Novel Anion and Osmolar Gap Metabolic Acidosis of Multiple

Novel Anion and Osmolar Gap Metabolic Acidosis of Multiple
Etiologies in a Type 1 Diabetic
March 2016
Taylor TL*, Spencer HC, Baldwin MD
Pacific Northwest University of Health Sciences and Skagit Valley Hospital, *ttaylor@pnwu.edu
INTRODUCTION
A rare but under diagnosed cause of high anion gap metabolic
acidosis is the accumulation of 5-oxoproline via disruption of the
γ-glutamyl cycle. Chronic alcohol use, sepsis, malnutrition and
possible acetaminophen ingestion are all risk factors in this
case for intracellular glutathione depletion and subsequent
generation of 5-oxoproline, causing a high anion gap metabolic
acidosis.
Chronic EtOH,
Lactic acidosis likely contributed to this case due to
hypoperfusion and cocaine ingestion. Lactic acid is produced
when tissues are hypoxic and the cells convert to anaerobic
metabolism of glucose. Metabolic byproducts of this pathway
have been shown to increase the osmolar gap.
In the setting of an elevated anion gap and osmolar
gap metabolic acidosis, it is customary to first
investigate ingestion of toxic alcohols. In the case
presented, the patient denied this ingestion, and his
claim was supported by normal physical exam findings
of the cardiovascular and ocular systems. Thus, this
case will review the possible etiologies of the anion
and osmolar gaps in a patient with diabetic
ketoacidosis (DKA) with recent exposure to ethanol
and cocaine. DKA is a classic contributor to the anion
gap,1 which can be precipitated by cocaine use.2
Alcoholic ketoacidosis is associated with increased
osmolar gap3 and was likely present in this patient.
Other novel anions and osmoles will also be reviewed
that potentially contributed to this presentation.
Routine assay used to measure lactate is only sensitive to the
L-lactate isomer, which may not account for all contributing
forms of lactate. D-lactate elevates the anion gap. In DKA, Dlactate is and inversely proportional to bicarbonate level.
Diabetes, Malnutrition,
Sepsis
Glutathione
Glycine
γ-Glutamylcysteine
5-oxoproline
γ-glutamyl-cyclotransferase
Cysteine
γ-glutamyl-cysteine
synthetase
L-Glutamate
DISCUSSION
CASE
A young male with a five year history of poorly controlled type
1 diabetes was admitted for vomiting and abdominal pain
following several days of binging on ethanol and cocaine.
This patient has a history of poor dietary and medication
compliance along with a history of drug and alcohol abuse.
Following his recent binge, he complained of retrograde
amnesia but denied the consumption of methanol or ethylene
glycol. The abdominal pain was moderate, diffuse and nonfocal and was associated with fever, chills, nausea and
vomiting. He denied any visual complaints. Aside from
diabetes, his past medical and surgical histories were
noncontributory.
Physical Exam
Vitals: T 36.6° C BP 156/69 HR 124 RR 25 POx 100% on RA
General: Pale, thin, young, white male
HEENT: mucous membranes dry, decreased skin turgor
Chest: CTAB, no W/R/R
Cardiovascular: Tachycardic, regular. No M/R/R
Abdomen: Bowel tones present, diffusely tender to palpation
EKG: Sinus Tachycardia
CXR: Normal
Hospital Course
Present to ER
AG: 36 OG: 45
Dx of DKA
D5W + NS iv
Insulin gtt
Bicarbonate gtt
Day 0,
18:08
Condition
Stabilized
AG resolved
Levofloxacin d/c
Day 0,
22:14
Admit to CCU
K+ po
Thiamine iv
Levofloxacin iv
Day 1,
07:38
Discharged to Home
on Insulin Glargine
32 U qHS
Day 1,
10:32
The serum anion gap represents the difference between
measured cations and measured anions, with a normal value
being 10-12 mEq/L. The serum osmolal gap is the difference
between the true osmolality, as measured by freezing point
depression, and the sum of the measured osmotically active
solutes. These are: serum Na+, BUN, glucose and ethanol.
Figure 6: Simplified schematic of 5-oxoproline formation. Red arrows
represent negative feedback. Blue arrows represent the direction of the
reaction. Chronic alcohol use, diabetes, malnutrition and sepsis contribute
to decreased glycine and glutathione stores and, via dysregulation of
negative feedback, this results in increased 5-oxoproline production. 7
Figure 4. Schematic representation of the formation of Dlactate from Glucose. The interaction between glycolysis
pathway (unboxed area) and the glyoxalase pathway
(boxed area) is shown.4,5
• DKA and alcoholic ketoacidosis are significant contributors to
the elevations in anion and osmolar gaps. Other causes are
reviewed in Table 2.
• In consideration of the novel case reviewed, future evaluation
of elevated anion and osmolar gaps in the setting of DKA
could include:
• Serum β-Hydroxybutarate, acetoacetate, and acetone
levels
• Ethanol level
• Toxicity screen
• Acetaminophen level
• 5-Oxyproline level
• Methanol, ethylene glycol, propylene glycol and isopropyl
alcohol level
• D-lactate (especially in the presence of low bicarbonate)
Another source of organic anions and osmoles is due to the in
vivo production of methanol from the combined consumption of
ethanol and cocaine. In the presence of alcohol, cocaine is
metabolized to cocaethylene and methanol, which causes an
increase in osmolar gap by 1 mmol/kg for every 2.5 mg/dl of
methanol. Methanol has a 15 hour half life, which is slowed by
contaminant ethanol ingestions, so it is likely that methanol
persisted as an osmole at time of presentation.
Figure 2: Schematic representation of three clinical
scenarios that lead to ketoacidosis.
Decreased glucose as a consequence of insulin depletion and
decreased intake leads to lipid metabolism, of which ketones
are a byproduct (Figure 2). Three important ketones are
produced: beta hydroxybuterate, acetoacetate, and acetone,
which account for much of the anion gap (Figure 3).3
Byproducts of ketone metabolism (acetone, glycerol, acetol,
1,2-proanediol) can elevate the osmolar and anion gaps.
Day 2,
08:00
Table 2: etiologies of elevated anion and osmolar gaps
Formic Acid
REFERENCES
1.
2.
Insulin gtt d/c
Figure 1. Hospital Course. Days and times of key events throughout
clinical course. AG=anion gap. OG=Osmolar gap
CONCLUSION
Figure 3: Simplified schematic of the transformation of ketones
generated during ketoacidosis. The final product, acetone, can act
to increase the osmolar gap.
Figure 5. Schematic of cocaine metabolism in the presence of
alcohol. Methanol, a byproduct of cocaethylene formation, is in turn
enzymatically converted to formic acid. This process is inhibited by
bicarbonate and ethanol.6
3.
4.
5.
6.
7.
Corey HE. The Anion Gap: Studies in the Nephrotic Syndrome and Diabetic Ketoacidosis. J Lab Clin Med. 147:121-125, 2006.
Warner EA, Greene GS, Buchsbaum MS. Diabetic Ketoacidosis Associated With Cocaine Use. Arch Intern Med.
1998;158(16):1799-1802. doi:10.1001/archinte.158.16.1799.
Schelling JR, Howard RL, Winter SD. Increased Osmolall Gap in Alcoholic Ketoacidosis and Lactic Acidosis. Ann Intern Med.
1990;113:580-582. doi:10.7326/0003-4819-113-8-580
Whyllie S, Fairlamb AH. Methylglyoxal Metabolism in Trypanosomes and Leishmania. Sem in Cell and Dev Biol.
2011;22(3):271-277. doi:10.1016/j.semcbd.2011.02.001.
Thornally PJ. The Glyoxalase System in Health and Disease. Mol Aspects Med. 1993;14(4):287-371.
Caspi R. MetaCyc Reaction. MetaCyc. www.biocyc.org/META/NEW-IMAGE?type=REACTION&object=RXN-13425. Published
2012. Accessed January 2016.
Fenves AZ, Kirkpatrick HM, Viralkumar PV. Increased Anion Gap Metabolic Acidosis as a Result of 5-Osoproline (pyroglutamic
acid): A Role for Acetaminophen. Clin J Am Soc Nephrol. 1:441-447, 2006. doi:10.2215/CJN.01411005