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Correcting a misrepresentation of hypervitaminosis A attributed to Herbalife product consumption

  • Ezra Bejar Art Gallery
Letter to the Editor
Correcting a misrepresentation of Hypervitaminosis A attributed
to herbalife product consumption
Hypervitaminosis A
In the Volume 88, Issue 2, April 2010 edition of this journal, a
report was published which associated a rare case of intra-hepatic
cholestasis in a 46-year-old male who was using Herbalife products.
Herbalife products included one daily Formula 1 Shake, which is a
food product, and two tablets of Formula 2 Multivitamin Complex, a
dietary supplement (Ramanathan et al., 2010).
The authors of this paper concluded that that the contribution of
vitamin A from Herbalife products was the causative agent for the
reported liver condition. We strongly question the authors' conclusion
for the following reasons:
1. Preformed vitamin A in Herbalife products, as consumed, did not
exceed the Food and Drug Administration Daily Value (DV) of
5000 IU.
2. No symptoms associated with vitamin A toxicity were observed.
3. Despite surgical intervention to insert a bile duct stent, the im-
provement in the liver condition was solely attributed to the
Herbalife product dechallenge.
As can be seen in the table below, the authors' calculation of
5082 IU of preformed vitamin A is incorrect.
Calculated vitamin A
as reported by
Ramanathan et al.,
2010 (IU)
Calculated preformed
vitamin A according to
our own calculation
vitamin A plus
milk added
Tolerable upper
limit for preformed
Vitamin A by IOM
5082 2917 3417 10,000
In reality, the contribution of relevant sources of vitamin A
(including preformed vitamin A as retinyl palmitate and retinyl
acetate), according to the reported product use of one Formula 1
shake and two tablets of Formula 2 Multivitamin Complex, is
2917 IU.
Specically, 1250 IU of preformed vitamin A is included in the
Formula 1 shake, and 1667 IU of preformed vitamin A is included in
two tablets of Formula 2 Multivitamin Complex. If the Formula 1
shake is prepared with 8 oz of nonfat milk, the vitamin A contribution
from milk is approximately 500 IU. Therefore, when prepared with
nonfat milk as directed, the daily consumption of preformed vitamin
A would total 3417 IU, which is approximately 68% of the FDA DV,
and is much less than the Tolerable Upper Limit (UL) for preformed
vitamin A, which has been set at 10,000 IU by the Food and Nutrition
Board (FNB) of the Institute of Medicine (IOM) (Hathcock, 2004).
Two tablets of Formula 2 Multivitamin Complex also contain
1667 IU of provitamin A, in the form of beta-carotene. This
distinction is important as there is no evidence that conversion of
beta-carotene to vitamin A contributes to vitamin A toxicity, even
when beta-carotene is ingested in large amounts (Shils et al., 1999).
In fact, the Observed Safe Limit (OSL) for beta-carotene has been set
at 25 mg per day for non-smokers, which would correspond to the
equivalent of 41,666.7 IU of vitamin A. To suggest that consump-
tion of vitamin A, at or below RDA recommended levels, would
put any consumer at risk of developing hypervitaminosis A is
contrary to the collective wisdom that formed the basis for their
In this report, the liver biopsy of this individual did not tthe
usual biochemical pattern of hypervitaminosis A, which includes
brosis. Furthermore, according to Kaplowitz and DeLeve (2003),
the chronicity of the brosis process that is initiated with
hypervitaminosis A consumption is not typically inuenced by
abrupt vitamin discontinuation. This is in sharp contrast to the
results reported in this paper, which attributes the full and gradual
resolution of symptoms to withdrawal of Herbalife products over a
two month period of time during which a biliary stent was in
place. Also, the authors failed either to obtain or report hepatic
vitamin A level, which would have been a useful tool to support
their theory of hypervitaminosis A as a causative agent in this case
In summary, the collective evidence does not support the theory
that chronic consumption of vitamin A from any source was causally-
linked to the reported case of intra-hepatic cholestasis in this
individual. The authors' calculation of 5082 IU of preformed vitamin
A is incorrect. The actual total amount of preformed Vitamin A
consumed was 3417 IU, from Herbalife products and nonfat milk,
which is below the FDA DV. To further speculate and extrapolate the
root cause to then be causally linked to vitamin A intake exclusively
provided through consumption of Herbalife products is simply not
supported by the facts.
Hathcock, J.N., 2004. Vitamin and Mineral Safety, 2nd. Edition. Council for Responsible
Nutrition, Washington DC.
Kaplowitz, N., DeLeve, L.D., 2003. Drug-induced Liver Disease. Marcel Dekker, Inc.,
New York.
Ramanathan, V.S., Pham, B.V., French, S., Hensley, G., Eysselein, V., Chung, D., Reicher, S.,
2010. Hypervitaminosis A inducing intra-hepatic cholestasis a rare case report.
Exp. Mol. Path. 88 (2), 324325.
Shils, M.E., Olson, J.A., Shike, M., Ross, A.C. (Eds.), 1999. Modern nutrition in health and
disease, 9th ed. Williams & Wilkins, Philadelphia.
Experimental and Molecular Pathology 90 (2011) 320321
0014-4800/$ see front matter © 2011 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Experimental and Molecular Pathology
journal homepage:
Ezra Bejar
Casey R. Smith
Kristy Appelhans
Y. Steve Henig
Herbalife International, USA
Corresponding author at: Herbalife International,
800 W. Olympic Blvd., Los Angeles, CA 90015, USA.
Fax: +1 213 765 9806.
E-mail address: (Y.S. Henig).
5 January 2011
Available online 20 February 2011
321Letter to the Editor
... First and foremost, it should be acknowledged that Herbalife has rebutted the various publications which are cited, none of which are referenced by this author. [1][2][3][4][5][6][7][8][9][10] The authors reference an article by Stickel et al, which implicates Herbalife products in 2 cases of Bacillus subtilis contamination. 11 Of note, Herbalife has previously rebutted these allegations in other publications to highlight critical deficiencies in the methodology used for the isolation of this bacteria from the product samples. ...
... The primary reasons for inaccurate assessments of these cases include misapplication of the Council for International Organizations of Medical Sciences (CIOMS) assessment criteria, which is the globally accepted method for the evaluation of liver-related adverse event cases and/or the fact that potential alternative etiologies were not properly ruled out. Furthermore, other causality criteria were often used in place of CIOMS (eg, World Health Organization causality criteria and Karch-Lasagna), 10,11,[15][16][17][18][19] which were not appropriate measures of causality for liverrelated case reports. [11][12][13] It should also be noted that no suspect ingredient or product has been common to all the published case reports involving Herbalife products to date and some reports even fail to identify the products involved. ...
... Considerable interest focused on the question whether few Herbalife products are potentially hepatotoxic like some other herbal products and dietary supplements [1][2][3][4][5][6][7][8][9][10] . These reports created safety concerns and led to editorials [11][12][13] , commentaries [14][15][16] , and critical Letters to the Editor [17][18][19][20][21][22][23][24][25][26][27] , all addressing relevant issues [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] . Speculations about bacterial contamination with Bacillus subtilis in Herbalife products emerged [8,12] , and potentially hepatotoxic ingredients such as green tea extracts, ephedra sinica, aloe, or vitamin A overdose have been proposed as culprits [2][3][4]10] . ...
... Considerable interest focused on the question whether few Herbalife products are potentially hepatotoxic like some other herbal products and dietary supplements [1][2][3][4][5][6][7][8][9][10] . These reports created safety concerns and led to editorials [11][12][13] , commentaries [14][15][16] , and critical Letters to the Editor [17][18][19][20][21][22][23][24][25][26][27] , all addressing relevant issues [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] . Speculations about bacterial contamination with Bacillus subtilis in Herbalife products emerged [8,12] , and potentially hepatotoxic ingredients such as green tea extracts, ephedra sinica, aloe, or vitamin A overdose have been proposed as culprits [2][3][4]10] . ...
Full-text available
To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none. Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.
... Therefore, these outcomes are much more reliable than the retrospective cases used to support their argument for further research on this matter. Additionally, the authors do not reference the rebuttals which Herbalife has published to date to counter the various allegations questioning the safety of our entire product line (Ignarro et al. 2008, Appelhans et al 2012, Bejar et al. 2011. We feel that it is important for the Journal and its readership to be aware of the different perspectives regarding this issue so that more informed conclusions can be made in future assessments involving our products. ...
... Herbalife has raised the aforementioned concerns and objected to other misconceptions about our products through various rebuttal articles. [2][3][4][5][6][7] The authors revisit many of these same issues. However, only two of our rebuttals are referenced by the authors, reflecting an unbalanced analysis. ...
Full-text available
The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r) products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r) products were retrieved. All of the studies lacked sufficient information to some degree, whether related to patients' history, concomitant use of medication and/or other compounds (including alcohol), observations on interrupted use (dechallenge), results found with markers, viral serology and autoantibodies or observations concerning re-exposure to the products. In addition to these items, the lack of clear information on the type of products evaluated and their respective composition is an important factor to be considered. Furthermore, data quality was also questionable due to the presence of confounding factors, absence of proper exclusion of alternative explanations, and the use of questionable methods for attributing causality. Hence, an association between hepatotoxicity and consumption of these products cannot be proven based on the data collected and rigorous scientific analysis.
This field has shown tremendous growth in recent years, primarily due to the recognition that drug-induced liver disease is the most common cause of liver failure and one of the major contributors to the withdrawal of drugs developed by the pharmaceutical industry. Drug-Induced Liver Disease, 3rd edition is a comprehensive reference that covers mechanisms of injury, diagnosis and management, major hepatotoxins, regulatory perspectives and much more. Written by highly respected authorities, this new edition is an updated and definitive reference for clinicians and scientists in academia, the pharmaceutical industry and government settings. This book contains 4 new chapters on key topics in the area and provides a current and extensive review of the latest developments concerning the toxicology, pharmacology, genetics and immunology of drug-induced liver disease. A multi-authored reference work written by leading clinical, academic and industry experts in drug-induced liver disease. Contains four new chapters on key areas in the field, including one on worldwide drug-induced liver injury networks. Each chapter has been updated to address the latest research and findings in the field and 16 new chapter authors have been added to this new edition. Includes coverage of the basic, clinical and practical aspects of drug-induced liver disease to provide the single most comprehensive reference on the subject.
The use of over-the-counter supplements is commonplace in today's health conscious society. We present an unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one HerbalifeTM shake with two multivitamin tablets of the same brand for 12 years. When calculated this equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care providers documenting non-prescribed dietary supplements and considering them in the etiology of cholestatic liver disease.
The liver is the main metabolizing organ in the body for drugs and toxins. The liver is therefore exposed to relatively high levels of electrophilic metabolites and free radicals that may induce toxicity. Furthermore, the liver performs many vital functions that may be disrupted by toxic metabolites. Despite the high exposure to reactive metabolites, drug-induced toxicity is relatively uncommon because of the redundancy of the detoxification systems present in the liver.
Vitamin and Mineral Safety, 2nd. Edition. Council for Responsible Nutrition
  • J N Hathcock
Hathcock, J.N., 2004. Vitamin and Mineral Safety, 2nd. Edition. Council for Responsible Nutrition, Washington DC.
Inc. All rights reserved
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