and Cirrhosis W Ray Kim MD Gastroenterology and Hepatology Stanford University School of Medicine Total Adult Per Capita Alcohol Consumption liters Per Capita Alcohol Consumption per Drinker ID: 779995
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Slide1
Management of Alcoholic Hepatitisand Cirrhosis
W. Ray Kim, MD
Gastroenterology and Hepatology
Stanford University School of Medicine
Slide2Total Adult Per Capita
Alcohol Consumption (
liters)
Slide3Per Capita Alcohol Consumption per Drinker
(2005)
Slide4Problematic DrinkingEpidemiologic Definitions
Binge drinker:
Five or more drinks on one occasion
Heavy drinker:
Adult men having more than two drinks per day
Adult women having more than one drink per day
Slide5DSM-IV Definitions
Abuse:
Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, home
Recurrent substance use in situations in which it is physically hazardous
Recurrent substance-related legal problems
Continued substance use despite having persistent or recurrent social or interpersonal problems
Dependence: Abuse accompanied by 1. Compulsive drinking behavior 2. Tolerance
3. Withdrawal
Slide6All
Drinkers
Heavy/Binge Drinkers
Abuse/
Dependence
ALD
Cirrhosis
HCC
Alcoholic
L
iver
D
isease
Slide7Alcoholic Liver Disease
Steatosis
Alcoholic Hepatitis Cirrhosis
/
Steatohepatitis
Slide8Powell and
Klatskin
, 1968
Importance of Abstinence
Survival after
Dx
of Cirrhosis Survival after Decompensation
n=278
n
=
233
Slide9Pharmacotherapy of Alcoholism
Drug
Class
Data for ALD
Disulfiram
Aldehyde dehydrogenase
Inhibitor
Potentially toxic
Naltrexone
Opioid antagonist
Potentially toxic
Acamprosate
Modulator of glutamate and GABA
Not studied in cirrhosis,
may
be usefulTopiramateNa channel blockerNot studied in cirrhosisBaclofen
Centrally acting muscle relaxant
Showed efficacy in 1 RCT in cirrhosis
Slide10Pharmacotherapy of Alcoholic Fibrosis/Cirrhosis
Drug
Results
Propylthiouracil
Equivocal
S-
adenosylmethionine
(SAME)
Equivocal
Colchicine
Negative
Silymarin
(
Milk thistle)
Negative
PhosphatidylcholineNegative
Slide11Alcoholic HepatitisSyndrome
consisting of
Excessive alcohol
consumption
Typical clinical presentation:
j
aundice, anorexia, fever, tender hepatomegalyModerately
elevated aminotransferase (100-300U/L) with higher AST than ALT (AST/ALT>2)Exclusion of other causes of acute and chronic liver disease. Spectrum: Mild injury to severe, life-threatening injuryAcute on chronic damage: 10%-35% of hospitalized alcoholic
patients
Concomitant
cirrhosis in more than 50
%
Slide12Slide13Re-analysis of 3 previous RCTs
Selecting patients with MDF < 32 (n=205)
P
rednisolone
40mg
qd
x 28 daysMathurin. J
Hep
2002;36:480, Mendenhall. NEJM
1984;311
:
1464,
Carithers
.
Ann Intern Med 1989;110:685, Ramond. NEJM 1992;326:507Corticosteroids
Slide14Pentoxyfylline
Placebo
Pentoxyfylline
Single center RCT (n=101)
Severe AH (MDF
>
32)
Pentoxyfylline
(400
mgs
tid
)
Versus Placebo x 28 days
Akriviadis
.
Gastroenterology. 2000;119:1637-48
n=49 n = 52In-hospital Fatality (%)Predictors of survivalPentoxyfylline
AgeCreatinine
Slide15STOPAH TrialMulticenter
, double-blind, randomized trial
in UK (n=1103)
2
-by-2
factorial design: Prednisolone and/or
PentoxyfyllinePatient selectionAverage
alcohol consumption > 80 g/d (M) and > 60 g/d (W)Bilirubin > 4.7 mg/dl, Discriminant function > 32EndpointsPrimary: Mortality at 28 daysSecondary: death or LTx at 90 days and at 1 year
Prednisolone
(40mg
qd
)
Placebo
Pentoxyfylline
(400mg
tid)n=273n=273Placebon=274n=272
Thursz. NEJM 2015;372:1619
Slide16STOPAH TrialPrimary End Point: 28 day mortality
Multivariable odds ratios:
Prednisolone: 0.61 (p=0.02)
Pentoxyfylline
: 1.10 (p=0.62)
Prednisolone
(p=0.06)
Pentoxyfylline
(p=0.69)
No evidence of benefit for combination
Slide17Pentoxyfylline
or Not?
Akriviadis
Trial
Main cause of death = HRS
PTX: 6/12 deaths
Placebo: 22/24 death
Serum creatinine trend
STOPAH
HRS: No major concern
Acute kidney injury reported in 2% overall
Terlipressin
was allowed according to the site PI discretion.
Serum
creatinine
at baseline:
0.88 ± 0.53cf. creatinine in Akriviadis TrialPTX = 1.2 ± 0.9Placebo = 1.3 ± 0.8
Slide18Slide19Treatment Algorithm
O’Shea. Hepatology 2010;307
Slide20Nutrition
Randomized trial of total enteral nutrition (TEN) versus corticosteroids (n=71)
TEN:
2,000
kcal/d polymeric enteral diet as the sole nutritional supply
Low
-sodium, low-fat, water-restricted, enriched in branched-chain amino
acidsContinuously infused into the stomach via feeding tube with a peristaltic pump8 TEN patients withdrawn
from
the trial (intolerance in 5)
Cabre
. Hepatology 2000;32
:36-
42
Slide21Total Enteral NutritionNo difference in short term mortality (25% versus 31%)
Earlier death with enteral feeding (7 versus 23 days, p=0.03)
Cabre
. Hepatology 2000;32
:36-
42
Mortality during follow-up was higher with
steroids: 10/27 vs. 2/24, p=0.04
TEN
Prednisolone
Slide22ALD and Overnutrition
Survival
BMI
Asrani
(unpublished data)
Slide23Medical Management of AH/ALD