The Effectiveness of Silymarin in the Prevention of Anti‑tuberculosis Drug‑induced Hepatotoxicity: A Randomized Controlled Clinical Trial

Ali Talebi, Rasool Soltani, Farzin Khorvash, Soroush Mohammadi Jouabadi

Abstract


Background: Several animal studies have shown the protective effect of silymarin (the extract of Silybum marianum seeds) against anti‑tuberculosis drug‑induced hepatotoxicity (ATDH). However, the knowledge of ATDH of silymarin in humans is scarce. In this study, we aimed to clinically evaluate it. Methods: During this randomized controlled clinical trial, 36 new cases of tuberculosis (TB) were enrolled to receive either silymarin 150 mg twice daily for two weeks along with a standard anti‑TB therapeutic regimen (experimental group; n = 16) or standard anti‑TB therapeutic regimen alone (control group; n = 21). Liver function tests (serum AST, ALT, ALP, and total bilirubin) at the end of weeks 1 and 2 as well as the rate of ATDH during the study were determined and compared between the groups. Results: No significant differences between the experimental and control groups were observed at the end of the first week regarding liver function tests; However, at the end of the second week, the mean serum levels of AST (P = 0.03) and ALP (P = 0.04) were significantly lower in the experimental group. ALT (P = 0.016) and ALP (P = 0.027) levels in the experimental group significantly decreased during the study, while the changes in the control group were not significant. Two patients in the control group (9.5%) developed ATDH, while no one in the experimental group manifested this adverse effect. Conclusions: Our study suggests that silymarin use has the potential for the reduction of anti‑TB drug‑induced hepatotoxicity.

Keywords


Anti‑tuberculosis drug; chemical and drug‑induced liver injury; silymarin

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References


Pourakbari B, Mamishi S, Banar M, Keshtkar AA, Mahmoudi S.

Prevalence of TB/HIV co‑infection in Iran: A systematic review

and meta‑analysis. Ann Ig 2019;31:333‑48.

Gopalan N, Santhanakrishnan RK, Palaniappan AN, Menon PA,

Lakshman S, Chandrasekaran P, et al. Daily vs intermittent

antituberculosis therapy for pulmonary tuberculosis in patients

with hiv: A randomized clinical trial. JAMA Intern Med

;178:485‑93.

Sun HY, Huang YW, Huang WC, Chang LY, Chan PC,

Chuang YC, et al. Twelve‑dose weekly rifapentine plus isoniazid

for latent tuberculosis infection: A multicentre randomised

controlled trial in Taiwan. Tuberculosis (Edinb) 2018;111:121‑6.

WHO. Global Tuberculosis Report. France: World Health

Organization; 2018.

Sharma R, Kaur R, Mukesh M, Sharma VL. Assessment of

hepatotoxicity of first‑line anti‑tuberculosis drugs on wistar rats.

Naunyn Schmiedebergs Arch Pharmacol 2018;391:83‑93.

Cao J, Mi Y, Shi C, Bian Y, Huang C, Ye Z, et al. First‑line

anti‑tuberculosis drugs induce hepatotoxicity: A novel mechanism

based on a urinary metabolomics platform. Biochem Biophy Res

Commun 2018;497:485‑91.

Hu X, Zhang M, Bai H, Wu L, Chen Y, Ding L, et al.

Antituberculosis drug‑induced adverse events in the liver,

kidneys, and blood: Clinical profiles and pharmacogenetic

predictors. Clin Pharmacol Ther 2018;104:326‑34.

Heo E, Kim DK, Oh SH, Lee JK, Park JH, Chung HS. Effect of

prophylactic use of silymarin on anti‑tuberculosis drugs induced

hepatotoxicity. Tuberc Respir Dis 2017;80:265‑9.

Sheikh A, Tasduq SA, Peerzada K, Koul S, Bhat R, Johri RK.

Biochemical manifestations of anti‑tuberculosis drugs induced

hepatotoxicity and the effect of silymarin. Hepatol Res

;31:132‑5.

Eminzade S, Uraz F, Izzettin FV. Silymarin protects liver against

toxic effects of anti‑tuberculosis drugs in experimental animals.

Nutr Metab 2008;5:18.

Singh M, Sasi P, Gupta VH, Rai G, Amarapurkar DN,

Wangikar PP. Protective effect of curcumin, silymarin and

N‑acetylcysteine on antitubercular drug‑induced hepatotoxicity

assessed in an in vitro model. Hum Exp Toxicol 2012;31:788‑97.

Pal R, Vaiphei K, Sikander A, Singh K, Rana SV. Effect of garlic

on isoniazid and rifampicin‑induced hepatic injury in rats. World

J Gastroenterol 2006;12:636‑9.

Rana SV, Attri S, Vaiphei K, Pal R, Attri A, Singh K. Role of

N‑acetylcysteine in rifampicin‑induced hepatic injury of young

rats. World J Gastroenterol 2006;12:287‑91.

Victorrajmohan C, Pradeep K, Karthikeyan S. Influence of

silymarin administration on hepatic glutathione‑conjugating

enzyme system in rats treated with antitubercular drugs. Drugs R

D 2005;6:395‑400.

Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS.

Flavonoid, silibinin, inhibits proliferation and promotes cell‑cycle

arrest of human colon cancer. J Surg Res 2007;143:58‑65.

Marjani M, Fahim F, Sadr M, Kazempour Dizaji M, Moniri A,

Khabiri S, et al. Evaluation of Silymarin for management of

anti‑tuberculosis drug induced liver injury: A randomized clinical

trial. Gastroenterol Hepatol Bed Bench 2019;12:138‑42.

Ebrahimpour Koujan S, Gargari BP, Mobasseri M, Valizadeh H,

Asghari‑Jafarabadi M. Effects of Silybum marianum (L.)

Gaertn. (silymarin) extract supplementation on antioxidant

status and hs‑CRP in patients with type 2 diabetes mellitus:

A randomized, triple‑blind, placebo‑controlled clinical trial.

Phytomedicine 2015;22:290‑6.

Wah Kheong C, Nik Mustapha NR, Mahadeva S. A randomized

trial of silymarin for the treatment of nonalcoholic steatohepatitis.

Clin Gastroenterol Hepatol 2017;15:1940‑9.e8.

El‑Gazayerly ON, Makhlouf AI, Soelm AM, Mohmoud MA.

Antioxidant and hepatoprotective effects of silymarin phytosomes

compared to milk thistle extract in CCl4 induced hepatotoxicity

in rats. J Microencapsul 2014;31:23‑30.

Shaker E, Mahmoud H, Mnaa S. Silymarin, the antioxidant

component and Silybum marianum extracts prevent liver damage.

Food Chem Toxicol 2010;48:803‑6.

Gao X, Xiao ZH, Liu M, Zhang NY, Khalil MM, Gu CQ, et al.

Dietary silymarin supplementation alleviates zearalenone‑induced

hepatotoxicity and reproductive toxicity in rats. J Nutr

;148:1209‑16.

Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle

for alcoholic and/or hepatitis B or C liver diseases‑a

systematic cochrane hepato‑biliary group review with

meta‑analyses of randomized clinical trials. Am J Gastroenterol

;100:2583‑91.

Marjani M, Baghaei P, Kazempour Dizaji M, Gorji Bayani P,

Fahimi F, Tabarsi P, et al. Evaluation of hepatoprotective

effect of silymarin among under treatment tuberculosis

patients: A randomized clinical trial. Iran J Pharm Res

;15:247‑52.

Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WC, van

der Ven AJ, Dekhuijzen R. Antituberculosis drug‑induced

hepatotoxicity: Concise up‑to‑date review. J Gastroenterol

Hepatol 2008;23:192‑202.

Bellemo G, Orrenius S. Altered thiol and calcium homeostasis in

oxidative hepatocellular injury. Hepatol 1985;5:876‑82.

Rolo PA, Oliveira PJ, Moreno AJM, Palmeira CM. Protection

against post‑ischemic mitochondrial injury in rat liver by

silymarin or TUDC. Hepatol Res 2003;26:217‑24.

Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M.

“Silymarin”, a promising pharmacological agent for treatment of

diseases. Iran J Basic Med Sci 2011;14:308‑17.

Gu J, Tang SJ, Tan SY, Wu Q, Zhang X, Liu CX, et al. An

open‑label, randomized and multi‑center clinical trial to evaluate

the efficacy of Silibinin in preventing drug‑induced liver injury.

Int J Clin Exp Med 2015;8:4320‑7.

Agal S, Baijal R, Pramanik S, Patel N, Gupte P, Kamani P, et al.

Monitoring and management of antituberculosis drug induced

hepatotoxicity. J Gastroenterol Hepatol 2005;20:1745‑52.

Saukkonen JJ, Powell K, Jereb JA. Monitoring for tuberculosis

drug hepatotoxicity: Moving from opinion to evidence. Am J

Respir Crit Care Med 2012;185:598‑9.