Fulminant liver failure and transplantation after use of dietary supplements

Over 900 drugs and herbs have been reported to cause hepatotoxicity.1 In the United States, the use of herbal and dietary supplements is the second most common cause of idiosyncratic drug-induced liver injury (DILI), after antimicrobial therapy.1 Of the herbal and dietary supplements, weight loss and body building supplements are most commonly implicated.2 In addition, contamination and adulteration of herbal supplements is common,3 with reported contaminants including undeclared antimicrobials, pharmaceuticals and heavy metals.2 Diagnosis of DILI is complicated by the tendency for herbal supplements to contain multiple ingredients,2 many of which are poorly characterised and could act synergistically. The protein supplement ingested by the patient in this case contained many ingredients, including green tea (Camellia sinensis) extract, green coffee extract, African mango extract, guarana, whey protein, and various vitamins and minerals. This, combined with his ingestion of a second supplement containing G. cambogia (active ingredient hydroxycitric acid), prohibits definitive identification of the causative agent or agents.

Historically, DILI has been overdiagnosed, with up to 48.5% of suspected cases of herb-induced hepatotoxicity being eventually attributed to other causes.4 To reduce the risk of misdiagnosis, causality assessments are routinely used. Many tools are available, but the Council for International Organizations of Medical Sciences (CIOMS) scale is most commonly used.4 This scale is liver specific and attributes a score based on seven items (Box 2), translating to causality grades of excluded, unlikely, possible, probable and highly probable for DILI. Using this scale, DILI secondary to the protein supplement in combination with the G. cambogia supplement is probable for the patient in this case (total score, 6).

Of the supplements ingested by the patient in this case, the main ingredients previously associated with hepatotoxicity are green tea extract and G. cambogia. Green tea and green tea extract have been demonstrated to have beneficial effects on total cholesterol levels, low density lipoprotein cholesterol levels, blood pressure,5 and fasting blood glucose levels.6 However, over 60 case reports linking green tea extract with hepatotoxicity have been published.3 In many of these cases, the ascertainment of causality was complicated by the ingestion of more than one potential hepatotoxin.3 Green tea differs from black tea in that it is unfermented, preserving the catechins that are the probable toxic agent. Green tea is present in many dietary supplements and protein powders available in supermarkets, health food shops and pharmacies. The usual clinical picture is a hepatocellular pattern of liver injury occurring within 3 months of ingestion (range, 10 days to 7 months).7 Although most patients recover rapidly on cessation, fatal instances of acute liver failure have been described. Results of liver histopathology tests typically resemble acute hepatitis, with necrosis, inflammation and eosinophils present. Autoimmune features are usually absent.7 This patient’s clinical picture, biochemistry results and histopathology results are consistent with a green tea extract-induced liver injury.

Products containing G. cambogia are widely available and advertised as weight loss supplements, although the evidence supporting this effect is conflicting. In comparison with green tea extract, the evidence for G. cambogia as a hepatotoxin is less robust and the safety profile of G. cambogia has not been extensively studied. The substance has been associated with hepatocellular pattern DILI in several case reports,8,9 but other potentially hepatotoxic pharmaceuticals or herbal supplements had also been ingested in these cases.

In 2009, the US Food and Drug Administration (FDA) recalled several Hydroxycut slimming supplements (Iovate Health Sciences International) following 23 case reports associating liver injury with ingestion of these products, including several cases in which the patient required liver transplantation or died.10 The implicated products varied in formulation, with some containing G. cambogia and all containing green tea extract. Following an investigation by the FDA Health Hazard Evaluation Board, it was concluded that Hydroxycut could cause idiosyncratic hepatotoxicity, although the exact causative agent was not identified. A subsequent case series examined the product constituents and concluded that green tea extract was the most likely causative agent, although this could not be definitively proven.10 There are similarities between the Hydroxycut scenario and the case described here, but, to our knowledge, no other cases of hepatotoxicity associated with whey protein powder and a weight loss supplement containing G. cambogia have been reported.