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CASE REPORT

Liver Toxicity of Anabolic AndrogenicSteroid Use in an Adolescent WithNonalcoholic Fatty Liver Disease

�Hannah I. Awai, �Elizabeth L. Yu, yLinda S. Ellis, and�

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gallstones. Further evautoimmune hepatitis

Received August 9, 2012From the �Division of

Department of PediatrMedicine, and the yDHospital, San Diego,

Address correspondenceMD, Division of Gastment of Pediatrics,Children’s Way, MC@ucsd.edu).

This work was supportedDK088925-02S1. Theof the authors and doNational Institutes of

The authors report no coCopyright # 2014 by E

Hepatology, and NutGastroenterology, He

DOI: 10.1097/MPG.0b01

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effrey B. Schwimme

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of AAS, there is a need for enhanced diagnosis, education, andawareness.

T he prevalence of obesity and related morbidities such asnonalcoholic fatty liver disease (NAFLD) is high among

adolescents. Present treatment recommendations for NAFLD focuson lifestyle optimization via nutrition and exercise. After encoura-ging exercise, many adolescents choose to participate in organizedsports, which may lead to use of illicit substances such as anabolicandrogenic steroids (AAS) to boost their athletic performance.Approximately 3 million individuals use nontherapeutic AAS atsupraphysiologic doses in the United States (1). In 2012, 5.9% ofadolescent boys reported steroid use in the previous year (2). Weanticipate adolescents with preexisting liver disease are at increasedrisk for AAS-induced hepatotoxicity. We present such a case withinstitutional review board approval and written individual patientconsent.

An 18-year-old boy with a history of nonalcoholic steato-hepatitis (NASH), obesity (body mass index [BMI] 36.5 kg/m2),and hypertension presented with 3 days of scleral icterus, inter-mittent emesis, and difficulty concentrating and staying awake.

The patient was diagnosed with NASH 5 years earlier—hisliver biopsy demonstrated diffuse moderately severe macrovesicu-lar steatosis, mild portal inflammation, and mild portal fibrosis withfocal areas of bridging fibrosis (Fig. 1). After lifestyle counseling,the patient lost 30 lb and played football and basketball in highschool. Liver chemistry improved substantially but did not reachnormal. Upon recent presentation, physical examination demon-strated BMI 34 kg/m2, scleral icterus, jaundice to the knees, andhepatomegaly to 3 cm below the costal margin with mild tendernessto palpation. Laboratory reports were notable for cholestasis, andelevated aminotransferases: aspartate aminotransferase 163 unit/L,alanine aminotransferase 229 unit/L, g-glutamyl transpeptidase 65U/L, total bilirubin 11 mg/dL, and direct bilirubin, 10 mg/dL(Table 1). Coagulation studies were normal. An abdominal ultra-sound demonstrated thickening of the gallbladder wall without

ESPGHAN and NASPGHAN. Un

aluation was negative, including acute andpanels, toxicology screen for drugs and

; accepted March 28, 2013.Gastroenterology, Hepatology, and Nutrition,

ics University of California, San Diego School ofepartment of Gastroenterology, Rady Children’sCalifornia.and reprint requests to Jeffrey B. Schwimmer,roenterology, Hepatology, and Nutrition, Depart-University of California, San Diego, 3020

5030 San Diego, CA 92123 (e-mail: jschwimmer

in part by National Institutes of Health grant no.contents of this work are solely the responsibilitynot necessarily represent the official views of theHealth.nflicts of interest.uropean Society for Pediatric Gastroenterology,rition and North American Society for Pediatricpatology, and Nutrition3e3182952e74

alcohol, and viral serologies (human immunodeficiency virus,Epstein-Barr virus, cytomegalovirus, adenovirus, and enterovirus).Therapy was initiated with ursodeoxycholic acid and lactulose.

The patient revealed that he took Beastrdrol, an AAS, for2 weeks before symptom onset to increase muscle mass. He took40 mg daily—the distributor’s recommended dose. He was nottaking other medications nor was he consuming alcohol. Despiteformally discontinuing AAS use, 8 days after presentation directbilirubin increased to 20.9. A liver biopsy was performed anddemonstrated cholestatic hepatitis with hepatocellular and intraca-nilicular cholestasis, portal and lobular inflammation, fibrousexpansion of the portal triads, and an inflammatory infiltrate withfrequent eosinophils and neutrophils suggestive of immunoallergicdrug-induced hepatotoxicity (Fig. 2).

Bilirubin levels peaked 1 month after symptom onset (totalbilirubin 38.5, direct 32.6). Cholestyramine was added to thetreatment regimen. The most debilitating symptom for this patientwas severe pruritus, impairing school performance, and sleep. Hewas treated with hydroxyzine and rifampin. Symptoms finallyabated after 3 months.

DISCUSSIONCase reports of AAS-induced liver toxicity in adults indicate

that most cases will resolve within a few months after discontinu-ation of AAS (3,4). Our patient’s liver histology was similar toprevious reports of AAS abuse–induced hepatic injury: cholestaticjaundice with intrahepatic cholestasis (3,5). This is the first casereport to our knowledge of AAS-induced liver toxicity in anadolescent with NASH. We speculate that preexisting NAFLDmay make adolescents more vulnerable to hepatotoxicity fromAAS. Although the exact mechanism for AAS-induced hepatotoxi-city is not well defined in the literature, data from mouse modelssuggest the mechanism is immunoallergenic, resulting from hyper-sensitivity (6). From a pathologic standpoint, the fatty liver may bemore vulnerable to injury because it has impaired microcirculation,Kupffer cell dysfunction, increased adhesion of leukocytes,impaired mitochondrial function, and adenosine triphosphatedepletion (7). Given the prevalence of NAFLD and the illicit use

authorized reproduction of this article is prohibited.

FIGURE 1. Hepatic parenchyma with panacinar large and small

droplet steatosis and focal expansion of portal tracts with mixed

chronic inflammation (H&E, original magnification �4).

JPGN � Volume 59, Number 3, September 2014

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TABLE 1. Trend in laboratory values

Initial diagnosis 1 y pre-AAS AAS presentation 1 mo post-AAS 3 mo post-AAS

AST, U/L 43 31 163 111 48

ALT, U/L 59 57 229 72 57

GGT, U/L 40 34 65 57 27

Alkaline phosphatase, U/L 358 69 94 218 71

Total bilirubin, mg/dL 0.2 0.5 11.4 28.0 1.1

Direct bilirubin, mg/dL <0.1 <0.1 10.4 26.5 0.5

AAS¼ anabolic androgenic steroid; ALT¼ alanine aminotransferase; AST¼

FIGURE 2. Hepatic parenchyma with hepatocellular and canalicular

JPGN � Volume 59, Number 3, September 2014 Case Report

In the United States, AAS have been listed as Schedule IIIcontrolled substances under the Controlled Substances Act since1990. The possession of AAS without a prescription is a federalcrime punishable by up to 1 year in prison; unlawful distribution orpossession with intent to distribute AAS is punishable by up to10 years in prison (8). The legal use of AAS is limited to physicianprescription for indications such as replacement of male sex steroidsin men with androgen deficiency and counteracting catabolic statessuch as trauma or human immunodeficiency virus wasting (1).Despite these laws, AAS can be purchased online without aprescription. When new AAS are marketed online, there is a naturallag before they are recognized by the Food and Drug Administrationand appropriately regulated or banned. Thus, our patient was able topurchase Beastdrol, an AAS, online for $52.99. Regardless of lawsand warnings, unrestricted Internet access promotes an increasedrisk for use in adolescents who can purchase AAS without theknowledge of parents or physicians.

In addition to legal risks, AAS abuse poses numerous well-

cholestasis with bile plugs (H&E, original magnification �40). Thin

arrows: hepatocellular cholestasis; thick arrows: canalicular cholestasis.

pyright 2014 by ESPGHAN and NASPGHAN. Un

arrhythmia, acne, hypotrophic hypogonadism, oligospermia,

www.jpgn.org

irregular menses, premature epiphyseal closure, and psychiatricdysfunction (1). The prevalence data are lacking because of fewempirical studies and speculative data. In addition, minimal litera-ture exists regarding the risk of liver disease among adolescentsusing AAS.

One factor that may increase the risk of liver toxicity inadolescent boys using AAS is that within the pediatric population,adolescent boys have the highest prevalence of NAFLD; however,because of a combination of a lack of specific symptoms andinadequate awareness, most cases remain undiagnosed. Becauseof their large body habitus, many adolescent boys with NAFLD areencouraged to play, and because of the nature of the sport, areencouraged to gain more weight. The intersection of the risk factorsfor NAFLD (adolescence, male sex, high BMI) and AAS use maycontribute to an increase of cases such as the one presented.

The novelty of this report of AAS-induced liver toxicity in anadolescent with preexisting NASH emphasizes the need for clin-icians to have an awareness of this possibility. We now routinelycounsel patients with NAFLD to avoid AAS. Moreover, we askabout AAS usage when assessing new-onset liver disease in ado-lescents. To prevent further cases of liver toxicity in adolescentpatients with NAFLD, it is of utmost importance to broaden anawareness and understanding among physicians, parents, and chil-dren of the dangers of steroid use.

REFERENCES1. Evans NA. Current concepts in anabolic-androgenic steroids. Am J Sports

Med 2004;32:534–42.

2. Eisenberg ME, Wall M, Neumark-Sztainer D. Muscle-enhancing beha-viors among adolescent girls and boys. Pediatrics 2012;130:1019–36.

3. Sanchez-Osorio M, Duarte-Rojo A, Martinez-Benitez B, et al. Anabolic-androgenic steroids and liver injury. Liver Int 2008;2:278–82.

4. Stimac D, Millic S, Dintinjana RD, et al. Androgenic/anabolic steroid-induced toxic hepatitis. J Clin Gastroenterol 2002;35:350–2.

5. Hall RC, Hall RC. Abuse of supraphysiologic doses of anabolic steroids.South Med J 2005;98:550–5.

6. Boada LD, Zumbado M, Torres S, et al. Evaluation of acute and chronichepatotoxic effects exerted by anabolic-androgenic steroid stanozol inadult male rats. Arch Toxicol 1999;73:465–72.

7. Varela AT, Rolo AP, Palmeira CM. Fatty liver and ischemia/reperfusion:are there drugs able to mitigate injury? Curr Med Chem 2011;18:4987–

aspartate aminotransferase; GGT¼g-glutamyl transpeptidase.

5002.

documented health risks: liver disease, hypertension, thrombosis,

authorized reproduction of this article is prohibited.

8. Controlled Substances Act, 21 USC §801-971 (2012).

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