The USMLE wants you to know about the effects of alcohol metabolism and why they occur. This can easily be turned into an overly convoluted topic by textbooks, so I’ll make this as short as possible regarding exactly what you need to know for USMLE.
For every molecule of EtOH metabolized, two NAD+ are converted to two NADH.
| EtOH ↑ the NADH/NAD+ ratio. This is why it causes a myriad of pathologies. |
One of the critical steps of gluconeogenesis is the conversion of oxaloacetate (OAA) from the TCA cycle into phosphoenolpyruvate (PEP), a glycolytic intermediate. PEP will then make its way back to glucose as you can see.
If EtOH is consumed and more NADH is synthesized, that will disfavor the conversion of malate to OAA in the TCA cycle, and it will even convert some OAA back to malate. This means lesser efficiency of PEP production, and therefore glucose, in the fasting state.
So the production of glucose decreases with EtOH consumption because gluconeogenesis is less efficient. This is why you get fasting hypoglycemia in alcoholics.
| In short: conversion of OAA → malate leads to less glucose. |
In addition, since OAA needs to be constantly recycled for the TCA cycle and its equilibrium is disrupted, less acetyl-CoA will combine with it to make citrate, and the TCA cycle loses efficiency. This acetyl-CoA is then instead shunted to ketone bodies in the setting of hypoglycemia. Since two acetyl-CoA combine to ultimately start the process of ketogenesis, this is why ketoacidosis can be seen in alcoholics.
| In short: conversion of OAA → malate means less OAA combining with acetyl-CoA. This means more acetyl-CoA available to make ketones. |
Similarly, glyceraldehyde-3-phosphate + NADH ↔ glycerol-3-phosphate + NAD+
Three fatty acids + monoacylglycerol → TGAs.
| This is one of the major reasons you get hepatosteatosis (fatty liver) in alcoholics. |
We also have pyruvate + NADH ↔ lactate + NAD+
| This is why you can get lactic acidosis in alcoholics. |
—
Some other HY notable/tangential points:
Lactic acid and uric acid compete for the same excretory transporter in the kidney. Increased lactic acid means uric acid under-excretion.
| This is why you can get acute gout with drinking. |
For acute gout, they will classically mention a man in his 40s or 50s who’s had a drink and now has a tender, erythematous nodule on his big toe (podagra). Then they’ll ask why. Over-production of uric acid is the wrong answer. Under-excretion of uric acid is correct.
Yes, alcohol causes a bit of both, but that doesn’t change what the USMLE wants in a vacuum.
With regard to uric acid over-production, the HY associations are Lesch-Nyhan syndrome (X-linked btw) and tumor lysis syndrome.
| Tumor lysis syndrome = ↑ uric acid (may present as kidney stones) and hyperkalemia following leukemia treatment (e.g., APL / AML M3)
Lesch-Nyhan syndrome = HGPRT deficiency → increased uric acid production |
—
Alcoholics tend to be B-vitamin deficient. Whilst B9 (folate) is technically the most common vitamin deficiency overall, nutritional deficiency in alcoholics leads to greater tendency for B1 (thiamine) deficiency. This leads to wet beriberi (dilated cardiomyopathy), dry beriberi (neuropathy), Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia), and Korsakoff psychosis (confabulation due to retrograde amnesia).
| The answer on the USMLE for Wernicke-Korsakoff syndrome (WKS) is mammillary bodies. Pretty standard. But they’ll often ask you to identify them on imaging after giving you a vignette of WKS. |
—
If an alcoholic comes in with frostbite (EtOH is an uncoupling agent that yields heat → cold-insensitivity), you are most worried about hyperkalemia. Warming + reperfusion of tissues → oxygen free radical damage → rhabdomyolysis → release of potassium, as well as greater risk for acute tubular necrosis due to myoglobin’s nephrotoxic effects (further increasing K+).
| There’s a question floating around that shows a picture of a dude’s feet. They say he is admitted to hospital following being outside in the cold. After rewarming his feet, what electrolyte are we most worried about? Potassium. |
For whatever reason, it’s a HY factoid to know that alcoholism increases the risk of rhabdomyolysis, the same way it can cause direct damage to myocardium (alcoholic DCM [not wet beriberi]) or bone marrow (non-megaloblastic macrocytic anemia).
The USMLE wants you to know that rhabdo will present as a false (+) blood on urine dipstick. The urinalysis will say ++ blood, but 0-1 RBCs per high-power field. That’s because myoglobin will register as blood on the dipstick.
—
HY associated drugs:
Fomepizole inhibits alcohol dehydrogenase. Used in ethylene glycol (anti-freeze) and methanol toxicity. In the setting of the latter only, because ethanol has greater affinity for the enzyme than methanol, ethanol can be used if fomepizole is not available. However, if they give you a combination of answers (i.e., ethanol then fomepizole; fomepizole then ethanol; fomepizole only; ethanol only, etc.), choose fomepizole only as the answer.
Disulfiram inhibits acetaldehyde dehydrogenase. Given to alcoholics to deter drinking. The drug leads to a buildup of acetaldehyde, the molecule that causes hangover symptoms.
—
Alcohol withdrawal
The excitatory syndrome of tachycardia, tremor, diaphoresis, and/or seizure, etc., in the setting of alcohol withdrawal is called delirium tremens.
This tends to occur 2-3 days after the last drink and is caused by downregulation of GABAA receptors.
It can also occur in patients who continue drinking but have significantly cut back (i.e., a guy abruptly goes from 12 beers per day to 4).
Classic presentation is a patient who has an onset of tachyardia, restlessness, and tremulousness (+/- seizures) 2-3 days after being in the hospital for surgery.
Treatment is a long-acting benzodiazepine – i.e., classically diazepam or lorazepam, but chlordiazepoxide is also a weird-sounding one that is exceedingly HY!
| Chlordiazepoxide, lorazepam, and diazepam are all long-acting benzodiazepines used for delirium tremens. But the USMLE is for some reason obsessed with chlordiazepoxide. |
Sometimes the USMLE might also mention tactile or visual hallucinations in the setting of alcohol withdrawal, often 2-4 days after the last drink. This is called alcoholic hallucinosis.
| Hallucinations (usually tactile) within a few days of alcohol withdrawal is called alcoholic hallucinosis. Treatment is also chlordiazepoxide. |
—
Miscellaneous point about metabolism:
The microsomal ethanol oxidizing system (MEOS) metabolizes a smaller percentage of ethanol via CYP-2E1.
Random, but know it.
—
All material is copyrighted and the property of mehlmanmedical.
Copyright © 2020 mehlmanmedical.
