Energy drinks: Another red flag for the liver allograft

A case of cholestatic hepatitis due to the consumption of the energy drink Red Bull in a liver transplant recipient is presented. This study was approved by the Université Catholique Louvain IRB. A 16-year-old male underwent liver transplantation in September 2003 because of a biliary tumor. In March 2006, retransplantation was performed because of biliary tract lesions. His immunosuppression regimen consisted of tacrolimus monotherapy. In January 2007, he presented with sudden elevations in his aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels [12 times the upper limit of normal (ULN)]; his bilirubin (BIL) and gamma-glutamyltransferase (GGT) levels were normal. He did not take any other medication. Three weeks later, his BIL level rose to 2.3 mg/dL, and his AST and ALT levels were 5 and 6 times the ULN; his GGT level was normal (Fig. 1). He refused liver biopsy. The liver test results returned to normal after 4 months, and the tacrolimus level remained approximately 6 ng/mL. In January 2008, he became jaundiced. His BIL level was 10.7 times the ULN, his AST and ALT levels rose to 36 and 26 times the ULN, and his GGT level was 3 times the ULN (Fig. 1). The international normalized ratio was normal. Viral hepatitis, autoimmune diseases, exposure to other hepatotoxins, and technical problems with the arterial and biliary tract reconstructions were excluded. A biopsy sample showed severe perivenular hepatocellular necrosis, major centrolobular and portal inflammation, and minor signs of endotheliitis and cholangitis. Evolution of the patient's liver tests since liver retransplantation in 2006. The 2 episodes of hepatitis, which occurred in 2007 and 2008 after the intake of Red Bull, are marked with arrows. The anamnesis revealed that 2 days before his second hepatitis episode, he had drunk 3 cans of Red Bull within 4 hours to stay fit for his examinations. The next day, he separately took 2 tablets (800 mg) of the nonsteroidal anti-inflammatory drug ibuprofen because of a headache. We discovered that 2 weeks before his first hepatitis episode, he had drunk 15 cans of Red Bull within 3 days. The diagnosis of severe drug toxicity was made. His immunosuppression regimen was left unchanged, and his test results normalized over a period of 8 months. Drug-induced liver injury (DILI) is the most common reason for drug disapproval or withdrawal and is the most common cause of acute liver failure.1 DILI is accepted to be a genetically based disease related to a metabolite accumulation due to modified metabolization within the cytochrome P450 enzymatic system. Interference with many factors (drug-drug and drug-food interactions, age, and other disease conditions) explains the unsatisfactory predictive power of clinical and nonclinical studies with respect to hepatotoxicity. The fact that multiple drug hits (rechallenge) cause DILI indicates that the immunological system is involved.1 For the confirmation of drug hepatotoxicity, thousands of patients need to be studied. Zimmerman, therefore, concentrated on well-documented case reports.2 Hepatocellular jaundice, which is reflected by the levels of biomarkers [aminotransferases (ATs) and BIL], indicates severe DILI and a ≥10% chance of developing acute liver failure.1-3 The presence of 1 marker is worrisome; the presence of 2 markers is highly predictive of severe DILI. The Food and Drug Administration uses a ≥3-fold elevation of the AT levels together with a ≥2-fold elevation of the BIL level without an initial elevation of cholestatic enzymes as a signal of potentially serious hepatotoxicity in the absence of other elements (eg, viral hepatitis, hepatotoxins, and preexisting acute liver disease) that can explain these modified test results.3 These modifications are called Hy's law. The clinical presentation of DILI is highly variable and depends on the extent of the damage. The type of injury is predominantly hepatocellular. DILI mainly occurs days to months after the ingestion of the toxic substance; it is dose-related and occurs after the intake of >1000 mg of the drug. Because of an adaptation, AT elevations may be resolved despite the continuation of drug usage. Biopsy frequently reveals cholangitis, hepatocellular zone III necrosis, granulomas, and inflammation. A pathological examination is not enough for a diagnosis, so a close collaboration between the pathologist and the clinician is important.1, 2 In our recipient, DILI was attributed to the energy drink Red Bull. The rarely reported condition of tacrolimus hepatotoxicity seemed unlikely because he had normal liver tests for a long period with an unchanged, low-dose monotherapy. Energy drinks such as Rip It, Monster, Amp, Full Throttle, and No Fear have become popular, especially since the introduction of Red Bull in Austria in 1997. Aggressive marketing has led to a steep increase in consumption. Red Bull, the third most sold soft drink after Pepsi and Coca-Cola, is mainly consumed by clubbers or students who want to remain fit for sports or studying. It is often mixed with alcohol or ecstasy. Two surveys have shown that 51% of those attending college regularly ingest energy drinks, and 99% mix alcohol and energy drinks.4, 5 Because of its side effects, Red Bull is prohibited in France and Switzerland and is accepted only as a natural product in Canada. All energy drinks contain high doses of caffeine, taurine, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B12, and sugars (saccharose, glucose, inositol, and glucuronolactone).6 The main components of Red Bull (250 mL) are taurine (1000 mg), glucuronolactone (600 mg), and caffeine (80 mg). Glucuronolactone, caffeine, vitamin B2, vitamin B5, vitamin B6, vitamin B12, and taurine are not toxic even in high doses. The toxicity of Red Bull is probably related to vitamin B3, which is better known as niacin or nicotinic acid. Niacin is a vital, water-soluble vitamin that plays an important role in the treatment of hypercholesterolemia and atherosclerosis. The daily requirement is 12 mg. Any dose of niacin can be toxic. Its toxicity, which is mostly related to the ingested dose and the extended-release formulation, ranges from disturbed liver test results to acute and even lethal liver failure. The typical DILI pattern for niacin is mixed hepatocellular-cholestatic injury.7, 8 This is the first report of severe hepatotoxicity due to the consumption of Red Bull in a liver transplant recipient. We should inform consumers and especially adolescent and teenaged liver transplant recipients about the potential harmful effects of (excessive) energy drink intake. Carlos A. Apestegui M.D.*, Olivier Julliard M.D.*, Olga Ciccarelli M.D.*, Dhang Khahn Ho Minh Duc M.D. , Jan Lerut M.D., Ph.D.*, * Departments of Abdominal and Transplantation Surgery (Starzl Unit of Abdominal Transplantation), Pathology, Saint Luc University Hospital, Université Catholique Louvain, Brussels, Belgium.

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