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Alcohol Metabolism

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Title: Alcohol Metabolism


1
ALCOHOL METABOLISM
AND ALCOHOLIC LIVER DISEASES
M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Rese
arch Scholar
2
  • Alcohol is not only an intoxicant but also a
    nutrient.
  • Excess intake of alcohol produces most serious
    health concerns all over the world.
  • Alcohol consumption in excess is associated
    especially with liver disorders (more than
    20-30g/day).

INTRODUCTION
3
  • At low doses alcohol have some beneficial
    effects-
  • 1. Decrease rate of myocardial infarction
  • 2. Decreases stroke and formation of
  • gallstones.
  • 3. vascular disorders
  • 4. alzehimers disease

4
  • Average drink of alcohol represents11-15g.
  • Energy yielding
  • A drink contains 300kcal or70-100kcal,it is
    devoid of nutrients such as minerals, proteins
    and vitamins.

5
  • Ethanol is readily absorbed from the intestine by
    passive diffusion.
  • A small of percentage of ethanol enters
    mucousmembraneof mouth ,oesophagus stomach in
    small amouts(0-5)where it is metabolised.The
    remaing enters the blood.Of this (85-98)is
    metabolised in liver.

ABSORPTION EXCRETION
6
  • The rate of absorption is increased by rapid
    gastric emptying in absence of proteins, fats and
    carbohydrate.
  • Alcohol can also interfere with absorption of
    vitamins in small intestine and decrease their
    storage in liver.
  • 2(at low blood alcohol con)10(high blood
    alcohol) of ethanol is excreated directly through
    lungs, sweat, or urine but greater part is
    metabolised to acetaldehyde.

7
  • Ethanol is both lipid soluble and water soluble
  • Ethanol is dietary fuel that is metbolised to
    acetate in the liver with generation of NADH.
  • The major route of Ethanol metabolism in liver is
    through liver alcohol dehydrogenase it oxidises
    ethanol to acetaldehyde with reduction of NAD to
    NADH.

METABOLISM
8
  • The acetaldehyde exits toxic effects in the
    liver, blood and other tissues.
  • 90 of acetaldehyde that is generated is
    metabolised to acetate in the liver. The enzyme
    involved is mitochondrial acetaldehyde
    dehydrogenase.
  • It oxidises acetaldehyde to acetate with
    generation of NADH.
  • Acetate has no toxic affects, and may be
    activated to acetyl Coa in liver ( Where it can
    enter TCA cycle or pathway of fatty acid
    synthesis

9
  • Most of the acetate generated enters the blood
    and it is activated to acetyl COA in skeletal
    muscles and other tissues.
  • Acetate is generally considered nontoxic and is
    normal constituent of the diet.

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Microsomal Ethanol Oxidising System(MEOS)
  • 10 to 20 ingested Ethanol is oxidised through
    MEOS.
  • Which also oxidises Ethanol to acetaldehyde. The
    microsomal enzyme involved is Cyt P450
  • It uses NADPH and molecule O2 forming water and
    acetaldehyde.
  • This route accounts only for moderate drinkers.

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  • Oxidation Of Ethanol In Liver Alters NAD/NADPH
    Ratio
  • Changes in fatty acid metabolism
  • The high NADH / NAD Generated inhibits fatty
    acid oxidation and fatty acids accumulate in
    liver.
  • These fatty acids are re-esterified into triacyl
    glycerol by fatty acyl COA transferase by combing
    with glycerol 3phospate.

15
  • The triacyl glycerol are incorporated in to VLDL
    it accumulate in liver enter blood causing
    Hyperlipidemia.
  • The sources of fatty acids can be dietary fat
    fatty acids synthesized in liver, or fatty acids
    released from adipose tissues stores.
  • Adipose tissue lipolysis increase after ethanol
    consumption, because of release of epinephrine.

16
  • Alcohol-induced ketoacidosis.
  • Fatty acids that are oxidized are converted to
    acetyl COA and subsequent to ketone bodies.
  • The high NADH NAD ratio shifts oxaloacetate in
    the TCA cycle to malate .
  • So availability of OAA is too low for citrate
    synthesis.
  • Thus acetyl COA enters pathway for ketone bodies
    synthesis instead of TCA cycle.

17
  • Lactic Acidosis Hyperuricemia, and Hypoglycemia
  • The high NADH level favours conversion of
    pyruvate to lactate leading to lactic acidosis.
  • The elevation of blood lactate decrease excretion
    of uric acid by kidney resulting in gout
    increased degradation of purines may also lead to
    Hyperuricemia
  • The Increased NADH / NAD can cause hypoglycemia
    in fasting individual and dependent on
    gluconeogenesis to maintain blood glucose.

18
  • Alanine lactate are gluconeogenic Precursors
    that enter gluconeogenesis as pyruvate so high
    NADH/ NAD ratio convert pyruvate to lactate
    cannot enter gluconeogenesis.
  • A part from this consumption of ethanol with meal
    lead to hyperglycemia because high NADH / NAD
    inhibit glycolysis at glyceraldehyde 3 P
    dehydrogenase.

19
  • Acetaldehyde reacts with sulfhydryl groups of
    various groups of enzymes reducing their activity
    it also causes tachycardia, hypotension,
    headache nausea.
  • It also causes CNS depression by inhibiting
    exitatory receptors (N methyl aspartate
    receptors).

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  • In chronic alcoholics there will be considerable
    risk of nutritional defeciencies.
  • But the neurological hematological symptoms are
    associated with thiamine, pyridoxine and folate
    deficiencies.
  • Folate deficience leads to Megaloblastic
    Erythropoiesis . Alcohol interfers with folate
    absorption.
  • Pryidoxine deficiency leads to sideroblastic
    anemia.

Nutritional Considerations in Alcoholics
22
  • Some alcoholics also develop a peripheral
    neuropatty due to impaired activation and
    increased degradation of pyridoxine.
  • Acetaldehyde displaces PLP from its carrier
    protein in plasma PLP degraded to inactive
    compound excreted.
  • Chronic ethanol consumption causes redistribution
    of vit A stores in the body it increases
    mobilization catabolism of liver vit A to
    inactive metabolites by hepatic cyt P450 system

23
  • Deficiency of thiamine leads to disorder
  • WERNICKE-KORSAKOFF syndrome
  • symptoms
  • mental disturbances
  • ataxia
  • un coordinated eye movements
  • congestive heart failure.

24
  • Defect in 25 hydroxylation step in liver
    increased rate of metabolism of Vit D to inactive
    products by activated cyt P450 leads to decreased
    bone density cause Osteoporosis.
  • A port from vitamins they will also have
    decreased serum levels of Zn, Ca, Mg, due to poor
    dietary intake increased urinary loss.
  • Iron deficiency anemia is very rare unless thre
    is gastro intestinal bleeding or chronic
    infections because alcoholic beverages contain
    high iron levels it enhance iron absorption.

25
  • Currently, 67 of the population 18 years of age
    or older drink alcohol suffer from serious
    health consequences.
  • More than 14 million Americans meet criteria for
    alcohol abuse and dependence, corresponding to a
    prevalence of 7.4. This is highe r inmen (11)
    than in women (4).
  • Alcohol abuse causes 2,00,000 deaths annually.
    40 of deaths from cirrhosis are attributed to
    alcohol induced liver disease.

Alcoholic Liver Disease
26
  • Acute Alcoholic Hepatitis
  • It is potentially reversible form of liver
    injury.
  • Alcoholic hepatitis can produce fever liver
    tenderness and Jaundice.
  • The hepatocytes of liver are accumulated by fat
    causing necrosis cell injury.
  • In acute hepatitis,bilirubin urobilinogen are
    readily detectable in urine by DIP-STICK
    technique.

27
  • The metabolites formed during Ethanol oxidation
    are toxic to hepatocytes.
  • This toxicity is mediated by glutathione
    depletion, mitochondrial injury, altered
    metabolism of methionine cytokines release from
    kupffer cell.
  • There is hepatocellular necrosis fibrosis
    around central vein due to hypoxia.

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  • Chronic Alcoholic Hepatitis
  • Irreversible liver damage or alcoholic
    cirrhosis.
  • It is characterized by hard shrunken liver with
    formation of micronodules, Surrounded by dense
    bound of Collagen.
  • The three dlistinctive form of liver diseases
    are
  • Hepatic steatosis
  • Alcoholic hepatitis
  • Alcoholic Cirrhosis

30
  • Hepatic Steatosis ( Fatty Liver)
  • Even moderate intake of alcohol lipid droplets
    accumulates in hepatocytes.
  • In chronic intake of alcohol there will be clear
    macro vesicular globules and displaces the
    nucleus to periphery.
  • The fatty liver in chronic alcoholism is large
    soft, organ which is yellow and gresy.
  • Fibrous tissue develops around terminal heapatic
    vein.
  • Clinical features
  • Mild elevation of serum bilirubin,ALP.

31
2. Alcohol Hepatitis It is characterised by
Hepatocyte Swelling Necrosis
  • Single or group of cells undergo swelling
    necrosis.
  • The swelling is due to accumulation of fat,
    water, and Proteins.
  • In some cases there is cholestasis in surviving
    hepatocytes mild deposition of iron in
    hepatocytes kupffer cells.

32
  • Clinical features
  • Hyper bilirubinemia
  • Elevated ALP
  • Mallory bodies
  • Tangled skeins of cyto keratin intermediate
    dilaments and other Proteins visible as
    Eosinophilic cytoplasmic inclusions.
  • They are also seen in primarybiliary cirrhosis,
    wilson disease, and hepato cellular tumours.

33
  • Neutrophilic reaction
  • Neutrophils permeate the lobule and accmulate
    around degenerating hepatocytes.
  • Lymphocytes and Macrophages also enter portal
    tracts and spill in to parenchyma.

34
  • Fibrosis
  • Activation of sinusoidal stellate cells and
    portal tract fibroblasts, give rise to fibrosis.
  • It splits the parenchyma apart.
  • The steatotic hepatocytes are also present they
    are interspersed with inflammatory cells
    activated stellate cells.
  • The Microscopic structure of liver is mottled red
    with bile stained areas. It often contains
    visible nodules.

35
  • Alcoholic Cirrhosis
  • It is final irreversible form of alcoholic
    liver disease.
  • The cirrhotic liver is yellow tan fatty, and
    enlarged.
  • The fibrous septae are delicate Extend through
    sinusoids from central to portal regions.
  • The Entrapped parenchymal hepatocytes form
    micronodules and give Hobnail appearance.

36
  • Clinical features
  • Impaired synthesis of albumin
  • Elevated serum amino transferase
  • Hyper bilirubinemia
  • Elevated serum ALP
  • hypoproteinemia

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  • Ethanol and Cancer
  • Use of alcoholic beverages is associated
  • with an increased incidence of cancer of
  • oral cavity, pharynx, oesophagus,liver
  • breast.
  • Ethanol is not a direct carcinogen the metabolite
    acetaldehyde act as tumor promoter.
  • It inhibits detoxification of chemical
    carcinogens such as nitrosamines which
  • are associated with tumors of upper GI tract.

39
  • Two other chemicals methanol ethylalcohol
  • are ingested and metabolized by ADH.
  • methanol formaldehyde,formicacid.
  • results1 metabolic acidosis
  • 2 dizziness
  • 3 vomiting
  • 4 blurred vision
  • 5 respiratory
    depression.

40
  • Ethyl alcohol aldehydes,
  • glycolate,
    oxalates,lactate.
  • resultsacute renal failure
  • obstruction
    of kidney by ca
  • oxalate
    crystals.

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