stanozolol-induced bland cholestasis

2
CARTAS CIENTÍFICAS 71 8. Levesque BG, Chua HK, Kane SV. Meckel’s ileitis: not all regional enteritis is Crohn’s disease. Inflamm Bowel Dis. 2011;17:E45, http://dx.doi.org/10.1002/ibd.21686. 9. Enc F, Yorulmaz E, Melikoglu L, et al. A case of Meckel’s diver- ticulitis treated on the assumption of Crohn’s Disease. Turk J Gastroenterol. 2010;21:175---8. PMID: 20872334. 10. Andreyev HJ, Owen RA, Thomas PA, Wright PL, Forbes A. Acid secretion from a Meckel’s diverticulum: the unsuspected mimic of Crohn’s disease? Am J Gastroenterol. 1994;89:1552---4. PMID: 8079937. Francisca Dias de Castro , Joana Magalhaes, Maria João Moreira, José Cotter Gastroenterology Department, Centro Hospitalar do Alto Ave, Guimarães, Portugal Corresponding author. E-mail address: [email protected] (F. Dias de Castro). http://dx.doi.org/10.1016/j.gastrohep.2013.07.011 Stanozolol-induced bland cholestasis Colestasis canalicular inducida por estanozolol Sr. Director: It is difficult to estimate the prevalence of toxic hepatitis, especially by anabolic-steroids, because frequently they are taken without medical prescription. The use of anabolic- steroids by sportsmen 1 and teenagers has dramatically increased, raising the question about their adverse effects, especially hepatotoxicity. The hepatotoxic effects include cholestasis, 2 hepatocellular carcinoma, 3 nodular regene- rative hyperplasia and variceal bleeding, secondary to portal hypertension presumably due to nodular regenerative hyperplasia. 4 Stanozolol is a 17-alkyl anabolic---androgenic steroid, which is used in therapeutic doses for some medi- cal indications such as hereditary angioedema 5 or aplastic anemia, 6 but its use is extended among sportsmen and body- builders. The effect of this drug is dose-dependent, although it is influenced by individual susceptibility and the presence of other toxic habits, such as alcohol abuse. 7 We report the case of a 37-year-old European Caucasian man, who was admitted to our hospital after developing acute severe jaundice and itching, but without fever or chill. Furthermore, he reported passing dark urine simultaneously. He did not have problems such as abdominal pain, nausea or vomiting. There was no history of pre-existing liver disease. Furthermore, he denied unsafe sexual practices, drug abuse or other toxic habits (except smoking twenty cigarettes a day). However, he ingested a protein-enriched diet for two years to increase the muscle mass. The patient did not take other medications. On admission, physical examination revealed jaundice. The biochemical test showed serum levels of bilirrubin of 19.16 mg/dL (normally <1) (direct fraction 15.84 mg/dL), with aspartate aminotransferase (AST) 45 U/L (normally 5---37), alanine aminotransferase (ALT) 58 U/L (nor- mally 5---41), alkaline phosphatase (AP) 152 U/L (normally 40---129) and gamma-glutamyl-transpeptidase (GGT) 19 U/L (normally 10---66). Other biochemical parameters such as creatinine, C reactive protein, sodium and potassium remained normal. Hemoglobin, leucocytes, platelet count and prothrombine time were normal as well. The presence of viral infection (hepatitis A, hepatitis B, hepatitis C, cyto- megalovirus, Epstein---Barr virus and HIV) and autoantibodies (including anti-mitochondrial antibody, anti-smooth muscle antibody, liver kidney microsomal type 1 antibody and antinuclear antibodies) was excluded. An ultrasound scan of the abdomen was performed, showing a normal volume of the liver and no evidence of biliary dilation. During admis- sion, he admitted to have self-administered high doses of stanozolol (Winstrol ® ) by injections (intramuscularly, three times a week) for three weeks prior to the onset of symptoms. After that, we thought of a toxic hepatitis so we used the CIOMS scale resulting in 9 points, supporting our impression. Thus, we decided not to perform a liver biopsy. Accordingly, during admission the patient was provided with supportive medical treatment and showed a good progress. Eight weeks after discontinuation of stanozolol, bioche- mical tests gradually improved, itching disappeared and he was completely asymptomatic. Finally, in three months, all tests were normal. Therefore, clinical signs and laboratory findings improved substantially in following weeks after dis- continuation of stanozolol. Discussion Our patient developed severe cholestasic jaundice with a slight elevation of liver enzymes and itching, after self-administration of stanozolol injections. The patient mentioned that he went to the gym and ingested a protein- enriched diet to increase the muscular strength but, at the beginning, he did not recognize to take steroids, which delayed the diagnosis. The temporal relationship between the administration and the appearance of symp- toms, and the return to normal values after drug withdrawal, clearly suggest the association. CIOMS scale is validated to find out the relationship between drugs and toxic hepatitis, being highly probable values over 8 points 8 (our patient sco- red 9 points). CIOMS scale has the following elements: type of liver injury, time of onset of the event, time from drug intake, until reaction onset, time from drug withdrawal until reaction onset, risk factors, and course of reaction. Finally, we considered that the liver biopsy was not necessary due to three reasons: (a) the temporal relationship; (b) the CIOMS scale score; and (c) exclusion of other causes. Bland cholestasis is almost always associated with the use of 17-alkyl anabolic---androgenic steroids. The course of ill- ness is marked by an insidious onset of itching followed by dark urine and jaundice, with minimal serum enzyme ele- vations or evidence of hepatocellular necrosis (ALT levels are usually <200 U/L, AP <230 U/L). Typically, bland choles- tasis shows a slow recovery (usually, more than 4 weeks).

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Page 1: Stanozolol-induced bland cholestasis

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RTAS CIENTÍFICAS 71

Levesque BG, Chua HK, Kane SV. Meckel’s ileitis: not all regionalenteritis is Crohn’s disease. Inflamm Bowel Dis. 2011;17:E45,http://dx.doi.org/10.1002/ibd.21686.

Enc F, Yorulmaz E, Melikoglu L, et al. A case of Meckel’s diver-ticulitis treated on the assumption of Crohn’s Disease. Turk JGastroenterol. 2010;21:175---8. PMID: 20872334.

Andreyev HJ, Owen RA, Thomas PA, Wright PL, Forbes A. Acidsecretion from a Meckel’s diverticulum: the unsuspected mimicof Crohn’s disease? Am J Gastroenterol. 1994;89:1552---4. PMID:8079937.

Francisca Dias de Castro ∗, Joana Magalhaes, Maria JoãoMoreira, José Cotter

Gastroenterology Department, Centro Hospitalar do AltoAve, Guimarães, Portugal∗ Corresponding author.E-mail address: [email protected](F. Dias de Castro).

http://dx.doi.org/10.1016/j.gastrohep.2013.07.011

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of 17�-alkyl anabolic---androgenic steroids. The course of ill-

anozolol-induced bland cholestasis

lestasis canalicular inducida por estanozolol

Director:

is difficult to estimate the prevalence of toxic hepatitis,ecially by anabolic-steroids, because frequently they areen without medical prescription. The use of anabolic-roids by sportsmen1 and teenagers has dramaticallyreased, raising the question about their adverse effects,ecially hepatotoxicity. The hepatotoxic effects include

olestasis,2 hepatocellular carcinoma,3 nodular regene-ive hyperplasia and variceal bleeding, secondary tortal hypertension presumably due to nodular regenerativeperplasia.4 Stanozolol is a 17�-alkyl anabolic---androgenicroid, which is used in therapeutic doses for some medi-

l indications such as hereditary angioedema5 or aplasticemia,6 but its use is extended among sportsmen and body-ilders. The effect of this drug is dose-dependent, althoughs influenced by individual susceptibility and the presenceother toxic habits, such as alcohol abuse.7

We report the case of a 37-year-old European Caucasiann, who was admitted to our hospital after developing

ute severe jaundice and itching, but without fever or chill.rthermore, he reported passing dark urine simultaneously.

did not have problems such as abdominal pain, nausea ormiting. There was no history of pre-existing liver disease.rthermore, he denied unsafe sexual practices, drug abuseother toxic habits (except smoking twenty cigarettes ay). However, he ingested a protein-enriched diet for twoars to increase the muscle mass. The patient did not takeer medications.On admission, physical examination revealed jaundice.e biochemical test showed serum levels of bilirrubin of.16 mg/dL (normally <1) (direct fraction 15.84 mg/dL),th aspartate aminotransferase (AST) 45 U/L (normally37), alanine aminotransferase (ALT) 58 U/L (nor-lly 5---41), alkaline phosphatase (AP) 152 U/L (normally

---129) and gamma-glutamyl-transpeptidase (GGT) 19 U/Lrmally 10---66). Other biochemical parameters suchcreatinine, C reactive protein, sodium and potassium

ained normal. Hemoglobin, leucocytes, platelet count

d prothrombine time were normal as well. The presenceviral infection (hepatitis A, hepatitis B, hepatitis C, cyto-galovirus, Epstein---Barr virus and HIV) and autoantibodiescluding anti-mitochondrial antibody, anti-smooth muscle

nedavaaretas

tibody, liver kidney microsomal type 1 antibody andtinuclear antibodies) was excluded. An ultrasound scan of

abdomen was performed, showing a normal volume of liver and no evidence of biliary dilation. During admis-n, he admitted to have self-administered high dosesstanozolol (Winstrol®) by injections (intramuscularly,ee times a week) for three weeks prior to the onset ofptoms. After that, we thought of a toxic hepatitis so we

ed the CIOMS scale resulting in 9 points, supporting ourpression. Thus, we decided not to perform a liver biopsy.cordingly, during admission the patient was provided withpportive medical treatment and showed a good progress.Eight weeks after discontinuation of stanozolol, bioche-cal tests gradually improved, itching disappeared and hes completely asymptomatic. Finally, in three months, allts were normal. Therefore, clinical signs and laboratorydings improved substantially in following weeks after dis-ntinuation of stanozolol.

scussion

r patient developed severe cholestasic jaundice withslight elevation of liver enzymes and itching, afterlf-administration of stanozolol injections. The patientntioned that he went to the gym and ingested a protein-

riched diet to increase the muscular strength but, at beginning, he did not recognize to take steroids,ich delayed the diagnosis. The temporal relationshiptween the administration and the appearance of symp-

s, and the return to normal values after drug withdrawal,arly suggest the association. CIOMS scale is validated tod out the relationship between drugs and toxic hepatitis,ing highly probable values over 8 points8 (our patient sco-

9 points). CIOMS scale has the following elements: typeliver injury, time of onset of the event, time from drugake, until reaction onset, time from drug withdrawal untilction onset, risk factors, and course of reaction. Finally,

considered that the liver biopsy was not necessary due toee reasons: (a) the temporal relationship; (b) the CIOMSle score; and (c) exclusion of other causes.Bland cholestasis is almost always associated with the use

ss is marked by an insidious onset of itching followed byrk urine and jaundice, with minimal serum enzyme ele-tions or evidence of hepatocellular necrosis (ALT levels

usually <200 U/L, AP <230 U/L). Typically, bland choles-is shows a slow recovery (usually, more than 4 weeks).

Page 2: Stanozolol-induced bland cholestasis

72 CARTAS CIENTÍFICAS

The mechanism most likely involves interference with hepa-tocyte canalicular efflux systems for bile salts, organicanions and phospholipids. Furthermore, flow cytometricanalysis demonstrated an increase in the S-phase fraction ofliver cells.9 Especially, stanozolol has been found to induceoxidative stress in rat liver despite the up-regulation ofenzymatic antioxidant activities.10

In conclusion, sportsmen, especially bodybuilders, takinganabolic androgenic steroids, even for a short period oftime, should be considered as a group at risk for developingsevere cholestasic jaundice.

Bibliografía

1. Yoshida EM, Karim MA, Shaikh JF, Soos JG, Erb SR. At what price,glory? Severe cholestasis and acute renal failure in an athleteabusing stanozolol. CMAJ. 1994;151:791---3.

2. Stimac D, Milic S, Dintinjana RD, Kovac D, Ristic S.Androgenic/anabolic steroid-induced toxic hepatitis. J Clin Gas-troenterol. 2002;35:350---2.

3. Socas L, Zumbado M, Pérez-Luzardo O, Ramos A, Pérez C, Her-nández JR, et al. Hepatocellular adenomas associated withanabolic androgenic steroid abuse in bodybuilders: a reportof two cases and a review of the literature. Br J Sports Med.2005;39:e27.

4. Winwood PJ, Robertson DA, Wright R. Bleeding oesophagealvarices associated with anabolic steroid use in an athlete. Post-grad Med J. 1990;66:864---5.

5. Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: safetyof long-term stanozolol therapy. J Allergy Clin Immunol.2007;120:654---8.

6. Zhang W, Zhou F, Cao X, Cheng Y, He A, Liu J, et al. Success-ful treatment of primary refractory anemia with a combinationregimen of all-trans retinoic acid, calcitriol, and androgen. LeukRes. 2006;30:935---42.

7. Ishak KG, Zimmerman HJ. Hepatotoxic effects of the anabo-lic/androgen steroids. Semin Liver Dis. 1987;7:230---6.

8. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, San-chez De La Cuesta F. Comparison of two clinical scales forcausality assessment in hepatotoxicity. Hepatology. 2001;33:123---30.

9. Boada LD, Zumbado M, Torres S, López A, Díaz-Chico BN,Cabrera JJ, et al. Evaluation of acute and chronic hepatoto-xic effects exerted by anabolic---androgenic steroid stanozololin adult male rats. Arch Toxicol. 1999;73:465---72.

10. Pey A, Saborido A, Blázquez I, Delgado J, Megías A. Effectsof prolonged stanozolol treatment on antioxidant enzymeactivities, oxidative stress markers, and heat shock protein

7:

,

HSP72 levels in rat liver. J Steroid Biochem Mol Biol. 2003;8269---77.

Javier Ampuero, Emilio Suárez García,Marina Millán Lorenzo, Raquel Calle, Paula Ferrero,Manuel Romero Gómez ∗

Unit for Clinical Management of Digestive Diseases andCIBERehd, Valme University Hospital, University of SevillaSevilla, Spain

∗ Corresponding author.E-mail address: [email protected] (M.R. Gómez).

http://dx.doi.org/10.1016/j.gastrohep.2013.09.009