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.
To Alcohol!
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).
Treatment
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).
Great post! This is one of my favorite topics to teach to residents as they all learned about it in medical school yet they don’t seem to realize how common it actually is nor how relatively straightforward it is to diagnose, as the patient often is telling you they have AKA.
One of the more intriguing subtleties of AKA and the most confusing part of the diagnosis is the ketones on the UA. Most UA assays actually don’t pick up betahydroxybutyrate very well, so the classic AKA patient will have “low” or even negative ketones.
I often get consults because the patient history was a solid AKA story (drink everyday, don’t make time to eat, denies toxic alcohols), but the UA doesn’t have the impressive ketones that the treating team expected. While testing for acetoacetate and acetone is certainly helpful in identifying DKA, the predominance of BHB in AKA makes many UA assays misleading.
While not advocating for routine BHB blood levels, as most hospitals cannot perform this test, if the story is classic for AKA even without significant urine ketones, I often recommend a similar or even more aggressive dextrose treatment regimen as you described with a repeat chemistry panel to ensure improving bicarb. Oh and hydration, thiamine and a meal are also important. Thanks again for remind everyone of the pathopjysiology.
Thanks Dan. That is a great point. And while it can happen that a AKA patient has negative ketones on a urine dip, in my experience it is more the exception then the rule. Most AKA patients still make some acetoacetate (AcAc).. Most will still test positive for ketones in the urine, albeit weaker than the degree of ketosis reflects. In fact one benefit of BHB is that it is a storage form energy that does not spontaneously degenerate into acetone (which has not benefit energetically). So you can keep some BHB in reserve and then convert it back to AcAc to generate acetyl-coA and Krebs cycle yada yada yada ATP. This why some suggest taking a suspected AKA patients urine which has BHB>>AcAc and adding peroxide. This will oxidize the BHB to AcAc and poof the urine dip will now be strongly ketone positive. The studies looking at this, however, suggest it may not be all that helpful (PMID:18637083 & PMID:6423353). Again great point. Thanks for bringing it up here and on twitter.
x
I have been asked if I might provide a bit more detail on impaired gluconeogenesis from high NADH/NAD+ ratios. I don’t seem to be able to superscript or subscript characters, so I am going to drop the + on NAD+ and just type NAD to keep things simple. It is extremely difficult/tricky to get arrows formatted when making comments, especially double-ended arrows. I’ll do my best.
First, what are ALL the reasons for elevated NADH/NAD ratios in AKA? Dan mentioned fatty acid oxidation (lypolysis). That is, beta oxidation of fatty acids converts NAD to NADH. (Conversely, fatty acid synthesis lowers the NADH/NAD ratio). Lipolysis is driven not just by starvation (and drop in insulin levels, which prevents fatty acid synthesis), but also by high levels of stress hormones and growth hormone in AKA patients.
Alcohol metabolism, as Dan noted, also results in conversion of NAD to NADH, raising the NADH/NAD ratio. But many to most patients who present with AKA have low or absent alcohol levels because they are vomiting, may have abdominal pain, and haven’t kept even alcohol or much else down for a day or longer. But this is not always true by any means.
Another factor that has been conjectured, based on animal studies, is that ethanol and/or acetaldehyde in some situations appears to produce impaired oxidative phosphorylation with structural changes in the mitochondrial inner membrane (cristae). If NADH made in the TCA cycle (Krebs Cycle) in the mitochondrial matrix cannot unload electrons onto complex I of the electron transport chain (to become NAD), then the NADH/NAD ratio also rises.
For whatever reasons, then, given a high NADH/NAD ratio in AKA, what are the major implications?
From a simplistic standpoint for the purposes of this brief discussion, we see three main abnormalities: 1) increased lactate 2) hypoglycemia; 3) increased shunting towards beta-hydroxybutyrate. Let’s look at each. But first, let’s go back to first semester college inorganic chemistry.
You remember those dissociation constants for inorganic acids? Let’s take our generic inorganic acid, HA (which could be HCl, HNO3, etc.). Recall:
HA H+ + A-
We learned that the mass action ratio at equilibrium, which we called the equilibrium constant, Ka, was given as such:
Ka = [H+] [A-] / [HA]
with molar concentrations represented by the brackets.
You know what? We can do the same for biochemical reactions, and the first one we will look at is gluconeogenesis. During times of starvation, especially when glycogen stores are low or absent, we must convert pyruvate first to oxaloacetate, and then to glucose-6-phosphate. In the liver and kidney, then, glucose-6-phosphatase will convert G-6-P to glucose to circulate in blood. How do we maintain pyruvate levels to fuel gluconeogenesis? Mainly through conversion of lactate to pyruvate. And where do we get lactate? Mainly from alanine from breakdown of protein. Thus, without considering all the equilibriums for now:
alanine –>> lactate –>> pyruvate –>> oxaloacetate –> G-6-P
ALT = alanine aminotransferase (alanine to lactate)
LDH = lactate dehydrogenase (lactate to pyruvate)
PC = pyruvate carboxylase (pyruvate to oxaloacetate)
We normally control the rate of gluconeogenesis through pyruvate carboxylase. This enzyme exists as a tetramer, adds CO2 to pyruvate and makes oxaloacetate. When acetylCoA levels are low, this tetramer is dissociated, and the enzyme is relatively inactive. When acetylCoA levels are high, the tetramers combine, and gluconeogenesis takes off. And in AKA, acetylCoA levels are HIGH from all the fatty acid beta oxidation. So what’s the problem? The problem becomes depletion of pyruvate. There isn’t much pyruvate formation from glycolysis because the patient is not eating. So we must get it from lactate. Let’s look at this reaction that occurs in the cytoplasm in more detail.
lactate + NAD pyruvate + NADH
Now, let’s name the mass action ratio “K” for our purposes. We recall that formula from inorganic chemistry:
K = [pyruvate] [NADH] / [lactate] [ NAD]
and with a little algebra:
K X [lactate] / [pyruvate] = [NADH] / [NAD]
and using : as a symbol for proportionality:
[lactate] / [pyruvate : [NADH] / [NAD]
or
[NADH] / [NAD] : [lactate] / [pyruvate]
So, we see that in cytoplasm, a high NADH/NAD ratio causes us to raise the lactate/pyruvate ratio, shifting the equilibrium so that it is difficult to convert lactate to pyruvate. A normal L/P ratio is about 10/1. With high NADH/NAD ratios, this can increase significantly. With lactate not going to pyruvate, we impair gluconeogenesis and, in the face of poor oral intake, develop hypoglycemia.
Of note, taking healthy human beings and simply having them fast for a day, and then do nothing but take their blood ethanol concentration to about 100 mg/dL will produce high NADH/NAD ratios from ethanol oxidation and hypoglycemia after a few hours, consistently. This is not AKA, but simply an example of how it is the NADH/NAD ratio that is the problem, regardless of how the elevated ratio is produced. This serves as the basis of ethanol-induced hypoglycemia. Ethanol also does a couple other things to cause hypoglycemia, including impairing release of alanine from skeletal muscle catabolism. But the elevated NADH/NAD ratio is the main factor producing hypoglycemia.
The elevated L/P ratio also explains why lactate levels rise in AKA, just as they do in DKA. Both conditions are characterized by lipolysis and high NADH/NAD ratios, and in both conditions, hyperlactatemia is expected. In fact, just drinking a few beers can raise arterial lactate levels significantly without acidemia, just from raising your NADH/NAD ratio from ethanol metabolism,.
But now let’s look in the mitochondrial matrix. Here we find all this acetylCoA accumulating from excessive lipolysis, and we can’t help but shunt a bunch over to form acetoacetate. We won’t show the CoA’s leaving just to keep things simple.
2 AcetylCoA acetoacetate
And acetoacetate has 2 fates, for our purposes, with acetoacetate in the middle:
CO2 + acetone <<– acetoacetate + NADH beta-hydroxybutyrate + NAD
And we can look in detail at the conversion of acetoacetate to beta-hydroxybutyrate, above, create a mass action ratio, do the algebra, and we find:
[NADH] / [NAD] : [beta-hydroxybutyrate] / [acetoacetate]
So, in the cytoplasm, high NADH/NAD ratios make us shunt towards lactate, while in mitochondria, the same high ratios make us shunt towards beta-hydroxybutyrate. And beta-hydroxybutyrate is not a ketone and not measured with a ketone dipstick (but is an acid).
One more item. Another major fuel for gluconeogensis is gluatamine released from protein. In the mitochondrial matrix, gluatmine ends up as alpha-ketoglutarate and moves through the TCA cycle to oxaloacetate where it enters the gluconeogenesis pathway. And, you guessed it, a high NADH/NAD ratio slows this pathway down as well, contributing to impairment of gluconeogenesis.
NADH/NAD : alpha-ketoglutarate / oxaloacetate
Thus, high NADH/NAD ratios present in AKA from all the aforementioned reasons produce 1) elevated lactate levels, 2) impaired gluconeogenesis with hypoglycemia, and 3) high beta-hydroxybutyrate levels. As noted by commenters, ketone dipsticks may be low or, uncommonly, zero, initially when most of the acetoacetate is shunted towards beta-hydroxybutyrate. And this holds true for DKA, as well. That is the entire reason our laboratories now offer measurement of beta-hydroxybutyrate levels. As the patient improves and the NADH/NAD ratio begins to fall, measurable ketones may actually increase since acetoacetate and acetone levels will rise as beta-hydroxybutyrate levels fall. This is fine as long as acidosis is improving.
It is important to realize that hypoglycemia is common, but certainly not always present, depending on underlying glycogen stores, severity of NADH/NAD ratio elevation, underlying diabetes mellitus and/or chronic pancreatitis with insulin deficiency, how much food has been kept down, etc. Those with glucose intolerance and/or pancreatic insufficiency from chronic pancreatitis may even be somewhat hyperglycemic. But when hypoglycemia is present, the high NADH/NAD ratio in the presence of fasting/starvation is the main problem.
One common question is, why does ingestion of isopropanol produce such profound ketosis, but no metabolic acidosis to speak of?
Isopropanol goes to acetone through alcohol dehydrogenase. If you develop high acetone levels from ingesting isopropanol, or even from ingesting acetone, itself (finger nail polish remover), the acetone will easily set off the ketone dip stick, and acetone levels in plasma and urine can exceed ethanol levels typical of ethanol intoxication. But look at that equation, above, demonstrating the two fates of acetoacetate. Note the arrow from acetoacetate to acetone only goes one direction. We do not take acetone to acetoacetate (an acid and ketone) and certainly don’t take it beta-hydroxybutyrate (an acid). Thus, no acidosis.
Hope this helps.
Well everyone, sorry, but a bunch of arrows have disappeared in formatting by our robot overlords. Looks kind of OK on the desktop, but terrible on the phone. Perhaps after learning a secret about making arrows there may be more success in the future.
Great article, thank you so much for helping! I will wait for more topics with such great words!
Great post. Do you think there is an increase chance of metabolic acidosis when someone is doing low carb/Leo diet and get somewhat of a storm of other risk factors – dehydration due to intense heated exercise with excessive sweating, asthma flare, alcohol binge, intermittent fasting. I had an episode I think was acidosis but undiagnosed by EMS, and these all may have lined up to put me into acidosis. Symptoms were lethargy, slow movements, lower consciousness, sluggish pupils, very rapid breathing, confusion. No nausea or vomiting so it wasn’t purely alcohol, consumed a few glasses of wine only.