What are the differential diagnoses for a patient with type 2 diabetes and a history of cannabis use who develops recurrent anion gap acidosis despite initial treatment with insulin and fluid resuscitation?

Differential Diagnoses for Recurrent Anion Gap Acidosis in a Type 2 Diabetic with Cannabis Use

The primary differentials are: (1) recurrent/incompletely resolved diabetic ketoacidosis, (2) euglycemic DKA (particularly if on SGLT2 inhibitors), (3) starvation ketosis, (4) cannabinoid hyperemesis syndrome with starvation ketosis, (5) 5-oxoproline (pyroglutamic acid) acidosis if taking acetaminophen, (6) metformin-associated lactic acidosis if on metformin, and (7) alcoholic ketoacidosis if concurrent alcohol use.

Most Likely Diagnoses Given Clinical Context

Recurrent or Incompletely Resolved DKA

• With a bicarbonate of 18 mEq/L and anion gap of 16, this represents moderate metabolic acidosis that has not fully resolved from the initial presentation 1
• The American Diabetes Association defines DKA resolution as glucose <200 mg/dL, **serum bicarbonate ≥18 mEq/L**, venous pH >7.3, and normalized anion gap (≤12 mEq/L) 1
• Your patient has bicarbonate exactly at 18 but anion gap remains elevated at 16 (normal ≤12), indicating incomplete resolution of ketoacidosis 1
• Check serum or urine ketones (beta-hydroxybutyrate preferred, not nitroprusside method which misses the predominant ketone) 1
• Clinical improvement does not equal biochemical resolution—patients often feel better before acidosis fully clears 2

Euglycemic DKA (if on SGLT2 Inhibitors)

• SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) cause euglycemic DKA with glucose levels often <200 mg/dL but persistent high anion gap acidosis and elevated ketones 3
• The glucose of 174 mg/dL fits this pattern perfectly 3
• Cannabis use may precipitate this through decreased oral intake and dehydration 3
• Confirm by checking urine and capillary ketones—will be markedly elevated despite relatively normal glucose 3
• Treatment requires IV insulin with concurrent dextrose 5% to clear ketones while preventing hypoglycemia 3

Starvation Ketosis with Cannabinoid Hyperemesis Syndrome

• Cannabis use is directly relevant here—cannabinoid hyperemesis syndrome causes cyclic vomiting, leading to starvation ketosis 2
• Starvation ketosis typically produces bicarbonate not lower than 18 mEq/L and glucose ranging from mildly elevated to hypoglycemic 2
• Your patient's bicarbonate of exactly 18 fits this pattern 2
• Distinguish from DKA by: lower glucose levels, less severe acidosis, and clinical history of prolonged vomiting with poor oral intake 2

5-Oxoproline (Pyroglutamic Acid) Acidosis

• If the patient received acetaminophen for symptom management, consider 5-oxoproline acidosis—presents as recurrent high anion gap acidosis that defies standard explanations 4, 5, 6
• This causes striking anion gap elevations (often 30+ mEq/L) with negative standard toxicology screens 4
• Risk factors include: renal dysfunction, sepsis, malnutrition, and chronic acetaminophen use (even therapeutic doses) 5
• Diagnosis requires urinary organic acid screen showing elevated 5-oxoproline levels (can be 58-fold above normal) 5, 6
• The anion gap cannot be explained by measured lactate or ketones alone 4, 6

Metformin-Associated Lactic Acidosis

• If the patient takes metformin, this is a critical consideration—characterized by elevated lactate >5 mmol/L, anion gap acidosis without ketonuria, and metformin levels >5 mcg/mL 7
• Presents with subtle onset: malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence 7
• Risk factors: renal impairment (eGFR <45 mL/min/1.73 m²), dehydration from vomiting, sepsis, or tissue hypoperfusion 7
• Check serum lactate immediately and discontinue metformin if suspected 7
• Hemodialysis is indicated for confirmed metformin-associated lactic acidosis (metformin is dialyzable) 7

Alcoholic Ketoacidosis

• Cannabis users may have concurrent alcohol use—alcoholic ketoacidosis presents with profound acidosis but glucose ranging from mildly elevated to hypoglycemic 2
• Distinguished from DKA by clinical history of alcohol binge followed by cessation and poor oral intake 2
• Treatment is IV dextrose-containing fluids and thiamine, not insulin 2

Critical Diagnostic Steps

Immediate Laboratory Testing

• Measure beta-hydroxybutyrate directly (not nitroprusside-based urine ketones which miss the predominant ketone in DKA) 1
• Check serum lactate to evaluate for lactic acidosis 7
• Obtain venous pH (0.03 units lower than arterial, adequate for monitoring) 1
• Calculate corrected anion gap for albumin level 6
• Review medication list specifically for: SGLT2 inhibitors, metformin, and acetaminophen 7, 3, 5

If Standard Workup Negative

• Order urinary organic acid screen to detect 5-oxoproline if acetaminophen exposure occurred and other causes ruled out 4, 5, 6
• Screen for toxic alcohols (methanol, ethylene glycol) if history unclear 2
• Consider D-lactate if history of short bowel syndrome or bacterial overgrowth 4

Common Pitfalls to Avoid

• Do not assume clinical improvement equals biochemical resolution—continue monitoring until anion gap normalizes to ≤12 mEq/L 1
• Do not rely on urine dipstick ketones using nitroprusside method—this only detects acetoacetate and acetone, missing beta-hydroxybutyrate which comprises 75% of ketones in DKA 1
• Do not overlook medication-induced causes—specifically SGLT2 inhibitors causing euglycemic DKA and metformin causing lactic acidosis 7, 3
• Do not dismiss acetaminophen as benign—even therapeutic doses can cause severe 5-oxoproline acidosis in susceptible patients with renal dysfunction or malnutrition 5, 6
• Do not stop investigating when common causes are negative—rare causes like 5-oxoproline acidosis are increasingly recognized and treatable 4, 5, 6