Zhao et al.
recent knowledge in pathogenesis and overview of clinical assessment. Liver Int 2015; 35: 1646–60. 2. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology (Baltimore, MD) 2014; 59: 1627–37. 3. Abrams GA, Jaffe CC, Hoffer PB, Binder HJ, Fallon MB. Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome. Gastroenterology 1995; 109: 1283–8.
Letters to the Editor
4. Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology 1998; 114: 305–10. 5. Krowka MJ, Wiseman GA, Burnett OL, et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99 m)Tc MAA lung scanning. Chest 2000; 118: 615–24.
DOI:10.1111/liv.12821 Liver Int. 2015; 35: 1919–1920
Response to ‘The role of macroaggregated albumin lung perfusion scan in hepatopulmonary syndrome: are we ready to draw conclusions?’ To the Editor: We appreciate the comments of Zhao et al. (1) on the topic of the current use of technetium 99 mlabelled macroaggregated albumin (MAA) lung scan for detecting intrapulmonary vascular dilations (IPVDs) as a criterion for detecting hepatopulmonary syndrome (HPS). As mentioned in our review (2), the presence of IPVDs is documented either on microbubble transthoracic echocardiography (MTTE) or MAA scan. Clinical recommendations on screening for HPS were mainly based on the European Respiratory Society Task Force guideline (3). MTTE has always been considered the gold standard for detecting HPS based on clinical studies. Important advantages include (i) its high sensitivity to detect IPVDs; (ii) its possibility to distinguish intrapulmonary from intracardiac shunting and (iii) the additional possibility of screening for portopulmonary hypertension (2–4). On the other hand, HPS can be diagnosed and the degree of shunting can even be quantified on MAA scan (2–4). However, this technique cannot distinguish between intrapulmonary and intracardiac shunting, and has been proven to be associated with lower sensitivity (3). Accordingly, the severity of HPS based on PaO2 is negatively correlated with the degree of brain uptake during MAA scan, as was nicely illustrated in figure 1 by Zhao et al. (1), by summarizing the patient data of earlier performed studies by Abrams et al. and Krowka et al. Indeed, patients with mild-tomoderate hypoxia are those patients with rather small or few IPVDs and shunts, resulting in lower brain uptake. We agree with the comment that the technical aspects of MAA scan lack standardization, which indeed affects its diagnostic accuracy (1). To address this issue, further prospective studies are certainly warranted. However, MAA scan yields important clinical information in specific situations. First, it has to be performed in severe hypoxic patients with underlying intrinsic lung
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
disease and suspected HPS (4). Significant brain uptake on MAA scan provides indirect evidence of HPS contributing to the hypoxic status. Second, MAA scan may offer complementary information to stratify HPS patients at greater risk of post-transplantation mortality (shunt fraction ≥20%) (4). Third, in case of extensive shunting, suggesting large arteriovenous connections, HPS patients should be referred for pulmonary angiography in order to plan coil embolization (4). In summary, current hepatology guidelines recommend microbubble transthoracic echocardiography as best screening tool to detect HPS. However, in specific clinical situations MAA scan may offer essential complementary information. Further prospective studies are needed to standardize the MAA scan technique. Acknowledgements
Financial support: Sarah Raevens received a scholarship (FWO14/ASP/200) from the Research Foundation – Flanders (Aspirant mandaat FWO Vlaanderen). Conflict of interest: The authors do not have any disclosures to report.
Sarah Raevens1, Christophe Van Steenkiste1,2 and Isabelle Colle1,3 1 Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium 2 Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium 3 Department of Gastroenterology and Hepatology, Algemeen Stedelijk Ziekenhuis ASZ, Aalst, Belgium
References 1. Zhao H, Tsauo J, Ma HY, Li X. The role of macroaggregated albumin lung perfusion scan in hepatopulmonary
1919
Zhao et al.
Letters to the Editor
syndrome: are we ready to draw conclusions? Liver Int 2015; 35: 1918–19. 2. Raevens S, Geerts A, Van Steenkiste C, et al. Hepatopulmonary syndrome and portopulmonary hypertension: recent knowledge in pathogenesis and overview of clinical assessment. Liver Int 2015; 35: 1646–60.
3. Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004; 24: 861–80. 4. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology 2014; 59: 1627–37.
DOI:10.1111/liv.12815 Liver Int. 2015; 35: 1920–1921
ELF cut-off points: aetiology is also a relevant factor To the Editor: We read with great interest the article published by Fagan et al. (1) entitled ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. In the article, the authors stated that the ELF manufacturer’s cut-off value (≥9.8) reliably identifies individuals with advanced fibrosis within patients with chronic liver diseases and that age and histological activity (HA) may influence its results. However, we think that there are some points to discuss about this study. The lack of a consistent ELF’s cut-off value throughout the various studies published, so far, has recently been demonstrated (2). We do agree that ELF is a good non invasive marker, but we are not convinced about the cut-off points proposed by the manufacturer. It is well-known that the aetiology of chronic liver disease may interfere in the performance of non invasive methods once fibrosis and HA vary significantly among distinct aetiologies (3). We recently verified that ELF performs well as a non invasive marker for chronic hepatitis C (CHC) patients (4). Unfortunately, this finding cannot be extrapolated to other clinical scenarios, such as hepatitis B or non alcoholic fat liver disease (5). We do think that any evaluation of cut-off points should be performed in populations with a single aetiology. In our CHC population, we also observed that results were influenced by HA, which was more intense among patients with discordant results. It is worth mentioning that HA correlates with aminotransferases levels, which should be considered when interpreting ELF results. Concerning age, we found the same influence in ELF‘s accuracy. However, the finding that 45 years should be considered as ‘increased age’ and a cause for false positive results is a matter of concern since our typical population of exclusively CHC patients had a mean age of 53 ± 11.3 years, and 77% were older than 45 years. If age was not adequately emphasized in the original formula some adjustments might be made so that ELF becomes applicable to CHC population. We are now proposing that new cut-off points should be adopted for ELF in CHC patients, with 9.4 (sensitivity 84% and negative predictive value 93%)
1920
for the detection of advanced fibrosis (6). Interestingly Fagan et al. (1) highlighted the same value as the optimal cut-off point. We are convinced that ELF is a valuable tool in determining advanced fibrosis, but we believe that there is still ground for debating its cut-off points, especially considering aetiology particularities. Acknowledgements
Conflict of interest: The authors do not have any disclosures to report.
Flavia F. Fernandes1,2, Renata M. Perez1,3,4 and Maria L. Ferraz4,5 1 Gastroenterology and Hepatology Department, University of the State of Rio de Janeiro, Rio de Janeiro, Brazil 2 Gastroenterology and Hepatology Department, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil 3 Internal Medicine Department, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil 4 D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil 5 Gastroenterology Department, Federal University of S~ao Paulo, S~ao Paulo, Brazil
References 1. Fagan KJ, Pretorius CJ, Horsfall LU, et al. ELF Score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int 2015; 35: 1673–81. 2. Xie Q, Zhou X, Huang P, et al. The performance of enhanced liver fibrosis (elf) test for the staging of liver fibrosis: a meta-analysis. PLoS ONE 2014; 9: E92772. 3. Sebastiani G, Castera L, Halfon P, et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: an international study of 2411 cases. Aliment Pharmacol Ther 2011; 34: 1202–16. 4. Fernandes FF, Ferraz ML, Andrade LE, et al. Enhanced liver fibrosis panel as a predictor of liver fibrosis in
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
recent knowledge in pathogenesis and overview of clinical assessment. Liver Int 2015; 35: 1646–60. 2. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology (Baltimore, MD) 2014; 59: 1627–37. 3. Abrams GA, Jaffe CC, Hoffer PB, Binder HJ, Fallon MB. Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome. Gastroenterology 1995; 109: 1283–8.
Letters to the Editor
4. Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology 1998; 114: 305–10. 5. Krowka MJ, Wiseman GA, Burnett OL, et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99 m)Tc MAA lung scanning. Chest 2000; 118: 615–24.
DOI:10.1111/liv.12821 Liver Int. 2015; 35: 1919–1920
Response to ‘The role of macroaggregated albumin lung perfusion scan in hepatopulmonary syndrome: are we ready to draw conclusions?’ To the Editor: We appreciate the comments of Zhao et al. (1) on the topic of the current use of technetium 99 mlabelled macroaggregated albumin (MAA) lung scan for detecting intrapulmonary vascular dilations (IPVDs) as a criterion for detecting hepatopulmonary syndrome (HPS). As mentioned in our review (2), the presence of IPVDs is documented either on microbubble transthoracic echocardiography (MTTE) or MAA scan. Clinical recommendations on screening for HPS were mainly based on the European Respiratory Society Task Force guideline (3). MTTE has always been considered the gold standard for detecting HPS based on clinical studies. Important advantages include (i) its high sensitivity to detect IPVDs; (ii) its possibility to distinguish intrapulmonary from intracardiac shunting and (iii) the additional possibility of screening for portopulmonary hypertension (2–4). On the other hand, HPS can be diagnosed and the degree of shunting can even be quantified on MAA scan (2–4). However, this technique cannot distinguish between intrapulmonary and intracardiac shunting, and has been proven to be associated with lower sensitivity (3). Accordingly, the severity of HPS based on PaO2 is negatively correlated with the degree of brain uptake during MAA scan, as was nicely illustrated in figure 1 by Zhao et al. (1), by summarizing the patient data of earlier performed studies by Abrams et al. and Krowka et al. Indeed, patients with mild-tomoderate hypoxia are those patients with rather small or few IPVDs and shunts, resulting in lower brain uptake. We agree with the comment that the technical aspects of MAA scan lack standardization, which indeed affects its diagnostic accuracy (1). To address this issue, further prospective studies are certainly warranted. However, MAA scan yields important clinical information in specific situations. First, it has to be performed in severe hypoxic patients with underlying intrinsic lung
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
disease and suspected HPS (4). Significant brain uptake on MAA scan provides indirect evidence of HPS contributing to the hypoxic status. Second, MAA scan may offer complementary information to stratify HPS patients at greater risk of post-transplantation mortality (shunt fraction ≥20%) (4). Third, in case of extensive shunting, suggesting large arteriovenous connections, HPS patients should be referred for pulmonary angiography in order to plan coil embolization (4). In summary, current hepatology guidelines recommend microbubble transthoracic echocardiography as best screening tool to detect HPS. However, in specific clinical situations MAA scan may offer essential complementary information. Further prospective studies are needed to standardize the MAA scan technique. Acknowledgements
Financial support: Sarah Raevens received a scholarship (FWO14/ASP/200) from the Research Foundation – Flanders (Aspirant mandaat FWO Vlaanderen). Conflict of interest: The authors do not have any disclosures to report.
Sarah Raevens1, Christophe Van Steenkiste1,2 and Isabelle Colle1,3 1 Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium 2 Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium 3 Department of Gastroenterology and Hepatology, Algemeen Stedelijk Ziekenhuis ASZ, Aalst, Belgium
References 1. Zhao H, Tsauo J, Ma HY, Li X. The role of macroaggregated albumin lung perfusion scan in hepatopulmonary
1919
Zhao et al.
Letters to the Editor
syndrome: are we ready to draw conclusions? Liver Int 2015; 35: 1918–19. 2. Raevens S, Geerts A, Van Steenkiste C, et al. Hepatopulmonary syndrome and portopulmonary hypertension: recent knowledge in pathogenesis and overview of clinical assessment. Liver Int 2015; 35: 1646–60.
3. Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004; 24: 861–80. 4. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology 2014; 59: 1627–37.
DOI:10.1111/liv.12815 Liver Int. 2015; 35: 1920–1921
ELF cut-off points: aetiology is also a relevant factor To the Editor: We read with great interest the article published by Fagan et al. (1) entitled ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. In the article, the authors stated that the ELF manufacturer’s cut-off value (≥9.8) reliably identifies individuals with advanced fibrosis within patients with chronic liver diseases and that age and histological activity (HA) may influence its results. However, we think that there are some points to discuss about this study. The lack of a consistent ELF’s cut-off value throughout the various studies published, so far, has recently been demonstrated (2). We do agree that ELF is a good non invasive marker, but we are not convinced about the cut-off points proposed by the manufacturer. It is well-known that the aetiology of chronic liver disease may interfere in the performance of non invasive methods once fibrosis and HA vary significantly among distinct aetiologies (3). We recently verified that ELF performs well as a non invasive marker for chronic hepatitis C (CHC) patients (4). Unfortunately, this finding cannot be extrapolated to other clinical scenarios, such as hepatitis B or non alcoholic fat liver disease (5). We do think that any evaluation of cut-off points should be performed in populations with a single aetiology. In our CHC population, we also observed that results were influenced by HA, which was more intense among patients with discordant results. It is worth mentioning that HA correlates with aminotransferases levels, which should be considered when interpreting ELF results. Concerning age, we found the same influence in ELF‘s accuracy. However, the finding that 45 years should be considered as ‘increased age’ and a cause for false positive results is a matter of concern since our typical population of exclusively CHC patients had a mean age of 53 ± 11.3 years, and 77% were older than 45 years. If age was not adequately emphasized in the original formula some adjustments might be made so that ELF becomes applicable to CHC population. We are now proposing that new cut-off points should be adopted for ELF in CHC patients, with 9.4 (sensitivity 84% and negative predictive value 93%)
1920
for the detection of advanced fibrosis (6). Interestingly Fagan et al. (1) highlighted the same value as the optimal cut-off point. We are convinced that ELF is a valuable tool in determining advanced fibrosis, but we believe that there is still ground for debating its cut-off points, especially considering aetiology particularities. Acknowledgements
Conflict of interest: The authors do not have any disclosures to report.
Flavia F. Fernandes1,2, Renata M. Perez1,3,4 and Maria L. Ferraz4,5 1 Gastroenterology and Hepatology Department, University of the State of Rio de Janeiro, Rio de Janeiro, Brazil 2 Gastroenterology and Hepatology Department, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil 3 Internal Medicine Department, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil 4 D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil 5 Gastroenterology Department, Federal University of S~ao Paulo, S~ao Paulo, Brazil
References 1. Fagan KJ, Pretorius CJ, Horsfall LU, et al. ELF Score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int 2015; 35: 1673–81. 2. Xie Q, Zhou X, Huang P, et al. The performance of enhanced liver fibrosis (elf) test for the staging of liver fibrosis: a meta-analysis. PLoS ONE 2014; 9: E92772. 3. Sebastiani G, Castera L, Halfon P, et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: an international study of 2411 cases. Aliment Pharmacol Ther 2011; 34: 1202–16. 4. Fernandes FF, Ferraz ML, Andrade LE, et al. Enhanced liver fibrosis panel as a predictor of liver fibrosis in
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
