Alcohol Metabolism

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ALCOHOL METABOLISM
AND ALCOHOLIC LIVER DISEASES
M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Rese
arch Scholar
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• 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
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• 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

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• 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.

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• 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
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• 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.

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• 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
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• 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

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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
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• 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

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

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• 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.

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• 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
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• 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.

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• 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

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• 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.

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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.

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• 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.

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

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• 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.

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• 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.

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• 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.

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• 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.

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

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