Liver Injury Associated with Sporting Activities

Abstract

Exertional heat stroke most commonly develops following prolonged levels of aerobic activity in a warm or humid environment. Hypoperfusion of the vital organs along with activation of the inflammasome can lead to progressive and potentially fatal multiorgan failure including acute liver failure. In the United States, herbal and dietary supplements that are marketed to improve performance, strength, and weight loss are increasingly being used by both amateur and professional athletes. Consumption of bodybuilding supplements that contain androgenic anabolic steroids can lead to adverse hepatic effects ranging from asymptomatic serum aminotransferase elevations to severe cholestatic hepatitis with prolonged jaundice. Various non-bodybuilding nutritional supplements that contain a mixture of botanicals, caffeine, and chemicals have also been associated with idiosyncratic hepatotoxicity. In particular, green tea extract derivatives that contain epigallocatechin gallate are hepatotoxic in animal models and have been associated with severe acute hepatocellular injury in humans.

Keywords

hepatotoxicity - herbal and dietary supplements - anabolic steroids - heat stroke

• References

• 1 Brancaccio P, Maffulli N, Buonauro R, Limongelli FM. Serum enzyme monitoring in sports medicine. Clin Sports Med 2008; 27 (01) 1-18, vii
• 2 Peake J, Nosaka K, Suzuki K. Characterization of inflammatory responses to eccentric exercise in humans. Exerc Immunol Rev 2005; 11: 64-85
• 3 Pettersson J, Hindorf U, Persson P. , et al. Muscular exercise can cause highly pathological liver function tests in healthy men. Br J Clin Pharmacol 2008; 65 (02) 253-259
• 4 Banfi G, Colombini A, Lombardi G, Lubkowska A. Metabolic markers in sports medicine. Adv Clin Chem 2012; 56: 1-54
• 5 Centers for Disease Control and Prevention (CDC). Heat-related deaths after an extreme heat event—four states, 2012, and United States, 1999-2009. MMWR Morb Mortal Wkly Rep 2013; 62 (22) 433-436
• 6 Gilchrist J, Haileyesus T, Murphy M, Collins C, McIlvain N. ; Centers for Disease Control and Prevention (CDC). Heat illness among high school athletes—United States, 2005-2009. MMWR Morb Mortal Wkly Rep 2010; 59 (32) 1009-1013
• 7 Lindstrom A, Ooyen C, Lynch ME, Blumenthal M, Kawa K. Sales of herbal dietary supplements increase by 7.9% in 2013, marking a decade of rising sales: turmeric supplements climb to top ranking in natural channel. HerbalGram 2014; 103: 52-56
• 8 Geller AI, Shehab N, Weidle NJ. , et al. Emergency department visits for adverse events related to dietary supplements. N Engl J Med 2015; 373 (16) 1531-1540
• 9 Navarro VJ, Barnhart H, Bonkovsky HL. , et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology 2014; 60 (04) 1399-1408
• 10 Fouillet A, Rey G, Laurent F. , et al. Excess mortality related to the August 2003 heat wave in France. Int Arch Occup Environ Health 2006; 80 (01) 16-24
• 11 Argaud L, Ferry T, Le Q-H. , et al. Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France. Arch Intern Med 2007; 167 (20) 2177-2183
• 12 Leon LR. Heat stroke and cytokines. Prog Brain Res 2007; 162: 481-524
• 13 Geng Y, Ma Q, Liu Y-N. , et al. Heatstroke induces liver injury via IL-1β and HMGB1-induced pyroptosis. J Hepatol 2015; 63 (03) 622-633
• 14 Dale G, Fleetwood JA, Inkster JS, Sainsbury JR. Profound hypophosphataemia in patients collapsing after a “fun run”. Br Med J (Clin Res Ed) 1986; 292 (6518): 447-448
• 15 Mohseni M, Chiota N, Roy A, Eidelman B. Severe hypophosphatemia and acute neurologic dysfunction in a marathon runner. Clin J Sport Med 2011; 21 (03) 269-270
• 16 Nanji AA, Anderson FH. Acute liver failure: a possible consequence of severe hypophosphatemia. J Clin Gastroenterol 1985; 7 (04) 338-340
• 17 Shieh S-D, Shiang J-C, Lin Y-F, Shiao W-Y, Wang J-Y. Circulating angiotensin-converting enzyme, von Willebrand factor antigen and thrombomodulin in exertional heat stroke. Clin Sci (Lond) 1995; 89 (03) 261-265
• 18 Hausfater P, Megarbane B, Dautheville S. , et al. Prognostic factors in non-exertional heatstroke. Intensive Care Med 2010; 36 (02) 272-280
• 19 Salathé C, Pellaton C, Carron P-N, Coronado M, Liaudet L. Acute liver failure complicating exertional heat stroke: possible role of hypophosphatemia. Curr Sports Med Rep 2015; 14 (01) 49-50
• 20 Weibrecht K, Dayno M, Darling C, Bird SB. Liver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury. J Med Toxicol 2010; 6 (03) 294-300
• 21 Apple FS, McGue MK. Serum enzyme changes during marathon training. Am J Clin Pathol 1983; 79 (06) 716-719
• 22 Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002; 65 (05) 907-912
• 23 Chavez LO, Leon M, Einav S, Varon J. Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Crit Care 2016; 20 (01) 135
• 24 McMahon GM, Zeng X, Waikar SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med 2013; 173 (19) 1821-1828
• 25 Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis: an overview for clinicians. Crit Care 2005; 9 (02) 158-169
• 26 Olerud JE, Homer LD, Carroll HW. Incidence of acute exertional rhabdomyolysis. Serum myoglobin and enzyme levels as indicators of muscle injury. Arch Intern Med 1976; 136 (06) 692-697
• 27 Hadad E, Rav-Acha M, Heled Y, Epstein Y, Moran DS. Heat stroke: a review of cooling methods. Sports Med 2004; 34 (08) 501-511
• 28 Bouchama A, Cafege A, Devol EB, Labdi O, el-Assil K, Seraj M. Ineffectiveness of dantrolene sodium in the treatment of heatstroke. Crit Care Med 1991; 19 (02) 176-180
• 29 Wexler RK. Evaluation and treatment of heat-related illnesses. Am Fam Physician 2002; 65 (11) 2307-2314
• 30 Reuben A, Tillman H, Fontana RJ. , et al. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med 2016; 164 (11) 724-732
• 31 Dematte JE, O'Mara K, Buescher J. , et al. Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med 1998; 129 (03) 173-181
• 32 Siegler RW. Fatal heatstroke in a young woman with previously undiagnosed Hashimoto's thyroiditis. J Forensic Sci 1998; 43 (06) 1237-1240
• 33 Kim SY, Sung SA, Ko GJ. , et al. A case of multiple organ failure due to heat stoke following a warm bath. Korean J Intern Med 2006; 21 (03) 210-212
• 34 Deutsch M, Koskinas J, Emmanuel T, Kountouras D, Hadziyannis S. Heat stroke and multi-organ failure with liver involvement in an asylum-seeking refugee. J Emerg Med 2006; 31 (03) 255-257
• 35 Lee C-W, Perng C-L, Huang Y-S, Luo J-C, Hung C-L, Lin H-C. Multiple organ failure caused by non-exertional heat stroke after bathing in a hot spring. J Chin Med Assoc 2010; 73 (04) 212-215
• 36 Erarslan E, Yüksel I, Haznedaroglu S. Acute liver failure due to non-exertional heatstroke after sauna. Ann Hepatol 2012; 11 (01) 138-142
• 37 Chen KJ, Chen TH, Sue YM, Chen TJ, Cheng CY. High-volume plasma exchange in a patient with acute liver failure due to non-exertional heat stroke in a sauna. J Clin Apher 2014; 29 (05) 281-283
• 38 Coenen S, Tran K, de Haan J, de Man R. Liver transplantation for non-exertional heat stroke-related acute liver failure. BMJ Case Rep 2017; 2017: bcr-2017-221029 Doi: 10.1136/bcr-2017-221029
• 39 Davis BC, Tillman H, Chung RT. , et al; Acute Liver Failure Study Group. Heat stroke leading to acute liver injury & failure: a case series from the Acute Liver Failure Study Group. Liver Int 2017; 37 (04) 509-513
• 40 Bailey RL, Gahche JJ, Lentino CV. , et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011; 141 (02) 261-266
• 41 Bailey RL, Gahche JJ, Miller PE, Thomas PR, Dwyer JT. Why US adults use dietary supplements. JAMA Intern Med 2013; 173 (05) 355-361
• 42 Snyder FJ, Dundas ML, Kirkpatrick C, Neill KS. Use and safety perceptions regarding herbal supplements: a study of older persons in southeast Idaho. J Nutr Elder 2009; 28 (01) 81-95
• 43 Whitsett M, Marzio DH, Rossi S. SlimQuick™-associated hepatotoxicity resulting in fulminant liver failure and orthotopic liver transplantation. ACG Case Rep J 2014; 1 (04) 220-222
• 44 Bjornsson E, Olsson R. Serious adverse liver reactions associated with herbal weight-loss supplements. J Hepatol 2007; 47 (02) 295-297 , author reply 297–298
• 45 Suk KT, Kim DJ, Kim CH. , et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol 2012; 107 (09) 1380-1387
• 46 Wai CT, Tan BH, Chan CL. , et al. Drug-induced liver injury at an Asian center: a prospective study. Liver Int 2007; 27 (04) 465-474
• 47 Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo H. Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients. Eur J Gastroenterol Hepatol 2013; 25 (07) 825-829
• 48 Devarbhavi H, Dierkhising R, Kremers WK, Sandeep M, Karanth D, Adarsh C. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105 (11) 2396-2404
• 49 Block G, Jensen CD, Norkus EP. , et al. Usage patterns, health, and nutritional status of long-term multiple dietary supplement users: a cross-sectional study. Nutr J 2007; 6 (01) 30
• 50 Navarro VJ, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology 2017; 65 (01) 363-373
• 51 Andrade RJ, Lucena MI, Fernández MC. , et al; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129 (02) 512-521
• 52 Koncic MZ, Tomczyk M. New insights into dietary supplements used in sport: active substances, pharmacological and side effects. Curr Drug Targets 2013; 14 (09) 1079-1092
• 53 Lieberman HR, Stavinoha T, Mcgraw S, White A, Hadden L, Marriott B. Use of dietary supplements among active duty US army soldiers: 1133. Med Sci Sports Exerc 2009; 41 (05) 185-186
• 54 Smith DA, Perry PJ. The efficacy of ergogenic agents in athletic competition. Part I: androgenic-anabolic steroids. Ann Pharmacother 1992; 26 (04) 520-528
• 55 McCabe SE, Brower KJ, West BT, Nelson TF, Wechsler H. Trends in non-medical use of anabolic steroids by U.S. college students: results from four national surveys. Drug Alcohol Depend 2007; 90 (2-3): 243-251
• 56 Kafrouni MI, Anders RA, Verma S. Hepatotoxicity associated with dietary supplements containing anabolic steroids. Clin Gastroenterol Hepatol 2007; 5 (07) 809-812
• 57 Robles-Diaz M, Gonzalez-Jimenez A, Medina-Caliz I. , et al; Spanish DILI Registry; SLatinDILI Network. Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids. Aliment Pharmacol Ther 2015; 41 (01) 116-125
• 58 Krishnan PV, Feng Z-Z, Gordon SC. Prolonged intrahepatic cholestasis and renal failure secondary to anabolic androgenic steroid-enriched dietary supplements. J Clin Gastroenterol 2009; 43 (07) 672-675
• 59 Shah NL, Zacharias I, Khettry U, Afdhal N, Gordon FD. Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases. Clin Gastroenterol Hepatol 2008; 6 (02) 255-258
• 60 El Sherrif Y, Potts JR, Howard MR. , et al. Hepatotoxicity from anabolic androgenic steroids marketed as dietary supplements: contribution from ATP8B1/ABCB11 mutations?. Liver Int 2013; 33 (08) 1266-1270
• 61 Timcheh-Hariri A, Balali-Mood M, Aryan E, Sadeghi M, Riahi-Zanjani B. Toxic hepatitis in a group of 20 male body-builders taking dietary supplements. Food Chem Toxicol 2012; 50 (10) 3826-3832
• 62 Schwingel PA, Cotrim HP, Santos Jr CR. , et al. Recreational anabolic-androgenic steroid use associated with liver injuries among Brazilian young men. Subst Use Misuse 2015; 50 (11) 1490-1498
• 63 Sánchez-Osorio M, Duarte-Rojo A, Martínez-Benítez B, Torre A, Uribe M. Anabolic-androgenic steroids and liver injury. Liver Int 2008; 28 (02) 278-282
• 64 Turani H, Levi J, Zevin D, Kessler E. Hepatic lesions in patients on anabolic androgenic therapy. Isr J Med Sci 1983; 19 (04) 332-337
• 65 Choi S-K, Jin J-S, Cho S-G. , et al. Spontaneous liver rupture in a patient with peliosis hepatis: a case report. World J Gastroenterol 2009; 15 (43) 5493-5497
• 66 Karasawa T, Shikata T, Smith RD. Peliosis hepatis: report of nine cases. Acta Pathol Jpn 1979; 29 (03) 457-469
• 67 Stolz ANV, Hayashi PH, Fontana RJ. , et al. Severe and protracted cholestasis in young men taking illicit body building supplements: assessment of genetic, clinical and chemical risk factors [abstract]. . Hepatology 2018
• 68 Navarro VKK, Avula B, Verma M. Herbal and dietary supplement mislabelling: experience of the Drug Induced Liver Injury Network [abstract]. Hepatology 2017; 66 (Suppl. 01) A16
• 69 Wolfram S, Wang Y, Thielecke F. Anti-obesity effects of green tea: from bedside to bench. Mol Nutr Food Res 2006; 50 (02) 176-187
• 70 Chen I-J, Liu C-Y, Chiu J-P, Hsu C-H. Therapeutic effect of high-dose green tea extract on weight reduction: a randomized, double-blind, placebo-controlled clinical trial. Clin Nutr 2016; 35 (03) 592-599
• 71 Lee MJ, Maliakal P, Chen L. , et al. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability. Cancer Epidemiol Biomarkers Prev 2002; 11 (10 Pt 1): 1025-1032
• 72 Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol 2010; 48 (01) 409-416
• 73 Moon H-S, Lee H-G, Choi Y-J, Kim T-G, Cho C-S. Proposed mechanisms of (-)-epigallocatechin-3-gallate for anti-obesity. Chem Biol Interact 2007; 167 (02) 85-98
• 74 Zheng EX, Rossi S, Fontana RJ. , et al. Risk of liver injury associated with green tea extract in SLIMQUICK® weight loss products: results from the DILIN prospective study. Drug Saf 2016; 39 (08) 749-754
• 75 Yu Z, Samavat H, Dostal AM. , et al. Effect of green tea supplements on liver enzyme elevation: results from a randomized intervention study in the United States. Cancer Prev Res (Phila) 2017; 10 (10) 571-579
• 76 Gavilán JC, Bermúdez FJ, Salgado F, Peña D. Phytotherapy and hepatitis [in Spanish]. Rev Clin Esp 1999; 199 (10) 693-694
• 77 Stickel F, Shouval D. Hepatotoxicity of herbal and dietary supplements: an update. Arch Toxicol 2015; 89 (06) 851-865
• 78 García-Cortés M, Borraz Y, Lucena MI. , et al. Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry [in Spanish]. Rev Esp Enferm Dig 2008; 100 (11) 688-695
• 79 Church RJ, Gatti DM, Urban TJ. , et al. Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice. Food Chem Toxicol 2015; 76: 19-26
• 80 Navarro VJ, Bonkovsky HL, Hwang S-I, Vega M, Barnhart H, Serrano J. Catechins in dietary supplements and hepatotoxicity. Dig Dis Sci 2013; 58 (09) 2682-2690
• 81 MuscleTech. Available at https://ww.muscletech.com . Accessed May 15, 2018
• 82 Neff GW, Reddy KR, Durazo FA, Meyer D, Marrero R, Kaplowitz N. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol 2004; 41 (06) 1062-1064
• 83 Haimowitz S, Hsieh J, Shcherba M, Averbukh Y. Liver failure after Hydroxycut™ use in a patient with undiagnosed hereditary coproporphyria. J Gen Intern Med 2015; 30 (06) 856-859
• 84 Laczek J, Duncan M. Three cases of acute hepatitis in patients taking Hydroxycut® bodybuilding supplement. Am J Gastroenterol 2008; 103: S143-S144
• 85 Sharma T, Wong L, Tsai N, Wong RD. Hydroxycut® (herbal weight loss supplement) induced hepatotoxicity: a case report and review of literature. Hawaii Med J 2010; 69 (08) 188-190
• 86 Fong T-L, Klontz KC, Canas-Coto A. , et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol 2010; 105 (07) 1561-1566
• 87 Araujo JL, Worman HJ. Acute liver injury associated with a newer formulation of the herbal weight loss supplement Hydroxycut. BMJ Case Rep 2015; 2015: bcr2015210303
• 88 Centers for Disease Control and Prevention (CDC). Notes from the field: acute hepatitis and liver failure following the use of a dietary supplement intended for weight loss or muscle building--May-October 2013. MMWR Morb Mortal Wkly Rep 2013; 62 (40) 817-819
• 89 Smith TB, Staub BA, Natarajan GM, Lasorda DM, Poornima IG. Acute myocardial infarction associated with dietary supplements containing 1,3-dimethylamylamine and Citrus aurantium. Tex Heart Inst J 2014; 41 (01) 70-72
• 90 Roytman MM, Pörzgen P, Lee CL. , et al. Outbreak of severe hepatitis linked to weight-loss supplement OxyELITE Pro. Am J Gastroenterol 2014; 109 (08) 1296-1298
• 91 Johnston DI, Chang A, Viray M. , et al. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ – Hawaii, 2013. Drug Test Anal 2016; 8 (3-4): 319-327
• 92 Heidemann LA, Navarro VJ, Ahmad J. , et al. Severe acute hepatocellular injury attributed to OxyELITE Pro: A case series. Dig Dis Sci 2016; 61 (09) 2741-2748
• 93 Foley S, Butlin E, Shields W, Lacey B. Experience with OxyELITE pro and acute liver injury in active duty service members. Dig Dis Sci 2014; 59 (12) 3117-3121
• 94 Klontz KC, DeBeck HJ, LeBlanc P. , et al. The role of adverse event reporting in the FDA response to a multistate outbreak of liver disease associated with a dietary supplement. Public Health Rep 2015; 130 (05) 526-532
• 95 Miousse IR, Skinner CM, Lin H. , et al. Safety assessment of the dietary supplement OxyELITE™ Pro (New Formula) in inbred and outbred mouse strains. Food Chem Toxicol 2017; 109 (Pt 1): 194-209
• 96 Moreira CT, Oliveira AL, Comar JF, Peralta RM, Bracht A. Harmful effects of usnic acid on hepatic metabolism. Chem Biol Interact 2013; 203 (02) 502-511
• 97 Favreau JT, Ryu ML, Braunstein G. , et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136 (08) 590-595
• 98 Hoofnagle JH. LiverTox: a website on drug-induced liver injury. In: Drug-Induced Liver Disease. 3rd ed. New York, NY: Elsevier; 2013: 725-732