Transcript - SlideBoom
M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar 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 2030g/day). At low doses alcohol have some beneficial effects1. Decrease rate of myocardial infarction 2. Decreases stroke and formation of gallstones. 3. vascular disorders 4. alzehimers disease 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. 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. 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. 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. 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 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. 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. 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. 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. 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. 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. 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. 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). 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. 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 • • • • Deficiency of thiamine leads to disorder WERNICKE-KORSAKOFF syndrome symptoms: mental disturbances ataxia un coordinated eye movements congestive heart failure. 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. 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. 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. 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. 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 1. Hepatic steatosis 2. Alcoholic hepatitis 3. Alcoholic Cirrhosis 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: 1. Mild elevation of serum bilirubin,ALP. 1. 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. Clinical features: 1. Hyper bilirubinemia 2. 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. Neutrophilic reaction: Neutrophils permeate the lobule and accmulate around degenerating hepatocytes. Lymphocytes and Macrophages also enter portal tracts and spill in to parenchyma. 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. 3. 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. Clinical features: 1. Impaired synthesis of albumin 2. Elevated serum amino transferase 3. Hyper bilirubinemia 4. Elevated serum ALP 5. hypoproteinemia 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. Two other chemicals methanol & ethylalcohol are ingested and metabolized by ADH. methanol formaldehyde,formicacid. results:1 metabolic acidosis 2 dizziness 3 vomiting 4 blurred vision 5 respiratory depression. Ethyl alcohol aldehydes, glycolate, oxalates,lactate. results:acute renal failure obstruction of kidney by ca oxalate crystals.