Alcoholic

Fatty Liver Disease

Lecture 21, 22

By Dr Mohammad Manzoor Mashwani BKMC Mardan

ETHANOL

1

ETH

CH3CH2OH Ethanol

Ethyl Alcohol

The five Ayat (Ayas) of the Quran that most directly address the consumption of alcohol are as follows:

• 1. They ask thee concerning wine and gambling. Say: "In them is great sin, and some profit, for men; but the sin is greater than the profit." (Al-Baqara; 2:219)

• 2. And from the fruit of the date palm and the vine, ye get out wholesome drink and food: behold, in this also is a sign for those who are wise. (An-Nahl; 16:67)

• 3. O ye who believe! Approach not prayers with a mind befogged, until ye can understand all that ye say…. (An-Nisa; 4:43)

• 4. O ye who believe! Intoxicants and gambling, (dedication of) stones, and (divination by) arrows, are an abomination, Of Satan’s handiwork: Eschew such (abomination) that ye may prosper. (Al Maeda; 5:90)

• 5. Satan’s plan is (but) to excite enmity and hatred between you, with intoxicants and gambling, and hinder you from the remembrance of God, and from prayer: Will ye not then refrain? (Al-Maeda; 5:91)

One gram of alcohol gives 7 calories. But alcohol cannot be stored in the body and must undergo obligatory oxidation, chiefly in the liver. Thus, these empty calories make no contribution to nutrition other than to give energy..

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Moderate amounts of alcohol (one drink per day) have been reported to increase serum levels of high-density lipoproteins (HDLs) and inhibit platelet aggregation, thus protecting against coronary heart disease.

ETHANOLExcessive alcohol (ethanol) consumption is

the leading cause of liver disease in

most Western countries.

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Excessive ethanol consumption causes more than 60% of chronic liver disease in Western countries and accounts for 40% to 50% of deaths due to cirrhosis.

Forms of alcoholic liver disease

(1)Hepatic steatosis (fatty liver disease)

(2) Alcoholic hepatitis (3) Cirrhosis.

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There are three sequential stages in alcoholic liver Disease:

I. Fatty Liver /SteatosisDefinition:• Fatty liver is the collection of excessive

amounts of triglycerides and other fats inside liver cells.

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The break down of fats in the liver can be disrupted by

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Morphology of

1.Hepatic Steatosis (Fatty Liver). After even moderate intake of alcohol,

microvesicular lipid droplets accumulate in hepatocytes.

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1.Hepatic Steatosis (Fatty Liver). After even moderate intake of alcohol,

microvesicular lipid droplets accumulate in hepatocytes.

Alcoholic cirrhosis. A, The characteristic diffuse nodularity of the surface reflects the processes of nodular regeneration and scarring. The greenish tint of some nodules is

due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the lower edge of the right lobe (lower left).

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Alcoholic cirrhosis. The characteristic diffuse nodularity of the surface is induced by the underlying fibrous scarring. The average nodule size is 3 mm in this close-up view. The greenish tint is caused by

bile stasis.

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With chronic intake of alcohol, lipid accumulates creating

that compress and displace the hepatocyte nucleus to the periphery of the cell.

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Fatty liver disease. Macrovesicular steatosis is most prominent around the central vein and extends outward to the portal tracts with increasing severity. The

intracytoplasmic fat is seen as clear vacuoles. Some fibrosis (stained blue) is present in a characteristic perisinusoidal“ chicken wire fence” pattern. (Masson trichrome stain.)

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The normal adult liver weighs 1400 -1600 gm

Macroscopically, the fatty liver of chronic

alcoholism is a large (as heavy as 4 to 6 kg), soft organ that is yellow and greasy.

The fatty change is completely reversible if there is abstention from further intake of alcohol.

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Morphology 2. Alcoholic Hepatitis (Alcoholic Steatohepatitis).

Alcoholic hepatitis is characterized by: 1. Hepatocyte swelling and necrosis2. Mallory bodies: Mallory bodies are visible as eosinophilic cytoplasmic clumps in hepatocytes.

3. Neutrophilic reaction 4. Fibrosis

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Eosinophilic Cytoplasmic Clumps

twisted-rope appearance

Mallory BodiesLarge, poorly defined accumulations of eosinophilic

material in the cytoplasm of damaged hepatic cells in certain forms of cirrhosis especially those due to alcoholism.

• Synonym(s): alcoholic hyalin, alcoholic hyaline bodies,

Mallory body, Mallory-Denk body, and Mallory's hyaline

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Twisted-rope appearance

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A, Alcoholic hepatitis with clustered inflammatory cells marking the site of a necrotic hepatocyte. A Mallory-Denk body is present in

another hepatocyte (arrow).

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B, Steatohepatitis with many ballooned hepatocytes (arrowheads) containing prominent Mallory-Denk bodies; clusters of inflammatory cells are also seen; inset shows immunostaining for keratins 8 and 18

(brown), with most hepatocytes, including those with fat vacuoles, showing normal cytoplasmic staining, but in the ballooned cell (dotted line), the keratins are collapsed into the Mallory-Denk body, leaving the

cytoplasm “empty.”

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ETHANOL 25 Mallory body with the characteristic twisted-rope appearance (centre of image - within a ballooning hepatocyte). H&E stain

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B, The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top (Masson trichrome).

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3. ALCOHOLIC CIRRHOSIS.Alcoholic cirrhosis is the most common form of lesion, constituting 60-70% of allcases of cirrhosis. Several terms have been used for this type of cirrhosis such as

Laennec’s cirrhosis, portal cirrhosis, hobnail cirrhosis, nutritional cirrhosis, diffuse cirrhosis and micronodular cirrhosis.

Grossly, alcoholic cirrhosis classically begins as micronodular cirrhosis (nodules less than 3 mm diameter), the liver being large, fatty and weighing usually above

2 kg .Eventually over a span of years, the liver shrinks to less than 1 kg in weight, becomes non-fatty, having macronodular cirrhosis (nodules larger than 3 mm

in diameter), resembling post-necrotic cirrhosis. The nodules of the liver due to their fat content are tawny yellow, on the basis of which Laennec in 1818 introduced the term cirrhosis first of all (from Greek kirrhos = tawny).

The surface of liver in alcoholic cirrhosis is studded with diffuse nodules which vary little in size, producing hobnail liver (because of the resemblance of the surface with the sole of an old-fashioned shoe having short nails with heavy heads). On cut section, spheroidal or angula nodules of fibrous septa are seen.

Microscopically, alcoholic cirrhosis is a progressive alcoholic liver disease. Its features include the following

i) Nodular pattern: Normal lobular architecture is effaced in which central veins are hard to find and is replaced with nodule formation.

ii) Fibrous septa: The fibrous septa that divide the hepatic parenchyma into nodules are initially delicate and extend from central vein to portal regions, or portal tract to portal tract, or both. As the fibrous scarring increases with time, the fibrous septa become dense and more confluent.

iii) Hepatic parenchyma: The hepatocytes in the islands of surviving parenchyma undergo slow proliferation

Alcoholic liver disease. The interrelationships among hepatic steatosis, hepatitis, and cirrhosis are shown, depicting key morphologic

features.

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1 2

3

Alcoholic Liver Disease

•Lecture

22

Risk Factors for Alcoholic Liver Disease• 1. Drinking pattern• 2.Gender- women• 3. Malnutrition• 4. Infections• 5.Genetic factors• 6. Hepatitis C infection

Why all alcoholics do not develop cirrhosis but only 10-15%?

Only 10% to 15% of alcoholics, develop cirrhosis.

Pathogenesis Ethanol→AcetateEthanol after ingestion and absorption from the smallbowel circulates through the liver where about 90% of it isoxidised to acetate by a two-step enzymatic process

involving two enzymes: alcohol dehydrogenase (ADH) present in the cytosol, and acetaldehyde dehydrogenase (ALDH) in the mitochondria of hepatocytes. The remaining 10%of ethanol is oxidised elsewhere in the body.

First step: Ethanol is catabolized to acetaldehyde in the liver by the following three pathways, one major and two minor:

i) In the cytosol, by the major rate-limiting pathway of alcohol dehydrogenase (ADH).

ii) In the smooth endoplasmic reticulum, via microsomal P-450 oxidases (also called microsomal ethanol

oxidising system, MEOS), where only part of ethanol is metabolised.

iii) In the peroxisomes, minor pathway via catalase such as H2O2.

Acetaldehyde is toxic and may cause membrane damage and cell necrosis.

Second step: The second step occurs in the mitochondria

where acetaldehyde is converted to acetate with ALDHacting as a co-enzyme. Most of the acetate on leaving the liver is finally oxidised to

carbon dioxide and water, or converted by the citric acid cycle to other compounds including fatty acids.

Simultaneously, the same cofactor, NAD, is reduced to NADH resulting in increased NADH: NAD redox ratio which is the basic biochemical alteration occurring during ethanol metabolism. A close estimate of NADH:NAD ratio is measured by the ratio of its oxidised and reduced metabolites in the form of lactate-pyruvate ratio and β-hydroxy butyrate-acetoacetate ratio.

I. Major Pathway

II. Minor Pathway

III. Minor Pathway

STEP I STEP II

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malon-di-aldehyde-acetaldehyde (MAA)

CMI- cell mediated immunityMarked increase in the NADH:NADredox ratio in the hepatocytes results in increased redox ratioof lactate-pyruvate, leading to lactic acidosis. This alteredredox potential has been implicated in a number of metabolic consequences such as in fatty liver, collagen formation occurrence of gout, impaired gluconeogenesis and altered steroid metabolism.

Microsomal P-450Oxidases /Microsomal ethanol oxidising system,MEOS

Pathogenesis. • Short-term ingestion of as much as 80 gm of

alcohol over one to several days generally produces mild, reversible hepatic steatosis.

• Daily intake of 80 gm or more of ethanol generates significant risk for severe hepatic injury, and daily ingestion of 160 gm or more for 10 to 20 years is associated more consistently with severe injury.

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•Only 10% to 15% of alcoholics, develop cirrhosis.

• Thus, other factors must also influence the development and severity of alcoholic liver disease.

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Hepatocellular steatosis results from(1) shunting of normal substrates away from

catabolism and toward lipid biosynthesis(2) impaired assembly and secretion of

lipoproteins; (3) increased peripheral catabolism of fat.

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A concentration of 80 mg/dL in the blood constitutes the legal definition of drunk driving in most states.

Drowsiness occurs at 200 mg/dL, stupor at 300 mg/dL, and coma, with possible respiratory arrest, at higher levels. The rate of metabolism affects the blood alcohol level.

Persons with chronic alcoholism can tolerate levels as high as 700 mg/dL, due in part to accelerated ethanol metabolism caused by a 5- to 10-fold increase in induction of the hepatic cytochrome P-450 system,

Pathogenesis• 1. Direct hepatotoxicity by ethanol.• 2. Hepatotoxicity by ethanol metabolites.• 3. Oxidative stress• 4. Immunological Mechanism• 5. Inflammation• 6. Fibrogenesis• 7. Increased redox ratio• 8. Retention of Liver cell water & proteins• 9. Hypoxia• 10. Increased liver fat

Effects of AlcoholismAlcohol consumption in moderation and socially acceptablelimits is practiced mainly for its mood-altering effects. Heavyalcohol consumption in unhabituated person is likely to causeacute ill-effects on different organs.Acute Alcoholism:1. CNS2 Stomach3. Liver

Chronic Alcoholism• 1. Liver• 2. Pancreas• 3. GIT• 4. CNS• 5. CVS• 6. Endocrine system• 7.Blood• 8. Immune System• 9. Cancer

Chronic alcoholism is defined as the regular imbibing of an amount of ethyl alcohol (ethanol) that is sufficient to harm an individual socially, psychologically or physically.

Clinical Features • 1.Hepatic steatosis (fatty liver):

Hepatomegaly, • with mild elevation of serum bilirubin and alkaline

phosphatase levels.• Severe hepatic dysfunction is unusual.

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Alcohol withdrawal and the provision of an adequate diet are sufficient treatment.

Clinical features2. Alcoholic hepatitis tends to appear acutely, usually following a bout of

heavy drinking.

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1. Malaise,2. Anorexia,3. Weight loss, 4. Upper abdominal discomfort, 5. Tender hepatomegaly,

An acute cholestatic syndrome may appear, resembling large bile duct obstruction.

Alcoholic Hepatitis• The outlook is unpredictable; each bout of

hepatitis incurs about a 10% to 20% risk of death. • With repeated bouts, cirrhosis appears in about

one third of patients within a few years. • Alcoholic hepatitis also may be superimposed on

established cirrhosis.

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Alcoholic Hepatitis

• With proper nutrition and total cessation of alcohol consumption, the alcoholic hepatitis may clear slowly.

• However, in some patients, the hepatitis persists, despite abstinence, and progresses to cirrhosis.

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Laboratory findings:

• Elevated serum aminotransferase,• Hyperbilirubinemia,• Elevation of serum alkaline phosphatase,• Hypoproteinemia, • Anemia.

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SGOT, SGPT

Cholestasis

Diagnosis

Hyperbilirubinemia, Elevated alkaline phosphatase, Neutrophilic leukocytosis.

• In some instances, liver biopsy may be indicated, since in about 10% to 20% of cases of presumed alcoholic cirrhosis, another disease process is found.

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III. CirrhosisCirrhosis typically develops after 10 to 15 years of

drinking or more, but only occurs in a small (10-15%)

proportion of chronic alcoholics; alcoholic cirrhosis has the same morphologic and clinical features as cirrhosis caused by viral hepatitis.

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Cirrhosis may be clinically silent, discovered only at autopsy or when stress such as infection or trauma tips the balance toward hepatic insufficiency.

Prognosis• Five-year survival approaches 90% in

abstainers who are free of jaundice, ascites, or hematemesis;

• it drops to 50% to 60% in those who continue to imbibe.

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In the end-stage alcoholic the proximate causes of death are

(1) hepatic coma, (2) massive gastrointestinal hemorrhage, (3) intercurrent infection (4) hepatorenal syndrome(5) hepatocellular carcinoma

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Complications of Alcoholism

Advantages of AlcoholModerate amounts of alcohol (one drink per day) have been

reported to increase serum levels of high-density lipoproteins (HDLs) and inhibit platelet aggregation, thus protecting against coronary heart disease.

One gram of alcohol gives 7calories.

Ethanol is a substantial source of energy

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