Sunday, July 8, 2012

EPHEDRA SIDE EFFECT


    


Introduction

Ephedra has been used in traditional Chinese medicine (known as Ma Huang) for centuries as a stimulant and antiasthmatic agent, and was recently introduced into use in the United States and Europe as a weight loss agent and aid in body building. Ephedra has been linked to multiple potentially severe side effects including clinically apparent liver injury and has been banned from sale in the United States and elsewhere.

 

Background

Ephedra is prepared from the aerial parts of plants belonging to the genus Ephedra, family Ephedraceae. The 45 species of Ephedra are found worldwide, but Ephedra sinica is used predominantly and is native to China where it was first used therapeutically. Ephedra is an herbaceous perennial with a strong pine odor and astringent taste which accounts for its Chinese name – Ma Huang – which can be translated as “yellow astringent” or “yellow hemp.” Ephedra is purported to increase mental acuity and to improve sexual performance, increase circulation, and decrease weight through an increase in sympathetic nervous system activity and thermogenesis. It is also used for allergies, allergic rhinitis, colds, flu, fever, chills, nasal congestion, bronchospasm and asthma. The active ingredient of ephedra appears to be ephedrine and other related sympathomimetic alkaloids, which probably account for its therapeutic efficacy as well as its adverse effects. Ephedra was a component of many herbal weight loss and body-building preparations, including Ma Huang, Herbalife, Hydroxycut and others. The typical dose is 1.5 to 9 grams of the decocted herb daily or as herbal tea prepared by boiling dried green stems in water. Side effects are not uncommon and include nervousness, anxiety, palpitations, tachycardia, gastrointestinal upset, nausea, diarrhea, headache, and dizziness. Ephedra has also been implicated in an increased risk for myocardial infarction, stroke and sudden death and was banned from sale in the United States in April 2004.


Hepatotoxicity

Despite its apparent safe use for centuries in Chinese traditional medicine, ephedra has been linked to many serious and potential fatal side effects since its wide-scale use in Western countries for weight loss. The major reported serious adverse events were cardiovascular, including hypertension, palpitations, myocardial infarction, seizures, transient ischemic attacks, cerebrovascular accidents and sudden death. Ephedra preparations have also been implicated in more than a dozen instances of clinically apparent, acute liver injury. The time to onset has ranged from a few weeks to more than 6 months, but averages 12 weeks, presenting with symptoms of fatigue, nausea and abdominal discomfort followed by jaundice. The serum enzyme elevations are typically hepatocellular and the clinical syndrome resembles acute viral hepatitis. Immunoallergic features (rash, fever and eosinophilia) are uncommon as are autoantibodies. Recovery occurs within 1 to 6 months of stopping the ephedra preparation, but instances with acute liver failure and death or need for emergency liver transplantation have been reported. 

 

Mechanism of Injury

Ephedra extracts contain multiple compounds including the sympathomimetic alkaloids ephedrine, pseudoephedrine, methylephedrine and norephedrine. The cardiovascular side effects and complications of ephedra use have been attributed to these sympathomimetic constituents. The liver injury has been attributed to ephedrine as well, but other constituents may be responsible for this idiosyncratic liver injury.

 

Outcome and Management

The severity of liver injury due to ephedra ranges from mild, asymptomatic elevations in serum enzymes to clinically apparent acute liver injury and to acute liver failure. Chronic use of ephedra has been linked to a chronic hepatitis-like syndrome, but recovery is prompt when ephedra is stopped. There have been no instances of vanishing bile duct syndrome attributed to ephedra. Recurrence of liver injury is typical when ephedra is restarted, and rechallenge should be avoided. There is no apparent cross sensitivity to liver injury between ephedra and other weight loss agents or herbal preparations, but ephedra was previously found in many commercial herbal preparations.

Other names: Ma Huang, belcho, Chinese ephedra, desert herb, ephedrine, heral ecstasy, Joint fir, Mongolian ephedra, Pakistani ephedra, popotillo, sea Grade, Teamster’s tea, yellow astringent, yellow horse.

 

Drug Class: Herbals and Dietary Supplements

Other drugs within this class:

 

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Case Report
Ephedra
 

Case 1. Acute hepatitis due to Ma Huang.
[Modified from: Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol 1996; 91: 1436-8. PubMed Citation]

A 33 year old woman developed nausea and abdominal discomfort a few days after starting Ma Huang for weight loss. She continued taking the product for another 3 weeks when she noted jaundice and sought medical attention. She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis and liver tests were known to be normal two years earlier. She was taking no other medications. Initially, she did not reveal that she was taking an herbal product. On examination, she was jaundiced and had hepatic tenderness but no fever, rash or signs of chronic liver disease. Laboratory tests showed raised serum bilirubin (4.5 mg/dL) and prominent elevations in serum aminotransferase levels (ALT 832 U/L, AST 376 U/L), with minimal increase in alkaline phosphatase (178 U/L). Tests for hepatitis A, B and C and a monospot were negative. Autoantibodies were present in moderate titers with ANA 1:160 and SMA 1:80. Ultrasound and computerized tomography of the liver were normal. She was initially thought to have viral hepatitis and sent home. She restarted Ma Huang but quickly felt worse, stopped and returned to the hospital where liver tests were found to be worse (Table). A liver biopsy showed changes of acute hepatitis with occasional eosinophils and plasma cells suggestive of drug-induced liver disease. She stopped taking Ma Huang and when seen four months later, all liver tests were again normal.

 

Key Points

 

Medication:Ma Huang (Ephedra: unknown dose)
Pattern:Hepatocellular (R=9.8)
Severity:3+ (Jaundice, hospitalization)
Latency:~4 Weeks
Recovery:Within 16 Weeks
Other medications:None

 

Laboratory Values

 
Time After Starting Time After Stopping
ALT
(U/L)
Alk P
(U/L)
Total Bilirubin (mg/dL) Other


Ma Huang taken for 3-4 weeks
4 weeks 0 832 178 4.5


Ma Huang restarted for a few days
5 weeks 0 1586 175 8.0 Protime 13.2 seconds
5 months 4 months 40 51 0.5
Normal Values <65 <136 <1.2

Comment

A typical case of an acute hepatitis due to Ma Huang. The time to onset was difficult to assess, because she reported having nausea and abdominal discomfort “soon after” starting Ma Huang, but the time to jaundice was about 4 weeks. The clinical presentation was similar to acute viral hepatitis, which was the initial diagnosis, because the patient did not admit to using an herbal product (and this was the first report of Ma Huang related acute liver injury). The finding of autoantibodies might suggest an autoimmune drug-induced hepatitis. Immunoglobulin levels and serial ANA titers were not provided, but the liver histology did not suggest autoimmune hepatitis. Moderate levels of autoantibodies are not infrequent in cases of acute liver injury due to Ma Huang, but autoimmune features (hyperglobulinemia, prolonged course, response to corticosteroids) are not found.



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SUMMARY & LABELING
Ephedra
 

REPRESENTATIVE TRADE NAMES
Ephedra – Generic

DRUG CLASS
Herbals and Dietary Supplements


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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Ephedra ID: OM54525000 Herbal mixture Not applicable



REFERENCES
Ephedra
 

References Last Updated: 10 March 2012



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  2. Liu LU, Schiano TD. Hepatotoxicity of herbal medicines, vitamins and natural hepatotoxins. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 733-54. (Review of hepatotoxicity of herbal and dietary supplements [HDS] published in 2007; Ma Huang has been linked to numerous instances of acute, clinically apparent liver injury presenting with an acute hepatitis, often with fever, resolving rapidly on stopping).

  3. No authors listed. Ma huang: ephedra sinica. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007, pp 543-52. (Compilation of short monographs on herbal medications and dietary supplements).

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  5. Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol 1996; 91: 1436-8. PubMed Citation  (33 year old woman developed nausea within days of starting Ma Huang for weight loss, followed at 3 weeks by jaundice [bilirubin 4.5 rising to 8 mg/dL, ALT 832 U/L, Alk P 178 U/L, ANA 1:160, asterixis], resolving within 4 weeks of stopping: Case 1).

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  18. Clark BM, Schofield RS. Dilated cardiomyopathy and acute liver injury associated with combined use of ephedra, gamma-hydroxybutyrate, and anabolic steroids. Pharmacotherapy 2005; 25: 756-61. PubMed Citation  (40 year old man developed congestive heart failure and jaundice several months after starting anabolic steroids, ephedra and γ-hydroxybutyrate [bilirubin 3.9 mg/dL, ALT 2173 U/L, Alk P normal, INR 1.9], with slow recovery over next 18 months).

  19. Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E, Keinan-Boker L, et al. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. J Hepatol 2007; 47: 514-20. PubMed Citation  (12 cases of liver injury attributed to Herbalife products in Israel, 11 women, 1 man, ages 32 to 78 years, onset after 2 to 35 months [mean peak bilirubin 9.1 mg/dL, ALT 1481 U/L, Alk P 282 U/L, 1 with ANA], on stopping, 11 recovered and one died of hepatitis B reactivation; 3 had a positive rechallenge).

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  21. Stickel F. Slimming at all costs: Herbalife-induced liver injury. J Hepatol 2007; 47: 444-6. PubMed Citation  (Editorial in reference to Schoepfer [2007] and Elinay [2007] discussing the difficulties in assigning causality and identifying the toxic component in herbal mixtures, many patients take multiple products and each includes multiple components).

  22. Duque JM, Ferreiro J, Salgueiro E, Manso G. [Hepatotoxicity associated with the consumption of herbal slimming products]. Med Clin(Barc) 2007; 128: 238-9. Spanish. PubMed Citation  (3 cases of hepatotoxicity attributed to Herbalife products, women ages 49-54 years, with onset of liver injury after 1, 6 and 36 months [bilirubin 0.7, 0.8, and 26.6 mg/dL, ALT 138, 505 and 1890 U/L, Alk P 112, 166 and 425 U/L], resolving in all 3 upon stopping).

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  24. Manso G, López-Rivas L, Duque JM, Salgueiro E. Spanish reports of hepatotoxicity associated with Herbalife products. J Hepatol 2008; 49: 289-90; author reply 290-1. PubMed Citation  (Discussion of 4 cases of Herbalife hepatotoxicity from Spain [3 reported by Duque 2007], 2 occurring in sisters, suggesting a genetic propensity and an idiosyncratic drug reaction).

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  28. García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. PubMed Citation  (Among 521 cases of drug-induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals but none were attributed to ephedra or Ma Huang).

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  34. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute
    liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation(Among 1198 patients with acute liver failure enrolled in a U.S. prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 12 [9%] were due to herbals including usinic acid [2], thermoslim [1], ma huang [1], horny goat weed [1], black cohosh [1], hydroxycut [1] and unspecified herbals [4]).

  35. Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N: Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. PubMed Citation(Among 30 children with suspected drug-induced liver injury, only one case was attributed to an herbal; hydroxycut).

  36. Stickel F, Kessebohm K, Weimann R, Seitz HK.  Review of liver injury associated with dietary supplements.  Liver Int 2011; 31: 595-605.  PubMed Citation(Review of current understanding of liver injury from herbals and dietary supplements focusing upon herbalife and hydroxycut products, green tea, usnic acid, Noni juice, Chinese herbs, vitamin A and anabolic steroids).



OTHER REFERENCE LINKS
Ephedra

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1 comment:

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