by Dan Rusyniak
Few things perk a toxicologist’s interest as much as a low bicarb and a high anion gap. To us an Anion Gap Metabolic Acidosis (AGMA, unlike MAGA) is a solvable mystery. You might remember from medical school the mnemonic MUDPILES or CAT MUDPILES. Looking at the list (from Wikipedia) of causes you can see why we love these cases. It has all the tox hits: aspirin, cyanide, iron, ethylene glycol etc. One of my favorite diagnoses on this list is alcoholic ketoacidosis (aka AKA). One reason I love it is that it is common. The other reason I love it is that it is commonly missed. But, it doesn’t have to be. It is actually a fairly easy disorder to diagnosis. For great reviews on this topic see articles by (Wrenn 1991 PMID: 1867237) and (Gerrity 2016 PMID: 27697197). Now let’s get nerdy.
When you are working a crazy 12h day and don’t have time to eat, or pee for that matter, why don’t you get hypoglycemic. The reason is that you have a food pantry in your liver – glycogen. This is a nice convenient source of glucose that you can use when you go long stretches without eating . If this pantry cannot provide enough glucose, you go to the store, spend some money (ATP), and make glucose. This process is called gluconeogenesis, which involves converting lactate to pyruvate which goes on to be converted to glucose. You can also make sugar from amino acids and glycerol. So, what happens when your glycogen stores start getting low and you can’t make enough glucose? You can get fuel from another source – fat. This is ketogenesis. Fat is broken down into ketones that can be used as an alternative fuel source. Two beneficiaries of this process are the heart and the brain (Stryer Biochemistry 5th edition. Section 30.2, Each Organ Has a Unique Metabolic Profile). Despite what Dunkin’ Donuts would lead you to think, the heart runs on fats and ketones (OK, maybe DD has a point). And boy are we glad it does. Imagine if it depended on glucose. You might wake up with a heart attack each morning (unless you woke up to eat in the middle of the night). They brain does not have glycogen stores, so during a fast it relies on ketones. If you did not make ketones, a bout of gastroenteritis would end in status. This whole process of generating fuel, whether from the breaking down of glycogen, making of new glucose, and making of ketones is tightly regulated by insulin, glucagon, catecholamines, and cortisol.
One way to screw up this up is to drink . . . a lot! Alcoholic ketoacidosis (AKA) is a starvation state in an alcoholic or binge drinker. Alcohol + No Food + Dehydration = AKA. Let me take you through the reason this happens. First off alcohol is not food. Yes, I know many of you will argue with me about this, but there is not a lot of nutritional value in vodka. Second, heavy drinking often results in GI problems that make it hard to eat (e.g. gastritis, pancreatitis, etc). Third, heavy drinking often results in volume loss through urinary diuresis and vomiting. And finally (?fourthly), drinking messes up all that stuff I talked about in the nerdy section of this post. Alcoholics have low glycogen stores. This means that when they can’t or don’t eat, their food pantry is empty (with the exception of the Popov they drank). No problem right? They can just make some sugar, right? Nope. Alcohol inhibits gluconeogenesis. Remember alcohol dehydrogenase, the enzyme that metabolizes ethanol (which, by the way, is the proof that we are designed to drink) requires the cofactor NAD+ (nicotinamide adenine dinucleotide). During the process of metabolizing ethanol, NAD+ is reduced to NADH (Fig 1).
The more you drink, the lower your NAD+ levels get. And, as it turns out, you need NAD+ to perform gluconeogenesis. NAD+ should stand for “Needs Additional Dextrose”. With less NAD+, you cannot convert lactate into pyruvate (Fig 1), which is also why AKA patients often have hyperlactemia. So, the drinker doesn’t have glycogen to break down and cannot make sugar, but at least they can use fat to make fuel, right?. Think again! Ethanol screws that up also. This is again because of the decreased amount of NAD+. Normally when you are starving, you make the ketones acetoacetate, and to a lesser extent acetone and beta hydroxybutyrate (BHB) (Fig 2). Acetoacetate is helpful because it can be converted to acetyl-coA and go through the Krebs cycle (nails meet chalkboard) to make ATP. BHB is not as helpful. For it to generate ATP it first needs to be converted to acetoacetate which requires – you guessed it – NAD+ (Fig 1). Unfortunately, with less reduced NAD+, you favor the formation of BHB over acetoacetate. Acetone is spontaneously generated from acetoacetate and does nothing in terms of generating ATP. You just breathe it out (‘AOB’ really should be ‘acetone on breath’). It does, however, make that one nurse who shouts “we got a DKA patient in room 3” look clairvoyant.
So, let me simplify this (nails off chalkboard). Someone who has been on a bender and shows up to your ED after two days of vomiting, has a low bicarb, elevated anion gap, elevated lactate, urine ketones, and an elevated BHB level, probably has AKA. This is a diagnosis that you can make in the ED with a good history and a few labs, and not only get the patient the treatment they need (see below) but avoid a treatment they don’t need – fomepizole. If you don’t think of AKA, the combination of labs can lead you down the path treating for ethylene glycol or methanol intoxication. This is because in addition to having an AGMA, these patients will commonly have an elevated osmolar gap (ketones increase osmolality). Furthermore these patients can be altered (true nerds see the note below) and if dehydrated can have a small bump in their creatinine. Watch for future posts on the other toxic alcohols, coming from a Hound near you.
A few other notes on AKA:
• AKA patients can be hypo- (more common) or hyperglycemic.
• AKA patients can be daily drinkers (more common) or binge drinkers.
• AKA patients can have elevated ethanol levels or have no measurable ethanol level.
• AKA patients can be mildly or profoundly acidotic (i.e. pH 7.0 and bicarb <5 mmol/L).
The last thing I will mention is treatment. Knowing the cause (Alcohol + No Food + Dehydration) makes treatment easy. Don’t let them drink (alcohol), and feed and water them (give them fluids and dextrose). Give them food if they’re able to eat. I like to give 1L LR bolus, 1L D5W bolus, and then start a drip of D5W at approximately 200 cc/h. You should also give these patients 100 mg thiamine as it facilitates pyruvate going into the Krebs cycle (nails meet chalkboard). Get a repeat basic metabolic panel and in a couple hours the bicarb should be improving. If things are not improving, or worse, going in the wrong direction, consider ethylene glycol or methanol poisoning. This is the time for fomepizole and a call to your local toxicologist or poison center. So, remember this post the next time an intoxicated patient comes in to your ED and asks for a peanut butter sandwich . . . maybe that is exactly what they need.
Nerd tip – Beta hydroxybutyrate is structurally similar to the drug of abuse GHB. This is may be why ketogenic diets, which increase BHB, may cause euphoria and why they may decrease seizures (Brown 20017 PMID:17011713).
- Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis, Part II - August 14, 2020
- Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis? - July 24, 2020
- The Dantastic Mr. Tox & Howard – S03E03 – Inside Out - July 6, 2020