Alcoholic Liver disease a future issue…?regist2.virology-education.com/presentations/2018/1COLDA/... · 2018-09-15 · Liver and muscle diseases, BMI, drugs ALT Serum Chronic excessive

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


• 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


Indirect markers of alcohol consumption


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


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:


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


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


Histological features and diagnosis of ALD types


• 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


• 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


• 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

Alcoholic Liver disease a future issue…?regist2.virology-education.com/presentations/2018/1COLDA/... · 2018-09-15 · Liver and muscle diseases, BMI, drugs ALT Serum Chronic excessive

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