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Alcoholic Liver disease
a future issue…?
Dr K Agarwal
Institute of Liver Studies
King’s College Hospital
London
1st COLDA Nairobi 2018
Disclosures:
Speaking/ consultancy:
AbbVie/Achillion/ Astellas/
BMS/ Gilead/ GSK/
Intercept/Janssen/ Merck/ Vir
Spectrum in audience
no easy answers
Data is problematic
Acknowledge Mark [Thursz]
A Kilner
Health disparities in liver disease in sub-Saharan Africa (SSA)
Sub-Saharan Africa has 11% of the world's population,
But disproportionately has 24% of the global disease burden
YET allocates <1% of global spend on health
It has 3% of the global healthcare workforce (mean 0.8
healthcare workers per 1000)
Barriers to healthcare access are many
Health disparities in liver disease SSA
• 2010 Global Burden of Disease study showed cirrhosis mortality in SSA doubled
between 1980 and 2010.
• Aetiologies : Hepatitis B (34%),
Hepatitis C (17%),
Alcohol (18%) and unknown in 31%
• Hepatitis B, C and alcohol accounted for 47, 23 and 20% of HCC respectively
• Liver disease reflects the broader disparities in healthcare in sub-Saharan Africa
• However these challenges are not insurmountable as vaccines and new
therapies could deal with the burden of viral hepatitis
• Access to and affordability of therapeutics remains the major barrier
Health disparities in liver disease in sub‐Saharan Africa
HIV
HBV
HCV
HIV
HBV
BMC Medicine 2014
Public health aspects:
Alcohol-related morbidity and mortality
1. WHO. Global status report on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018;EASL CPG ALD. J Hepatol 2018;69:154–81
• Worldwide, harmful use of alcohol is associated with:– ~3.3 million deaths every year 1
• 5.9% of all deaths overall (7.6% in men, 4.0% in women)1
– ~139 million disability-adjusted life years• 5.1% of the global burden of disease and injury
• Alcohol has an impact on over 200 diseases and types of injuries
• Most deaths attributable to alcohol consumption from:– Cardiovascular diseases
– Injuries
– Gastrointestinal diseases• Mainly cirrhosis
– Cancers
• Alcohol-attributable fraction is highest for liver diseases and foetal alcohol syndrome
Characteristics of adult alcohol consumption in sub-Saharan Africa (SSA) Vs the world
Young population
Public health aspects:
Data are conflicting around a safe alcohol limit
EASL CPG ALD. J Hepatol 2018;69:154–81
• Light–moderate intake: reduced risk of coronary artery disease
• Heavy chronic alcohol intake: increased risk of cardiomyopathy, hypertension, atrial arrhythmias and haemorrhagic stroke
• Alcohol is a recognized carcinogen
– No threshold level of consumption known for cancer risk
• Chronic use of alcohol is a risk factor for cirrhosis• Unclear whether there is a continuous dose–response relationship
• Unclear whether there is a threshold at which the risk emerges
• Risks of binge drinking vs. daily drinking remain controversial
• Cessation of drinking at any point reduces risk of disease progression and occurrence of complications
Recommendation
Limit daily intake to ≤2 standard drinks for women and ≤3 for men.
This amount is not associated with significant increase in cirrhosis mortality
HBV Transmission and Alcohol
• HBV infection still affects some 240 million people globally, with the highest
rates of infection in Asia and Africa
• Parenteral route like unprotected sex / IVDU is an important pathway of
transmission .
• Alcohol use is an independent risk factor for intentions to engage in unprotected
sex
• Risky sex intentions have been shown to be linked to actual risk behaviour
• Systematic review and meta-analysis shows an increase in BAC of 0.1 mg/ml
resulted in an increase of 5.0% (95% CI: 2.8-7.1%) in the likelihood of
engaging in unprotected sex
• There was a high prevalence of anti-hepatitis C virus antibodies and HIV
infection in AUD
Alcohol and CHB interaction: Risk of HCC
• Patients with CHB and heavy alcohol consumption were
more likely to develop HCC than those with either HBV or
alcoholism alone (28.8%, 15.8%, and 10.4%, respectively).
• The 10-year cumulative HCC incidence higher in cirrhotic
patients with HBV infection and alcoholism than for those
with HBV or alcoholism alone (52.8%, 39.8%, and 25.6% )
• A similar pattern was seen for annual HCC incidence in
above three groups (9.9%, 4.1%, and 2.1% ).
Alcohol and attrituable CHB interaction
• Needs strategies/ policies/ neglected
• Targeted by the industry - yikes
• Embedded in cultural activities ‘emblem of success’
• Availability – illicit production (shebeens)
• Pricing
• 30% unrecorded intake
• 2010: 6L APC – episodic
• 10/46 any form policy: WHO framework not enacted
• 2000-09- 50% funding HIV/ malaria
• Regulation of industry
Nigerian J Clin Pract 2013
5 years
Alcohol: the price of globalisation?
• Demographics
• Rapid Urbanisation
• Economic development
• Increased availability
• Corporate targeting
• Weak policy structure – price/ availability/ marketing/ drink driving
• Trade agreements
Guideline panel :EASL
EASL CPG ALD. J Hepatol 2018;69:154–81
• Chair – Mark Thursz
• Panel members– Antoni Gual, Caroline Lackner,
Philippe Mathurin, Christophe Moreno, Laurent Spahr, Martina Sterneck, Helena Cortez-Pinto (EASL Governing Board representative)
• Reviewers – Ewan Forrest, Fabio Caputo,
Vijay Shah, EASL Governing Board
Public health aspects
*Either directly or indirectlyEASL CPG ALD. J Hepatol 2018;69:154–81
• Harmful alcohol use is associated with considerable mortality and morbidity
• Policies aimed at reducing harmful alcohol consumption and screening for AUD and for ALD should be implemented
Recommendations
Excess alcohol consumption should be addressed using
pricing-based policies and regulation of availabilityA 1
Advertising and marketing of alcohol* should be banned A 2
Primary care facilities for managing AUD must be widely available A 2
Screening for harmful alcohol consumption should be performed by
GPs and in emergency departmentsA 2
Screening for ALD should be performed in high-risk populations,
such as those in alcohol rehabilitation clinics, or harmful drinkers
identified by their GP
A 2
Patients identified through screening should undergo brief
intervention and referral to a multidisciplinary teamA 1
Grade of recommendation Level of evidence
Terminology
*Histologically-defined lesion;†At this point the term alcoholic hepatitis has become too standardized to change (may be reviewed in future guidelines)EASL CPG ALD. J Hepatol 2018;69:154–81
• The term ‘alcoholic’ is stigmatizing
– Undermines patient dignity and self-esteem
• These guidelines use the following terms
Previous term Current term Abbreviation
Alcoholic Alcohol use disorder AUD
Alcoholic liver disease Alcohol-related liver disease ALD
Alcoholic cirrhosisCirrhosis due to
alcohol-related liver diseaseALD cirrhosis
Alcoholic steatohepatitis* Steatohepatitis due to ALD ASH
Alcoholic fibrosis Fibrosis due to ALD ALD fibrosis
Alcoholic hepatitis Alcoholic hepatitis† AH
Does it matter what you drink?
Grønbæk M et al.
Ann.Intern.Med 2000
Detection of Alcohol Use Disorders
• CAGE– Brief (4 question) screening tool
• AUDIT– 10 domain questionnaire to determine if alcohol
dependence is present
• SADQ – The SADQ measures the severity of dependence:– · physical withdrawal symptoms– · affective withdrawal symptoms– · relief drinking– · frequency of alcohol consumption– · speed of onset of withdrawal symptoms
Diagnostic tests in the management of ALD:
Screening investigations
*Platelets >150,000 and Fibroscan® <20EASL CPG ALD. J Hepatol 2018;69:154–81
Rule out alternative or additional
causes of liver injury• HBV and HCV serology
• Autoimmune markers
• Transferrin and transferrin saturation
• α1-antitrypsin
Suspected advanced fibrosis
or cirrhosis
Evaluate liver function and evidence of
portal hypertension:• Serum albumin, prothrombin time or INR
• Serum bilirubin levels
• Platelet and WBC counts
Upper GI endoscopy for oesophageal
varices unless low risk based on Baveno
criteria*
Abnormalities on initial screening
Liver function tests (including GGT, ALT, AST)
+
Liver fibrosis (e.g. TE)
Ultrasound
Diagnostic tests in the management of ALD:
Indirect markers of alcohol consumption
EASL CPG ALD. J Hepatol 2018;69:154–81
BiomarkerBiological material
Detectionwindow
EtOHamount Sens. Spec. Confounding factors
GGT SerumChronic
excessive42–86% 40–84% Liver disease, BMI, sex, drugs
AST SerumChronic
excessive43–68% 56–95%
Liver and muscle diseases, BMI, drugs
ALT SerumChronic
excessive30–50% 51–92% Liver disease, BMI, drugs
MCV SerumChronic
excessive24–75% 56–96%
Vitamin B12, folic acid deficiency,
haematological diseases
% CDT Serum 1–2 weeks50–80 g/d for >1–2 weeks
25–84% 70–98%Liver cirrhosis/disease, nicotine,
transferrin level, weight, sex, pregnancy, rare genetic variations
Diagnostic performance of indirect markers is not adequate
Diagnostic tests in the management of ALD:
Non-invasive tests to estimate liver fibrosis
*PGAA index: combines α2alpha-2-macroglobulin, prothrombin time, serum GGT, serum apolipoprotein A1;†ELF combines hyaluronic acid (HA), the N-terminal pro-peptide of collagen type III (PIIINP) and tissue inhibitor of metalloproteinase-1 (TIMP-1). The test is validated for diagnosis of >F3 fibrosisEASL CPG ALD. J Hepatol 2018;69:154–81
• Tests can distinguish mild from severe fibrosis
– Less well suited to classify intermediate fibrosis stages
• Not helpful in the early diagnosis of ALD
Test Cut-off
F4 prevalence
(%)
AUROC
(95% CI)
PPV
(%)
NPV
(%)
Hyaluronic acid 250 μg/L 0.78 35 98
PGAA index* 10 27 0.87 (0.79–0.92) 72 92
FibroTest ≥0.70 31 0.94 (0.90–0.96) 73.4 93.5
≥0.75 15 0.88 (0.79–0.93) 43.9 92.8
ELF test† ≥10.5 23 0.92 (0.89–0.96) 71 94
Fibrometer ≥0.5 31 0.94 (0.90–0.97) 53.7 98.9
FIB-4 <1.45 31 0.80 (0.72–0.86) NA NA
<1.45 15 0.80 (0.71–0.87) NA NA
Diagnostic performance of some non-invasive serum fibrosis tests for cirrhosis diagnosis:
Diagnostic tests in the management of ALD:
Non-invasive tests to estimate liver fibrosis
Figure reproduced with permission from Mueller S, et al. World J Gastroenterol 2014;20:14626–41 (see notes). Liver stiffness scale with cut-off values for various fibrosis stages in patients with ALD without pronounced inflammation, congestion, tumours or mechanic cholestasis. EASL CPG ALD. J Hepatol 2018;69:154–81
• Liver stiffness measurement (TE)
– Correlates with degree of fibrosis
<6 kPa 6−8 kPa 8−12.5 kPa >12.5 kPa
Soft Stiff
Normal Grey zone F3 fibrosis F4 cirrhosis
6 8 12.5 75Liver stiffness (kPa)
• ALD is associated with greater liver stiffness compared with viral hepatitis/cirrhosis
• AH also markedly increases LSM in patients with ALD independent of fibrosis stage
– Inflammation, cholestasis or liver congestion and alcohol consumption may interfere with LSM, independently of fibrosis
• Elevated LSM in patients with ALD and AST serum levels >100 U/L should therefore be interpreted with caution
Diagnostic tests in the management of ALD:
Histological features and diagnosis of ALD types
Images provided courtesy of Lackner C.EASL CPG ALD. J Hepatol 2018;69:154–81
• Lesions predominate in centrilobular regions (in pre-cirrhotic stages)– Alcoholic steatosis
o Macro and eventually variable blend of macro- and microvesicles
– Alcoholic steatohepatitis (ASH)o Variable degree of macrovesicular
steatosis
o Hepatocellular injury with ballooning, potentially necrosis
o Lobular inflammation
– Alcoholic fibrosis/cirhosiso Pericellular fibrosis (PCF) and/or septal
F in precirrhotic stage
o Micronodular cirrhosis ± PCF
• A single lesion or any combination may be found in a given individual
Main histological diagnoses:
Steatosis
Steatohepatitis
Cirrhosis
Diagnostic tests in the management of ALD:
Histological features and diagnosis of ALD types
EASL CPG ALD. J Hepatol 2018;69:154–81
• Types of ALD differ with respect to prognosis
• About 90% of heavy drinkers have hepatocellular steatosis
– Prognosis is debated; may be associated with progression to cirrhosis (particularly mixed steatosis pattern)
• ASH is considered a progressive lesion
– Increases the risk of cirrhosis and HCC
• Morphological lesions of ALD and metabolic syndrome-associated NAFLD show broad overlap:
– Hepatocellular injury and fibrosis are often more severe in ALD
– Some lesions of ALD are very rare or have not been described in patients with pure NAFLD:
• Sclerosing hyaline necrosis, alcoholic foamy degeneration (i.e., large portions of the parenchyma affected by microvesicular steatosis), fibro-obliterative changes in hepatic veins, portal acute inflammation, cholestasis
Management of alcoholic hepatitis:
Evaluation of severity
*Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81
• Different prognostic models aim to identify patients at high risk of early death
– Often incorporate the same variables and have similar efficacy in predicting short-term survival
• Lille model can predict pattern of response to corticosteroid treatment
– Based on pre-treatment data plus the response of serum bilirubin
Score Bilirubin PT/INR
Creatinine/ur
ea Leucocytes Age Albumin
Change in
bilirubin
(Day 0 to 7)
Maddrey DF* + + – – – – –
MELD + + + – – – –
GAHS + + + + + – –
ABIC + + + – + + –
Lille + + + – + + +
Management of alcoholic hepatitis: General measures
EASL CPG ALD. J Hepatol 2018;69:154–81
• Alcohol abstinence is the cornerstone of therapy
– Early management of AUD is recommended in all patients with AH
• Considering the potential risk of Wernicke’s encephalopathy, supplementation with B-complex vitamins is recommended
• Other general approaches include:
– Treatment of hepatic encephalopathy (lactulose, rifaximin)
– Treatment of ascites (salt restriction)
– Prevention of renal failure in patients with severe AH
• Avoidance of diuretics and nephrotoxic drugs
• Volume expansion if needed
• Use of beta-blockers may increase the risk of AKI
Effect of Nutrition in Alcoholic Hepatitis
• VA Co-operative Study Group:
• 273 patients Oxandrolone + Enteral Food Supplements
Moderate Malnutrition Active Placebo
1 Month Mortality 9.4% 20.9%
6 Month Mortality 21.3% 38.3% p =0.03
Improvement in severity of liver injury
Severe Malnutrition No difference
All comers
>2500 kcal/day 19% Mortality
<2500 kcal/day 51% Mortality
Mendenhall et al Hepatology 1993
STeroids Or Pentoxifylline for Alcoholic Hepatitis
STOPAH
Randomised, Double blind
Placebo controlled
Factorial 2 x 2
Prednisolone efficacy
Pentoxifylline efficacy
Definitive (power 90%)Thursz NEJM
Primary Endpoint
P = 0.056 P = 0.686
OR = 0.72 (0.52 - 1.01) OR = 1.07 (0.77 - 1.49)
Management of suspected alcoholic hepatitis: Treatment algorithm
*Particularly in null responders (Lille score ≥0.56).EASL CPG ALD. J Hepatol 2018;69:154–81
Stop treatment*and assessment for early liver transplantation in highly
selected patients
Continue treatment for 28 days
Lille score ≥0.45Lille score <0.45
mDF <32 and GAHS <9
Assess treatment response at Day 7 (Lille score)
Prednisolone 40 mg/day ± NAC No specific therapy
mDF ≥32 or GAHS ≥9
Assessment of disease severity (prognostic scores)
• Systematic evaluation of nutritional status and energy intake
• Daily target 35–40 kcal/kg BW• Prefer oral route as first-line intervention• Supplementation with B-complex vitamins
Consider liver biopsy if diagnosis is uncertain
Perform systematic extensive screening for infection
Treatment of alcohol dependence
Clinical diagnosis of AH
Alcohol-related fibrosis and cirrhosis
EASL CPG ALD. J Hepatol 2018;69:154–81
• Treating comorbid conditions must be encouraged together with interventions targeting alcohol misuse
– Obesity and other components of the metabolic syndrome
• Management of patients with ALD cirrhosis focuses on:
– Alcohol abstinence
– Nutritional support including calories, vitamins and micronutrients
– Primary and secondary prophylaxis of cirrhotic complications
Recommendations
Advise complete abstinence from alcohol in patients with alcohol-related cirrhosis to reduce the risk of liver-related complications and mortality
A 1
Identify and manage cofactors, including obesity and IR, malnutrition, smoking, iron overload and viral hepatitis
A 1
Apply general recommendations for screening and management of complications of cirrhosis to ALD cirrhosis
A 1
Grade of recommendation Level of evidence
Survival according to continued use / abstinence
Compensated alcoholic cirrhosis
N=278
Decompensated alcoholic
cirrhosis N=233
Powell & Klatskin 1968
A multi-faceted issue…
‘The illusion of
knowledge is
more dangerous
than a lack of
knowledge…’
D Bronstein