Metformin-associated lactic acidosis in a patient with vertebral artery dissection.

To the Editor: Metformin, a biguanide antidiabetic drug, has been implicated as a cause of lactic acidosis, usually in a setting of renal failure, IV contrast administration, shock, sepsis, hypoxemia, heart failure, or liver disease. Although metformin can cause mild lactic acidemia in type 2 diabetes mellitus patients with normal renal function, (1,2) there are very few reports of lactic acidosis (blood lactate >5 mEq/L, anion gap > 15, arterial pH <7.35) in patients with normal renal function and no other obvious precipitating cause. In the following case, a metformin-treated man with mild and limited stroke symptoms and normal renal function developed lactic acidosis in the absence of other risk factors.

A 64-year-old man with type 2 diabetes mellitus, hypertension, hypothyroidism, and a left cerebellar infarct 4 weeks before was admitted with acute onset of dizziness and vertigo. He had had only mild problems with balance after the left cerebellar infarct, with steady improvement until the day of admission. At admission, his only complaint was vertigo; he denied fevers, chills, sweats, nausea, vomiting, orthostatic lightheadedness, chest pain, shortness of breath, diaphoresis, abdominal pain, or edema. He was not taking any nonprescribed medications, and denied any toxic ingestions. His medications were levothyroxine 0.15 mg q.d., meclizine 25 mg t.i.d., niacin SA 1000 mg q.h.s., nortriptyline 25 mg q.h.s., simvastatin 40 mg q.h.s., promethazine 25 mg q.6 hours p.r.n., and metformin 500 mg b.i.d., all of which he had been taking regularly. On physical examination, vital signs were temperature 96.0[degrees], blood pressure 138/84, pulse 102, and respiratory rate 24. Pulse oximetry was 98% on room air. There were no orthostatic pulse or blood pressure changes. The oral mucous membranes were moist. There was no jugular venous distention or hepato-jugular reflux; the heart was regular without murmurs, rubs or gallops. Lungs were clear; the abdomen was soft and nontender, with faint bowel sounds and no organomegaly. The extremities showed no cyanosis or edema. Neurologic examination was significant only for an abnormal finger-to-nose test on the left side. Initial laboratory testing showed sodium 140 mEq/L, potassium 4.5 mEq/L, chloride 102 mEq/L, C[O.sub.2] 17 mmol/L, BUN 31 mg/dL, creatinine 1.4 mg/dL, and anion gap 21. Liver function tests were normal. Troponin-I was normal at 0.06 ng/mL. Urinalysis showed trace protein and no ketones. The lactate level was 5.2 mEq/L (normal 0.5-2.2 mEq/L). CPK was 51 U/L (normal 0-225). Metformin was held, and the patient was hydrated with IV normal saline. Over the course of four days, the lactic acidosis resolved and the anion gap normalized (Table). Head computed tomography (CT) scan showed a left inferior cerebellar infarct with volume loss and no hemorrhagic transformation. CT of the neck showed a subacute vertebral artery dissection, which was confirmed with magnetic resonance angiography (MRA) of the neck. The patient was anticoagulated with enoxaparin and then Coumadin. His symptoms of dizziness and vertigo continued to improve, and had resolved completely by the time of his neurology clinic follow-up 2 months after discharge.

There are very few reports of metformin-associated lactic acidosis (MALA) in the absence of risk factors for lactic acidosis, which include renal failure, hypotension, shock, sepsis, hypoxemia, and severe cardiac, respiratory, or liver disease. In a review of 47 high-quality case reports by Stades et al in 2003, only one did not have identifiable risk factors. (3) This was a 40-year-old woman with type 2 diabetes mellitus and asthma, who presented with an asthma exacerbation complicated by lactic acidosis (blood lactate 6.9 mmol/L) despite normal renal function, adequate oxygenation, hemodynamic stability, and a therapeutic metformin level. (4) The normal renal function and therapeutic metformin level ruled out metformin accumulation as the cause of lactic acidosis. The authors postulate that a subset of patients have an intrinsic predisposition to lactic acidosis, possibly a mitochondrial defect, that can be unmasked by metformin.

In this case of MALA in a patient with vertebral artery dissection, there were no clear risk factors for lactic acidosis. There was no hypoxemia, and no orthostatic pulse or blood pressure changes to support dehydration. Liver function was normal, and cardiac enzymes and electrocardiogram did not show evidence of an acute coronary syndrome. The patient presented with mild prerenal azotemia which resolved overnight with IV hydration; his maximum serum creatinine level of 1.4 mg/dL did not exceed the recommended cutoff of > 1.5 mg/dL for metformin treatment in males. MRI and CT of the brain showed only a small cerebellar infarct, the limited extent of which was also supported by the patient's mild symptoms and normal CPK level. In itself, stroke is not associated with lactic acidosis except either in cases of massive stroke affecting respiratory or cardiac function, or in the very rare syndrome known as mitochondrial encephalopathy with lactic acidosis and stroke (MELAS), which is described only in children and young adults. (5) Interestingly, lactic acidosis can disturb the normal balance between elastase and its inhibitors in arterial tissues, and may therefore increase the risk of arterial dissection. (6)

This case report adds to the evidence that metformin can trigger lactic acidosis in a small subset of patients with normal renal function and no other evident risk factors. The cause is unclear, but an otherwise subclinical inborn or acquired error of lactate metabolism might predispose some metformin-treated patients to lactic acidosis. Physicians should be alert to the possibility of lactic acidosis in any metformin-treated patient with an unexplained anion gap metabolic acidosis, regardless of risk factors and renal function.

Clifford D. Packer, MD

Louis Stokes Cleveland VA Medical Center

Case Western Reserve University School of Medicine

Cleveland, OH

References

1. Abbasi AA, Kasmikha R, Sotingeanu DG. Metformin-induced lacticacidemia in patients with type 2 diabetes mellitus. Endocr Pract 2000;6:442-446.

2. Khan JK, Pallaki M, Tolbert SR, et al. Lactic acidemia associated with metformin. Ann Pharmacother 2003;37:66-69.

3. Stades AM Heikens JT, Erkelens DW et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004;255:179-187.

4. Al-Jebawi AF, Lassman MN, Abourizk NN. Lactic acidosis with therapeutic metformin blood level in a low-risk diabetic patient. Diabetes Care 1998;21:1364-1365.

5. Matsumoto J, Saver JL, Brennan KC, et al. Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). Rev Neurol Dis 2005;2:30-34.

6. Trofymova IM Dosenko Vie, Byts' IuV. [Activity of elastase and its inhibitors in tissues of aorta and blood serum in various types of acidosis] Fiziol Zh 2001;47:24-29.

Table. Laboratory values

                    20 days
                    before     On         Hospital  Hospital  Hospital
Variable            admission  admission  day 2     day 3     day 4

Lactate (mEq/L)      -          5.2        4.9       2.6       0.9
CO2 (mmol/L)        27         17         22        26        22
Anion gap           11         21         15        10        14
BUN (mg/dL)         14         31         18        13        11
Creatinine (mg/dL)   1.0        1.4        1.2       1.0       1.1
CPK (IU/L)           -         51          -         -         -