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Metformin-induced lactic acidosis with emphasis on the
anion gap
Britton Blough, MD, Amber Moreland, MD, and Adan Mora Jr., MD
The presence of an anion gap in a diabetic patient, especially if associated with evidence of compromised renal function, should prompt clinicians to consider metformin as a contributing factor. This consideration
is especially important in patients with severe anion gaps associated
with lactic acidosis out of proportion to the patient’s clinical presentation.
M
easurement of serum electrolytes and determination of acid-base status is beyond routine in today’s
clinical practice. The importance of recognizing and
treating disturbances in normal physiology cannot be
overstated, as this information can provide clues to the existence
of many reversible, yet if left untreated fatal, disease processes.
The most commonly used scenario for calculating the serum
anion gap (AG) is determining the etiology of metabolic acidosis
(Table 1). Disturbances of the AG can be seen in a variety of conditions, and if accurately recognized can yield critical diagnostic
information. Presented is a case of compound AG acidosis.
850 mg twice a day, Novolin R sliding scale, and metoprolol
tartrate 100 mg daily.
On examination, her blood pressure was 100/54 mm Hg;
heart rate, 123 beats per minute; respiratory rate, 22 breaths
per minute; and temperature, 97.9°F. She was intubated and
sedated. She was tachycardic without precordial murmurs and
tachypneic on the ventilator with coarse breath sounds bilaterally. Her abdomen was soft with hypoactive bowel sounds
and without masses. She had palpable pulses that were equal
bilaterally. Key laboratory data are outlined in Table 2. A transthoracic echocardiogram showed an ejection fraction of 75%,
a dilated pulmonary artery, and a suggestion of moderate pulmonary hypertension with a right ventricular systolic pressure
of 44.4 mm Hg.
The patient was admitted to the intensive care unit for
refractory shock, acute respiratory failure, oliguric acute
kidney injury, severe AG metabolic acidosis, and presumed
Table 2. Principal laboratory findings
CASE PRESENTATION
A 71-year-old woman with type 2 diabetes mellitus, hypertension, and coronary artery disease presented to the emergency
department because of altered mental status. She had been seen
in an emergency department 9 days earlier for nausea, emesis, diarrhea, and abdominal pain when her creatinine was
1.8 mg/dL and AG was 20 mEq/L. She was discharged home
with antiemetics. Her symptoms persisted and she returned via
paramedic transport. She was intubated shortly upon arrival
secondary to a decreased level of consciousness and concern for
airway protection. Her family denied knowledge of hematemesis, melena, fevers, or chills. Her home medications included
potassium 20 mEq daily, Lasix 80 mg twice a day, metformin
Table 1. Causes of increased anion gap metabolic acidosis
L-lactic acidosis
D-lactic acidosis
Ketoacidosis
Alcohol
Methanol
Proc (Bayl Univ Med Cent) 2015;28(1):31–33
Propylene glycol
Aspirin overdose
Toluene
Pyroglutamic acid
Ethylene glycol
Test
Result
Chemistry
Test
Result
Hematology
Sodium (mEq/L)
142
WBC (K/uL)
8.1
Potassium (mEq/L)
3.6
Chloride (mEq/L)
87
Hemoglobin (g/dL)
11.3
CO2 (mEq/L)
8
pH
BUN (mg/L)
53
pCO2 (mm Hg)
35
Creatinine (mg/dL)
3.0
pO2 (mm Hg)
288
Arterial blood gas
6.85
Anion gap (mEq/L)
47
Lactate (mmol/L)
30.5
Albumin (g/dL)
3.7
Lipase (U/L)
3211
Beta-ketone (mmol/L)
3.4
BUN indicates blood urea nitrogen; CO2, carbon dioxide; pCO2, partial pressure of
carbon dioxide; pO2, partial pressure of oxygen; WBC, white blood cells.
From the Department of Internal Medicine, Baylor University Medical Center at
Dallas.
Corresponding author: Adan Mora, Jr., MD, Department of Internal Medicine,
Division of Pulmonary and Critical Care Medicine, Baylor University Medical
Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: adam.mora@
BaylorHealth.edu).
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pancreatitis. Her blood was cultured, and she was started on
empiric antibiotics. After fluid resuscitation, her mean arterial
pressure remained low, requiring norepinephrine and stress
dose steroids. Her severe lactic acidosis was refractory to a
bicarbonate drip. She required an elevated compensatory high
minute ventilation and eventually continuous veno-venous
hemodialysis. While her lactic acidosis slowly down-trended,
it remained abnormally high relative to the degree of her hypoperfused state. A metformin level ordered on admission
returned as 2.7 mcg/mL. The usual therapeutic metformin
blood level is in the range of 0.5 to 2.5 mcg/mL (1).
The patient became progressively hypotensive despite aggressive measures. No source of infection could ever be identified
and all cultures remained negative. A mesenteric Doppler was
unable to visualize vascular structures due to body habitus, and
a contrast study could not be performed due to the patient’s
severe iodine allergy. Her respiratory status deteriorated with
decreasing lung compliance. On day 6 of her hospitalization,
she remained unstable and a decision was made by the family to withdraw life-sustaining therapy. The family declined a
postmortem examination.
DISCUSSION
In their article initially describing the clinical implications
of the AG, Emmett and Narins defined the AG and detailed its
utility in evaluating a patient’s acid-base status (2). The serum
AG is calculated from the laboratory measurement of electrolytes
and provides important information regarding a patient’s acidbase status. By definition, the AG is the difference between the
measured serum cations and anions: (Na + K) – (Cl + HCO3).
Since the influence of potassium in regards to the AG is minimal,
the equation is accepted as simply the following: (Na) – (Cl +
HCO3).
In the hospitalized patient, one of the most common causes
of metabolic acidosis is lactic acidosis, which produces an unmeasured anion resulting in an elevated AG. Lactate is formed
during gluconeogenesis as a product of pyruvate metabolism.
This formation requires the presence of the catalytic enzyme
lactate dehydrogenase to convert nicotinamide adenine dinucleotide hydrate into nicotinamide adenine dinucleotide.
Lactic acid in the serum is buffered by bicarbonate to lactate,
which in turn is converted back to pyruvate in the liver and
kidney. An increase in lactic acid can thus be thought of as either
an overproduction of lactate in the serum or an underutilization of lactate by the liver. The former most commonly results
from an inhibition of oxidative metabolism that decreases the
available ATP and shunts the reaction to formation of additional lactate. The types of lactic acidosis can further be broken
down into types A and B (Table 3). In general, type A can be
attributed to tissue hypoxia or global hypoperfusion, as seen
in circulatory collapse or in the setting of increased anaerobic
activity (3). Type B lactic acidosis occurs in the absence of
tissue hypoperfusion and comprises a heterogeneous group of
etiologies, including intoxications, liver failure, malignancy,
rare hereditary enzyme deficiencies, and certain medications,
as seen in our patient (4).
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Table 3. Types of lactic acidosis
Type
Etiology
A
Shock (septic, cardiogenic, hypovolemic)
Hypoxemia
Severe anemia
Carbon monoxide
B
Mitochondrial defects
Cyanide toxicity
Beriberi (thiamine deficiency)
Drugs (metformin, salicylates, nucleoside reverse transcriptase
inhibitors)
Liver failure
Ethanol intoxication
Metformin-associated lactic acidosis can occur acutely in
an overdose but typically has a more gradual onset in patients
with hepatic or renal dysfunction due to decreased excretion. It
often presents with nausea, abdominal pain, tachycardia, hypotension, and tachypnea (5). The lactic acidosis from metformin
is primarily type B. In an overdose, the lactic acidosis can be
compounded by type A when the drug’s lactic acid accumulation leads to cardiovascular collapse, tissue hypoperfusion, and
hepatic dysfunction.
In 1918, guanidine, the active ingredient of the plant Galega
officinalis, demonstrated hypoglycemic effects in animals and led
to the development of the class of drugs known as biguanides.
These drugs act to reduce blood glucose levels and insulin concentrations by suppressing basal hepatic gluconeogenesis and
improving peripheral tissue insulin sensitivity; however, their
association with the development of lactic acidosis has been well
reported (5). The biguanides contain two guanide molecules
linked together with an elimination of an amino group. In the
1920s, several synthetic biguanides were used clinically, but
their toxicities limited their use (6, 7). Metformin, currently the
only biguanide available in the United States, is less associated
with lactic acidosis and was not approved until 1995 by the US
Food and Drug Administration (8). Several other more potent
biguanides were also developed, including phenformin and buformin, but these were discontinued in many countries by the
late 1970s secondary to the development of lactic acidosis (6, 7).
Metformin lowers blood glucose in multiple ways, including suppression of hepatic gluconeogenesis, increased peripheral
insulin-mediated glucose uptake, decreased fatty acid oxidation,
and increased intestinal glucose consumption (7). Metformin
reaches maximal plasma concentration approximately 2 hours
after ingestion, and its half-life ranges from 2.5 to 4.9 hours.
Approximately 90% of it is eliminated in the urine in 12 hours
(7). The most common side effects of metformin use are gastrointestinal, including diarrhea, nausea, vomiting, abdominal
bloating, and anorexia. These side effects may occur in 20% to
30% of patients receiving this drug, usually at the onset of therapy,
but rarely persist (9). Current contraindications for metformin
use include chronic kidney disease (creatinine levels >1.5 mg/dL
Baylor University Medical Center Proceedings
Volume 28, Number 1
in men and >1.4 mg/dL in women), liver disease, heart failure,
age >65, pulmonary disease, use of intravenous contrast agents
within 48 hours, or any condition with relative tissue hypoxia (9).
Lactic acidosis is a rare but serious side effect of metformin
use. The estimated incidence is 6 cases per 100,000 patient-years
(9). The presence of metformin-associated hyperlactatemia in
critical care patients has been associated with a mortality >30%
(10).
Metformin inhibits mitochondrial cellular respiration,
which increases anaerobic metabolism and lactate levels (3).
This effect is most profound in the gut due to its affinity for
intracellular proteins in the gastrointestinal tract (11). The
pathophysiology of lactic acidosis from metformin is likely due
to inhibition of gluconeogenesis by blocking pyruvate carboxylase, the first step of gluconeogenesis, which converts pyruvate
to oxaloacetate. Blocking this enzyme leads to accumulation
of lactic acid. Biguanides also decrease hepatic metabolism of
lactate and have a negative ionotropic effect on the heart, both
of which elevate lactate levels (11). Metformin dose, along with
the duration of exposure from accumulation in patients with
decreased renal clearance, can cause lactic acidosis (3). Gradual
toxicity, as demonstrated in our patient, is usually multifactorial
and related to the drug’s decreased renal excretion. The lipophilic nature of the drug allows for its accumulation, causing a
severe lactic acidosis but only minimally elevated serum drug
levels (12). As previously mentioned, while there is an accepted
therapeutic range of metformin, the amount of drug required to
cause toxicity is unclear (3). A study by Lalau et al demonstrated
that the lactic acidosis seen is not necessarily due exclusively
to metformin accumulation (13). This leads to the conclusion
that a mixed type of lactic acidosis (A and B) is seen in most
cases, and it is the severity of the underlying disease process that
determines the overall prognosis (14).
Hemodialysis continues to be the definitive treatment for
metformin accumulation leading to toxicity, as 90% of the drug
is eliminated via the kidneys. A report by Pearlman et al demonstrated through serial measurements of metformin levels during
hemodialysis that the drug can be dialyzed; however, there can be
a rebound phenomenon due to its lipophilic properties and increased tissue binding (15). Despite metformin having minimal
protein binding, hemodialysis does not remove large amounts
of the drug due to its large volume of distribution. However,
hemodialysis does improve acid-base status and clinical outcomes in patients with severe lactic acidosis due to metformin.
January 2015
Our patient did not have extremely high plasma concentrations of metformin in the setting of profound shock. This leads
us to the conclusion that she likely had a slow accumulation
over a period of days and likely stopped taking the medication
at some point prior to her arrival due to her illness. Her severe
lactic acidosis was likely of a mixed type from the combination
of tissue hypoxia as well as metformin toxicity, both of which
contributed to her overall mortality. Although metformin does
cause a lactic acidosis, this by itself is not an independent predictor of mortality in these patients.
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Metformin-induced lactic acidosis with emphasis on the anion gap
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