Tuesday, July 17, 2012

HERBALIFE VS LIVER DAMAGE

UPDATE ON LIVER DAMAGE FROM HERBALIFE, BLACK COHOSH and KAVA

 

neil.burman@gmail.com
16 March 2012
it is comforting to note that there have been no new reports the past year of toxicity from these products.
In fact  some lab work seems to favour black cohosh for cancer prevention;
Anticancer Res. 2012 Jan;32(1):21-30.   Chemopreventive potential of black cohosh on breast cancer in Sprague-Dawley rats. Einbond LS, Soffritti M, Degli Esposti D, Tibaldi E, Lauriola M, Bua L, He K, Genovese G, Su T, Huggins L, Wang X, Roller M, Wu HA.  Columbia University, HHSC-1518, 701 W. 168th Street, New York, NY 10032, USA. lseinbond@gmail.com     This study examines the chemopreventive potential and action of the herb black cohosh on Sprague-Dawley rats. CONCLUSION:Our results suggest that black cohosh may have chemopreventive potential for mammary cancer.
while Herbalife has published objective rebuttals of toxicity from Herbalife other than in isolated countries where irregular ingredients were used in local manufacture:
World J Hepatol. 2011 Oct 27;3(10):275-7. Revisiting acute liver injury associated with herbalife products.  Appelhans K, Smith C, Bejar E, Henig YS  Herbalife International of America Inc., Torrance, CA 90502, United States.   In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.
Pharmacoepidemiol Drug Saf. 2012 Mar;21(3):333-4. doi: 10.1002/pds.3203. Misconceptions regarding the association between Herbalife products and liver-related case reports in Spain.
Appelhans K, Frankos V, Shao A.  Source  Product Compliance and Safety, Herbalife International of America, Inc, Torrance, CA, USA.
2 Feb 2011
Since June 2010 there have been no new cases of toxicity from Black Cohosh, herbalife or kava reported on Pubmed.
   BLACK COHOSH: BEGGING THE QUESTION OF INDICATION- NEED.
 The new literature analysis Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract  by Naser et al from Yale , and Germany(the main producer of black cohosh BC products)- begs the question.
As this colunm has previously reviewd about BC,  women have died from or needed liver transplants after taking it.. Hence most Authorities have Black Box warning requirements Recurrences of liver reaction have been reported on rechallenge. These scattered cases can be argued away on metanalysis, but they cannot be ignored. One death or acute liver failure is unacceptable when BC is never an essential drug without other safe options. 
Another study also published now (Wang ea from the FDA Centre for Drug Evaluation ) http://www.ncbi.nlm.nih.gov/pubmed/20920542 contradicts the German metanalysis with more basic toxicological data: “Computational analysis of positively predicted constituents showed … specifically, protocatechuic acid from black cohosh… predicted positive for liver toxicity endpoints also confirmed with literature findings”
Black cohosh is not physiological hormone replacement, BC is recommended by its proponents solely for menopause symptoms (it has no other benefits) for up to 6 months.
So why risk, use black cohosh at all?
Appropriate balanced hormone replacement – preferably human hormones, not xenohormones ie hormones not found in the healthy women, and not by swallowing it- is indicated permanently in all women .
As previouslly pointed out in this column, the International Menopause Society has summed it up in putting approriate HRT as the main agent(s) for menopause symptoms as well as  for its permanent multisuystem benefits;  and the human hormone gamma-aminobutyric acid GABA as the only alternative that is both safe and cleearly proven better than placebo for improving both hot flashes and sleep, anxiety. Used appropriately and with sensible monitoring and dose titration, all such hormone balance has no longterm risks.
MDICOLEGAL LIABILITY: under the new Conumae Protection Act CPA in South Africa, the pendulum has gone ridiculously too far. irrespective of the onus on manufacturers and promoters of any product, the onus is on the end-prescriber, end-dispenser to warn consumers of potential risks,  and any consumer claim for consequent damages is legally against only the final and retail supplier.
So no supplier of black cohosh is protected against consequent liability unless he gets a signed waiver from the purchaser after the recorded warning about its potential toxicity.

16 June 2010
there are no new adverse toxicity reports on Hebalife, black cohosh or kava  so far in 2010 .
Both Herbalife,  and black cohosh products, remain marketed and in demand  in South SAfrica.
There are  no new serious adverse reports or concerns published  on Pubmed or Google about Herbalife products in 2009.
On Pubmed there were 2 new cases of liver and coagulation problems associated with black cohosh in mid2009, from a Germanic and an Italian institute; and 14 hepatitis cases associated with kava ingestion confirmed  from around the world .
4 Jan 2009
This review  is not about benefit of black cohosh (independent trials show none for menopause symptoms) or Herbalife (trials support that Herbalife is indeed a weight loss aid), or kava (it is a confirmed anxiolytic analgesic euphoriant); but about toxicity potential however rare – considering that none of these  products can make any claim to being a necessity.
Contamination aside, there are no new  relevant reports  on Herbalife the past two months on Pubmed,
but indeed  4 new reports on black cohosh; and one on kava.
Lessons for black cohosh and Herbalife may be learnt from kava. Kava-kava was hastily banned  eg  in Europe and South Africa early this decade owing to reputed association with hepatotoxic deaths. But on careful study these toxicity claims appear to be uncertain.
The claimed benefits of kava are analgesic, euphoriant and relaxant, without addiction potential. The four trials of Kava (between 1991 and 2003, in Italy and Germany) confirmed that kava has anxiolytic benefits in the menopause syndrome.) . The hepatotoxicity (not reported from the source – Polynesia - unless taken by alcoholics) was reported largely from western countries, where commercially sold  kava extract was apparently differently extracted, and from the aerial leftovers of the kava; whereas in Polynesia it is extracted only from the root. A recent website from the NIH shows it is not banned there, but expresses much caution.
A careful analysis of kava hepatotoxicity by Teschke ea in Germany last month again finds little evidence of toxicity if kava is taken from a reputable manufacturer  at prescribed dose and for short duration  – as applies equally to alcohol, and most drugs.
Herbalife

An objective  NICUS  Nutritional Institute of University of Stellenbosch Report critical of  Herbalife is quoted verbatim in the Summer 2008  Newsletter of the Association of Dieticians of SA. NICUS- a world authority in Nutrition – confirms it stands by this report. It could thus be taken as a directive (to condemn Herbalife)- to dieticians for whose professional advice some patients wrongly substitute diet supplements;  where these modalities- careful  professional diet advice and counselling, and supplements-  are actually complementary..
But there does not appear to be any  more  evidence to condemn Herbalife than there was a year ago. As far as Pubmed and Google reveals,  the reports  [to date end of 2008 on Pubmed) of adverse effects  were from 4 discrete European regions [ Iceland; Switzerland; Spain & Israel) , apparently wth locally formulated Herbalife, not the USA main factory product, leading to assumption of a local production fault. There appear to have been 2 cases of liver failure in some 33 affected patients, in one of whom liver transplant became necessary but the patient died.. .
One cannot condemn all  babyfood because some is deliberately adulterated with melamine by ruthless Chinese sham factories. Commercial babyfood is arguably a necessity for many.
We await an updated rebuttal from Herbalife in the new year- but there does not seem to be anything for them to add to their rebuttal of last year..There has been no published evidence to justify update on Herbalife during 2008.
The accusation (by one patient, and a  convicted fraudster, Minkow) of a claimed lead-contaminated  Herbalife batch  in California   has, strangely, generated no updates for months now- but on the wiki herbalife update , it says "In August 2008, Minkow retracted all accusations against Herbalife and removed any mention of the company from his Web site.[30]” – there is no report of whether Herbalife bought his silence or not , which is a pity- see also. ;   but see also heavy flak against Minkow , suggesting that his whole campaign was a successful bear scam  to profit from Herbalife shares.
The  current  Wiki Herbalife  review also quotes a new trial validating benefit for weightloss. Caveat Emptor.
It may be asked why a Nutritional authority like NICUS:  warns  against Herbalife but not against the potentially fatal black cohosh. New independent analyses are both for and against them:
ie
Black Cohosh:
Analyses of case reports from Univ Florida (Palacio 2009) and Italy (Borrelli 2008)  recommend caution about black cohosh for humans in view of adverse case reports; while a German analysis (Teschke 2008) exonerates black cohosh in every single case till then.
A trial from USA (Davis 2008) found that “black cohosh significantly increased the incidence of lung metastases in tumor-bearing mice compared with mice fed the isoflavone-free control diet”.
Clearly the valid divergence of opinion comes down to complex statistics of probability.
Black cohosh has been associated with severe liver failure and  transplantation in a number of women on a number of continents, for which reason the local Health Products Association, like all responsible authorities , finally agreed and issued recommendations that Black Cohosh label must be black-boxed- there is no justification for it’s sale as a useful product, unlike the role than can be argued for food substitute powders.
So why should anyone use black cohosh for menopause symptoms (when it’s benefit seems to be largely placebo, with grave doubt about safety) , when there are proven safe symptom relievers eg GABA (no adverse reports); or lowdose balanced appropriate parenteral human sex hormones (no adverse reports, and have numerous longterm multisystem benefits- which neither black cohosh nor GABA can claim..).
This review  is not about benefit, but safety. Regulators remain silent about drastically curtailing sale of the most lethal substances in widespread unregulated (and unnecessary)  use- paracetamol, other nonsteroidal anti-inflammatories, statins for uncomplicated  mild-to-moderate lipidemia, alcohol, tobacco and sugar, and pollution of everything by industrial adulteration with synthetic (often estrogenic) endocrine disruptors and virtually all fast foods with cornstarch and/or sugar.
The hysterical approval of diethylstilbestrol  DES by the FDA by 1950, and for a massive  1950 maternity trial  against all evidence (even though it’s toxicity was recognized by 1953,  it’s sale anywhaere was finally banned only 20 years later) continues to torment the original myriads of  guineapig women, their children and now grandchildren. These scandals are dictated by individual opportunist, corporate and governmental greed, and indifference to medical evidence and prevention.
The analogy for black cohosh, kava  and Herbalife  is perhaps:
#the ~20year delays before the FDA would licence the lifesaving lithium salt, and metformin, in USA;
#the ~5year hysteria over HRT after the Women’s Health Initiative – when the over-estimated risks of inapproriate use of  OHT in elderly women were stupidly and harmfully (for thousands of women) extrapolated to young women and other  HRT preparations;
and
#the melamine- baby milk formula catastrophe – the problem for the latter was exclusively some contaminated  babyfood batches made in China especially for the lucrative export market. .
The jury can thus be considered as still out on both black cohosh, kava  and Herbalife,  until manufacturers of commercial  products (not traditional preparations of  eg kava and black cohosh taken by residents who grow these)  can produce evidence, confirm  that the risk was limited  to specific batches of the commercial product  and adherence to accepted recommendations, and not due to other possible risk factors.

( Black Cohosh: Side effects in wikipedia )

Studies on human subjects who were administered two commercially available black cohosh preparations did not detect estrogenic effects on the breast.[15]
No studies exist on long-term safety of black cohosh use in humans.[20] In a transgenic mouse model of cancer, black cohosh did not increase incidence of primary breast cancer, but increased metastasis of pre-existing breast cancer to the lungs.[21]
Liver damage has been reported in a few individuals using black cohosh,[2] but many women have taken the herb without reporting adverse health effects,[22] and a meta-analysis of several well-controlled clinical trials found no evidence that black cohosh preparations have any adverse effect on liver function.[23] Despite a lack of conclusive evidence for a link between black cohosh and liver damage, Australia has added a warning to the label of all black cohosh-containing products, stating that it may cause harm to the liver in some individuals and should not be used without medical supervision.[24] Other studies conclude that liver damage from use of black cohosh is unlikely,[25] and that the main concern over its safe use is lack of proper authentication of plant materials and adulteration of commercial preparations with other plant species.[26]
Reported direct side-effects also include dizziness, headaches, and seizures; diarrhea; nausea and vomiting; sweating; constipation; low blood pressure and slow heartbeats; and weight problems.[27]
Because the vast majority of black cohosh materials are harvested from plants growing in the wild,[2] a recurring concern regarding the safety of black cohosh-containing dietary supplements is mis-identification of plants causing unintentional mixing-in (adulteration) of potentially harmful materials from other plant sources.[2]


================================

Herbal hepatotoxicity: a tabular compilation of reported cases.

Source

Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University, Frankfurt/Main, Germany.

Abstract

BACKGROUND:

Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide.

AIMS:

To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity.

METHODS:

A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity.

RESULTS:

A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®) . In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences).

CONCLUSIONS:

This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future

==============================

A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione.

Source

Viplove Senadhi, Division of Gastroenterology and Hepatology and Brater Scholar, Indiana Institute for Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.

Abstract

The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients.

Few consumers hear about the reports in the medical literature of liver and other toxicities from herbal products. Dr. Leonard B. Seeff, M.D., of the National Institutes of Health, reviewed the herbal products that have been associated with liver damage in the journal Clinical Liver Disease. His concerns about the growing numbers of medical cases were similar to an earlier 2005 comprehensive review for the European Association for the Study of the Liver in the Journal of Hepatology, led by Dr. Felix Stickel, M.D.. These doctors reported that, depending on the geographic region, 21% to 65% of patients seen for liver disease have been taking herbal preparations. Most evident is that women are at greatest risk not only because they use more herbals, but because of their higher susceptibility to herbal- and pharmaceutical-induced liver damage. Because many practitioners and consumers believe herbals are safe, the doctors noted the many times patients will even continue to take them as their liver diseases worsen.
Dr. Stickel and colleagues added:

Another problem is that herbals are usually mixtures of several ingredients or plants harvested during different seasons and extracted through variable procedures, which makes the identification of both the pharmacologically active and toxic compounds difficult. Also, contamination of herbals with microorganisms, fungal toxins such as aflatoxin, with pesticides, heavy metals and synthetic drugs has been described. Interactions between herbs and chemical drugs are another source of problems associated with the intake of herbal compounds.
While liver damage appears infrequently, the consequences are serious enough for patients that these cases are getting the notice of doctors. Another article in this month’s issue of the Journal of Hepatology by researchers at Hadassah-Hebrew University Medical Center in Israel reported on 12 patients (11 women) with acute liver injury after using Herbalife products. Incredibly, after three patients recovered, they resumed taking Herbalife products and succumbed to a second bout of hepatitis.
Another article in the same issue reported on a study by doctors in Switzerland. They had become concerned after seeing several patients with severe liver damage who had been using Herbalife products and tried to determine how prevalent liver toxicity due to Herbalife products might be. They surveyed all departments of medicine at 121 Swiss public hospitals, divisions of gastroenterology/hepatology, pathology and the Swiss pharmacovigilance database and identified 10 cases of liver toxicity in otherwise healthy people not taking any other herbal products or medications from 1998-2004. Rigorous questioning proved necessary as patients consistently underreported their use of herbal products, they said. They carefully documented the cases, including obtaining liver biopsies in most. Three of the ten patients had potentially life-threatening liver failure requiring liver transplants.
“The lack of labeling of contents of these products renders causality assessment impossible,” they reported. But using the WHO criteria for Causality Assessment of Suspected Adverse Reactions and expert hepatopathologists blinded to the patient information of herbal use, they determined that two were certainly caused by the Herbalife products, seven cases were probably and one case possibly.
This is not the first time that Herbalife has been in the news and the target of governmental regulatory agencies and concerned medical professionals. As recently reported, it is one of the oldest multi-level marketing companies selling vitamin and herbal products promising better health and slimness. Herbalife has found it especially lucrative to take advantage of poor people in developing countries. MLM is a sales technique where people, working as independent distributors, buy sales kits and products which they sell and, in return, are promised they’ll make money from those sales as well as from a percentage of the sales of those who they recruit as new distributors. However, fewer than 1% of distributors ever earn much money and many are stuck with thousands of dollars of products. MLM and pyramid schemes are listed on many attorney generals' top ten lists of consumer complaints. At MLM Watch.org, you can read more about MLM, including a summary of complaints that have previously been submitted to the FTC on Herbalife products.
A few years ago, the National Council Against Health Fraud issued a position paper on MLM health product companies. It listed important precautions for consumers, as well as described the harm that’s come to people who’ve gotten mixed up in them. Dr. Stephen Barrett, M.D., NCAHF Vice President, examined more than 100 MLM companies offering health-related products and concluded “that every one of them has made false or misleading claims in their promotional materials.” He said:
The products promoted as remedies are either bogus, unproven or intended for conditions that are unsuitable for self-medication...Most supplement companies get their raw ingredients from the same bulk wholesalers and merely repackage them...During the past several years, many physicians have begun selling health-related multilevel products to patients in their offices. Doctors are typically recruited with promises that the extra income will replace income lost to managed care....During the past 20 years, more than 25 health-related MLM companies have faced regulatory actions for false advertising, operating a pyramid scheme, or both. Although such actions usually improve future behavior, they rarely provide adequate redress for victims. Moreover, the number of MLM frauds known to Federal Trade Commission vastly exceeds its capacity to prosecute them on a case-by-case basis.
The growing reports of life-threatening health risks among users of these products remind us to not to be taken in by claims of magical benefits of any dietary intervention. Beyond preventing deficiencies — which is easily achieved by virtually everyone simply when enjoying all sorts of foods — no food or supplement is supernatural. When we hear claims that optimal or personalized nutrition is science-based and can improve our heart, digestive or immune health; help us age healthfully, improve our memory or eyesight, or remove wrinkles; increase our energy and fitness; or manage weight, control our appetite or boost metabolism...we know it sounds too good to be true.
The pursuit of optimal nutrition, ‘wellness’ and slim bodies has become fertile ground for the marketing of products, diets and regimens that promise “a lifetime of good health.” Herbal and natural dietary and weight loss supplements can be alluring because they may seem safe. Three new studies, however, have documented liver toxicity among healthy people using natural herbal supplements — more than 20 cases were just among Herbalife customers in two small countries.

Continuous reporting of new cases in Spain supports the relationship between Herbalife® products and liver injury.

Pharmacoepidemiol Drug Saf. 2011 Oct;20 (10):1080-7. doi:10.1002/pds.2180. Epub 2011 Jul 12.   

Manso G, López-Rivas L, Salgueiro ME, Duque JM, Jimeno FJ, Andrade RJ, Lucena MI.

Source 

Centro de Farmacovigilancia de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain. gmanso@uniovi.es

Abstract

PURPOSE:

Previous publications have linked Herbalife® products to hepatotoxicity. The identification of earlier cases in which the culprit agent could not be established raised the hypothesis of a possible contamination of some specific batches of Herbalife products.

METHODS:

We searched the Spanish Pharmacovigilance Centres' database of adverse reactions for reports of liver injury associated with the use of Herbalife products from 2003, when the first case was submitted, through September 2010.

RESULTS:

The search resulted in 20 reports of liver damage (mean age, 49 years; 16 women), with 12 patients (60%) requiring hospitalization. Hepatocellular damage predominated, and nine (53%) of the hepatocellular cases with bilirubin values were jaundiced, fulfilling the Hy's law criteria, which increases the risk for serious outcomes. Two patients experienced a positive rechallenge. One patient developed cirrhosis, whereas all the others recovered. Causality assessment by the Karch and Lasagna modified algorithm showed a category of definite in 1 case, probable in 14, and possible in 5. Analysis of the different Herbalife products that each patient had taken did not enable us to identify any commonly known hepatotoxic ingredient.

CONCLUSIONS:

Our results support the relationship between the consumption of Herbalife products and hepatotoxicity, underscore the concern regarding the liver-related safety of this dietary supplement, and emphasize the need to establish further regulatory measures.

 =============================
BACTERIA IN HERBALIFE DAMAGES LIVER
‘Bacteria in Herbalife damages liver’

Two years ago liver doctors sounded the alarm about cases of liver damage in users of Herbalife products. They were unable to say which component in Herbalife products was causing the liver damage, but researchers at the University of Bern made an attempt to do so in an article published this year in the Journal of Hepatology. They found the bacteria Bacillus subtilis in Herbalife products.



In the article the doctors discuss two cases of people who became ill after using Herbalife products: a man aged 78 and a woman aged 50. The man's urine had turned dark brown, he had hepatitis and had been feeling unwell for a couple of weeks. He had been using the Herbalife F1 Shake [Strawberry and Cappuccino flavours] for three years on his daughter’s advice [she was a Herbalife salesperson], as well as various other medicines. According to the analyses, the man had a liver complaint. When the doctors took him off the shake his blood values recovered, but they deteriorated again later. The doctors gave the man corticosteroids and ursodeoxycholic acid, after which he recovered completely. You can see the fluctuations in the man’s blood values in the graph below.




The woman sold Herbalife supplements. She took half a dozen different Herbalife supplements, including the Personalized Protein Powder Mix Formula 3. She had stomach pain and hepatitis and the doctors found signs of liver damage in her blood. They got the woman to stop taking the supplements and the graph below shows how the liver values in her blood improved.



The researchers examined samples from the livers of the man and the woman and found signs of damage in both. The doctors turned the supplements that the men and women had used inside out, but found no contaminants: no heavy metals, no pesticides, no antibiotics, nothing. But when they examined the Herbalife products for micro-organisms, they did come across something. The meal substitutes the man and woman had been using contained the bacteria
Bacillus subtilis. [see photo.] This was the cause of the liver complaints, according to the researchers.
Hmm.


Honestly speaking, we’re not sure what to make of this. As far as we know, B. Subtilis is found in pretty much everything, and it’s not particularly dangerous. [Wikipedia] Some studies even regard it as a probiotic. It would seem pretty unlikely then that B. subtilis is the cause of such serious liver damage.

Source: J Hepatol. 2009 Jan;50(1):111-7.


 
Bodybuilder drugs his liver to oblivion – twice


A medical case study that will give you goose bumps, this report from doctors at the US Massachusetts General Hospital. The article tells the story of a 27-year-old competitive bodybuilder and part-time policeman who turned up at the Emergency Department.

The man’s been using anabolics for five years, but now he's got stomach pains and is nauseous. The doctors do blood tests and discover that the man’s liver is no longer functioning properly. For a start, the concentration of the enzyme ALT is 2457 units per litre: 35 is the healthy maximum. The bodybuilder’s blood is syrupy and his haematocrit level is fifty percent. The bodybuilder says he injects nandrolone and takes androstenedione.



The scan the doctors make of his liver shows a real mess, shown in Picture A below. The light patches are swellings, the biggest of which measures 10 x 10 cm.


The doctors operate and discover that the liver is in an even worse state than they had feared. The organ contains swellings that are filled with blood. Peliosis hepatis is the doctors’ diagnosis, the same complaint as killed Andreas Muenzer.


The doctors also found a swelling with a diameter of 23 cm. This kind of swelling doesn’t usually get bigger than 3 cm. The doctors decide to amputate part of the liver.


After the operation the bodybuilder recovers and is allowed home. When the doctors make another scan three months later they see that the swellings in the remaining part of the liver have shrunk by 40 percent, Picture B above. The bodybuilder thinks it's time to start doping again, and says he’s going to start again with androstenedione.


After three years the bodybuilder returns to the doctors. Six weeks previously he had treated himself to injections of a nandrolone derivative. And bingo, he’s got stomach pains again.


Three days after admission to the hospital, the bodybuilder’s heart rate starts to increase. When the doctors make another scan – the picture above on the right – they see that his liver is in a bad way again. The swellings have started to grow again, and the liver has a protuberance that has started to bleed.


The doctors discuss briefly whether they should give the guy a new liver, but reject the idea. It would be a waste: he would only destroy it again with pills and injections. Alcoholics are not given a new liver either. So they just stop the bleeding and send the bodybuilder home again.


Thinking about it, we find it difficult to believe that the bodybuilder was only using deca and androstenedione. True, a number of cases have been published of bodybuilders who, as the result of a mild course of deca, developed a blood clot the size of a brick in their stomach, or became psychotic after one single deca injection. But to be honest, we don’t believe those studies.


Moreover, neither androstenedione nor nandrolone is harmful to the liver. Laboratory research on liver cells has shown this. And, by the time the doctors were seeing their patient, George Bush had already outlawed androstenedione. Although androstenedione is still on the market, bodybuilders hardly ever use it. Why would they? In countries like the US there are much more effective legal anabolic steroids available. But among these, there are a number of substances that are notoriously bad for the liver.


The most dangerous is Superdrol, an anabolic that was developed at the end of the fifties by Syntex. Doctors have recorded damaged livers and destroyed kidneys in users of Superdrol more than once.


This is what makes us suspect that the bodybuilder in this case study used stronger stuff than androstenedione and deca. Bodybuilders are often not entirely honest about what they have been using when they visit a doctor about medical problems. Even when being honest could have saved their life.

Sources:
World J Gastroenterol. 2008 Jul 28;14(28):4573-5.

Bodybuilder gets jaundice from creatine and protein supplements


A healthy man of 27, a fanatical bodybuilder, developed liver damage and jaundice after using sports supplements containing creatine and whey protein. Liver specialists at The Mount Sinai Medical Center in New York describe the case in Seminars in Liver Disease.


The man in the case study had no pain and did not feel unwell, but because he showed signs of jaundice he went to hospital. There the doctors discovered that his blood contained high levels of bilirubin, a substance that should have been removed by the liver. The man’s blood also contained high amounts of the enzyme alkaline phosphatase and creatinine. The first substance can be an indication of liver malfunction. The second is a waste product of creatine.


In people with jaundice, the skin and whites of the eyes turn yellow [see pic below], but this is not necessarily cause for alarm. Bilirubin is not a dangerous substance, and may even be an endogenous antioxidant. But jaundice is a sign that something is wrong with the liver, and it therefore needs to be taken seriously.




When the doctors examined the bodybuilder’s liver they saw that the organ was no longer removing bile. The ducts that should have been doing so were blocked. The scientific term for this is cholestasis.


The bodybuilder had been taking creatine for nine months and whey protein for one month. The doctors thought that this might be responsible for his condition. When the man stopped taking the supplements, his liver returned to normal and the jaundice disappeared. If doctors come across healthy athletes with an abnormal liver, the researchers write, then they should ask whether the athletes are using potentially 'dangerous' supplements like whey protein and creatine.




We put ‘dangerous’ in quotes advisedly. We don’t actually believe that healthy people can get jaundice from creatine and proteins. We agree with the opinion of a blogger – who by the way also works at Gaspari Nutrition – at bodybuilding.com who suspects that the bodybuilder in question was also using steroids, and developed jaundice as a result of these. [bodybuilding.com 2008/05/23]


It wouldn’t be the first time that bodybuilders have run into trouble for using hardcore doping materials, go to a doctor and then don’t tell the whole truth about what they are using. In the past we have written about a bodybuilder who had taken an overdose of DNP, got sick and went to hospital – where he died because he didn’t dare to say what he had been using. In another article a bodybuilder almost lost a testicle because at first he didn’t tell the doctors that he had been using Pregnyl.


There are plenty of reports in the medical literature of the side-effects supplements or low doses of doping drugs, which should be enough to make the readers’ hair stand on end. But these reports are probably the result of silent use of forbidden substances – and in high quantities. For example, there was the bodybuilder who said he had developed gyno from using Tribulus terrestris supplements. [Breast. 2004 Oct;13(5):428-30.] Other bodybuilders have said that they got liver damage from androstenedione and a blood clot the size of a brick from taking deca and proviron. [N Engl J Med. 1999 Apr 8;340(14):1123-4.]

Sources:
Semin Liver Dis. 2008 May;28(2):226-31.



Supplement protects steroids users’ livers


A preparation made by Natterman, which supposedly protects the liver and which chemical athletes are using more and more often: Greek researchers refer to it in their study as compound N. The researchers, at Thessaly University, set up an experiment to determine whether compound N really works.


After a bit of surfing we worked out that Compound N is Essentiale forte. [Google]


A packet contains a couple of dozen capsules, each of which contains 300 mg of polyene phosphatidylcholine. This is choline-phosphoric acid with two unsaturated fatty acids attached, usually linoleic acid. It probably resembles the phosphatidylcholine found in soya.


In addition, each capsule contains 6 mg of vitamin B1, 6 mg of vitamin B2, 6 mg of vitamin B6, 6 mcg of vitamin B12, 30 mg of nicotinamide and 6 mg of vitamin E.


The Greeks, who by the way have also done research on the psychological effects of anabolic steroids, did an experiment with three hundred and twenty athletes. Half of them, one hundred and sixty athletes, used steroids. Of these chemical athletes, the researchers gave forty Essentiale forte: two capsules a day taken with food.


All of the chemical athletes took steroids and the researchers monitored them for eight weeks. The list below gives you an idea of what the Greek bodybuilders were using.






Yes, the list puzzled us too. Quinbolone? [An enol-ether of boldenone – Ed.] Oxabolone? [Nandrolone with a hydroxyl group on C4 – Ed.] Are these products still on the market? And where are the 'new' designer steroids? Surely athletes in Greece use products like 1-Test and Madol too?


Still.


During the eight-week period the researchers measured the athletes’ concentrations of the following enzymes: aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (gamma-GT) and creatine kinase (CK).


The more enzymes in the blood, the harder a time the liver is having.


The figure below shows what happened to the liver enzyme concentrations. Group A = chemical athletes who took Essentiale forte as well. Group B = chemical athletes who did not take a liver-protection supplement. Group C = ‘natural’ athletes.




The researchers are not sure how phosphatidylcholine and vitamins protect steroids users’ livers. They suspect that the mixture strengthens the membranes of the liver cells. The livers of steroids users have to work hard to break down all the extra substances they are subjected to. And as a result the liver cells ‘cut down’ on metabolising fats. The liver gets fattier because the liver cells are no longer burning fat well [beta-oxidation – Ed.] and maintenance of the cell membranes made up of fatty acid chains gets neglected. The supplement helps the liver cells to perform these functions.


Sounds attractive, but to be honest we find it difficult to believe that simply taking vitamin B pills and lecithin capsules can protect steroids users’ livers. And we’re probably not the only ones who are sceptical. Reading between the lines you can also see that the Greeks had trouble getting their study published.


That’s why they use long-winded sentences like: "the results from our cohort of similarly exercising individuals suggest that polyunsaturated phospholipids in combination with vitamins of the B complex protect hepatic cells from AAS-induced damage." According to the Greeks Compound N is not a supplement but "a controlled pharmaceutical agent".


But still. It’s not totally impossible that the Greeks have discovered something that will enable thousands of steroids users to juice more safely.






More damaged livers from superdrol and madol


Liver specialists at the Henry Ford Hospital in Detroit have reported another three cases of bodybuilders who developed liver damage as a result of using designer supplements. The men used Anabolic Xtreme’s Superdrol or BMF Hardcore’s M-Test 2, a product containing the steroid madol.


The Superdrol user was 21. He was nauseous, had stopped eating, had jaundice and itched all over. He’d been using
Superdrol for a couple of months and his liver was not functioning properly. His data is shown in the table below, under the heading Patient 1.
When the symptoms had got worse after two weeks, the doctors gave him prednisone. The anti-inflammatory worked and after another six weeks, he'd made a pretty good recovery.


Superdrol is a steroid whose structure and synthesis resemble those of oxymetholone. It was also developed and tested in the late fifties by the makers of oxymetholone, the American pharmaceutical company Syntex. Although superdrol [see structural formula below] looked like a promising anabolic steroid in animal tests, in subsequent tests potential side effects showed up.
Superdrol
Syntex decided not to put Superdrol on the market. But that didn’t stop designer supplement makers from marketing the forgotten steroid years later.
The effects of this move are clearly seen in the medical journals. In 2006 doctors in Phoenix, Arizona published an article on the case of bodybuilder who became fatally ill after using superdrol. [Am J Gastroenterol. 2006 Nov;101(11):2659-62.] A few months later doctors at Johns Hopkins University published another case and a case in which another designer steroid – Halodrol – had caused liver damage. [Clin Gastroenterol Hepatol. 2007 Jul;5(7):809-12.] And another few months after that, doctors from Burlington wrote about five more bodybuilders who had developed liver problems as a result of superdrol. [Clin Gastroenterol Hepatol. 2008 Feb;6(2):255-8.]


What patient 2 used was not clear, but it contained at least DHEA. Of the three men referred to in the study, number 2 got off the most lightly. He recovered spontaneously a couple of weeks after he had stopped using the supplement.





Patient 3 used M-Test 2, a designer supplement containing the steroid madol. [Structural formula shown below.] Madol was rediscovered by Patrick Arnold, who produced it as an invisible steroid for Balco, but it was picked up later by designer supplement manufacturers. Madol was also developed by Syntex, a manufacturer that carried out promising animal tests on it in the sixties.


Madol
Not much is known about the side-effects of madol. It is not carcinogenic, say German researchers. But they did discover that it enlarged the heart muscle in animal tests. The enlargement itself was not dangerous, but the researchers were not entirely convinced. In the bodybuilding circuit however there are few stories around of users who have developed liver problems as a result of using madol.


The sick madol user had to be given prednisone in the end, after which he recovered.


The doctors did not test the preparation the patient had used. And we wonder quite honestly if it only contained madol. According to the study, the bodybuilder became ill after he had taken 57 capsules over a period of a few weeks. That would be impossible with
just madol. Methyl-1-testosterone and superdrol are a different kettle of fish, but with madol we can hardly imagine this kind of thing happening.
BMF Hardcore, the maker of M-Test, has heavier oral designer supplements among its products. The Canadian government has issued warnings about these. Maybe something went wrong during the production of M-Test 2. Or perhaps the doctors got it wrong that Patient 3 used the BMF product.


The doctors also read a couple of articles written by colleagues and summarized the information they found. This resulted in the table you see here below.




Liver specialists should get extra training on designer supplements that contain oral anabolic steroids, the article concludes. "The rapid reporting of several cases of AAS-induced liver injury from dietary supplements emphasizes the growing emergence and importance of this condition and the need for clinicians to become aware of the sequelae of jaundice and renal failure, especially among young men who are unknowingly consuming hepatotoxic agents."

=============================


Acute liver injury induced by weight-loss herbal supplements

World J Hepatol. 2010 November 27; 2(11): 410–415.

NCBI The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.

Published online 2010 November 27. doi:  10.4254/wjh.v2.i11.410
PMCID: PMC3004035

Abstract

We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.
Keywords: Hydroxycut, Herbalife, Hepatotoxicity, Herbal, Weight-loss

INTRODUCTION

We have seen a significant increase in the popularity and usage of over the counter herbal supplements over the past few years[1]. Unfortunately, the majority of these herbal supplements are not regulated by drug administrations worldwide. Many herbal supplements contain compounds that carry potentially severe side effects including hepatotoxicity. We report three cases of acute liver injury induced by weight-loss herbal supplements. Hydroxycut (MuscleTech, Mississauga, Ontario, Canada) (case 1) and Herbalife (Herbalife, Los Angeles, USA) (cases 2 and 3) supplements were the suspected culprits of acute liver injury. Hydroxycut is a popular dietary supplement consisting of a variety of herbal mixtures that claims to enhance the weight loss process[2]. Acute liver injury associated with Hydroxycut use has been previously reported, but only one case had liver biopsy data showing cholestasis and portal inflammation[3-6]. Similarly, Herbalife weight-loss dietary products are popular supplements consisting of a variety of herbal mixtures that claim to facilitate weight reduction[7]. Cases of acute liver injury after consumption of Herbalife products have been previously reported, with two patients developing fulminant liver failure requiring liver transplantation. The first patient survived while the second died[8-11]. In all of our cases, we were able to demonstrate drug-induced acute liver injury on liver biopsy specimens.

CASE REPORT

Case 1

A 31-year-old woman presented to our hospital complaining of 2-wk history of fatigue, jaundice, and nausea. She denied any prior medical or surgical conditions, family history of liver disease, and acetaminophen or prescription medication use. She further denied history of blood transfusion, tattoo, alcohol use, or recreational drug use. She had been taking Hydroxycut for one year to enhance her weight loss. She had been taking the recommended dose of 2 tablets twice a day.
The patient was afebrile with normal hemodynamics upon presentation. Her physical examination was remarkable for generalized jaundice, scleral icterus, and mild upper quadrant tenderness to palpation without rebound or guarding. Initial laboratory studies were significant for serum aspartate aminotransferase (AST) level of 1407 U/L (normal range 15-41), serum alanine aminotransferase (ALT) level of 1278 U/L (normal range 7-35), serum alkaline phosphatase of 256 U/L (normal range 38-126), serum total bilirubin (TB) of 7.1 mg/dL (normal range 0.2-1.2), and international normalized ratio (INR) of 1.3 I/U (normal range 0.8-1.2). Given these findings, patient was admitted to the hospital for a higher level of care.
Standard blood tests were negative for hepatitis A, B, C, E, Ebstein Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal antibody, alpha-1-antitrypsin deficiency, and anti-mitochondrial antibody. Serum acetaminophen and urine toxicity screens were negative. Serum ceruloplasmin, ferritin, iron studies, and immunoglobulins were all within the normal range. Right upper quadrant ultrasound showed diffuse echogenicity of the liver. Liver biopsy was performed and showed multi-lobular necrosis consistent with acute toxic necrosis and fulminant hepatitis (Figure (Figure11).
Figure 1
Liver biopsy showed extensive patchy areas of multilobular necrosis with only bile ducts remaining, extensive ductal metaplasia, severe lymphocytic and macrophages infiltration of portal tracts and lobular parenchyma and patchy plasma cell infiltrates. ...
The patient’s liver function tests peaked 4 d after admission with serum AST level of 1613 U/L, ALT level of 1227 U/L, serum alkaline phosphatase of 268 U/L, serum TB of 10.5 mg/dL, and INR staying at 1.3 I/U. She did not develop evidence of hypoglycemia or portal-systemic encephalopathy. Her jaundice and scleral icterus resolved over the following 2-wk. Her liver tests gradually improved within the following few months.

Case 2

A 37-year-old woman presented to our hospital with a 1-mo history of diffuse abdominal pain, mild nausea, and painless jaundice. She denied any past medical or surgical history, family history of liver disease, or any alcohol or illicit substance abuse. She admitted that she had been taking Herbalife dietary supplements for the past 3-mo in an attempt to lose weight. Her Herbalife regimen consisted of the Formula One Nutritional Shake Mix, the Multivitamin Complex, the Cell Activator, the Cell-U-Loss, the Herbal Concentrate Original, and the Total Control formula.
The patient was afebrile with normal vital signs on presentation. Her physical exam was noticeable for bilateral scleral icterus and generalized jaundice. Her abdominal exam revealed a non-tender, non-distended abdomen with no stigmata of liver disease. Initial laboratory studies were significant for an AST level of 2199 U/L, serum ALT level of 2068 U/L, serum alkaline phosphatase of 185 U/L, and TB of 15.3 mg/dL. All other laboratory values, including amylase, lipase, and INR, were within normal limits. Given these lab abnormalities, the patient was admitted to the hospital for further work-up.
Standard blood tests were negative for hepatitis A, B, C, E, EBV, CMV, HIV, antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal antibody, alpha-1-antitrypsin deficiency, and anti-mitochondrial antibody. Serum acetaminophen and urine toxicity screens were negative. Serum ceruloplasmin, ferritin, iron studies, and immunoglobulins were all within normal range. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous (IV) contrast showed multiple low-density lesions in the liver measuring up to 8-mm. A liver biopsy revealed acute necrotizing hepatitis both centrolobular and periportal, consistent with a drug-induced etiology (Figure (Figure2).2). However, her liver biopsy specimens also showed evidence of bridging fibrosis, which suggest some degree of chronic liver disease but with drug-induced injury in addition.
Figure 2
Liver biopsy was performed and showed periportal bridging fibrosis, ductal metaplasia, cholestasis, moderate intralobular lymphocytic infiltration, and troxis necrosis and apoptosis consistent with drug-induced hepatitis on top chronic liver disease. ...
The patient was treated supportively with fluids and nutrition. Her liver tests steadily declined from the day of admission and on hospital day 8 (day of discharge) her liver tests revealed a AST level of 1788 U/L, ALT level of 1501 U/L, and serum alkaline phosphatase of 183 U/L. The only laboratory value to increase was the patient's serum TB, which was at 29.9 mg/dL on discharge. The patient did not develop encephalopathy, hypoglycemia, or any other complications. The patient was followed for several months, throughout which her symptoms continued to improve.
At her 2-mo follow-up, the patient's icterus and jaundice had resolved completely. Her labs at this time showed a serum AST level of 51 U/L, serum ALT level of 43 U/L, serum alkaline phosphatase of 65 U/L, and serum TB of 1.1 mg/dL.

Case 3

A 53-year-old previously healthy woman presented with a 3-wk history of painless jaundice and pruritus. She denied any family history of liver disease, or any alcohol or illicit substance abuse. She had not been taking any new prescribed medications. On further questioning about over-the-counter supplements she divulged a 4-mo history of consuming various Herbalife weight loss products in the form of shakes, teas and pills.
On physical exam the patient’s vital signs were within normal limits. On general inspection she had scleral icterus and jaundice, with evidence of excoriations. A 2-cm palpable liver edge could be appreciated, that was tender to touch. There were no other signs of chronic liver disease. Initial laboratory values revealed a hepatocellular pattern of injury, with an AST of 1282 U/L, ALT of 983 U/L, and alkaline phosphatase of 292 U/L, with a TB of 18.2 mg/dL. An ultrasound showed borderline hepatomegaly of 17-cm.
Standard blood tests for hepatitis A, B, C, E, EBV, CMV, HIV, antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal antibody, alpha-1-antitrypsin deficiency, and anti-mitochondrial antibody were negative. Serum acetaminophen and urine toxicity screens were negative. Serum ceruloplasmin, ferritin, iron studies, and immunoglobulins were all within normal range.
Liver biopsy was performed and showed cholestasis, consistent with drug induced hepatitis (Figure (Figure3).3). 2-mo after complete abstinence from the Herbalife supplements her jaundice resolved, as did her liver tests.
Figure 3
A liver biopsy revealed acute hepatitis characterized by hepatocellular injury, with periportal fibrosis, cholestasis, ductal metaplasia and diffuse intralobular and periportal troxis necrosis consistent with a drug-induced etiology. Intralobular lymphocytic ...

DISCUSSION

Acute liver injury induced by over the counter weight-loss herbal supplement Hydroxycut and Herbalife products have been reported previously[3-6,8-11]. These case reports were limited by the fact that liver biopsies were performed in only a few patients, confirming clinical suspicions histologically. In terms of our patients, all three had liver biopsy performed and all showed some common morphological features including diffuse lymphocytic infiltration of sinusoids and portal tracts, ductal metaplasia and toxic necrosis. Some variations of morphological features could be explained by predominance of intrinsic or idiosyncratic mechanisms of hepatic injury, individual patient response to the affecting drug and duration of injury. The patients’ liver biopsy specimens were stained with periodic acid-Schiff (PAS) stain with diastase. No hyaline globules were identified in any of the three cases. The absence of histological findings and the fact that our patients had no history of chronic obstructive pulmonary disease excluded diagnosis of alpha-1-antitripsin deficiency in all three cases. Prussian blue and copper stains did not reveal excessive iron or copper depositions in the hepatocytes and Kupffer cells.
Only one previous case of Hydroxycut-induced acute liver injury had reported findings on liver biopsy. Although the most likely explanation for the mechanism of liver injury caused by these herbal products is idiosyncratic reaction, one of the ingredients in Hydroxycut, green tea extract (Camellia sinensis), has been linked with acute liver injury in other over the counter weight-loss herbal supplements[12-20]. In fact, the weight-loss herbal supplement Exolise (Arkophama, Carros, France), which also contained C. sinensis, was withdrawn from the market because it was linked to multiple cases of liver injury[13]. Furthermore, several cases of hepatotoxicity were associated with another herbal weight-loss supplement, Cuur (Scandinavian Clinical Nutrition, Sweden), which also contains the ethanolic dry extract of green tea (C. sinensis)[15]. Rechallenging patients with the same product led to hepatotoxicity, confirming the role of C. sinensis[12,16]. In all reported cases of acute liver injury induced by Hydroxycut, patients’ liver function tests recovered over time following cessation of the product. However, there have been cases of liver failure caused by green tea extract C. sinensis, requiring orthotopic liver transplantation[13,16].
The liver biopsy obtained in our patient who took Hydroxycut showed multi-lobular necrosis consistent with acute toxic necrosis and fulminant hepatitis. These findings are similar to the findings in patients with liver injury associated with green tea extract C. sinensis, where prominent necrosis with inflammatory reaction is the hallmark presentation[15,16].
The exact mechanism of hepatotoxicity induced by Hydroxycut is unknown. However, as this product contains green tea extract C. sinensis, it is possible that this may play a role in acute liver injury caused by Hydroxycut. Prior investigation into the mechanism of hepatotoxicity by green tea extract was inconclusive[21]. Others have hypothesized that a possible allergic reaction to the green tea extract, contamination during the production of the extract or a metabolic idiosyncrasy are possible mechanisms of liver injury in these patients[16].
Both of our patients took several Herbalife weight-loss herbal products concurrently, similar to most of the previously reported cases of hepatotoxicity due to Herbalife products[8-11]. Therefore, it is difficult to identify the exact ingredient or mechanism that causes the liver injury, as in the previously documented cases[8-11]. In a previously reported case, one investigator was able to isolate contamination with Bacillus subtilis, in which the bacterial supernatant caused dose-dependent increase of LDH leakage in HepG2 cells[8]. Although not commonly known as a human pathogen, B. subtiliis has been reported to cause food poisonings and a case of cholangitis in an immunocompromised patient[22-23]. Investigators have also suggested that another explanation for hepatotoxicity due to Herbalife products could be secondary to locally restricted contamination with chemicals such as softeners, preservatives, flavor enhancers, pesticides, or heavy metals either intentionally added during the production process or contained in the unrefined raw herb extracts[24].
To date, Herbalife has refused to provide detailed analyses of their products’ composition and ingredients[25]. This contamination hypothesis could also explain the different patterns of pathology seen on liver biopsy specimens previously observed in patients with hepatotoxicity from Herbalife products as both predominantly cholestatic injury pattern and acute hepatitis pattern have been reported[8-11]. Our patients had findings consistent with acute hepatitis due to drug-induced liver injury on their liver biopsy specimens.
Due to the obesity epidemic, the usage of weight-loss herbal supplements has flourished. Green tea extract is one of the key components in many of the over-the-counter weight-loss herbal supplements. Although significant liver injury induced by herbal supplements taken for weight loss purposes is a rare event, we cannot ignore the fact that there have been multiple reported cases in the medical literature of hepatotoxicity associated with weight-loss herbal supplements including Hydroxycut and Herbalife products. Even though our patients successfully recovered from the adverse reactions, we must bear in mind that the hospitalization and medical care of these patients were associated with significant cost and healthcare resource utilization, while there is no evidence that herbal supplements can help with weight-loss[26]. We must also consider the impact on patients with underlying chronic liver disease, in whom herbal weight loss medications could cause worsening in their synthetic function and even fulminant failure. In May of 2009, the US Food and Drug Administration warned consumers to immediately stop using Hydroxycut products, citing linkage to liver damage in one patient who died due to liver failure[27]. However, Hydroxycut products are currently still available in many parts of the world. Likewise, Herbalife products are widely available globally. Therefore, it is these authors’ view that closer monitoring of patients taking weight-loss herbal supplements as well as tighter regulation from government drug agencies is warranted. Furthermore, our cases once again demonstrated the importance of questioning patients regarding the usage of herbal or nutritional supplements at the time of evaluation.

Footnotes

Supported by Harbor UCLA Medical Center and The Division of Gastroenterology
Peer reviewers: Mary Ko Manibusan, Co-Chair, US Environmental Protection Agency, Office of Pesticide Programs, Health Effects Division - Crystal City, 8136 Viola Street, Springfield, VA 22152, United States; Ferruccio Bonino, Professor, Chief, Scientific Officer, Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Via F. Sforza 28, Milano 20122, Italy
S- Editor Zhang HN L- Editor Hughes D E- Editor Liu N

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Aloe-induced Toxic Hepatitis

J Korean Med Sci. 2010 March; 25(3): 492–495.
Published online 2010 February 17. doi:  10.3346/jkms.2010.25.3.492
PMCID: PMC2826749

Ha Na Yang,1 Dong Joon Kim,corresponding author1 Young Mook Kim,1 Byoung Ho Kim,1 Kyoung Min Sohn,1 Myung Jin Choi,1 and Young Hee Choi2

Abstract

Aloe has been widely used in phytomedicine. Phytomedicine describes aloe as a herb which has anti-inflammatory, anti-proliferative, anti-aging effects. In recent years several cases of aloe-induced hepatotoxicity were reported. But its pharmacokinetics and toxicity are poorly described in the literature. Here we report three cases with aloe-induced toxic hepatitis. A 57-yr-old woman, a 62-yr-old woman and a 55-yr-old woman were admitted to the hospital for acute hepatitis. They had taken aloe preparation for months. Their clinical manifestation, laboratory findings and histologic findings met diagnostic criteria (RUCAM scale) of toxic hepatitis. Upon discontinuation of the oral aloe preparations, liver enzymes returned to normal level. Aloe should be considered as a causative agent in hepatotoxicity.
Keywords: Aloe, Hepatitis, Toxic

INTRODUCTION

The demand for dietary supplements has continually increased in recent years as the concept of 'well being' widely spread in Korea. The market value for dietary supplements in Korea was approximately 600 billion won (600 million USD) in year 2005 (1), and personal spending was approximately 950,000 won (950 USD) per year in 2005 (2). One of the leading products in Korea's dietary supplements market is aloe.
Aloe has been purported to have positive effects on wound healing, recovery from burn injury, cell growth, and immune modulation. However, cases of aloe-induced toxic hepatitis have been reported since 2005. In particular, there have been one each in Germany (3), Turkey (4), and USA (5). In Switzerland (6), 10 cases of hepatotoxicity associated with dietary supplements from Herbalife® products were reported. Although 2 of those 10 cases took aloe preparation, the causality assessment between aloe and toxic hepatitis could not be done due to multiple Herbalife® products.
We report 3 cases of aloe-induced toxic hepatitis in Korea.

CASE REPORTS

Case 1

A 57-yr-old female patient with a 2 month history of dyspepsia was presented to our department. Past medical history and family history did not reveal any significant disease. She also used drugs for arthralgia intermittently for several years. She did not take any alcohol. She had taken aloe tablets containing 250 mg of an extract of Aloe arborescens and 28.5 mg of an extract of Aloe vera (Fig. 1) for about 6 months prior to the admission. On admission, the patient's physical examination was normal.
Fig. 1
Preparation of aloe which the patient had taken. (A) Container bottle and tablets. (B) Packs of aloe extract.
Laboratory abnormalities included aspartate aminotransferase (AST) 331 IU/L, alanine aminotransferase (ALT) 565 IU/L, alkaline phosphatase (AP) 309 IU/L. Anti-HAV IgM, anti-HCV, HCV PCR, and anti-HEV IgM were negative. Anti-HBs IgG was positive. There was no serologic evidence for recent infections with cytomegalovirus (CMV), Epstein-Barr-virus (EBV), or herpes simplex virus (HSV). Autoimmune markers were all negative. Abdominal ultrasonography showed reduced echogenicity of liver. Dilatation of intra- or extrahepatic bile ducts was absent. Liver biopsy revealed moderate portal infiltrates consisting of eosinophilis, neutrophils, and monocytes. There were inflammatory cell infiltration and acidophil body on the hepatic lobule. There was no bile stasis (Fig. 2).
Fig. 2
Histopathological findings of the liver. (A) The portal area and lobular area show inflammatory cell infiltration (H&E, ×100). (B) The acidophilic body and ballooning cell change are noted (H&E, ×200).
Aloe tablets was immediately discontinued. ALT was highest (926 IU/L) on the 12th day of admission and gradually decreased to 452 IU/L on the 25th day of admission. ALT as well as total bilirubin gradually returned to normal level over several weeks (Fig. 3). Using the Roussel Uclaf Causality Assessment Method for determining drug hepatotoxicity (RUCAM) scale, this case was scored as 'probable' (Table 1). The type of liver injury was determined as 'hepatocellular' since R ratio (serum activity of ALT/serum activity of AP) was 10 (7).
Fig. 3
Case 1. Upon discontinuation of the oral aloe preparation, liver enzymes returned to normal level.
Table 1
RUCAM score of these cases

Case 2

A 62-yr-old female patient was presented to our department with a week history of fatigue. Past medical history and family history did not reveal any significant disease. The patient did not take any alcohol or durgs. She had taken aloe powder containing 420 mg of an extract of Aloe vera (Fig. 1B) for about 3 months prior to the admission. Physical examination revealed jaundice on her sclera. She was the sales person of the aloe product she was taking.
Laboratory abnormalities included AST 1,477 IU/L, ALT 1,564 IU/L, total bilirubin 14.64 mg/dL. Anti-HAV IgM, anti-HCV, HCV PCR, and anti-HEV IgM were negative. Anti-HBs IgG was positive. IgM antibody for HSV was in trace, IgM antibody for CMV was negative. Abdominal ultrasonography was normal. Liver biopsy revealed severe portal and lobular infiltrates consisting of neutrophils and monocytes. There were several acidophilic bodies and ballooning cell change in hepatic lobule. There were bile-stasis and bile stained Kupffer cells (Fig. 2B).
Aloe extract was immediately discontinued. ALT gradually decreased to 452 IU/L which was lower than half of the peak value on the 17th day of admission. When she was discharged ALT and AST were normal. We explained to her about the aloe-induced hepatotoxity and advised not to take it anymore. However, the patient started taking the same aloe extract again 1 month after her discharge from the hospital. A month later, follow-up liver function test showed AST 477 IU/L, ALT 785 IU/L, and AP 165 IU/L (Fig. 4). Since a hepatitis recurred after re-challenge of aloe extract, we could confirm her diagnosis as aloe-induced toxic hepatitis. The RUCAM scale was scored as 'definite' (Table 1). The type of liver injury was determined as 'hepatocellular' since R ratio was 39.
Fig. 4
Case 2. Upon discontinuation of the oral aloe preparation, liver enzymes returned to normal level. After re-challenge (arrow), liver enzymes go up again.
Six months later, the patient was presented to our department with a 2 week history of jaundice. Laboratory test showed AST 752 IU/L, ALT 1,135 IU/L, AP 243 IU/L and total bilirubin 15.81 mg/dL. We recommended admission, but she refused to be admitted and she never visited our hospital again.

Case 3

A 55-yr-old female patient was presented to our department with a 3 month history of epigastric discomfort. Past medical history and family history did not reveal any significant disease. The patient did not take any alcohol or drugs. She had taken aloe extracts (Fig. 1) for about 5 months prior to the admission. On admission, the patient's physical examination was normal except mild tenderness on epigastric area.
Laboratory abnormalities included AST 344 IU/L, ALT 666 IU/L, AP 298 IU/L. Anti-HAV IgM, anti-HCV, HCV PCR, and anti-HEV IgM were negative. Anti-HBs IgG was positive. Autoimmune markers were negative. Abdominal ultrasonography showed increased echogenicity of liver. Dilatation of intra- or extrahepatic bile ducts was absent.
Aloe extract was immediately discontinued. ALT was highest (666 IU/L) on the 2nd day of admission, and gradually decreased. ALT was 484 IU/L on her discharge (on the 5th day of admission). After 4 days, she visited our department for follow-up. Liver function test was normal at that time (AST 29 IU/L, ALT 11 IU/L, AP 190 IU/L) (Fig. 5). The RUCAM scale was scored as 'probable' (Table 1). The type of liver injury was determined as 'hepatocellular' since R ratio was 11.
Fig. 5
Case 3. Upon discontinuation of the oral aloe preparation, liver enzymes returned to normal level.

DISCUSSION

The major driving force for the growth of the dietary supplements market is the perception that 'they are safe because they are natural'. However, the recently reported cases of hepatotoxicity induced by natural substances (8) indicate that natural substances may not be entirely safe.
There are about 400 species of aloe. Among them, particularly aloe vera has been used in phytomedicine. There have been positive reports on aloe vera as anti-inflammatory, anticancer, analgesic, anti-aging as well as liver protective. But, clinical effectiveness of aloe vera was not sufficiently defined because there were no large and randomized studies (9). In 1994, Korea's National Institute of Safety Research conducted an experiment on the efficacy and toxicity of aloe (10). There was no difference of natural killer cell activity between the aloe vera gel treated and control animals. To observe the toxicity of aloe gel, rats were given the high dose aloe orally. Any adverse effects were not detected in hematological test, serum biochemistry, and histopathological examination.
There are no specific tests or diagnostic criteria for herbinduced hepatic injury. Careful history taking, laboratory finding, and histopathology are used to diagnose it. The best way to determine causing agent is re-challenging. But it is not ethical and not applicable. Instead, the RUCAM scale is used (7, 11).
Since patients usually do not regard dietary supplements as 'real' medicine, they may fail to mention it when physicians query medication history. Physicians should keep in mind that dietary supplements can be the cause of hepatotoxicity when querying medication history, and should educate the lay public.
There are three types of acute liver injury by drug or herb (12): hepatocellular, cholestatic, and mixed type. Our cases are characterized as hepatocellular; there is a predominant initial elevation of the ALT level. There are two proposed pathogeneses of drug induced liver disease (13): direct toxicity and idiosyncratic mechanism. It is more likely that an idiosyncratic immunological mechanism (hypersensitivity) is responsible for the cases. A role for hypersensitivity is further supported by the presence of eosinophilic granulocytes in the periportal fields seen in the biopsy. Hypersensitivity to aloe has been described in humans (14), and the patch test or allergic skin test showed positive results (15).
Herb induced liver injury is an important problem in clinical setting, because it can be an etiology of undiagnosed acute hepatitis. However, there are few available data about the incidence and clinical manifestation of dietary supplements such as aloe. Our cases emphasize that physicians should consider various dietary supplements as causative agents for hepatotoxicity.

References

1. Food and Drug Statistical Yearbook. Korea Food and Drug Administration. 2006. Aug, [accessed 2008 0ct 27]. Available at: URL: http://www.kfda.go.kr/open_content/main/main.php.
2. Yoo TW, Kim BI, Kim JB, Kim DJ, Kim JW, Baik SK, Kim KS, Cheon GJ. The survey for the actual condition of drug medication and development of health care cost associated with toxic liver injury in Korean: a multicenter study for the detection and the development of nationwide reporting system of toxic liver injury. Korean J Hepatol. 2007;13:34–43. [PubMed]
3. Rabe C, Musch A, Schirmacher P, Kruis W, Hoffmann R. Acute hepatitis induced by an aloe vera preparation: a case report. World J Gastroenterol. 2005;11:303–304. [PubMed]
4. Kanat O, Ozet A, Ataergin S. Aloe vera-induced acute toxic hepatitis in a healthy young man. Eur J Intern Med. 2006;17:589. [PubMed]
5. Bottenberg MM, Wall GC, Harvey RL, Habib S. Oral aloe vera-induced hepatitis. Ann Pharmacother. 2007;41:1740–1743. [PubMed]
6. Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D, Reichen J, Zimmermann A, Oneta CM. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from herbalife products. J Hepatol. 2007;47:521–526. [PubMed]
7. Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11:272–276. [PubMed]
8. Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol. 2005;43:901–910. [PubMed]
9. Vogler BK, Ernst E. Aloe vera: a systematic review of its clinical effectiveness. Br J Gen Pract. 1999;49:823–828. [PMC free article] [PubMed]
10. Jang DD, Cho JC, Choi KS, Kil HI. Studies of the effectiveness and toxicity of aloe vera gel. The report of National Institute of Safety Research. 1994;7:225–233.
11. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731–739. [PubMed]
12. Chae HB. Clinical features and diagnosis of drug induced liver injury. Korean J Hepatol. 2004;10(Suppl1):7–18.
13. Kang DY. Pathologic features of toxic and drug induced liver injury. Korean J Hepatol. 2004;10(Suppl1):19–29.
14. Morrow DM, Rapaport MJ, Strick RA. Hypersensitivity to aloe. Arch Dermatol. 1980;116:1064–1065. [PubMed]
15. Lee EG, Kwon SH, Kim SH, Myung SJ, Choi JW, Kim YJ, Ahn Y. A case of hypersensitivity associated with oral aloe agent. J Asthma Allergy Clin Immunol. 2003;23:833–836.
===========================

Revisiting acute liver injury associated with herbalife products

Abstract

In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.
Keywords: Herbalife, Liver, Hepatotoxicity, Weight loss products, Dietary supplements

TO THE EDITOR

In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. Case 1 involved a patient who did not consume Herbalife products, while Cases 2 and 3 each reportedly consumed various Herbalife products. Herbalife fundamentally disagrees with the conclusions made by the authors with regard to any cause and effect relationship related to the intake of Herbalife products. First, Herbalife is not a single product and no unique suspect product or ingredient has been implicated in this paper amongst the reported cases. In addition, the authors arbitrarily compared cases involving the use of a single product (Hydroxycut) with patients who consumed a group of totally unrelated products produced by the company Herbalife. To bundle a brand of products such as Herbalife with another company that sells different products simply because they are all dietary supplements is not valid. Finally, there are specific considerations, in regard to the two patients who consumed Herbalife products, that would render many of the observations and conclusions discussed by the authors as speculative and unsubstantiated. The specific and factual points supporting these views are further detailed below.
Case 2 describes a 37-year-old female who developed symptoms of abdominal pain, mild nausea, and painless jaundice 1 mo prior to presenting at the hospital[1]. Several pertinent negatives were disclosed by the authors, including autoimmune markers and viral serology. According to the authors, the patient did not report any pre-existing medical conditions for which the onset had preceded the use of Herbalife products. However, the pathology assessment concluded that this patient’s biopsy result was consistent with chronic liver disease, in which case Herbalife products were thought to have had an additive effect. This opinion contradicts repeated statements by the authors that acute liver injury in each case report was due to the use of herbal weight loss products. In addition, the etiology of the pre-existing condition was not identified by the authors, and there was no discussion regarding the role of the condition in the acute onset of her symptoms. Furthermore, the dosage and frequency at which this patient consumed Herbalife products is unknown. Finally, the inconsistency of the objective findings with the patient’s reported medical history would suggest that further investigation is warranted. This should include a review of the patient’s pre-existing condition, potential use of medications prescribed for her condition, other compounds she may have been consuming, and the status of her health prior to the reported incident. In the absence of the aforementioned data, the exclusion of possible differential diagnoses is not well-supported.
Case 3 describes a 53-year-old female who developed symptoms of painless jaundice and pruritus 3 wk prior to presenting at the hospital[1]. This patient denied family history of liver disease, but no discussion was provided regarding her own medical history, other than the fact that she reportedly denied the use of alcohol and did not engage in “illicit substance abuse”. The authors further stated that the patient had not been prescribed any new medications, which implies that she may have been taking other agents concomitantly. However, information regarding the use of concomitant medications, or the conditions for which she may have been receiving treatment, was not disclosed. Such information is critical and should have been obtained through follow-up review of the patient’s previous medical records. Without this information, it is unknown whether concomitant medication(s) were withdrawn and/or accounted for during the dechallenge process. The patient’s use of Herbalife products was also not specified by product names and it is unknown whether the dosage and frequency of consumption was adherent to recommendations indicated on the product label(s). In addition to the absence of the aforementioned pertinent patient data, there are various refutable facts that remain in regard to the comments and conclusions made by the authors.
In their WJH article, the authors concluded that it was difficult to isolate a single ingredient or mechanism associated with acute liver injury for either patient consuming Herbalife products[1]. In an effort to discuss potential causative agents for the reported conditions in these patients, the authors extraneously reference previously published case reports involving Herbalife products, including those of two consumers who reportedly developed hepatotoxicity following exposure to Bacillus subtilis (B. subtilis)[2].
In review of this reference, it has been noted that there were various critical deficiencies in the scientific methodology used to isolate B. subtilis in the Herbalife samples reported to have been contaminated. For example, a dose dependent increase in LDH leakage in HepG2 cells was observed in the experimental assay, but investigators did not present any control data for their experiments, nor did they present any data that suggested this assay is a valid proxy for liver injury in healthy individuals “in vivo”. Neither patient reported symptoms consistent with classical B. subtilis food poisoning and they did not report testing the product for the detection of cerulide or any of the reported heat-stable toxins associated with certain strains of B. subtilis. Furthermore, the investigators did not enumerate the levels of B. subtilis in the products tested or report testing relevant specimens from the patients for these organisms or their toxins. This was a crucial step missing in the reported investigation as all previous documented reports find that high levels of the organism must be consumed to cause illness. Herbalife products, consumed by the patients described in the WJH article, to date show no evidence of B. subtilis contamination. B. subtilis infections are relatively rare and seldom contracted through food sources. This bacterium is actually ubiquitous in nature and generally recognized as safe with a history of safe use in food, and is considered to be safe for the production of enzymes or ingredients for use in food[3]. There have been reported cases of B. subtilis-related gastroenteritis and other complications, usually involving immuno-compromised patients or those with other underlying chronic illnesses, which did not appear to be the case for any of the patients presented in the WJH article. Therefore, it is highly unlikely that B. subtilis could be the cause or have contributed to the severe hepatotoxicity of patients in either the referenced article or the two patients discussed in the WJH article.
The WJH authors also suggest intentional or incidental contamination of Herbalife ingredients and identify various potential sources, including unrefined raw herbal extracts, heavy metals, pesticides, and additives[1]. However, some of the additives mentioned as potential contaminants by the authors (e.g., flavoring, colors, and preservatives) are commonly used and well-documented industry-wide as safe for consumption in conventional foods, as well as dietary supplements,. In addition, authors also reference an article from 2002 that reviews possible contamination sources inherent to herbal remedies marketed without proper quality control measures in place[5]. Herbalife is not specifically implicated in the referenced article, yet the authors imply that Herbalife product contamination and lack of quality control contributed to the liver injury. The authors’ assumption is wrong and does not take into consideration that the United States FDA requires dietary supplement manufacturers to use current Good Manufacturing Practices (cGMPs) in the production of dietary supplements[4]. The goal of these regulations is to “ensure that a dietary supplement contains what the manufacturer intends” and meets specifications to ensure the dietary supplement contains the correct ingredient, purity, strength and composition intended. Herbalife has rigorous processes in place concerning quality control, including extensive safety reviews based on existing literature for product ingredients, testing to confirm that labeled ingredients are present in finished goods, and to assure all tested ingredients meet product specifications on an ongoing basis. In addition to complying with cGMP regulations, Herbalife acts in accordance with other generally recognized industry standards or requirements by sourcing and testing raw materials to further ensure that the final product complies with specifications for identity, purity, potency and contaminants.
The authors also try to implicate the Camellia sinensis (C. sinensis) used in Herbalife’s tea drink products by citing case reports of liver injury in association with ethanolic extracts of C. sinensis, which contain a concentrated fraction of EGCG[1]. The most important safety consideration for green tea is the extraction method. The historical data supporting the safety of green tea is based on the consumption of an aqueous extract over thousands of years, specifically, the typical three cups per day that are commonly consumed in Asian countries. Aqueous extracts of green tea are quite different from solvent extractions, which are commonly used to concentrate select fractions of green tea, such as EGCG or caffeine. Again, the WJH authors have not considered the clinical significance of potential differences in raw material processing amongst manufacturers, controls for contamination and identification of raw materials, and the implication of these differences when reviewing published case reports of liver injury. In addition, the authors state that Herbalife has refused to provide detailed analyses of ingredients and formulations, although no attempt was made by these authors to contact Herbalife to obtain further information regarding Herbalife products or ingredients. Herbalife has, to date, remained compliant with all formal regulatory requests and requirements for product information.
The authors state that significant liver injury induced by herbal supplements is a rare event[1]. This statement is true as approximately 20 to 50 percent of all cases presenting as hepatotoxicity are cryptogenic leading to the incidental association of liver disease with a group of products in the absence of specific evidence[5]. While this disease is the most common cause of drug withdrawal during post-marketing surveillance, it is an uncommon cause of liver disease. The background incidence of hepatotoxicity in populations is clearly comparable to the reported incidence of immunoallergic and individualistic reactions to allergens in foods, supplements, or the environment. For example, in a study of 71 000 North Americans in 1992, the background rate of idiopathic or cryptogenic liver disease was 24 cases per 100 000 individuals compared to 14 per 100 000 attributed to cases of hepatitis B, 25 per 100 000 due to alcoholism, and 7 per 100 000 to other viral illnesses[6]. While the spectrum of liver diseases may well have changed since 1992 when this survey was done, idiopathic liver disease remains a significant percentage of all cases. Therefore, it is particularly important in making such associations to have incontrovertible evidence such as is often available for prescription drugs where, under controlled conditions, a cause-effect relationship can be established.
Finally, the authors also state that existing case reports of dietary supplement-induced hepatotoxicity include patients with pre-existing liver disease and that weight loss supplements could worsen such conditions in these patients. However, this effect could occur from many different substances, including over-the-counter and prescription medications, as these patients may be “pre-sensitized” due to an underlying hepatic condition.
In conclusion, the reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. Further information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage is indicated to assess fully the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.

Footnotes

Peer reviewers: Jordi Muntan¨¦, PhD, Unidad de Investigacion, Hospital Universitario Reina Sof¨ªa, Av. Men¨¦ndez Pidal s/n, Cordoba 14004, Spain
S- Editor Zhang SJ L- Editor Hughes D E- Editor Zheng XM

References

1. Chen GC, Ramanathan VS, Law D, Funchain P, Chen GC, French S, Shlopov B, Eysselein V, Chung D, Reicher S, et al. Acute liver injury induced by weight-loss herbal supplements. World J Hepatol. 2010;2:410–415. [PMC free article] [PubMed]
2. Stickel F, Droz S, Patsenker E, Bögli-Stuber K, Aebi B, Leib SL. Severe hepatotoxicity following ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis. J Hepatol. 2009;50:111–117. [PubMed]
3. Biotechnology Program Under the Toxic Substances Control Act (TSCA) Bacillus subtilis Final Risk Assessment; 1997. Feb, Available from: http: //www.epa.gov/biotech_rule/pubs/fra/fra009.htm.
4. De Smet PA. Herbal remedies. N Engl J Med. 2002;347:2046–2056. [PubMed]
5. Implementation of FDA's Current Good Manufacturing Practices for Dietary Supplements. [cited 2007 Oct 24]. Available from: http://www.fda.gov/Food/DietarySupplements/GuidanceComplianceRegulatoryInformation/RegulationsLaws/ucm174152.htm#slide.
6. Walker AM, Cavanaugh RJ. The occurrence of new hepatic disorders in a defined population. Post-marketing Surveill. 1992;6:107–117.
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Do Herbalife Products Cause Hepatitis?











Christopher Pascale Posted on Dec 21, 2010
SUITE101











Christopher Pascale  Posted on Dec 21, 2010

    Multiple medical resources have found that there are 2,000,000 people around the world who are offering products that may make you very sick.

Are Your Vitamins Making you Sick? - Julie Elliott-Abshire (http://www.sxc.hu/photo/151747)
Herbalife is a publicly traded company based out of Los Angeles, California. Since 1980 it has allowed people the opportunity to become independent sales reps with the opportunity to lead others to do the same in the form of multi-level marketing, or network marketing.
Like any large organization with several decades of experience, there are some controversies behind this one. For example, in 1986, the state of California claimed that the company made inflated claims regarding income potential for which Herbalife settled for $850,000, and in 2004 thousands of current and former distributors took the company to court on the grounds of running a pyramid scheme. Herbalife settled the latter case for $6,000,000 (less than $700 each).
Along with these legal matters are much more pressing health concerns. Several medical resources have found that Herbalife products may actually cause hepatitis.
What is Hepatitis and How is it Caused?
Hepatitis can be characterized as an inflammation of the liver. One visible symptom is jaundice, and less visible ones are lack of appetite and a feeling of overall discomfort.
Hepatitis is typically caused by a virus, but it can also be caused by toxins when taken regularly, such as alcohol or an infection that is already present. The question on many people's minds regarding Herbalife products would be, how could these products be linked to infecting those who take them?
The answer is in the ingredients. There has to be something toxic in some or all of the products released by the company, but it is hard to know which ones because the FDA does not regulate herbal supplements the same way it does medicine. This is why athletes find out via heart attack that ephedrine is not so great, and how health conscious people discover that they may be poisoning themselves the hard way, as reported in a 2007 article published in The Journal of Hepatology titled "Herbal Does not Mean Innocuous."
Countries That Have Reported Illness Links to Herbalife
It is important to note where the sources are that have reported on Herbalife. This is because some people go on the attack against networking companies because they think they are dangerous or terrible, and some governments are anti-capitalistic, so they would be against a company like Herbalife because they do not want their people to have too much freedom and control.
In 2004, 12 patients in Israeli hospitals with severe liver problems had one thing in common. They were taking an Herbalife supplement that aided digestion. When their liver enzymes normalized, they resumed their normal regimen of the product and were sick again.
The 2007 article noted from the European Journal of Hepatology had several sources, one of which was medical professionals from Switzerland. In it, the ten most severe cases covered showed two patients with "certain causality" while the other eight had "probable causality." The duration of the illness ranged from two months to twelve years.
The objective here is not to demonize a company or industry, but to alert consumers that when Herbalife distributors pitch the quality of their products, they may be pitching high-end hepatitis. And while the ingredients linked to causing disease in the past may have been rid of, it does not mean that today's products are safe.
Without FDA interaction, humans are the test subjects for herbal supplements. The best way to go when it comes to supplements is to use one with a long track record of not hurting its users.
Jan. 5 update from the author: On December 23, George Fischer and one of his doctors had a conference call with me. During the course of that conversation, they promised that they would send me information contradicting the reporting in the Journal of Hepatology. No such contact has been made since.


===========================================

LIVER DAMAGE IN EUROPE ASSOCIATED WITH HERBALIFE USE:

4 Sept 2007 Review
The following reports below of HerbaLife-associated liver failure appear on Medline – from Spain, then Israel and Switzerland.
:The July 2007 reports of the two dozen Herbalife-associated hepatitis cases from Israel & Switzerland reveal that liver problems occurred after about 5 months on the products; and that relapse occurred in about 20% on rechallenge with Herbalife ie in this percentage the association is proven.

Herbalife results for weight control have been reported as good. The only problem is historical according to the current Wikipedia entry: “Some of the original Herbalife weight loss products contained the active ingredient Ma Huang or Sida cordifolia, two herbs containing ephedrine alkaloids.
Adverse reactions involving the company’s Thermojetics original green tablets were recorded by the U.S. Food and Drug Administration and Herbalife subsequently stopped using ephedrine in its products in the face of rising insurance premiums.[3][4] The U.S. FDA banned supplements containing ephedra in 2004.[5]“
It is possible that the case reports below are unrelated to Herbalife itself , or that in those countries ephedra-containing Herbalife was still in use at the time, or that potentially hazardous herbs etc were added locally.
From Yahoo.com, there is an authoritative rebuttal from Iceland dated February 2007.
A score of drugs and herbs can cause liver damage, topical ones – albeit rarely- include mushrooms; black cohosh and kava – see a recent list.
Drugs like ticrynafen, methyldopa and cerivastatin were discarded among other reasons because of liver problems, which are among many reasons why necessary sex hormone contraception and replacement should rather not use designer patent ie synthetic drugs, and especially not by mouth (hepatic first pass effect).
So it is always difficult to blame a single product, as the ongoing debate about black cohosh shows – which many “first world” regulators have “black boxed” ie added a compulsory warning to black cohosh warnings.
As with black cohosh, with a rare adverse event report, users of such products must weigh up for themselves.
As they say, since Herbalife tends to be custom-made in each country, with numerous ingredients (some undisclosed), it is so far impossible to incriminate whether the cause was local product corruption, or some appreoved component, of which the known possible culprits are ephedra and camelia.
Other known hepatotoxic herbs like black cohosh, kava and mushrooms were not mentioned. A few of the patients had viral hepatitis. Only 7 cases had also taken other known potential liver sensitizers – some synthetic sex hormones (4), aspirin (3), statin (1) and hydrochlorothiazide(1), of which 2 cases had positive recurrence of hepatitis on rechallenge with Herbalife.
UCT Medicines Information Centre is unaware of any such problems locally, and can recollect only perhaps 2 queries about Herbalife in some 23 years. Clarification is awaited from Herbalife headquarters.
From Swiss data the estimated incidence was below 2 cases per million Herbalife users, but both studies were based only on hospital records.
Considering the severe global problem of hepatitis from other causes (due to alcohol; obesity/diabetes (steatohepatitis, sulphonylureas, glitazones); numerous infections; carbon tetrachloride; synthetic sex hormones (oral contraception and postmenopausal hormone therapy) , mushrooms, antibiotics and antivirals, , autoimmune disease, antiepileptics, nifedipine, amitryptiline, allopurinol, nonsteroidal anti-inflammatories including aspirin and paracetamol , black cohosh, kava, antifungals and paracetamol), and that the rare adverse association of herbalife with liver damage may well have been limited only to Herbalife products made in those three “European” countries at that time, there is clearly no cause for alarm about Herbalife – just awareness.
The urgent problem of endemic liver disease is rather the avoidance of infections and potentially hazardous antimicrobials; mushrooms; carbon tetrachloride, alcohol excess; sale pf paracetamol without inclusion of protective vitamins and N-acetyl cysteine; and avoidance of potential hepatotoxins which are rarely if ever justified considering their risks, and safe effective alternatives available for eg statins, sulphonylureeas, glitazones, black cohosh, kava, non-steroidal anti-inflammatories; oral sex hormones; and sulphonylureas.
The centuries-proven plant galega officinalis (extract) metformin after 85years of modern use remains the only drug proven in longterm use to both reduce liver damage, lipidemia, thrombosis, adiposity and insulin resistance, and thus almost halve the incidence of new diabetes, hypertension/vascular disease, cancer and thus all-cause premature medical mortality.
Thus appropriate general use of metformin with long-proven vitamins, minerals, biologicals, safe herbs, fish oil and systemic human sex hormones – combined with prudent lifestyle and largely natural fresh foodstuffs- – does away with most of the well-known potential hepatitis drug risks listed above.
In defence of free market enterprise and choices, those who choose convenience safe proven food substitutes or other complementary products as part of an acceptable balanced regime advocated by suppliers like Herbalife do well, they should just be sure of the ingredients and supplier; and they should report and discuss what they use with some knowledgable up-to-date healthcare provider.
Response from Herbalife
04.09.07
Herbalife’s South Africa CEO responds reassuringly:

Good day,
Herewith a statement from Herbalife in response to the issues raised by yourself earlier in the week:

While we are aware of reports of abnormal liver function blood tests such as those reported by Dr. Oneta, our extensive consultation with internationally recognised liver experts has led repeatedly to the conclusion that these associations in time cannot be linked to any Herbalife product.
These small numbers of reports are anecdotal and millions of satisfied customers all over the world have been using our products for more than 27 years. All Herbalife products are formulated and manufactured in accordance with strict standards overseen by the Herbalife Scientific Advisory Board, which is chaired by David Heber, M.D., Ph.D., F.A.C.P., F.A.C.N. Quality control is overseen by our Scientific Affairs Group, chaired by Y. Steve Henig PhD and made up of an international panel of experts in nutrition and botanical dietary supplements.
Herbalife products, which are now sold in 65 countries, are formulated, registered and labelled in accordance with the regulatory requirements in every market where sold. All Herbalife products are safe to consume as directed.
Many consumers who choose to use Herbalife weight-management products for weight loss are overweight, some significantly so. Pre-existing medical conditions such as obesity and diabetes can be associated with non-alcoholic fatty liver disease, a disorder that may return certain types of abnormal blood test results. These test results, therefore, may have nothing to do with any herbal supplement, but rather are the result of a pre-existing medical condition. In addition, it is possible for an individual to have an allergic reaction to our products, the same way one might to any food product; for example, strawberries or shellfish. Herbalife supports the recommendation that consumers visiting their doctors for medical treatment inform them of any supplements they may be taking.
As a socially responsible company, we operate an adverse event reporting procedure that deals with the small number of queries we have from doctors and consumers and we operate an open dialogue policy with the medical community. All adverse event reports are investigated thoroughly in consultation with the consumer and the physician (if they are available) to fully understand the facts. None have resulted in the compulsory withdrawal of any product, ever. In the United States, Herbalife actively lobbied Congress to pass legislation mandating the submission of all dietary supplement and over-the-counter drug serious adverse events to the Food & Drug Administration. That new law takes effect December 22, 2007.”
REFS:
J Hepatol. 2007 Oct;47(4):521-526. Herbal does not mean innocuous: Ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife((R)) products. Schoepfer AM, ea.University Hospital Bern, Switzerland.
METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife((R)) products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife((R)) preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis.     Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife((R)) products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.

J Hepatol. 2007 Oct;47(4):514-520. Association between consumption of Herbalife((R)) nutritional supplements and acute hepatotoxicity. Elinav E, ea -Hebrew University Medical Center, Israel.
: In 2004, identification of four index cases of acute hepatitis associated with Herbalife((R)) intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife((R)) products were investigated.
RESULTS: Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife((R)) consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation.
. CONCLUSIONS: An association between intake of Herbalife((R)) products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife((R)) products for possible hepatotoxicity.

Med Clin (Barc). 2007 Feb 17;128(6):238-9.
[Hepatotoxicity associated with the consumption of herbal slimming products] Duque JM,ea. [Article in Spanish] Letter


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  J Hepatol (2007) 0: .

Herbal does not mean innocuous: Ten cases of severe hepatotoxicity associated with dietary


AM Schoepfer, A Engel, K Fattinger, UA Marbet, D Criblez, J Reichen
A Zimmermann, CM Oneta

BACKGROUND/AIMS: Herbal agents are popular and perceived as safe because they are supposedly 'natural'. We report 10 cases of toxic hepatitis implicating Herbalife((R)) products. METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife((R)) products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife((R)) preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis. Sinusoidal obstruction syndrome was observed in one case. Three patients without liver biopsy presented with hepatocellular (2) or mixed (1) liver injury. Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife((R)) products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.

Results of a search for studies that show the effects of using Herbalife products for weight loss. 
The official website is: http://www.ncbi.nlm.nih.gov/pubmed?term=herbalife


HERBALIFE SUPPLEMENT LIVER TOXICITY VIDEO>>>>

  Supplements

Contrary to the claims of many sellers of supplements (including bad advice from health food stores), we should strive to get most of our nutrients from produce not pills, though there are rare diseases that require supplementation.
There are tens of thousands of phytonutrients in plants that can display synergistic effects and have not been successfully isolated efficaciously in supplement form. For example iron, which is important during pregnancy, may be harmful in pill form. Similarly, folate in beans and greens is preferable to folic acid in pills. Flax seed, but not flax seed oil, lowers cholesterol. Citrulline supplements may aid erectile dysfunction, but a better source is watermelon. Similarly, eating soy foods, rather than taking soy supplements, may reduce the risk of breast cancer recurrence. And it is whole produce, not pills, which has been shown to increase physical attractiveness.

However, for those on plant-based diets, there are two vitamins not produced by plants that may require supplementation. They are vitamin D from sun but not from tanning beds (see also here, here, here, here, here, here, here) and vitamin B12 (see also here, here, here, here, here). Among vegans, B12 deficiency is an epidemic if no supplements are used, which can have devastating consequences for their infants (see also here). Vegetarian’s myelopathy is a syndrome coined to describe vitamin B12 decficiency, which can result in paralysis. Another nutrient vegans should keep an eye on is iodine, which is especially important during pregnancy (though harmful in too too great quantities).

One of the most commonly used supplements is fish oil. It has been found to contain DDT as well as other industrial pollutants, including high levels of dioxin, PCBs and mercury (which are neural and cardiac toxins). This includes distilled fish oil, cod liver oil and those labeled ‘Toxin-Free’. Instead, there are safe plant sources of omega-3; alternatives include algae and yeast derived EPA and DHA, which also lower inflammation.

While there are some harmless vitamin supplements such as vitamin C and Airborne supplements, others may do more harm than good, such as multivitamins, which may actually increase breast and prostate cancer risk, and antioxidant vitamin supplements such as Vitamin E that may shorten one’s lifespan.

A variety of other potentially harmful supplements exist including: Herbalife (for its liver toxicity, possibly due to vitamin A), Juice Plus+ (which is really just another vitamin supplement), glyconutrient supplements, lutein pills, creatine, copper supplements (which may contribute to Alzheimer’s), zinc gel, kombucha tea, noni juice, and rice bran. Ayurvedic medicine (see also here) has been found to contain lead. Spirulina and blue-green algae supplements may contain neurotoxins and/or liver toxins (a safer alternative is chlorella).

See also the related blog posts: Vitamin D: Shedding some light on the new recommendations, Multivitamins and Mortality, Vegan B12 deficiency: putting it into perspective

Topic summary contributed by Eitan

To help out on the site, email NutritionFactsVolunteers@gmail.com

liver disease

The USDA has failed to safeguard the meat supply from drug residues and toxic metals, which may result in jaundice and other liver issues. The discovery of infectious hepatitis E virus in retail pork products may help explain the purported association between liver failure and pork consumption. The transfer of blood on cutting machines may explain hepatitis C transmission between deli workers. Potentially toxic to the liver: noni juice, Herbalife® supplements (see here, here), spirulina (see here, here), cod liver oil, BPA in plastics, JuicePlus+® supplements, and shark cartilage.
The good news is that a vegetable protein diet appears to treat liver failure. Indian gooseberries may also protect the liver. And Ceylon cinnamon is the safest because it does not contain coumarin, which may damage the liver at toxic doses. Lastly, chamomile tea may not be safe to consume if you have a liver disease.

Dr. Greger covers liver disease in his full-length presentation, Uprooting the Leading Causes of Death, where he explores the role diet may play in preventing, treating, and even reversing our top 15 killers.

Topic summary contributed by Denise

To help out on this site, email NutritionFactsVolunteers@gmail.com

liver health

The liver is a detoxifying machine (see also here). The following appear to promote liver health: green tea, Indian gooseberries (see also here), and broccoli. Possibly protective against liver cancer: black beans, and coffee (see also here).
Possibly toxic to the liver: noni juice, Herbalife supplements (see also here), Juice Plus+ supplements, spirulina (see also here), BPA in plastics, cod liver oil, drugs and toxic metals in meat, pesticides, coumarin (found in some types of cinnamon), kava kava, and green tea supplements.

Hepatitis E is now known to be a zoonotic (animal-to-human) disease that may be contracted from pigs via pork consumption. Hepatitis C may be transmitted between deli workers via blood contamination of slicers. And poultry workers have been found to have an excess of liver cancer, among other types of cancer.


Topic summary contributed by Denise

To help out on this site, email NutritionFactsVolunteers@gmail.com





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