What is the differential diagnosis for a 45-year-old diabetic patient on Jardiance (empagliflozin) and metformin XR, presenting with dizziness, vomiting, and loose stool, without fever or upper respiratory tract infection (URTI) symptoms, and with a negative urine ketone test and elevated total white cell count (TWCC)?

Differential Diagnosis

This presentation most likely represents acute gastroenteritis with volume depletion, though metformin-associated lactic acidosis (MALA) must be urgently excluded given the combination of gastrointestinal symptoms, dizziness, and SGLT2 inhibitor use in a diabetic patient. 1

Immediate Priority: Rule Out Life-Threatening Conditions

1. Metformin-Associated Lactic Acidosis (MALA)

This is the most critical diagnosis to exclude immediately given the clinical presentation of vomiting, diarrhea, and dizziness in a patient on metformin. 2, 3

Key diagnostic features:

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) are the classic presenting symptoms of MALA, often preceding severe acidosis 3, 4
• Dizziness suggests volume depletion or metabolic derangement 4
• Elevated WBC (20) could indicate stress response or concurrent infection precipitating MALA 3
• Negative urine ketones do NOT exclude MALA - this is a common pitfall 3

Urgent laboratory workup required:

• Serum lactate level (>2 mmol/L elevated, >5 mmol/L abnormal, >10 mmol/L life-threatening) 3
• Arterial blood gas with pH (MALA: pH <7.35) 3
• Anion gap calculation (Na - [Cl+CO2]; >16 suggests lactic acidosis) 3
• Serum creatinine and eGFR (acute kidney injury precipitates MALA) 2, 4
• Complete metabolic panel with electrolytes 3

Risk factors present in this patient:

• Acute illness with vomiting and diarrhea causing volume depletion 2, 3
• Potential acute kidney injury from dehydration 2, 4
• SGLT2 inhibitor (Jardiance) causing additional volume contraction 1

Critical management if MALA confirmed:

• Discontinue metformin immediately 3
• Hemodialysis is the definitive treatment and often reverses symptoms 3
• Mortality rate 30-50% if not promptly treated 2, 3

2. SGLT2 Inhibitor-Related Complications

Jardiance (empagliflozin) can cause two serious conditions that present similarly:

A. Euglycemic Diabetic Ketoacidosis (euDKA):

• Despite negative urine ketones, serum ketones must be checked 1
• Jardiance causes ketoacidosis that can occur even with blood glucose <250 mg/dL 1
• Presenting symptoms: nausea, vomiting, abdominal pain, generalized malaise 1
• Precipitating factors: reduced caloric intake due to illness, vomiting, dehydration 1
• Management: Discontinue Jardiance immediately, check serum beta-hydroxybutyrate, initiate insulin/fluid/carbohydrate replacement 1

B. Volume Depletion with Acute Kidney Injury:

• Jardiance causes intravascular volume contraction 1
• Must temporarily discontinue in settings of reduced oral intake or fluid losses (exactly this patient's presentation) 1
• Symptomatic hypotension and dizziness are expected 1
• Can progress to acute kidney injury requiring dialysis 1

Most Likely Diagnosis: Acute Gastroenteritis

Given no fever and no URTI symptoms, viral or bacterial gastroenteritis remains the primary differential. 3

Supporting features:

• Classic triad: vomiting, diarrhea, and volume depletion (dizziness) 3
• Elevated WBC (20) suggests inflammatory/infectious process 3
• No fever does not exclude gastroenteritis (can be absent in viral causes) 3

Critical management considerations:

• Both metformin AND Jardiance should be held immediately due to reduced oral intake and fluid losses 2, 1
• Aggressive fluid resuscitation (15-20 mL/kg/h isotonic saline initially if shock present) 3
• Monitor for progression to sepsis (lactate ≥2 mmol/L = sepsis criteria) 3

Additional Differential Considerations

3. Metformin-Induced Chronic Diarrhea (Acute Exacerbation)

• Metformin causes diarrhea in 10-12% of patients, can occur years after stable therapy 5, 6
• Presents with explosive watery diarrhea, abdominal cramping, nausea 5, 6
• Often misdiagnosed as irritable bowel syndrome 6
• However, acute vomiting and dizziness suggest more than chronic metformin side effects 5, 6

4. Sepsis Without Obvious Source

• Elevated WBC (20) with gastrointestinal symptoms and dizziness 3
• Lactate ≥2 mmol/L defines sepsis even without hypotension 3
• Obtain blood cultures and initiate antibiotics within 3 hours if sepsis suspected 3
• Monitor for progression to septic shock 3

5. Mesenteric Ischemia (Less Likely but Critical)

• Combination of lactic acidosis with elevated BUN/creatinine suggests this diagnosis 3
• 88% of patients with acute mesenteric ischemia present with metabolic acidosis and elevated lactate 3
• Lactate >2 mmol/L associated with irreversible intestinal ischemia (HR 4.1) 3
• Requires immediate CT angiography if suspected - diagnostic delay is the dominant mortality factor (30-70%) 3
• Do NOT ignore mesenteric ischemia when lactate elevated with abdominal symptoms and elevated BUN 3

Diagnostic Algorithm

Step 1: Immediate laboratory assessment

• Serum lactate, arterial blood gas, anion gap 3
• Serum beta-hydroxybutyrate (not just urine ketones) 1
• Complete metabolic panel, serum creatinine/eGFR 3
• Blood cultures if infection suspected 3

Step 2: Risk stratification

• If lactate >2 mmol/L: Treat as sepsis, consider MALA, evaluate for mesenteric ischemia 3
• If pH <7.35 with elevated lactate: MALA until proven otherwise 3
• If serum ketones elevated: euDKA from Jardiance 1
• If eGFR <45 mL/min/1.73 m²: High risk for MALA 2, 4

Step 3: Medication management

• Discontinue metformin immediately in any acute illness with vomiting/diarrhea 2, 3
• Discontinue Jardiance immediately in reduced oral intake or fluid losses 1
• Do not restart until patient stable and renal function confirmed adequate 2, 1

Common Pitfalls to Avoid

• Do not assume negative urine ketones exclude euDKA - serum beta-hydroxybutyrate is required 1
• Do not ignore elevated lactate even without hypotension - indicates tissue hypoperfusion or metabolic dysfunction 3
• Do not continue metformin or Jardiance during acute illness with GI losses - both require temporary discontinuation 2, 1
• Do not delay CT angiography if mesenteric ischemia suspected - combination of lactate elevation with abdominal pain and elevated BUN is high-risk 3
• Do not use sodium bicarbonate for lactic acidosis with pH ≥7.15 - no benefit and may cause harm 3