Buyer Beware: Supplement at Your Own Risk

Although I’m a pretty good swimmer, I am always a little uneasy when I see signs that say “Swim at Your Own Risk.” Perhaps, signs like that should accompany ‘dietary supplements’ since they are unregulated and often pose a significant unknown danger.

A fascinating perspective article discusses the myriad of problems with over-the-counter supplements (NEJM 2014; 370: 1277-80).  The article begins by detailing the cases of severe hepatitis and death due to OxyElite Pro, a supplement marketed for weight loss and muscle building.  This agent was linked to 97 patients, 47 required hospitalizations, 3 resulted in liver transplantation (that’s one way to lose weight!), and one death.  An astute liver-transplant surgeon was the first to suspect this supplement.

Since then “nothing has been done to prevent another supplement from causing organ failure or death.”

Key points:

  • Supplement industry: $32 billion spent in U.S. per year on 85,000 different combinations of vitamins, minerals, botanicals, amino acids, probiotics, and other ingredients
  • Supplements do not require premarketing approval.  “Under the Dietary Supplement Health and Education Act of 1994, anything labeled as a dietary supplement is assumed to be safe until proven otherwise.”
  • More than 500 supplements have already been found to be adulterated with pharmaceuticals like anabolic steroids, unapproved antidepressants, banned weight-loss medications, untested sildenafil analogues, and even methamphetamine analogues.
  • The FDAs ability to monitor these supplements is poor.  The MedWatch ( is plagued with underreporting and lack of timeliness.  Local health departments have frequently stumbled upon the problem first.

Some common problems with current supplements include the following:

  1. Arrhythmias with agents like Ephedra, horny goat weed, and oleander
  2. Bleeding with Ginkgo
  3. Cancer with anabolic steroids (hepatoma), Beta-carotene (lung cancer), and Vitamin E (prostate cancer)
  4. Hepatotoxicity with numerous supplements including chaparral, comfrey, fo-ti, gerrymander, and kava
  5. Other problems: stroke, kidney stones, panic attacks, rashes, and mood alterations

The perspective notes that a bill in a Senate committee if passed would require that manufacturers register their products and provide some safety information.  This is unlikely to make any significant change.  The author recommends that “every supplement ingredient should undergo rigorous safety testing before marketing.”

Bottomline: when a patient asks you if “this supplement” is OK, the honest answer is nobody knows.

Related blog post:

Revising the Textbooks on Isoniazid Hepatotoxicity

Previously, isoniazid (INH) hepatoxicity has generally been described as “idiosyncratic.”  New research shows that INH-induced hepatotoxicity is often associated with anti-INH and anti-cytochrome P450 antibodies (Hepatology 2014; 59: 1084-93, editorial 746-48).

Background: INH is a crucial treatment for tuberculosis.  About 10% of patients receiving monotherapy may develop mild elevations (<3-fold the upper limit of normal) of alanine aminotransferase.  However, 0.5-1% develop overt hepatitis and some develop acute liver failure (ALF).  Risk factors for ALF include female gender, age >35 years, cotreatment with other tuberculosis medications, INH dose >50 mg/kg, ethanol use, and slower metabolic pathways (slow acetylator N-acetyltransferase 2 or cytochrome (CYP) P450 2E1 genotype).

The authors utilized two patient groups: 19 from the ALF study group registry who had >50% likelihood of IHN toxicity and 20 control patients who were receiving INH prophylaxis.  In this control group, 15 had no liver injury and 5 had mild hepatitis. The authors utilized several immunoassays.

Key findings:

  • 15 of 19 cases of INH-associated ALF had detectable antibodies: 8 anti-INH and 11 had antiCYP2E1 Abs.
  • None of these antibodies were detected from INH-treated controls

Bottomline: from the authors of the study “Although the presence of these antibodies only in INH-induced liver failure suggests that INH-induced liver injury is immune mediated, there is no evidence that these Abs are actually responsible for the liver injury.”

In this same issue is a lengthy guideline on the “Evaluation for Liver Transplantation in Adults”:

Related blog post:

Liver toxicity -where to look online | gutsandgrowth

Teaching an Old Drug New Tricks

A couple recent articles focused on the new uses of methotrexate (MTX) and how to handle potential hepatotoxicity:

  1. J Pediatr 2014; 164: 231-36
  2. Inflamm Bowel Dis 2014; 20: 47-59

In the first medical review article, the authors note the efficacy of MTX for the following:

  • Juvenile idiopathic arthritis
  • Uveitis
  • Psoriasis
  • Crohn disease
  • Juvenile dermatomyositis
  • Localized scleroderma
  • Vasculitis

This review article discusses mechanism of action which is poorly understood along with pharmacogenomics and practical issues in usage.  The latter includes the need for supplemental folic acid.  Other points:

  • “The long-term safety of MTX is remarkable”
  • “The issue of nausea and vomiting…can be especially disturbing.”  They note that one study demonstrated that ondansetron 1 hour prior to MTX from the first injection prevented nausea, which was often difficult to treat once developed.
  • “Liver enzyme abnormalities occur frequently (up to 30% of patients) but are usually of minimal clinical significance.”  Best to draw blood tests 1-2 days before MTX dosing.
  • “In children, unlike adults, MTX-related pulmonary adverse events are very rare.”
  • “In recent years it was shown that live vaccine boosters are effective and safe during MTX use (caution may be needed if MTX is used with other immunosuppression medications)” Ref: JAMA 2013; 309: 2449–56.
  • “Use during pregnancy or within 3 months of planning pregnancy is contraindicated”

The second article was a systemic review which identified 12 high-quality studies which focused on MTX hepatotoxicity in children.  Key findings:

  • 57 of 457 developed some degree of abnormal liver biochemistries.
  • Due to hepatotoxicity, dose reductions were undertaken in 6.4% and 4.5% discontinued MTX.

The authors note that studies of MTX in adults with IBD have not demonstrated cumulative liver toxicity from MTX.  In addition, many of the patients with hepatotoxicity may have had  other reasons for abnormal liver biochemistries including other medications (eg. glucocorticoids).  “Confirmation of MTX hepatotoxicity with a liver biopsy is seldom performed in children;” as a consequence, the exact rate of MTX hepatotoxicity is unknown.

The authors propose that liver biochemistry monitoring occur at baseline, biweekly x 2, then every 2-3 months.  Also, the authors recommend:

  • If ALT < 2 times upper limit of normal (ULN), check liver biochemistries every 2 weeks
  • If persistent abnormalities, the authors recommend an ultrasound
  • If ALT ≥ 2 times ULN, repeat testing should be obtained and consider consultation with a hepatologist

Bottomline: Methotrexate is an important medication for Crohn disease –there are not very many available.  If there are persistent liver enzyme elevations, dose reduction of MTX (or cessation) may be necessary.  As a practical matter, it is advisable to obtain blood draws 1-2 days prior to MTX rather than afterwards. Nausea can be minimized with ondansetron and weekend dosing.

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Therapeutic Misadventures with Acetaminophen

I first heard the title expression “Therapeutic Misadventure” from one of my mentors, Jim Heubi (J Pediatr 1998; 132: 22-27), though he did not coin the term.  As a personal aside, Jim interviewed me prior to my pediatric residency and helped convince me to train in Cincinnati.

Some have said the phrase is a ‘nice medical term for a mistake.’  A more precise definition: “therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease” (from the following link: Therapeutic misadventure).

The latest data on therapeutic misadventures with acetaminophen has emerged in a recent report: Pediatrics 2013; 131; e740-e746.

This observational cohort study analyzed a group of 666 children from 22 sites who were enrolled in the Pediatric Acute Liver Failure (PALF) study.  The children were subdivided based on acetaminophen (N-acetyl-p-aminophenol [APAP]) exposure: 85 with single toxic dose exposure (SE), 83 with chronic exposure (CE) ≥ 2 doses, and 498 with no exposure.

Among the CE group, 22% were assigned a final diagnosis of APAP toxicity; the majority in the CE group had 3 to 7 days of exposure to APAP.  The median dose was 31 mg/kg/day. Only 31 CE patients had serum APAP levels performed; in this group, a similar proportion to SE patients had elevated APAP levels ≥10 mg/L (68% in CE and 66% in SE).   Besides APAP toxicity, final diagnosis included indeterminate in 31 (37%), autoimmune (7%), metabolic (5%), infection (8%), and other (21%).

Among the SE group, 82 (96.5%) had APAP overdose as final diagnosis and 3 (3.5%) as indeterminate.

Among the NE group, 234 (47%) had a final diagnosis of indeterminate; other diagnosis in the remaining: infection 51 (10.2%), metabolic 72 (14.5%), autoimmune 34 (6.8 %), and other 107 (21.5%)

Clinical outcomes: 21 days after enrollment, 68% of CE patients were alive without liver transplantation; this compared with 92% of SE patients and 48% of NE patients.  In both the CE and NE patients, there was a high percentage of patients with indeterminate etiology.  Indeterminate ALF is associated with increased risk of liver transplantation and death.

Conclusions from the authors: a low serum bilirubin and high ALT should raise suspicion for CE to APAP.  CE patients outcomes were not as favorable as SE patients.  Better communication between physicians and families about the risk of prolonged use of APAP is needed.

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