ALCOHOLIC LIVER DISEASE - bel1.semmelweis.hu

1st Dept of Internal Medicine

Semmelweis University, Budapest, Hungary

Aniko Folhoffer MD, PhD

1st Dept. of Internal Medicine

SEMMELWEIS UNIVERSITY

Budapest, Hungary

ALCOHOLIC LIVER

DISEASE

16 Oct 2019

Alcoholic liver disease Aniko FOLHOFFER MD, PhD

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Harmful alcohol consumption

causes ˜ 3.3 million deaths every year

(5.9% of all deaths)

- owning to a large number of alcohol-associated diseases in

different organs,

- as well as injuries caused by traffic accidents and violence

Blachier M 2013 J Hepatol


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Alcohol related morbidity and mortality

Globally the mean alcohol consumption (>15yrs) is

6.2 litres per person per year

In the European Region is 10.9 liters per person per year.

A dicrease between 1990-2014 in alcohol consumption,

especially in the central and western EU, while still increase in eastern and

southeastern parts.

Helmuth K Seitz et al Alcoholic Liver Disease 2018


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The proportion of global deaths attributable

to alcohol is 7.6% among men and 4% among

women

139 million disability-adjusted life years

5.1% of the global burden of disease and injury,

were attributable to alcohol consumption


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Alcohol-attributable liver cirrhosis deaths


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The Global Burden Disease project estimated, that there were

1,256,900 deaths in 2016 due to

cirrhosis and chronic liver disease

Among those, 334,900 (27%) were attributable to alcohol

245,000 deaths caused by HCC associated with alcohol –

30% of all HCC deaths

Alcohol-attributable liver cirrhosis represented 47.9%

of all liver cirrhosis deaths

In France 1970-2018 there has been a reduction of alcohol

consumption, that is associated with a 3.5-fold reduction

in liver-related mortality Naghavi et al 2017 Lancet

Akinyemiju et al 2017 JAMA Oncol


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IN MODERATION!

A moderate alcohol

consumption is

cardio-protective


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http://www.plantbasedpharmacist.com


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For most adults, moderate alcohol use is probably

not harmful

About 18 million adult Americans have an alcohol use

disorder (AUD)

Alcoholism, or alcohol dependence, is a disease that

causes

Craving - a strong need to drink

Loss of control - not being able to stop drinking once

you've started

Physical dependence - withdrawal symptoms

Tolerance - the need to drink more alcohol to feel the same

effect


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Alcohol abuse = physically dependency,

but you still have a serious problem.

- cause problems at home, work, or

school.

- cause you to put yourself in dangerous

situations,

- or lead to legal or social problems.


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Binge drinking

It is drinking about five or more drinks in two hours for

men. For women, it is about four or more drinks in two

hours.

Heavy drinking

- can increase the risk of certain cancers.

- It can cause damage to the liver, brain, and other organs.

- Drinking during pregnancy can harm your baby.

- Alcohol also increases the risk of death from car crashes,

injuries, homicide, and suicide.


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Screening and prevention

Early detection of

alcohol-related

disease

Alcohol

consumption

should be assessed

routinely

with an empathic,

non-judgemental

attitude

*


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Alcoholic liver diease

Chronic alcohol ingestion is one of the major causes of liver

disease.

Three major lesions:

Fatty liver (hepatic steatosis, accumulation of TG in hepatocytes)

Alcoholic steatohepatitis (inflammation, hepatic injury and ballooning)

Cirrhosis

HCC


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Disease course of ALD



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Risk factors for alcoholic liver disease

Quantity: in men

40-80g/d of ethanol → fatty liver disease;

160g/d for 10-20 yrs → hepatitis or cirrhosis

Gender: women –

increased susceptibility to ALD at amounts >20g/d

HCV infection - an important comorbidity in progression of ALD;

associated with younger age for severity, more advanced histology,

decreased survival.

Genetics: alcohol dehydrogenase, CYP2E1

Malnutrition: vigorous attention to nutritional support


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Alcohol and nutrition

C.S. Lieber / Alcohol 34 (2004) 9–19

• 7.1kcal (29.7kJ) per gram

exceeds the energy

of carbohydrates and protein

• On average, ethanol accounts for

half an alcoholic’s caloric intake

• Therefore displaces normal

nutrients, causing malnutrition

• Secondary malnutrition due to GI

complications (pancreatic insuff.,

impaird hepatic metabolism)


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Pathophysiology, mechanism

Genetic factors:

modifiers of neurotransmitters, such as GABA and modifiers of

alcohol metabolism.

PNPLA3: Patatinlike phospholipase domain containing protein 3 –

involved in lipid metabolism, a risk factor of NAFLD and HCC.

TM6SF2: transmembrane 6 superfamily member 2 and MBOAT7:

membrane-bound O-acyltransferase domain containing protein 7 –

are important genetic determinants of risk and severity of ALD.

Epigenetics: alcohol-induced epigenetic changes (acetylation,

phosphorilation, hypomethylation, of DNA and alterations of

miRNAs) can lead to dysregulated hepatocyte and immune cell

functions.


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Hepatic steatosis - pathophysiology

Chronic alcohol consumption → accumulation of fat (TGs,

phospholipids,and cholesterol esters) in hepatocytes

→ elevates the ratio of NADH/NAD+ → interrupts

mitochondrial -oxidation of fatty acids and results in steatosis.

→ upregulate hepatic expression of SREBP1c, a transcription

factor of lipogenic genes

→ inactivates PPARA (peroxisome proliferator-activated rec. ) –

via the metabolite acetaldehyde or multiple factors: bacterial

translocation of pathogen-associated molecular patterns (PAMPs), such as

lipopolisacharids, complement activation, ER stress, decrease of adiponectin, etc.

→ inhibits 5’AMP activated protein kinase – inhibits fatty

acid synthesis, but promote fatty acid oxidation


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Hepatic steatosis - pathophysiology

→ affect fatty acid mobilisation and clearance

- Lipolysis

- Adipocyte death

- Elevation of circulating FA and their

subsequent hepatic accumulation

- Increase the supply of lipids

to the liver from small intestine

Micro- and macro steatosis,

Ballooning, ..


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Pts may not show clinical symptoms and signs,

search for signs of AUD

US: bright echo pattern

Special US technic based on attenuation of shear

wave CAP: controlled attenuation parameters – more

accurate for the quantification of AFL in pts with ALD

– superior to bright echo

MRI – excellent accuracy

Hepatic steatosis – clinical feature and imaging technics


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Hepatic inflammation - pathophysiology

Inflammation is a prerequisite of fibrosis, cirrhosis and

HCC.

Primarily triggered by gut-derived PAMPs with the

release of citokines and chemokines from Kupffer cells

and damage-associated molecular patterns (DAMPs)

released by dying hepatocytes

An increase in adaptive immune responses induced by

neoantigens (protein adducts with acetaldehyde and ROS)

→ further contribute to inflammation


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Clinical features

Tender hepatomegaly

Right upper quadrant discomfort, abdominal pain

Nausea, anorexia, weight loss

Sudden jaundice

Fever

Spider nevi

Palmar erythema, gynecomasthia

Portal hypertension, varicel bleeding and ascites

can occur in the absence of cirrhosis

Signs of hepatic failure


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Laboratory tests in alcoholic hepatitis Elevation of serum -glutamyltransferase (GGT) up to 3000U/l

(DD: cholestasis, cardiac insuff., drug induced)

Aspartate aminotransferase (AST) > (ALT) alanine

aminotransferase, DeRitis > 1

typically > 1, in 70% > 2

Modest AST > 300 U/l rarely observed

Serum bilirubin > 137uM (8mg/dl)

Coagulopathy (prothrombin time > 5s),

Serum albumin concentration < 25g/l (2.5mg/dl)

Renal failure and ascites

lower folic acid, vitamin B12 and D3, MCV

AFP – focal lesion??


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Laboratory tests in alcoholic hepatitis

Novel markers: CK 18 (caspase-cleaved

cytokeratin 18) fragments M30 and M65 are more

sensitive than transaminase and more specifically

detect apoptotic death of hepatocytes


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Differential diagnosis

Severe sepsis

Biliary obstruction

Diffuse HCC

Drug-induced liver injury

Ischaemic hepatitis


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Alcoholic steatohepatitis -Histopathology

Hepatocytes contains large lipid droplets displacing nucleus

towards the plasma membrane (macrovesicular steatosis)

Hepatocellular injury, ballooning,

Mallory-Denk bodies,

lobular inflammation with mononuclear and neutrophilic

granulocytes

In severe cases bile pigment in hepatocytes, canaliculi and

ductular reaction – independent risk factor for short-term

mortality


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Assessing disease severity Discriminant function score

4.6x (prothr time of pt – control prothr time in sec) + serum bilirubin in mg/dl

Severe >32 1-month mortality 20-30%

Modified Maddrey’s discriminant-function score

MELD (Model for End-stage Liver Disease)

ABIC (Age, Bilirubin, INR and Creatinin)

Glasgow

Lille modell – a dinamic score

(complete, partial or null responder for th)


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Treatment

Complete alcohol abstinence

- Liver stiffness improve shortly after alcohol withdrawal in > 80% of individuals with heavy

alcohol consumption presenting for alcohol detoxification

Nutrition

A daily energy intake of 35-40kcal per kg body weight

(2000-3000kcal) per os

A daily protein intake of 1,2-1,5g per kg bw (75-110g)

Corticosteroid treatment – confirmation of the clinical dg is

important, because unnecessary st. th should be avoided owing

potential life-threatening immunosuppressive side effects

N-acetyl cysteine (antioxidant) and pentoxiphylline

Sylibum marianum

…


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Treatment - steroid

Corticosteroid treatment

prednisolone at a dose of 40mg per day

Data of a randomized study (n=1103p) confirmed

effectiveness

OR for 28-day mortality was 0.61

Acceptability of steroid treatment is limited by

concerns about heightened risk of sepsis and GI

bleeding.

The Lilly score allows clinicians to predict poor

response to corticosteroids at seven days of therapy.


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EASL Clinical Practice Guidelines: Management of alcohol-related liver disease

2018 J Hepatol


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Treatment - outlook

GCSF – in animal models GCSF was able to mobilise

haemopoetic stem cells, induce liver regeneration, and

improve survival.

In human there were two study with improved short-term

survival and dicreased risk of infection and kidney injury, but

later a European study in decompensated cirrhosis reported

negative results, so further trials are required.

N-acetyl cysteine (antioxidant) and pentoxiphylline

Anti-TNF α (infliximab and etanercept) – higher risk of

infection

Extracorporated liver support – no clear benefit


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Management of alcohol withdrawal sy

Suddenly discontinue or decrease alcohol consumption

Light/moderate AWS within 6-24h:

RR↑ and fr ↑, tremor, hyperreflexia, irritability, anxiety,

headache, nausea, vomiting,

→ progress to more severe form: delirium tremens, seizure,

coma, cardiac arrest, death

Benzodiazepin is the gold standard

Long-acting provide more protection

against seizure and delirium

Disulfiram, naltrexone, acamprosate


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Fibrosis and cirrhosis

Liver fibrosis is a wound healing response to

chronic liver damage.

Extracellular matrix production by the activated

HSCs is the key event in fibrogenesis.

Portal fibroblasts, bone-marrow derived

myofibroblasts are also involved.

In ALD the pattern of fibrosis is characterized by

pericellular and perisinusoidal matrix

accumulation with a ‚chicken-wire’ appearance.


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Fibrosis and cirrhosis

Persistent alcohol intake → activates Kupffer

cells through gut-derived endotoxins and promotes

hepatic inflammation.

Alcohol acetaldehyde and ROS can promote

fibrogenesis by directly activating HSCs and by

stimulating immune cells to produce pro-

fibrogenic mediators.

Alcohol-mediated inhibition of several anti-

fibrotic pathways.


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Management of pt with liver cirrhosis

As in case of cirrhosis with other etiology

Differential dg (viral markers, autoantibodies…

Complications (ascites, HE, HRS)

Endoscopy should be performed to screen

oesophagela varices , unless there is a low risk of

having varices requiring treatment based on Baveno

criteria

(PLT > 150G/l, and Fibroscan < 20kPa)

Non-invasive tests

Liver biopsy if it is needed


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Treatment - infection

Frequent and severe complication – 20-50%

Infections accounted for 24% of deaths

Cirrhosis-induced immundeficiency, resulting from

bacterial overgrowth, dysbiosis, and increased translocation

on one side, and impaired innate and adaptive immunity on

the other.

Pts treated with corticosteroids had no increased risk of

infection or higher mortality from infection, than those

treated with placebo.


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Hepatocellular carcinoma - pathophysiology

Alcohol is a group 1 carcinogen – known to be carcinogenic to human

- per classification by International Agency for Research on Cancer

Procarcinogen – requires its bioconverion to a primary carcinogenic

metabolits, acetaldehyde. ALDH2*2 loss-of-function individuals have

an increased risk of oesophageal cancer

Oxidative stress, DNA mutations. Acetaldehyde also inhibits the

activity of the DNA repair enzyme.

Aldehyde-lipid metabolites (4-HNE, MDA), CYP2E1 also converts

other carcinogens, including nitrosamines, hypermethylation of

promoters for oncogenes.

Ectopic expression of TL4R and its activation by LPS induces HCC

-catenin-dependent tumor growth

Immunsuppression with decreased CD8+cells and by loss of miR-122.


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Hepatocellular carcinoma

The diagnosis of HCC is typically delayed in pts

with ALD associated cirrhosis owing the lack of

surveillance and poor pt compliance.

The management of HCC with ALD does not

differ from pts with HCC due to other aetiologies.


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Alcohol-mediated liver tumour initiation and promotion



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Treatment – liver transplantation

The most effective therapeutic options for pt with end-stage liver disease

Pts transplanted for ALD

- return to society and live active and productive lives

- disclose similar ability for work and physical activity as non-alcohol-

related tx recipients

Abstinence can be accuretely monitored by measurement of EtG in urine

or hair


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The future…


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Pharmacological chaperone therapies: Can aldehyde dehydrogenase activatormake us healthier?Journal of Hepatology. D Laurent et al 2015

The future…


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Thank you for your attention!

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ALCOHOLIC LIVER DISEASE - bel1.semmelweis.hu