alcoholic liver disease - bel1.semmelweis.hu
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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
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Alcohol-attributable liver cirrhosis deaths
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
IN MODERATION!
A moderate alcohol
consumption is
cardio-protective
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
http://www.plantbasedpharmacist.com
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Screening and prevention
Early detection of
alcohol-related
disease
Alcohol
consumption
should be assessed
routinely
with an empathic,
non-judgemental
attitude
*
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Disease course of ALD
Helmuth K Seitz et al Alcoholic Liver Disease 2018
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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)
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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, ..
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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??
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Differential diagnosis
Severe sepsis
Biliary obstruction
Diffuse HCC
Drug-induced liver injury
Ischaemic hepatitis
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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)
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
…
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
EASL Clinical Practice Guidelines: Management of alcohol-related liver disease
2018 J Hepatol
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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.
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Alcohol-mediated liver tumour initiation and promotion
Helmuth K Seitz et al Alcoholic Liver Disease 2018
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
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
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
The future…
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Pharmacological chaperone therapies: Can aldehyde dehydrogenase activatormake us healthier?Journal of Hepatology. D Laurent et al 2015
The future…
Alcoholic liver disease Aniko FOLHOFFER MD, PhD
lecturer
Thank you for your attention!
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