Anion gap acidosis- CUTE DIMPLES

We know MUDPILES

Then came GOLDMARK

 

Now let's welcome-- CUTE DIMPLES

There are other causes of a true high anion gap metabolic acidosis that are not captured by the MUDPILES and GOLDMARK mnemonics that should be kept in mind and are included in the recently published and modified CUTE DIMPLES mnemonic presented in CJASN by Anika A et al. 

Detective Nephron: A new case

 Here is the next case on Detective Nephron - a tough case of acidosis
http://www.kidneynews.org/kidney-news/fellows-corner/detective-nephron/detective-nephron

Topic Discussion: Euglycemic Diabetic Ketoacidosis

The first time the term Euglycemic DKA(eDKA) was mentioned was in 1973- in British Medical Journal in patients who were diabetic but didn't have the full blown hyperglyecmic part.  Compared to classic DKA, eDKA presents with mild to moderate hyperglycemia typically <300mg/dl blood glucose levels.  

Why is this more important now?

In 2013, many SGLT2 inhibitors got approved for DM management( the glucoretics).  The FDA performed a FAERS search of adverse effects with these agents and 73 cases were identified of ketoacidosis linked to SGLT-2 inhibitors.  All patients required hospitalization, and 60% had DMII. Blood glucose levels ranged from 90mg/dl - 1300mg/dl( median 211).  Timing of onset was around 43 days or starting or dose change of the agent.  Majority of the cases also had dehydration, infection or change in insulin doses.   No mortality has been reported with this effect.  All patients respond quickly with intravenous hydration and insulin once recognized. The FDA did acknowledge that some of the cases occurred in DMI, where it's an off label use. More detail here. 



Is it a class effect? 
Yes. The initial FDA reporting was done with canagliflozin(invokana). A more recent study found an incidence rate of 0.07% with this agent.  In a large study with dapagliflozin( Farxiga), 0.1% of patients got eDKA.  Empagliflozin(Jardiance) also has been found to cause eDKA. 

What are the risk factors for development of eDKA with SGLT2 inhibitors?

Dehydration
Alcohol use
decrease in insulin use
Infection
Low carbohydrate diet
Reduction in caloric intake
Advance age

Mechanism of action

Ketosis results from restriction of carbohydrate usage with increased reliance on fat oxidation for energy production. The pathogenesis of hyperglyemic DKA is well established. Since SGLT2 are glucoretics as described before, they can lead to volume depletion- like a diuretic and perhaps leading to a "starvation" like ketoacidosis with normal glucose levels. SGLT2 induced glycosuria can happen over 24 hours and this artificial low plasma glucose do not stimulate insulin. In eDKA, insulin deficiency and insulin resistance are milder; therefore, glucose overproduction and under-utilization are quantitatively lesser than in DKA. More importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as large with eDKA than with DKA. Ketoacidosis follows with the same sequence of events in eDKA as in DKA. Insufficient insulin levels will then decrease glucose utilization and promote lipolysis and ketogenesis. In addition, these drugs can increase glucagon levels leading to increase ketone production.

In summary, eDKA is pathophysiologically similar to DKA except for the circumstance—SGLT2-induced glycosuria—that “artificially” lowers plasma glucose levels and predisposes to increased ketogenesis.

Prevention and treatment
Blood and urine monitoring of ketones is essential especially when patients get ill or are experiencing one of the risk factors.  Adequate hydration and carbohydrate intake will help and holding the offending agent is indicated.  No data exists on a safe time to restart the agent. 

Here is a nice review on this topic
http://onlinelibrary.wiley.com/doi/10.1111/jdi.12401/pdf

Topic Discussion: Anion Gap

What are the limitations of the anion gap use? A recent article in CJASN has some key points.

A.Uses of anion gap
1. evaluate met acidosis
2. detect paraproteins
B. Classically AG has been using HCO3, Cl and Na for calculations. Should K be used? The rationale for not using K is because the absolute change in its concentration observed clinically is small. It might be useful if the K is too low or too high. So if K was 7meEg/L, it should be included in the calculation.
C. Based on the research done on what normal AG is, the span of population is from 8-10meq/L.

D. Figge equation: correction for albumin
So corrected AG= anion gap + 0.25 *( normal albumin- measured albumin (g/dl)
E. Interestingly the article points out from their review that the sensitivity of increased anion gap in detecting hyperlactatemia is very poor. Range is from 44% to 78%. If lactic acidosis is suspected, perhaps directly measuring that rather than relying on AG might be useful.
F. Baseline value for individuals AG to optimize the use of the calculation of AG in the detection of acidosis is what the authors suggest.

Consult Rounds: Alkalemia causing Metabolic Acidosis

Can severe metabolic or resp alkalemia lead to Metabolic Acidosis?
Yes it can!!

Metabolic alkalosis, if from vomiting or diuretic use can be associated with a small increment of anion gap ( around 4-6meq/L) and this is ofcouse if no other disorder has been identified.  Why? Largely due to increase in albumin and some due to other increase in anionic proteins.  

Serum anion gap does not change notably in acute respiratory alkalosis, but small increases up to 3meq/L have been observed in chronic respiratory alkalosis.  

Alkalemia also causes glycolysis in the liver and a mild lactic acidosis (seen in our patient). In addition, in a volume contracted patient, the change in anion gap can be due to the change in valence of circulating proteins to preserve extracellular volume.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/401925

http://www.ncbi.nlm.nih.gov/pubmed/17699401

http://www.ncbi.nlm.nih.gov/pubmed/18974769