What are the causes of metabolic acidosis in individuals, particularly those with diabetes, kidney disease, or a history of severe illness?

Causes of Metabolic Acidosis

Metabolic acidosis results from either accumulation of endogenous acids that consume bicarbonate (high anion gap) or loss of bicarbonate from the gastrointestinal tract or kidneys (normal anion gap). 1, 2

Classification by Anion Gap

The anion gap calculation ([Na+] - [HCO3- + Cl-]) is essential for categorizing metabolic acidosis and guiding diagnosis. 3

High Anion Gap Metabolic Acidosis (>12 mmol/L)

High anion gap acidosis indicates the presence of unmeasured organic anions accumulating in the body. 1 The major causes include:

Lactic Acidosis

• Primary contributor in shock states, resulting from inadequate oxygen delivery to tissues and tissue hypoperfusion. 1
• Occurs in septic shock with multiple contributors including tissue hypoxia and hyperchloremic components. 1
• Metformin-associated lactic acidosis (MALA) can occur, particularly when combined with acute kidney injury and dehydration. 4
• Serial lactate measurements provide critical information about shock severity and treatment response. 1

Ketoacidosis

• Diabetic ketoacidosis (DKA) is characterized by hyperglycemia, arterial pH <7.35, bicarbonate <18 mmol/L, and positive serum/urine ketones. 1, 5
• Alcoholic ketoacidosis presents with lower glucose levels than DKA and requires clinical history of alcohol use for distinction. 1
• Starvation ketosis shows mildly elevated glucose and less severe bicarbonate reduction. 1

Renal Failure

• Chronic kidney disease impairs the kidney's ability to excrete hydrogen ions and synthesize ammonia, leading to acid accumulation. 6, 1
• Advanced renal failure almost invariably causes metabolic acidosis, though severity varies widely. 7
• Patients with diabetes and diabetic nephropathy paradoxically show less severe acidosis (mean bicarbonate 20.7 vs 18.2 mmol/L) compared to non-diabetic renal failure patients. 7

Toxic Ingestions

• Salicylate, methanol, and ethylene glycol poisoning cause high anion gap acidosis. 1, 8
• The osmolal gap is elevated in methanol, ethylene glycol, and propylene glycol ingestions. 1
• Less common causes include pyroglutamic acid (5-oxoproline) and djenkol bean poisoning. 2

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

Normal anion gap acidosis results from bicarbonate loss or impaired renal acid excretion with chloride retention. 2, 3

Gastrointestinal Bicarbonate Loss

• Severe diarrhea causes direct loss of bicarbonate-rich intestinal secretions, depleting the body's primary buffer system. 9, 8
• Fluid loss decreases renal perfusion, impairing the kidney's ability to excrete hydrogen ions and regenerate bicarbonate. 9
• Infants are particularly vulnerable due to lower bicarbonate reserves and higher intestinal pH promoting nitrate-reducing bacteria. 9

Renal Tubular Acidosis

• Represents impaired renal acidification despite relatively preserved glomerular filtration. 2
• Can occur as a primary disorder or secondary to various systemic conditions. 2

Early Renal Failure

• Before significant anion gap accumulation develops, hyperchloremic acidosis may predominate. 2
• Patients with chronic kidney disease have limited ability to excrete acid loads, making them vulnerable to additional insults. 9

Drug-Induced Causes

• Drugs causing hyperkalemia can impair renal acid excretion. 2
• Administration of acidifying chloride salts produces normal anion gap acidosis. 10

Special Clinical Contexts

Dietary-Induced Chronic Acidosis

• Western diets high in animal protein and low in fruits/vegetables create an imbalance between nonvolatile acids and available alkali. 1, 6
• Animal proteins contain sulfur-containing amino acids that produce nonvolatile acids during metabolism. 6
• Fruits and vegetables provide potassium citrate salts that generate alkali to buffer acids. 6

Circulatory Insufficiency

• Shock states and severe dehydration cause metabolic acidosis through multiple mechanisms including lactic acidosis and impaired renal perfusion. 8
• Cardiac arrest produces severe metabolic acidosis requiring urgent intervention. 8

Extracorporeal Circulation

• Blood circulation outside the body during procedures can lead to metabolic acidosis. 8

Critical Diagnostic Pitfalls

Mixed acid-base disorders are common and can mask the severity of metabolic acidosis. 1 For example:

• Septic shock often exhibits both high anion gap (lactic acidosis) and hyperchloremic components simultaneously. 1
• Patients recovering from DKA may develop normal anion gap acidosis as ketones clear but bicarbonate remains depleted. 6

In chronic kidney disease patients, the anion gap may be falsely normal due to hypoalbuminemia, as albumin is an unmeasured anion. 7 This can lead to underestimation of the severity of uremic acidosis.

Patients with diabetes and advanced renal failure show less severe metabolic acidosis (bicarbonate 20.7 vs 18.2 mmol/L in non-diabetics), possibly due to more efficient extrarenal bicarbonate generation. 7 This should not lead to complacency, as treatment thresholds remain the same.