CAM/Drug-Induced Hepatotoxicity: Implications in Viral Hepatitis

Mohammad K. Parvez, Mohammed S. Al-Dosari

Mohammad K. Parvez, Mohammed S. Al-Dosari, Department of Pharmacognosy, King Saud University College of Pharmacy, Riyadh 11451, Saudi Arabia

Correspondence to: Mohammad K. Parvez, PhD, Assistant Professor, Department of Pharmacognosy, King Saud University College of Pharmacy, PO Box 2457, Riyadh 11451, Saudi Arabia.
Email: khalid_parvez@yahoo.com
Telephone: +966-1-4675132
Fax: +966-1-4677254
Received: July 10, 2015
Revised: July 23, 2015
Accepted: July 28, 2015
Published online: Juauary 17, 2016


In recent times, complementary and alternative medicine (CAM) has gained much popularity in the treatment of various chronic diseases. However, CAM/drug-related heptotoxicity is a serious public health problem where over- or misdiagnosis is a common phenomenon. For example, the initially assumed drug-induced liver injury was actually due to hepatitis E. In clinical practices, casualty assessment of suspected hepatotoxicity is hampered by the lack of a standardized approach that requires simplicity of the methodology. This could be best achieved by the combination of clinical judgment and a liver-specific causality assessment algorithm issued by the Council for International Organizations of Medical Sciences (CIOMS). Therefore, patients with chronic hepatitis should be counseled and screened by physicians on potential risks associated with CAMs and dietary supplementations.

© 2016 ACT. All rights reserved.

Key words:Complementary and alternative medicine; Hepatotoxicity; Viral hepatitis; Acute liver failure; CAM-drug interaction

Parvez MK, Al-Dosari MS. CAM/Drug-Induced Hepatotoxicity: Implications in Viral Hepatitis. Journal of Gastroenterology and Hepatology Research 2016; 5(1): 1921-1923 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/1555


Complementary and alternative medicine (CAM) has gained much popularity and is preferentially used for various chronic diseases, worldwide[1,2]. Compared to a single chemically-characterized drug, CAM is a mixture of phytochemical constituents present in the herbal extract. Although CAM is generally thought to be safer than conventional drugs, there are many reports about hepatotoxicity and other adverse effects of some common herbal products or dietary supplements[1,3]. CAM/drug-related morbidity is therefore, a serious public health problem with broad implications for clinicians, the pharma industries and health regulatory agencies. In CAM/drug-induced liver injury, over- or misdiagnosis is a common phenomenon[4-7]. Of ample such reports, the initially assumed drug-induced liver injury was actually due to hepatitis E virus (HEV) infection[5,6]. Similarly, in a recent assessment of initially suspected CAM-induced liver injury, correct diagnoses were missed in about 50% cases[7]. Recently, the importance of CAMs as a cause of liver injury has been reported in a retrospective study wherein about 10% of cases were attributed to dietary supplements and 7% to Chinese herbal drugs[8]. Therefore, CAM-induced liver pathogenesis should be considered as a neglected disease that requires special attention. Presently, potential genetic risk factors and biomarkers, including micro-RNAs are being investigated to explain molecular basis of CAM/drug-related liver diseases[9-11]. Though these data are valuable and provide promising insights, they contribute little to correct and timely diagnosis. Owing to unavailability of the best approach in clinical practices, the physician needs a pragmatic guideline to quickly evaluate suspicious cases of liver injury and reach a conclusive diagnosis.

Hepatotoxicity or liver injury

The Council for International Organizations of Medical Sciences (CIOMS) defines liver injury as increase in serum aminotransferases (ALT/AST) and/or alkaline phosphatase (ALP) levels of at least 2-fold of the upper limit of normal (2N)[12]. Though serum γ-glutamyltranspeptidase (γGT) alone is not an appropriate parameter for assessing liver cell injury[13,14], it is recommended to rule out isolated increases of ALP due to bone rather than hepatobiliary disease. The lower threshold of ALT above 2N may include nonspecific liver enzyme elevations and requires more stringent exclusion of causes unrelated to CAMs and drugs[14]. An ALT cut-off of 5N may not be applicable to some types of chronic liver injuries, such as methotrexate liver fibrosis or nodular regenerative hyperplasia. Misdiagnosis and/or misinterpretation is however, possible in some forms of acute liver injury by valproate- or fialuridine-induced mitochondrial toxicity[14].

Acute liver failure

Acute liver failure, also known as fulminant hepatic failure is described as a syndrome characterized by the rapid development of liver damage (80-90% of hepatocytes), decreased hepatic metabolizing of enzymes and drugs. Though it is less common than chronic liver failure, can further lead to serious complications such as encephalopathy and coagulopathy. While hepatitis viruses are among the most common causes of acute liver failure in developing countries, CAM/drug intoxication by kava, ephedra, skullcap, pennyroyal and acetaminophen etc. predominates in the USA and Europe[15-17].

CAM-drug interactions in viral hepatitis

In CAM-induced hepatotoxicity, a major concern is the knowledge and awareness while considering using CAM that whether or not drug-CAM interactions may exist and could impact the therapy. Garlic extracts, grapefruit juice, and germander have been already reported to interact with drug-metabolizer gene cytochrome P450 3A4 (CYP3A4)[18]. St. John’s wort, a common CAM used for the treatment of depression, is a known inducer of CYP3A4[19]. In recent years, a substantial increase of reports on efficacies of natural- or phytoproducts against hepatitis B and C viruses (HBV and HCV) has been published[20]. The issue of CAM-drug interaction becomes even more complicated with the addition of new herbal medications for the treatment of chronic hepatitis C. Notably, CYP3A4 is also the primary metabolizer of many antiviral drugs, including the inhibitors of HCV protease (Telaprevir, Boceprevir and Simeprevir) and reverse-transcriptase (Sofosbuvir). Since, St. John’s wort is also a potent inducer of intestinal P-glycoprotein, it may lead to altered absorption and therefore, reduced therapeutic effect of Sofosbuvir[21].

In addition to drugs, several herbal flavonoids such as apigenin, quercetin, kaempferol and green tea catechins, interact with drug uptake transport proteins of the organic anion-transporting polypeptides (OATP) family[22] Silymarin, a purified extract from milk thistle, is a popular herbal supplement that is used by approximately one-third of patients with chronic liver disease including hepatitis C. Very recently, interaction of silymarin, silybin A, silybin B and silychristin with OATAP has been described[22]. Also, concomitant use of silymarin is contraindicated with Simeprevir because of possible hepatotoxicity[23]. Glycyrrhizin, the main active component of licorice, is another widely used therapeutic against hepatitis C. Due to its widespread, multifaceted use, potential drug interactions of glycyrrhizin have recently gained attention showing its effects on drug-metabolizing enzymes (CYP3A and PXR) and efflux transporters[24].


In clinical practices, causality assessment of suspected hepatotoxicity is hampered by the lack of a standardized approach that requires simplicity of the methodology. This could be best achieved by the combination of clinical judgment and a liver-specific causality assessment algorithm issued by CIOMS. Moreover, patients with chronic hepatitis should be counseled and screened by physicians on potential risks associated with CAMs and dietary supplementation


The authors declare that they do not have conflict of interests.


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Peer reviewer:Limin Chen, PhD, Professor, Institute of Blood Transfusion (IBT), Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Chengdu, Sichuan, China; Aydin Seref Koksal, Associate Professor, Türkiye Yüksek İhtisas Education and Research Hospital, Department of Gastroenterology, Ankara, Ankara, Turkey.


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