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Ischemic Colitis Associated With Use of a Bitter Orange-Containing Dietary Weight-Loss Supplement

      Since the US Food and Drug Administration banned the use of dietary supplements containing ephedra in February 2004, numerous “ephedra-free” weight-loss products have appeared on the market. Many of these supplements contain compounds such as bitter orange that are similar in structure and action to ephedra. We describe a patient in whom ischemic colitis developed 1 week after initiation of a bitter orange-containing weight-loss supplement. The patient had no other predisposing factors, and discontinuation of the supplement led to immediate improvement and ultimate resolution of her symptoms. Both consumers and health care professionals should be aware of the potential harm that bitter orange-containing dietary supplements can cause and report such adverse events to the US Food and Drug Administration.
      ED (emergency department), FDA (Food and Drug Administration)
      Since the US Food and Drug Administration (FDA) banned the use of ephedra-containing weight-loss drugs in February 2004, a steady increase of new “ephedra-free” drugs have appeared on the market. However, many of these drugs contain compounds such as bitter orange that are similar in structure and action to ephedra. We present a case in which a woman developed ischemic colitis 1 week after she started taking a bitter orange-containing weight-loss supplement.

      REPORT OF A CASE

      A 52-year-old woman with no remarkable medical or surgical history presented to the emergency department (ED) with a 1-day history of acute-onset, diffuse lower abdominal cramping associated with passage of 30 to 50 mL of bright red blood per rectum. She had experienced a total of 5 such episodes before presenting to the ED. She had no fever, light-headedness, nausea, or vomiting and no history of recent travel.
      The patient had no known drug allergies and was taking no prescription medications. However, she admitted that she had started taking NaturalMax Skinny Fast (Nutraceutical Corporation, Park City, Utah), a dietary weight-loss supplement, 1 week before presentation. In the ED, she was hemodynamically stable. Abdominal examination revealed an obese abdomen with hypoactive bowel sounds and mild tenderness to deep palpation in the left lower quadrant but no evidence of abdominal masses or organomegaly. Rectal examination showed red blood in the rectal vault. Laboratory studies yielded the following results: serum hemoglobin, 12 g/dL; white blood cell count, 11.2 × 109/L; and a normal platelet count. Results of serum chemistries and liver function tests were within normal ranges. Computed tomography with oral and intravenous contrast medium showed circumferential thickening involving the sigmoid colon.
      A presumptive diagnosis of ischemic colitis was made on the basis of the patient's clinical presentation and computed tomographic findings. The precipitating agent was believed to be the weight-loss supplement NaturalMax Skinny Fast that the patient had started taking 1 week previously. She was hospitalized for 3 days, and the supplement was discontinued. The patient's symptoms resolved over 24 to 48 hours with conservative management.

      DISCUSSION

      In this patient, the temporal relationship between the initiation of the supplement and the onset of symptoms was consistent with a diagnosis of ischemic colitis caused by decreased vascular flow to the gastrointestinal tract and resultant ischemic insult. Ischemic colitis has been associated with the use of vasoconstrictive drugs known to decrease splanchnic blood flow, such as cocaine, ma huang (ephedra), and pseudoephedrine.
      • Dowd J
      • Bailey D
      • Moussa K
      • Nair S
      • Doyle R
      • Culpepper-Morgan JA
      Ischemic colitis associated with pseudoephedrine: four cases.
      According to the manufacturer, each capsule of the supplement our patient was taking contained 5 active ingredients—bitter orange (334 mg), Garcinia cambogia (300 mg), L-carnitine (250 mg), chitosan (250 mg), and chromium arginate (200 μg)—and the recommended dosage was 3 capsules once a day by mouth to achieve optimal weight loss. Bitter orange (Citrus aurantium), also known as sour orange, Seville orange, or zhi shi, has been shown to increase mean arterial pressure and decrease portal blood flow in rat studies.
      • Huang YT
      • Wang GF
      • Chen CF
      • Chen CC
      • Hong CY
      • Yang MC
      Fructus aurantii reduced portal pressure in portal hypertensive rats.
      This effect may be mediated by synephrine, a key active compound found in the C aurantium plant. Synephrine, an indirect β-sympathomimetic agent and sympathomimetic α-adrenergic agonist, has effects on the cardiovascular system similar to those of ephedra.
      • Haller CA
      • Benowitz NL
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      None of the other 4 active ingredients in NaturalMax Skinny Fast have been shown to have sympathomimetic properties. Furthermore, none of the 4 ingredients have been known to cause any gastrointestinal adverse effects other than L-carnitine, which can cause diarrhea if consumed in high doses. We attributed our patient's ischemic colitis to the action of bitter orange and did not perform toxicologic or pharmacological analysis. It is plausible that the supplement may have contained a contaminant that could have caused the patient's symptoms. Nevertheless, we believe that bitter orange was the likely agent responsible for the adverse effects.
      Several reports of toxic effects associated with bitter orange have appeared in the literature. The recent case report by Gange et al
      • Gange CA
      • Madias C
      • Felix-Getzik EM
      • Weintraub AR
      • Estes III, NAM
      Variant angina associated with bitter orange in a dietary supplement.
      described the occurrence of variant angina in an individual who was taking a bitter orange-containing weight-loss drug, and use of bitter orange has also been associated with acute myocardial infarction
      • Nykamp DL
      • Fackih MN
      • Compton AL
      Possible association of acute lateral-wall myocardial infarction and bitter orange supplement.
      and exercise-induced syncope with QT prolongation in a young woman.
      • Nasir JM
      • Durning SJ
      • Ferguson M
      • Barold HS
      • Haigney MC
      Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine [published correction appears in Mayo Clin Proc. 2004;79:1591].
      Additionally, a case of ischemic colitis, similar to that in our patient, was reported in a woman taking supplements that contained both ephedra and bitter orange.
      • Ryan CK
      • Reamy B
      • Rochester JA
      Ischemic colitis associated with herbal product use in a young woman.
      In this latter case, ischemic colitis may have been caused by either agent or may have been attributable to the combined effects of ephedra and bitter orange. Our patient was taking a weight-loss supplement that was “ephedra free” and thus contained only bitter orange.
      As bitter orange increases in popularity and consumption, more individuals may be at risk of adverse effects. Consumers should be aware of the potential harm that these dietary supplements can cause, and health care professionals should report these adverse events to the FDA. MedWatch is an FDA program that allows both health care professionals and consumers to report serious problems that they suspect are associated with the medical products they prescribe, dispense, or use. Such reports, along with follow-up investigations, can help to identify important safety concerns (see www.fda.gov/medwatch/ for more information or to report an event online).

      CONCLUSION

      The FDA banned the use of ephedra-containing supplements in February 2004 after they were linked to adverse cardiovascular effects, including sudden death. Unfortunately, this first-ever ban of a dietary supplement was overturned by a judge in 2005. Bitter orange is being used increasingly in “ephedra-free” weight-loss supplements, but its safety profile remains questionable. In our patient, ischemic colitis occurred within days after initiation of a supplement containing bitter orange. The patient had no other predisposing factors, and discontinuation of the supplement led to immediate improvement and ultimate resolution of her symptoms.

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        Ischemic colitis associated with pseudoephedrine: four cases.
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        • Wang GF
        • Chen CF
        • Chen CC
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        Fructus aurantii reduced portal pressure in portal hypertensive rats.
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        • Felix-Getzik EM
        • Weintraub AR
        • Estes III, NAM
        Variant angina associated with bitter orange in a dietary supplement.
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        • Fackih MN
        • Compton AL
        Possible association of acute lateral-wall myocardial infarction and bitter orange supplement.
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        • Durning SJ
        • Ferguson M
        • Barold HS
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        Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine [published correction appears in Mayo Clin Proc. 2004;79:1591].
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