What are the causes of metabolic acidosis?

Causes of Metabolic Acidosis

Metabolic acidosis results from either accumulation of unmeasured organic anions (high anion gap) or loss of bicarbonate (normal anion gap), with the anion gap calculation being the essential first step in determining etiology. 1, 2

Classification by Anion Gap

High Anion Gap Metabolic Acidosis

The presence of unmeasured organic anions characterizes high anion gap acidosis, with the following major causes:

Lactic Acidosis

• Primary contributor in shock states, resulting from inadequate oxygen delivery to tissues and tissue hypoperfusion 1, 3
• Lactate levels serve as a key indicator of tissue hypoxia and correlate with mortality 3
• Serial lactate measurements provide critical information about shock severity and treatment response 1, 3

Ketoacidosis

• Diabetic ketoacidosis (DKA) is characterized by hyperglycemia, arterial pH <7.35, low bicarbonate, and positive serum/urine ketones 4, 1
• The pathogenesis involves insulin deficiency coupled with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), leading to lipolysis and unrestrained hepatic fatty acid oxidation to ketone bodies (β-hydroxybutyrate and acetoacetate) 4
• Alcoholic ketoacidosis is distinguished from DKA by lower plasma glucose levels and clinical history of alcohol use 1
• Starvation ketosis presents with serum bicarbonate >18 mmol/L and mildly elevated glucose 1

Renal Failure

• Chronic kidney disease impairs the kidney's ability to excrete hydrogen ions and synthesize ammonia, leading to acid accumulation 1, 5
• CKD presents as high anion gap acidosis due to impaired renal acid excretion 1

Toxic Ingestions

• Salicylate, methanol, and ethylene glycol poisoning cause high anion gap metabolic acidosis 1, 6
• The osmolal gap can be elevated in methanol, ethylene glycol, and propylene glycol ingestions 1
• Drug-induced metabolic acidosis can occur with antiretroviral therapy, biguanides (metformin), and various other pharmaceutical compounds 7, 8

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

Bicarbonate Loss Mechanisms

• Gastrointestinal bicarbonate loss from severe diarrhea, which is often accompanied by significant bicarbonate depletion 6, 9
• Renal tubular acidosis (types I, II, and IV) represents renal inability to excrete dietary H+ load or reabsorb bicarbonate 1, 7, 9
• Recovery phase from diabetic ketoacidosis can present with normal anion gap acidosis 5

Drug-Induced Causes

• Medications causing renal tubular acidosis or impaired bicarbonate reabsorption 7
• Administration of hyperalimentation solutions 7

Special Clinical Contexts

Septic Shock

• Exhibits complex metabolic acidosis with multiple contributors, including lactic acidosis, hyperchloremic acidosis, and increased strong ion gap 1, 3

Dietary Factors in Chronic Acidosis

• Western diet high in animal protein (containing sulfur-containing amino acids) and low in fruits/vegetables creates an imbalance between nonvolatile acid production and available alkali 1, 5
• This dietary pattern can lead to chronic low-grade metabolic acidosis, particularly in CKD patients 1, 5

Diagnostic Approach Algorithm

Step 1: Calculate Anion Gap

• Anion gap = Na+ - (Cl- + HCO3-) 2, 9
• High anion gap (>12 mEq/L) indicates unmeasured anions present 2, 9

Step 2: If High Anion Gap Present

• Measure blood lactate to assess for lactic acidosis 1, 3
• Check serum ketones (β-hydroxybutyrate, acetoacetate) to distinguish ketoacidosis 1
• Calculate osmolal gap if toxic ingestion suspected 1
• Assess renal function (BUN, creatinine) for uremic acidosis 1

Step 3: If Normal Anion Gap Present

• Assess for gastrointestinal bicarbonate losses (diarrhea history) 6, 9
• Evaluate for renal tubular acidosis by checking urine pH and serum potassium 7, 2
• Review medication list for culprit drugs 7
• Consider recovery phase of DKA if applicable 5

Critical Clinical Pitfalls

Do not delay treatment while pursuing extensive workup in life-threatening acidosis (pH <7.1), as vigorous bicarbonate therapy is required in cardiac arrest, circulatory insufficiency due to shock, and severe diabetic or lactic acidosis 6

Avoid assuming single etiology in critically ill patients, as septic shock commonly presents with mixed metabolic acidosis from multiple contributors 1, 3

Do not overlook drug-induced causes by obtaining detailed medication history, including recent changes or overdoses, as drug-related metabolic acidosis requires immediate discontinuation of the culprit agent 7, 8

Monitor for evolving etiologies in metformin overdose, where lactic acidosis may transition to euglycemic ketoacidosis over time 8