What are the causes of low bicarbonate levels in patients?

Causes of Low Bicarbonate

Low serum bicarbonate (<22 mmol/L) almost always indicates metabolic acidosis, which results from either increased acid production, decreased renal acid excretion, or gastrointestinal bicarbonate losses. 1

Primary Mechanisms

Decreased Renal Acid Excretion

• Chronic kidney disease is the strongest risk factor for low bicarbonate, as impaired kidney function reduces the ability to excrete hydrogen ions and synthesize ammonia, leading to acid accumulation. 2, 3
• Lower estimated glomerular filtration rate (eGFR) has the strongest relationship with low serum bicarbonate among all risk factors. 3
• The prevalence of metabolic acidosis increases progressively as GFR falls, though individual variation exists based on other contributing factors. 3

Increased Acid Production

• High dietary protein intake, particularly from animal sources containing sulfur-containing amino acids, generates nonvolatile acids during metabolism that must be buffered by bicarbonate. 2, 1
• Western dietary patterns high in animal protein, cereals, and grains but low in fruits and vegetables create chronic low-grade metabolic acidosis that worsens with age. 1
• Chronic inflammatory states and hypercatabolic conditions accelerate endogenous acid production. 1

Gastrointestinal Bicarbonate Losses

• Diarrhea, particularly chronic or severe, causes direct loss of bicarbonate-rich intestinal fluid. 1
• Small bowel fistulas, ileostomy, or ureterosigmoidostomy result in ongoing bicarbonate losses. 1

Additional Risk Factors Beyond GFR

Urinary and Metabolic Factors

• Albuminuria ≥10 mg/g is independently associated with higher odds of low serum bicarbonate, even after adjusting for eGFR. 3
• Anemia correlates with reduced bicarbonate levels independent of kidney function. 3
• Hyperkalemia is associated with low serum bicarbonate. 3

Lifestyle and Medication Factors

• Active smoking increases the odds of low serum bicarbonate independent of other factors. 3
• Non-use of diuretics (conversely, diuretic use may elevate bicarbonate through contraction alkalosis). 3
• Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers associates with lower bicarbonate levels. 3

Nutritional and Body Composition

• Higher waist circumference correlates with lower bicarbonate concentrations. 3
• Paradoxically, higher serum albumin is associated with low bicarbonate, possibly reflecting higher protein intake and acid load. 3

Clinical Context-Specific Causes

Diabetic Ketoacidosis

• Insulin deficiency leads to ketone body production (beta-hydroxybutyrate and acetoacetate), which consume bicarbonate as they are buffered. 2
• Bicarbonate levels <15 mmol/L indicate moderate to severe DKA. 2

Lactic Acidosis

• Tissue hypoperfusion in sepsis, shock, or severe illness causes anaerobic metabolism and lactate accumulation. 2
• The liver's impaired ability to metabolize lactate in cirrhosis can contribute to acidosis. 4

Renal Tubular Acidosis

• Defects in renal tubular hydrogen ion secretion or bicarbonate reabsorption cause normal anion gap metabolic acidosis. 2

Diagnostic Approach

When evaluating low bicarbonate, obtain arterial blood gas analysis to measure pH and PaCO2 to distinguish primary metabolic acidosis from compensatory changes. 2, 1

• Metabolic acidosis is characterized by pH <7.35, bicarbonate <22 mmol/L, with compensatory respiratory alkalosis (low PaCO2). 1
• Calculate the anion gap [Na - (Cl + HCO3)] to differentiate high anion gap (>12 mEq/L) from normal anion gap acidosis. 2
• In CKD patients stages 3-5, monitor serum bicarbonate monthly to detect and manage metabolic acidosis early. 2, 1

Clinical Significance

Maintaining bicarbonate ≥22 mmol/L is critical to prevent protein catabolism, bone disease, and faster kidney disease progression. 2, 1

• Low serum bicarbonate shows a U-shaped association with mortality, with highest mortality observed in patients with bicarbonate <22 mmol/L. 5
• In dialysis patients, bicarbonate <22 mmol/L confers a 13-fold increased risk of death compared to levels of 24-26 mmol/L. 6
• Low bicarbonate is associated with peripheral vascular disease and diastolic dysfunction in dialysis patients. 7
• In hospitalized cirrhotic patients, low admission bicarbonate predicts complications, longer hospital stays, ICU admission, and increased mortality. 4