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Metabolism of Alcohol

1) – A 47-year-old female is brought to the emergency department with complaints of malaise, nausea, vomiting, and fatigue. The patient reveals a long history of alcohol abuse for the last 10 years requiring drinks daily especially in the morning as an “eye opener.” She has been to rehab on several occasions for alcoholism but has not been able to stop drinking. She is currently homeless and jobless. She denies cough, fever, chills, upper respiratory symptoms, sick contacts, recent travel, hematemesis, or abdominal pain. She reports feeling hungry and has not eaten very well in a long time. She appears malnourished but in no distress. Her physical exam is normal. Her blood count reveals a normal white blood cell count but does show an anemia with large red blood cells. Her amylase, lipase, and liver function tests were normal. Which of the following nutrients might help to relieve her symptoms?

A. Iron and folic acid

B. High protein diet

C. Ketogenic diet

D. Supplementation with carnitine

E. Folic acid and B12

2) – A 50-year-old homeless man was brought to the emergency room in a stuporous state. Below are his lab results, Bicarbonate 10mEq/L (22-28), pH 7.2 (7.35-7.45), PCO2 25mmHg (35-45), Alcohol 40mmol/L (0), Osmolality 370mOsm/L (280-295), Glucose 50mg/dl (65-110) BUN 40mg/dl (8-25). What is the acid-base status?

A. Metabolic acidosis and metabolic alkalosis

B. Metabolic acidosis with partial respiratory compensation

C. Respiratory acidosis and partial metabolic compensation

D. Respiratory acidosis

E. Metabolic alkalosis.

3) – A 3-year-old girl was brought into the Emergency Room. She was cold and clammy and was breathing rapidly. She was obviously confused and lethargic. Her mother indicated that she had accidentally ingested automobile antifreeze while playing in the garage. Following gastrointestinal lavage and activated charcoal administration, a nasogastric tube for ethanol was administered. How will ethanol help in relieving the symptoms?

A. Conjugate with ethylene glycol to form a soluble compound

B. Inhibit the activity of alcohol dehydrogenase

C. Inhibit the binding of ethylene glycol to alcohol dehydrogenase

D. Promote the excretion of metabolite of ethylene glycol

E. Stimulate the activity of acetaldehyde dehydrogenase.

4) – After excessive drinking over an extended period of time while eating poorly, a middle-aged man is admitted to the hospital with “high output” heart failure. Which of the following enzymes is most likely inhibited?

A. Aconitase

B. Citrate synthase

C. Isocitrate dehydrogenase

D. α-Ketoglutarate dehydrogenase

E. Succinate thiokinase

5)- Asians and Native Americans may flush and feel ill after drinking a small amount of ethanol in alcoholic beverages. This reaction is due to genetic variation in an enzyme that metabolizes the liver metabolite of alcohol, which is-

A. Methanol

B. Acetone

C. Acetaldehyde

D. Glycerol  

E. Propionate    

6) – A 25-year-old man is brought to the emergency room after a motor vehicle accident. He has a dislocated hip, rib fractures and a facial laceration. Toxicology screen shows a high level of ethanol in his blood. Oxidation of ethanol produces acetaldehyde and NADH. A high level of NADH relative to NAD + promotes the conversion of which of the following reactions?

A. Dihydroxyacetone phosphate to glycerol-3-P

B. Citrate to Isocitrate

C. Pyruvate to Acetyl co A

D. Malate to oxaloacetate

E. Succinate to Fumarate

7) – A 57-year-old alcoholic is transported to the emergency room after sustaining an injury in a motor vehicle accident. A comprehensive metabolic panel and a serum γ- glutamyl transferase (GGT) level are ordered. The GGT is shown to be dramatically elevated. Apart from its role as a marker of alcoholism, this enzyme is also important for which of the following digestive processes?

A. Recycling of bile salts

B. Absorption of carbohydrates

C. Digestion of triglycerides

D. Absorption of amino acids

E. Digestion of carbohydrates

8) – A 55-year-old chronic alcoholic was brought to emergency by his friends. During their night-time gathering in the local bar he fell unconscious and they had been unable to revive him. The attending physician ordered for I/V Glucose and an injection of Thiamine. The patient was well oriented and alert next morning, his vital signs were stable, blood glucose was normal and he was discharged from the hospital. Which of the following enzymes is thiamine dependent and vital for glucose oxidation in brain?

A. Glucokinase

B. Transaldolase

C. Lactate dehydrogenase

D. Pyruvate dehydrogenase complex

E. Citrate synthase.

9) A 42-year-old executive complained of fatigue and some recent alterations in mental status, such as forgetting appointments. He traveled outside the United States 2 months ago on a business meeting. He had vague right upper quadrant pain on deep palpation and borderline enlargement of the liver.  Lab findings include-Serum AST = 120 U/L, ALT = 80 U/L, ALP = 68 U/L , GGT = 170U/L, Total bilirubin = 0.8mg/dL, Blood glucose = 60 mg/dL, Serum uric acid = 9.8 mg/dL, CBC and urinalysis results are normal. The patient is suffering from alcohol related liver disease. Which of the enzyme estimations is most diagnostic for alcohol related liver disease?

A. AST

B. ALT

C. ALP

D. GGT

E. LDH

10) A 45 -year-old male was brought to the emergency department after a family member found him extremely confused and disoriented. He had an unsteady gait and strange irregular eye movements. The patient had been a known heavy drinker from the past 6 years. 

There was no history of any known medical problem and he denied any other drug usage. On examination, he was afebrile with a pulse of 90 beats per minute and a normal blood pressure of 110/80 mmHg. Chest and abdominal examination were normal. He was extremely disoriented and agitated. Horizontal rapid eye movements on lateral gaze were noted bilaterally. His gait was very unsteady. The remainder of his examination was normal. The urine drug screen was negative and he had a positive blood alcohol level. Blood pyruvate and lactate levels were high. Which of the following nutrients might help in relieving the symptoms of this patient?

A. High carbohydrate diet

B. Ketogenic diet

C. Supplementation with Thiamine

D. Both A and B

E. Both B and C.

Key to answers

1) – E- Folic acid and B12

Most probably the patient is suffering from megaloblastic anemia due to cobalamine deficiency. The cause for this anemia is dietary deficiency which is very common in chronic alcoholics. Abstinence from alcohol and supplementation with B12 and folate.

2) – B- Metabolic acidosis with partial respiratory compensation.

Low pH and low bicarbonate are indicative of metabolic acidosis, which is usually compensated by hyperventilation to maintain the bicarbonate to carbonic acid ratio. The pCO2 is not very low in this patient, signifying partial compensation. The patient is alcoholic and has hypoglycemia, thus the underlying cause for metabolic acidosis is apparently lactic acidosis and ketoacidosis.

3) – C. Inhibit the binding of ethylene glycol to alcohol dehydrogenase.

Ethylene glycol is metabolized by the same enzyme system as ethanol to form toxic products that can cause severe acidosis and renal damage. Ethanol with least km is a true substrate for alcohol dehydrogenase and hence given as an antidote, it inhibit the binding of ethylene glycol to enzyme. The metabolism of ethylene glycol is thus inhibited.

4) – D. α-Ketoglutarate dehydrogenase.

The patient is most probably suffering from cardiac beriberi. The above said patient is a known alcoholic, mal nourished, and has heart failure .The probable diagnosis is Thiamine deficiency, which can be confirmed by Erythrocyte transketolase activity.  In the given list of enzymes, α-Ketoglutarate dehydrogenase is the only enzyme which is Thiamine dependent. It is a multienzyme complex, requiring thiamine, lipoic acid, pantothenic acid, riboflavin and niacin as coenzymes.

5) – C. Acetaldehyde.

In some Asian populations and Native Americans, alcohol consumption results in increased adverse reactions to acetaldehyde owing to a genetic defect of mitochondrial aldehyde dehydrogenase. The acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH).

6) – A. – Dihydroxyacetone-P to Glycerol-3-P

Alcohol is metabolized  in two steps by two  NAD + requiring enzymes. Chronic alcohol consumption leads to build up of NADH, that changes the redox state of the hepatocytes. As a result the equilibrium of many reactions is shifted towards regeneration of NAD +. Out of the given list, its only the conversion of dihydroxyacetone-P which is likely to be effective.

7) – D. Absorption of amino acids

8) D- Pyruvate dehydrogenase complex

9)-A- AST

10) – E- Both B and C- Ketogenic diet and thiamine supplementation

 

 

 

 

 

 

 

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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 50mg/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.

Other Effects of Ethanol

  • Between one-half and two-thirds of alcoholics have skeletal muscle weakness caused by acute alcoholic myopathy
  • Hormonal changes include Alcohol intake can result in inflammation of the esophagus and stomach causing epigastric distress and gastrointestinal bleeding. Alcohol is one of the most common causes of hemorrhagic gastritis. Violent vomiting can produce severe bleeding through a Mallory-Weiss lesion, a longitudinal tear in the mucosa at the gastro esophageal junction.Acute pancreatitis is almost threefold higher in alcoholics than in the general population.Chronic high doses cause peripheral neuropathy in 5–15% of alcoholics.Few alcoholics develop Wernicke’s Korsakoff syndromes. These occur as a result of thiamine deficiency, especially in predisposed individuals, e.g., those with transketolase deficiency.While alcohol supplies calories (a drink contains ~300 kJ, or 70–100 kcal), these are devoid of nutrients such as minerals, proteins, and vitamins. Alcohol can also interfere with absorption of vitamins in the small intestine and decreases their storage in the liver with modest effects on folate (folacin or folic acid), pyridoxine (B6), thiamine (B1), nicotinic acid (niacin, B3), and vitamin A.
    • an increase in cortisol levels,
    • inhibition of vasopressin secretion at rising blood alcohol concentrations and enhanced secretion at falling blood alcohol concentrations (with the final result that most alcoholics are likely to be slightly over hydrated);
    • a modest and reversible decrease in serum thyroxine (T4); and a more marked decrease in serum triiodothyronine (T3).
  • Chronic intake of modest doses of alcohol can have some beneficial effects. A maximum of one to two drinks per day may decrease the risk for cardiovascular death, perhaps through an increase in high-density lipoprotein (HDL) cholesterol or changes in clotting mechanisms.
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