What is the appropriate workup for a patient presenting with symptoms of an unspecified condition?

AGMA (Anion Gap Metabolic Acidosis) Workup

The workup for AGMA should systematically identify the underlying cause using the clinical context, laboratory testing, and targeted investigations to differentiate between common etiologies (diabetic ketoacidosis, lactic acidosis, toxic ingestions, renal failure) and rare causes (starvation ketoacidosis, 5-oxoproline accumulation). 1

Initial Laboratory Assessment

The foundational workup begins with calculating the anion gap and confirming true metabolic acidosis:

• Calculate the anion gap: [Na+] - ([Cl-] + [HCO3-]). A normal AG is 8-12 mEq/L; values >12 mEq/L indicate AGMA 1
• Correct for hypoalbuminemia: For every 1 g/dL decrease in albumin below 4 g/dL, add 2.5 mEq/L to the calculated AG, as hypoalbuminemia artificially lowers the measured AG 1
• Calculate the delta-delta ratio: (Change in AG)/(Change in HCO3-) to identify mixed acid-base disorders. A ratio of 1-2 suggests pure AGMA; <1 suggests concurrent hyperchloremic acidosis; >2 suggests concurrent metabolic alkalosis 1
• Obtain arterial blood gas to confirm metabolic acidosis and assess respiratory compensation 1

Systematic Etiologic Investigation

Once AGMA is confirmed, pursue the following algorithm based on clinical presentation:

Common Causes (Address First)

• Diabetic ketoacidosis: Check serum glucose, beta-hydroxybutyrate (or urine ketones), and assess for hyperglycemia with ketonemia 1
• Lactic acidosis: Measure serum lactate. Type A (tissue hypoxia) requires assessment of perfusion status, blood pressure, and oxygen delivery. Type B (non-hypoxic) requires evaluation for medications (metformin), toxins, malignancy, or liver disease 1
• Renal failure: Check serum creatinine and blood urea nitrogen. Uremia typically causes AGMA when GFR <20 mL/min 1
• Toxic ingestions:
  • Calculate osmolal gap: Measured osmolality - calculated osmolality (2[Na+] + glucose/18 + BUN/2.8). An osmolal gap >10 mOsm/kg suggests toxic alcohol ingestion 1
  • Check salicylate level if aspirin ingestion suspected 1
  • Consider ethylene glycol or methanol if osmolal gap elevated with severe acidosis 1

Rare Causes (Consider When Common Causes Excluded)

• Starvation ketoacidosis: Obtain detailed nutritional history. Check beta-hydroxybutyrate and glucose (typically normal or low, distinguishing it from DKA). ISK can present with severe acidosis (pH <7.0) in malnourished patients 2
• 5-oxoproline (pyroglutamic acid) accumulation: Suspect in patients with chronic acetaminophen use, especially with malnutrition, female sex, or chronic liver disease. Urine organic acid analysis confirms elevated 5-oxoproline. This entity causes severe AGMA and is frequently missed 3
• D-lactic acidosis: Consider in patients with short bowel syndrome or intestinal bypass. Standard lactate assays measure L-lactate only; specific D-lactate assay required 1

Critical Pitfalls to Avoid

• Failing to correct AG for hypoalbuminemia leads to missed AGMA in critically ill patients with low albumin 1
• Not calculating the delta-delta ratio misses concurrent acid-base disorders that alter management 1
• Overlooking medication history misses acetaminophen-induced 5-oxoproline acidosis, which is reversible with cessation and N-acetylcysteine 3
• Assuming normal glucose excludes ketoacidosis misses starvation ketoacidosis, which presents with euglycemia or hypoglycemia 2
• Not measuring osmolal gap in unexplained AGMA delays diagnosis of toxic alcohol ingestion requiring urgent hemodialysis 1

Algorithmic Approach Summary

1. Confirm AGMA: Calculate AG (corrected for albumin), verify metabolic acidosis on ABG 1
2. Calculate delta-delta: Identify mixed disorders 1
3. Screen common causes: Glucose/ketones (DKA), lactate (lactic acidosis), creatinine (uremia), osmolal gap/toxin levels (ingestions) 1
4. If unexplained: Detailed medication/nutritional history, consider urine organic acids for 5-oxoproline, D-lactate assay if appropriate clinical context 2, 3, 1
5. Treat underlying cause: ISK responds to dextrose-containing fluids; 5-oxoproline acidosis responds to acetaminophen cessation and N-acetylcysteine; toxic alcohols require hemodialysis 2, 3, 1