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Alcoholic liver disease

Assoc Prof.. Dr. Mircea Manuc


premises
Alcohol consumption represents a daily part of
modern society, being almost a "behavioral
norm
is legal, easily accessible and inexpensive.

excessive and sustained can lead to addiction


and generate multiple diseases, among which
alcohol-induced liver disease (ALD) has the
largest impact on overall morbidity and mortality,
and thus public health services.
ALD is probably the oldest known liver disease
(alcohol known Neolithic - 10000 BC)
* premises (II)
ALD is a very frquent disease all over the world
There are large geographycal differences, depending
on several factpros ex. religion
Alcohol consumption is raising in the world
Consumul de alcool este in crestere in lume
Asociayion between alcohol cirrhosis = 1793 (M.
Baillie)
Cirrhosis 4-th causeof death in USA
80-90% of drinkers has nos ALD
Evaluation of alcohol consuption

"Standard unit" - which corresponds to 14 grams


of absolute alcohol.
To calculate the amount of absolute alcohol
consumed, you must know the various alcohol
concentrations:
beer - about 5% alcohol
Table wines - about 12% alcohol
dessert wine (port, sherry) - about 17% alcohol
liqueurs, aperitifs - about 24% alcohol
spirits (brandy, whiskey, vodka, gin) - about 40%
alcohol.
According to epidemiological data, are at
risk of developing chronic liver disease
M - over 4 units / day or 14 units / week
F - more than 3 units / day or 7 units / week

Daily consumption of alcohol over 40-80 gr /


day in men or 20-40 g / day for women will
definitely lead to the development of BHA
after an interval of 10 years
Epidemiology
Populational studies show that in the U.S. and Western
Europe,

- 68% of the population consumes alcohol at least once


a month.
- 10% of the population consumes at least 2 units / day.
The consequences of this are:
- 10% of consumers of ethanol are responsible for 50%
of total consumption
- 7.4 to 8.5% of Americans meet the conditions of abuse
or alcohol dependence (American Psychiatric
Association)
- 15% of consumers will develop BHA
- 44% of mortality from chronic liver disease is
alcohol induced

- 3 to 5% of overall mortality can be attributed


directly or indirectly ethanol consumption,
alcoholism is in the top 10 causes of death
Mortality is lower in young to middle age but
increases exponentially, reaching a peak in the
age group> 60 years.
Significant share of deaths by age group, but the
group is 45-54 years age group which is the 4 th
leading cause of death
ALD in alcoholics risk factors
Dose and duration of alcohol
High-dosage drinkers, after at least 5 years
no matter the type (?) but only the amount (studies show
that beer and distillates generate more problems than
wines)
daily consumption more dangerous than the occasional
consumption
* at least 2 days / week not to drink
Gender
F more likely than M (Active gastric ADH?, Estrogen
intestinal Hpermeabilitatea endotoxinemie?)
genetic factors
Behavioral patterns (gene polymorphisms)
Nutritional Facts
Protein-calorie malnutrition (low
socioeconomic level)
Infection with hepatitis viruses
Coexistence virus + alcohol more severe
ex. VHC- alcohol

70% of patients infected with C had a history of ethanol


consumption,
30% of patients with chronic HCV infection have ALD

Alcolol consumption in patients with HCV chronic


hepatitis leads to cirrhosis faster
Ingestion > 50 g / day, represents an independent risk
factor for the development of cirrhosis.

alcoholics have higher levels of HCV viremia and a lower


response rate to antiviral therapy.

This combination produces a greater number of


hepatocarcinomas.
Liver toxicity of alcohol
Glucoza (hipoglicemie)
Droguri
hormoni
lactat
ETANOL
piruvat
hiperlacticedimie
NAD
NADPH
Acidoza renala
MEOS ADH hidrogen
(P450-2E1) NADH hiperuricemie
NADP
Inlocuieste acizii grasi
acetaldehida ca sursa de enerigie

Acizi grasi
acetat cetoza
trigliceride

Metab. Ficat gras hiperlipidemie


polari
ALD
clinical and histological aspects

1. Fatty liver (steatosis)


2. Alcoholic hepatitis
3. Alcoholic cirrhosis
4. hepatocarcinoma
Fatty liver

diagnosis
Ficatul gras alcoolic
caracteristici

presence of lipids in more than 5% of hepatocytes, or


more than 5g fat per 100g liver
Macroscopic
enlarged, firm, often yellow
histopathology:
Macrovezicular steatosis,
affected hepatocytes die and break lipogranulom
fatty cyst.
Lipogranulomas can be confused with other types of
granulomas, but can be easily identified by the
presence of lipid-filled macrophages.
Alcoholic steatosis
clinic

75% = asymptomatic hepatomegaly

Stigmates of alcohol consumption


contracturi Dupuytren-like
Facial eritema
Hypogonadism in men
tremor
Alcoholic steatosis
laboratory
25% - hyperbilirubinemia (rarely exceeding 5mg/dl).
AST increased (no more than 300 IU / liter)
AST is often high (with a ratio AST / ALT > 2 in 80% of cases) in alcoholic liver
disease (explanation: pyridoxine deficiency, release of AST from other extrahepatic
tissues and intracellular pools hepatocyte)
Only moderately elevated alkaline phosphatase (usually in 300UI/dl
without cholestasis).
Often GGT increased, with report GGT / alkaline phosphatase > 5 in
50% of cases
Serum albumin and globulin levels are abnormal in more than 25% of
the alcoholic patients with alcoholic fatty liver (serum globulin level rarely
exceeds 4g/dl).
Alcoholic steatosis
diagnostic

Accurate diagnosis is given by liver biopsy


No need in majority of cases

Abdominal ultrasound can only suggest


the existence of an alcoholic steatosis
Alcoholic steatosis
ultrasound aspects
Steatosis is revealed in ultrasound at a
hepatocyte lipid load over 10-20%
relatively typical ultrasound aspects:
(1) uniform hyperecogeniity of parenchyma
(2) pseudodilations of hepatic venoula,
dispersed over the surface of the liver

(4) Mitigation back of ultrasound waves (in the


absence of hepatomegaly may suggest the
development of fibrosis)
Alcoholic steatosis
differential diagnosis
Other causes of steatosis
1. Nutritional disorders:
prolonged starvation, protein-caloric malnutrition,
Obesity, jejunoileal bypass surgery for obesity,
carnitine deficiency, diabetes mellitus,
total parenteral nutrition, pregancy
2. Drugs: methotrexate, corticosteroids, sd Reye
3. Hereditary diseases:
cystic fibrosis, galactosemia, tyrosinemia, fructose intolerance,
glycogen storage disease type Ia, Abetalipoproteinemia, acyl-CoA
dehydrogenase deficiency, glutamic acidaemia type II, Wilson's
disease, lipodystrophy, Porphyria cutanea tarda
4. Infections: malaria, Q fever
Alcoholic steatosis
complications and prognostic

Benign condition potentially reversible after


stopping alcohol (in 4-6 weeks)
Up to 15% of patients may progress to other
clinical forms despite abstinence
Up to 37% of patients evolves to other forms if
drank> 40 g / day
Sudden death incidentally reported:
fatty embolia , alcohol withdrawal,
hypoglycemia
Alcoholic hepatitis

diagnostic
Alcoholic hepatitis
Necroinflammatory lesions of varying
degrees associated with lesions
of of steatosis
can be reversed, but it is a more
serious injury than alcoholic fatty liver
most important precursor of alcoholic
cirrhosis
Alcoholic hepatitis

Epidemiology
prevalence unknown
necropticall studies. 10-35% of patients
hospitalized has alcoholic hepatitis
50% of cases has associated cirrhosis
diagnostic difficulties
Alcoholic hepatitis
pathology

Most important characteristics are:


vacuolated degeneration and necrosis
inflammatory infiltrate (PMN)
Mallory bodies
Megamitocondria
+ / - Perivenular and perisinusoidal fibrosis
independent risk factor of evolution to
cirrhosis
Alcoholic hepatitis
clinic
(1) asymptomatic patients
a small proportion of all patients with alcoholic hepatitis
Diagnosis is based on liver biopsy
(2) dyspeptic symptoms
anorexia, nausea, asthenia, fatigue, vague abdominal pain,
jaundice, weight loss, fever

(3) patients whose disease is expressed clinically


evident with complications
encephalopathy, gastrointestinal bleeding, ascites, renal
insufficiency
rapidly progresses to death
Alcoholic hepatitis
clinical examination
hepatomegaly (95%),
a liver large (over 16 cm), is a strong argument against the existence of a viral or drug-
induced liver disease
hepatic sensitivity (50-70%)
signs of portal Hypertension (splenomegaly, abdominal veins visible,
ascites) (40-70%)
stigmata of chronic liver disease and alcoholism
(bruising, leuconichie, palmar erythema, angiomas, enlarged parotids, gynaecomastia,
testicular atrophy) (30-60%)
jaundice (55%)
fever (50%)
upper gastrointestinal bleeding (30%)
evidence of hepatic encephalopathy (20%
Alcoholic hepatitis laboratory data

ASAT/ALAT , GGT ,ALKP ,


: globulines with IgA
hemato leucocytosis/ neutrophylia
liver hypofunction (halb., AP, fibrinogen)
cholestasis: cholesterol, BT,
Renal failure - uree, creat.
Electrolytic disturbances :hyponatremia,
hypopotasemia , hypomagneziemia, phosphate
depleion, acidosis (50% of patients).
Alcoholic hepatitis
differential diagnosis
diagnosed with certainty only by liver biopsy
differential diagnosis (NASH)
Diabetes
Morbid obesity with or without intestinal bypass surgery
Massive small bowel resection
Bulimia
Hyperlipidaemia
Lipodystrophy
Medications: glucocorticoids, amiodarone, perhexilin
maleate, estrogen (in high doses), nifedipine, colchicine
Alcoholic hepatitis
complications
Reversible portal hypertension
resulting from hepatocyte ballooning (accumulation of lipids,
proteins secreted export failure, dysfunction of the
cytoskeleton)
If the patient stops drinking, portal hypertension is likely to
subside.
Portal hypertension irreversible
caused by the development of fibrosis and obliteration
especially sclerosis of terminal hepatic veins,
if the patient survives the acute phase of hepatitis, severe
portal hypertension persists due to permanent changes of
hepatic architecture
Alcoholic hepatitis
short term prognostis

Early mortality rates ranging from 19% to 78% (average 49%)


Prognostic tests
report BT to 7 days after onset
Prothrombin time 4 seconds longer than the witness, despite treatment
with vitamin K
total bilirubin over 5mg/dl
the serum creatinine rises above 0.6 mg / dL from baseline in the first 10
days of hospitalization
1. Maddrey (modified) discriminant function (1989)

MDF=4.6 (patient's PTcontrol PT) + total bilirubin (mg/dl)

Poor prognosis if score 32

2. MELD score (2001)

MELD score = 3.8 loge(bilirubin in mg/dl)


+11.2 loge(INR)+9.6 loge(creatinine mg/dl)+6.4
Poor prognosis if >18
3. Glasgow alcoholic hepatitis score (2005)

Score 1 2 3

Age <50 50
WCC <15 15
Urea (mmol/l) <5 5
PT ratio <1.5 1.52.0 2
Bilirubin (mg/dl) <7.3 7.314.6 >14.6

Poor prognosis if score >8 (for score calculated on hospital day 1 or day 7)
Alcoholic hepatitis
long term prognosis
chronic disease with clinical, laboratory and
histological abnormaliyies persisting for months
Evolution to livr cirrhosis in> 50% of cases
Pronostic factors
Severity of fibrosis = an important prognostic
factor
minimal fibrosis causes a 5-year survival rate of
72%
Severe fibrosis determines survival rate at 5 years
only 48%
Coexistence of cirrhosis = a poor prognosis
Extension of inflammation = poor prognosis
Alcoholic hepatitis
the most important precursor to cirrhosis

* Follow-up study over a period of six years, conducted with


patients who continued to consume alcohol, it was found:
none, did not return to normal liver structure
58% had persistent alcoholic hepatitis
42% progressed to cirrhosis

In other studies:
rate of progression to cirrhosis even reached 80%
of those who stopped / reduced alcohol consumption,
70% returned the normal,
15% remained with alcoholic hepatitis,
15% developed cirrhosis;
mortality rate of 24% in 7 years
those who continued to drink too much alcohol,
mortality rate of 50% in seven years,
Alcoholic cirrhosis

diagnostic
Alcoholic cirrhosis
Main feature:
deposition of collagen and other proteins
(extracellular matrix) around hepatocytes,
with nodular regeneration
End-stage of alcoholic liver disease
Alcoholic cirrhosis
manifestari clinice
fairly wide spectrum:
about 10-20% are asymptomatic
commonly, patients present with classical painting with
complications and stigmata of chronic liver disease
sometimes liver disease is detected at an assessment related to
an event unrelated to liver disease
male hypogonadism and feminization are much more
common than in those with hemochromatosis or viral
cirrhosis
Alcoholic cirrhosis complications are similar to those of
any form of cirrhosis:
ascites, spontaneous bacterial peritonitis, hepatorenal
syndrome, hepatic encephalopathy, hepatocellular carcinoma
faecal
Alcoholic cirrhosis
laboratory data
Liver test abnormalities are less
pronounced than in alcoholic hepatitis,
many are within normal limits
moderate increases in AST and ALT
low levels of albumin
elevated serum globulins (more than 4 g / dL)
elevated serum levels of IgG and IgA
prolonged prothrombin time
thrombocytopenia, anemia
Alcoholic cirrhosis
positive diagnostic

Signs of portal hypertension in an alcoholic


confirmed the absence elements to support
another cause of cirrhosis
liver biopsy
element of certainty in the diagnosis of cirrhosis is not
compulsory, but is necessary to:
differentiate between fatty liver, alcoholic hepatitis or cirrhosis
reason to exclude a non-alcoholic liver disease
determining disease severity
Alcoholic cirrhosis
differential diagnosis

Two traps:
(1) lack of consideration of alcoholic liver
disease in patients who do not fit into the
profile of chronic alcoholic
(2) the assumption that abnormal liver
function tests in an alcoholicpatient are
strictly related to alcoholic liver disease
Alcoholic cirrhosis
differential diagnosis
cirrhosis of other etiologies
other pathological conditions that can
mimic cirrhosis
constrictive pericarditis,
Budd-Chiari sd., veno-occlusive disease,
idiopathic PHT, MMM
chronic active hepatitis
Alcoholic cirrhosis
prognostic and evolution

PROGNOSTIC
better for. abstinent (60% survived 5 years compared with
40% of those who continued to drink)
better male> female
! poor prognosis: cholestasis, encephalopathy, ascites,
hypocoagulation, anemia, hyperazotaemia,
SURVIVAL
5-year survival is highly variable:
90% in those patients who have ascites, jaundice or HDS,
remaining abstinent
70% of those who continue to use alcohol and without
complications above
50% in those with jaundice or ascites, but are abstinent
30% of those who develop jaundice or ascites and continue
to drink
Liver cancer
Alcohol can be incriminated in the development of HCC.
The idea that alcohol is carcinogenic agent was postulated, but
the presence of liver cirrhosis appears to be important for the
development of liver cancer.
Intervention may be
direct - various mechanisms (oxidative stress, production of
acetaldehyde which is mutagenic, DNA methylation
abnormalities by decreasing glutathione, increased iron
intrahepatocitar, altered gene expression)
Indirect - by stimulating the action of various environmental
carcinogens (viruses, aflatoxin, vinyl chloride), or by decreasing
immune tolerance neopalzice
association of alcohol with chronic viral infections (HCV) causes
a synergistic effect in the development of HCC.
there is a relationship between HCC and dosage, HCC
does not appear at doses below 50 g alcohol / day, and
under 10 years of consumption.
treatment
1. abstinence
Steatoza alcoholic steatosis can be
completely reversible within several weeks
Persistence of alcohol intake is an
independent risk factor for poor prognosis in
cirrhosis
Take care of withdraw sd !!!
2. nutritional support
Malnutrition is an independent risk factor for
poor prognosis in alcoholic hepatitis
In 30 days
2%decease if mild malnutrition
52% deceseif severe malnutrition
Enteral or parenteral nutrition according to
severity
1g/kg additional protein, calories 2000 kcal / day,
vitamins (B1, B2, B6, C, E, K)
3. corticosteroids
Mec action: immunosuppressive, anti-inflammatory
and antifibrotic
indication alcoholichepatitis
Adm.
Oral - prednisolone 40 mg / day, 28 days
Parenteral - 32 mg / day,
Survival at 30 days
85% of CS
64% without CS
CI gastrointestinal hemorrhage, infections, kidney
failure
Val BT to 7 days medium term prognostic factor
84% suypravietuire if BT low-day 7 (6 months)
23% guardi if BT persist
Pentoxifylline
Phosphodiesterase inhibitor that decreases TNF
alpha
Dose 400 mg * 3/day
Recommended ethanolic hepatitis moderate,
severe
The benefit seems to be related to the decrease the
rate of complications related hepatorenal syndrome
decreases overall mortality of this complication
anti TNF alfa drugs
Infliximab
5 mg / kg single dose or 0,2,4 weeks
Being evaluated for severe forms of hepatitis
ethanolic
Promising results decreases mnortality
Relatively well tolerated?
Etanercept
Under evaluation, can not yet be recommended
outside clinical trials
Vit E
antifibrotic mechanisms
1000 UI/zi
Recommendedt in moderate forms
Debatable benefit
Sylimarine
Antioxidant, antifibrotic ?
Recommended in cirrhotic alcoholics
140 450 mg/zi long term
Debatable benefit but no adverse reactions
S-adenosyl-methionine
Decreases oxidative stress and increases glutathione
levels
Dose of 1200 mg / day 2 years at initial stages
ciroticii
Inconclusive results for now
Dilinoleoylfosfatidilcolina
Antifibrotic
under evaluation but so far are not conclusive results
Colchicine
Anti inflammatory and antifibrotic
Dose 1 mg / day, the long
Not proven effective, but shows adverse events
can not be recommended
hepatic transplantation
A long period was not accepted on the transplant list
useful for alcoholic cirrhosis with Child score C
Better prognosis if abstinent
about one third of patients started to drink after transplant
Recom
Minimum 6 months of abstinence
Capability of social reinsertion
Psychiatric approval
Absence of alcohol-induced extrahepatic pathology
(neurological, pancreatic, etc.)
Participation in special programs for alcohol addicts