Metformin-Associated Functional Vitamin B12 Deficiency Presenting as Subacute Combined Degeneration in a 57-Year-Old Man With Diabetes Mellitus

Introduction

Subacute combined degeneration (SCD) of the spinal cord – an acquired neurological disorder predominantly caused by reversible deficiencies of vitamin B12 or copper – is characterized by selective involvement of the dorsal and lateral columns [1]. The classic clinical presentation includes progressive sensory ataxia, spastic weakness of the lower limbs, and impaired proprioception, often accompanied by megaloblastic anemia or a relevant systemic medical history [2]. Early diagnosis requires a high index of suspicion in at-risk populations; it is supported by elevated serum methylmalonic acid and homocysteine levels, along with characteristic symmetrical T2 hyperintensity in the posterior columns on spinal magnetic resonance imaging (MRI), commonly described as the “inverted V sign” [3]. The condition is highly reversible, and prompt parenteral supplementation of vitamin B12 or the deficient nutrient can substantially improve neurological outcomes. Thus, improved clinical recognition and standardized management of SCD are essential to prevent irreversible neurological damage.

Metformin, a mainstay of hypoglycemic therapy for diabetes mellitus, is well documented as a cause of vitamin B12 deficiency [4]. Thewjitcharoen et al described an 84-year-old man who presented with frequent falls and fatigue, which were ultimately attributed to severe vitamin B12 deficiency secondary to long-term metformin therapy [5]. The most widely accepted mechanism is that metformin induces vitamin B12 deficiency by impairing its absorption through calcium cation antagonism. This effect prevents calcium-dependent binding of the intrinsic factor-vitamin B12 complex to the cubilin receptor in the ileum, thereby suppressing receptor-mediated endocytosis of vitamin B12 [6].

Here, we describe a patient with diabetes mellitus and metformin-associated functional vitamin B12 deficiency who presented with SCD of the spinal cord and gastrointestinal symptoms. This report is intended to: (1) increase clinician awareness that patients with diabetes represent a high-risk population for SCD; (2) emphasize the importance of including vitamin B12 deficiency and SCD in the differential diagnosis when patients with diabetes exhibit gastrointestinal symptoms and weight loss; and (3) highlight the critical impacts of early diagnosis and prompt replacement therapy on reversal of neurological deficits.

Case Report

A 57-year-old man was admitted to the hospital with the primary symptom of elevated blood glucose (present for >1 year), accompanied by poor appetite, vomiting, and substantial weight loss (all present for 2 months). One year earlier, he had been diagnosed with type 2 diabetes mellitus at a local hospital and received a prescription for metformin 0.5 g twice daily. Two months before admission, he developed anorexia and experienced pronounced weight loss of 25 kg, which led to metformin discontinuation. One month before admission, the patient developed gait ataxia accompanied by sensory ataxia. Symptoms of dizziness, fatigue, mid-to-lower abdominal pain, and vomiting persisted. He also reported complete cessation of bowel movements, with only occasional passage of flatus; he did not experience fever, chills, palpitations, or chest pain. Worsening of these symptoms over the week prior to presentation prompted his hospital visit. In the emergency department, urinalysis showed red blood cells ±, white blood cells 2+, glucose ±, and ketones 2+. The patient’s symptoms did not improve with supportive care, and a barium swallow examination was unremarkable except for antral gastritis. He was thus admitted for further evaluation and management of diabetes mellitus. His medical history was notable for decades of heavy alcohol consumption (approximately 250 mL daily).

Physical examination revealed that vital signs were stable. Height was 169 cm, weight was 60 kg, waist circumference was 88 cm, and body mass index was 21.01 kg/m2. Neurological examination revealed impaired superficial sensation at the T10 to L1 level, absent bowel sounds, bilaterally diminished patellar reflexes, and muscle strength graded at 4−/5 in all extremities. The remaining physical examination findings were unremarkable.

After admission, laboratory tests were performed (Table 1). Fasting blood glucose was 7.8 mmol/L, and glycosylated hemoglobin (HbA1c) was 4.8% (reference range, 4.27–6.07%). To clarify the diagnosis of diabetes and cause of the patient’s symptoms, additional tests were conducted to evaluate islet β-cell function and screen for diabetes-related autoantibodies. Tests for glutamic acid decarboxylase antibodies, islet cell cytoplasmic autoantibodies, and insulin autoantibodies were negative. The fasting insulin level was 13 μIU/mL, and the C-peptide level was 5.21 ng/mL, indicating preserved basal insulin secretion with probable insulin resistance. Arterial blood gas analysis showed metabolic acidosis with the following values (reference ranges in parentheses): pH 7.342 (7.35–7.45), pCO2 28.7 mmHg (35–45), pO2 114 mmHg (80–100), actual bicarbonate 15.1 mmol/L (21–28), standard bicarbonate 17.4 mmol/L (21–25), base excess −8.9 mmol/L (−3 to 3), and base excess of extracellular fluid −9.5 mmol/L (−3 to 3). Serum ketone levels were substantially elevated, with β-hydroxybutyrate at 6.6 mmol/L (0.02–0.27). Urinalysis showed ketonuria. Additionally, impaired renal function was noted, with an estimated glomerular filtration rate of 50.8 mL/min/1.73 m2 (> 90), elevated serum creatinine of 133 μmol/L (45–84), and blood urea nitrogen of 9.7 mmol/L (3.1–8.0). To exclude pituitary insufficiency and secondary adrenal insufficiency as possible causes of the gastrointestinal symptoms, adrenal function testing was performed. The plasma adrenocorticotropic hormone level (8 AM) was low at 6.3 pg/mL (7.2–63.3). The cortisol rhythm was abnormal, with cortisol levels of 8.8 μg/dL at 12 AM (6.7–22.6), 14.9 μg/dL at 8 AM (6.7–22.6), and 19.9 μg/dL at 4 PM (2.0–14). Hematological testing showed the following results: red blood cell count 3.49×1012/L (4.3–5.8×1012/L), hemoglobin 115 g/L (130–175), mean corpuscular volume 90 fL (82–100), mean corpuscular hemoglobin 33 pg (27–34), and mean corpuscular hemoglobin concentration 366 g/L (316–354). Laboratory evaluation showed serum vitamin B12 level of 319 pg/mL (180–914 pg/mL) and folate level of 6.48 ng/mL (≥4 ng/mL), both within normal ranges. Furthermore, autoimmune serology findings, including parietal cell and intrinsic factor antibodies, were negative; the homocysteine level was elevated at 18.4 μmol/L (0–15). Electromyography showed axonal neuropathy in the right upper limb, involving both motor (axonal and demyelinating) and sensory (demyelinating) fibers. Abdominal computed tomography revealed no acute intra-abdominal abnormalities. Follow-up abdominal plain radiography demonstrated extensive residual barium (Figure 1B) from the previous barium swallow examination (Figure 1A) performed 1 week earlier. MRI of the spinal cord demonstrated linear T2 hyperintensities within the posterior columns of the mid-thoracic cord and the conus medullaris, which were more prominent on fat-suppressed sequences (Figure 2A, 2B). This constellation of MRI findings was characteristic of SCD.

Following admission, given the clinical presentation of limb weakness and sensory abnormalities from T10 to L1, together with the characteristic MRI findings and elevated homocysteine level, a diagnosis of SCD was established. Initial treatment focused on symptom control and correction of metabolic disturbances. As gastrointestinal management, metoclopramide hydrochloride injection and esomeprazole were administered for antiemesis and gastric mucosal protection. A nasogastric tube was placed for decompression; glycerol enemas were given to facilitate evacuation of intestinal contents and promote recovery of intestinal motility. For correction of metabolic derangements, fluid resuscitation, electrolyte replacement, and nutritional support were provided in response to concomitant ketoacidosis and inadequate oral intake, using infusions of glucose-sodium chloride solution, potassium chloride, and fat-soluble vitamins. Blood glucose levels were closely monitored with a continuous glucose monitoring system. Based on the clinical suspicion of SCD, targeted neurotrophic therapy was initiated along with supportive care. This regimen included injections of vitamin B1, methylcobalamin, and alpha-lipoic acid. After receipt of the integrated treatment described above, the patient’s clinical condition substantially improved. Nausea, vomiting, and abdominal distension gradually resolved over several days, followed by successful resumption of oral intake and return of normal spontaneous bowel movements.

Discussion

This case of metformin-associated cobalamin deficiency culminating in SCD highlights the importance of vigilant monitoring of vitamin B12 status and neurological symptoms in patients with metformin-treated diabetes. Vitamin-B12-deficiency-induced SCD is a neurodegenerative disorder affecting the central and peripheral nervous systems; the deficiency may result from disturbances in intake, absorption, transport, or metabolism [7]. In the present case, the patient’s serum vitamin B12 level was within the normal range; however, the substantially elevated homocysteine level indicated a functional deficiency. The diagnosis was further supported by the patient’s clinically significant improvement after methylcobalamin supplementation, together with the characteristic radiological findings. The etiology of vitamin B12 deficiency can be broadly classified into 5 categories: impaired absorption, dietary insufficiency, increased physiological demand, autoimmune mechanisms (eg, gastric parietal cell or intrinsic factor antibodies), and congenital disorders of cobalamin metabolism [3]. Based on our patient’s clinical presentation and diagnostic findings, 3 probable etiologies for his vitamin B12 deficiency were identified. (1) Inadequate dietary intake: The patient’s markedly reduced oral intake and recurrent vomiting over the preceding 2 months likely impaired nutritional absorption of vitamin B12. (2) Chronic heavy alcohol consumption: Given his long history of consuming approximately 250 mL of alcohol daily, the patient had an increased risk of alcohol-related vitamin B12 deficiency [8]. (3) Metformin use: Gao et al reported that the prevalence of metformin-associated vitamin B12 deficiency (defined as metformin ≥1000 mg/day for ≥1 year) was 2.14% [9]. Compared with our patient, the patient described by Thewjitcharoen et al received a higher dose (metformin 1700 mg/day) for a longer duration (25 years) and showed more pronounced neurological impairment [5]. Notably, the duration of metformin therapy has not consistently shown a correlation with the severity of vitamin B12 deficiency [10]. In the present case, despite a moderate dose (1000 mg/day) and relatively short duration (1 year) of metformin therapy, our patient’s history of chronic heavy alcohol use and prolonged feeding difficulty likely contributed to the development of functional vitamin B12 deficiency. Metformin is known to impair vitamin B12 absorption through several proposed mechanisms, including reduced intestinal motility, structural changes in the ileum, and bacterial overgrowth leading to competitive utilization of the vitamin [11]. Importantly, metformin may interfere with calcium-dependent absorption of the cobalamin-intrinsic factor complex in the ileum, possibly by affecting intrinsic factor activity, cubilin receptor function, or intracellular calcium signaling [12]. These mechanisms can result in functional vitamin B12 deficiency [13], which involves cellular deficiency despite near-normal serum levels.

Following diagnostic confirmation, we systematically excluded conditions that can mimic SCD. (1) Diabetic peripheral neuropathy (DPN): In contrast to SCD, which predominantly involves the dorsal columns and corticospinal tracts, DPN typically manifests as a small-fiber neuropathy characterized by pain, burning sensations, and distal numbness; it is not associated with ataxia or pyramidal signs. Electrophysiologically, DPN often demonstrates slowed nerve conduction velocities [14], whereas SCD more commonly shows axonal loss. Importantly, DPN does not exhibit the biochemical findings (low or normal vitamin B12, elevated homocysteine or methylmalonic acid) or radiological features (dorsal column T2 hyperintensity) characteristic of SCD. (2) Copper deficiency myelopathy: This disorder displays clinical and imaging features nearly identical to those of SCD; it is often accompanied by refractory macrocytic anemia and neutropenia [15]. Although our patient declined confirmatory testing (serum copper and ceruloplasmin), the substantial clinical improvement after vitamin B12 supplementation strongly argues against copper deficiency, which would not respond to such treatment. (3) Other myelopathies: Spinal MRI effectively excluded structural (eg, compressive) and inflammatory (eg, multiple sclerosis) causes. In summary, the clinical presentation, characteristic neuroimaging, supportive laboratory findings, and clear response to treatment consistently support the diagnosis of SCD.

The management of SCD requires prompt, adequate, and sustained replacement of vitamin B12 to reverse neurological dysfunction and prevent progression. Our patient was administered intramuscular methylcobalamin (0.5 mg daily), supplemented with intravenous alpha-lipoic acid (0.6 g daily) and intramuscular vitamin B1 (0.1 g daily) to achieve rapid tissue repletion. Treatment response is determined by improvement in neurological deficits and normalization of biochemical markers, including homocysteine and methylmalonic acid. Therapy is often continued for an extended duration, although reversible contributing factors (eg, medications or nutritional deficiency) should be addressed concurrently. Severe or prolonged neurological damage may be irreversible, underscoring the importance of early diagnosis and treatment. Our patient was lost to formal follow-up after symptom resolution due to relocation for work; however, subsequent telephone contact confirmed adherence to oral maintenance therapy without symptom recurrence.

Conclusions

This case demonstrates that severe vitamin B12 deficiency, resulting from the combined effects of long-term metformin therapy and chronic heavy alcohol use, can lead to SCD in patients with diabetes. Our report highlights the need to maintain a high index of suspicion for vitamin B12 deficiency in high-risk populations, particularly those with multiple risk factors related to medication use and lifestyle. Proactive screening and timely treatment are essential to prevent irreversible neurological damage.