Anion Gap and Non-Anion Gap Metabolic Acidosis

Etiology

High Anion Gap Metabolic Acidosis

HAGMA can be a life-threatening acid-base disorder resulting from the accumulation of unmeasured anions in the plasma. These unmeasured anions arise from various exogenous toxins or endogenous metabolic products. Recognizing and addressing the underlying cause is critical for management. The following mnemonic, “GOLD MARKeT,” is widely used to categorize the major causes of HAGMA, each associated with distinct pathophysiological mechanisms:

• G – Glycols (ethylene glycol, propylene glycol): Ethylene glycol and propylene glycol are metabolized into organic acids, including glycolic acid, oxalic acid, and lactic acid. These acids increase the unmeasured anion load, resulting in HAGMA. Ethylene glycol toxicity additionally causes renal tubular injury through oxalate crystal deposition, exacerbating acid-base disturbances and renal dysfunction.[1]
• O – Oxoproline (5-oxoproline or pyroglutamic acid): Chronic acetaminophen use or certain antibiotic regimens can disrupt the gamma-glutamyl cycle, leading to the accumulation of 5-oxoproline. This organic acid accumulation is particularly pronounced in patients with malnutrition or chronic illness, contributing to metabolic acidosis with an elevated anion gap.[10] Possible exposures are through IV lorazepam and e-cigarett/e-vapor products.[11][12]
• L – Lactic Acid (L-lactic acidosis): Common in shock, sepsis, or mitochondrial dysfunction, L-lactic acidosis results from increased anaerobic metabolism. Lactic acid is a strong organic acid that contributes significantly to the anion gap.[13] Lactic acidosis can result from decreased oxygen delivery to organs (eg, sepsis, shock, emboli) or impaired oxygen utilization or lactate accumulation (eg, liver failure, kidney insufficiency, genetic abnormalities, metformin, linezolid, cocaine).[13] Notably, at physiologic pH, lactic acid is fully dissociated and exists in the deprotonated form of lactate. So when "lactic acid" levels are measured, the lactate anion is actually being measured. Please see StatPearls' companion reference, "Lactic Acidosis," for further information.
• D – D-lactic acid: D-lactic acidosis arises from abnormal bacterial fermentation of carbohydrates in the gastrointestinal tract, notably in patients with short bowel syndrome. D-lactate, an isomer not efficiently metabolized by humans, accumulates and leads to HAGMA.[14]
• M – Methanol: Methanol poisoning results in the hepatic metabolism of methanol to formic acid, a highly toxic metabolite. The accumulation of formic acid causes increased unmeasured anions, contributing to metabolic acidosis and clinical manifestations such as visual disturbances and central nervous system depression.[15]
• A – Aspirin (salicylates): Salicylates uncouple oxidative phosphorylation, leading to lactic acid and ketoacid accumulation, causing HAGMA. Early toxicity often presents with concurrent respiratory alkalosis due to respiratory center stimulation.[16]
• R – Renal failure and rhabdomyolysis: Impaired renal function diminishes the excretion of sulfate, phosphate, and other organic acids, causing retention of unmeasured anions and metabolic acidosis. Rhabdomyolysis releases intracellular acids and phosphate, often leading to acute kidney injury.[17]
• Ke – Ketones (diabetic, alcoholic, starvation ketoacidosis): In states of insulin deficiency or prolonged fasting, ketone bodies (acetoacetate and β-hydroxybutyrate) accumulate. These acidic metabolites increase the anion gap and contribute to metabolic acidosis in diabetic ketoacidosis, alcoholic ketoacidosis, and starvation.[18]
• T - Toluene:  Toluene can cause gap or non–anion gap metabolic acidosis. Most commonly, toluene causes non–anion gap metabolic acidosis, but it can also cause anion gap metabolic acidosis less commonly. Toluene typically causes a distal renal tubular acidosis picture; however, related to hippurate accumulation, toluene can also produce an anion gap metabolic acidosis. Toluene toxicity can occur from occupational exposure to paint, paint thinner, and petrol, as well as from abuse of glue sniffing.[19][20]

Metformin presents a well-recognized cause of lactic acidosis. Used for over 60 years, metformin is one of the most commonly prescribed drugs for diabetes and prediabetes. Due to primarily being cleared by the kidneys, metformin is contraindicated when eGFR is lower than 30 mL/min/1.73 m². Metformin blocks aerobic glycolysis in the mitochondria, thereby increasing anaerobic glycolysis and lactic acid accumulation.[21] The risk of this may be increased with concurrent use of sodium-glucose cotransporter 2 (SGLT2) inhibitors.[22] Please see StatPearls' companion reference, "Metformin-Associated Lactic Acidosis."

 Another mnemonic for anion gap metabolic acidosis differential is "CAT MUDPILES" which represents the following etiologies:

• C: Cyanide and carbon monoxide poisoning
• A: Arsenic
• T: Toluene
• M: Methanol, Metformin
• U: Uremia
• D: Diabetic ketoacidosis
• P: Paraldehyde
• I: Iron, INH
• L: Lactate
• E: Ethylene glycol
• S: Salicylates

Non–Anion Gap Metabolic Acidosis

Non–anion gap metabolic acidosis is primarily caused by the loss of bicarbonate or the gain of chloride, and the main causes of this condition are diarrhea and renal tubular acidosis. Additional and less common etiologies include Addison disease, ureterosigmoid or pancreatic fistulas, carbonic anhydrase use, and chronic laxative use.[23] Other exogenous causes include the addition of hydrochloric acid (or substances with HCl as a metabolite), which causes a compensatory loss of bicarbonate, TPN administration, or administration of normal saline as described below.[13] Rarely are genetic syndromes associated with renal tubular acidosis.[23] 

Renal tubular acidosis primarily causes NAGMA by decreased ammonium (NH₄) production, which is needed for bicarbonate regeneration. In the absence of sufficient NH₄, anions produced from metabolism and dietary intake are excreted with Na or K, causing avid retention of Na and Cl by the kidney. The Cl replaces the lost HCO₃, resulting in hyperchloremic metabolic acidosis. A similar mechanim occurs with the presence of toluene or ketoacidosis (metabolized to hippurate and ketoanions) where these anions are excreted with Na or K.[24]

Gastrointestinal causes of NAGMA include loss of pancreatic, duodenal, biliary, or intestinal fluids, which are high in HCO₃. Of the gastrointestinal causes of NAGMA, diarrhea is by far the most common, causing a lack of HCO₃ reabsorption and loss through the intestinal tract. Secretory diarrhea causes a higher incidence of NAGMA than inflammatory diarrhea, as it contains a higher concentration of HCO3. Diversion of the ureters to the ileum or sigmoid colon after bladder removal (eg, bladder cancer) can also cause NAGMA, as the intestine will reabsorb NH₄ and Cl and secrete HCO₃.[23][24]

A common cause of non–anion gap metabolic acidosis is the administration of large amounts of normal saline. Examples would be intraoperative administration, shock, or burn victims.[25][26][27] This is related in part to the chloride load (the concentration in normal saline being 154 mEq/L, while about 100 to 106 mEq/L in plasma), as well as a dilutional effect, since normal saline contains no bicarbonate. NAGMA is also common in children with diarrhea who receive large volumes of normal saline.[28] Normal saline is associated with hyperchloremic metabolic acidosis in both hospitalized and healthy individuals, as well as children and adults. In addition, hyperchloremia itself is associated with increased mortality.[29][30] Multiple studies have shown that infusion of high-chloride fluid reduces renal perfusion through vasoconstriction and also decreases GFR. Some evidence also suggests that chloride-rich fluids may impair coagulation. For these reasons, many experts now suggest using fluids with a more physiologic chloride concentration, eg, lactated Ringer's or plasmalyte.[26][31]

A rare cause of non–anion gap metabolic acidosis is cholestyramine. This medication is a bile acid sequestrant used for hypercholesterolemia. It exchanges chloride anions for bile acids in the ileum, resulting in the excretion of bile acids through the feces. This exchange results in the excretion of bicarbonate and the reabsorption of chloride through the duodenal apical brush border bicarbonate/chloride antiporter. Usually, the kidney can compensate for this by reabsorbing bicarbonate; however, in settings of renal insufficiency or aldosterone insensitivity (or antagonism), these mechanisms are not available, and metabolic acidosis will ensue.[32][33]

Total parenteral nutrition (TPN) can also cause non–anion gap metabolic acidosis. If TPN does not contain acetate as a buffer, no source of bicarbonate. In addition, some amino acids (particularly arginine and lysine) are metabolized to HCl.[23][24]

Addison disease, or medications that block the action of aldosterone, can cause hyperchloremic metabolic acidosis. Aldosterone acts on the epithelial Na channel, located on the apical side of the distal convoluted tubule and collecting duct of the nephron, and the basolateral Na/K ATPase pump. Through these mechanisms, sodium is reabsorbed from the tubular lumen, and potassium and hydrogen ions are excreted. The resulting pattern is similar to Type IV RTA. Acquired hypoaldosteronism may be more common than previously thought, especially in hospitalized patients aged older than 65 and patients on multiple medications.[34][35]

Epidemiology

HAGMA is a prevalent acid-base disturbance among critically ill patients. Studies show that HAGMA is commonly encountered in intensive care units and is often related to conditions, eg, lactic acidosis, ketoacidosis, renal failure, toxin ingestion, and many other causes. Although the majority of ICU patients present with metabolic alkalosis, those with metabolic acidosis had higher mortality. Lactic acidosis, sepsis, and multiorgan failure were contributing factors.[36]

The clinical significance of HAGMA is underscored by its association with increased mortality rates. Elevated anion gap levels correlate strongly with higher in-hospital, 30-day, and 90-day mortality in critically ill patients, highlighting their prognostic value.[37] The presence of unmeasured anions, eg, lactate and ketones, reflects underlying pathophysiological states (eg, sepsis and renal failure).[38] Chronic acetaminophen use or certain antibiotic regimens can disrupt the gamma-glutamyl cycle, leading to the accumulation of 5-oxoproline. This organic acid accumulation is particularly pronounced in patients with malnutrition or chronic illness, contributing to metabolic acidosis with an elevated anion gap.

In terms of NAGMA, a comprehensive review found that 19% to 41% of patients in ICU settings demonstrated non–anion gap metabolic acidosis. In addition, 20% to 55% of people with chronic renal insufficiency had a NAGMA.[24]

Pathophysiology

High Anion Gap Metabolic Acidosis

Anion gap

The anion gap compares sodium concentration (and sometimes potassium) with the sum of chloride and bicarbonate concentrations. The main negatively charged anion causing the anion gap is albumin. Calculating the anion gap helps distinguish between HAGMA and NAGMA, thereby aiding in determining the etiologies. The change in anion gap should then be compared to the change in bicarbonate to evaluate for further acid-base disorders. Whenever possible, the change in anion gap should be measured against the patient's baseline anion gap, which is typically obtained when the patient is relatively healthy.[24]

Compensatory respiratory alkalosis

Metabolic acidosis causes a compensatory hyperventilation response within 12 to 24 hours, which can be calculated through Winter's formula: PaCO₂ = (1.5 x HCO₃ +8 ) ±2. The minimum PaCO2 level that can be reduced to is 8 to 12 mEq/L. Conventionally, the bicarbonate level used is from a venous blood sample, which is generally 2 to 4 mEq/L higher than an arterial sample.[8] An anion gap >18 almost always indicates the presence of an organic acid. Rarely, the accumulation of phosphates and sulfates in kidney failure can create a large anion gap, but the gap is rarely >18.[13]

Hypoalbuminemia

The albumin level must also be taken into account because albumin is a negatively charged protein; therefore, albumin loss leads to the retention of negatively charged ions, eg, bicarbonate and chloride, which can underestimates the severity of the anion gap.[39] For each 1 g/100 mL below the normal value of 4.5 g/100 mL, the anion gap falls by about 2.5 mEq/L. The following formula can estimate this correction: 

[anion gap](corrected) = [anion gap](measured) + 2.5 × (4.0 - [albumin]) [8][40]

This correction ensures more accurate identification of HAGMA, particularly in patients with hypoalbuminemia due to conditions, eg, sepsis, malnutrition, liver disease, or chronic illness.[38] For example, a patient with a measured anion gap of 10 and an albumin of 2.0 g/dL would have a corrected anion gap of 15, indicating a true HAGMA that might otherwise be overlooked. 

Delta/delta or delta gap

After calculating the anion gap and determining that the patient has HAGMA, the next critical step is to calculate the delta gap (also called the delta-delta) to evaluate for mixed acid-base disorders. The delta gap compares the change in the anion gap to the change in serum bicarbonate, based on the principle that in pure HAGMA, the increase in the anion gap should be approximately equal to the decrease in bicarbonate. The delta gap ratio is calculated as: Δanion gap / ΔHCO₃ = (corrected anion gap − 12) / (24 − measured HCO₃), where 12 mEq/L is the upper limit of the normal anion gap and 24 mEq/L is the normal bicarbonate level. The following interpretations of this ratio helps identify concurrent acid-base disturbances:

• A ratio between 1 and 2 generally indicates a pure HAGMA.
• A ratio <1 suggests a concurrent normal anion gap (non–anion gap) metabolic acidosis.
• A ratio >2 indicates an additional metabolic alkalosis or preexisting elevated bicarbonate (see Image. Algorithm for Assessing Anion Gap and Non–Anion Gap Acidosis).

Calculating the delta gap ratio is crucial, particularly in critical care settings where multiple disorders may coexist.[7][9][41]

Osmolar gap

The osmolar gap is a valuable tool in evaluating HAGMA, particularly in cases of suspected toxic alcohol ingestion. Osmolar gaps can also be caused by iatrogenic factors, eg, radiocontrast administration, sorbitol (from TPN), maltose, dextrose, or mannitol. Osmolar gap is calculated by subtracting the calculated serum osmolality from the measured serum osmolality, using the following formula: 

Calculated osmolality = 2 × (Na + K) + (glucose ÷ 18) + (BUN ÷ 2.8) + (ethanol ÷ 4.6)

A normal osmolar gap is typically <10 mOsm/kg, while an elevated gap (>10 mOsm/kg) suggests the presence of exogenous osmoles, including methanol, ethylene glycol, or isopropanol.[8] The coexistence of HAGMA with an elevated osmolar gap is highly suggestive of toxic alcohol ingestion. Each toxic alcohol has characteristic metabolites and the following clinical manifestations: 

• Methanol is metabolized to formic acid and presents with altered mental status (AMS), blurry vision, dilated pupils, and papilledema.
• Ethylene glycol forms oxalic acid and can cause AMS, cranial nerve palsies, flank pain, hematuria, hypocalcemia with tetany, and calcium oxalate crystals (envelope shaped crystals) leading to acute kidney injury (AKI).
• Propylene glycol is converted to lactic acid and may cause AKI and liver injury.
• Diethylene glycol is metabolized to diglycolic acid and presents with AKI, nausea/vomiting, hepatitis, pancreatitis, neuropathy, AMS, and elevated lactate.
• Isopropyl alcohol is converted to acetone and typically causes AMS, fruity breath, pancreatitis, and elevated lactate with a normal or mildly elevated anion gap.
• Ethanol is metabolized to acetaldehyde and may result in ketoacidosis, lactic acidosis, and metabolic alkalosis due to vomiting.

Despite its utility, the osmolar gap has limitations—it may be normal early in intoxication, unreliable in rapidly evolving cases, and confounded by rare toxins like bromide.[42][43] Accurate lab interpretation and clinical context are essential, as other conditions like diabetic ketoacidosis (DKA) or sepsis can also affect the osmolar and anion gaps.

Nonanion Gap Metabolic Acidosis

In nonanion gap metabolic acidosis, gastrointestinal and renal losses of bicarbonate can be distinguished via urine anion gap analysis:

• Urine anion gap = Urine Na + Urine K – Urine Cl, if urine pH is <6.5
• Urine anion gap = Urine Na + Urine K - (Urine Cl + Urine HCO3), if urine pH is >6.5 [44]

The urine anion gap can help estimate the urinary ammonium. The urinary anion concentration decreases and can become negative if ammonium (a cation) is elevated as part of a normal adaptive renal response to an extrarenal etiology of metabolic acidosis, eg, diarrhea or another gastrointestinal source. When the urine anion gap is positive, this suggests decreased ammonium excretion, which, in the presence of metabolic acidosis, suggests renal impairment such as distal renal tubular acidosis or chronic kidney disease.[44] The urine pH is often not a reliable indicator of urine acidification, as the body will produce more ammonia to buffer the excess hydrogen in the setting of prolonged metabolic acidosis.[44]

Histopathology

Microscopy has limited utility in the evaluation of metabolic acidosis; however, an important exception is the assessment for ethylene glycol ingestion. Ethylene glycol is metabolized into toxic compounds, including oxalate, which can bind calcium to form calcium oxalate crystals. At sufficiently high toxic doses, calcium oxalate monohydrate crystals can deposit in tissues such as the kidneys and brain, and precipitate in the urine.[42] 

On urine microscopy, these calcium oxalate monohydrate crystals appear as dumbbells, spindles, ovals, or “picket fence” shapes.[45] These can be distinguished from calcium oxalate dihydrate crystals, which are classically octahedral and described as “envelope-shaped”.[3] Identifying these crystals in the urine can support the diagnosis of ethylene glycol poisoning, particularly when combined with clinical and laboratory findings, eg, elevated anion and osmolar gaps (see Image. Calcium Oxalate Dihydrate Crystals).[46]

History and Physical

Clinical History

A detailed patient history plays a crucial role in diagnosing metabolic acidosis in both hospitalized and nonhospitalized individuals. Clinicians must inquire thoroughly about medication use, including over-the-counter and ingested substances. Identifying a history of diabetes, chronic alcohol use, attempted self-harm, and gastrointestinal disturbances such as diarrhea remains essential. For hospitalized patients, documentation should include whether large volumes of normal saline or other medications were administered in the emergency department.

Comprehensive symptom assessment contributes significantly to diagnostic accuracy. Although often nonspecific, symptoms of acidosis, including anorexia, fatigue, headache, nausea, and vomiting, warrant attention. Clinicians should specifically ask about gastrointestinal symptoms, eg, diarrhea or vomiting. Signs of renal insufficiency, including nocturia, pruritus, or oliguria, should be explored.[18][47] Additionally, clinicians must consider symptoms suggestive of diabetes, eg, polyuria or polydipsia.

Physical Examination

Physical examination should include a careful review of vital signs. Hypotension may suggest volume depletion from gastrointestinal losses or a hypoaldosterone state. The presence of Kussmaul respirations—deep, labored breathing—often indicates a compensatory response to metabolic acidosis. Findings, eg, dry mucous membranes and a characteristic ketotic, chemical odor on the breath, may suggest diabetic ketoacidosis. Asterixis and changes in mental status can reflect renal insufficiency.[48] In advanced stages, metabolic acidosis may present with respiratory failure, altered consciousness, arrhythmias, and hemodynamic instability.

Evaluation

Metabolic acidosis is primarily diagnosed through a thorough history and laboratory values in plasma and urine. Initial studies that are conducted include the following:

• Basic metabolic panel (BMP)
• ABG (of VBG if the patient is not septic or severely hypoperfused)
• Lactate level
• Plasma and urine osmolarity
• Urine sodium, potassium, chloride, and bicarbonate

Evaluation of metabolic acidosis begins with assessing the pH on either a VBG or ABG analysis. A low pCO2 level in the setting of low pH indicates the presence of metabolic acidosis. Although the body initiates compensatory mechanisms, these responses rarely normalize the serum pH. Following this initial assessment, clinicians should calculate the anion gap, regardless of whether the serum pH appears close to normal. This calculation must be adjusted for the patient’s albumin level to ensure accuracy.

An elevated corrected anion gap requires further analysis, beginning with evaluation of the delta gap to assess for the presence of concurrent metabolic processes. Additionally, the osmolar gap should be measured to identify potential toxic ingestions or unmeasured solutes.

When the corrected anion gap remains within the normal range, additional urine studies become necessary. Assessment should include the urine anion gap, urine pH, and urine electrolyte concentrations. These values help differentiate between renal and gastrointestinal causes of NGMA. If the patient reports urinary, abdominal, or groin pain suggestive of renal colic, abdominal computed tomography imaging may be indicated, as nephrolithiasis may underlie or contribute to the acid-base disturbance.

Treatment / Management

Metabolic Acidosis Management

Management of metabolic acidosis begins with prompt identification and treatment of the underlying cause, eg, sepsis, while providing supportive measures including intravenous fluid resuscitation and respiratory support.[49] In cases of severe acidosis with pH below 7.1, the use of intravenous sodium bicarbonate may be considered, although its routine administration remains controversial. Findings from the BICAR-ICU multicenter randomized controlled trial demonstrated no significant mortality benefit from bicarbonate therapy in patients with severe metabolic acidosis (pH <7.2), except in those with concurrent acute kidney injury.[50](A1)

The cautious use of sodium bicarbonate stems from its potential adverse effects, including hypernatremia, hypocalcemia, intracellular acidification, increased lactate production, and reduced myocardial contractility. Continuous renal replacement therapy (CRRT) also provides limited effectiveness in clearing lactic acid, reinforcing the importance of supportive care and targeted treatment of the underlying condition in cases of lactic acidosis.[13] 

Etiology-specific management

Treatment strategies must be tailored to the specific etiology of metabolic acidosis.

Thiamine is commonly administered in patients with lactic acidosis. When metformin-induced lactic acidosis occurs, hemodialysis may be required. Methanol undergoes hepatic metabolism to form formaldehyde, a toxic compound. Effective treatments for methanol toxicity include fomepizole—or ethanol if fomepizole is unavailable—and hemodialysis when methanol levels exceed 500 mg/L, or when severe acidemia, visual disturbances, obtundation, kidney failure, or hemodynamic instability are present. Ethylene glycol poisoning requires the same therapeutic approach.[13][51]

Management of diabetic ketoacidosis focuses on insulin therapy, continued until anion gap closure occurs. Treatment does not begin with bicarbonate, even when acidosis is present. Potassium repletion and volume restoration remain essential components of therapy. Euglycemia must be achieved before correction is considered complete. Alcoholic ketoacidosis requires thiamine supplementation and correction of electrolyte imbalances, along with volume repletion. Studies have shown no improvement in outcomes with intravenous bicarbonate administration in diabetic ketoacidosis.[13] Current guidelines from the American Diabetes Association recommend IV bicarbonate only when serum pH falls below 6.9.[52](B2)

Salicylate toxicity, which typically presents with a combination of respiratory alkalosis and metabolic acidosis, requires rapid gastrointestinal decontamination with activated charcoal and alkalinization of the serum and urine using intravenous bicarbonate. This approach helps reduce central nervous system penetration and enhances renal excretion. Blood pH must be monitored closely during treatment to avoid alkalemia (pH >7.6). Hemodialysis becomes necessary when salicylate concentrations surpass 100 mg/dL or when patients present with obtundation or pulmonary edema.[13]

Differential Diagnosis

Differential diagnoses that should also be considered in patients with metabolic acidosis:

• Compensation for respiratory alkalosis
• Hyperkalemia
• Anion gap acidosis uncorrected for albumin level
• Hemolysis
• Laboratory errors

Prognosis

The prognosis of metabolic acidosis largely depends on the underlying cause, the severity of acidemia, and the timeliness of diagnosis and treatment. When the primary etiology is promptly identified and effectively managed—eg, in diabetic ketoacidosis, sepsis, or toxic ingestions—patients often recover fully with minimal long-term sequelae. However, delayed treatment or severe acidemia (pH <7.1) significantly increases the risk of complications, including organ failure, cardiac arrhythmias, hemodynamic instability, inflammation, and death.[27]

Acute metabolic acidosis with a pH around 7.20 has been associated with mortality rates exceeding 50% if not promptly corrected.[38] Patients with comorbidities such as chronic kidney disease (CKD) or advanced liver disease typically have a worse prognosis. In particular, studies have shown that an increased anion gap in CKD patients correlates with higher all-cause mortality and faster progression to kidney failure.[53] Overall, early recognition and coordinated interprofessional care are critical to improving outcomes in metabolic acidosis.[54]

Complications

If not promptly recognized and treated, metabolic acidosis can lead to life-threatening complications. Severe acidemia (pH <7.1) may impair myocardial contractility, cause hypotension, and significantly increase the risk of cardiac arrhythmias. Respiratory muscle fatigue can occur due to sustained compensatory hyperventilation.

In cases involving toxic ingestions (eg, methanol or ethylene glycol), complications may include irreversible organ damage, eg, blindness, acute kidney injury, or neurologic impairment. Persistent or recurrent metabolic acidosis may worsen outcomes in patients with diabetes or chronic kidney disease. Ultimately, death is a potential complication, particularly in critically ill patients or those with delayed treatment.[55]