Liver International ISSN 1478-3223

Letters to the Editor

DOI: 10.1111/j.1478-3231.2011.02547.x

Revisiting liver injury associated with dietary supplements

To the Editor:
In the 11 January, 2011 issue of Liver International, a
review article discussed various case reports of liver-related
adverse reactions associated with the use of dietary supplements (1). The studies presented in this review occurred
over a significant duration of time and the discussion does
not address relevant changes to the ingredient profile of
dietary supplements during this period or how that may
impact conclusions related to the mechanism of liver injury
in these patients. It is important to note that some of the
ingredients in this review are no longer marketed and that
even the same ingredient can have different safety concerns
depending on how they are formulated, extracted, etc.
which is often unique to a product and its manufacturer.
We feel it is important to address some of these fundamental components as it relates to consumer safety.
The increasing regulatory requirements for dietary supplements including good manufacturing practices (2) and
mandatory adverse event reporting (3) are key considerations
for the evaluation of products associated with liver injury. It
is prudent to incorporate this perspective during case assessment to better identify potential contributing factors unrelated to the ingredient or product. In addition, providing a
comprehensive view of the various chronologically specific
factors associated with these cases is essential for the reader to
form an unbiased opinion about literature related to Herbalife and the dietary supplement industry in general. We
acknowledge that some manufacturers may engage in unsafe
practices, but the implication that all dietary supplements are
adulterated or contaminated is not supportable.
Finally, Herbalife has previously submitted a response
(4) to an editorial regarding our products (5) written by
the main author of this review. In fact, Herbalife
welcomes information or discussions regarding our consumers and is particularly interested in the anecdotal case
reports that are mentioned in this review (1). Additionally, several of the regulatory investigations referenced in
this article including those in Spain, Switzerland and
Finland were closed without having established a causal

link between consumption of Herbalife products and the

reported incidents. Since January 2005, Herbalife has met
and cooperated with 25 regulatory agencies, including
the Swiss BAG, to address liver-related case reports and
articles in the literature. None of the 25 agencies has
taken any regulatory action affecting Herbalife products.
Most recently, on 22 December 2010, Evira, the food
safety authority in Finland, closed its multi-year inquiry
involving Herbalife case reports, with the agency stating
that all requirements were satisfied, and indicating Herbalife acted properly and in a thorough manner to
demonstrate its commitments to food safety.
Kristy Appelhans1 and Leonard Goldstein2
1 Herbalife International of America Inc., Torrance, CA, USA
2 UCLA Medical Center Department of Hepatology, UCLA
Medical Center Suite, Los Angeles, USA

References
1. Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of
liver injury associated with dietary supplements. Liver Int
2011; 31: 595605.
2. CFR Code of Federal Regulations Title 21 Part 111. Current
Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements.
Available at http://www.accessdata.fda.gov/scripts/cdrh/cfdo
cs/cfCFR/CFRSearch.cfm (accessed 1 April 2010).
3. Federal Food, Drug, and Cosmetic Act (FDCA) Sec 761 [21
USC 379aa1]. Serious Adverse Event Reporting for Dietary
Supplements. Available at http://www.fda.gov/RegulatoryInfor
mation/Legislation/FederalFoodDrugandCosmeticActFDCAct/
FDCActChapterVIIGeneralAuthority/ucm111158.htm (accessed September 2007).
4. Ignarro L, Heber D, Henig YS, Bejar E. Herbalife nutritional
products and liver injury revisited. J Hepatol 2008; 49: 2913.
5. Stickel F. Slimming at all costs: herbalife-induced liver
injury. J Hepatol 2007; 47: 4446.

DOI: 10.1111/j.1478-3231.2011.02568.x

Herbalifes-associated hepatotoxicity: authors reply

To the Editor:
Dietary supplements are widely used, and numerous
case reports and series have established a causal role of
Liver International (2011)
2011 John Wiley & Sons A/S

several products in precipitating liver injury, including some

of those from Herbalifes (Los Angeles, CA, USA) (1). We
ourselves have reported on two well-characterized cases of

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Letters to the Editor

severe liver damage including cirrhosis and severe cholestatic

hepatitis after patients took numerous Herbalifes products
which were later found to be contaminated with Bacillus
subtilis and/or Bacillus cereus. Cellular suspensions thereof
proved to be hepatotoxic in a basic but widely used toxicity
assay (2). Causality was assessed by validated scores and was
found to be probable. In other series, causality was considered certain after liver abnormalities relapsed following
rechallenge to the products.
Altogether, published material describe 34 cases of
liver injury, mostly of hepatocellular or mixed type,
following the consumption of various Herbalifes products, often in combination and over long periods of
time. In a recent summary on liver injury precipitated by
dietary supplements, we review published reports of
Herbalifes-associated liver injury (and that from many
other dietary supplements) and summarize main data in
an overview table, but emphasize that the underlying
mechanisms of liver injury remain unclear to date (3).
However, we provide some thoughts on what these could
be based on histology imaging and in vitro assaying, but
did not exaggerate, overemphasise or add speculations
unsupported by data from publications.
We appreciate the Letter to the Editor by Appelhans and
Goldstein (4) commenting on our review, and adding
some important information. For example, we are delighted to learn that some of the ingredients contained in
Herbalifes products are no longer marketed maybe as a
reaction to the published reports on their potential
hazards? We have so far not observed any further cases in
Switzerland indicating that the products distributed here
may now be safer than they used to be. If so, this would be
just what the spontaneous reports on adverse reactions
related to certain health products attempted to achieve:
increase the awareness of consumers and manufacturers,
and prompt appropriate responses.
Appelhans and Goldstein allude that regulatory requirements for dietary supplements are in place to ensure
consumers safety, however, this may differ if products

are produced in different countries. Interestingly, none of

the reported cases came from the USA, but from different
European countries and Israel suggesting that locally
produced, spoiled batches could have been the cause of
liver injury. Ample data describe contamination of herbal
medicines, foodstuff, dietary supplements and synthetic
drugs with pesticides, heavy metals such as lead and
mercury, softeners and others. However, we clearly
repudiate that we are making generalizations on the
contamination of dietary supplements as a rule, but
mention openly those in which this seemingly occurred.
In contrast to Herbalifes Inc., we have no financial
interest to disclose, but as physicians, we are responsible
for the well-being of our patients and shall advise them to
refrain from potentially harmful products for which
scientifically proven benefits have not been shown.
Clearly, our critical standpoint is not restricted to
Herbalifes products, but applies to synthetic drugs,
herbal and complementary medicine, and to all other
dietary supplements as well.
Felix Stickel
Department of Visceral Surgery and Medicine, Inselspital,
University of Berne, Berne, Switzerland

References
1. Navarro VJ. Herbal and dietary supplement hepatotoxicity.
Semin Liver Dis 2009; 29: 37382.
2. Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of
liver injury associated with dietary supplements. Liver Int
2011; 31: 595605.
3. Stickel F, Droz S, Patsenker E, Boegli-Studer K, Aebi B, Leib
SL. Severe hepatotoxicity following ingestion of Herbalifes
nutritional supplements contaminated with Bacillus subtilis.
J Hepatol 2009; 50: 1117.
4. Appelhans K, Goldstein L. Revisiting liver injury associated
with dietary supplements. Liver Int 2011; 31: 1239.

DOI: 10.1111/j.1478-3231.2011.02552.x

Increased liver steatosis in anabolic-androgenic steroid users: more evidence

towards toxicant-associated fatty liver disease development
Nonalcoholic fatty liver disease (NAFLD) is generally
related to metabolic conditions (1). In addition, drug use
and chemical exposure could lead to NAFLD/non-alcoholic steatohepatitis development (2). In this sense, we
have recently established that long-term anabolic/androgenic steroid (AAS) high dose-use leads to toxicantassociated fatty liver disease (TAFLD) (3). Although
several markers of AAS abuse-induced TAFLD are
known, the testosterone levels as well as liver morphology
were not addressed. Thus, we aimed to investigate

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testosterone levels and fat liver accumulation in chronic

AAS users.
Twenty male competitive bodybuilders, matched by
body composition and training history, as detailed elsewhere (3), were divided into two groups. The AAS users
group (n = 10) was composed of subjects using high
doses of AAS during the last 2 years or more. The
remaining participants who reported no AAS use in their
lives made up the control group (n = 10). All subjects
denied alcohol consumption and use of any other drug

Liver International (2011)

2011 John Wiley & Sons A/S