Research Original Investigation
Transient Elastography and FibroTest Monitoring
20. Bray AP, Barnova I, Przemioslo R, Kennedy CT. Liver fibrosis screening for patients with psoriasis taking methotrexate: a cross-sectional study comparing transient elastography and liver biopsy. Br J Dermatol. 2012;166(5):1125-1127. 21. Leonard O, Woolf R, Jiyad Z, Martyn-Simmons CL, Barker JNWN, Smith CH. Risk factors for liver fibrosis in patients with severe psoriasis established on methotrexate: a cross-sectional cohort study. Br J Dermatol. 2012;167(suppl 1):68. 22. Laharie D, Seneschal J, Schaeverbeke T, et al. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study. J Hepatol. 2010;53(6): 1035-1040. 23. Barbero-Villares A, Mendoza J, Trapero-Marugan M, et al. Evaluation of liver fibrosis by transient elastography in methotrexate treated patients. Med Clin (Barc). 2011;137(14): 637-639.
individuals: role of antiretroviral drugs and insulin resistance. J Viral Hepat. 2011;18(1):11-16. 30. Poynard T, Zoulim F, Ratziu V, et al. Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection. Am J Gastroenterol. 2005;100(9): 1970-1980. 31. Fraquelli M, Rigamonti C, Casazza G, et al. Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C. J Hepatol. 2011;54(4):621-628. 32. Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. Ann Intern Med. 2013; 158(9):658-666. 33. Masuzaki R, Tateishi R, Yoshida H, et al. Risk assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. J Clin Gastroenterol. 2008;42(7):839-843.
24. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2010;51 (3):828-835.
34. de Lédinghen V, Barreiro P, Foucher J, et al. Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy. J Viral Hepat. 2008;15(6):427-433.
25. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41(1):48-54.
35. de Lédinghen V, Vergniol J, Gonzalez C, et al. Screening for liver fibrosis by using FibroScan and FibroTest in patients with diabetes. Dig Liver Dis. 2012;44(5):413-418.
26. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. doi:10.1186 /1476-5926-3-8.
36. Petit JM, Guiu B, Masson D, et al. PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes. Liver Int. 2011;31(9):1332-1336.
27. Montaudié H, Sbidian E, Paul C, et al. Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol. 2011;25(suppl 2):12-18.
37. Poynard T, Lebray P, Ingiliz P, et al. Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest). BMC Gastroenterol. 2010;10:40. doi:10.1186/1471-230X-10-40.
28. Suárez-Zarracina T, Valle-Garay E, Collazos J, et al. Didanosine (ddI) associates with increased liver fibrosis in adult HIV-HCV coinfected patients. J Viral Hepat. 2012;19(10):685-693.
38. Zelber-Sagi S, Ratziu V, Zvibel I, et al. The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease–induced liver injury: a study in the general population. Eur J Gastroenterol Hepatol. 2012;24 (3):262-269.
29. Blanco F, Barreiro P, Ryan P, et al. Risk factors for advanced liver fibrosis in HIV-infected
39. Sirli R, Sporea I, Tudora A, Deleanu A, Popescu A. Transient elastographic evaluation of subjects
without known hepatic pathology: does age change the liver stiffness? J Gastrointestin Liver Dis. 2009; 18(1):57-60. 40. Salles N, Dussarat P, Foucher J, Villars S, de Lédinghen V. Non-invasive evaluation of liver fibrosis by transient elastography and biochemical markers in elderly inpatients. Gastroenterol Clin Biol. 2009;33(2):126-132. 41. Poynard T, Ingiliz P, Elkrief L, et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers. PLoS One. 2008;3(12):e3857. doi:10.1371/journal.pone.0003857. 42. Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51(4): 758-764. 43. Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexateinduced liver injury. J Gastroenterol Hepatol. 2001; 16(12):1395-1401. 44. Anastasiou J, Alisa A, Virtue S, Portmann B, Murray-Lyon I, Williams R. Noninvasive markers of fibrosis and inflammation in clinical practice: prospective comparison with liver biopsy. Eur J Gastroenterol Hepatol. 2010;22(4):474-480. 45. Boffa MJ, Smith A, Chalmers RJ, et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol. 1996;135(4):538-544. 46. Halfon P, Munteanu M, Poynard T. FibroTest-ActiTest as a non-invasive marker of liver fibrosis. Gastroenterol Clin Biol. 2008;32(6)(suppl 1):22-39. 47. Poynard T, Morra R, Ingiliz P, et al. Biomarkers of liver fibrosis. Adv Clin Chem. 2008;46:131-160. 48. Teare JP, Sherman D, Greenfield SM, et al. Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis. Lancet. 1993;342(8876):895-898.
Invited Commentary PRACTICE GAPS
Methotrexate-Induced Liver Toxicity Replacing the Liver Biopsy Bruce E. Strober, MD, PhD
Methotrexate-induced hepatotoxicity in patients with psoriasis occurs rarely and unpredictably. Although liver monitoring must occur, dermatologists currently lack a reliable test. Unfortunately, many of the current recommendations for the monitoring of patients with psoriasis are poorly substantiated by rigorous data. For example, cumulative methotrexate dosage appears to be irrelevant. In addition, the liver biopsy, considered the criterion standard, suffers from sampling er862
ror, intraobserver and interobserver variability, and procedural pain and morbidity, making it a poor test. Most relevant, approximately 50% of patients with moderate to severe psoriasis have nonalcoholic fatty liver disease,1 a condition that displays histopathologic features indistinguishable from those associated with methotrexate-induced toxicity. Therefore, the liver biopsy cannot distinguish between drug-induced and disease-associated liver disease. Furthermore, with increasing age,
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 05/28/2015
jamadermatology.com
Transient Elastography and FibroTest Monitoring
Original Investigation Research
patients with psoriasis are at increased risk for nonalcoholic fatty liver disease; thus, long-term therapy with methotrexate with signs demonstrating steatosis or fibrosis might represent the natural aging of the psoriatic liver. SummarRelated article page 856 ily, the additive toxicity of methotrexate on the inherently unhealthy psoriatic liver remains uncertain, and our understanding of liver risk is based on studies that are poorly controlled—devoid of large comparator groups of patients with psoriasis who are not receiving methotrexate. Dermatologists should seek noninvasive tests to replace the liver biopsy. Because nonalcoholic fatty liver disease also is the most common cause of elevated hepatic enzymes, serial measurements of the enzymes may be nonspecific. In Europe, serial procollagen III peptide levels often are measured during therapy, with consistent elevation necessitating liver biopsy. As a sole test, procollagen III peptide is inadequate for many patients because it lacks specificity (elevated in patients with psoriatic arthritis) and has limited worldwide availability. Alternatively, FibroTest (FibroSURE in the United States) is an evaluation of 5 serum markers (α2-macroglobulin, haptoglobin, apolipoprotein A-I, γ-glutamyltranspeptidase, and total bilirubin) and has been extensively studied in many hepatotoxic conditions. The values of each marker translate into a composite score that correlates with the presence and degree ARTICLE INFORMATION Author Affiliations: Department of Dermatology, University of Connecticut Health Center, Farmington; Probity Medical Research, Waterloo, Ontario, Canada. Corresponding Author: Bruce E. Strober, MD, PhD, Department of Dermatology, University of Connecticut Health Center, 21 South Rd, Second Floor, Farmington, CT 06032 ([email protected]). Published Online: June 25, 2014. doi:10.1001/jamadermatol.2014.681. Conflict of Interest Disclosures: Dr Strober reports serving on speakers’ bureaus for AbbVie; being a
of hepatic fibrosis. Although attractive in its simplicity, FibroTest has low sensitivity. In addition, only validated laboratories can perform FibroTest. Transient elastography (TE or FibroScan) is a noninvasive medical imaging modality that measures liver parenchymal stiffness. It has low interobserver variability and, without adverse effects, is able to evaluate a much larger amount of tissue than the liver biopsy. Transient elastography shows acceptable specificity and, depending on the study, variable sensitivity. Unfortunately, obesity, a common feature of patients with psoriasis, often renders TE either unreliable or impossible. Furthermore, widespread availability of TE is limited. Concordant with most other medical specialties, dermatology should abandon the liver biopsy. However, in the same patient, the results of noninvasive tests with regard to fibrosis detection may often disagree.2 For this reason, no test should stand alone.3 Instead, currently available noninvasive measures need to be used in combination and studied as such in large, prospective, well-controlled studies of patients with psoriasis. Moreover, static assessments of liver abnormalities have little meaning. Therefore, reliable monitoring should rest on changes that occur from baseline to present status. In their evaluation of any noninvasive test, future studies must determine the relevant magnitude in change from baseline that dictates both methotrexate discontinuation and subsequent therapeutic switch.
consultant for AbbVie, Amgen, Celgene, Dermira, Janssen, Leo, Lilly, Maruho, Medac, Merck, Novartis, Pfizer, Stiefel/GlaxoSmithKline, and UCB; being an investigator for AbbVie, Amgen, Novartis, Lilly, Janssen, and Merck; and having obtained grant support to the University of Connecticut for fellowship programs from AbbVie and Janssen. REFERENCES 1. van der Voort EA, Koehler EM, Dowlatshahi EA, et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: results from a population-based study. J Am Acad Dermatol. 2014;70(3):517-524.
jamadermatology.com
2. Lynch M, Higgins E, McCormick PA, et al. The use of transient elastography and FibroTest for monitoring hepatotoxicity in patients receiving methotrexate for psoriasis [published online June 25, 2014]. JAMA Dermatol. doi:10.1001 /jamadermatol.2013.9336. 3. Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. Diagnostic accuracy of non-invasive markers of liver fibrosis in patients with psoriasis taking methotrexate: a systematic review and meta-analysis [published online March 4, 2014]. Br J Dermatol. doi:10.1111/bjd.12905.
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 05/28/2015
863
Transient Elastography and FibroTest Monitoring
20. Bray AP, Barnova I, Przemioslo R, Kennedy CT. Liver fibrosis screening for patients with psoriasis taking methotrexate: a cross-sectional study comparing transient elastography and liver biopsy. Br J Dermatol. 2012;166(5):1125-1127. 21. Leonard O, Woolf R, Jiyad Z, Martyn-Simmons CL, Barker JNWN, Smith CH. Risk factors for liver fibrosis in patients with severe psoriasis established on methotrexate: a cross-sectional cohort study. Br J Dermatol. 2012;167(suppl 1):68. 22. Laharie D, Seneschal J, Schaeverbeke T, et al. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study. J Hepatol. 2010;53(6): 1035-1040. 23. Barbero-Villares A, Mendoza J, Trapero-Marugan M, et al. Evaluation of liver fibrosis by transient elastography in methotrexate treated patients. Med Clin (Barc). 2011;137(14): 637-639.
individuals: role of antiretroviral drugs and insulin resistance. J Viral Hepat. 2011;18(1):11-16. 30. Poynard T, Zoulim F, Ratziu V, et al. Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection. Am J Gastroenterol. 2005;100(9): 1970-1980. 31. Fraquelli M, Rigamonti C, Casazza G, et al. Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C. J Hepatol. 2011;54(4):621-628. 32. Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. Ann Intern Med. 2013; 158(9):658-666. 33. Masuzaki R, Tateishi R, Yoshida H, et al. Risk assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. J Clin Gastroenterol. 2008;42(7):839-843.
24. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2010;51 (3):828-835.
34. de Lédinghen V, Barreiro P, Foucher J, et al. Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy. J Viral Hepat. 2008;15(6):427-433.
25. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41(1):48-54.
35. de Lédinghen V, Vergniol J, Gonzalez C, et al. Screening for liver fibrosis by using FibroScan and FibroTest in patients with diabetes. Dig Liver Dis. 2012;44(5):413-418.
26. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. doi:10.1186 /1476-5926-3-8.
36. Petit JM, Guiu B, Masson D, et al. PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes. Liver Int. 2011;31(9):1332-1336.
27. Montaudié H, Sbidian E, Paul C, et al. Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol. 2011;25(suppl 2):12-18.
37. Poynard T, Lebray P, Ingiliz P, et al. Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest). BMC Gastroenterol. 2010;10:40. doi:10.1186/1471-230X-10-40.
28. Suárez-Zarracina T, Valle-Garay E, Collazos J, et al. Didanosine (ddI) associates with increased liver fibrosis in adult HIV-HCV coinfected patients. J Viral Hepat. 2012;19(10):685-693.
38. Zelber-Sagi S, Ratziu V, Zvibel I, et al. The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease–induced liver injury: a study in the general population. Eur J Gastroenterol Hepatol. 2012;24 (3):262-269.
29. Blanco F, Barreiro P, Ryan P, et al. Risk factors for advanced liver fibrosis in HIV-infected
39. Sirli R, Sporea I, Tudora A, Deleanu A, Popescu A. Transient elastographic evaluation of subjects
without known hepatic pathology: does age change the liver stiffness? J Gastrointestin Liver Dis. 2009; 18(1):57-60. 40. Salles N, Dussarat P, Foucher J, Villars S, de Lédinghen V. Non-invasive evaluation of liver fibrosis by transient elastography and biochemical markers in elderly inpatients. Gastroenterol Clin Biol. 2009;33(2):126-132. 41. Poynard T, Ingiliz P, Elkrief L, et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers. PLoS One. 2008;3(12):e3857. doi:10.1371/journal.pone.0003857. 42. Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51(4): 758-764. 43. Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexateinduced liver injury. J Gastroenterol Hepatol. 2001; 16(12):1395-1401. 44. Anastasiou J, Alisa A, Virtue S, Portmann B, Murray-Lyon I, Williams R. Noninvasive markers of fibrosis and inflammation in clinical practice: prospective comparison with liver biopsy. Eur J Gastroenterol Hepatol. 2010;22(4):474-480. 45. Boffa MJ, Smith A, Chalmers RJ, et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol. 1996;135(4):538-544. 46. Halfon P, Munteanu M, Poynard T. FibroTest-ActiTest as a non-invasive marker of liver fibrosis. Gastroenterol Clin Biol. 2008;32(6)(suppl 1):22-39. 47. Poynard T, Morra R, Ingiliz P, et al. Biomarkers of liver fibrosis. Adv Clin Chem. 2008;46:131-160. 48. Teare JP, Sherman D, Greenfield SM, et al. Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis. Lancet. 1993;342(8876):895-898.
Invited Commentary PRACTICE GAPS
Methotrexate-Induced Liver Toxicity Replacing the Liver Biopsy Bruce E. Strober, MD, PhD
Methotrexate-induced hepatotoxicity in patients with psoriasis occurs rarely and unpredictably. Although liver monitoring must occur, dermatologists currently lack a reliable test. Unfortunately, many of the current recommendations for the monitoring of patients with psoriasis are poorly substantiated by rigorous data. For example, cumulative methotrexate dosage appears to be irrelevant. In addition, the liver biopsy, considered the criterion standard, suffers from sampling er862
ror, intraobserver and interobserver variability, and procedural pain and morbidity, making it a poor test. Most relevant, approximately 50% of patients with moderate to severe psoriasis have nonalcoholic fatty liver disease,1 a condition that displays histopathologic features indistinguishable from those associated with methotrexate-induced toxicity. Therefore, the liver biopsy cannot distinguish between drug-induced and disease-associated liver disease. Furthermore, with increasing age,
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 05/28/2015
jamadermatology.com
Transient Elastography and FibroTest Monitoring
Original Investigation Research
patients with psoriasis are at increased risk for nonalcoholic fatty liver disease; thus, long-term therapy with methotrexate with signs demonstrating steatosis or fibrosis might represent the natural aging of the psoriatic liver. SummarRelated article page 856 ily, the additive toxicity of methotrexate on the inherently unhealthy psoriatic liver remains uncertain, and our understanding of liver risk is based on studies that are poorly controlled—devoid of large comparator groups of patients with psoriasis who are not receiving methotrexate. Dermatologists should seek noninvasive tests to replace the liver biopsy. Because nonalcoholic fatty liver disease also is the most common cause of elevated hepatic enzymes, serial measurements of the enzymes may be nonspecific. In Europe, serial procollagen III peptide levels often are measured during therapy, with consistent elevation necessitating liver biopsy. As a sole test, procollagen III peptide is inadequate for many patients because it lacks specificity (elevated in patients with psoriatic arthritis) and has limited worldwide availability. Alternatively, FibroTest (FibroSURE in the United States) is an evaluation of 5 serum markers (α2-macroglobulin, haptoglobin, apolipoprotein A-I, γ-glutamyltranspeptidase, and total bilirubin) and has been extensively studied in many hepatotoxic conditions. The values of each marker translate into a composite score that correlates with the presence and degree ARTICLE INFORMATION Author Affiliations: Department of Dermatology, University of Connecticut Health Center, Farmington; Probity Medical Research, Waterloo, Ontario, Canada. Corresponding Author: Bruce E. Strober, MD, PhD, Department of Dermatology, University of Connecticut Health Center, 21 South Rd, Second Floor, Farmington, CT 06032 ([email protected]). Published Online: June 25, 2014. doi:10.1001/jamadermatol.2014.681. Conflict of Interest Disclosures: Dr Strober reports serving on speakers’ bureaus for AbbVie; being a
of hepatic fibrosis. Although attractive in its simplicity, FibroTest has low sensitivity. In addition, only validated laboratories can perform FibroTest. Transient elastography (TE or FibroScan) is a noninvasive medical imaging modality that measures liver parenchymal stiffness. It has low interobserver variability and, without adverse effects, is able to evaluate a much larger amount of tissue than the liver biopsy. Transient elastography shows acceptable specificity and, depending on the study, variable sensitivity. Unfortunately, obesity, a common feature of patients with psoriasis, often renders TE either unreliable or impossible. Furthermore, widespread availability of TE is limited. Concordant with most other medical specialties, dermatology should abandon the liver biopsy. However, in the same patient, the results of noninvasive tests with regard to fibrosis detection may often disagree.2 For this reason, no test should stand alone.3 Instead, currently available noninvasive measures need to be used in combination and studied as such in large, prospective, well-controlled studies of patients with psoriasis. Moreover, static assessments of liver abnormalities have little meaning. Therefore, reliable monitoring should rest on changes that occur from baseline to present status. In their evaluation of any noninvasive test, future studies must determine the relevant magnitude in change from baseline that dictates both methotrexate discontinuation and subsequent therapeutic switch.
consultant for AbbVie, Amgen, Celgene, Dermira, Janssen, Leo, Lilly, Maruho, Medac, Merck, Novartis, Pfizer, Stiefel/GlaxoSmithKline, and UCB; being an investigator for AbbVie, Amgen, Novartis, Lilly, Janssen, and Merck; and having obtained grant support to the University of Connecticut for fellowship programs from AbbVie and Janssen. REFERENCES 1. van der Voort EA, Koehler EM, Dowlatshahi EA, et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: results from a population-based study. J Am Acad Dermatol. 2014;70(3):517-524.
jamadermatology.com
2. Lynch M, Higgins E, McCormick PA, et al. The use of transient elastography and FibroTest for monitoring hepatotoxicity in patients receiving methotrexate for psoriasis [published online June 25, 2014]. JAMA Dermatol. doi:10.1001 /jamadermatol.2013.9336. 3. Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. Diagnostic accuracy of non-invasive markers of liver fibrosis in patients with psoriasis taking methotrexate: a systematic review and meta-analysis [published online March 4, 2014]. Br J Dermatol. doi:10.1111/bjd.12905.
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 05/28/2015
863
