- Email: [email protected]
A case report: Ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis
Journal of Crohn's and Colitis (2012) 6, 724–727
Available online at www.sciencedirect.com
SHORT REPORT
A case report: Ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis Urpo Kinnunen a,⁎, Martti Färkkilä b , Heikki Mäkisalo c a
Lapland Central Hospital, Rovaniemi, Finland Department of Internal Medicine, Helsinki University Hospital, Helsinki, Finland c Department of Surgery, Helsinki University Hospital, Helsinki, Finland b
Received 4 November 2011; received in revised form 4 February 2012; accepted 4 February 2012
KEYWORDS Infliximab; Toxicity; Liver failure; Hepatic transplantation
Abstract In recent years, the use of antibodies against tumor necrosis factor α (TNFα) has expanded in rheumatology, gastroenterology, and dermatology. In addition to the more common side effects such as infections and hypersensitivity reactions, elevations of liver enzymes have been reported during anti-TNFα therapy, although severe liver failure has been extremely uncommon. This report describes a patient with severe liver failure after induction therapy with the TNFα antibody infliximab (Remicade®). A 46-year old female patient received two infusions of infliximab at a dose of 400 mg on weeks 0 and 8 for steroid-dependent ulcerative colitis. Eight weeks after the second infusion, she suffered acute liver failure with necrosis, requiring liver transplantation. © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction In addition to rheumatology and dermatology, antibodies against tumor necrosis factor α (TNFα) are increasingly used to treat inflammatory bowel disease (IBD). Infliximab (Remicade®) was the first of the anti-TNFα agents to achieve widespread use in IBD. At first, it was used to treat moderately and severely active Crohn's disease (CD). More ⁎ Corresponding author. E-mail address: [email protected] (U. Kinnunen).
recently, severe ulcerative colitis (UC) has been approved as an indication for infliximab (IFX) treatment. IFX is a genetically constructed IgG1 murine-human chimeric antibody against TNFα and it is known to cause early and late hypersensitivity reactions. Since it is a potent immunosuppressant, it can also predispose patients to severe infections. Elevated liver enzymes have been reported during IFXtreatment, 1 although outright liver failure has been a rare consequence. However, cases of liver injury requiring liver transplantation (LT) have been reported in a review of voluntary post-marketing data 2 and one of these cases occurred in a CD patient. One case report described a 39-year-old
1873-9946/$ - see front matter © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2012.02.004
Ulcerative Colitis, Anti-TNFα, and Liver Necrosis female patient with rheumatoid arthritis who developed severe cholestatic liver disease with hepatic failure necessitating LT. 3 Of the TNFα blockers, adalimumab and certolimumab have been also shown to be effective in CD. A case of subacute liver failure during therapy with adalimumab for psoriatic arthritis has been reported. 4 Here, we describe a patient requiring LT after liver necrosis which developed during IFX therapy.
2. Case report A 46-year-old native Finnish female patient received two infusions of IFX at a dose of 5 mg/kg of body weight on weeks 0 and 8, for steroid-dependent UC diagnosed 22 years earlier. The presentation of the colitis had mainly been proctosigmoiditis but twice total colitis was observed in both endoscopic and histopathologic examinations. No granulomas or mucosal dysplasia were observed during the colonoscopy surveillance. The biopsies of the terminal ileum had been normal on four occasions. She had suffered also from an ankylosing spondylitis diagnosed 9 years earlier. After the diagnosis of UC, the patient – who increasingly suffered from symptoms of spondylitis – was treated at different times with sulfasalazine or mesalazine (or both), of which the latter appeared to be more effective in suppressing the activity of the colitis. Azathioprine was initiated 11 years after the diagnosis of colitis for her steroiddependent disease. However, when the dose was elevated to 2 mg/kg/day, the patient complained of epigastric pain, plasma aminotransferase levels rose to a level of three times the upper normal limit and the drug was withdrawn with the duration of treatment being only 3½ months. After the diagnosis of spondylitis, mesalazine was discontinued and thereafter the patient was treated with 3 g/day of sulfasalazine. Four years before starting IFX treatment, the colitis became active again. Due to the steroiddependent distal colitis, in addition to colectomy treatment with IFX was also considered. However, the combination therapy with sulfasalazine 2 g/day and olsalazine 1.5 g/ day, accompanied by topical therapy with corticosteroids and mesalazine, gradually alleviated the symptoms of colitis and the doses of the oral steroids could be tapered. About 7 months prior to the start of the IFX treatment, the signs of colitis reappeared again. Colonoscopy revealed that 30 to 40 cm of rectum and colon were moderately inflamed, whereas the rest of the colon and ileum appeared normal. Due to the presence of bloody diarrhea, three courses of corticosteroids had to be given. The available treatment options were discussed with the patient. Colectomy was considered as a reasonable option, but due to the lack of signs of mucosal dysplasia during the colonoscopy surveillance and the presence of the spondylitis, it was decided to initiate TNF blockade, if steroid-free remission could not be achieved otherwise. The first IFX infusion at a dose of 400 mg was given after the patient had begun the fourth oral steroid course of that year. The steroids could be discontinued soon after the start of anti-TNF treatment. The second IFX infusion at the same dose was given 8 weeks after the first one. Sulfasalazine 2 g/day and olsalazine 1.5 g/day were the only other medications being used at that time. About 5 weeks after the second infusion of IFX, the patient displayed no
725 symptoms related to colitis and endoscopic and histological remission was observed in the colonoscopic evaluation. The levels of plasma aminotransferases and alkaline phosphatase were normal before the two infusions of IFX. The third infusion was due to be delivered 8 weeks after the second dose. However, about 7 weeks after the second infusion of IFX, the patient began to feel ill and 1 week later, markedly elevated plasma aminotransferase levels were recorded (Fig. 1). The patient was admitted to a secondary care hospital where values for liver biochemistry were as follows: plasma AST 2627 U/L (normal range b 35 U/L), ALT 1826 U/L (b 45 U/L), ALP 283 U/L (b 105 U/L) and bilirubin 16.6 mg/ dL (b 1.2 mg/dL). The plasma internationalized normalized ratio (INR) became also highly elevated to a value of 3.6. No serum smooth-muscle, anti-nucleic, or antimitochondrial antibodies could be detected and the serology for hepatitis B- and C-viruses was negative. Serum ceruloplasmin and antitrypsin levels were normal. After 5 days of treatment, the patient was transferred to the liver transplant unit, where the clinical condition further deteriorated. Preoperatively performed computer tomography demonstrated liver damage and a reduction of the liver volume to 885 cm. 3 The liver biopsy revealed bridging necrosis that covered 80% of the liver tissue (Fig. 2). Grade IV hepatic encephalopathy was observed 4 days after admission to the transplant unit. An uneventful LT was performed 2 days later. After LT, the patient had to be dialyzed until the fourth postoperative day. Three weeks later, acute rejection was verified histologically and was successfully treated with steroids. Cytomegalovirus viremia was treated with oral ganciclovir therapy and a second acute rejection again with steroids 4 months after the LT. Thereafter some mild elevations of aminotransferases were found and adjustments of the immunosuppressive medication were conducted. The present immunosuppressive medication is a combination of tacrolimus, mycophenolate mofetil and steroids and after 16 months follow-up the patient is doing fine.
80 70 60 50 AST 40 ALT 30
AFOS
20
BIL
10 0 1st Remicade
2nd Remicade
3rd Remicade
(not given)
Figure 1 Transaminases (AST and ALT), alkaline phosphatase (AFOS) and total bilirubin (BIL) at the time of the Remicade infusions given at 8 week intervals. The 3rd infusion was not given because of elevated liver values. Hepatic transplantation was performed 10 days later. The laboratory values are represented as times the normal upper limit.
726
Figure 2 Panacinar hepatic necrosis with ductular proliferation. H&E staining, original magnification 100×.
3. Discussion IFX has been reported to induce acute liver failure by at least three mechanisms: induction of autoimmune hepatitis, cholestatic liver injury and direct toxicity. Moreover, a fulminant hepatitis B infection related to IFX therapy has been reported in a patient with CD 5and in patients with rheumatoid diseases. 6,7 Induction of autoimmune hepatitis in patients with IBD, 8 psoriatic disease, 9 and rheumatoid arthritis 3 has been reported. A patient with rheumatoid arthritis treated with IFX required an LT for cholestatic liver injury. 3 IFX was claimed to have been responsible for causing acute toxic hepatitis in a patient with CD. 10 In that case, the patient had no history of alcohol abuse and the only treatment the patient was receiving was IFX. Serological tests or methods based on the polymerase chain reaction to test for hepatitis viruses, HIV virus and cytomegalovirus as well as serologic tests for autoimmune diseases were negative. The histopathological study of the liver revealed acute toxic hepatitis with areas of converging necrosis. Another report was also suggestive of direct liver damage induced by IFX treatment. 11 In both of these cases of putative direct liver toxicity caused by IFX treatment, a full recovery of hepatic function occurred after cessation of the IFX treatment. Most of the cases of severe hepatic reactions associated with the use of IFX have been confounded by the use of other hepatotoxic medications concomitantly 2 and serious comorbid diseases may also increase toxicity. Thus, it has been difficult to establish a causal relationship between IFX and the hepatic adverse effects. In the present case, the only other medications in use were sulfasalazine and mesalamine. Acute liver failure has been reported after treatment with sulfasalazine in both adult and pediatric populations. 12,13 Mesalamine only rarely causes acute liver injury. 14 One case of an apparent cross-reactive hypersensitivity reaction with mesalamine after a prior hypersensitivity reaction to sulfasalazine has been reported. 15 However, in the present case, sulfasalazine and mesalamine had been
U. Kinnunen et al. used for a prolonged period before the manifestation of liver necrosis, whereas IFX had been quite recently added to the regimen. The present case is believed to represent direct toxicity of IFX resulting in severe liver necrosis that certainly would have been lethal without LT. The patient did not fulfill the criteria of autoimmune hepatitis, nor were there any signs of viral hepatitis or cholestatic liver injury. The reason for liver toxicity associated with IFX remains unknown. Pre-existing liver disease and concomitant medication with potentially hepatotoxic drugs may increase the risk. It is noteworthy that in the present case, azathioprine had had to be withdrawn earlier, because of elevated liver enzymes. The potential hepatotoxicity of IFX was taken into account in a recent consensus statement. 2 It was recommended that IFX therapy may be considered in selected patients with clinically significant liver disease, but overall treatment with IFX should be avoided or discontinued in patients with aminotransferases more than three times normal and that liver functions tests should be determined prior to IFX treatment, after induction treatment and at least every 4 months while on maintenance treatment. However, in the present case, with the exception of the elevated aminotransferase levels noted during azathioprine treatment, the patient did not exhibit any signs of liver disease and plasma aminotransferases were determined before each IFX infusion. Thus, the abovementioned precautions would not have prevented the development of liver necrosis during IFX treatment. In the present case, the liver toxicity appeared in a clinical situation in which two treatment options were considered, namely proctocolectomy and IFX. Until quite recently, it was the clinical guideline that in steroiddependent or steroid-refractory UC, the patient should be referred for colectomy if full dose immunomodulatory treatment with azathioprine/mercaptopurine was already in use or if the patient was intolerant to these drugs. Nowadays IFX is a generally accepted alternative to surgery also in steroid-dependent/-refractory UC and in addition, it is usually preferred by the patients. Consequently, the use of IFX to treat UC has greatly increased, at least in northern Europe. Although most cases of liver toxicity associated with TNFα-antagonists have been linked to IFX (and to a lesser extent to etanercept), IFX induced liver necrosis of the magnitude presented in this article is probably a very rare phenomenon. Nonetheless, proctocolectomy remains a reasonable alternative in the treatment of steroiddependent/-refractory UC.
Conflict of interest None.
References 1. Sokolove J, Strand V, Greenberg JD, Curtis JR, Kavanaugh A, Kremer JM, et al. CORRONA Investigators. Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis. Ann Rheum Dis 2010;69(9):1612–7. 2. Miehsler W, Novacek G, Wenzl H, Vogelsang H, Knoflach P, Kaser A, et al. Austrian Society of Gastroenterology and Hepatology. A decade of infliximab: the Austrian evidence
Ulcerative Colitis, Anti-TNFα, and Liver Necrosis
3.
4.
5.
6.
7.
8.
9.
based consensus on the safe use of infliximab in inflammatory bowel disease. J Crohns Colitis 2010;4(3):221–56. Tobon GJ, Cañas C, Jaller JJ, Restrepo JC, Anaya JM. Serious liver disease induced by infliximab. Clin Rheumatol 2007;26(4):578–81. Hagel S, Bruns T, Theis B, Herrmann A, Stallmach A. Subacute liver failure induced by adalimumab. Int J Clin Pharmacol Ther 2011;49(1):38–40. Esteve M, Saro C, González-Huix F, Suarez F, Fornė M, Vivier JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 2004;53(9):1363–5. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatits B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003;62(7):686–7. Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset Still's disease. J Rheumatol 2003;30(7):1624–5. Cravo M, Silva R, Serrano M. Autoimmine hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab. BioDrugs 2010;24(Suppl 1): 25–7. Mancini S, Amorotti E, Vecchio S, Ponz de Leon M, Roncucci L. Infliximab-related hepatitis: discussion of a case and review of the literature. Intern Emerg Med 2010;5(3):193–200.
727 10. Haennig A, Bonnet D, Thebault S, Alric L. Infliximab-induced acute hepatitis during Crohn's disease therapy: absence of cross-toxicity with adalimumab. Gastroenterol Clin Biol 2010;34(8–9):e7–8. 11. Carlsen KM, Riis L, Madsen OR. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept. Clin Rheumatol 2009;28(8): 1001–3. 12. Haines Jr JD. Hepatotoxicity after treatment with sulfasalazine. Postgrad Med 1986;79(6):193–4 197–198. 13. Besnard M, Debray D, Durand P, Fabre M, Chardot C, Cézard JP. Fulminant hepatitis in two children treated with sulfasalazine for Crohn disease. Arch Pediatr 1999;6(6):643–6. 14. Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002;51(4):536–9. 15. Hautekeete ML, Bourgeois N, Potvin P, Duville L, Reynaert H, Devis G, et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology 1992;103(6):1925–7.
Available online at www.sciencedirect.com
SHORT REPORT
A case report: Ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis Urpo Kinnunen a,⁎, Martti Färkkilä b , Heikki Mäkisalo c a
Lapland Central Hospital, Rovaniemi, Finland Department of Internal Medicine, Helsinki University Hospital, Helsinki, Finland c Department of Surgery, Helsinki University Hospital, Helsinki, Finland b
Received 4 November 2011; received in revised form 4 February 2012; accepted 4 February 2012
KEYWORDS Infliximab; Toxicity; Liver failure; Hepatic transplantation
Abstract In recent years, the use of antibodies against tumor necrosis factor α (TNFα) has expanded in rheumatology, gastroenterology, and dermatology. In addition to the more common side effects such as infections and hypersensitivity reactions, elevations of liver enzymes have been reported during anti-TNFα therapy, although severe liver failure has been extremely uncommon. This report describes a patient with severe liver failure after induction therapy with the TNFα antibody infliximab (Remicade®). A 46-year old female patient received two infusions of infliximab at a dose of 400 mg on weeks 0 and 8 for steroid-dependent ulcerative colitis. Eight weeks after the second infusion, she suffered acute liver failure with necrosis, requiring liver transplantation. © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction In addition to rheumatology and dermatology, antibodies against tumor necrosis factor α (TNFα) are increasingly used to treat inflammatory bowel disease (IBD). Infliximab (Remicade®) was the first of the anti-TNFα agents to achieve widespread use in IBD. At first, it was used to treat moderately and severely active Crohn's disease (CD). More ⁎ Corresponding author. E-mail address: [email protected] (U. Kinnunen).
recently, severe ulcerative colitis (UC) has been approved as an indication for infliximab (IFX) treatment. IFX is a genetically constructed IgG1 murine-human chimeric antibody against TNFα and it is known to cause early and late hypersensitivity reactions. Since it is a potent immunosuppressant, it can also predispose patients to severe infections. Elevated liver enzymes have been reported during IFXtreatment, 1 although outright liver failure has been a rare consequence. However, cases of liver injury requiring liver transplantation (LT) have been reported in a review of voluntary post-marketing data 2 and one of these cases occurred in a CD patient. One case report described a 39-year-old
1873-9946/$ - see front matter © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2012.02.004
Ulcerative Colitis, Anti-TNFα, and Liver Necrosis female patient with rheumatoid arthritis who developed severe cholestatic liver disease with hepatic failure necessitating LT. 3 Of the TNFα blockers, adalimumab and certolimumab have been also shown to be effective in CD. A case of subacute liver failure during therapy with adalimumab for psoriatic arthritis has been reported. 4 Here, we describe a patient requiring LT after liver necrosis which developed during IFX therapy.
2. Case report A 46-year-old native Finnish female patient received two infusions of IFX at a dose of 5 mg/kg of body weight on weeks 0 and 8, for steroid-dependent UC diagnosed 22 years earlier. The presentation of the colitis had mainly been proctosigmoiditis but twice total colitis was observed in both endoscopic and histopathologic examinations. No granulomas or mucosal dysplasia were observed during the colonoscopy surveillance. The biopsies of the terminal ileum had been normal on four occasions. She had suffered also from an ankylosing spondylitis diagnosed 9 years earlier. After the diagnosis of UC, the patient – who increasingly suffered from symptoms of spondylitis – was treated at different times with sulfasalazine or mesalazine (or both), of which the latter appeared to be more effective in suppressing the activity of the colitis. Azathioprine was initiated 11 years after the diagnosis of colitis for her steroiddependent disease. However, when the dose was elevated to 2 mg/kg/day, the patient complained of epigastric pain, plasma aminotransferase levels rose to a level of three times the upper normal limit and the drug was withdrawn with the duration of treatment being only 3½ months. After the diagnosis of spondylitis, mesalazine was discontinued and thereafter the patient was treated with 3 g/day of sulfasalazine. Four years before starting IFX treatment, the colitis became active again. Due to the steroiddependent distal colitis, in addition to colectomy treatment with IFX was also considered. However, the combination therapy with sulfasalazine 2 g/day and olsalazine 1.5 g/ day, accompanied by topical therapy with corticosteroids and mesalazine, gradually alleviated the symptoms of colitis and the doses of the oral steroids could be tapered. About 7 months prior to the start of the IFX treatment, the signs of colitis reappeared again. Colonoscopy revealed that 30 to 40 cm of rectum and colon were moderately inflamed, whereas the rest of the colon and ileum appeared normal. Due to the presence of bloody diarrhea, three courses of corticosteroids had to be given. The available treatment options were discussed with the patient. Colectomy was considered as a reasonable option, but due to the lack of signs of mucosal dysplasia during the colonoscopy surveillance and the presence of the spondylitis, it was decided to initiate TNF blockade, if steroid-free remission could not be achieved otherwise. The first IFX infusion at a dose of 400 mg was given after the patient had begun the fourth oral steroid course of that year. The steroids could be discontinued soon after the start of anti-TNF treatment. The second IFX infusion at the same dose was given 8 weeks after the first one. Sulfasalazine 2 g/day and olsalazine 1.5 g/day were the only other medications being used at that time. About 5 weeks after the second infusion of IFX, the patient displayed no
725 symptoms related to colitis and endoscopic and histological remission was observed in the colonoscopic evaluation. The levels of plasma aminotransferases and alkaline phosphatase were normal before the two infusions of IFX. The third infusion was due to be delivered 8 weeks after the second dose. However, about 7 weeks after the second infusion of IFX, the patient began to feel ill and 1 week later, markedly elevated plasma aminotransferase levels were recorded (Fig. 1). The patient was admitted to a secondary care hospital where values for liver biochemistry were as follows: plasma AST 2627 U/L (normal range b 35 U/L), ALT 1826 U/L (b 45 U/L), ALP 283 U/L (b 105 U/L) and bilirubin 16.6 mg/ dL (b 1.2 mg/dL). The plasma internationalized normalized ratio (INR) became also highly elevated to a value of 3.6. No serum smooth-muscle, anti-nucleic, or antimitochondrial antibodies could be detected and the serology for hepatitis B- and C-viruses was negative. Serum ceruloplasmin and antitrypsin levels were normal. After 5 days of treatment, the patient was transferred to the liver transplant unit, where the clinical condition further deteriorated. Preoperatively performed computer tomography demonstrated liver damage and a reduction of the liver volume to 885 cm. 3 The liver biopsy revealed bridging necrosis that covered 80% of the liver tissue (Fig. 2). Grade IV hepatic encephalopathy was observed 4 days after admission to the transplant unit. An uneventful LT was performed 2 days later. After LT, the patient had to be dialyzed until the fourth postoperative day. Three weeks later, acute rejection was verified histologically and was successfully treated with steroids. Cytomegalovirus viremia was treated with oral ganciclovir therapy and a second acute rejection again with steroids 4 months after the LT. Thereafter some mild elevations of aminotransferases were found and adjustments of the immunosuppressive medication were conducted. The present immunosuppressive medication is a combination of tacrolimus, mycophenolate mofetil and steroids and after 16 months follow-up the patient is doing fine.
80 70 60 50 AST 40 ALT 30
AFOS
20
BIL
10 0 1st Remicade
2nd Remicade
3rd Remicade
(not given)
Figure 1 Transaminases (AST and ALT), alkaline phosphatase (AFOS) and total bilirubin (BIL) at the time of the Remicade infusions given at 8 week intervals. The 3rd infusion was not given because of elevated liver values. Hepatic transplantation was performed 10 days later. The laboratory values are represented as times the normal upper limit.
726
Figure 2 Panacinar hepatic necrosis with ductular proliferation. H&E staining, original magnification 100×.
3. Discussion IFX has been reported to induce acute liver failure by at least three mechanisms: induction of autoimmune hepatitis, cholestatic liver injury and direct toxicity. Moreover, a fulminant hepatitis B infection related to IFX therapy has been reported in a patient with CD 5and in patients with rheumatoid diseases. 6,7 Induction of autoimmune hepatitis in patients with IBD, 8 psoriatic disease, 9 and rheumatoid arthritis 3 has been reported. A patient with rheumatoid arthritis treated with IFX required an LT for cholestatic liver injury. 3 IFX was claimed to have been responsible for causing acute toxic hepatitis in a patient with CD. 10 In that case, the patient had no history of alcohol abuse and the only treatment the patient was receiving was IFX. Serological tests or methods based on the polymerase chain reaction to test for hepatitis viruses, HIV virus and cytomegalovirus as well as serologic tests for autoimmune diseases were negative. The histopathological study of the liver revealed acute toxic hepatitis with areas of converging necrosis. Another report was also suggestive of direct liver damage induced by IFX treatment. 11 In both of these cases of putative direct liver toxicity caused by IFX treatment, a full recovery of hepatic function occurred after cessation of the IFX treatment. Most of the cases of severe hepatic reactions associated with the use of IFX have been confounded by the use of other hepatotoxic medications concomitantly 2 and serious comorbid diseases may also increase toxicity. Thus, it has been difficult to establish a causal relationship between IFX and the hepatic adverse effects. In the present case, the only other medications in use were sulfasalazine and mesalamine. Acute liver failure has been reported after treatment with sulfasalazine in both adult and pediatric populations. 12,13 Mesalamine only rarely causes acute liver injury. 14 One case of an apparent cross-reactive hypersensitivity reaction with mesalamine after a prior hypersensitivity reaction to sulfasalazine has been reported. 15 However, in the present case, sulfasalazine and mesalamine had been
U. Kinnunen et al. used for a prolonged period before the manifestation of liver necrosis, whereas IFX had been quite recently added to the regimen. The present case is believed to represent direct toxicity of IFX resulting in severe liver necrosis that certainly would have been lethal without LT. The patient did not fulfill the criteria of autoimmune hepatitis, nor were there any signs of viral hepatitis or cholestatic liver injury. The reason for liver toxicity associated with IFX remains unknown. Pre-existing liver disease and concomitant medication with potentially hepatotoxic drugs may increase the risk. It is noteworthy that in the present case, azathioprine had had to be withdrawn earlier, because of elevated liver enzymes. The potential hepatotoxicity of IFX was taken into account in a recent consensus statement. 2 It was recommended that IFX therapy may be considered in selected patients with clinically significant liver disease, but overall treatment with IFX should be avoided or discontinued in patients with aminotransferases more than three times normal and that liver functions tests should be determined prior to IFX treatment, after induction treatment and at least every 4 months while on maintenance treatment. However, in the present case, with the exception of the elevated aminotransferase levels noted during azathioprine treatment, the patient did not exhibit any signs of liver disease and plasma aminotransferases were determined before each IFX infusion. Thus, the abovementioned precautions would not have prevented the development of liver necrosis during IFX treatment. In the present case, the liver toxicity appeared in a clinical situation in which two treatment options were considered, namely proctocolectomy and IFX. Until quite recently, it was the clinical guideline that in steroiddependent or steroid-refractory UC, the patient should be referred for colectomy if full dose immunomodulatory treatment with azathioprine/mercaptopurine was already in use or if the patient was intolerant to these drugs. Nowadays IFX is a generally accepted alternative to surgery also in steroid-dependent/-refractory UC and in addition, it is usually preferred by the patients. Consequently, the use of IFX to treat UC has greatly increased, at least in northern Europe. Although most cases of liver toxicity associated with TNFα-antagonists have been linked to IFX (and to a lesser extent to etanercept), IFX induced liver necrosis of the magnitude presented in this article is probably a very rare phenomenon. Nonetheless, proctocolectomy remains a reasonable alternative in the treatment of steroiddependent/-refractory UC.
Conflict of interest None.
References 1. Sokolove J, Strand V, Greenberg JD, Curtis JR, Kavanaugh A, Kremer JM, et al. CORRONA Investigators. Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis. Ann Rheum Dis 2010;69(9):1612–7. 2. Miehsler W, Novacek G, Wenzl H, Vogelsang H, Knoflach P, Kaser A, et al. Austrian Society of Gastroenterology and Hepatology. A decade of infliximab: the Austrian evidence
Ulcerative Colitis, Anti-TNFα, and Liver Necrosis
3.
4.
5.
6.
7.
8.
9.
based consensus on the safe use of infliximab in inflammatory bowel disease. J Crohns Colitis 2010;4(3):221–56. Tobon GJ, Cañas C, Jaller JJ, Restrepo JC, Anaya JM. Serious liver disease induced by infliximab. Clin Rheumatol 2007;26(4):578–81. Hagel S, Bruns T, Theis B, Herrmann A, Stallmach A. Subacute liver failure induced by adalimumab. Int J Clin Pharmacol Ther 2011;49(1):38–40. Esteve M, Saro C, González-Huix F, Suarez F, Fornė M, Vivier JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 2004;53(9):1363–5. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatits B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003;62(7):686–7. Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset Still's disease. J Rheumatol 2003;30(7):1624–5. Cravo M, Silva R, Serrano M. Autoimmine hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab. BioDrugs 2010;24(Suppl 1): 25–7. Mancini S, Amorotti E, Vecchio S, Ponz de Leon M, Roncucci L. Infliximab-related hepatitis: discussion of a case and review of the literature. Intern Emerg Med 2010;5(3):193–200.
727 10. Haennig A, Bonnet D, Thebault S, Alric L. Infliximab-induced acute hepatitis during Crohn's disease therapy: absence of cross-toxicity with adalimumab. Gastroenterol Clin Biol 2010;34(8–9):e7–8. 11. Carlsen KM, Riis L, Madsen OR. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept. Clin Rheumatol 2009;28(8): 1001–3. 12. Haines Jr JD. Hepatotoxicity after treatment with sulfasalazine. Postgrad Med 1986;79(6):193–4 197–198. 13. Besnard M, Debray D, Durand P, Fabre M, Chardot C, Cézard JP. Fulminant hepatitis in two children treated with sulfasalazine for Crohn disease. Arch Pediatr 1999;6(6):643–6. 14. Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002;51(4):536–9. 15. Hautekeete ML, Bourgeois N, Potvin P, Duville L, Reynaert H, Devis G, et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology 1992;103(6):1925–7.