RIFAMPIN INDUCED HEPATOTOXICITY DURING TREATMENT FOR CHRONIC CENTRAL SEROUS CHORIORETINOPATHY Joel Nelson, DO,* David D. Saggau, MD,† Jared S. Nielsen, MD†
Purpose: The purpose of this report is to present a case of hepatotoxicity secondary to off-label rifampin therapy for the treatment of chronic central serous choroidopathy. Methods: Case report. Results: A patient with chronic central serous chorioretinopathy was treated with oral rifampin. Three weeks after the initiation of therapy, fatigue, nausea, and malaise associated with elevated liver enzyme elevations were noted. Symptoms resolved and liver enzymes normalized after discontinuing rifampin. Conclusion: Rifampin-induced hepatic injury can occur during therapy for chronic central serous chorioretinopathy. Potential hepatotoxicity must be considered and followed closely during off-label rifampin treatment. RETINAL CASES & BRIEF REPORTS 8:70–72, 2014
in both eyes treated with anti-vascular endothelial growth factor agents in both eyes in combination with photodynamic therapy (PDT) in left eye. Corrected Snellen visual acuity measured 20/40 in right eye and counting fingers 6 feet in left eye. Examination revealed macular thickening and extensive diffuse pigmentary changes in left eye greater than in right eye with a gravitational drip pattern in left eye. Fluorescein angiography demonstrated diffuse macular leakage in both eyes (Figure 1A). Indocyanine green angiography demonstrated extensive choroidal hyperpermeability. No evidence of choroidal neovascular activity was noted in both eyes. Spectral domain optical coherence tomography demonstrated severe retinal pigment epithelium alterations and extensive cystoid thickening in both eyes, in left eye greater than in right eye (Figure 1B). At this point, reduced fluence PDT was offered for the better seeing in right eye. Our patient was concerned about reports of vision loss related to PDT, and a decision was made to defer laser and proceed with 600 mg oral rifampin. After demonstrating a normal baseline liver profile (ALT 21 U/L [ref range, 0–40 U/L], AST 25 U/L [ref range, 15–40 U/L]), the patient initiated daily 600 mg oral rifampin. He was counseled to abstain from alcohol consumption at that time. Six days later, the patient returned with improvement in metamorphopsia and stable acuity (20/40 in right eye, counting fingers 6 feet in left eye), and was noted to have an improvement in optical coherence tomography thickening in right eye greater than in left eye. Oral rifampin was continued. Three weeks after starting rifampin therapy, the patient returned with improving metamorphopsia and stable vision (20/40 in right eye, counting fingers 6 in left eye) but had severe fatigue, nausea, and malaise. Optical coherence tomography demonstrated continued improvement in macular anatomy (Figure 1C). A medical evaluation was performed
From the *Des Moines University, Des Moines, Iowa; and †Wolfe Eye Clinic, West Des Moines, Iowa.
R
ifampin has emerged as a possible treatment for chronic central serous chorioretinopathy (CSC), and has been used with success in reported cases.1,2 Rifampin induces CYP450 metabolism of glucocorticoids that have been implicated in the pathogenesis of CSC.3 Although rifampin has a history of safety in long-term antituberculosis regimens, there is a known risk of hepatotoxicity.4 This case demonstrates the need for clinical awareness of potential hepatotoxicity when implementing systemic rifampin therapy for chronic CSC. Case Report A 66-year-old white man, diet controlled diabetic patient with a 7-year history of CSC with extensive scarring from chronic exudation and secondary choroidal neovascularization in left eye presented with worsening vision and increased metamorphopsia in right eye. He has a remote history of choroidal neovascularization None of the authors have any financial/conflicting interests to disclose. Reprint requests: Jared S. Nielsen, MD, Wolfe Eye Clinic, 6200 Westown Parkway, West Des Moines, IA 50266; e-mail: jnielsen@ wolfeclinic.com
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Fig. 1. A 66-year-old white man with chronic CSC and choroidal neovascularization in both eyes. Fluorescein angiogram (A) and horizontal spectral domain optical coherence tomography (B) before oral rifampin therapy. Macular optical coherence tomography findings improved in both eyes (C) after 2 weeks of oral rifampin therapy. Rifampin therapy was discontinued after he developed hepatotoxicity.
by his primary medical doctor. Liver panel drawn at that time revealed elevated transaminases: ALT 88 U/L (ref range, 0–40 U/L), AST 65 U/L (ref range, 15–40 U/L). Oral rifampin therapy was discontinued. His systemic symptoms quickly improved and liver profile normalized within 2 weeks of rifampin cessation. Reduced fluence PDT was eventually performed in right eye for increasing metamorphopsia from progressive macular edema.
Discussion Unlike acute CSC which is usually self-limited with a benign course, chronic CSC is often difficult to treat and can result in permanent vision loss. Many patients with chronic CSC respond to local control with verteporfin PDT,5 but in some cases exudation persists. Other proposed local treatment strategies include antivascular endothelial growth factor therapy6 and various forms of laser photocoagulation (TTT,7 micropulsed laser8). Although the pathogenesis of CSC is poorly understood, it has a relationship with serum glucocorticoid levels that has been well documented.9 Systemic
control of CSC has been attempted with several oral agents including ketaconazole,10,11 mifepristone (RU-486),12 and methotrexate.13 Ravage et al1 reported success with daily oral rifampin. While being used as a part of an antituberculosis regimen, it was discovered to significantly improve symptoms in a patient with comorbid chronic CSC. Subsequent small-scale studies and case reports have demonstrated improvements in both visual acuity and optical coherence tomography for patients with CSC taking rifampin.2 Rifampin’s mechanism of effect is not well understood but has been known to reduce the levels of serum steroids.3 Recognized as a potent inducer of the CYP450 system,14 rifampin likely exerts its effect by increasing the metabolism of serum cortisol. It has also been shown in animal models to possess a retinal antineovascularization effect.15 Rifampin’s availability, relatively inexpensive cost, and relatively benign side effect profile make this therapy appealing for CSC. Although rifampin has demonstrated long-term safety in anti-tuberculosis therapy (ATT), hepatotoxicity is
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a well known adverse effect. Since rifampin is commonly used as a component of ATT, a majority of the literature assesses the adverse effects of rifampin in combination with pyrazinamide, isoniazid, and/or ethambutol. Rifampin has been shown to have a lower rate of liver injury (0.7–1.1%) when used in isolation than when included with other antituberculosis medications.4,16 Risk factors for hepatotoxicity during rifampin therapy include: advanced age, poor nutrition status, alcoholism, HIV positive status, and chronic Hepatitis B and C infection.17 Patients must be advised to avoid alcohol during treatment.18 Full ATT regimens in individuals with these risk factors have shown a greatly increased rate of elevated serum transaminases than those with lower risk.19 Although there is no standard safety monitoring protocol, Agal et al20 suggest obtaining liver function tests (ALT, AST, bilirubin) weekly for the first month, every 2 weeks for 1 month, and monthly for the remainder of treatment. They define hepatotoxicity as ALT or AST elevation of twice the upper limit of normal accompanied by any of the typical symptoms associated with hepatitis which include: nausea, vomiting, malaise, jaundice, easy bruising, and encephalopathy.20 Asymptomatic transaminitis greater than five times the upper limit of normal and bilirubin greater than two times the upper limit of normal were also classified as hepatotoxicity.20 The literature suggests that rifampin may be restarted if necessary after a rifampin-induced liver injury. Following hepatotoxicity triggered ATT discontinuation, reinstitution of ATT after normalization of laboratory values has been demonstrated to be safe and effective.20 Chronic CSC can persist and result in permanent vision loss. Oral rifampin may be helpful in patients who are unresponsive or not amenable to PDT. Although rifampin-associated hepatotoxicity is uncommon, it is a serious potential risk that must be weighed against treatment benefits and monitored closely during treatment. Key words: central serous chorioretinopathy, rifampin, hepatotoxicity, optical coherence tomography, glucocorticoids, antiglucocorticoid therapy, antituberculosis therapy. References 1. Ravage ZB, Packo KH, Creticos CM, et al. Chronic central serous chorioretinopathy responsive to rifampin. Retin Cases Brief Rep 2012;6:129–132.
2. Steinle NC, Gupta N, Yuan A, et al. Oral rifampin utilization for the treatment of chronic multifocal central serous retinopathy. Br J Ophthalmol 2012;96:10–13. 3. Edwards OM, Courtenay-Evans RJ, Galley JM, et al. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548–551. 4. Menzies D, Long R, Trajman A, et al. Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection. Ann Intern Med 2008;149:689–697. 5. Chan WM, Lai TY, Lai RY, et al. Half-dose verteporfin photodynamic therapy for acute central serous chorioretinopathy: one-year results of a randomized controlled trial. Ophthalmology 2008;115:1756–1765. 6. Seong HK, Bae JH, Kim ES, et al. Intravitreal bevacizumab to treat acute central serous chorioretinopathy: short-term effect. Ophthalmologica 2009;223:343–347. 7. Kawamura R, Ideta H, Hori H, et al. Transpupillary thermotherapy for atypical central serous chorioretinopathy. Clin Ophthalmol 2012;6:175–179. 8. Koss MJ, Beger I, Koch FH. Subthreshold diode laser micropulse photocoagulation versus intravitreal injections of bevacizumab in the treatment of central serous chorioretinopathy. Eye (Lond) 2012;26:307–314. 9. Garg SP, Dada T, Talwar D, et al. Endogenous cortisol profile in patients with central serous chorioretinopathy. Br J Ophthalmol 1997;81:962–964. 10. Golshahi A, Klingmuller D, Holz FG, et al. Ketoconazole in the treatment of central serous chorioretinopathy: a pilot study. Acta Ophthalmol 2010;88:576–581. 11. Meyerle CB, Freund KB, Bhatnager P, et al. Ketoconazole in the treatment of chronic idiopathic central serous chorioretinopathy. Retina 2007;27:943–946. 12. Nielsen JS, Jampol LM. Oral mifepristone for chronic central serous chorioretinopathy. Retina 2011;10:1–9. 13. Kurup S, Oliver A, Emanuelli V, et al. Utility of metronomic MTX in chronic central serous retinopathy. European VitreoRetinal Society. Available at: http://www.evrs.eu/utility-of-metronomic-mtx-in-chronic-central-serous-retinopathy/. Accessed April 30, 2012. 14. Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992;90:1871–1878. 15. Chikaraishi Y, Matsunaga N, Shimazawa M, et al. Rifampicin inhibits the retinal neovascularization in vitro and in vivo. Exp Eye Res 2008;86:131–137. 16. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465–471. 17. Tostmann A, Boeree MJ, Aarnoutse RE, et al. Antituberculosis drug-induced hepatotoxicity: consise up-to-date review. J Gastroenterol Hepatol 2008;23:192–202. 18. Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology 2006;11:699–707. 19. Fernández-Villar A, Sopeña B, Fernández-Villar J, et al. The influence of risk factors on the severity of anti-tuberculosis druginduced hepatotoxicity. Int J Tuberc Lung Dis 2004;8:1499–1505. 20. Agal S, Baijal R, Pramanik S, et al. Monitoring and management of antituberculosis drug induced hepatotoxicity. J Gastroenterol Hepatol 2005;20:1745–1752.
Purpose: The purpose of this report is to present a case of hepatotoxicity secondary to off-label rifampin therapy for the treatment of chronic central serous choroidopathy. Methods: Case report. Results: A patient with chronic central serous chorioretinopathy was treated with oral rifampin. Three weeks after the initiation of therapy, fatigue, nausea, and malaise associated with elevated liver enzyme elevations were noted. Symptoms resolved and liver enzymes normalized after discontinuing rifampin. Conclusion: Rifampin-induced hepatic injury can occur during therapy for chronic central serous chorioretinopathy. Potential hepatotoxicity must be considered and followed closely during off-label rifampin treatment. RETINAL CASES & BRIEF REPORTS 8:70–72, 2014
in both eyes treated with anti-vascular endothelial growth factor agents in both eyes in combination with photodynamic therapy (PDT) in left eye. Corrected Snellen visual acuity measured 20/40 in right eye and counting fingers 6 feet in left eye. Examination revealed macular thickening and extensive diffuse pigmentary changes in left eye greater than in right eye with a gravitational drip pattern in left eye. Fluorescein angiography demonstrated diffuse macular leakage in both eyes (Figure 1A). Indocyanine green angiography demonstrated extensive choroidal hyperpermeability. No evidence of choroidal neovascular activity was noted in both eyes. Spectral domain optical coherence tomography demonstrated severe retinal pigment epithelium alterations and extensive cystoid thickening in both eyes, in left eye greater than in right eye (Figure 1B). At this point, reduced fluence PDT was offered for the better seeing in right eye. Our patient was concerned about reports of vision loss related to PDT, and a decision was made to defer laser and proceed with 600 mg oral rifampin. After demonstrating a normal baseline liver profile (ALT 21 U/L [ref range, 0–40 U/L], AST 25 U/L [ref range, 15–40 U/L]), the patient initiated daily 600 mg oral rifampin. He was counseled to abstain from alcohol consumption at that time. Six days later, the patient returned with improvement in metamorphopsia and stable acuity (20/40 in right eye, counting fingers 6 feet in left eye), and was noted to have an improvement in optical coherence tomography thickening in right eye greater than in left eye. Oral rifampin was continued. Three weeks after starting rifampin therapy, the patient returned with improving metamorphopsia and stable vision (20/40 in right eye, counting fingers 6 in left eye) but had severe fatigue, nausea, and malaise. Optical coherence tomography demonstrated continued improvement in macular anatomy (Figure 1C). A medical evaluation was performed
From the *Des Moines University, Des Moines, Iowa; and †Wolfe Eye Clinic, West Des Moines, Iowa.
R
ifampin has emerged as a possible treatment for chronic central serous chorioretinopathy (CSC), and has been used with success in reported cases.1,2 Rifampin induces CYP450 metabolism of glucocorticoids that have been implicated in the pathogenesis of CSC.3 Although rifampin has a history of safety in long-term antituberculosis regimens, there is a known risk of hepatotoxicity.4 This case demonstrates the need for clinical awareness of potential hepatotoxicity when implementing systemic rifampin therapy for chronic CSC. Case Report A 66-year-old white man, diet controlled diabetic patient with a 7-year history of CSC with extensive scarring from chronic exudation and secondary choroidal neovascularization in left eye presented with worsening vision and increased metamorphopsia in right eye. He has a remote history of choroidal neovascularization None of the authors have any financial/conflicting interests to disclose. Reprint requests: Jared S. Nielsen, MD, Wolfe Eye Clinic, 6200 Westown Parkway, West Des Moines, IA 50266; e-mail: jnielsen@ wolfeclinic.com
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Fig. 1. A 66-year-old white man with chronic CSC and choroidal neovascularization in both eyes. Fluorescein angiogram (A) and horizontal spectral domain optical coherence tomography (B) before oral rifampin therapy. Macular optical coherence tomography findings improved in both eyes (C) after 2 weeks of oral rifampin therapy. Rifampin therapy was discontinued after he developed hepatotoxicity.
by his primary medical doctor. Liver panel drawn at that time revealed elevated transaminases: ALT 88 U/L (ref range, 0–40 U/L), AST 65 U/L (ref range, 15–40 U/L). Oral rifampin therapy was discontinued. His systemic symptoms quickly improved and liver profile normalized within 2 weeks of rifampin cessation. Reduced fluence PDT was eventually performed in right eye for increasing metamorphopsia from progressive macular edema.
Discussion Unlike acute CSC which is usually self-limited with a benign course, chronic CSC is often difficult to treat and can result in permanent vision loss. Many patients with chronic CSC respond to local control with verteporfin PDT,5 but in some cases exudation persists. Other proposed local treatment strategies include antivascular endothelial growth factor therapy6 and various forms of laser photocoagulation (TTT,7 micropulsed laser8). Although the pathogenesis of CSC is poorly understood, it has a relationship with serum glucocorticoid levels that has been well documented.9 Systemic
control of CSC has been attempted with several oral agents including ketaconazole,10,11 mifepristone (RU-486),12 and methotrexate.13 Ravage et al1 reported success with daily oral rifampin. While being used as a part of an antituberculosis regimen, it was discovered to significantly improve symptoms in a patient with comorbid chronic CSC. Subsequent small-scale studies and case reports have demonstrated improvements in both visual acuity and optical coherence tomography for patients with CSC taking rifampin.2 Rifampin’s mechanism of effect is not well understood but has been known to reduce the levels of serum steroids.3 Recognized as a potent inducer of the CYP450 system,14 rifampin likely exerts its effect by increasing the metabolism of serum cortisol. It has also been shown in animal models to possess a retinal antineovascularization effect.15 Rifampin’s availability, relatively inexpensive cost, and relatively benign side effect profile make this therapy appealing for CSC. Although rifampin has demonstrated long-term safety in anti-tuberculosis therapy (ATT), hepatotoxicity is
72
RETINAL CASES & BRIEF REPORTS´ 2014 VOLUME 8 NUMBER 1
a well known adverse effect. Since rifampin is commonly used as a component of ATT, a majority of the literature assesses the adverse effects of rifampin in combination with pyrazinamide, isoniazid, and/or ethambutol. Rifampin has been shown to have a lower rate of liver injury (0.7–1.1%) when used in isolation than when included with other antituberculosis medications.4,16 Risk factors for hepatotoxicity during rifampin therapy include: advanced age, poor nutrition status, alcoholism, HIV positive status, and chronic Hepatitis B and C infection.17 Patients must be advised to avoid alcohol during treatment.18 Full ATT regimens in individuals with these risk factors have shown a greatly increased rate of elevated serum transaminases than those with lower risk.19 Although there is no standard safety monitoring protocol, Agal et al20 suggest obtaining liver function tests (ALT, AST, bilirubin) weekly for the first month, every 2 weeks for 1 month, and monthly for the remainder of treatment. They define hepatotoxicity as ALT or AST elevation of twice the upper limit of normal accompanied by any of the typical symptoms associated with hepatitis which include: nausea, vomiting, malaise, jaundice, easy bruising, and encephalopathy.20 Asymptomatic transaminitis greater than five times the upper limit of normal and bilirubin greater than two times the upper limit of normal were also classified as hepatotoxicity.20 The literature suggests that rifampin may be restarted if necessary after a rifampin-induced liver injury. Following hepatotoxicity triggered ATT discontinuation, reinstitution of ATT after normalization of laboratory values has been demonstrated to be safe and effective.20 Chronic CSC can persist and result in permanent vision loss. Oral rifampin may be helpful in patients who are unresponsive or not amenable to PDT. Although rifampin-associated hepatotoxicity is uncommon, it is a serious potential risk that must be weighed against treatment benefits and monitored closely during treatment. Key words: central serous chorioretinopathy, rifampin, hepatotoxicity, optical coherence tomography, glucocorticoids, antiglucocorticoid therapy, antituberculosis therapy. References 1. Ravage ZB, Packo KH, Creticos CM, et al. Chronic central serous chorioretinopathy responsive to rifampin. Retin Cases Brief Rep 2012;6:129–132.
2. Steinle NC, Gupta N, Yuan A, et al. Oral rifampin utilization for the treatment of chronic multifocal central serous retinopathy. Br J Ophthalmol 2012;96:10–13. 3. Edwards OM, Courtenay-Evans RJ, Galley JM, et al. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548–551. 4. Menzies D, Long R, Trajman A, et al. Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection. Ann Intern Med 2008;149:689–697. 5. Chan WM, Lai TY, Lai RY, et al. Half-dose verteporfin photodynamic therapy for acute central serous chorioretinopathy: one-year results of a randomized controlled trial. Ophthalmology 2008;115:1756–1765. 6. Seong HK, Bae JH, Kim ES, et al. Intravitreal bevacizumab to treat acute central serous chorioretinopathy: short-term effect. Ophthalmologica 2009;223:343–347. 7. Kawamura R, Ideta H, Hori H, et al. Transpupillary thermotherapy for atypical central serous chorioretinopathy. Clin Ophthalmol 2012;6:175–179. 8. Koss MJ, Beger I, Koch FH. Subthreshold diode laser micropulse photocoagulation versus intravitreal injections of bevacizumab in the treatment of central serous chorioretinopathy. Eye (Lond) 2012;26:307–314. 9. Garg SP, Dada T, Talwar D, et al. Endogenous cortisol profile in patients with central serous chorioretinopathy. Br J Ophthalmol 1997;81:962–964. 10. Golshahi A, Klingmuller D, Holz FG, et al. Ketoconazole in the treatment of central serous chorioretinopathy: a pilot study. Acta Ophthalmol 2010;88:576–581. 11. Meyerle CB, Freund KB, Bhatnager P, et al. Ketoconazole in the treatment of chronic idiopathic central serous chorioretinopathy. Retina 2007;27:943–946. 12. Nielsen JS, Jampol LM. Oral mifepristone for chronic central serous chorioretinopathy. Retina 2011;10:1–9. 13. Kurup S, Oliver A, Emanuelli V, et al. Utility of metronomic MTX in chronic central serous retinopathy. European VitreoRetinal Society. Available at: http://www.evrs.eu/utility-of-metronomic-mtx-in-chronic-central-serous-retinopathy/. Accessed April 30, 2012. 14. Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992;90:1871–1878. 15. Chikaraishi Y, Matsunaga N, Shimazawa M, et al. Rifampicin inhibits the retinal neovascularization in vitro and in vivo. Exp Eye Res 2008;86:131–137. 16. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465–471. 17. Tostmann A, Boeree MJ, Aarnoutse RE, et al. Antituberculosis drug-induced hepatotoxicity: consise up-to-date review. J Gastroenterol Hepatol 2008;23:192–202. 18. Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology 2006;11:699–707. 19. Fernández-Villar A, Sopeña B, Fernández-Villar J, et al. The influence of risk factors on the severity of anti-tuberculosis druginduced hepatotoxicity. Int J Tuberc Lung Dis 2004;8:1499–1505. 20. Agal S, Baijal R, Pramanik S, et al. Monitoring and management of antituberculosis drug induced hepatotoxicity. J Gastroenterol Hepatol 2005;20:1745–1752.
