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Case details

A 65-year-old man was admitted to the emergency department in an unconscious state. Apparently he had become increasingly depressed after death of his younger son two months ago. Previously before his death he had been a moderate drinker, but consumption of alcohol had increased markedly over the last few weeks. He had also been eating poorly,

His elder son had dropped around to see him on Sunday morning and found him unconscious in the living room couch with two empty bottles of whisky. Three  more bottles were also found on the living room table.

On examination he could not be roused, his breathing was deep and noisy,

Alcohol could be smelt in his breath, and his temp was 36.6° C.

Lab findings:

Blood alcohol 550 mg/dl

Blood glucose 50 mg/dl

Blood lactate 8 mmol/L

pH 7.21

 What is the biochemical basis for all the laboratory findings in this patient?

Case Discussion

This is a case of Alcohol (Blood alcohol-550mg/dL) induced hypoglycemia (Low glucose-50 mg/dl) and metabolic acidosis. Metabolic acidosis as apparent from low p H (7.21), is due to underlying lactic acidosis (Blood Lactate-8mmol/L).

Alcohol-related hypoglycemia is due to hepatic glycogen depletion combined with alcohol-mediated inhibition of Gluconeogenesis. It is very common in malnourished alcohol abusers but can occur in anyone who is unable to ingest food after an acute alcoholic episode followed by gastritis and vomiting.

The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a cytosolic enzyme that catalyzes the conversion of alcohol to acetaldehyde. This enzyme is located mainly in the liver, but small amounts are found in other organs such as the brain and stomach.

 During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from alcohol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH (Figure- Step-1).


Much of the acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH) (Figure-Step-2) .

 The product of this reaction is acetate, which can be further metabolised to CO2 and water, or used to form acetyl-CoA. As a net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to contribute to the metabolic disorders that accompany chronic alcoholism.

 1)   The NADH produced in the cytosol by ADH must be reduced back to NAD+ via either the malate-aspartate shuttle or the glycerol-phosphate shuttle. Thus, the ability of an individual to metabolize ethanol is dependent upon the capacity of hepatocytes to carry out either of these 2 shuttles, which in turn is affected by the rate of the TCA cycle in the mitochondria whose rate of function is being impacted by the NADH produced by the ALDH reaction.

 2)   The reduction in NAD+ impairs the flux of glucose through glycolysis at the glyceraldehyde-3-phosphate dehydrogenase reaction, thereby limiting energy production.

 3)   Additionally, there is an increased rate of hepatic lactate production due to the effect of increased NADH on direction of the hepatic lactate dehydrogenase (LDH) reaction. This reversal of the LDH reaction in hepatocytes diverts Pyruvate from Gluconeogenesis leading to a reduction in the capacity of the liver to deliver glucose to the blood.

 4)   Similar to lactate formation, Malate is also produced from Oxaloacetate. Deficiency of Oxaloacetate negatively affects Gluconeogenesis as well as the functioning of TCA cycle.

 5)   In addition to the negative effects of the altered NADH/NAD+ ratio on hepatic Gluconeogenesis, fatty acid oxidation is also reduced as this process requires NAD+ as a co factor.

 6)   In fact the opposite is true, fatty acid synthesis is increased and there is an increase in triglyceride production by the liver. In the mitochondria, the production of acetate from acetaldehyde leads to increased levels of acetyl-CoA. Since the increased generation of NADH also reduces the activity of the TCA cycle, the acetyl-Co A is diverted to fatty acid synthesis.

 7)    The reduction in cytosolic NAD+ leads to reduced activity of glycerol-3-phosphate dehydrogenase (in the glycerol 3-phosphate to DHAP direction) resulting in increased levels of glycerol 3-phosphate which is the backbone for the synthesis of the triglycerides. Both of these two events lead to fatty acid deposition in the liver leading to fatty liver syndrome.

 8)   Increased [lactate]/[Pyruvate] ratio, results in hyperlacticacidemia. Lactate accumulation causes lactic acidosis (Metabolic acidosis).

 9)    Lactate competes with uric acid for excretion, decreasing its excretion and thus aggravating gout. Gout is a common finding in chronic alcoholics.

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One Response to Alcohol induced metabolic changes

  • My students we have yet to cover shuttles in the class, so dont feel confused about it, only keep in mind that excess of NADH is an inhibitor of TCA cycle also ,which is governed by electron transport chain. The functioning of ETC depends on availability of ADP.
    So the only left out option for regeneration of NAD+ is through reactions where NADH is used up and NAD+ is produced, like formation of lactate from pyruvate , Malate from oxaloacetate and glycerol-3-p from DHAP. I shall try to show the reactions with the forthcoming contents .