KETOACIDOSIS Ketoacidosis arises when ketone body production level is higher than the level of utilization. Mitochondria in the liver can convert acetyl CoA originated from fatty acid oxidation to ketone bodies and acetoacetate. Oxidization of 3-hydroxybutyrate to acetoacetate takes place in peripheral tissues having mitochondria. This can be linked to two acetyl CoA, thus creating cellular energy. The brain uses ketone bodies and are vital fuels throughout fasting. Since the liver does not have thiophorase needed to break down ketone bodies, it produces it particularly for the peripheral tissues. A low quantity of OAA permits acetyl CoA to be redirected to ketone body production inside the liver and can lead to alcoholic ketosis which may cause ketoacidosis. HEPATIC STEATOSIS Hepatic steatosis represents an early and repairable) phase of liver disease due to alcohol.? The original acceptor of FA in triacylglycerol production is glycerol 3-phosphate. FA are existing because of intensified production, strengthened accessibility in adipose tissue from lipolysis, and reduced deprivation. The triacylglycerol formed inside the liver amass and result in fatty liver known as steatosis. VITAMIN DEFICIENCY Individuals with alcoholism have a greater chance of vitamin deficiencies because of low consumption and absorption.? Thiamine deficiency is prevalent and may lead to severe implications like Wernicke-Korsakoff syndrome along with the neuroglial effects. The coenzyme form, Thiamine pyrophosphate, is necessary for the oxidation of a-keto acids mediated by dehydrogenase and the transport of two-carbon ketol groups through transketolase. ACETALDEHYDE TOXICITY Initially, ethanol is transformed to acetaldehyde via alcohol dehydrogenase that contains zinc.? Then, acetaldehyde is oxidized to acetate by ALDH. Disulfiram, a drug which is utilized during the management of chronic alcoholism, inhibits ALDH. The subsequent increase in acetaldehyde leads to flushing, nausea, hyperventilation, and tachycardia. ROLE OF ETHANOL IN CELLULAR ENERGY SUPPLY With the production of NADH, ethanol is processed to acetate primarily in the liver. The key path for ethanol metabolism is by hepatic alcohol dehydrogenases, oxidizing ethanol in the cytosol to acetaldehyde. Acetaldehyde is then oxidized to acetate by acetaldehyde dehydrogenase, predominantly in mitochondria. The NADH generated by these processes is utilized through oxidative phosphorylation for the production of adenosine triphosphate (ATP). Almost all of the acetate passes into the blood and is absorbed by skeletal muscles and other tissues, in which it is stimulated to acetyl CoA and oxidized in the tricarboxylic acid cycle. Nearly 10 to 20 percent of the consumed ethanol is oxidized via a microsomal oxidizing system involving cytochrome P450 enzymes, particularly CYP2E1, inside the endoplasmic reticulum. CYP2E1 has strong ethanol induction and high Km for ethanol. The amount of ethanol metabolized via this path is thus higher at strong levels of ethanol, and higher upon prolonged ethanol consumption. Ethanol accelerates redox pressure via NADH and facilitates reactive oxygen species (ROS) generation. Mitochondrial components are indeed ROS targets, and the mitochondrial regulation of oxidative stress has implications for both the metabolism of cellular energy and the mechanisms that regulate the initiation and development of cell death response. 1,2 METABOLISM Ethanol, a small molecule, is soluble in both water and lipid. Thus, it is immediately taken up by passive diffusion from the intestine. Up to five percent of consumed ethanol passes into the gastric mucosal cells of the tongue, mouth, esophagus, and stomach, in which it is metabolized.What is left then enters into the blood. From that, the liver metabolizes 85 to 98 percent, and only two to ten percent is emitted through the kidneys or lungs. Liver alcohol dehydrogenase is the primary path of ethanol metabolism inside the liver. If acetaldehyde is not eliminated through metabolism, it will apply harmful activities inside the liver or other tissues and can pass into the blood. Of the acetaldehyde that is produced, 90% is metabolized again to acetate inside the liver. The primary enzyme included is mitochondrial acetaldehyde dehydrogenase that has a low Km. Having no toxic effects, acetate can be stimulated into acetyl CoA inside the liver, in which it can go through the tricarboxylic acid cycle or the route of fatty acid production. Nevertheless, a great amount of the acetate that is produced passes into the blood and is stimulated into acetyl CoA in the skeletal muscles. In general, acetate is regarded as non-toxic and is a common component of the diet. There is another primary route of ethanol oxidation inside the liver, which is known as the microsomal ethanol oxidizing system. This system also plays a role in oxidizing ethanol to acetaldehyde. CYP2E1, the main microsomal enzyme involved, utilizes NADPH as and extra donor of an electron and O as an acceptor of an electron. This path makes up just 10 to 20% of ethanol oxidation in an average drinker. All of the activities involving enzymes during ethanol metabolism, which include CYP2E1, acetaldehyde dehydrogenase, and alcohol dehydrogenase are present as a group of isoenzymes. Separate distinctions in the extent of these isoenzymes affect various factors that include the level of ethanol elimination in the blood, the intensity of intoxication presented by a person, and variations in personal vulnerability to the formation of liver disease induced by alcohol. HYPOGLYCEMIA Hypoglycemia is represented by low blood glucose followed by signs of adrenergic and neuroglycopenia, which are easily treated by glucose management. 3 The ethanol-mediated rise in NADH triggers these gluconeogenic precursors to be redirected into different routes, leading to diminished glucose synthesis. This can initiate hypoglycemia specifically in people that have drained their liver glycogen supplies. Hypoglycemia can result in several actions related to intoxication of alcohol. These actions can include anxiety, combativeness, and impaired judgement. Thus, consumption of alcohol may develop hypoglycemia in susceptible people and may further add to the behavioral effects of alcohol. Since consuming alcohol can raise the chance of hypoglycemia in those patients that use insulin, they are advised about the high chance of hypoglycemia that usually occurs several hours after consuming alcohol. Ethanol is composed of molecules that are lipid and water soluble which makes it is easily absorbed from the intestine. A small percentage of ingested ethanol enters the gastric mucosal cells of the upper GI tract where it is metabolized. The rest of the ethanol molecules enters the blood. Out of molecules entering the blood, 85 to 98% is metabolized in the liver, and only 2 to 10% is excreted through the lungs or kidneys. Low amounts of ethanol acts as a carbon source of energy but high levels of ethanol interfere with mitochondria which is the source of cellular energy. The reason why it acts as a source of cellular energy is because it is a hydrocarbon. Consumption of alcohol leads to slowing down of metabolism as it makes the kidneys work slower. There are several enzymatic pathways that the body uses to metabolize ethanol. The main enzymatic pathway of ethanol is through hepatic alcohol dehydrogenases which is the conversion of alcohol into acetaldehyde by the enzyme alcohol dehydrogenase (ADH). Alcohol dehydrogenase exists as a family of isoenzymes with varying specificity for chain length of the alcohol substrate. ADH is a NAD+-requiring catalyst communicated at high fixations in hepatocytes. Acetaldehyde is then entered in the mitochondria where it is oxidized into acetate derivation by mitochondrial acetaldehyde dehydrogenase. A cytosolic acetaldehyde dehydrogenase is in charge of just a minor percentage of acetaldehyde oxidation. NADH is produced by these reactions and is used to produce ATP through oxidative phosphorylation. More than 80% of acetaldehyde oxidation in the human liver is catalyzed by mitochondrial acetaldehyde dehydrogenase. Metabolism of acetate requires activation to acetyl COA by acetyl CoA synthetase. In the liver, the isoform of acetyl CoA synthetase is a cytosolic enzyme that generates acetyl CoA for the cytosolic pathways of cholesterol and fatty acid synthesis. Acetate entry into these 5 pathways is under regulatory control by mechanisms involving cholesterol or insulin. Thus, most of the acetate generated enters the blood. Most of the acetate enters the blood and is taken up by skeletal muscles and other tissues, where it is activated to acetyl CoA and is oxidized in the citric acid cycle.5 Another pathway for ethanol digestion is the microsomal ethanol oxidizing framework (MEOS) which includes the cytochrome P450 compound CYP2E1 and requires NADPH. Ethanol and NADPH both donate electrons in the reaction, which reduces 02 to 2H20. The cytochrome P450 protein contains the binding sites for O2 and the substrate and carries out the reaction. The enzymes are present in the endoplasmic reticulum. Approximately 10 to 20% of ingested ethanol is oxidized through the microsomal oxidizing system (MEOS). This pathway is used more at people who consume high levels of alcohol because CYP2E1 has a high Km for ethanol and is inducible by ethanol. The third pathway includes a non-oxidative pathway catalyzed by unsaturated fat ethyl ester (FAEE) synthase. This pathway happens fundamentally in the liver and pancreas which are very sensitive to alcohol.4 Oxidation of ethanol also happen in peroxisomes by means of the movement of catalase. However, this oxidation pathway requires the nearness of a hydrogen peroxide (H2O2) producing framework and therefore has no significant part in alcohol oxidation under typical physiological conditions. There is a minimal regulation of alcohol metabolism under hormonal control like insulin and glucagon. Thus, the liver is mainly responsible to oxidize alcohol to remove it from the body According to a recent research. humans with small body weight metabolize alcohol at faster rates than humans with large body weight. These rate of alcohol metabolism correlate with the basal metabolic rate for the body, indicating that the capacity to oxidize ethanol parallels the capacity to oxidize nutrients. Alcohol-derived calories are produced at the expense of the metabolism of normal nutrients since alcohol will be oxidized preferentially over other nutrients. Several liver diseases can occur as a result of alcohol consumption which are common and can be fatal. It has three forms: fatty liver, alcohol-induced hepatitis, and cirrhosis. Each may occur alone, or they may be present in any combination. Alcohol affects liver where it becomes unable to release glucose into the bloodstream causing hypoglycemia. Consuming too much alcohol can cause diabetes as a result of ketoacidosis because the acid-base levels in body gets disturbed. Hepatic steatosis is another condition caused by methanol metabolism deficiency. It happens as a result of alcohol affecting the liver causing it to be dysfunctional. As a result, the liver become unable to metabolize fat. Alcohol causes a defect in vitamin and muscle weakness. The liver breaks down excessive alcohol to form acetaldehyde and causes cirrhosis, ulcers, and metabolic disorders. Another condition caused by toxic effects of ethanol metabolism is hepatic cirrhosis and loss of liver function. Liver injury is irreversible at the stage where hepatic cirrhosis develops. At the first stage, the liver will be enlarged, full of fat, crossed with collagen fibers, and have nodules of regenerating hepatocytes ballooning between the fibers. As the liver starts losing its function gradually, it becomes shrunken. During the development of the disease, many of the normal metabolic functions of the liver are lost. A decrease in the synthesis of blood proteins, including blood coagulation factors and serum albumin, also occurs. The metabolism of amino groups into urea is decreased, resulting in the accumulation of toxic levels of ammonia in the blood. Also, the excretion of the bilirubin, a product of heme degradation, is eliminated, and bilirubin accumulates in the blood where it is deposited in many tissues, including the skin and sclerae of the eyes. RE: Forum 1 Hannah, this is a great post regarding ethanol metabolism in the human body. I was surprised to learn that 5% of consumed ethanol is actually metabolized in the tongue, mouth, esophagus, and stomach.1 This makes sense after I thought about how the human body also begins the digestive process of other carbohydrates in the mouth through enzymes in the saliva. I was also impressed by how detailed your explanation was when discussing where exactly metabolic pathways are occurring and in what ratios the are pathways are being used. It is critical in understanding ethanol metabolism that reactive oxygen species, free radicals, are produced and present problems for the body to solve. In particular is the use of glutathione to neutralize the reactive oxygen species and prevent further cell lysis from peroxisomal exposure.2 I liked your phrasing that this oxidative stress is what can cause cellular death. The biochemical changes that we discussed lead to physical changes as well. The most acute issue you discussed was the impending hypoglycemic affect due to gluconeogenesis not occurring in the presence of NADH due to the lack of substrates pyruvate and oxaloacetate. Swift glucose administration can easily prevent hypoglycemia, this is especially important in a patient with diabetes who my lose consciousness and require intravenous glucose. As you mentioned about chronic alcohol abuse, patients can develop fatty liver and in time cirrhosis of the liver. When a patient begins to show signs of hepatic steatosis, a more complex treatment plan is required to heal the body. Management often includes nutritional support and control of co- morbidites such as diabetes and the need for weight loss.3 The best solution for these patients is to quit alcohol use entirely. Sudden alcohol cessation can lead to a life-threatening condition called delirium tremens and will require hospitalization and monitoring. Other patients who are seeking self-control management can start a regimen of disulfiram. Disulfiram therapy is highly dependent on the patient to be medication compliant and a lapse in administration will allow the patient to return to alcohol use without the consequences. RE: Ethanol Metabolism and Its Toxic Effects I liked how your post was so easy to understand and read. I think it made a lot of things regarding the pathways click in my head. Also, it was really interesting to see that people who have a smaller BMI are able to process alcohol more efficiently than those of bigger BMIs. This goes against the thought of social norms, where it is the opposite; those who are bigger will be able to drink better than those who are smaller. I suppose it makes sense that if you are smaller, compared to those who are larger your basic metabolic rate will be less. Due to this, your body will be able to more efficiently handle toxins in your body. I was also wondering why the metabolism of alcohol is preferred over nutrients. I can assume it’s to get rid of the toxins that in the body rather than hold it. As well as, the fact that acetaldehyde causes some detours of cellular metabolism. However, I was wondering if there was a specific reason you found. Lastly your 3rd pathway sounds like it includes catalase. In another discussion post, it was mentioned that this pathway creates reactive oxygen species from the partial splitting of the oxygen species. I thought this was intriguing. While I knew ethanol was toxic to the body, I never really imagined why or what it was doing to the body. But, with that explanation along with the other pathway ways, I feel as if I got a clearer bigger of why excessive drinking is bad.
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