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Cocaine-Induced Acute Hepatitis and Thrombotic Microangiopathy
To the Editor: Cocaine abuse has been separately associated with acute hepatitis and thrombotic microangiopathy (TMA); however, we are not aware of prior case reports of their simultaneous occurrence.
Report of a Case
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A 22-year-old woman was hospitalized because of weakness, vomiting, fever, and jaundice for 3 days. She had consumed ethanol (80 g/d) and intravenous cocaine (1-2 g/wk) for the last 3 years but reported an increase in cocaine consumption in the previous week (>2 g/d). Chronic hepatitis C virus (HCV) was diagnosed 1 year earlier; at that time, her levels of transaminases, serum bilirubin, serum albumin, and her international normalized ratio (INR) were normal. On admission, physical examination was normal except for the presence of jaundice. She initially had markedly elevated transaminases (aspartate aminotransferase: 1264 U/L; alanine aminotransferase: 1305 U/L); increased alkaline phosphatase (308 U/L),  -glutamyltransferase (110 U/L), and serum total bilirubin (12 mg/dL [205.2 µmol/L]); an albumin level of 34 g/L, INR of 1.10, and partial thromboplastin time of 33 seconds; and normal complete blood cell count and renal function. Urine toxicology screening was positive only for cocaine.
In the following 48 hours, she developed rapidly progressive respiratory and renal failure, hypotension, and tonic-clonic seizures, requiring tracheal intubation and admission to the intensive care unit. Creatinine level was 5.4 mg/dL (477.4 µmol/L), aspartate aminotransferase was 860 U/L, alanine aminotransferase was 950 U/L, total bilirubin was 71.4 mg/dL (1220.9 µmol/L), and troponin I level was 28.6 ng/mL. She had developed severe thrombocytopenia (platelet cell count, 21 000/µL) and hemolytic anemia (hematocrit: 23%; lactate dehydrogenase: 5060 U/L; indirect bilirubin: 49 mg/dL [837.9 µmol/L]; haptoglobin: 50 mg/dL; reticulocyte count: 3.9%; and negative direct and indirect Coombs test). Peripheral blood smear sample showed 6 to 7 schistocytes per field. Coagulation test results showed an INR of 2.0, partial thromboplastin time of 33 seconds, fibrinogen of 3.8 g/L, and negative qualitative D-dimer. Blood and urine culture test results were negative. Chest radiograph demonstrated bilateral alveolar infiltrates compatible with acute respiratory distress syndrome and electrocardiogram indicated acute inferior myocardial infarction. The test results of abdominal ultrasonography, viral hepatitis serology other than HCV, serum ceruloplasmin and copper levels, and antinuclear and anti–smooth muscle antibodies were normal. Transjugular liver biopsy showed multifocal hepatic necrosis as well as microvesicular steatosis consistent with toxic hepatitis.
These findings were diagnostic of cocaine-induced TMA and acute hepatitis. Plasma exchange using 5% albumin as replacement solution was instituted and performed daily for 8 days until normalization of platelet cell count. Acute respiratory distress syndrome and neurological changes resolved 6 days after intensive care unit admission. Hemolytic anemia also resolved, with no further blood transfusion requirement after 4 days of plasma exchange. Hepatic function normalized over the following 3 weeks. Hemodialysis was performed during the first 2 weeks after intensive care unit admission. The patient was discharged from the hospital 26 days after admission. Blood test results 1 month later showed an INR of 1.0, and hematological and renal test results were normal.
Comment
Cocaine-induced liver damage has been well-reported, with a clinical spectrum ranging from minimal elevation of transaminases in chronic users, to acute hepatitis, to hepatic failure associated with rhabdomyolysis.1 Liver biopsy usually shows hepatic necrosis and microvesicular steatosis. The zonality of the necrosis varies according to the activity of cytochrome P450 enzymes.1 In contrast, TMA induced by cocaine consumption is rare, with only 3 previously reported cases.2-3 The main diagnostic criteria include intravascular hemolytic anemia and thrombocytopenia. Other findings, such as renal impairment, neurological deterioration, and normal coagulation test results, are considered minor criteria and not necessary for TMA diagnosis.4 The simultaneous presence of acute hepatitis and TMA has not been previously reported.
For TMA, early institution of plasma exchange is essential since this treatment dramatically reduces mortality rates from approximately 90% to between 10% and 30%.5 In cases in which TMA is associated with extensive systemic endothelial cell damage, as in this patient, plasma exchange can be performed using a replacement solution of 5% albumin solution rather than plasma, which has a higher rate of adverse events.6 Several toxic metabolites of cocaine including N-hydroxynorcocaine and norcocaine, produced by the P450 cytochromes, are responsible for the acute hepatitis. Ethanol consumption increases hepatotoxicity by inducing these enzymes and increasing free radical activity and hepatic lipid peroxidation. The pathogenesis of TMA is unclear. Proposed mechanisms include an immune reaction and direct damage of vascular endothelium such as occurs in malignant hypertension, pre-eclampsia, and burns.2-3 Physicians should be aware that cocaine may cause TMA in association with toxic acute hepatitis in order to promptly institute plasma exchange.5
Francesc Balaguer, MD;
Javier Fernández, MD
jfdez{at}clinic.ub.es
Liver Unit
Institut de Malalties Digestives
Miguel Lozano, MD
Hemotherapy and Hemostasis Department
Rosa Miquel, MD
Pathology Department
Antoni Mas, MD
Liver Unit
Institut de Malalties Digestives
Hospital Clinic Barcelona
University of Barcelona
Barcelona, Spain
1. Miscellaneous drugs and diagnostic chemicals. In: Zimmerman HJ, ed. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:709-742.
2. Volcy J, Nzerue CM, Oderinde A, Hewan-Iowe K. Cocaine-induced acute renal failure, haemolysis, and thrombocytopenia mimicking thrombotic thrombocytopenic purpura. Am J Kidney Dis. 2000;35:E3.
3. Keung YK, Morgan D, Cobos E. Cocaine-induced microangiopathic haemolytic anaemia and thrombocytopenia simulating thrombotic thrombocytopenia purpura. Ann Hematol. 1996;72:155-156.
PUBMED
4. Dlott JS, Danielson CF, Blue-Hnidy DE, McCarthy LJ. Drug-induced thrombotic thrombocytopenic purpura/haemolytic uremic syndrome: a concise review. Ther Apher. 2004;8:102-111.
5. Yarranton H, Machin SJ. An update on the pathogenesis and management of acquired thrombotic thrombocytopenic purpura. Curr Opin Neurol. 2003;16:367-373.
PUBMED
6. Espinosa G, Bucciarelli S, Cervera R, et al. Thrombotic microangiopathic hemolytic anemia and antiphospholipid antibodies. Ann Rheum Dis. 2004;63:730-736.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2005;293:797-798.
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