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.

Alcoholic Hepatitis

Today's morning report featured an interesting case of Alcoholic hepatitis.

There were multiple learning points including:

a)     Alcoholic hepatitis is a frequently under-diagnosed condition which has a high morbidity and mortality.  It is characterized by elevations in liver enzymes (typically with AST:ALT ratio greater than 2:1, though rarely over 300, fever, altered mentation, elevated bilirubin and elevated INR.  The diagnosis is made clinically based on the previous historical and laboratory elements and a clinical history consistent with alcohol abuse.  The alcohol ingestion may precede the development of hepatitis by weeks in some cases.  Maddrey’s discriminant function, based predominantly on the Prothrombin Time (not the INR) and the bilirubin level is useful in distinguishing whether or not the patient would benefit from corticosteroid therapy.

b)    Abdominal pain in a patient with known cancer has a wide differential including bony metastases/hypercalcemia.

c)     Gastrointestinal bleeding in a patient with suspected liver disease could be the result of variceal hemorrhage.

Further Reading:

Lucey, M. R., Mathurin, P., & Morgan, T. R. (2009). Alcoholic hepatitis. New England Journal of Medicine, 360(26), 2758-2769.

Thursz, M. R., Richardson, P., Allison, M., Austin, A., Bowers, M., Day, C. P., ... & Forrest, E. H. (2015). Prednisolone or Pentoxifylline for Alcoholic Hepatitis. New England Journal of Medicine, 372(17), 1619-1628.

Thrombotic Microangiopathies (TTP)

Chief Resident Morning Report

Today's case was a patient presenting with microangiopathic hemolytic anemia, most likely thrombotic thrombocytopenic purpura (TTP) on the basis of either congenital/acquired ADAMTS13 deficiency, or an experimental chemotherapy drug.

Important learning points:

-Pathophysiologically, TTP results from multimers of Von Willebrand Factor (I erroneously said platelets) due to congenital or acquired deficiency of the enzymes responsible for degrading said multimers, ADAMTS13

-The classical clinical pentad of fever, altered mental status/seizures, renal failure, thrombocytopenia, and hemolytic anemia is rarely seen all together.

-The alterations in mentation are often fluctuating changes in LOC rather than discrete focal neurologic symptoms.

-The condition is 100% fatal if left untreated, and treatment consists of plasmapheresis (PLEX) at a centre like ours, or steroids and fresh frozen plasma while en route to a centre like ours.

-There is a wide differential of thrombocytopenia, and we discussed immune thrombocytopenic purpura as a potential diagnosis of exclusion among other causes.

-Be careful committing someone to a diagnosis of Evan’s syndrome (ITP and autoimmune hemolytic anemia) without ruling out a microangiopathic cause such as TTP/HUS.

-We discussed blood film findings (fragments/Schistocytes) and laboratory findings of hemolysis.

Further Reading:

George, J. N., & Nester, C. M. (2014). Syndromes of thrombotic microangiopathy. New England Journal of Medicine, 371(7), 654-666.

Fever in the Returned Traveller

 Today's case involved a 63-year-old man with longstanding, drug-resistant HIV returning from a trip to Asia with persistent fever and atypical pulmonary infiltrates.

Learning points discussed:

-Differential diagnosis of fever in the returned traveler and that the infection that cannot be missed is Malaria

-We discussed some of the clinical features of Pneumocystis jirovecii (formerly carinii) pneumonia

-We discussed opportunistic infections in HIV and their relationship to CD4 counts as well as the fact that tuberculosis infection is on the differential regardless of CD4 count – the guidelines for prophylaxis depending on CD4 count can be found here: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf

-It was discussed that, anytime a differential diagnosis of pulmonary tuberculosis is considered fungal infection and malignant processes must also be considered

-We discussed some of the endemic fungi including Aspergillus, Blastomycosis, Coccidiomycosis, and Histoplasmosis

Further Reading:

Ryan, E. T., Wilson, M. E., & Kain, K. C. (2002). Illness after international travel. New England Journal of Medicine, 347(7), 505-516.

Cerebral Vasculitis and Tolosa Hunt Syndrome

Rheumatology Morning Report

Today's case involved a young woman with known p-ANCA-associated vasculitis with manifestations of pulmonary hemorrhage, end-stage renal disease, and possible CNS involvement.  She presented to hospital with a history of headache and oculomotor nerve palsy (albeit sparing her extraocular movements) as well as trigeminal nerve (V1) involvement.  Her CT Angiogram was consistent with diffuse vasculitis of the CNS, while her MRI was much less impressive.  Lumbar puncture (performed several days following admission, after antibiotics) had mild pleiocytosis (8 lymphocytes) and hypoglycorrhachia (low glucose in spinal fluid).  Cultures have been negative to date despite impressive fevers on admission.  At this point, she is being treated with steroids for a presumed inflammatory CNS condition.

Learning points:

-We discussed vasculitis and the diagnostic elements and associations including cytoplasmic and perinuclear ANCA

-We discussed the systemic fibrosis that can take place when patients with ESRD are given gadolinium repeatedly

-We discussed the differential diagnosis of a third nerve palsy (CNIII) and that, if the pupil is spared, the patient typically has an infarction of the central portion of the nerve rather than a compressive etiology – a common cause of this would be diabetes

-We discussed Tolosa-Hunt syndrome, a granulomatous inflammation of the cavernous sinus which can cause damage to multiple cranial nerves – typically treated with immune suppression and can be an HIV-associated illness

-We discussed drug-induced lupus (usually a benign illness associated with drugs like Hydralazine) but also drug-induced vasculitis which can be quite severe and organ-damaging caused by drugs such as PTU and methimazole

-We discussed the rarity of CNS vasculitis and that a normal cerebrospinal fluid and a normal MRI brain has an extremely high negative predictive value to rule out this challenging-to-diagnose condition

Further Reading:

Jennette, J. C., & Falk, R. J. (1997). Small-vessel vasculitis. New England Journal of Medicine, 337(21), 1512-1523.

Hajj-Ali, R. A., & Calabrese, L. H. (2009). Central nervous system vasculitis. Current opinion in rheumatology, 21(1), 10-18.

Kline, L. B., & Hoyt, W. F. (2001). The Tolosa-Hunt syndrome. Journal of Neurology, Neurosurgery & Psychiatry, 71(5), 577-582.