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ABSTRACT |
 TOP ABSTRACT CASE REPORTDISCUSSIONREFERENCES |
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CASE REPORT |
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TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
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Her general condition worsened and she came to the University Hospitals of Geneva on May 29. On admission, she was apyretic, jaundiced, and weak. Clinical examination showed right hypochondral tenderness but no hepatosplenomegaly. Apart from asterixis, she had no other neurologic symptoms. Her liver enzyme levels were highly elevated: aspartate aminotransferase = 1,137 U/L (normal = 11–24 U/L), alanine aminotransferase = 1,475 (normal = 9–42 U/L), and 
-glutamyl transpeptidase = 124 U/L (normal = 9–35 U/L). Other biochemical test results were total bilirubin = 410 µmol/L (normal = 7–25 µmol/L), conjugated bilirubin = 204 µmol/L (normal = 2–9 µmol/L), and alkaline phosphatase = 108 U/L (normal = 30–125 U/L), prothrombin time = 17% (normal = 80–120%), factor V = 22% (normal = 65–130%), factors VII–X = 10% (normal = 80–120%), fibrinogen = 0.7 g/L (2.0–4.0 g/L), hemoglobin = 123 g/L (normal = 120–160 g/L), platelets 206 x 109/L (normal = 150–350 x 109/L), and serum or plasma creatinine = 78 µmol/L (normal = 35–88 µmol/L).
Ultrasound results of the abdomen were normal. Laboratory test results for malaria parasites, hepatitis A, B, and C viruses, cytomegalovirus, and Epstein Barr virus were negative. Autoantibodies to liver kidney microsomes, smooth muscle enzymes, and mitochondria were absent. Results of genetic analysis of hepatic cytochrome P450 isozymes 2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5), 2C9 (2C9*1, 2C9*2, 2C9*3), 2D6, and 2E1 were normal.
Within approximately four days her liver enzyme levels decreased slightly, but the prothrombin time and factor V levels did not change. Her clinical condition deteriorated with the onset of stage II of hepatic encephalopathy (confusion and disorientation). She was immediately put on the waiting list for hepatic transplantation, and received a liver transplant on the sixth day of hospitalization. The operation was successful, she completely recovered, and was discharged on the 19th day of hospitalization.
Histologic analysis of the liver showed subtotal hepatocellular necrosis and lobular collapse associated with portal and lobular inflammation characterized by lymphocytes, eosinophils, and some neutrophils. There were rare hepatocellular nodules and neo-ductules compatible with regeneration. There was discrete chronic cholecystitis.
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DISCUSSION |
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Amodiaquine has caused serious and, in some cases, fatal liver and bone marrow toxicity in travelers when used as prophylaxis.3–6 The reported rate of serious hepatic reaction is 1 in 15,650 amodiaquine users.4–6 Although amodiaquine-induced hepatitis is uncommon, it is serious and could lead to encephalopathy and death. The patient described herein survived only because of a liver transplant. A few cases of cytolytic hepatitis have occurred as early as three weeks after exposure. With the long half-life of amodiaquine (9–18 days), jaundice could persist for as long as 3–6 months. Liver test results remain abnormal approximately 7–27 months after the onset of hepatitis.7,8 The pathogenesis of amodiaquine-induced hepatitis remains unclear. However, this drug may have a direct toxic effect on the liver through production of a quinine imino intermediate or through anti-amodiaquine IgG antibodies.9
It has been reported that amodiaquine clearance and its metabolism to N-desethyl amodiaquine is mediated mainly by cytochrome CYP2C8 enzyme activity. The cytochrome P450-dependent mono-oxygenase system is the product of a multigene family of central importance in the metabolism of drugs. Genetic polymorphism is believed to play an important role in clinical toxicology for a number of cytochrome CYP subfamilies.10,11 The CYP2C subfamily constitutes a major group of expressed P450 in the human liver, with four isozymes identified (cytochrome P450 2C8, 2C9/10, 2C18, and 2C19) Genetic polymorphisms have been identified in all members of this subfamily. Because aamodiaquine clearance and its metabolism to N-desethyl amodiaquine is mediated mainly by CYP2C8, our patient was genotyped for CYP2C8, 2C9*1, 2C9*2, and 2C9*3 variant alleles. She did not have any mutations. Single-nucleotide polymorphism of the CYP2C subfamily is unlikely to have contributed to this case of fulminant hepatitis, which suggests that a toxic metabolite of amodiaquine could have contributed to the cause of this disease.
Amodiaquine is more palatable and effective in the treatment of malaria than chloroquine. However, since the mid-1980s, there were reports of fatal adverse drug reactions described in travelers using amodiaquine as antimalarial prophylaxis.3–6 Since 1990, amodiaquine has not been recommended for malaria prophylaxis because of serious side effects, especially agranulocytosis and hepatotoxicity. However, its combination with sulfadoxine-pyrimethamine appears to be an effective treatment regimen for uncomplicated Plasmodium falciparum malaria in areas of low resistance to those drugs; even more effective is the combination amodiaquine and atesunate.12–14
The patient in this case report was prescribed amodiaquine by her doctor in Algeria. This implies that some people are still being prescribed amodiaquine to prevent malaria. When they have similar signs and symptoms, they could be misdiagnosed as having malaria or viral hepatitis, which could result in liver failure that is not recognized as drug-induced. This supposition warrants further investigation, and education of physicians, pharmacists and the public to increase awareness of the potential risks of using amodiaquine as antimalarial prophylaxis.
Received August 15, 2006. Accepted for publication February 5, 2007.
Disclosure: The authors have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of this case report.
* Address correspondence to Lydia Novisi Markham, University Hospitals of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. E-mail: markham-lydia{at}diogenes.hcuge.ch 
Authors’ addresses: Lydia Novisi Markham, Emiliano Giostra, Antoine Hadengue, Michel Rossier, Michela Rebsamen, and Jules Desmeules, University Hospitals of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland, Telephone: 41-22-3723311, Fax: 41-22-3729366, E-mail: markham-lydia{at}diogenes.hcuge.ch.
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This article has been cited by other articles:
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  D. L. Doolan, C. Dobano, and J. K. Baird Acquired Immunity to Malaria Clin. Microbiol. Rev., January 1, 2009; 22(1): 13 - 36. [Abstract] [Full Text] [PDF]
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