Ingredients Other Than Noni May Be Culprits in Acute Hepatotoxicity in 14-year-old Boy

To the Editor: Yu et al recently reported a case of acute hepatotoxicity involving a 14-year-old boy ⁽¹⁾. The cause was thought to be ingestion of ten 2-fluid-ounce bottles of an antioxidant drink containing Morinda citrifolia (noni). The ingredient and packaging description identified the product as “Mind,” a dietary supplement distributed by Ultra International (Lee's Summit, MO). This identity was confirmed by Yu (personal communication, December 2, 2010). Samples of “Mind” (lot 073090, exp. April 2011) were purchased from the company and analyzed by high-performance liquid chromatography (HPLC), following published methods for the identification of marker compounds in noni fruit, as well as anthraquinones ^(2–4). In the samples, all but 1 of the marker compounds was below detectable limits, indicating a small concentration of noni fruit juice. The content of the only detectable noni-specific compound, deacetylasperulosidic acid, revealed that “Mind” contained < 1% noni fruit juice. Furthermore, no anthraquinones from noni were detectable in the samples. The discrepancy in our chemical analysis and the quantity reported by Yu et al (based on statements from the manufacturer) may be caused by the inclusion of a commercial ingredient misidentified as M citrifolia, as has been reported previously ^(3,5). Even so, the patient could have consumed no more than 0.2 fluid ounces of noni juice. This is much less than what has been determined to be safe in toxicity tests and by government agencies ^(6–8). Aloe vera, however, was listed in the ingredient statement of “Mind” as the major ingredient, being first in order of predominance in the product. HPLC analysis of the samples revealed that the product contained approximately 0.1% each of sodium benzoate and potassium sorbate, which were not declared in the ingredient list on the product label. Commercial aloe vera gel is “stabilized” by the addition of these preservatives ⁽⁹⁾, and their concentrations are consistent with amounts reported in other commercial aloe vera gel ingredients ^(10,11). Even so, no standardized analysis has been developed for the determination of aloe vera in multiherbal products. Therefore, the exact aloe vera dose consumed by the boy in this case is difficult to determine through chemical analysis.

At least 15 cases of hepatotoxicity associated with ingestion of aloe vera products have been published, but none were discussed by Yu et al. Hepatocellular injury seems to be the predominant type in these cases, with some mixed types also described. The index case was reported in Germany, in which a 57-year-old woman consumed 500 mg of aloe vera extract daily for 4 weeks ⁽¹²⁾. Since then, 6 additional cases of aloe vera–associated hepatotoxicity have been reported in the United States, Argentina, and South Korea, where patients consumed between 28.5 and 500 mg daily, for as few as 2 weeks and as many as 6 months ^(13–15). Eight more cases were reported in Sweden, Turkey, and other nations, but no dose information was provided ^(16,17). Some in vivo tests have suggested hepatoprotective properties of both aloe vera and noni ^(18,19); however, a small subset of the population may be uniquely sensitive to any given food, drug, or botanical ingredient. Elevated immunoglobulin E levels in the Argentine case and the presence of eosinophilic granulocytes in the German case suggest that the liver injuries were caused by hypersensitivities to aloe vera ^(11,13). There are no previously known correlations for the combined effects of aloe vera and noni. Green tea extract, a well-documented hepatotoxic substance ⁽²⁰⁾, is also listed as an ingredient of “Mind,” but HPLC analysis of the product failed to detect the presence of epigallocatechin gallate, a major constituent of green tea extract. Considering the instances of mislabeling found in this investigation, it also is possible that a combination of unknown factors could be responsible for the liver injury, such as the presence of other undeclared or misidentified ingredients.