Artemisinin is an ancient Chinese herbal therapy for malarial fevers which has been recently found to have potent activity against many forms of malarial organisms, including chloroquine-resistant Plasmodium falciparum. Several artemisinin derivatives have been developed for clinical use in prevention and treatment of malaria, some of which have been linked to rare instances of acute liver injury.
The artemisinins (ar tem' is in in), including artesumate, arteeter, artemether, artemisinin, and dihydroartemisinin, are derivatives of the Chinese herb known as "qing hao" or sweet wormwood plant (Artemisia annua). The artemisinins have antimalarial activity in vitro and in vivo and are believed to act by release of free radicals into the parasite vacuoles. Artemisinin derivatives are currently the most active antimalarial drugs available and have been introduced around the world as an integral part of therapy of active malaria, always in combination with other antimalarials to prevent resistance such as amodiaquine, lumefantrine and mefloquine. Several oral and parenteral formulations of artemisinin derivatives are available worldwide. In the United States, the combination of artemether (20 mg) and lumefantrine (120 mg) was approved for therapy of P. falciparum malaria in 2009 under the brand name Coartem. The recommended dose for adults is 4 tablets twice daily for 3 days (6 doses). Artesunate (Adamsunate) is also available on a named-patient basis from the Centers for Disease Control and Prevention (CDC) Malaria Hotline (770-488-7788, M-F, 8 am to 4:30 pm, Eastern time). General recommendations on use of artemisinin and other antimalarial agents are available at the CDC website: http://www.cdc.gov/malaria/. Common side effects of artesunate include nausea, vomiting, anorexia, and dizziness. Potentially severe adverse events include prolongation of the QTc interval and cardiac arrhythmias.
Artemisinin derivatives have been associated with a low rate of serum aminotransferase elevations (1% to 4%) that are generally asymptomatic, mild-to-moderate and self-limited, often resolving even with continuing therapy. In most studies, the rate of serum ALT elevations during artemisinin therapy was similar to that of patients on comparator agents. Importantly, there have been increasing numbers of reports of idiosyncratic acute liver injury in patients taking artemisinin derivatives. Complicating the interpretation of these reports, however, is that most severe cases of liver injury occurred in patients who were also receiving other antimalarial agents, some of which are known to be hepatotoxic (amodiaquine, sulfamethoxazole, sulfadiazine/pyrimethamine). The onset of injury was usually within a few days to weeks of starting artemisinin, and the pattern of serum enzyme elevations was typically hepatocellular. Features of hypersensitivity such as rash, fever and eosinophilia were uncommon and autoantibodies have not been described. Symptoms can resemble those of acute viral hepatitis and the hepatitis can be severe, and several fatal instances or cases requiring emergency liver transplantation have been reported. Nevertheless, clinically apparent liver injury due to artemisinin derivatives is very rare and was not reported in several large clinical trials of malaria treatment. Most published reports of hepatotoxicity of artemisinin were linked to use of herbal supplements containing artemisinin and with extended treatment.
Liklihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which artemisinin derivatives cause liver injury is unknown. Clinical factors and testing for serum antibodies suggest an idiosyncratic immunological reaction to a hepatic metabolite may be responsible. Artemisinin derivatives are extensively metabolized by the liver (primarily via CYP 3A4) and are prone drug-drug interactions if given with strong CYP 3A4 inducers such as rifampin, phenytoin or St. John's wort or inhibitors such as intraconazole or ritonavir.
Outcome and Management
There does not seem to be cross reactivity to hepatic injury of the artemisinin derivatives with other antimalarial agents, but it is likely that sensitivity will be shared among the various artemisinin.
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Case 1. Acute liver injury due to artemisinin exposure.
[Modified from: Centers for Disease Control and Prevention (CDC). Hepatitis temporally associated with an herbal supplement containing artemisinin – Washington, 2008. MMWR Morb Mortal Wkly Rep 2009; 58: 854-6. PubMed Citation]
A 52 year old man with irritable bowel syndrome was treated with an herbal powder that contained artemisinin and developed fatigue and dark urine 10 days later. He had no history of liver disease, alcohol abuse, recent travel or risk factors for viral hepatitis. His only other medication was an occasional acetaminophen tablet. Analysis of the powder indicated that he had been taking the equivalent of 600 mg of artemisinin daily. Physical examination revealed jaundice and mild abdominal tenderness without fever or rash. Laboratory testing suggested a mild hepatitis (Table). His serum enzymes had been normal on routine testing five months earlier. Tests for hepatitis A, B and C were negative. Acetaminophen was not detected. He was monitored on no therapy and improved rapidly. Symptoms had resolved and all tests were negative two weeks later.
|Medication:||Herbal powder containing artemisinin|
|Pattern:|| Hepatocellular (R=9.6)|
|| 3+ (jaundice, hospitalization)|
|| 2 weeks |
|| 2 weeks|
|Other medications:||Occasional acetaminophen|
|Time After Starting
||Time After Stopping
Cases of artemisinin hepatotoxicity have been characterized by rapid onset within a few days to 3 weeks of starting therapy and a hepatocellular pattern of serum enzyme elevations, but without signs of hypersensitivity such as rash, fever or eosinophilia. The cause of the injury is unknown, but it has many features of hypersensitivity such as short latency and occurrence upon reexposure. Fatal instances have been reported. The current case was distinctive in that the patient was taking artemesinin not for malaria, but as a part of an herbal medication for gastrointestinal complaints. Artemisinin was taken in very high doses and for a longer period than is typical for acute malaria (active therapy of which is typically for 3 days).
REPRESENTATIVE TRADE NAMES
Artemisinin Derivatives (artemether, lumefantrine) – Coartem®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 08 February 2017
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