History: A 24 yo female with cobalamin C deficiency (CblC; fig.1), autoimmune thyroiditis, and diabetes mellitus (DM) presented to the emergency department with a 3 week history of emesis and abdominal pain, acutely exacerbated 1 day prior. Related chronic problems were CblC retinopathy, intellectual impairment and seizures. DM was diagnosed 5 months prior based on random hyperglycemia (256 mg/dL) and HbA1c (6.5%). After Metformin initiation with poor tolerance, she was switched to ertugliflozin, a sodium-glucose co-transporter (SGLT2) inhibitor 4 months prior; alogliptin was added for persistent hyperglycemia 3 months prior. She also had anorexia, fatigue, and a 37-lb weight loss over 5 months.
Physical exam: She had high-normal pulse (90) and respiratory rate (20), BP 115/67mmHg, temperature 36.9°C, and features consistent with her genetic condition.
Laboratory studies: Venous blood gas demonstrated pH 7.19, CO2 16.0mmol/L, HCO3 6.1mmol/L, and base excess -20mmol/L. Glucose was 138mg/dL, with urinary ketones 80mg/dL. WBC count, lipase, and lactate were unremarkable. Additional studies included beta-hydroxybutyrate (β-OHB) 11.0mmol/L (ref 0.1-0.3mmol/L), HbA1c 8.2%, homocysteine 125.4umol/L (ref 10.5-16.7umol/L), and methylmalonic acid (MMA) 4500nmol/L (ref 0-370nmol/L).
Final diagnosis: Initially, her acidosis was attributed to CblC associated metabolic decompensation. Marked ketonemia with ertugliflozin use led to the diagnosis of SGLT2 inhibitor induced euglycemic diabetic ketoacidosis (DKA). She responded well to insulin infusion and transitioned to basal-bolus insulin. Testing demonstrated elevated insulin, GAD65, ISA512, and ZnT8 antibodies, consistent with autoimmune DM.
Discussion: CblC deficiency, the most common inherited disorder of Cbl metabolism, has multi-systemic effects. Acute metabolic decompensation with acidosis is rare. Treatment includes hydroxycobalamin, methionine, and betaine, a methyl donor. The coincidence of CblC and DM is unusual. Multi-disciplinary review identified the following DKA risk factors: SGLT2 inhibitor use (previously reported), CblC (competition for MMA and β-OHB excretion, obligate high carbohydrate diet, intellectual disability impairing symptom communication), and insulin deficiency (unrecognized autoimmune DM). In individuals with inherited metabolic disorders associated with acidosis who develop DM, it is important to assess for insulin deficiency and to consider risk/benefit balance of glucose-lowering therapies that may also predispose to acidosis.
