DISCUSSION
The public’s increasing demand for alternative medicine, the newly found global interest in phytomedicine and herbal therapies, the rising cost of conventional prescription drugs, and a loss of faith in Western medicine, have led to a rapid rise in the use of unregulated herbal supplements and therapies. An estimated 80% of the world population uses herbal medicines, largely outside the U.S.[4]. In a study performed at an outpatient liver clinic, over 21% of patients were taking herbal supplements in the setting of chronic liver disease[5]. The FDA describes dietary supplements as a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. The “dietary ingredients” in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Most of these products have not been rigorously studied through placebo-controlled, blinded, randomized trials[6].
Hydroxycut is one of the most popular dietary supplements for weight loss on the market today, including two formulations Hydroxycut and Hydroxycut hardcore. Hydroxycut contains several different herbs, including: Garcinia Cambogia extract, chromium polynicotinate, Gymnema sylvestre extract and Camellia Sinenesis (C. Sinenesis) (Table 1). Both patients in this report used the dietary supplement Hydroxycut within a short time frame before presenting with acute hepatitis, suggesting Hydroxycut as the most likely etiology for acute liver injury. Neither patient had a history suggestive of other exposures or risk factors for viral hepatitis, alcoholic hepatitis, other toxinmediated injury, or chronic liver disease. A comprehensive serologic and radiographic evaluation performed in both patients did not reveal alternative sources for liver toxicity. Although causation is difficult to confirm in cases of suspected drug-associated hepatotoxicity, the temporal relationship to acute liver injury and rapid resolution upon withdrawal of Hydroxycut make this likely. Hydroxycut has previously been associated with both a cholestatic and hepatocellular pattern of injury. The specific components likely implicated in liver toxicity include G. Cambogia, Chromium, and green tea root extract (Camellia Sinensis) based on prior data suggesting liver toxicity. Patient 1 experienced a more typical hepatocellular pattern of injury, patient 2 demonstrated an immune-mediated pattern of injury, which has not previously been described.
There has been one prior report of two cases of possible hepatotoxicity with Hydroxycut in the literature[7]; both cases were young males who had documented periods of Hydroxycut exposure and experienced similar clinical syndromes marked by fatigue, jaundice, and pruritus with marked hepatocellular or cholestatic pattern and complete resolution upon supplement withdrawal. Our case series validates the likely causative relationship between Hydroxycut exposure and liver toxicity, and further suggests that an autoimmune pattern of hepatotoxicity may be observed. Although less common, drugassociated autoimmune hepatitis has been reported in several herbal supplements including Greater Celadine, Dai-Saiko-To, and Black Cohosh. Herein we review key ingredients of Hydroxycut that have been implicated in liver toxicity.
G. Cambogia is a fruit native to southeastern Asia and western Africa used to make meals more “filling”[8]. Its main component hydroxycitric acid (HCA) is an inhibitor of the citrate cleavage enzyme (ATP citrate lyase) blocking de novo synthesis of fatty acids[9]. HCA was initially studied in rodents for the dietary treatment of obesity and the results seemed to be promising. Unfortunately randomized controlled trials in humans for this purpose showed very conflicting results. Nevertheless, HCA is a primary component of many weight loss supplements in the market, and similar to others in its class, the toxicity profile is poorly studied. In the recent literature a case of fatal liver failure was reported in a patient taking HCA and monteleukast suggesting the synergistic hepatotoxic effect of these two agents[10]. There have also been reports of G. Cambogia toxicity by the WHO database, mostly describing an increase in hepatic enzymes[6].
Chromium is an essential trace element and cofactor to insulin most commonly occurring in hexavalent (‡Y) and trivalent (‡V) states. The hexavalent form is found in the dye and leather industry and is responsible for occupational toxicity ranging from dermatitis to lung cancer[11]. In 1989, the National Academy of Sciences established an “estimated safe and adequate daily dietary intake” range for chromium of 50 to 200 mg[12]. In 2001 the Institute of Medicine and the National Academy of Sciences established Dietary Reference Intakes (DRI) for Chromium, ranging from 0.2 mg for infants to a maximum of 45 mg in lactating mothers[13]. Chromium is used in weight loss supplements due to purported effects of decreasing body fat and increasing basal metabolic rate[14,15]. A recent meta-analysis of available RCTs concluded that weight reduction with chromium although statistically significant was not clinically meaningful[2]. There have been case reports of chromium toxicity causing acute hepatitis, thrombocytopenia and renal failure due to both environmental[16,17] and dietary supplements[18]. Although renal failure requiring dialysis is a more common concern[19], those presenting with liver toxicity frequently elaborate aminoteransferase elevations greater than 1000 mg/dL. Each Hydroxycut serving contains 133 mg of Chromium, which is taken three times daily, resulting in a cumulative daily consumption greater than twice the NAS safe maximum dose.
Camellia Sinensis is the scientific name for green tea, which is widely regarded by the public as safe, and commonly incorporated into supplements due to purported anti-cancer potential[20], weight reduction[21] and antioxidant properties[22]. Acute hepatotoxicity from C. Sinensis is well-described, and may range from acute hepatitis to acute liver failure. Based on 17 published cases in the literature[23-27], most cases appear to occur following large ingestions of green tea, with resolution following withdrawal, and recurrence with re-challenge[28]. Consequently, C. Sinesis has been banned in France and Spain, although it remains unregulated in weight loss supplements commercially available in the U.S.
Other Hydroxycut components for which liver toxicity have not been described include Gymnema Sylvestre, Rhodiola Rosea, and Withania Somnifera. Gymnema Sylvestre has been used to control hyperglycemia[29] and hyperlipidemia[30] in rats. Toxicity studies in rodents have not shown hepatotoxicity[31] and no case report of liver injury has been reported. Rhodiola Rosea extract is used to decrease fatigue[32] and improve exercise tolerance[33]. Withania Somnifera has been used for its anti-inflammatory properties[34,35]. Neither R Rosea or W Somnifera have been associated with liver toxicity, although W Somnifera may result in renal impairment in rats[36].
Of note, the more concentrated Hydroxycut HardCore product contains additional herbal formulations such as White Willow extract and Yohimbine. These have not been demonstrated to result in liver injury, whereas Willow bark extract may have anti-inflammatory effects in vitro, this was not observed in patients with rheumatoid arthritis or osteoarthritis in a randomized controlled trial[37]. Yohimbine is an indole alkaloid from the bark of the African Pausinystalia Yohimbe, and serves as an alpha-2 receptor antagonist which may treat male impotence[38]. Although nausea, vomiting and abdominal pain have been described, liver toxicity has not been observed.
The FDA has issued warnings on several herbal supplements known to have hepatotoxic potential including Comfrey (2001), Kava (2002) and the dietary supplement Lipokinetix (2001). This review does not seek to provide a comprehensive review of all known hepatotoxins, but highlight a short list of ingredients within best selling weight loss supplements which have been demonstrated to have hepatotoxic potential.