AST/platelet ratio index associates with progression to hepatic failure and correlates with histological fibrosis stage in Japanese patients with primary biliary cirrhosis
Authors: Satoru Joshita, Takeji Umemura, Masao Ota, Eiji Tanaka
Journal: Journal of Hepatology (2014)

Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid responseJournal of HepatologyVol. 60Issue 6PreviewOutcomes in primary biliary cirrhosis (PBC) can be predicted by biochemical response to ursodeoxycholic acid (UDCA). Such stratification inadequately captures cirrhosis/portal hypertension, recognised factors associated with adverse events. Full-Text PDF Reply to: "AST/platelet ratio index associates with progression to hepatic failure and correlates with histological fibrosis stage in Japanese patients with primary biliary cirrhosis"Journal of HepatologyVol. 61Issue 6PreviewWe read with interest the letter by Joshita and colleagues regarding our original article [1]. In taking the time to present their important Japanese data [2], the authors provide further independent validation of the AST/platelet ratio (APRI) in the risk stratification of patients with primary biliary cirrhosis (PBC). As the authors surmise, the demography of our cohorts was varied but was not representative of all populations globally, and the robustness of any observation – even if simple and low cost as in this case – is in validation more so than in discovery. Full-Text PDF Open Access We read with great interest the study by Trivedi, Bruns and colleagues [[1]Trivedi P.J. Bruns T. Cheung A. Li K.K. Kittler C. Kumagi T. et al.Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.J Hepatol. 2014; 60: 1249-1258Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] on the association between the AST/platelet ratio index (APRI) and long-term transplant-free survival in patients with primary biliary cirrhosis (PBC). The authors demonstrated that elevated APRI (>0.54) at diagnosis and/or 1 year afterward (APRI-1y) was significantly associated with a future risk of adverse events independently and additively of the ursodeoxycholic acid (UDCA) therapy response, using a deviation cohort from the Elizabeth Hospital, Birmingham (UK), and a validation cohort from the Toronto Center for Liver Diseases (Canada) and the Jena University Hospital (Germany). Since APRI is a simple, widely studied, non-invasive, and easily calculated marker of liver disease, it represents a useful tool in clinical practice, especially at outpatient clinics, to assess patient prognosis and help clinicians identify individuals in need of greater care.Although the racial background of the study groups was not described by Trivedi and Bruns [[1]Trivedi P.J. Bruns T. Cheung A. Li K.K. Kittler C. Kumagi T. et al.Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.J Hepatol. 2014; 60: 1249-1258Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar], we presumed that the majority of subjects were Caucasian according to the authors' well known prior studies. Racial background has been linked to the polymorphisms of genes involved in liver disease, which are associated with disease status, prognosis and response to UDCA therapy [2Joshita S. Umemura T. Yoshizawa K. Katsuyama Y. Tanaka E. Nakamura M. et al.Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients.J Hepatol. 2010; 53: 537-541Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 3Poupon R. Ping C. Chretien Y. Corpechot C. Chazouilleres O. Simon T. et al.Genetic factors of susceptibility and of severity in primary biliary cirrhosis.J Hepatol. 2008; 49: 1038-1045Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 4Joshita S. Umemura T. Nakamura M. Katsuyama Y. Shibata S. Kimura T. et al.STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.Dis Markers. 2014; 2014: 8Crossref Scopus (17) Google Scholar]. Therefore, we examined the association between APRI and progression to hepatic failure in Japanese patients with PBC to evaluate whether APRI could be a clinical indicator of disease outcome across multiple ethnicities.A total of 272 patients (230 women, 84.6%) who were diagnosed at the Shinshu University Hospital, Matsumoto, Japan, as having PBC between 1981 and 2012 were analysed in accordance with the principles of the Declaration of Helsinki. The genetic background of all subjects was uniformly Japanese as described in previous association studies [4Joshita S. Umemura T. Nakamura M. Katsuyama Y. Shibata S. Kimura T. et al.STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.Dis Markers. 2014; 2014: 8Crossref Scopus (17) Google Scholar, 5Umemura T. Joshita S. Ichijo T. Yoshizawa K. Katsuyama Y. Tanaka E. et al.Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis.Hepatology. 2012; 55: 506-511Crossref PubMed Scopus (60) Google Scholar]. The median age of our cohort at diagnosis was 58 (range: 28–85) years. The follow-up period ranged from 0.5 to 28 years with a median of 9 years. Anti-mitochondrial antibody (AMA) and anti-nuclear antibody were positive in 256 (94.1%) and 201 (74.0%) of cases, respectively. Liver biopsy was performed in 192 (70.6%) patients, which histologically demonstrated Scheuer's stage I, II, III, and IV in 121, 39, 21, and 11 subjects, respectively. A total of 265 patients (97.4%) were treated with UDCA during the study period. Among them, 205 (77.4%), 42 (15.8%), and 18 (6.8%) patients were given a daily dose of 600 mg (median dose 11.1 mg/kg for a median of 8 years; Paris-I responders: 85.6%, APRI-1y ⩽0.54: 66.7%), 300 mg (median dose 5.8 mg/kg for 9 years; Paris-I responders: 81%, APRI-1y ⩽0.54: 65.0%), and 900 mg (median dose 15.0 mg/kg for 5 years; Paris-I responders: 73.3%, APRI-1y ⩽0.54: 64.3%), respectively, according to the recommended initial dosage of 600 mg in Japan [[6]Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan.Hepatol Res. 2014; 44: 71-90Crossref PubMed Scopus (76) Google Scholar]. 19 patients (7.5%) experienced disease progression to hepatic failure, which was defined as decompensated liver cirrhosis status, including jaundice, encephalopathy, ascites, gastrointestinal bleeding, and/or hepatorenal syndrome. 7 patients (2.6%) were complicated with hepatocellular carcinoma. 4 patients (1.5%) required orthotopic liver transplantation. The 5-, 10-, and 20-year cumulative incidences of hepatic failure were 3.5%, 5.8%, and 12.7%, respectively, after Kaplan-Meier testing. The median value of APRI at diagnosis was 0.55 (range: 0.08–8.58). When applied as a continuous variable predictive of progression to hepatic failure, APRI at diagnosis provided high prognostic accuracy (AUROC: 0.789, 95% confidence interval: 0.742–0.835) (Fig. 1A). We observed that the cumulative incidence of hepatic failure was significantly higher in patients having an APRI of >0.54 by Kaplan-Meier testing (Fig. 1B). These data closely resembled the results of Trivedi et al. that elevated APRI (>0.54) at diagnosis was associated with a risk of disease progression, although our cohort size was insufficient to determine whether APRI or APRI-1y could be independent prognostic markers of a response to UDCA.Liver biopsy in PBC is appropriate for certain patients [[7]EASL Clinical Practice Guidelines Management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar] but not always necessary for diagnosis. Specifically, a biopsy should be considered in patients with atypical clinical presentation, including AMA negativity, as described in EASL, AASLD, and Japanese guidelines [7EASL Clinical Practice Guidelines Management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 8Lindor K.D. Gershwin M.E. Poupon R. Kaplan M. Bergasa N.V. Heathcote E.J. Primary biliary cirrhosis.Hepatology. 2009; 50: 291-308Crossref PubMed Scopus (979) Google Scholar]. However, we routinely perform percutaneous liver biopsy, except in patients who are over 75 years of age, have a short life expectancy due to comorbidities, or have contraindications for a definitive diagnosis and important information on disease stage and prognosis. We assessed the association between APRI and histological stage and uncovered that the numbers of patients with APRI >0.54 in Scheuer's stage I, II, III, and IV were 43 (35.8%), 21 (56.8%), 16 (76.2%), and 10 (100.0%), respectively (p = 6.85 × 10−5, Fisher's exact test). Furthermore, APRI positively correlated with histological disease progression (rs = 0.403, p = 1.01 × 10−8, Spearman's rank correlation coefficient test) (Fig. 1C).In conclusion, our findings agree closely with those of Trivedi et al. [[1]Trivedi P.J. Bruns T. Cheung A. Li K.K. Kittler C. Kumagi T. et al.Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.J Hepatol. 2014; 60: 1249-1258Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] and strengthen the postulate that elevated APRI is associated with an increased risk of disease progression in PBC. We additionally revealed that APRI was related to histological progression in liver biopsy specimens. APRI appears to be a useful tool in the clinical assessment of patients with PBC in multiple ethnicities.Conflict of interestThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We read with great interest the study by Trivedi, Bruns and colleagues [[1]Trivedi P.J. Bruns T. Cheung A. Li K.K. Kittler C. Kumagi T. et al.Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.J Hepatol. 2014; 60: 1249-1258Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] on the association between the AST/platelet ratio index (APRI) and long-term transplant-free survival in patients with primary biliary cirrhosis (PBC). The authors demonstrated that elevated APRI (>0.54) at diagnosis and/or 1 year afterward (APRI-1y) was significantly associated with a future risk of adverse events independently and additively of the ursodeoxycholic acid (UDCA) therapy response, using a deviation cohort from the Elizabeth Hospital, Birmingham (UK), and a validation cohort from the Toronto Center for Liver Diseases (Canada) and the Jena University Hospital (Germany). Since APRI is a simple, widely studied, non-invasive, and easily calculated marker of liver disease, it represents a useful tool in clinical practice, especially at outpatient clinics, to assess patient prognosis and help clinicians identify individuals in need of greater care. Although the racial background of the study groups was not described by Trivedi and Bruns [[1]Trivedi P.J. Bruns T. Cheung A. Li K.K. Kittler C. Kumagi T. et al.Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.J Hepatol. 2014; 60: 1249-1258Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar], we presumed that the majority of subjects were Caucasian according to the authors' well known prior studies. Racial background has been linked to the polymorphisms of genes involved in liver disease, which are associated with disease status, prognosis and response to UDCA therapy [2Joshita S. Umemura T. Yoshizawa K. Katsuyama Y. Tanaka E. Nakamura M. et al.Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients.J Hepatol. 2010; 53: 537-541Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 3Poupon R. Ping C. Chretien Y. Corpechot C. Chazouilleres O. Simon T. et al.Genetic factors of susceptibility and of severity in primary biliary cirrhosis.J Hepatol. 2008; 49: 1038-1045Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 4Joshita S. Umemura T. Nakamura M. Katsuyama Y. Shibata S. Kimura T. et al.STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.Dis Markers. 2014; 2014: 8Crossref Scopus (17) Google Scholar]. Therefore, we examined the association between APRI and progression to hepatic failure in Japanese patients with PBC to evaluate whether APRI could be a clinical indicator of disease outcome across multiple ethnicities. A total of 272 patients (230 women, 84.6%) who were diagnosed at the Shinshu University Hospital, Matsumoto, Japan, as having PBC between 1981 and 2012 were analysed in accordance with the principles of the Declaration of Helsinki. The genetic background of all subjects was uniformly Japanese as described in previous association studies [4Joshita S. Umemura T. Nakamura M. Katsuyama Y. Shibata S. Kimura T. et al.STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.Dis Markers. 2014; 2014: 8Crossref Scopus (17) Google Scholar, 5Umemura T. Joshita S. Ichijo T. Yoshizawa K. Katsuyama Y. Tanaka E. et al.Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis.Hepatology. 2012; 55: 506-511Crossref PubMed Scopus (60) Google Scholar]. The median age of our cohort at diagnosis was 58 (range: 28–85) years. The follow-up period ranged from 0.5 to 28 years with a median of 9 years. Anti-mitochondrial antibody (AMA) and anti-nuclear antibody were positive in 256 (94.1%) and 201 (74.0%) of cases, respectively. Liver biopsy was performed in 192 (70.6%) patients, which histologically demonstrated Scheuer's stage I, II, III, and IV in 121, 39, 21, and 11 subjects, respectively. A total of 265 patients (97.4%) were treated with UDCA during the study period. Among them, 205 (77.4%), 42 (15.8%), and 18 (6.8%) patients were given a daily dose of 600 mg (median dose 11.1 mg/kg for a median of 8 years; Paris-I responders: 85.6%, APRI-1y ⩽0.54: 66.7%), 300 mg (median dose 5.8 mg/kg for 9 years; Paris-I responders: 81%, APRI-1y ⩽0.54: 65.0%), and 900 mg (median dose 15.0 mg/kg for 5 years; Paris-I responders: 73.3%, APRI-1y ⩽0.54: 64.3%), respectively, according to the recommended initial dosage of 600 mg in Japan [[6]Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan.Hepatol Res. 2014; 44: 71-90Crossref PubMed Scopus (76) Google Scholar]. 19 patients (7.5%) experienced disease progression to hepatic failure, which was defined as decompensated liver cirrhosis status, including jaundice, encephalopathy, ascites, gastrointestinal bleeding, and/or hepatorenal syndrome. 7 patients (2.6%) were complicated with hepatocellular carcinoma. 4 patients (1.5%) required orthotopic liver transplantation. The 5-, 10-, and 20-year cumulative incidences of hepatic failure were 3.5%, 5.8%, and 12.7%, respectively, after Kaplan-Meier testing. The median value of APRI at diagnosis was 0.55 (range: 0.08–8.58). When applied as a continuous variable predictive of progression to hepatic failure, APRI at diagnosis provided high prognostic accuracy (AUROC: 0.789, 95% confidence interval: 0.742–0.835) (Fig. 1A). We observed that the cumulative incidence of hepatic failure was significantly higher in patients having an APRI of >0.54 by Kaplan-Meier testing (Fig. 1B). These data closely resembled the results of Trivedi et al. that elevated APRI (>0.54) at diagnosis was associated with a risk of disease progression, although our cohort size was insufficient to determine whether APRI or APRI-1y could be independent prognostic markers of a response to UDCA. Liver biopsy in PBC is appropriate for certain patients [[7]EASL Clinical Practice Guidelines Management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar] but not always necessary for diagnosis. Specifically, a biopsy should be considered in patients with atypical clinical presentation, including AMA negativity, as described in EASL, AASLD, and Japanese guidelines [7EASL Clinical Practice Guidelines Management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 8Lindor K.D. Gershwin M.E. Poupon R. Kaplan M. Bergasa N.V. Heathcote E.J. Primary biliary cirrhosis.Hepatology. 2009; 50: 291-308Crossref PubMed Scopus (979) Google Scholar]. However, we routinely perform percutaneous liver biopsy, except in patients who are over 75 years of age, have a short life expectancy due to comorbidities, or have contraindications for a definitive diagnosis and important information on disease stage and prognosis. We assessed the association between APRI and histological stage and uncovered that the numbers of patients with APRI >0.54 in Scheuer's stage I, II, III, and IV were 43 (35.8%), 21 (56.8%), 16 (76.2%), and 10 (100.0%), respectively (p = 6.85 × 10−5, Fisher's exact test). Furthermore, APRI positively correlated with histological disease progression (rs = 0.403, p = 1.01 × 10−8, Spearman's rank correlation coefficient test) (Fig. 1C). In conclusion, our findings agree closely with those of Trivedi et al. [[1]Trivedi P.J. Bruns T. Cheung A. Li K.K. Kittler C. Kumagi T. et al.Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.J Hepatol. 2014; 60: 1249-1258Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] and strengthen the postulate that elevated APRI is associated with an increased risk of disease progression in PBC. We additionally revealed that APRI was related to histological progression in liver biopsy specimens. APRI appears to be a useful tool in the clinical assessment of patients with PBC in multiple ethnicities. Conflict of interestThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.