Metabolism of Ethanol and Hepatic Cirrhosis - Case Study Example

BIO3109 Pathology 1- Assignments Assignment 2: АLСОHОLIС LIVЕR DISЕАSЕ: FRОM THЕ MЕTАBОLISM ОF ЕTHАNОL TО HЕРАTIС СIRRHОSIS Name Institutional Affiliation Abstract The metabolic pathways of alcohol are related with the progression of alcohol liver disease from steatosis to cirrhosis due to release of toxic compounds during the metabolism. The three main metabolic pathways involved in alcohol metabolism are the oxidative aldehyde dehydrogenase and microsomal ethanol oxidizing system pathways and the non-oxidative Fatty Acid Ethyl Ester (FAEE) Synthase pathway. Oxidative stress and mitochondrial damage in the hepatocytes results in chronic alcohol consumption as the cells attempt to maintain an optimum ionic environment for their function. Liver damage occurs through steatosis, the fatty change stage, steatohepatitis, the inflammation stage, and cirrhosis the necrosis and end stage. The metabolic pathway imparts haematological consequences resulting in low blood cell count and impaired blood cell production. Major biomarkers in the biochemistry of alcohol liver disease are serum ferritin, prothrombin, bilurubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, urea, creatinine, blood glucose and full blood count parameters. Introduction Alcoholic Liver Disease in an illness resulting from chronic overconsumption of alcohol. The metabolites resulting from ethanol metabolism such as acetaldehyde are toxic to the cells. With increasing consumption, the cells become exposed to these toxic metabolites which change their biochemical function, and the onset of alcoholic hepatic cirrhosis. This paper discusses the metabolism of alcohol, mechanisms of alcohol toxicity, morphology of alcohol liver disease, haematological effects of alcoholic liver disease and the biochemistry of alcohol liver disease are discussed. General discussion a) Metabolism of alcohol Alcohol is metabolised in the liver by three distinct enzymes -Alcohol Dehydrogenase (ADH), Aldehyde Dehydrogenase (ALDH), and Cytochrome P450 (CYP2E1) (Neuman et al. 2014). Alcohol metabolism is achieved through both oxidative and non-oxidative pathways. Aldehyde Dehydrogenase is the primary enzyme that initiates the oxidative pathway of ethanol metabolism (Neuman et al. 2014). It is found in the cytosol of the cell and requires NAD+ (Nicotinamide adenine dinucleotide) to oxidise ethanol into acetaldehyde, a toxic substance (Cederbaum 2012). Acetaldehyde enters the mitochondria where it is oxidised to acetate by ALDH. Acetate is then broken down into carbon dioxide and water for elimination (Lucey, Mathurin, Morgan 2009). CH3CH2OH ADH CH3CHO ALDH CH3COO- Ethanol Acetaldehyde Acetate The second major pathway for alcohol metabolism is the microsomal ethanol oxidizing system (MEOS). The pathway involves the CYP2E1 which requires NADPH (Nicotinamide Adenine Dinucleotide Phosphate) (Ji 2014). This pathway is triggered in individuals with chronic alcohol consumption. At elevated alcohol concentration, CYP2E1 assumes the important role of oxidising ethanol to the toxic acetaldehyde compound (Forsyth, Voigt & Keshavarzian 2014). The third pathway is a non-oxidative pathway which is catalysed by the enzyme Fatty Acid Ethyl Ester (FAEE) Synthase. Fatty acid ethyl esters are formed from the reaction of alcohol with fatty acids (Rocco et al. 2014). Phosphatidyl ethanol can also be formed from the non-oxidative process where the enzyme phospholipase D (PLD) breaks down phospholipids resulting in phosphatidic acid (Rocco et al. 2014). b) Mechanisms of alcohol toxicity Mechanisms of alcohol toxicity include oxidative stress, mitochondrial injury, and inflammation (Louvet, A & Mathurin 2015). Oxidative stress and mitochondrial injury occurs when NADH produced during the main ADH oxidative pathway enters into the mitochondrial electron transport system to form water through oxidation of hydrogen protons (Louvet, A & Mathurin 2015). However, when the blood alcohol concentration is too high, the hepatocytes are forced to take up more molecular oxygen than normal from the blood to ensure (Neuman et al. 2014). It reaches a level where there the oxygen in the blood supply is inadequate to be supplied to the rest of the liver tissue. This results to hypoxia, where oxygen supply to hepatocytes is cut and injures the tissues (Ji 2014). Inflammation is triggered with formation of adducts (Hideto et al. 2013). Alcohol metabolism by ADH and CYP2E1 usually produces reactive compounds such as acetaldehyde and ROS which interact with amino acids to form adducts that damage other cell components (Hideto et al. 2013). In the formation of acetaldehyde adducts, acetaldehyde interacts with certain amino acids such as lysine, cysteine and the aromatic amino acids. Proteins that easily form adducts with acetaldehyde include erythrocytes, lipoproteins, tubulin, haemoglobin, albumin and collagen (Rocco et al. 2014). The body recognises adducts as foreign and triggers the release of antibodies against them, hence, the immune system begins to destroy the hepatocytes. The mediated process is knows as antibody-dependent cell-mediated cytoxicity (ADCC) or immune-mediated hepatoxicity (Forsyth, Voigt & Keshavarzian 2014). c) The morphology of alcoholic liver damage The gross appearance of a normal liver is a soft, reddish brown mass that has a consistently smooth surface (Klein et al. 2014). However, the morphology changes with alcoholic liver damage. The main pathophysiologic manifestations of alcoholic liver damage include steatosis, steatohepatitis and cirrhosis. Steatosis also known as fatty change is characterised by the abnormal accumulation of triglycerides within the hepatocytes. Nevertheless, this is a reversible stage and no gross change may occur when it is mild steatosis (Lucey, Mathurin, Morgan 2009). However, when the state persists, the liver appears yellow, soft, greasy and larger in size. Fat cysts occur due to the accumulation and rupture of fatty hepatocytes (Rocco et al. 2014). In moderate alcohol consumption, there are microvesicular lipid droplets that accumulate in the hepatocytes but do not compress and displace their nucleus to the periphery (Cederbaum 2012). In chronic alcohol consumers, globules are macrovesicular and compress and displace the nucleus to the periphery of the hepatocytes (Cederbaum 2012). Centrilobular fat depositions are observed because of initial cell damage but without perivenular fibrosis (Hideto et al. 2013). At steatohepatitis, the liver becomes mottled red with bile stained areas of normal or increased size and the surface often contains visible nodules and fibrosis (Bysani et al. 2013).Accumulation of fats, protein and water and infiltration of neutrophilic leukocytes and nectrotic hepatocytes cause hepatocyte inflammation (Bysani et al. 2013). Necrosis is evident in the sinusoidal and perivenular central zone and consists of ballooning degeneration of the inflamed hepatocytes. Degeneration occurs due to the apoptosis of the inflamed hepatocytes. A neutrophilic reaction ensues and they surround the Mallory bodies (Klein et al. 2014). Cirrhosis is the irreversible stage of liver disease. Fibrosis occurs in the entire liver tissue and there are appearances of nodules (Klein et al. 2014). The lobular architecture cannot be identified and the central veins are hard to find. The fibrous septa that divide the heptocytes into modules are initially delicate and extend through the sinusoids from the central vein to portal regions and from one portal tract to another (Miranda-Mendez, Lugo-Baruqui & Armendariz-Borunda, 2010). The hepatocyte regenerations results in micronodules. The fibrous septa widen and surround nodules, making the liver become more fibrotic, smaller and loses fat. Micronodular formation occurs in people who continue alcohol consumption, while macronodular formation occurs in people who stop drinking. (Cederbaum 2012). Laennec cirrhosis which entails ischemic necrosis and fibrous obliteration of nodules creating a broad surface of tough, pale, scar tissue occurs. Inflammation occurs by sparse infiltrate of mononuclear cells in the fibrous septa. Bile production stops (Rocco et al. 2014). d) The haematological effects of alcoholic liver disease Toxic effects of alcohol metabolism result in antibody-dependent cell-mediated cytoxicity against the haematopoietic system leading to low count of blood cells and impairment of plasma proteins (Pai et al. 2012) Newly formed blood cells are destroyed or structurally abnormal blood cell precursors that do not mature into functional cells are produced. Alcohol damages erythroid precursors leading to macrocytosis, this being the formation of enlarged red blood cells with low haemoglobin content leading to an anaemic state of the alcoholic (Pai et al. 2012). The alcohol-induced anti- haematopoietic reaction interferes with heme synthesis leading to sideroblastic anaemia (Torruellas et al. 2014). Alterations in the erythrocyte membrane lipids due to ethanol effects result in haemolytic anaemia (Torruellas et al. 2014). Anaemic symptoms include fatigue, shortness of breath, light-headedness and arrhythmia (Pai et al. 2012). Decreased function and number of white blood cells, especially the neutrophilis, increase the alocoholic’s risk to infections. Most chronic alcoholics are at risk for an array of bacterial infections including bacterial pneumonia (Pai et al. 2012). Impaired platelet function and production interfere with blood clotting processes (Torruellas et al. 2014). Thrombocytopenia results through symptoms ranging from simple nose bleeds to haemorrhagic stroke (Cederbaum 2012). Alcohol-induced abnormalities in the plasma proteins that are also needed for blood clotting may lead to thrombosis, and eventually stroke, due to inability of adequate oxygenated blood to rich the brain cells (Cederbaum 2012). e) The clinical biochemistry profile of alcoholic liver disease Excessive chronic alcohol consumption results in significant alterations in the biochemistry of the hepatocytes resulting in a wide range of clinical and biochemical changes in Alcoholic Liver Disease (Louvet & Mathurin 2015). Alcohol consumption decreases the rate of hepatic protein metabolism. Triglyceride accumulation in the hepatocytes triggers membrane lipid-peroxidation (Rocco et al. 2014). Significant biomarkers in alcoholic liver disease include liver function indicators such as serum ferritin, prothrombin time, total bilurubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), renal parameters such as urea and creatinine and haemoglobin, red blood cell counts, and blood glucose (Lucey, Mathurin, Morgan 2009). These biomarkers are associated with the pathogenesis of alcoholic liver disease. The ratio of AST to ALT is elevated due to deficiency of pyridoxal-6-phosphate needed in the ALT enzyme synthetic pathway. Oxidative stress and injury of hepatocytes’ mitochondria result in AST isoenzyme release. Clinical manifestations of acute alcoholic liver disease include jaundice, fever and hepatomegaly (Lucey, Mathurin, Morgan 2009). Conclusion Alcohol Liver Disease occurs in people who over-consume alcohol for a long period of time. The metabolism of alcohol entails the release of compounds such as acetaldehyde which is toxic to cells directly, or by formation of adducts. The oxidation process in alcohol metabolism also involves gradual damage to the mitochondria which experience an overload in the metabolic pathways as they struggle to simplify the metabolites into water. Alcoholic liver damage begins taking place by steatosis which is reversible with reduced alcohol intake, to steatohepatitis and cirrhosis which is the irreversible stage signifying necrosis of the hepatocytes and liver tissue. Chronic alcoholics usually experience anaemic conditions because ethanol and its metabolites are toxic to the haemopoietic system responsible for blood cell production and function. 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