Multiple Sclerosis and Related Disorders (2013) 2, 57–59
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta in a multiple sclerosis patient$ Kaarina Kowaleca,b,c, Eric M. Yoshidad, Anthony Traboulseee, Bruce Carletonb,c,f, Helen Tremletta,e,n a
Neuroscience Program, University of British Columbia (UBC), Vancouver, Canada Child & Family Research Institute, Vancouver, Canada c Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, Canada d Division of Gastroenterology, UBC, Vancouver, Canada e Division of Neurology, UBC, Vancouver, Canada f Division of Translational Therapeutics, Department of Pediatrics, UBC, Vancouver, Canada b
Received 26 May 2012; received in revised form 12 July 2012; accepted 17 July 2012
KEYWORDS
Abstract
Primary biliary cirrhosis; Autoimmune hepatitis; Interferon-beta; Multiple sclerosis; Liver injury; Drug safety
The use of interferon-beta in multiple sclerosis is associated with various forms of hepatotoxicity, including autoimmune hepatitis and liver failure. We describe a case with features of autoimmune liver disease and primary biliary cirrhosis occurring during long-term treatment with interferon-beta in a patient with relapsing-remitting multiple sclerosis. This case highlights the importance of monitoring biochemical liver test results throughout interferonbeta treatment of multiple sclerosis. & 2012 Elsevier B.V. All rights reserved.
Case report
modifying therapy, IFN-b-1a (44 mcg subcutaneous injection, thrice weekly; Rebifs EMD Serono Canada, Inc., Oakville, ON) for 5 months, but discontinued due to injection site reactions. This was followed by 28 months of IFN-b1b (250 mcg subcutaneous injection, alternate days; Betaserons Bayer Pharmaceuticals, Montville, NJ, USA) but discontinued due to perceived lack of effectiveness. The biochemical liver test results were within normal range preIFN-b treatment (‘baseline’) and during the first 33 months of IFN-b-1a (44 mcg) and IFN-b-1b treatment (see Figure 1). The patient was restarted on IFN-b-1a (44 mcg) due to increasing MS disease activity. No biochemical liver testing
1.
A 42-year-old woman with clinically definite RRMS (Poser criteria) (Poser et al., 1983) and symptom onset 14 years previously, was initially treated with her first MS disease-
$
This case report was written with the consent of the patient. Corresponding author at: Room S178, 2211 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5. Tel.: +1 604 822 0957. E-mail address: [email protected] (H. Tremlett). n
2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.07.004
58
K. Kowalec et al.
Times the upper normal limit
8 7
ALT
ALP
AST
TBILI
6 5 4 3 2 1
15
15
-N
ov
-0 -A 5 p 15 r-06 -S ep 15 -06 -F eb 15 -07 -J u 15 l-07 -D e 15 c-0 -M 7 ay 15 -08 -O c 15 t-08 -M a 15 r-0 -A 9 ug 15 -09 -J an 15 -10 -J un 15 -10 -N ov 15 -10 -A p 15 r-11 -S e 15 p-1 -F 1 eb 15 -12 -J ul -1 2
0
Figure 1 Longitudinal biochemical liver test results of an MS patient treated over 68 months with different formulations of interferon-beta. Key: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TBILI, total bilirubin. TBILI levels were within normal range throughout.
was done immediately prior to switching to IFN-b-1a; the last liver test results prior to the switch had been normal (12 months prior), as were the subsequent results 5 months after re-starting. Approximately 34 months into this second course of IFN-b-1a (44 mcg), the patients’ biochemical liver test results were: alanine aminotransferase (ALT)=260 (Normal (N)o36 U/l; 7 times the upper normal limit); aspartate aminotransferase (AST)=221 (No36 U/l; 6 times the upper normal limit); alkaline phosphatase (ALP)=157 (No125 U/l; 1.3 times the upper normal limit); total bilirubin (TBILI)=8 (No25 mmol/l). No clinical symptoms of acute liver injury were reported, but she was advised to discontinue IFN-b-1a. Three weeks later, her liver biochemistry was repeated and remained similarly elevated. The liver biochemistry normalized within 2 months, following drug cessation. Serologic autoimmune marker testing was completed 2 months following the highest liver test elevations and was strongly positive for anti-mitochondrial antibodies (titer= 1:1280). In addition, she was positive at a 1:1280 dilution with a centromere pattern for antinuclear antibodies (ANA), but was negative for parietal cell and antitissue transglutaminase antibodies. No baseline serologic autoimmune marker testing was done, as this was not considered standard of care in our MS clinic and was not clinically indicated at baseline. Concomitant medications around the time of the elevated biochemical liver test results included occasional acetaminophen (unknown quantity) and modafinil (alertecs 100 mg daily; Shire Canada Inc., Saint-Laurent, QC), for MS-related fatigue (unlicensed indication). The patient had been on modafinil for 4 years with no other adverse reactions reported. She was negative for hepatitis viruses A, B and C and denied any substance abuse, with the exception of tobacco cigarettes (unknown quantity per day). She reported occasional alcohol intake when she would consume 1–2 beers (3–4 units of alcohol) on a given day. A liver biopsy was not considered clinically justifiable, in part due to normalization of liver biochemistry, although an
abdominal ultrasound performed 3 months following drug discontinuation demonstrated mild fatty infiltration of the liver, with no calculi, obstruction or focal hepatic abnormalities. Her medical history was negative for acute liver injury and no family history of liver disease was found. To date, the patient has not been re-challenged with IFN-b-1a. Two doses of ursodiol (Ursos 500 mg BID; Aptalis Pharma Canada Inc., Mont-Saint-Hilaire, QC) for primary biliary cirrhosis (PBC) were given, but ursodiol was not continued because of stabilizing liver biochemistry. As of 7 months after stopping IFN-b-1a, the patient remains positive for anti-mitochondrial antibody and ANA, with liver biochemistry also normal, except for a mild increase in serum gamma-glutamyltransferase (GGT) at 80 U/L (No55 U/L).
2.
Discussion
The use of IFN-b in MS is associated with autoimmune hepatitis (Durelli et al., 1998; Pulicken et al., 2006; Grieco et al., 2007), hepatotoxicity (Tremlett et al., 2004) and fulminant liver failure (Yoshida et al., 2001) and can occur years into treatment (Grieco et al., 2007). The use of IFN-b for MS has not been associated with unmasking PBC or precipitating de novo antimitochondrial antibodies (the classic serologic marker of PBC). We describe a case with features of autoimmune liver disease occurring during treatment with IFN-b for MS, presumably exposing preexisting, but clinically silent PBC. The strong presence of antimitochondrial antibodies are suggestive of PBC (Muratori et al., 2003, 2008), while the antinuclear antibody along with ALT and AST elevations were consistent with autoimmune hepatitis (Mieli-Vergani and Vergani, 2011). In the absence of a liver biopsy, which could not be justified on clinical grounds, or any remarkable elevations in ALP, the accepted criteria of PBC-autoimmune hepatitis overlap syndrome are not fulfilled (Chazouilleres et al., 1998),
Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta although the suggestion is of PBC with features of autoimmune hepatitis (Boberg et al., 2011). Similar to the development of MS, PBC and autoimmune hepatitis are thought to begin once a genetically susceptible individual encounters an unknown environmental trigger (Bhandari et al., 2011; Mieli-Vergani and Vergani, 2011); for this patient, the trigger may have been long-term exposure to IFN-b. Although no HLA typing was performed on this patient, therefore conclusions on the patients’ genetic predisposition to PBC cannot be made (Invernizzi et al., 2012). The exact mechanism behind the induction of autoimmunity by IFN-b in MS patients is unknown (Durelli et al., 1998; Pulicken et al., 2006). PBC may have remained subclinical, although fatigue was present in this patient, which, in hindsight could have also been related to PBC (Bhandari et al., 2011). The long-term use of IFN-b may have aggravated the presumed pre-existing PBC, triggering the elevations in ALT and AST, appearing as autoimmune hepatitis. Other potential causes of the patients’ elevated liver enzymes include consumption of acetaminophen and alcohol. However, the AST/ALT ratio is typically much higher in cases of alcoholic liver damage (Hannuksela et al., 2007) and neither the history of alcohol nor acetaminophen consumption appeared significant enough to account for the degree of liver biochemical derangement or the presence of autoantibodies. In conclusion, this case suggests IFN-b-related liver toxicity may occur years into treatment (apparently without any overt worrisome signs or symptoms) and further exhibits the importance of monitoring biochemical liver test results. The recommended frequency of testing varies, with some recommending baseline screening, followed by monthly tests for the first 6 months, then 6 monthly thereafter during IFN-b treatment (Health Canada, 2003).
Conflict of interest Mrs. Kowalec reports no conflicts of interest. Funding for Mrs. Kowalec was provided by the Canadian Institutes of Health Research (CIHR) and the University of British Columbia. Dr. Yoshida: reports no conflicts of interest in regards to this work. Dr. Traboulsee: Data safety monitoring board membership (Merck Serono), steering committee membership (Roche) and speaker honoraria (Biogen Idec, Bayer Pharmaceuticals, Teva Neuroscience, EMD Serono, Sanofi Genzyme). Dr. Carleton: reports no conflicts of interest in regards to this work. Dr. Tremlett: is funded by the Multiple Sclerosis Society of Canada (Don Paty Career Development Award), Michael Smith Foundation for Health Research and is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received: research support from the US National Multiple Sclerosis Society, CIHR, and UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres, US National MS Society,
59
the University of British Columbia Multiple Sclerosis Research Program, Bayer Pharmaceutical (speaker, 2010, honoraria declined), Teva Pharmaceuticals (speaker 2011), ECTRIMS (2011), UK MS Trust and the Chesapeake Health Education Program, US Veterans Affairs (2012, honorarium declined). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group.
References Bhandari BM, Bayat H, Rothstein KD. Primary biliary cirrhosis. Gastroenterology Clinics of North America 2011;40:373–86. Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. Journal of Hepatology 2011;54:374–85. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998;28:296–301. Durelli L, Bongioanni MR, Ferrero B, Oggero A, Marzano A, Rizzetto M. Interferon treatment for multiple sclerosis: autoimmune complications may be lethal. Neurology 1998;50:570–1. Grieco A, Montalto M, Vero V, Maria Vecchio F, Gasbarrini G. Severe acute hepatitis after resumption of interferon-beta therapy for multiple sclerosis: a word of caution. American Journal of Gastroenterology 2007;102:2606–7. Hannuksela ML, Liisanantti MK, Nissinen AE, Savolainen MJ. Biochemical markers of alcoholism. Clinical Chemistry and Laboratory Medicine 2007;45:953–61. Health Canada. Hepatic injury associated with beta-interferon treatment for multiple sclerosis. Retrieved January 1, 2003 from /http://www.hc-sc.gc.ca/dhp-mps/medeff/advisoriesavis/prof/_2003/beta_interferon_hpc-cps-eng.phpS. Invernizzi P, Ransom M, Raychaudhuri S, Kosoy R, Lleo A, Shigeta R, et al. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis. Genes and Immunity 2012, http://dx.doi.org/10.1038/gene.2012.17. Mieli-Vergani G, Vergani D. Autoimmune hepatitis. Nature Reviews Gastroenterology and Hepatology 2011;8:320–9. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. American Journal of Gastroenterology 2003;98:431–7. Muratori L, Granito A, Muratori P, Pappas G, Bianchi FP. Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clinics in Liver Disease 2008;12:261–76. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology 1983;13:227–31. Pulicken M, Koteish A, DeBusk K, Calabresi PA. Unmasking of autoimmune hepatitis in a patient with MS following interferon beta therapy. Neurology 2006;66:1954–5. Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between the three products. Neurology 2004;62:628–31. Yoshida EM, Rasmussen SL, Steinbrecher UP, Erb SR, Scudamore CH, Chung SW, et al. Fulminant liver failure during interferon beta treatment of multiple sclerosis. Neurology 2001;56:1416.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta in a multiple sclerosis patient$ Kaarina Kowaleca,b,c, Eric M. Yoshidad, Anthony Traboulseee, Bruce Carletonb,c,f, Helen Tremletta,e,n a
Neuroscience Program, University of British Columbia (UBC), Vancouver, Canada Child & Family Research Institute, Vancouver, Canada c Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, Canada d Division of Gastroenterology, UBC, Vancouver, Canada e Division of Neurology, UBC, Vancouver, Canada f Division of Translational Therapeutics, Department of Pediatrics, UBC, Vancouver, Canada b
Received 26 May 2012; received in revised form 12 July 2012; accepted 17 July 2012
KEYWORDS
Abstract
Primary biliary cirrhosis; Autoimmune hepatitis; Interferon-beta; Multiple sclerosis; Liver injury; Drug safety
The use of interferon-beta in multiple sclerosis is associated with various forms of hepatotoxicity, including autoimmune hepatitis and liver failure. We describe a case with features of autoimmune liver disease and primary biliary cirrhosis occurring during long-term treatment with interferon-beta in a patient with relapsing-remitting multiple sclerosis. This case highlights the importance of monitoring biochemical liver test results throughout interferonbeta treatment of multiple sclerosis. & 2012 Elsevier B.V. All rights reserved.
Case report
modifying therapy, IFN-b-1a (44 mcg subcutaneous injection, thrice weekly; Rebifs EMD Serono Canada, Inc., Oakville, ON) for 5 months, but discontinued due to injection site reactions. This was followed by 28 months of IFN-b1b (250 mcg subcutaneous injection, alternate days; Betaserons Bayer Pharmaceuticals, Montville, NJ, USA) but discontinued due to perceived lack of effectiveness. The biochemical liver test results were within normal range preIFN-b treatment (‘baseline’) and during the first 33 months of IFN-b-1a (44 mcg) and IFN-b-1b treatment (see Figure 1). The patient was restarted on IFN-b-1a (44 mcg) due to increasing MS disease activity. No biochemical liver testing
1.
A 42-year-old woman with clinically definite RRMS (Poser criteria) (Poser et al., 1983) and symptom onset 14 years previously, was initially treated with her first MS disease-
$
This case report was written with the consent of the patient. Corresponding author at: Room S178, 2211 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5. Tel.: +1 604 822 0957. E-mail address: [email protected] (H. Tremlett). n
2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.07.004
58
K. Kowalec et al.
Times the upper normal limit
8 7
ALT
ALP
AST
TBILI
6 5 4 3 2 1
15
15
-N
ov
-0 -A 5 p 15 r-06 -S ep 15 -06 -F eb 15 -07 -J u 15 l-07 -D e 15 c-0 -M 7 ay 15 -08 -O c 15 t-08 -M a 15 r-0 -A 9 ug 15 -09 -J an 15 -10 -J un 15 -10 -N ov 15 -10 -A p 15 r-11 -S e 15 p-1 -F 1 eb 15 -12 -J ul -1 2
0
Figure 1 Longitudinal biochemical liver test results of an MS patient treated over 68 months with different formulations of interferon-beta. Key: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TBILI, total bilirubin. TBILI levels were within normal range throughout.
was done immediately prior to switching to IFN-b-1a; the last liver test results prior to the switch had been normal (12 months prior), as were the subsequent results 5 months after re-starting. Approximately 34 months into this second course of IFN-b-1a (44 mcg), the patients’ biochemical liver test results were: alanine aminotransferase (ALT)=260 (Normal (N)o36 U/l; 7 times the upper normal limit); aspartate aminotransferase (AST)=221 (No36 U/l; 6 times the upper normal limit); alkaline phosphatase (ALP)=157 (No125 U/l; 1.3 times the upper normal limit); total bilirubin (TBILI)=8 (No25 mmol/l). No clinical symptoms of acute liver injury were reported, but she was advised to discontinue IFN-b-1a. Three weeks later, her liver biochemistry was repeated and remained similarly elevated. The liver biochemistry normalized within 2 months, following drug cessation. Serologic autoimmune marker testing was completed 2 months following the highest liver test elevations and was strongly positive for anti-mitochondrial antibodies (titer= 1:1280). In addition, she was positive at a 1:1280 dilution with a centromere pattern for antinuclear antibodies (ANA), but was negative for parietal cell and antitissue transglutaminase antibodies. No baseline serologic autoimmune marker testing was done, as this was not considered standard of care in our MS clinic and was not clinically indicated at baseline. Concomitant medications around the time of the elevated biochemical liver test results included occasional acetaminophen (unknown quantity) and modafinil (alertecs 100 mg daily; Shire Canada Inc., Saint-Laurent, QC), for MS-related fatigue (unlicensed indication). The patient had been on modafinil for 4 years with no other adverse reactions reported. She was negative for hepatitis viruses A, B and C and denied any substance abuse, with the exception of tobacco cigarettes (unknown quantity per day). She reported occasional alcohol intake when she would consume 1–2 beers (3–4 units of alcohol) on a given day. A liver biopsy was not considered clinically justifiable, in part due to normalization of liver biochemistry, although an
abdominal ultrasound performed 3 months following drug discontinuation demonstrated mild fatty infiltration of the liver, with no calculi, obstruction or focal hepatic abnormalities. Her medical history was negative for acute liver injury and no family history of liver disease was found. To date, the patient has not been re-challenged with IFN-b-1a. Two doses of ursodiol (Ursos 500 mg BID; Aptalis Pharma Canada Inc., Mont-Saint-Hilaire, QC) for primary biliary cirrhosis (PBC) were given, but ursodiol was not continued because of stabilizing liver biochemistry. As of 7 months after stopping IFN-b-1a, the patient remains positive for anti-mitochondrial antibody and ANA, with liver biochemistry also normal, except for a mild increase in serum gamma-glutamyltransferase (GGT) at 80 U/L (No55 U/L).
2.
Discussion
The use of IFN-b in MS is associated with autoimmune hepatitis (Durelli et al., 1998; Pulicken et al., 2006; Grieco et al., 2007), hepatotoxicity (Tremlett et al., 2004) and fulminant liver failure (Yoshida et al., 2001) and can occur years into treatment (Grieco et al., 2007). The use of IFN-b for MS has not been associated with unmasking PBC or precipitating de novo antimitochondrial antibodies (the classic serologic marker of PBC). We describe a case with features of autoimmune liver disease occurring during treatment with IFN-b for MS, presumably exposing preexisting, but clinically silent PBC. The strong presence of antimitochondrial antibodies are suggestive of PBC (Muratori et al., 2003, 2008), while the antinuclear antibody along with ALT and AST elevations were consistent with autoimmune hepatitis (Mieli-Vergani and Vergani, 2011). In the absence of a liver biopsy, which could not be justified on clinical grounds, or any remarkable elevations in ALP, the accepted criteria of PBC-autoimmune hepatitis overlap syndrome are not fulfilled (Chazouilleres et al., 1998),
Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta although the suggestion is of PBC with features of autoimmune hepatitis (Boberg et al., 2011). Similar to the development of MS, PBC and autoimmune hepatitis are thought to begin once a genetically susceptible individual encounters an unknown environmental trigger (Bhandari et al., 2011; Mieli-Vergani and Vergani, 2011); for this patient, the trigger may have been long-term exposure to IFN-b. Although no HLA typing was performed on this patient, therefore conclusions on the patients’ genetic predisposition to PBC cannot be made (Invernizzi et al., 2012). The exact mechanism behind the induction of autoimmunity by IFN-b in MS patients is unknown (Durelli et al., 1998; Pulicken et al., 2006). PBC may have remained subclinical, although fatigue was present in this patient, which, in hindsight could have also been related to PBC (Bhandari et al., 2011). The long-term use of IFN-b may have aggravated the presumed pre-existing PBC, triggering the elevations in ALT and AST, appearing as autoimmune hepatitis. Other potential causes of the patients’ elevated liver enzymes include consumption of acetaminophen and alcohol. However, the AST/ALT ratio is typically much higher in cases of alcoholic liver damage (Hannuksela et al., 2007) and neither the history of alcohol nor acetaminophen consumption appeared significant enough to account for the degree of liver biochemical derangement or the presence of autoantibodies. In conclusion, this case suggests IFN-b-related liver toxicity may occur years into treatment (apparently without any overt worrisome signs or symptoms) and further exhibits the importance of monitoring biochemical liver test results. The recommended frequency of testing varies, with some recommending baseline screening, followed by monthly tests for the first 6 months, then 6 monthly thereafter during IFN-b treatment (Health Canada, 2003).
Conflict of interest Mrs. Kowalec reports no conflicts of interest. Funding for Mrs. Kowalec was provided by the Canadian Institutes of Health Research (CIHR) and the University of British Columbia. Dr. Yoshida: reports no conflicts of interest in regards to this work. Dr. Traboulsee: Data safety monitoring board membership (Merck Serono), steering committee membership (Roche) and speaker honoraria (Biogen Idec, Bayer Pharmaceuticals, Teva Neuroscience, EMD Serono, Sanofi Genzyme). Dr. Carleton: reports no conflicts of interest in regards to this work. Dr. Tremlett: is funded by the Multiple Sclerosis Society of Canada (Don Paty Career Development Award), Michael Smith Foundation for Health Research and is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received: research support from the US National Multiple Sclerosis Society, CIHR, and UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres, US National MS Society,
59
the University of British Columbia Multiple Sclerosis Research Program, Bayer Pharmaceutical (speaker, 2010, honoraria declined), Teva Pharmaceuticals (speaker 2011), ECTRIMS (2011), UK MS Trust and the Chesapeake Health Education Program, US Veterans Affairs (2012, honorarium declined). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group.
References Bhandari BM, Bayat H, Rothstein KD. Primary biliary cirrhosis. Gastroenterology Clinics of North America 2011;40:373–86. Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. Journal of Hepatology 2011;54:374–85. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998;28:296–301. Durelli L, Bongioanni MR, Ferrero B, Oggero A, Marzano A, Rizzetto M. Interferon treatment for multiple sclerosis: autoimmune complications may be lethal. Neurology 1998;50:570–1. Grieco A, Montalto M, Vero V, Maria Vecchio F, Gasbarrini G. Severe acute hepatitis after resumption of interferon-beta therapy for multiple sclerosis: a word of caution. American Journal of Gastroenterology 2007;102:2606–7. Hannuksela ML, Liisanantti MK, Nissinen AE, Savolainen MJ. Biochemical markers of alcoholism. Clinical Chemistry and Laboratory Medicine 2007;45:953–61. Health Canada. Hepatic injury associated with beta-interferon treatment for multiple sclerosis. Retrieved January 1, 2003 from /http://www.hc-sc.gc.ca/dhp-mps/medeff/advisoriesavis/prof/_2003/beta_interferon_hpc-cps-eng.phpS. Invernizzi P, Ransom M, Raychaudhuri S, Kosoy R, Lleo A, Shigeta R, et al. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis. Genes and Immunity 2012, http://dx.doi.org/10.1038/gene.2012.17. Mieli-Vergani G, Vergani D. Autoimmune hepatitis. Nature Reviews Gastroenterology and Hepatology 2011;8:320–9. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. American Journal of Gastroenterology 2003;98:431–7. Muratori L, Granito A, Muratori P, Pappas G, Bianchi FP. Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clinics in Liver Disease 2008;12:261–76. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology 1983;13:227–31. Pulicken M, Koteish A, DeBusk K, Calabresi PA. Unmasking of autoimmune hepatitis in a patient with MS following interferon beta therapy. Neurology 2006;66:1954–5. Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between the three products. Neurology 2004;62:628–31. Yoshida EM, Rasmussen SL, Steinbrecher UP, Erb SR, Scudamore CH, Chung SW, et al. Fulminant liver failure during interferon beta treatment of multiple sclerosis. Neurology 2001;56:1416.
