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Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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Division of Human Genetics, Section of Biochemical Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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Division of Human Genetics, Section of Biochemical Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Neuroendocrine Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Mitochondrial Medicine Frontier Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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A 24-year-old woman with cobalamin C deficiency (CblCD), autoimmune thyroiditis, and recently diagnosed diabetes mellitus presented with weight loss, emesis, and abdominal pain. She had been placed on sodium-glucose cotransporter inhibitor (SGLT2i) therapy because of metformin intolerance, with the addition of a dipeptidyl peptidase-4 inhibitor. Biochemical analyses demonstrated severe acidosis, initially attributed to CblC-associated metabolic decompensation. Subsequent evaluation led to the diagnosis of SGLT2i-induced euglycemic diabetic ketoacidosis in a patient with type 1 diabetes mellitus. This case highlights the importance of assessing for insulin deficiency when evaluating acidosis and the management challenges of common diseases in adults with inherited metabolic disorders.
Cobalamin C deficiency (CblCD) is the most common inherited disorder of cobalamin metabolism, leading to impaired methionine production and branched-chain amino acids catabolism (Figure 1, A) (1). A progressive multisystemic disorder, it leads to intellectual disability (ID), seizures, retinopathy, macrocytic anemia, cardiomyopathy, pulmonary lesions, and renal disease. CblCD is primarily diagnosed through newborn screening, but later onset variants present in childhood with lethargy, feeding difficulties, or atypical hemolytic uremia, or in adulthood with gait abnormalities, disorientation, incontinence, and macrocytic anemia. Treatment involves high-dose parenteral hydroxocobalamin and betaine (a methyl donor) to reduce homocysteine levels and methionine supplementation (1). Previously implemented protein-restricted diets are no longer recommended because associated amino acid deficiencies may worsen neurocognitive outcomes (2). Medication adherence minimizes sequelae without preventing ID, retinopathy, or renal disease. Acute metabolic decompensation with anion gap metabolic acidosis (AGMA) rarely occurs (3). As this cohort ages, new challenges arise in managing common adult-onset comorbid conditions.
To highlight the importance of a broad differential diagnosis and choosing treatment carefully when diabetes mellitus (DM) and a rare metabolic disorder coexist. To provide an example of new care challenges for adults with inherited metabolic disorders (IMDs).
A 24-year-old female of South Asian descent with congenital CblCD (OMIM 609831), autoimmune thyroiditis, and DM presented to the emergency department with 3 weeks of intermittent nonbloody, nonbilious emesis, and abdominal pain, acutely worsened 1 day prior. Her CblCD diagnosed in infancy manifested with microcephaly, progressive pigmentary retinopathy, mild ID, and well-controlled seizures, and had been treated with dietary protein restriction. She had been diagnosed with type 2 DM 5 months previously with a random hyperglycemia test (14.2 mmol/L [256 mg/dL]) and elevated hemoglobin A1c of 47.5 mmol/mol (6.5%). She did not tolerate initial management with metformin and was switched to ertugliflozin, a sodium-glucose cotransporter inhibitor (SGLT2i), 4 months prior. Alogliptin, a dipeptidyl peptidase 4 inhibitor, was added 1 month later for persistent hyperglycemia. She consistently took her medications, which also included l-thyroxine, levocarnitine, hydroxocobalamin, methionine, betaine, carbamazepine, calcium carbonate, sodium citrate-citric acid, a multivitamin, and cholecalciferol. A review of systems was notable for anorexia, fatigue, and unintentional 16.5-kg weight loss over the preceding 5 months. There was no recent infection. Her family history was negative for DM. Physical examination demonstrated a heart rate of 98 beats/min, blood pressure 115/67 mm Hg, respirations of 20 per minute, temperature 36.9 °C, body mass index (BMI) 18.1 kg/m2 (reduced from 25.1 kg/m2 5 months prior), and signs of dehydration. Biochemical studies demonstrated an AGMA with mild hyperglycemia, elevated beta-hydroxybutyrate (β-OHB) and normal lactate concentrations, and stably elevated homocysteine and methylmalonic acid (MMA) levels consistent with her CblCD (Table 1).
Bolded values indicate values outside of the test’s reference range. Ab = antibody; ED = emergency department; GAD = glutamic acid decarboxylase; ICA = islet cell antigen; Znt = Zinc.
*Elevations in methylmalonic acid and homocysteine above prediagnosis baseline indicate poorly controlled cobalamin C deficiency likely because of persistent catabolism in the setting of deficient insulin.
Initially, her AGMA was attributed to CblC-associated metabolic decompensation. When elevated serum levels of β-OHB were noted, suspicion arose for SGLT2i-induced euglycemic DKA given the mild hyperglycemia. She responded well to intravenous insulin infusion and transitioned to basal-bolus insulin. Ertugliflozin and alogliptin were discontinued. Subsequent evaluation demonstrated undetectable insulin and low C-peptide concentrations with elevated diabetes-associated pancreatic antibodies titers, consistent with autoimmune DM (Table 1). Eighteen months after DM presentation, she had regained weight (BMI 20.9 kg/m2) and had no further episodes of DKA. Her hemoglobin A1c level was 64 mmol/mol (8.0%).
Multidisciplinary review identified 3 main DKA risk factors. First, unrecognized insulin-deficient DM predisposed this patient to DKA. Her age at presentation and South Asian ancestry may have led clinicians to diagnose type 2 DM, rather than autoimmune insulin deficiency. Yet, presentation with a BMI of only 25.1 kg/m2, absent type 2 DM family history, weight loss, and a preexisting autoimmune condition should have triggered evaluation for type 1 DM.
Second, CblCD exacerbated DKA severity. MMA likely competes with β-OHB for urinary excretion because of similar size and structure (Figure 1, B) (4, 5). Reduced β-OHB excretion augments the risk for developing DKA. Our patient’s β-OHB concentration was significantly elevated with only moderately increased urinary ketones, despite fairly concentrated urine (Table 1). With mitochondrial dysfunction, urinary acetoacetate measurements can underestimate ketosis because of accumulation of reduced nicotinamide adenine dinucleotide relative to oxidized nicotinamide adenine dinucleotide and therefore increased β-OHB compared with acetoacetate (6). Additionally, CblCD-related ID may have impaired communication of symptoms and fluid intake in response to dehydration. Finally, the patient’s protein-restricted, high-carbohydrate diet potentially exacerbated DKA severity.
Third, SGLT2i use can lower blood glucose levels to near normal while promoting ketosis, decreasing suspicion for DKA. Blood ketone concentration increases via multiple mechanisms still under investigation (Figure 1, C). Impaired urinary ketone excretion and possible stimulation of glucagon secretion promote ketone production (7). The hypovolemia resulting from glycosuria also increases levels of glucagon and other counterregulatory hormones that promote lipolysis and insulin resistance, worsening ketosis (8). By decreasing blood glucose levels and removing the stimulus for insulin secretion and/or administration, an SGLT2i can produce a “mismatch” between insulin concentration and effect–namely, insufficient lipolysis and ketogenesis suppression (7). A state of relative insulin deficiency and resistance and hyperketonemia results (7, 8). The persistent catabolic state from insulin deficiency may provoke metabolic decompensation in an individual with CblCD, compounding the SGLT2i effects of increased production and decreased ketone clearance.
The cause of AGMA can be elusive in individuals with IMD, particularly those with multiple risk factors. There are at least 10 published cases of pediatric patients with impaired MMA metabolism who were mistakenly initially diagnosed with primary DKA in countries without universal newborn screening for these disorders (9, 10). Six of 9 patients died in 1 series (10). Defects in methylmalonyl-CoA mutase (an enzyme for which adenosylcobalamin is a required cofactor) have been associated with concurrent methylmalonic acidemia and neonatal diabetes secondary to pancreatic β-cell agenesis (11). To our knowledge, ours is the first report of coexistent autoimmune diabetes and CblCD. Together, these reports highlight the importance of accurate ascertainment of the cause of AGMA.
The case also highlights that choosing DM therapies for individuals with IMDs warrants special consideration (Table 2). For instance, metformin carries a risk for lactic acidosis (for which our patient was monitored) and cobalamin deficiency. Consequently, the appropriateness of metformin DM treatment is unclear for individuals with concomitant inherited disorders of cobalamin metabolism or other IMDs with renal manifestations or mitochondrial dysfunction. On the other hand, SGLT2i use has been associated with reductions in cardiovascular death, heart failure hospitalizations, and progression of renal disease, even in those without DM (12), which may be of benefit in IMD-related cardiomyopathy and renal disease, as seen in CblCD (1). However, these benefits should be balanced with the increased ketosis risk with an SGLT2i.
Commonly used and familiar to most medical providers
Well-tolerated without off-target effects based on extensive long-term safety data
Necessary in insulin-deficient diabetes
Hypoglycemia
Excess weight gain in T2D
Dose adjustments are needed in CKD
Promotes anabolism
Frequent treatment for acute metabolic decompensations
Extensive long-term safety data available, including in early-stage CKD
Gastrointestinal distress with nausea, vomiting, and diarrhea may increase risk of metabolic decompensation; can be mitigated by starting with the lowest metformin dose followed by slow incremental dose adjustments
Cobalamin (B12) deficiency (from metformin-associated impaired ileal cobalamin absorption)
Review safety in CKD stages 3b–5
Risk of lactic acidosis in patients with mitochondrial disease, renal dysfunction
Decreased intestinal lipoprotein absorption and hepatic steatosis in animal models, though unclear benefit to liver transaminases in humans
Linagliptin can be used in CKD
Possible improved mitochondrial function (brain, hippocampus in animal models)
Gastrointestinal distress with nausea, vomiting, and diarrhea
Risk of pancreatitis
Gastrointestinal side effects may precipitate metabolic decompensation
Risk of exacerbating gastroparesis in individuals with primary or secondary mitochondrial dysfunction
Potentially cardioprotective
Possible positive impact on central nervous system function
Possible improved mitochondrial function (pancreatic β cells, cardiomyocytes, and retinal ganglion cells in animal models)
Weight loss for individuals with obesity
Possible risk of pancreatitis
Risk of cholelithiasis
Typically discontinued in stages 4–5 CKD
Case reports noted benefit for individuals with mitochondrial diabetes (i.e., Wolfram syndrome)
May compound underlying pancreatitis risk in organic acidemias
GI side effects may precipitate metabolic decompensation
Weight loss (possible benefit or risk depending on patient)
Risk of tachycardia could be a concern depending on underlying condition
Benefit in heart failure
Benefit in CKD
Euglycemic ketosis/DKA
Urinary tract infections
Typically discontinued in stages 3b–5 CKD
Increase β-oxidation of long-chain fatty acids
Decrease PDH activity through PDH kinase upregulation
Improve neutropenia in GSD1b
CKD = chronic kidney disease; DKA= diabetic ketoacidosis; GSD = glycogen storage disease; IMD = inherited metabolic disorder; PDH = pyruvate dehydrogenase; T2D = type 2 diabetes.
For a comprehensive review of these and other agents used to manage diabetes mellitus, see PMID 34964831 (2022 American Diabetes Association pharmacologic treatment guidelines).
This case is a reminder to assess for insulin deficiency in adults presenting with DM and introduces a growing patient cohort: adults with IMDs, individually rare but collectively common with an incidence of 1:1500 (13). More than 90% of individuals diagnosed with IMDs reach age 20 years because of expanded newborn screening and detection and intensive medical management (14). Adults with IMDs face challenges transitioning to adult health care, including lack of knowledgeable clinicians and the loss of a medical home (15). Inexperienced clinicians may be quick to attribute symptoms to a patient’s underlying IMDs leading to diagnostic delays. Close collaboration between adult clinicians and biochemical geneticists will be necessary to tailor management and prevent adverse outcomes.
1Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
2Division of Human Genetics, Section of Biochemical Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
3Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
4Neuroendocrine Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
5Mitochondrial Medicine Frontier Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
6Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Acknowledgment
We thank Dr. Michael A. Levine for his helpful feedback on drafts of this manuscript.
Funding
Dr. Kamoun is supported by NIH grant T32 DK063688 from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Tamaroff is supported by GRT-00000432 Friedreich’s Ataxia Research Alliance Post-Doctoral Fellowship Grant from the Friedreich’s Ataxia Research Alliance.
Disclosures
Disclosure forms are available with the article online.
Corresponding Author
Camilia Kamoun, MD; Division of Endocrinology, University of North Carolina School of Medicine, 127 Medical School Wing E, CB# 7039, Chapel Hill, NC 27514; e-mail, [email protected].
Copyright © 2023 by Authors. Published in partnership by the American College of Physicians and American Heart Association. All Rights Reserved.
This is an open access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND), which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. See: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode.
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