
15
10
5
0
PTX
CTR
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Hepato--Renal Syndrome
Hepato
z
z
z
z
z
z
Major criteria:
Chronic or acute liver disease with advanced liver failure
and portal hypertension
Low GFR, as indicated by a serum creatinine of > 1.5
mg/dL
mg/
dL (133 μmol/l) or a 24
24--h creatinine clearance < 40
mL/min
mL
/min
Exclusion of shock, ongoing bacterial infection, volume
depletion, and the use of nephrotoxic drugs
No improvement in renal function despite stopping
diuretics and volume repletion with 1.5 L of saline
No proteinuria or ultrasonographic evidence of
obstructive uropathy or parenchymal renal disease
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Minor criteria:
criteria:
z 1. Urine volume lower than 500 ml/day
z 2. Urine sodium lower than 10 mEq
mEq/L
/L
z 3. Urine osmolality > plasma osmolality
z 4. Urine blood cells < 50 per highhigh-power fi
eld
z 5. Serum sodium concentration lower than
130 mEq
mEq/L
/L
z
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Pathophysiology
Increase in splanchnic vasodilation in
cirrhosis
z Activation of ReninRenin-Angiotensin system
z Renal
R
l vasoconstriction
t i ti ffrom sympathetic
th ti
nervous system activation.
z All these lead to reduced renal perfusion
and reduced GFR
z
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HRS
Type I:
I: more serious type.
z At least a 50 percent lowering of the
creatinine clearance to below 20 mL
mL/min
/min
in less than a two week period or at least a
twofold increase in serum creatinine to a
level greater than 2.5 mg/dL
mg/dL (221 µmol/L).
z Such patients often oliguric
oliguric..
z
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HRS
Type II :less severe renal insufficiency
than that observed with type I disease.
z Often characterized by ascites that is
resistant to diuretics
z
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Treatment
Stop all diuretics
z Exclude and treat sepsis, especially SBP
z Volume expansion with IV Albumin ( 20 to
40 g per d
day))
z IV Terlipressin (1
(1--2 mg 4 hourly)
z
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Survival in Cirrhosis
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Conclusions
Alcohol has a serious impact on society
society-psychological, social and health.
z 25% of A&E attendance alcoholalcohol-related.
z Increasing
I
i pressures on healthcare.
h lth
z Poor access to residential detoxification
programs.
z Vicious
Vicio s circle of patient readmission
z More awareness at both public and
political level needed for what is a growing
public health problem
z
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Thank You
62