Tuesday, 4 December 2012

HERBALIFE SIDE EFFCETS-2010



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

References

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3. Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement hydroxycut. Ann Intern Med. 2005;142:477–478. [PubMed]
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8. 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]
9. Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E, Keinan-Boker L, Broide E, Ackerman Z, Kaluski DN, et al. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. J Hepatol. 2007;47:514–520. [PubMed]
10. 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]
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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.

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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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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.
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Side Effects of Herbal Life Products

Jul 20, 2010 | By Brian Willett


Herbal Life is a company that produces a wide range of nutrition products, from vitamin supplements and diet pills to protein snacks and digestive health supplements. While these supplements may be beneficial to your health, you should research the ingredients in each supplement to avoid possible side effects. Even if a product has positive reviews, your results may vary. Consult your doctor before using any Herbal Life supplements to discuss their safety and efficacy.

Hypotension: Cell-U-Loss
Cell-U-Loss is a supplement marketed by Herbal Life to help you decrease bodily fluid retention. This product contains a number of ingredients, most of them herbs. One herb in the Cell-U-Loss formula is hydrangea, which may cause hypotension, or low blood pressure, according to the Silberg Center for Dental Science. Hypotension is a condition that may cause fainting, shock and dizziness. The Silberg Center notes that hydrangea may be especially dangerous when used in conjunction with high blood pressure medication.

Cancer Risk: Total Control

Total Control is a weight management supplement that is intended to increase your metabolism, increase your energy levels, and promote healthy weight loss. Total Control is similar to many other weight loss supplements because it contains stimulants such as caffeine and yerba mate. According to Katherine Zeratsky, R.D., L.D., yerba mate may promote weight loss, but it also has a number of side effects--including increased cancer risk. According to Zeratsky, regular intake of yerba mate may increase your risk of cancers such as those of the lungs, mouth and esophagus. Zeratsky does note that the risk is probably small, however.

Difficulty Sleeping: LiftOff

LiftOff is an energy supplement produced by Herbal Life. This product comes in the form of a tablet that dissolves in water. LiftOff contains a number of stimulants to increase energy, but these ingredients may also cause side effects, including difficulty sleeping, or insomnia. Herbal Life LiftOff contains caffeine, a common stimulant that may cause sleeping problems, according to the University of Maryland Medical Clinic. In addition, LiftOff contains guarana, which the website Drugs.com explains may cause anxiety, nervousness and trouble sleeping. Due to these side effects, you should not take LiftOff within several hours of bed time.

References

    The Silberg Center for Dental Science: Herbal Medications
    Katherine Zeratsky, R.D., L.D.: Yerba Mate: Is It Safe To Drink?
    University of Maryland Medical Center: Caffeine In The Diet
    Drugs.com: Guarana Side Effects

Article reviewed by GlennK Last updated on: Jul 20, 2010
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  The C.A.M. Report  

Niteworks increases anaerobic threshold in elderly men

Researchers at the David Geffen School of Medicine at UCLA, in Los Angeles, California, studied the effects of arginine + antioxidants on exercise performance in older people.
First, the details.
  • 16 elderly male cyclists were randomly assigned to a treatment group for 3 weeks.
    • A proprietary supplement (Niteworks, Herbalife International Inc.)
    • A placebo powder
  • Exercise parameters were assessed by maximal incremental exercise testing performed on a stationary cycle ergometer using breath-by-breath analysis at the start and weeks 1 and 3.
  • Neither the patients nor researchers knew the treatment given — double blind.
And, the results.
  • In the Niteworks group, anaerobic threshold significantly increased 17% at week 1, and the effect was significantly sustained by week 3.
  • In the placebo group, there was no change in anaerobic threshold.
  • The anaerobic threshold for the Niteworks group was significantly higher vs placebo at week 1 and week 3.
  • There were no significant changes in VO2 max (a measure of aerobic capacity) between placebo and Niteworks groups at either week 1 or 3 when compared to the start of the study.
  • There were no side effects in either group.
The bottom line?
The authors concluded, “An arginine and antioxidant-containing supplement increased the anaerobic threshold at both week one and week three in elderly cyclists. No effect on VO2 max was observed. This study indicated a potential role of L-arginine and antioxidant supplementation in improving exercise performance in elderly.”
It’s not stated in the study whether aside from positive changes in anaerobic threshold there were clinically meaningful benefits. Does a 17% change result in better quality of life, greater activities of daily living, etc.?
More background on arginine and exercise performance is here.
NOTE: The study, conducted at UCLA and funded by Herbalife, used Herbalife’s original formula Niteworks. The current product has a slightly different formula, although no changes were made to the active ingredients, according to the article published on Medical News Today.

  The C.A.M. Report  

Niteworks increases anaerobic threshold in elderly men

Researchers at the David Geffen School of Medicine at UCLA, in Los Angeles, California, studied the effects of arginine + antioxidants on exercise performance in older people.
First, the details.
  • 16 elderly male cyclists were randomly assigned to a treatment group for 3 weeks.
    • A proprietary supplement (Niteworks, Herbalife International Inc.)
    • A placebo powder
  • Exercise parameters were assessed by maximal incremental exercise testing performed on a stationary cycle ergometer using breath-by-breath analysis at the start and weeks 1 and 3.
  • Neither the patients nor researchers knew the treatment given — double blind.
And, the results.
  • In the Niteworks group, anaerobic threshold significantly increased 17% at week 1, and the effect was significantly sustained by week 3.
  • In the placebo group, there was no change in anaerobic threshold.
  • The anaerobic threshold for the Niteworks group was significantly higher vs placebo at week 1 and week 3.
  • There were no significant changes in VO2 max (a measure of aerobic capacity) between placebo and Niteworks groups at either week 1 or 3 when compared to the start of the study.
  • There were no side effects in either group.
The bottom line?
The authors concluded, “An arginine and antioxidant-containing supplement increased the anaerobic threshold at both week one and week three in elderly cyclists. No effect on VO2 max was observed. This study indicated a potential role of L-arginine and antioxidant supplementation in improving exercise performance in elderly.”
It’s not stated in the study whether aside from positive changes in anaerobic threshold there were clinically meaningful benefits. Does a 17% change result in better quality of life, greater activities of daily living, etc.?
More background on arginine and exercise performance is here.
NOTE: The study, conducted at UCLA and funded by Herbalife, used Herbalife’s original formula Niteworks. The current product has a slightly different formula, although no changes were made to the active ingredients, according to the article published on Medical News Today.4/11/10 20:31 JR

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