Metformin Induced Lactic Acidosis and Ischemic Colitis

Today's case involved an 80-year-old woman with a history of type 2 diabetes mellitus, decompensated heart failure with an EF of 20% as a result of a non-ischemic cardiomyopathy, hypertension, previous GIST (gastrointestinal stromal tumour) treated with Whipple procedure in 2012, and previous Non-Hodgkin Lymphoma treated with R-CHOP in 2011.  She was brought in my family due to profound weakness and decreased appetite for one month with two days of nausea and vomiting.  Her review of systems indicated dysphagia to liquids and solids but no significant constitutional symptoms.  Her physical examination did not reveal further clues to her current decline.  Her laboratory studies were remarkable for a lactic acidosis, ketosis, and acute kidney injury.  She was found to have a large post-void residual volume in her urinary bladder, and was catheterized.  A CT scan was performed to rule out ischemic colitis on the basis of elevated lactate and non-specific symptoms – the scan was normal.  The working diagnosis is pre-renal and post-renal acute kidney injury leading to non-specific symptoms, as well as the possibility of metformin-induced lactic acidosis given that she was on the drug, and her clearance would have been impaired.

Learning points:

-Patients frequently present with non-specific symptoms that cannot be readily applied to any diagnostic heuristic that we may have in our minds.  In those cases, it is helpful to carefully review pertinent historical and exam findings, and look for systemic problems with blood work.  Common things that cause syndromes like this are endocrinopathies (thyroid and adrenal disease, diabetic emergencies, hypercalcemia), malignancies such as leukemias/lymphomas as well as solid tumour malignancies, autoimmune conditions, etc.

-The patient was found to have an anion gap metabolic acidosis.  We discussed the differential diagnosis for this.  While commonly-used acronyms like MUDPILES are routinely taught in medical school, paraldehyde is so rarely used as a drug that I don’t think it deserves its own place in limited memory-spans.  Instead, it is helpful to think of things that cause an elevated anion gap and possible mechanisms that those could be produced:

                  -Lactic acid – shock, hypoperfusion, metformin

                  -Ketoacids (note that ketones themselves are not acidic but betahydroxybutyrate and acetoacetic acid are) – Diabetic Ketoacidosis, Alcoholic ketoacidosis, Starvation Ketoacidosis

                  -Renal failure – leads to buildup of inorganic acids like sulphates

                  -Toxins – salicylates, toxic alcohols (methanol, ethylene glycol), note that ethanol does not produce an acidosis directly but can produce alcoholic ketoacidosis as mentioned above through other hepatic mechanisms

-We discussed the less common scenario of a low anion gap, which can occur with bromine toxicity, and hyperparaproteinemia.

-The patient was treated for a diabetic emergency with intravenous insulin and fluids.  While that was not the scope of this morning report, diabetic ketoacidosis is typically treated with high volumes of intravenous fluids, electrolyte replacement, and intravenous insulin.

-Dysphagia can be grouped into mechanical causes (obstructing intraluminal or extraluminal tumours, etc) and propulsive causes (neuromuscular junction disesase, systemic sclerosis/CREST syndrome, coordination as in Alzhemiers, etc).

-Ischemic colitis is a diagnosis with which many of us are uncomfortable.  Typically, these patients are referred to surgery and we often have a nihilistic attitude about the prognosis of these patients.  Ischemic colitis typically results in pain out of proportion to the patient’s physical findings, an elevate lactate, and often a bloody diarrhea.  Gut can become ischemic for the same reasons that myocardial tissue does – a clot embolism from the left ventricle can obstruct one of the mesenteric vessels (think of STEMI), a plaque can rupture and impair blood flow to the mesenteric vessels (think of STEMI if complete occlusion, or NSTEMI if partial), or much more commonly, systemic hypotension/shock can result in impaired gut perfusion (think demand ischemia).  Finally, vasoactive medications like norepinephrine (Levophed®) tend to sacrifice gut perfusion to maintain systemic perfusion when used in critical care settings.  In the latter two types of gut ischemia, watershed areas of the gut (particularly at the hepatic flexure which is partially supplied by the end-artieries of two major arterial systems) tend to become infarcted.  Just like myocardial ischemia, there are treatments: most commonly, restoring effective circulatory perfusion is adequate.  Occasionally, clot-directed therapy and anticoagulation may be appropriate.

-Metformin lactic acidosis is one of those diagnoses that some people seem to ‘believe in’ and others do not.  Metformim works by inhibiting hepatic mitochondrial enzymes and impairing gluconeogenesis, lowering plasma glucose – in doing so, lactic acid is produced in small quantities.  In addition, it promotes promotes conversion of glucose to lactate in the splanchnic vasculature.  Significant lactic acidemia is extremely rare and typically results from either excessive metformin ingestion (intoxication) or impaired renal clearance, typically with a serum creatinine well above 120µM.

Further Reading:

Lalau, J. D. (2010). Lactic acidosis induced by metformin. Drug Safety, 33(9), 727-740.

Stades, A. M. E., Heikens, J. T., Erkelens, D. W., Holleman, F., & Hoekstra, J. B. L. (2004). Metformin and lactic acidosis: cause or coincidence? A review of case reports. Journal of internal medicine, 255(2), 179-187.

Kalantar-Zadeh, K., Uppot, R. N., & Lewandrowski, K. B. (2013). Case 23-2013: A 54-year-old woman with abdominal pain, vomiting, and confusion. New England Journal of Medicine, 369(4), 374-382.

Theodoropoulou, Α., & Κoutroubakis, I. E. (2008). Ischemic colitis: clinical practice in diagnosis and treatment. World journal of gastroenterology: WJG, 14(48), 7302.