Severe lactic acidosis with euglycemic diabetic ketoacidosis due to metformin overdose

Abstract

Metformin-associated lactic acidosis is a well-known metformin treatment complication; however, the development of euglycemic diabetic ketoacidosis (euDKA) has rarely been reported. Here we report a case of lactic acidosis and euDKA after metformin overdose. A 57-year-old female patient was transferred to our hospital with severe metabolic acidosis and acute kidney injury. She had type 2 diabetes mellitus and was on oral antidiabetic therapy of vildagliptin metformin hydrochloride daily. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She had severe lactic acidosis 5 h after overdosing. However, after 34 h of overdosing, serum lactate levels decreased while serum anion gap levels increased. She received single hemodialysis treatment. Serum total ketone bodies, β-hydroxybutyrate acetoacetic acid, and acetone were increased even after hemodialysis treatment. Her blood glucose levels have never exceeded 250 mg/dL since admission. Therefore, we considered that the cause of metabolic acidosis in this patient was not only lactic acidosis but also euDKA. The causes of euDKA in our patient might be hepatic production of ketone bodies due to metformin overdose in addition to type 2 diabetes mellitus, starvation, infection, and stressful physical conditions such as vomiting and diarrhea. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdose.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13730-023-00783-w.

Introduction

Metformin-associated lactic acidosis (MALA) is a recognized metformin treatment adverse effect, with an estimated prevalence of < 0.01–0.09 cases/1000 patient-years, and overdose-related MALA is approximately 20% of all MALA. Additionally, 84% of patients with MALA who develop overdose-related MALA require extracorporeal treatment, which is a major clinical problem [1]. On the other hand, euglycemic diabetic ketoacidosis (euDKA), complicated by MALA at normal doses of metformin, was reported; however, euDKA, complicated by overdosage in a short period, has not been reported [2].

Thus, we report a patient who developed lactic acidosis and euDKA, due to metformin overdosage at 25,000 mg and vildagliptin at 2500 mg and received hemodialysis.

Case report

A 52-year-old female patient was transferred to our hospital with severe metabolic acidosis. She had been treated for type 2 diabetes mellitus with 2 tablets of vildagliptin metformin hydrochloride daily, which was equivalent to 1000 mg/day of metformin and 100 mg/day of vildagliptin. Although she had a history of suspected syndrome of resistance to thyroid hormone, she had no clinical symptoms and did not require treatment. She has attempted suicide twice in the past. She was prescribed the following medications for depression: benidipine hydrochloride 4 mg/day, diazepam 6 mg/day, and lorazepam 0.5 mg/day. Recently, she was tired of caring for her mother and was suffering from mental stress. Her baseline creatinine was 0.42 mg/dL. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She visited the emergency department of a hospital near her home with vomiting and diarrhea 5 h after overdosing. She had metabolic acidosis (pH: 7.24, pCO₂: 43.1 mmHg, Na⁺: 145 mmol/L, K⁺: 4.7 mmol/L, Cl⁻: 103 mmol/L, anion gap: 20.9 mmol/L, HCO₃⁻: 18.1 mmol/L, and lactate: 10.5 mmol/L on arterial blood gas analysis), but her vital signs were normal. Her serum creatinine was above baseline but within normal limits (serum creatinine: 0.92 mg/dL). She was sent home at the discretion of the hospital doctor. However, she had constant vomiting and diarrhea, and she could not eat anything. She drank only small amounts of water and did not drink alcohol or soft drinks. She re-visited the hospital 31 h after overdosing. Blood gas analysis revealed severe metabolic acidosis (pH: 7.08, pCO₂: 33.8 mmHg, Na⁺: 140 mmol/L, K⁺: 5.7 mmol/L, Cl⁻: 97 mmol/L, anion gap: 34.3 mmol/L, HCO₃⁻: 8.5 mmol/L, and lactate: 8.4 mmol/L). After a 1000 ml normal saline infusion, she was transferred to our hospital for intensive treatment.

She arrived at our hospital 34 h after overdosing. Her weight was 41.0 kg, her height was 150 cm, and her body max index was 18.2 kg/m². She had a body temperature of 37.6 °C, blood pressure of 88/40 mmHg, heart rate of 126 beats per minute, respiratory rate of 25 breaths per minute, and oxygen saturation of 97% on room air. Her consciousness was normal. She had moderate abdominal tenderness without any other abnormalities. Table 1 shows her laboratory data upon admission. She had marked leukocytosis, high C-reactive protein levels, and profound metabolic acidosis with a high anion gap and hyperkalemia (pH: 7.13, pCO₂: 28.8 mmHg, Na⁺: 142 mmol/L, K⁺: 6.1 mmol/L, Cl⁻: 101 mmol/L, anion gap: 31.9 mmol/L, lactate: 4.2 mmol/L, and HCO₃⁻: 9.1 mmol/L). Additionally, she had acute kidney injury (serum creatine: 4.87 mg/dL). Urine ketone was negative on the dipstick test. Routine urine toxicology screening did not reveal phencyclidine, benzodiazepine, cocaine, antihypnotic agent, cannabis sativa, hydromorphone, barbiturate sedative, and tricyclic antidepressant. Insulin, C-peptide, and cortisol were not measured. The chest computed tomography (CT) without contrast revealed right lower lobe consolidation. She was diagnosed with aspiration pneumonia and ceftriaxone at 2 g q 24 h was started. Head and abdominal CT scans without contrast revealed no intracranial abnormalities and urinary tract obstructions.

Table 1.

Laboratory data on admission

Variable	Reference range	Results
Blood
Hemoglobin (g/dL)	11.6–14.8	11.3
White-cell count (/mm3)	3300–8600	23,400
Platelet count (/mm3)	158,000–348,000	272,000
Sodium (mmol/L)	138–145	142
Potassium (mmol/L)	3.6–4.8	6.1
Chloride (mmol/L)	101–108	101
Calcium (mg/dL)	8.8–10.1	7.6
Phosphorus (mg/dL)	2.7–4.6	10.5
Urea nitrogen (mg/dL)	8–20	75.3
Creatinine (mg/dL)	0.46–0.79	4.87
Estimated glomerular filtration rate (ml/min/1.73 m2)a	60–	8.0
Glucose (mg/dL)	73–99	196
Hemoglobin A1c (%)	4.9–6.0	6.5
Total protein (g/dL)	6.6–8.1	6.0
Albumin (g/dL)	4.1–5.1	3.7
Alanine aminotransferase (U/L)	7–23	19
Aspartate aminotransferase (U/L)	13–30	20
Alkaline phosphatase (U/L)	38–113	73
Lactate dehydrogenase (U/L)	124–222	175
Γ-Glutamyltransferase (U/L)	9–32	17
C-reactive protein (mg/dL)	0–0.04	4.40
Acetaminophen (μg/mL)		< 10.0
Salicylic acid (mg/mL)		< 1.0
Ethanol (mg/mL)		< 10.0
Thyroid stimulating hormone (μIU/mL)	0.45–4.95	0.335
Free thyroxine (pg/mL)	1–1.04	2.13
Arterial blood gasesb
pH	7.35–7.45	7.13
The partial pressure of carbon dioxide (mmHg)	35–45	28.8
Partial pressure of oxygen (mmHg)	80–100	118.0
HCO3− (mmol/L)	22–26	9.1
Lactic acid (mmol/L)	0.36–0.75	4.20
Anion Gap (mmol/L)		31.9
Urinec
pH		< 5.0
Protein		2+
Occult blood		2+
Glucose		±
Ketones		–

^aCalculated by Japanese equation[3]

^bWe used ABL 825 FLEX analyzer (Radiometer, Copenhagen, Denmark)

^cWe used automated dipstick reader (US-3500; Eiken Chemical, Tokyo, Japan)

She received an additional 1000 ml of Ringer’s solutions, but her urine volume was < 20 ml/h. She received hemodialysis with a blood flow rate of 200 ml/min and a dialysate flow rate of 500 ml/min for severe metabolic acidosis and acute kidney injury. Her metabolic acidosis and hyperkalemia were improved after 4 h of hemodialysis (pH: 7.34, pCO₂: 35.3 mmHg, Na⁺: 137 mmol/L, K⁺: 4.1 mmol/L, Cl⁻: 108 mmol/L, anion gap: 17.3 mmol/L, lactate: 1.4 mmol/L, and HCO₃⁻: 18.7 mmol/L on arterial blood gas analysis).

Her acid–base status did not deteriorate (44 h after overdosing) (pH: 7.34, pCO₂: 36.2 mmHg, Na⁺: 140 mmol/L, K⁺: 4.1 mmol/L, Cl⁻: 104 mmol/L, anion gap: 16.8 mmol/L, lactate: 1.0 mmol/L, and HCO₃⁻: 19.2 mmol/L on arterial blood gas analysis) and her serum creatinine was not rebounded 6 h after hemodialysis. Her urine volume was adequate on the second hospital day. On the fourth hospital day, her renal function recovered, and she was transferred to the mental hospital for psychiatric treatment.

Figure 1 shows the changes over time in acid–base balance. We also described trends of acid–base balance, electrolytes and renal function in Supplementary Table 1. Interestingly, from the first (5 h after overdose) to the second hospital visit (31 h after overdose), serum anion gap levels were increased although serum lactate levels were decreased. The total ketone body, β-hydroxybutyric acid acetoacetic acid, and acetone were measured in the collected residual blood after 4 h of hemodialysis, which were all increased (Table 2). Additionally, urine ketone was positive on the second hospital day and her blood glucose levels have never exceeded 250 mg/dL since admission (Supplementary Table 1). We haven’t administered insulin to our patient during hospitalization.

Fig. 1.

Renal function and anion gap acidosis in patients after overdosage. AG anion gap, HCO₃⁻ bicarbonate; Lac lactate; Cr creatinine

Table 2.

Laboratory data after hemodialysis

Variable	Reference range	Results
Blood
Total ketone body (μmol/L)	26–122	6150
Acetoacetic acid (μmol/L)	13–69	1520
Acetone (μmol/L)	0–5	82
β-hydroxybutyric acid (mmol/L)	0–76	4630

Discussion

This study reports a 57-year-old female patient who developed severe metabolic acidosis and acute kidney injury after metformin overdosage of 25,000 mg and vildagliptin of 2500 mg. The major toxicity from acute or chronic metformin use is lactic acidosis. MALA had several mechanisms. First, metformin promotes glucose to lactate conversion in the intestinal mucosa. Second, metformin blocks mitochondrial oxidative metabolism, leading to a decreased hepatic gluconeogenesis from lactate, pyruvate, and alanine. Hence, anaerobic glycolysis occurs and blood lactate concentrations rise to clinical intoxication level [4–7]. Metformin overdosage seldom causes MALA, but patients will have severe acidosis if they develop MALA. Approximately 80% of patients who develop metformin overdosage-related MALA require hemodialysis [1]. The Extracorporeal Treatments in Poisoning Workgroup recommends hemodialysis for patients with any of the following findings associated with severe metformin poisoning: severely elevated serum lactate concentration, severe metabolic acidosis, standard therapy failure, and comorbid conditions, such as impaired kidney function [1]. Our patient underwent hemodialysis due to acute kidney injury and severe metabolic acidosis.

The patient’s serum anion gap increased despite the blood lactate level improvement. Furthermore, the total ketone body, β-hydroxybutyric acid acetoacetic acid, and acetone were increased even after hemodialysis treatment, and urine ketone was positive in the dipstick test on the second hospital day (Table 2 and Supplementary Table 1). Therefore, the cause of metabolic acidosis in this patient was not only lactic acidosis but also ketoacidosis. Ketoacidosis is a metabolic state that is associated with pathologically high serum and urine concentrations of ketone bodies. Diabetic ketoacidosis (DKA) is the most common cause of ketoacidosis in patients with diabetes. DKA typically occurs with relative or absolute insulin deficiency and an increased concentration of counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone), and its diagnosis requires plasma glucose of > 250 mg/dL, a pH of < 7.30, an elevated anion gap, and decreased serum bicarbonate [8, 9]. In euglycemic DKA (euDKA), insulin deficiency and insulin resistance are often mild and limit the surge in plasma glucose levels, therefore the definition of euDKA requires plasma glucose of < 250 mg/dL [9]. Our patient’s plasma glucose level was not so high (196 mg/dL) on admission. Therefore, we diagnosed our patient as euDKA.

A case series reported three patients with chronic metformin treatment who developed ketoacidosis combined with MALA [2]. The blood glucose level of these patients was not high, and the dosage of metformin was normal (850–1000 mg/day). Of the three patients, two suffered from acute gastroenteritis and one lasted 6 days before admission. Therefore, the authors concluded that starvation was the cause of ketoacidosis in these patients. In general, ketone bodies were generated in the liver as a normal physiological response to fasting. Blood levels of ketone bodies in healthy individuals rise from 2 to 4 days after fasting, and it takes 2 weeks for the total blood ketone bodies to rise above 5000 μmol/L [10]. Interestinglly, in our patient, the total ketone bodies were 6150 μmol/L after hemodialysis although the fasting time was only 34 h. EuDKA is induced by one or more of the following precipitating factors: severe infection, discontinuation of or inadequate insulin therapy, low carbohydrate intake or prolonged fasting, alcohol consumption, intercurrent acute events, drugs that affect carbohydrate metabolism, surgery, and other stressful physical and medical conditions [9, 11]. Therefore, the causes of euDKA in our case might include not only insulin deficiency due to diabetes mellitus and production of ketone bodies due to starvation, but also increase in counterregulatory hormones due to aspiration pneumonia and stressful physical conditions such as vomiting and diarrhea. Additionally, an animal study revealed that metformin suppressed liver triglyceride output and increased hepatic ketone body production in rats. Such an effect was accompanied by a significant reduction of plasma glucose, triglyceride, and insulin concentrations [12]. Therefore, we considered that metformin overdosage made our patient susceptible to euDKA during the short fasting time. Interestingly, to the best of our knowledge, this is the first case of euDKA combined with MALA in a patient with metformin overdosage.

The treatment in patients with euDKA is similar to that for hyperglycemic DKA. Management guidelines for DKA recommend rapid rehydration, continuous intravenous insulin administration, and electrolyte imbalance corrections. Additionally, administration of glucose-containing solutions is recommended when blood glucose levels fall below 250 mg/dL [7]. In our patient, one of the hemodialysis indications was severe metabolic acidosis. Therefore, the patient might not develop severe metabolic acidosis and needed no hemodialysis if we performed the treatment for euDKA, such as the administration of glucose-containing solutions and intravenous insulin. Patients with metformin overdosage might be susceptible to ketoacidosis as well as lactic acidosis. Therefore, assessing the relationship between blood lactate level and serum anion gap is important for MALA management. Patients with combined ketoacidosis should be considered if the serum anion gap remains high or worsens despite lactate improvement. The blood glucose levels should be checked and external fluid or glucose should be supplemented for ketoacidosis when we consider MALA with euDKA.

This is the first report that shows MALA with euDKA due to metformin overdose. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdosage.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

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