Chapter 8

Elevated Anion Gap Metabolic Acidoses

Learning Objectives
After completing this chapter, you should be able to:
 Know the differential diagnosis of an elevated anion gap metabolic acidosis.
 Understand the pathophysiology behind the generation of pathologic acids in the
etiologies of an elevated anion gap metabolic acidosis.
 Identify the specific etiology of an elevated anion gap metabolic acidosis in an
individual patient.

Overview of the Etiologies

As discussed in Chapter 5, an elevated anion gap metabolic acidosis is always caused by the
accumulation of a pathologic acid, with the exception of advanced renal failure, in which it is due to
the accumulation of phosphates and sulfates. Because these etiologies represent a diverse range of
biochemical processes, they lack a clear means of grouping and categorization, and are therefore,
particularly prone to result in pneumonics to assist clinicians’ memories.

By far, the most common is MUDPILES (Figure 1). Despite its

nearly ubiquitous adoption by clinicians throughout the world,
use of this pneumonic is not recommended for a number of
reasons. First, there is no recognition of the extreme variation
in prevalence between the listed conditions. It mixes
pathologic processes (e.g. uremia) with accumulating acids
(e.g. lactic acidosis). It also ignores that some listed diagnoses
lead to an elevated anion gap via another listed process. For
example, INH, infection, and salicylic acid lead to an elevated
anion gap acidosis via lactic acidosis, and ethanol leads to an Figure 1: MUDPILES pneumonic for
elevated anion gap acidosis via either lactic acidosis or remembering the etiologies of an
ketoacidosis. Finally, inclusion of paraldehyde is unnecessary, elevated anion gap metabolic acidosis.
as this drug is no longer in widespread use.
There are two other pneumonics for remembering
these etiologies, shown in Figures 2a and 2b.
GOLDMARK has the advantages of the inclusion of
oxoproline (a newly appreciated cause of clinically
relevant acidosis) and removal of the obsolete
paraldehyde. KULT is a great pneumonic as it is
short, and places emphasis on the three most
common causes of an elevated anion gap acidosis
(e.g. lactic acid, “ketoacids”, and uremia). Figure 2a: GOLDMARK Figure 2b: KULT
pneumonic. pneumonic.

Lactic Acidosis

Physiology and Biochemistry

Lactic acidosis is the most common, clinically

relevant cause of an elevated anion gap
metabolic acidosis. Its major importance is in
the detection of hypoperfusion, which can be
a sign of shock, limb ischemia from an acute
embolism, or bowel infarction – all of which
have high mortality rates if not quickly
recognized. Elevation of lactic acidosis,
within the right context, is prognostic factor
in some of these pathologic states (Figure 3),
and its timely resolution can be predictive of
improved survival. Lactic acidosis can also be Figure 3: The relationship between serum lactate,
systolic blood pressure, and mortality, among
a sign of various toxic ingestions or
patients presenting with suspected infection. (Data
exposures, as well as systemic illness; in the adapted from Howell MD, et al. Occult
latter, its presence has much less prognostic hypoperfusion and mortality in patients with
value. suspected infection. Int Care Med. 2007; 33:1892-9.)

To understand lactic acidosis and its causes, it is necessary to have

some understanding of the biochemistry and physiology involved.
Lactic acid (which is referred to as lactate when in its deprotonated,
anionic form) is a small molecule that plays a critical role in normal
human biochemistry (Figure 4).

Figure 4: Lactate
The formation of lactate typically begins with glucose, which undergoes the regulated, multistep
process of glycolysis to form pyruvate, along the way generating a few ATP and reducing NAD+ to
NADH (Figure 5). Under normal circumstances, pyruvate is converted into acetyl Co-A with the help of
thiamine and some more NAD+. Acetyl CoA can then enter the citric acid cycle (a.k.a. Krebs cycle or
TCA cycle), where its chemical energy is converted into a form that can be used by the electron
transport chain to generate many ATP in a process known as oxidative phosphorylation. All of these
steps here require the presence of oxygen and functioning mitochondria.

Figure 5: A summary of the biochemical processes involved in the production of lactate,

along with pyruvate’s alternate fate as Acetyl Co-A.

In some circumstances however, pyruvate is redirected elsewhere. For example, in anaerobic

conditions there is inadequate oxygen to allow the citric acid cycle and electron transport chain to
function. There are also places where mitochondria aren’t found (e.g. red blood cells), and
circumstances where mitochondria are not functional (e.g. cyanide poisoning). In these circumstances,
pyruvate is reduced into lactate with the catalytic assistance of lactate dehydrogenase. This reaction
oxidizes NADH back to NAD+, which can then be recycled in the process of glycolysis.

Looked at from a larger scale, lactate commonly comes from three locations. First, as mentioned, red
blood cells lack mitochondria and therefore are unable to perform oxidative phosphorylation, meaning
pyruvate becomes converted to lactate as part of anaerobic respiration. This is ironic as it means that
RBCs are incapable of using the oxygen they are responsible for delivering. It also means that a small
amount of lactate in the blood is normal and always present. Second, whenever cells are either
starved from oxygen, or have non-functional mitochondria, they rely on anaerobic respiration and thus
produce lactate. Finally, in exercising skeletal muscle, production of NADH exceeds the oxidative
capacity of the electron transport chain. The increased NADH:NAD + ratio kinetically favors reduction of
pyruvate to lactate.
Once lactate has been formed, it is
normally converted back into pyruvate in
the liver. Some pyruvate will then enter
the citric acid cycle, while some will enter
the process of gluconeogenesis, and be
transformed back into glucose, at which
point it will reenter the systemic
circulation. This conversion of pyruvate
into lactate and back again is known as
the Cori cycle (Figure 6). An alternate fate
of lactate is filtration in the kidneys and
elimination in the urine. This is usually
only relevant once the blood lactate level
Figure 6: The Cori cycle, demonstrating the potential sources
exceeds a certain threshold, commonly and fates of lactate.
believed to be about 5 mmol/L.

There are some rarer, pathologic sources of lactate. In some patients with bacterial overgrowth and
high glucose delivery to the colon, intracolonic bacteria can produces excessive amounts of lactate,
which can be absorbed through the gut wall. This condition, known as D-lactic acidosis will be
discussed in a minute. In addition, certainly malignancies can produce lactate themselves, for reasons
which are not fully understood. The malignancies most commonly implicated in this are lymphoma,
leukemia, and multiple myeloma.

Medications and Lactic Acidosis

There are a number of medications and

toxins that have been associated with Medications Toxins
lactic acidosis (Figure 7). The known
mechanisms are too diverse to review in Acetaminophen Linezolid Carbon Monoxide
any detail here, but they generally involve Anti-retrovirals Nitroprusside Cocaine
disruption of oxidative phosphorylation β agonists Propofol Cyanide
either by direct enzyme inhibition or by a
5-Flurouracil Salicylates Diethyl Ether
more general disruption of mitochondrial
function. The specific mechanisms by Halothane Sorbitol Ethanol
which ethanol and the toxic alcohols lead Iron Sulfasalazine Toxic Alcohols
to acidosis are discussed below. Carbon Isoniazid Valproic Acid
monoxide will be discussed in Chapter 19.
Figure 7: Medications and toxins associated with lactic acidosis.
In addition to the meds and toxins listed in Figure 7, the
diabetic medication metformin (Figure 8a) has also long
been attributed as the cause of many cases of lactic acidosis
in the literature. Metformin is a biguanide, and acts by
reducing gluconeogenesis by the liver. Concern regarding
the link between metformin and lactic acidosis began even
prior to the medication’s initial approved by the FDA in the
U.S., as a consequence of the link between lactic acidosis Figure 8a: Metformin
and an earlier biguanide, phenformin (Figure 8b). Because
of this potentially lethal side effect, phenformin was pulled
from the market in 1977. Physicians, regulatory agencies,
and the public all assumed that metformin shared some of
the same risk, as its structure and mechanism of action was
phenformin. However, over time, suspicion has mounted
that this assumption has either been exaggerated, or may
Figure 8b: Phenformin
even be completely erroneous.

A Cochraine Review was published in 2003 and updated in 2010 in which 347 separate studies of
metformin were examined, comprising 70,490 patient-years of metformin use. Many of these patients
had conditions generally considered to be contraindications for metformin, and one trial even explicitly
included only patients with renal insufficiency. Among all of this data, not a single case of lactic
acidosis was reported that wasn’t attributable to an alternative explanation (e.g. shock, infection, renal
failure, etc…). The Cochrane authors concluded “There is no evidence from prospective comparative
trials or from observational cohort studies that metformin treatment increases the incidence of lactic
acidosis compared with other anti-hyperglycemic treatments”. In other words, the incidence of lactic
acidosis among diabetics on metformin is likely identical to that among diabetics not on metformin.

There certainly remains much skepticism in the medical community about this issue. Of additional
concern is whether metformin can lead to lactic acidosis during an episode of acute kidney failure, as
well as whether it should be withheld for 48 hours before and/or after administration of IV contrast.
There is insufficient evidence available to comment on those two questions. In addition, due to
ongoing debate in the medical community, use of metformin in the setting of chronic conditions
commonly considered to be contraindications (e.g. chronic kidney disease) may expose the prescribing
physician to civil liability, irrespective of scientific evidence, and should still be done only with great
caution and discussion of risk and benefits with the patient.
D-lactic acidosis

D-lactic acidosis is a relatively unique form of lactic

acidosis that occurs as a consequence of lactate having
two enantiomers (Figure 9). The L enantiomer is the
common form, which is produced in humans primarily
via the reduction of pyruvate by lactate
dehydrogenase. There also exists the mirror image of
L-lactate, which is D-lactate. D-lactate does not L-lactate D-lactate
normally occur in the body, but can be produced by
colonic bacteria in patients who have undergone Figure 9: The two enantiomers of lactate.
either jejunoileal bypass or extensive resection of
small bowel.

In these patients, unusually high amounts of carbohydrates reach the colon, where the bacteria there
metabolize it into D-lactate, which is then absorbed through the gut wall. Unfortunately, lactate
dehydrogenase, normally responsible for catalyzing lactate’s oxidation back into pyruvate within the
liver, does not recognize D-lactate. Therefore, D-lactate accumulates as it is slowly eliminated via the
kidneys, or metabolized without the benefit of an enzyme catalyst.

Many patients who have undergone significant resections of the small bowel have asymptomatic, mild
D-lactic acidosis. When symptoms occur, they are largely non-specific, but always include altered
mental status, with the consistent, subjective observation that affected patients appear drunk. The
labs of an affected patient will reveal an elevated anion gap acidosis after eating that resolves with
fasting. Since standard assays for measuring lactate actually utilize lactate dehydrogenase, they are
specific for L-lactate. Thus these patients initially appear to have normal lactate levels. A special assay
that utilizes D-lactate dehydrogenase exists, but is not readily available at most hospitals.

Lactic Acidosis in Alcoholics

In alcoholics, there is an additional complicating biochemical pathway, which is the breakdown of

ethanol itself (Figure 10). The first step in this process is the oxidation of ethanol to acetaldehyde,
which is catalyzed by an important enzyme called alcohol dehydrogenase. This oxidation converts
NAD+ to NADH. The next step in ethanol metabolism is conversion of acetaldehyde to acetate, which is
assisted by an enzyme called aldehyde dehydrogenase. Finally acetate is converted into acetyl-CoA, at
which point it can enter the citric acid cycle and provide energy for the generation of ATP, which is how
ethanol can be a major source of calories for alcoholics. Alternatively, the acetyl Co-A can be used as a
precursor for ketoacids, discussed later.
Figure 10: Metabolism of ethanol.

The shift in the ratio of NAD+ to NADH that occurs during ethanol’s metabolism creates a propensity to
develop lactic acidosis in alcoholics, related to the possible fates of pyruvate (Figure 11). Pyruvate can
be oxidized to form acetyl Co-A, which will either enter the citric acid cycle or be converted to
ketoacids. Alternatively, pyruvate can be reduced to form lactate. The former reaction requires NAD+
and converts it to NADH, while the latter reaction requires NADH and converts it to NAD+. Thus, one of
the major determinants as to whether pyruvate enters the citric acid cycle or is diverted into the
formation of lactic acid is the relative concentrations of NAD+ and NADH. Kinetically, this relationship
can be described as: [NADH]:[NAD+] ∝ [lactate]:[pyruvate]. As ethanol metabolism results in the
production of NADH, this helps to drive this balance more towards lactate than normal. Considering
that most alcoholics have some degree of hepatic dysfunction, and that the liver is responsible for the
majority of lactate clearance, it is evident as to why the development of lactic acidosis in alcoholics is
so common, even in the absence of tissue hypoperfusion. In addition, alcoholics may also be
predisposed to lactic acidosis in the setting of concurrent thiamine deficiency, as thiamine is a cofactor
for pyruvate dehydrogenase, the enzyme responsible for catalyzing the conversion of pyruvate into
acetyl Co-A. The ethanol-associated type B lactic acidosis generally occurs only in the setting of very
recent heavy intake (most patients will still have measurable serum levels of ethanol), and resolves
within hours of ethanol’s clearance from the body.

Figure 11: Two possible fates of pyruvate. The ratio of acetyl-CoA production to lactate
+
production is partially dependent upon the relative availability of NAD and NADH.
Classification System for Lactic Acidosis

There is a popular system of classifying

lactic acidosis formally known as the Type A Type B
Cohen-Woods classification (Figure 12), (Tissue Hypoperfusion) (No Tissue Hypoperfusion)
which divides the etiologies into type A
and type B. In type A, there is evidence of Shock B1 – Secondary to
tissue hypoperfusion, such as that seen other medical
with shock, profound hypoxia, acute limb Profound Hypoxemia
disorder
ischemia, or bowel infarction. In type B, Limb Ischemia
there is no hypoperfusion. Type B has B2 – Meds/Toxins
been further subdivided: B1 which is Bowel Infarction
B3 – Inborn errors of
secondary to another medical disorder metabolism
(e.g. liver failure), B2 which is secondary to
medications or toxins, and B3 is secondary Figure 12: Cohen-Woods classification system for lactic
to inborn errors of metabolism. acidosis.

Ketoacidosis

Ketoacids, also known as ketone

bodies, are small compounds
synthesized by the liver to be
used as alternative fuel by cells
during periods of relative glucose
deficiency. Acidosis caused by
the presence of ketoacids is well
described in three situations:
diabetes (known as diabetic
ketoacidosis or DKA), starvation
(known as starvation
ketoacidosis), and chronic heavy
alcohol intake (known as
alcoholic ketoacidosis, or rarely
as AKA). Ketoacidosis from both
diabetes and heavy alcohol
intake is commonly found in
conjunction with lactic acidosis,
as well as a mild metabolic Figure 13: An overview of the biochemical synthesis of ketone bodies.
alkalosis from vomiting, both of
which can complicate the ability
to make an accurate diagnosis.
To understand why these three conditions produce ketoacidosis, it’s important to understand the
relevant biochemistry (Figure 13). Formation of ketoacids requires lipolysis of triacylglycerols in
adipose tissue. Once triacylglycerols have been broken down into fatty acids, these travel in the blood
bound to albumin. While some circulating fatty acids will get taken up by tissues and directly oxidized
for energy, in the liver, excess acetyl Co-A that is derived from the β oxidation of those fatty acids and
not utilized in the citric acid cycle is diverted into the formation of acetoacetate. Some acetoacetate
undergoes spontaneous breakdown into acetone, which is responsible for the fruity smell sometimes
detected on the breath of patients with severe ketoacidosis. Acetoacetate can also be enzymatically
reduced to β hydroxybutyrate. These 3 compounds – acetoacetate, acetone, and β hydroxybutyrate –
are known as ketone bodies or ketoacids, although only acetoacetate is technically both a ketone and
an acid.

The initial step – the lipolysis of triacylglycerols – is under regulation. It is inhibited by insulin, which
helps to explain why diabetics lacking insulin can develop DKA. This step is stimulated by epinephrine,
cortisol, growth hormone, and glucagon. The influence of these four “stress hormones” explains why
diabetics in states of physiologic stress are prone to develop DKA. Finally, patients in fasting states
characterized by low carbohydrate intake (e.g. starvation or alcoholism) have relatively low levels of
insulin and relatively high levels of glucagon, also predisposing to ketoacidosis.

The diagnosis of ketoacidosis is suggested by finding an elevated anion gap metabolic acidosis in a
susceptible individual (i.e. diabetic, extreme fasting, or alcoholic), and is further supported by a normal
lactic acid level. (Although as mentioned above, lactic acidosis and ketoacidosis are not mutually
exclusive.) A reasonably definitive diagnosis of ketoacidosis can be made when an elevated gap
acidosis is seen together with an elevated serum or urine ketone level, which is usually measured using
a test called the nitroprusside assay, which is only able to measure acetoacetate and acetone.
Unfortunately, β hydroxybutyrate is the predominant ketone formed during states of ketoacidosis,
particularly in alcoholic ketoacidosis on account of a high NADH to NAD+ ratio. Therefore, there is a
relatively high false negative rate with urine and serum tests for ketones. To reflect this type of
uncertainty, some labs have stopped routinely reporting the presence or absence of ketones in the
urine, and some physicians were inappropriately using a negative urine ketone level to rule out the
diagnosis. β hydroxybutyrate can be measured directly, but this is often a test that needs to be
submitted to an outside lab, and therefore the result does not come back within a clinically useful time
frame.

Renal Failure

Advanced renal failure is another frequent cause of a metabolic acidosis. Unfortunately, renal failure
frequently leads to a mixed normal gap acidosis and elevated gap acidosis. This occurs because there
are multiple simultaneous mechanisms at work. First, there is a decrease in the excretion of hydrogen
ions in kidney due to decreased excretion of ammonium ion, as well as decreased excretion of
titratable acids such as phosphoric acid. This is the primary cause of the acidosis. The primary cause of
the increase anion gap is the accumulation of unmeasured anions, including phosphate, sulfate, urate,
and hippurate. The anion gap that can occur solely from renal failure, even when advanced, rarely
exceeds 20 mEq/L. The measurement of a gap of this severity or worse should always prompt an
investigation for an alternative or additional explanation. Also, as many unmeasured anions are
cleared from the body via the kidneys, renal failure may make an elevated gap acidosis from another
cause (e.g. lactic acidosis) more severe or persistent.

Methanol

Methanol is a tiny molecule, the biochemically simplest of all alcohols. It has various industrial uses,
and is found in some windshield wiper fluid, antifreeze, and paint remover. Although it’s commonly
taught that methanol poisoning is primarily seen among alcoholics who use methanol in place of
ethanol, outside of extraordinary circumstances, this common teaching is likely untrue for the simple
reason that ethanol is far easier to obtain, and far more palatable than methanol-containing products.
Methanol poisoning is more often observed in accidental ingestions in children and in psychotic
patients, and is rarely seen in suicide attempts. Unlike most other alcohols, clinically relevant amounts
of methanol can also be inhaled or directly absorbed through the skin, though this is rare. Symptoms
of methanol poisoning include vision loss, photophobia, abdominal pain, confusion, and lethargy.

Regarding its metabolism, methanol first undergoes oxidation to formaldehyde with assistance from
alcohol dehydrogenase – the same enzyme responsible for the first step in ethanol’s metabolism
(Figure 14). Next, formaldehyde is quickly further oxidized to formate (or formic acid in its uncharged
form). Formate is the compound that is actually responsible for both the increased anion gap acidosis
and the pathology caused by methanol ingestion, which is mediated by direct inhibition of oxidative
phosphorylation. Finally, formic acid is broken down into carbon dioxide and water, a reaction which
requires the presence of tetrahydrofolate. It would seem logical that patients who were folate
deficient might be more prone to methanol toxicity, though this is unproven.

Interestingly, although formaldehyde is an intermediate step in methanol metabolism, formaldehyde

poisoning typically presents quite differently. As formaldehyde is highly volatile, poisoning from it is
usually via inhalation, and thus most symptoms and signs are pulmonary in nature.

Figure 14: The metabolism of methanol. ADH = alcohol dehydrogenase. FDH = formaldehyde dehydrogenase.
THF = tetrahydrofolate.
Ethylene Glycol

Ethylene Glycol toxicity shares a number of features in common with methanol poisoning, and utilizes
very similar biochemical pathways. Ethylene glycol is a colorless, odorless, but sweet compound that
is found in antifreeze and liquid coolants. Its sweetness is one of the reasons poisoning from it is
disproportionately present in children and animals. The symptoms of ethylene glycol poisoning are
usually divided into three stages:

1. Confusion (first 12 hours post ingestion)

2. Heart failure, myocarditis, and pulmonary edema (12-24 hours post ingestion)
3. Acute kidney injury (24-72 hours post ingestion)

Understanding the metabolism of ethylene glycol is important to understanding the key features of its
toxicity (Figure 15). As with almost all alcohols, the first step in metabolism is oxidation by alcohol
dehydrogenase. This results in glycoaldehyde, which is further oxidized by aldehyde dehydrogenase to
glycolate. Glycolate is one of the direct contributors to the elevated gap acidosis seen with ethylene
glycol toxicity; however, it also impairs cellular respiration at the mitochondrial level, and thus results
in a concurrent lactic acidosis. Finally, after several additional steps, glycolate is metabolized into
oxalate. Oxalate forms complexes with calcium, and these complexes are deposited into the heart,
brain, lungs, and kidneys, and are responsible for the pathologic features not attributable to the
concurrent lactic acidosis.

Figure 15: The metabolism of ethylene glycol. ADH = alcohol dehydrogenase. ALDH = aldehyde dehydrogenase.

Ethylene glycol toxicity is diagnosed from levels directly measured in the blood, but strong supporting
evidence includes the discovery of calcium oxalate crystals in the urine, which can be seen on light
microscopy, and which is likely to be quicker to obtain than an ethylene glycol level. Antifreeze, which
is the most common source of ethylene glycol poisoning, usually also includes fluorescein, added to
help trace the source of leaks in automobiles. When ingested by humans, fluorescein is eliminated via
the kidneys. As a consequence, there is a long-held belief that looking for fluorescence when shining a
UV light on urine can be helpful in making the diagnosis. Although this is the type of fascinating “in the
trenches” bedside technique that often makes its way into teaching rounds, it is a poor diagnostic test
with poor sensitivity, specificity, and interobserver agreement.

There is, however, a type of lab error that may prove helpful in
making an early diagnosis of ethylene glycol toxicity. The error is
a consequence of significant structural similarity between lactate
and glycolate (Figure 16). The method that some point-of-care
analyzers utilize will confuse glycolate for lactate, and report a
lactate level significantly higher than true. Laboratory analyzers,
on the other hand, generally utilize a completely different Figure 16a: Glycolate
method for measuring lactate, one which may not be susceptible
to this error. Therefore, a large discrepancy between lactate
levels simultaneously measured by different analyzers,
colloquially known as a lactate gap, should raise suspicion for this
diagnosis.

Figure 16b: Lactate

Propylene Glycol

The final toxic alcohol to talk about in detail is propylene glycol. This is used as a solvent for a number
of IV medications, including lorazepam, phenobarbital, diazepam, and phenytoin. The typical
presentation of propylene glycol toxicity is the onset of renal failure and an unexplained lactic acidosis
in a patient who has been on a continuous infusion of IV lorazepam for at least several days. For its
metabolism, propylene glycol is oxidized first to lactaldehyde, and then again to lactate, which is
presumably the cause or a contributing factor to the lactic acidosis (Figure 17). Eventually, the lactate
is cleared by reduction back into pyruvate.

An acceptable level of propylene glycol administration has not been formally defined, but commentary
in the literature recommends a limit of 69 g/day in patients with normal renal and hepatic function,
which is the equivalent of 7mg/hr of lorazepam. Other drugs are not infused at high enough rates to
lead to propylene glycol toxicity by themselves, but will contribute to this problem if combined with IV
lorazepam.
Figure 17: Metabolism of propylene glycol.

Summary of the Metabolism of Clinically Relevant Alcohols

Figure 18 summarizes the metabolism of simple alcohols in the body. The first step is always oxidation
with alcohol dehydrogenase to form an aldehyde. And the next step is further oxidation to form a
carboxylic acid. It’s this carboxylic acid that causes most of the pathology seen with toxic alcohols,
with the addition of oxalate which is also very problematic.

An important connection between

these pathways is the fact that the
affinity of alcohol dehydrogenase
for ethanol is greater than that of
methanol or ethylene glycol.
Historically, this has been taken
advantage of when treating
methanol or ethylene glycol
poisoning, as an ethanol infusion
will slow down metabolism of the
more toxic alcohols into their
dangerous carboxylic acid forms.
Ethanol infusion has now fallen out
of favor due to a new medication
called fomepizole, which is a
competitive inhibitor of alcohol
dehydrogenase, and which is Figure 18: A summary of the metabolic pathways of the simple
generally considered safer. alcohols most frequently associated with pathology.
Osmolal Gap

The serum osmolal gap is an important concept used to identify the presence of a toxic alcohol (e.g.
methanol, ethylene glycol, propylene glycol). The osmolal gap is the difference between the measured
osmolality and the calculated osmolality (Figure 19). The calculated osmolality is determined by adding
up the osmolality of each easily measured osmotically active ion or molecule that is normally found in
the serum in large amounts. These are limited to sodium, bicarbonate, chloride, glucose, and urea
(a.k.a. blood urea nitrogen, or BUN). Since the serum sodium is approximately equal to the sum of
bicarbonate and chloride (the difference between them being the anion gap), estimated serum
osmolality is classically calculated as shown in Figure 20.

Osmolal Gap = Serum Osmmeasured – Serum Osmcalculated

Figure 19: Calculation of the osmolal gap.

𝑩𝑼𝑵 𝒈𝒍𝒖𝒄𝒐𝒔𝒆 𝒆𝒕𝒉𝒂𝒏𝒐𝒍

𝑺𝒆𝒓𝒖𝒎 𝑶𝒔𝒎𝒄𝒂𝒍𝒄𝒖𝒍𝒂𝒕𝒆𝒅 = 𝟐 × 𝑵𝒂+ + + +
𝟐.𝟖 𝟏𝟖 𝟒.𝟑

+
Figure 20: Calculation of estimated serum osmolality. For this form of the equation, Na is measured in mEq/L, while
urea, glucose, and ethanol are all measured in mg/dL. BUN = blood urea nitrogen.

A small gap (< 10 mOsm/L) is normal (largely a Indications to Check

consequence of phosphates, sulfates, and Serum Osmolal Gap
albumin), but accumulation in the serum of
additional compounds of low molecular weight 1) Suspected poisoning with an unknown toxin
(e.g. alcohols) will raise the measured osmolality 2) Elevated anion gap in the presence of normal
above this. (An osmolal gap of 10-20 mOsm/L is lactate, negative ketones, and normal renal
function
considered indeterminate, with the exception of
3) Unexplained altered mental status
patients on IV lorazepam, in which any gap (particularly in an alcoholic, child, or patient
>10mOsm/L should be considered highly suffering from psychosis)
suggestive of propylene glycol toxicity.) Although 4) Periodic monitoring for patients on high dose
imperfect, use of the osmolal gap can be helpful IV lorazepam (i.e. >7 mg/hr for >48 hrs)
at the bedside because many clinical labs will be
Figure 21: Indications for determining the serum
able to result a serum osmolality faster than a
osmolal gap.
serum methanol or ethylene glycol level.

The general indications for determining the osmolal gap are listed in Figure 21, and in practice, are
most commonly suspected poisoning with an unknown toxin, and to identify the etiology of an
elevated anion gap in a patient with normal lactate, negative ketones, and normal renal function.
There are a few compounds that can cause an elevated osmolal gap without necessarily causing an
elevated anion gap acidosis (e.g. isopropyl alcohol, diethyl ether, mannitol).

There is an important limitation to using the

osmolal gap when diagnosing methanol
poisoning, demonstrated by Figure 22.
Immediately after an acute ingestion of
methanol, it is quickly absorbed into the
bloodstream, leading to an elevated osmolal
gap. However, as methanol’s metabolite,
formic acid is the actual cause of both the
elevated anion gap acidosis and the symptoms
of poisoning, at the time when the osmolal
gap is elevated, patients may still have a Figure 22: Relationship of the timing of symptoms to
normal anion gap and be asymptomatic. This levels of methanol and formic acid, as well as the
phenomenon has also been described in osmolal and anion gaps, as seen in methanol poisoning.
ethylene glycol poisoning.

By the time enough methanol has been metabolized into formic acid that an acidosis and symptoms
appear, the osmolal gap may be normalized. As a consequence, a clinician should not necessarily rule
out methanol ingestion on the basis of a normal osmolal gap, if the remainder of a patient’s
presentation is consistent with that diagnosis.

Toluene

Toluene is an aromatic hydrocarbon, commonly found in glues, adhesives, shoe

polish, and paint thinner (Figure 23). While there are many organic solvents that
are available for abuse, toluene has among the highest abuse potential, and is
particularly common among children and adolescents where they get exposure
from sniffing glue. It has a complex and incompletely understood effect on
neurochemistry, but at least partially acts as an NDMA receptor antagonist,
similar to PCP, nitrous oxide, and ketamine, which explains its acute effects of
euphoria, loss of inhibition, and amnesia. In higher doses it can result in slurred
speech, ataxia, seizures, and coma. In chronic abuse, patients can develop
Figure 23: Toluene cerebellar dysfunction and dementia, as well as renal tubular acidosis, profound
hypokalemia, and renal failure.

Toluene is metabolized in several steps to hippuric acid, which is both filtered across the glomerular
membrane, as well as secreted in the proximal tubule. It is the hippuric acid that is responsible for the
elevated gap metabolic acidosis. Since it is quickly eliminated via the kidneys, the anion gap acidosis
will only be apparent in blood chemistries are checked very shortly after the toluene exposure, unless
there is concurrent renal dysfunction. Direct measurement of hippuric acid has been advocated as a
means to detect toluene ingestion; however, other investigators have suggested that the sensitivity and
specificity are both too low for this to be considered clinically reliable.

Oxoproline

The naturally occurring metabolic intermediary, 5-oxoproline, is the

most recently discovered cause of an elevated anion gap metabolic
acidosis, and its biochemistry is not yet completely understood
(Figure 24). 5-oxoproline, also known as pyroglutamic acid, is part of
an interesting metabolic derangement seen almost exclusively in
chronic acetaminophen use, with additional risk factors of advanced
age, malnutrition, chronic illness, and alcoholism – all of which are
associated with decreased glutathione production. Figure 24: 5-oxoproline

An understanding of how chronic

Figure 25: The γ-glutamyl cycle, and how it’s affected by chronic
acetaminophen use. See text for details.
acetaminophen use leads to high
levels of 5-oxoproline requires some
knowledge of the incompletely
understood γ-glutamyl cycle (Figure
25). The γ-glutamyl cycle is a
sequence of pathways important in
the transmembrane transport of
amino acids and the breakdown of
xenobiotics (compounds that are not
normally produced or processed by
the body). Within this multibranched
cycle, there is one key enzymatic step
of which to be aware: γ-glutamyl
cysteine synthetase’s catalysis of the
conversion of glutamate to γ-glutamyl
cysteine. Activity of this enzyme is
usually under negative feedback from
glutathione.

However, in patients on chronic acetaminophen, glutathione levels are reduced. This removes the
negative inhibition, leading to excessive γ-glutamyl cysteine, which exceeds the body’s capacity to
convert it into glutathione. Instead, it is shunted through an alternative pathway, one only minimally
used normally, that converts it back to 5-oxoproline. Since conversion of 5-oxoproline to glutamate is
relatively slow, 5-oxoproline begins to accumulate. Even more recently, another slightly revised
hypothesis to the generation of 5-oxoprolinemia-related acidosis proposes that concurrent cysteine
depletion is required for the condition, and that the shunting “backwards” to 5-oxoproline occurs in
the middle of the theoretical two steps of the γ-glutamyl cysteine synthetase reaction, such that there
is a build-up of γ-glutamyl phosphate, instead of γ-glutamyl cysteine.

The symptoms and signs of oxoprolinemia are the non-specific consequences of a severe metabolic
acidosis. Diagnosis requires an organic acid screen of the urine and/or serum, which can take weeks to
be resulted. Acetaminophen levels are typically not elevated in the toxic range.

Paraldehyde

Finally, the last cause of an elevated anion gap acidosis to

mention is paraldehyde (Figure 26). Paraldeyhyde is a sedative
and an anticonvulsant that was previously used as a sleep aid and
in the treatment of status epilepticus and delirium tremens – a
potential fatal complication of alcohol withdrawal. Usage
dropped off in the 1970s and 1980s as safer alternatives such as
benzodiazepines became more popular. Paraldehyde is no longer
manufactured in the United States, and its mention here is only
for historical interest, and because of its frequent inclusion in the
obsolete pneumonic MUDPILES, often used by medical trainees to
remember the etiologies of elevated anion gap acidoses. The Figure 26: Paraldehyde
mechanism by which it induced a metabolic acidosis was never
conclusively determined.

A General Approach to an Elevated Anion Gap Metabolic Acidosis

A diagnostic algorithm for an elevated anion gap metabolic acidosis is shown in Figure 27. The first
steps in approaching an unknown elevated anion gap are to adjust the anion gap to account for
hypoalbuminemia (if present), and confirm that the patient doesn’t have an elevated gap without
acidosis (which has its own, brief differential diagnosis discussed in Chapter 5). Once the presence of
acidosis is confirmed, the next step is to check a serum lactate and ketones. Together, these two tests
will determine the overwhelming majority of causes of an elevated anion gap acidosis. They should
always be checked together as lactic acidosis and ketoacidosis may coexist. If both lactate and ketones
are unremarkable, if the patient has both significant renal dysfunction (arbitrarily defined here as GFR
< 40 mL/min) and a relative modest elevation of the anion gap (AG ≤ 20 mEq/L), renal failure is the
likely explanation. If either of those two criteria is not met, the patient may have a rarer etiology such
as toxic alcohol exposure, oxoproline, or D-lactic acidosis. Although this writer is unaware of any
literature supporting this, in his experience, 99% of elevated anion gap acidoses are attributable to
some combination of lactic acidosis, ketoacidosis, and/or renal failure.
Figure 27: Algorithm for the diagnostic evaluation of an elevated anion gap metabolic acidosis.
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