Hypertensive Retinopathy Associated With Use of the Ephedra-Free Weight-Loss Herbal Supplement Hydroxycut

Abstract

The use of performance-enhancing and weight-loss supplements is prevalent in the United States, and over the past decade, there has been growing concern with regard to the safety and efficacy of these products. It is well documented that ephedra-based products are associated with adverse reactions, including serious cardiovascular and neurologic injuries. With new restrictions placed on such products, companies are now marketing caffeine-based ephedra-free herbal supplements. Less is known about the potential side effects of these products. We present the case of a 42-year-old, previously healthy man who developed malignant hypertension and hypertensive retinopathy while taking Hydroxycut, a caffeine-based ephedra-free supplement. To our knowledge, this is the first documented case of hypertensive retinopathy associated with the use of Hydroxycut. Given the lack of investigative studies in regard to their safety and efficacy, judicious care should be taken with the use of all herbal supplements, including those designated as ephedra-free.

Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email: glundberg@medscape.net

Introduction

The use of performance-enhancing and weight-loss supplements is prevalent in the United States. Over the past decade, there has been growing concern with regard to the safety and efficacy of these products. Ephedra-based products have been associated with several adverse reactions, including serious cardiovascular and neurologic injuries.[1–3] Because the US Food and Drug Administration has banned the sale of ephedra-based products, many companies are now marketing ephedra-free products. Although these products are marketed as being safer, recent reports suggest that they may have potential, serious side effects that are similar to that of ephedra-based products.[4–6] We report the case of a patient who developed malignant hypertension and hypertensive retinopathy associated with the use of Hydroxycut (MuscleTech, Mississauga, Ontario, Canada), a caffeine-based ephedra-free herbal supplement.

Case Report

A 42-year-old, previously healthy man with no significant past medical history and no prior history of hypertension presented to the ophthalmology clinic with complaints of headache associated with blurry vision in his left eye for 2 days. For 3 weeks prior to presentation, he had been taking 8 tablets of Hydroxycut daily, the recommended dose for performance enhancement. He denied the use of other medications, stimulants, illicit drugs, and other herbal or dietary supplements. On presentation, his blood pressure was found to be 238/115 mm Hg, which prompted an immediate referral to the emergency department and transfer shortly thereafter to the medical intensive care unit (ICU) for definitive management. His initial work-up included a head computed tomographic (CT) scan, which was negative, and an electrocardiogram that showed normal sinus rhythm with no evidence of left ventricular hypertrophy. A complete blood count, serum chemistries, urinalysis, and cardiac enzymes were within normal limits, and a urine toxicology screen was negative.

A dilated retinal exam was performed with results shown in the Figure. The exam was significant for flare hemorrhages, deep retinal hemorrhages, and arteriovenous nicking, which were consistent with a grade 3 hypertensive retinopathy.

Figure 1.

Grade 3 hypertensive changes of the left retina with AV nicking (AVN) involving the inferior temporal retinal vasculature. Also noted are deep retinal hemorrhages (RH) and flare hemorrhages (FH).

In the ICU, his blood pressure was controlled with intravenous metoprolol and hydralazine. His headache resolved and his vision improved with control of his blood pressure. Upon follow-up 1 week later, the patient reported complete resolution of symptoms and normalization of his vision. He discontinued use of Hydroxycut, and his blood pressure was managed temporarily with hydrochlorothiazide daily — which was discontinued 4 weeks later. Upon follow-up 4 weeks thereafter, he remained normotensive and asymptomatic.

The differential diagnosis for this presentation of hypertensive retinopathy was broad initially, including essential hypertension, hyperaldosteronism, pheochromocytoma, and renovascular disease. However, given his dramatic response to medical therapy and the need for only 1 antihypertensive agent, along with the temporal relation between his onset of symptoms and initiation of Hydroxycut, further evaluation of these other causes was deferred.

Discussion

To our knowledge, the patient described above represents the first reported case of hypertensive retinopathy associated with the use of Hydroxycut. The patient had no previous history of hypertension, and his symptoms resolved following the discontinuation of Hydroxycut. His retinal findings were consistent with grade 3 retinopathic changes. The presence of deep and flare retinal hemorrhages is typically seen in more acute or severe hypertension.[7] The patient also had arteriovenous-crossing changes (or nicking), which are classically associated with chronic hypertension but can be seen in early and severe cases of hypertension.[8] The patient's history suggests that his retinopathy was acute in nature and his retinal exam supports this conclusion.

Hydroxycut is an “ephedra-free” dietary supplement designed to enhance weight loss and improve performance by increasing metabolism.[4] The original formulation contained the ephedra-type alkaloid, ma huang, a sympathomimetic with a serious side-effect profile that is known to include seizures, hepatitis, and myocarditis.[1] In 2004, the US Food and Drug Administration banned the use of ephedra as a dietary supplement.[9] As a consequence of that decision, Hydroxycut, along with most other dietary and herbal supplements, has been reformulated to exclude ephedra.

The safety of the new formulation is being challenged as case reports of adverse events are now being reported. A recent association with hepatotoxicity was reported with the new formulation.[4] Stevens and colleagues[4] reported the cases of 2 men, ages 27 and 30, who presented with acute liver injury following the administration of Hydroxycut for 5 weeks and 5 days, respectively. The former developed a severe transaminitis with an aspartate aminotransferase level of 1969 U/L and an alanine aminotransferase level of 3962 U/L. The latter presented with a cholestatic liver pattern with a serum bilirubin level of 7.8 mg/dL and an alkaline phosphatase level of 530 U/L. Both patients underwent a thorough work-up that included viral serologies (hepatitis A, B, and C; Epstein-Barr virus; and cytomegalovirus), antinuclear and antismooth muscle antibodies, acetaminophen level, and toxicology screening. The work-up for these other etiologies was negative, and both patients recovered with supportive treatment and discontinuation of Hydroxycut.

It is unclear which ingredient in Hydroxycut might be responsible for the increased blood pressure and retinal changes that were seen in our patient. Presumably, the causative agent has sympathomimetic effects. Caffeine is a major ingredient in Hydroxycut and has known hypertensive effects.[10] At recommended daily doses Hydroxycut has a caffeine content of 600 mg, which is equivalent to 6 cups of coffee.[11]

A recent study evaluated the effects of 2 weight-loss supplements, one of which was caffeine-based (Xenadrine EFX) and the other synephrine-based (Advantra Z). The researchers found that the caffeine-based product significantly increased blood pressure by 9.6 mm Hg and heart rate by 16.7 beats per minute, whereas the synephrine-based product did not, again, suggesting that caffeine may be playing a significant sympathomimetic role in these supplements.[12] It is important to note that the caffeine-based product also contained a small amount of synephrine (5.5 mg). This raises the possibility that caffeine may be working synergistically with synephrine to cause the elevations in blood pressure that are seen with Xenadrine EFX, but this relationship has not been studied.

Xenadrine EFX has also been implicated in a case of exercise-induced syncope associated with QT prolongation.[5] Nasir and colleagues[5] reported the case of a 22-year-old woman who experienced a syncopal episode after her second dose of Xenadrine. An electrocardiogram showed significant QT prolongation that resolved within 24 hours upon discontinuation of Xenadrine. The active ingredient of this supplement is caffeine, although it contains a host of other plant extracts and amino acids, as previously stated.[13] Of interest, Xenadrine contains 239 mg of caffeine, whereas Hydroxycut contains nearly 3 times that amount.

With respect to Hydroxycut, it is unclear whether caffeine alone is the causative agent, or whether caffeine is working synergistically with one of the other active ingredients (Garcinia cambogia, Gymnema sylvestre, glucomannan, guarana extract, green tea, or willow bark). A Medline search failed to reveal any information about the hemodynamic effects of caffeine mixed with these other agents. Unlike Xenadrine, Hydroxycut does not contain synephrine or any other ingredients with known sympathomimetic or vasoactive effects, with the exception of caffeine.

Conclusion

The annual prevalence of dietary supplement use in the United States increased from 14.2% in 1998–1999 to 18.8% in 2002.[14] As the use of these products increases, more cases associated with serious side effects will be recognized. The newer ephedra-free products have been associated with hepatotoxicity, dysrhythmias, and ischemic stroke, and now malignant hypertension and hypertensive retinopathy can be added to that list.[4–6,12] Given the lack of controlled studies with regard to their safety and efficacy, judicious care should be taken with the use of all herbal supplements, including those deemed ephedra-free.

The opinions or assertions contained herein are those of the authors and should not be construed as reflecting the views of the US Department of the Army or Department of Defense.