J. Ryan Altman, MD AM Report 6 October 2009 Lactic Acidosis J. Ryan Altman, MD AM Report 6 October 2009

Lactic Acidosis Most common cause of metabolic acidosis in hospitalized patients Associated with elev anion gap and plasma [lactate] > 4mEq/L Result of both overproduction and underuse of lacate Normal plasma [lactate] is 0.5 to 1.5 mEq/L Causes Impaired tissue oxygenation (Type A) Systemic impairment in oxygenation is not apparent (Type B)

Lactic Acidosis Type A Type B Impairment of tissue oxygenation Circulatory or respiratory failure, sepsis, ischemic bowl, carbon monoxide, marked tissue hypoperfusion (shock), hypovolemia Type B No impairment of tissue oxygenation (toxin-induced impairment of cellular metabolism or regional areas of ischemia) Malignancy, alcoholism, NRTIs, salicylates, metformin Predisposing conditions to metformin toxicity: renal insufficiency (Cr>1.5mg/dl), concurrent HF req pharmacologic therapy, liver disease or EtOH abuse Malignancy: pathogenesis unclear, but removal of tumor (chemo, irradiation, or surgery) leads to correction of acidosis Alcoholism: lactate production is nl, but utilization is diminished b/c of impaired hepatic gluconeogenesis. HIV infection: may be from serious infections leading to sepsis induced lactic acidosis (Type A) or drug induced mitochondrial dysfunction in absence of sepsis or hypoperfusion (Type B)

Lactic Acidosis D-lactic acidosis Seen in pts c jejunoileal bypass, small bowel resection, or other causes of short bowel syndrome Glc and starch are metabolized in the colon to D-lactic acid, which is then absorbed in to the systemic circulation. Acidemia persists as D-lactate is not recognized by L-lactate dehydrogenase (which normally catalyzes conversion of L-lactate into pyruvate)

Lactic Acidosis (Etiologies) Increased lacate production Increased pyruvate production Enzymatic defects in glycogenolysis or gluconeogenesis (type I glycogen storage disease) Respiratory alkalosis, including salicylate intoxication Pheochromocytoma Impaired pyruvate utilization Decreased activity of pyruvate dehydrogenase or pyruvate carboxylase Congenital ? Role in DM, Reye’s syndrome

Lactic Acidosis (Etiologies) Increased lactate production Altered redox state favoring pyruvate conversion to lactate Enhanced metabolic rate Grand mal seizure Severe exercise Hypothermic shivering Severe asthma Decreased O2 delivery Shock Cardiac arrest Acute pulmonary edema Carbon monoxide poisoning Severe hypoxemia (PO2 <25-30mmHg) Pheochromocytoma Reduced O2 utilization Cyanide intoxication (decr oxidative metabolism): from cyanide poisoning or during a fire from smoke inhalation of vapors Drug induced mitochondrial dysfunction due to zidovudine or stavudine D-lactic acidosis

Lactic Acidosis (Etiologies) Primary decrease in lactate utilization Hypoperfusion and marked acidemia Alcoholism Liver disease Mechanism uncertain Malignancy DM, including metformin in absence of tissue hypoxia AIDS Hypoglycemia Idiopathic

Lactic Acidosis Trizivir (nucleoside reverse transcriptase inhibitor x3) Abacavir/Lamivudine/Zidovudine Black Box Warning Hypersensitivity Rxn (Abacavir) Pts with HLA-B*5701 allele are at higher risk of hypersensitivity reaction Hematologic Toxicity (Zidovudine) Neutropenia and severe anemia Myopathy (Zidovudine) Symptomatic myopathy associated with prolonged use Lactic Acidosis Both lactic acidosis and severe hepatomegaly c steatosis incl fatal cases, associated with NRTI alone or in combination Hep B exacerbation Severe acute Hep B exacerbations in HBV/HIV co-infected pts upon lamivudine d/c. Monitor hepatic function closely for at least several months in HBV/HIV co-infected pts who d/c abacavir/lamivudine; initiate Hep B tx if needed

Bibliography Causes of Lactic Acidosis. www.uptodateonline.com 6 Oct 2009. Sabatine, Marc. Pocket Medicine 3rd Ed. Epocrates

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