High Anion Gap Metabolic Acidosis

Ross H. Brubaker; Rishik Vashisht; Marcelle Meseeha.

Last Update: May 10, 2022.

High anion gap metabolic acidosis (HAGMA) is a type of metabolic acidosis. Differentiation of
acidosis into a particular subtype, whether high anion gap metabolic acidosis or non-anion gap
metabolic acidosis aids in the determination of the etiology and hence appropriate treatment.
First, to determine whether there is a high anion gap, the anion gap must be calculated. However,
in patients with abnormal levels of albumin this must be corrected. If the corrected anion gap is
greater than 12, this suggests an increased presence of unmeasured anions. Subsequently, the
osmolar gap should be calculated to screen for the presence of alcohols, and ethanol,
acetaminophen, lactate, salicylic acid, creatinine, and ketones should be measured. Additional
testing includes arterial or venous blood gas, urinalysis, complete blood count, and evaluation of
concomitant respiratory or metabolic disturbances. Calculating the delta/delta ratio of anion gap
and bicarbonate can aid in this. Checking for D-lactate would be appropriate in a patient with
short gut syndrome (post gastric-bypass surgery), as delivery of a large amount of carbohydrate
to the colon could promote bacterial secretion of said chemical not typically tested for. EKG could
detect changes caused by abnormal electrolytes, and abdominal radiography could be employed
to evaluate for renal stones or iron ingestion. This activity describes the pathophysiology,
evaluation, and management of high anion gap metabolic acidosis and highlights the role of the
interprofessional team in enhancing care delivery for affected patients.

Objectives:

• Describe the causes of high anion gap metabolic acidosis.

• Summarize the treatment options for high anion gap metabolic acidosis.
• Explain the pathophysiology of high anion gap metabolic acidosis.
• Explain the importance of enhancing coordination amongst interprofessional team
members to improve outcomes for patients with high anion gap metabolic acidosis.

Introduction
High anion gap metabolic acidosis (HAGMA) is a subcategory of acidosis of metabolic (i.e., non-
respiratory) etiology. Differentiation of acidosis into a particular subtype, whether high anion gap
metabolic acidosis or non-anion gap metabolic acidosis (NAGMA), aids in the determination of
the etiology and hence appropriate treatment.[1][2][3][4]

Etiology
Although there have been many broadly inclusive mnemonic devices for high anion gap
metabolic acidosis, the use of "GOLD MARK" has gained popularity for its focus on causes
common to the 21st century.[5][6][7]

• Glycols (ethylene glycol, propylene glycol)

 • Oxoproline (pyroglutamic acid, the toxic metabolite of excessive acetaminophen or
paracetamol)
• L-Lactate (standard lactic acid seen in lactic acidosis)
• D-Lactate (exogenous lactic acid produced by gut bacteria)
• Methanol (this is inclusive of alcohols in general)
• Aspirin (salicylic acid)
• Renal Failure (uremic acidosis)
• Ketones (diabetic, alcoholic and starvation ketosis)

Of note, metformin has been omitted from this list due to a lack of evidence for metformin-
induced lactic acidosis. In fact, a Cochrane review found substantial evidence that metformin was
not a cause of lactic acidosis. The same could not be said of the older biguanide, phenformin,
which does increase the incidence of lactic acidosis by approximately tenfold.

Furthermore, the addition of massive rhabdomyolysis would be appropriate given the potentially
large amounts of hydrogen ions released by muscle breakdown.[8][9]

Epidemiology
High anion gap metabolic acidosis is one of the most common metabolic derangements seen in
critical care patients. Exact numbers are not readily available.

Pathophysiology
[10]The most common method of evaluation of metabolic acidosis involves the Henderson-
Hasselbalch equation and the Lewis model interpretation of biological acidosis which evaluates
the plasma concentration of hydrogen ions. An alternative method outside of the scope of this
article is the Strong Ion Difference (SID), which describes acid-base abnormalities regarding
differences in the strong ions (sodium and chloride).[11][10]

Equations:
Anion Gap: AG = Na - (Cl + HCO3)Calculated Osmolarity: Osm = (2 x Na) + (BUN / 2.8) + (Blood
Glucose / 18) + (EtOH / 3.7)Osmolar Gap: OG = (Measured Osm) - (Calculated Osm)

Histopathology
Microscopy has limited value in the evaluation of high anion gap metabolic acidosis. One
exception is the ingestion of ethylene glycol. Given that the breakdown products of ethylene
glycol include oxalate, sufficient doses can produce calcium oxalate monophosphate crystal that
deposits into tissues (e.g., kidneys, brain) and precipitates in the urine. Calcium oxalate
monophosphate can be seen on urine microscopy and are shaped like dumbbells, spindles, ovals
or picket fences. These are differentiated from calcium oxalate diphosphate crystals, which are
octahedral and traditionally described as "envelope shaped."
Toxicokinetics
Among the various causes of high anion gap metabolic acidosis, several involve oxidative
pathways of alcohol metabolism through alcohol dehydrogenase. Substances such as methanol
and ethylene glycol have limited intrinsic toxicity but are converted into more toxic substances
(formic acid and oxalic acid respectively). Due to this fact, the inhibition of alcohol dehydrogenase
is the primary treatment for toxic alcohol ingestions.

History and Physical

Symptoms of high anion gap metabolic acidosis are generally non-specific, with dyspnea being
common secondary to stimulation of the central respiratory center. A review of signs and
symptoms associated with the various causes of acidosis can be helpful. Therefore, screening for
toxic ingestions, including over-ingestion of aspirin and acetaminophen, is of utmost importance.
Additionally, screening for features suggestive of diabetes (e.g., polyuria, polydipsia, polyphagia)
or renal failure (e.g., nocturia, pruritus, anorexia) is essential. Physical examination is similarly
non-specific for metabolic acidosis in general, with Kussmaul respirations (i.e., deep, slow breaths
instead of shallow rapid breathing) being a common finding. Evaluation for features of specific
causes aids in narrowing the differential diagnosis. For example, a patient might have dry mucous
membranes and ketotic scent in diabetic ketoacidosis. Alternatively, a patient may demonstrate
excoriations, asterixis, and confusion in uremia.

Evaluation
Given that patients generally present non-specifically in high anion gap metabolic acidosis,
evaluation requires recognition of basic chemistry value changes and further characterization
with laboratory tests. Starting with a basic metabolic panel (BMP) or serum electrolyte panel, the
anion gap (AG) should be calculated by subtracting the major anions (chloride & bicarbonate)
from the major cation (sodium). Some sources argue for the use of potassium, but it has
traditionally been omitted. Consider integrating it in patients with grossly abnormal potassium
values. The single largest source of unmeasured anions in the healthy population is albumin,
which is why evaluation of, and correction for, hypo/hyperalbuminemia will improve the
accuracy of the high anion gap Metabolic Acidosis evaluation. The correction factor of +2.5 mEq
per 1 g/dL of albumin below the baseline of four is standard. Therefore, failure to correct for a
low albumin would falsely depress the AG, potentially masking the presence of high anion gap
Metabolic Acidosis.

Although there are differences between laboratories and assays, the normal anion gap has
traditionally been set between 8 mEq/L to 12 mEq/L. If the anion gap is greater than 12, this
suggests an increased presence of unmeasured anions. Determination of the source of said
anions, while somewhat dependent on a high-quality history and physical exam, generally
requires screening for common etiologies. Therefore, evaluation typically includes screening for
an elevated osmolar gap (measured osmolarity minus calculated osmolarity), ethanol,
acetaminophen, lactate, salicylic acid, creatinine, and ketones. Although some large hospital
networks have access to more specific tests like methanol, ethylene glycol, these tests usually
require several days to return for the majority of hospitals. For this reason, the osmolar gap is
evaluated to screen for the presence of alcohols. The normal value for the osmolar gap is
generally set to less than or equal to 10 mEq/L.

Do not underestimate the utility of the osmolar gap. Since the presence of toxic alcohols is not
easily evaluated, and there are effective treatments to prevent the formation of their toxic
metabolites, this test is key to evaluating for such ingestion. It must be noted, however, that the
presence of an elevated osmolar gap is expected in ketoacidosis, as acetone can also elevate
serum osmolarity. In such a situation, trending the osmolar gap can demonstrate improvement
with appropriate treatment. Failure of the osmolar gap to decrease following treatment for
ketoacidosis should prompt consideration of toxic alcohol ingestion and administration of an
alcohol dehydrogenase inhibitor.

Additional testing includes arterial or venous blood gas, urinalysis, complete blood count (CBC),
and evaluation of concomitant respiratory or metabolic disturbances. Calculating the delta/delta
ratio of anion gap and bicarbonate can aid in this (see mixed acid-base disorders). Checking for
D-lactate would be appropriate in a patient with short gut syndrome (post gastric bypass
surgery), as delivery of a large amount of carbohydrate to the colon could promote bacterial
secretion of said chemical not typically tested for by the standard serum lactate. EKG could detect
changes caused by abnormal electrolytes, and abdominal radiography could be employed to
evaluate for renal stones or iron ingestion.

Treatment / Management
Primary treatment of high anion gap metabolic acidosis requires correction of the underlying
cause. In mild to moderate acidosis, treatment could be limited to supportive measures including
intravenous fluids and respiratory support. Alkalization therapy should be reserved for those
individuals with severe acidosis (pH less than 7.1). In the case of diabetic ketoacidosis (DKA), this
value is even lower (pH less than 6.9). The most common alkalizing agent is sodium bicarbonate,
but sodium and potassium citrate are alternative options. In the event of severe, recalcitrant
acidosis, it may be appropriate to treat empirically with alcohol dehydrogenase inhibitors
(fomepizole or ethanol) and prepare the patient for emergent hemodialysis. Fomepizole prevents
the conversion of alcohols into toxic metabolites through competitive inhibition of alcohol
dehydrogenase. Ethanol is not preferred, but it has a similar mechanism of action because alcohol
dehydrogenase has a greater affinity for ethanol than for methanol or ethylene glycol.
Importantly, fomepizole has the greatest impact on outcomes when given within six hours of
presentation; however, given it is frequently in short supply and prohibitively expensive,
universal treatment of all high anion gap metabolic acidosis with fomepizole is not advised.

Treatment of the underlying disorder may require glucose and insulin in the case of DKA,
antibiotics and goal-directed fluid administration in the case of sepsis or administration of specific
antitoxins (e.g., fomepizole or n-acetylcysteine) in the case of toxic ingestions.
Differential Diagnosis
• Diabetic ketoacidosis
• Ethyl glycol
• Isoniazid
• Lactate
• Methanol
• Propylene glycol
• Salicylates
• Uraemia

Pearls and Other Issues

Although outside the scope of this article, it is important to evaluate all acid-base disturbances
for the presence of a mixed disorder. Therefore, evaluation for high anion gap metabolic acidosis
is only the first step in the complete acid-base workup. Further evaluation of the delta/delta ratio
and the change in the partial pressure of carbon dioxide is mandatory in any case of high anion
gap metabolic acidosis, as mixed acid-base disorders are common.

Enhancing Healthcare Team Outcomes

HAGMA is best mannaged by an interprofessional team including pharmacists. The key is to treat
the primary disorder responsible for HAGMA. In most cases, when the primary condition is
treated, the electrolyte disorder resolves.

Figure
Anion gap, Osmolar gap. Contributed by Ross H. Brubaker, DO
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