The Low Anion Gap Conundrum

I was in clinic a few weeks ago, and overheard a conversation about a low anion gap, and needing to test for multiple myeloma, I was buried in notes, but I tucked it away in the back of my head to review causes of low anion gaps. I’m so used to MUDPILES or whatever other acronym you use to remember high anion gap associated metabolic acidosis that low anion gaps…honestly, don’t generally catch my eye.

What is an anion gap? 

It’s the difference between unmeasured anions and unmeasured cations. Basically all the positive charges and all the negative charges are equal in our blood, but we don’t measure absolutely everything in a basic metabolic panel so we have unmeasured cations and unmeasured anions. So to figure out if we have any “abnormal” anions in our body, we take the measured cations and measured anions and test the difference.

[Na+] – [Cl- + HCO3-] and normal is around 12+/- 2 

This means that there are more unmeasured anions than there are unmeasured cations, but our bodies remain electroneutral so ultimately all the positive charges = all the negative charges. Otherwise things would be…weird.

What makes the gap bigger or smaller?

So, if you have more acids in your body (say you have increased ketoacids in your body from being in diabetic ketoacidosis), the extra protons are buffered by the main buffering anion in our body, HCO3-. So functionally, this changes the measured cation-anion difference and we get a higher gap (less bicarb in that equation = higher gap).

BUT what if there are more cations? Or low albumin or phosphorus (which make up most of the anion gap)? That’s where low anion gaps come into play

What could drive low anion gaps? 

Low albumin or low phosphorus = these make up most of the anion gap (the unmeasured anions in the formula). If they’re low, you’re going to get an elevation in Cl- to maintain electroneutrality, so you get a low anion gap.

Paraproteins – This is where multiple myeloma comes in, increase in IgG (which has a net positive charge at physiologic pH) = more unmeasured cations in the blood = lower anion gap. Notably, this is WHY you can get hyponatremia with paraproteinemia (increase in unmeasured cations like paraproteins -> lower sodium to maintain electroneutrality). Fun fact, IgA is anionic, so not all immunoglobulins would cause this.

Hyperkalemia, hypercalcium, hypermagnesemia = more positive (cations) in the body = increased umeasured cations = smaller gap

Lithium = same thing as above

So with multiple myeloma, the hypercalcemia + the hypoalbuminemia + the paraproteinemia all contribute to a low anion gap. Boom, that’s how you get there.

Though keep in mind, the most common cause of a low anion gap is still hypoalbuminemia (which makes up about 75% of the unmeasured anions at physiologic pH).


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