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Spleen Stiffness: The New Kid on the Block for Diagnosing Portal Hypertension?
1152
CORRESPONDENCE
On the other hand, Berzigotti et al2 studied a smaller sample, composed of only 117 compensated cirrhotic patients. They found that varices risk score (VRS) and liver stiffness ⫻ spleen size/platelet count (LSPS), 2 methods requiring TE, could predict EV with sensitivities of 80.0%– 91.9% (VRS) and of 80.8%-91.9% (LSPS), with negative predictive value of 86.7%–95.4% (VRS) and of 86.0%–94.5% (LSPS), according to different cutoffs. For VRS, they presented accuracies of 90.9% and 75.9% for the training and validation sets, respectively; for LSPS, they were 88.2% and 80.8%, respectively.2 The most interesting characteristic of the study was the use of a validation set. However, it was also rather small (56 patients), and the authors chose to include 6 patients whose biopsies were not compatible with cirrhosis. Besides, we consider it would have been important if they had evaluated decompensated cirrhotics, because not all Child B/C patients have EV; evaluating only compensated cirrhotic patients could be a correct approach when screening only for clinically significant portal hypertension, but not for EV. Moreover, the low prevalence of EV in the training set (32%) could have limited the results of the study and probably was related to the inclusion of only compensated cirrhotics. The authors stated that 10.6% of patients evaluated for the training set were excluded due to failure of TE; this is a relevant percentage and, because their results were not presented in an intention-to-diagnose manner, this weakens their findings. This was also a problem for the study by Takuma et al.1 Finally, depending on the chosen cutoff and on the analysis of the findings of training or validation sets, the results presented, even in a “per diagnostic protocol” approach, might not be acceptable for ruling out EV and avoiding endoscopy. It seems that great advances in noninvasively predicting EV are happening, but we understand the studies published so far are not enough for any of the abovementioned methods to be used in clinical practice as a substitute for endoscopy. Besides, if they all respect an important characteristic of a good screening test, the fact of being noninvasive, neither is ready to give an appropriate answer to important issues like high costs and to wide availability: equipment/software for TE and ARFI are expensive and limited to highly specialized centers. ÂNGELO ZAMBAM DE MATTOS Universidade Federal de Ciências da Saúde de Porto Alegre and Hospital Nossa Senhora da Conceiçao de Porto Alegre Porto Alegre, Brazil ANGELO ALVES DE MATTOS Universidade Federal de Ciências da Saúde de Porto Alegre Porto Alegre, Brazil 1. 2. 3. 4. 5. 6.
Takuma Y, et al. Gastroenterology 2013;144:92–101. Berzigotti A, et al. Gastroenterology 2013;144:102–111. De Franchis R, et al. J Hepatol 2010;53:762–768. Castéra L, et al. Gastroenterology 2013;144:19 –22. Ying L, et al. Dig Dis Sci 2012;57:1672–1681. Chawla S, et al. Eur J Gastroenterol Hepatol 2012;24:431– 436.
GASTROENTEROLOGY Vol. 144, No. 5 7. Mattos AZ, et al. Arq Gastroenterol 2010;47:275–278. 8. Colecchia A, et al. Gastroenterology 2012;143:646 – 654.
Conflicts of interests The authors disclose no conflicts. http://dx.doi.org/10.1053/j.gastro.2013.02.048
Spleen Stiffness: The New Kid on the Block for Diagnosing Portal Hypertension? Dear Sir:
We would like to congratulate Takuma et al1 for presenting their remarkable data on using spleen stiffness measured by acoustic radiation force impulse (ARFI) as a sensitive predictor of esophageal varices in cirrhosis. This work is important and evidence that we continue to embrace the concept of primum non nocere in clinical practice, from invasive diagnostics (intraoperative direct measurement of portal pressure) to minimally invasive (hepatic venous pressure gradient measurement and esophagogastroduodenoscopy [EGD]) and now noninvasive techniques (spleen stiffness by ultrasound-based elastography). This paper further supports previous work on the role of spleen stiffness in portal hypertension by Colecchia et al2 and Hirooka et al.3 All of these studies showed that spleen stiffness measured by any type of ultrasound-based elastography method could identify patients with clinically significant portal hypertension (hepatic venous pressure gradient measurement ⱖ10 mmHg) and detect esophageal varices. Essentially, 3 subgroups of patients with cirrhosis can be identified: Patients who are least likely to develop varices and may yet benefit from screening EGD; patients who may or may not have varices, who will benefit from screening EGD at regular intervals; and patients who most likely have varices, whom primary prophylaxis with -blocker therapy may be considered. The caveat is that the presence of red signs or other stigmata of recent bleed on esophageal varices may only be appreciated during EGD. In the first subgroup, these patients may benefit from serial spleen stiffness measurements at regular intervals and EGD may only be indicated if progressive increase in stiffness is noted. Hence, serial measurements may not only confirm the reproducibility of this method, but also screen patients for disease progression. In patients with extrahepatic portal vein obstruction, spleen stiffness measured by transient elastography (TE) has been shown to predict the risk of bleeding from esophageal varices.4 Further work would be required to confirm if this also applies to cirrhotic patients. ARFI has advantages over TE in the evaluation of spleen stiffness because it is an add-on feature of B-mode ultrasonography and offers a flexible region of interest. Moreover, if serial splenic stiffness measurements were required, spleen stiffness by ARFI could be conveniently and routinely measured every 6 –12 months during sur-
May 2013
veillance ultrasound imaging for hepatocellular carcinoma in cirrhosis. In this study, the authors reported that 5 measurements were taken at a defined depth of 10 mm below the splenic capsule. However, whether the authors measured the same region or different areas within the enlarged spleen was not clear. In the absence of any valid criteria for spleen stiffness, identical criteria for measuring liver stiffness by TE was applied to previous studies assessing spleen stiffness (ⱖ10 valid measurements; success rate, ⱖ60%; interquartile range, ⬍30%). In contrast with liver stiffness measurement estimating hepatic fibrosis, spleen stiffness probably measures 3 parameters, namely, splenic congestion, tissue hyperplasia, and the hyperdynamic circulation owing to portal hypertension. Hence, the same criteria may not apply and standardization for spleen stiffness measurement is required. In this study, 22.6% of patients with ascites were included. These patients are likely have clinically significant portal hypertension and they are unlikely to benefit from noninvasive tests. We expect all of these patients to have esophageal varices, but this was not reported in the study. Including patients with ascites demonstrates the feasibility of ARFI in this situation compared with TE. In our experience, measuring spleen stiffness with TE is still possible by changing the position of the patient from the supine to the right lateral decubitus position in patients with mild to moderate ascites. However, spleen stiffness measured in the right lateral position may be lower compared with measurements in the supine position. This study again demonstrates the nonspecificity of using spleen size as a marker for clinically significant portal hypertension. Although splenomegaly may be relevant in the clinical context, assessing splenomegaly with imaging continues to lend itself to subjectivity. At present, spleen size can be determined accurately with a variety of imaging modalities. However, what constitutes normal size may vary by age, body mass, and surface area, and perhaps even racial group of the patient.5 Similarly, the age of onset of chronic liver disease has been shown to influence spleen size.6 In this study, 48% of cirrhotic patients with spleen size of ⱕ100 mm had esophageal varices. Hence, the margin of error in using spleen size to predict esophageal varices is considerably significant. We believe that the clinical utility of spleen stiffness as a noninvasive tool for the diagnosis of portal hypertension remains promising. Future studies would confirm the application of spleen stiffness in clinical practice. JUN LIONG CHIN GRACE CHAN P. AIDEN MCCORMICK Liver Unit St. Vincent’s University Hospital University College Dublin Dublin, Ireland 1. 2. 3. 4.
Takuma Y, et al. Gastroenterology 2013;144:92–101. Colecchia A, et al. Gastroenterology 2012;143:646 – 654. Hirooka M, et al. Radiology 2011;261:960 –968. Sharma P, et al. Radiology 2012;263:893– 899.
CORRESPONDENCE
1153
5. Kaneko J, et al. Surg Radiol Anat 2008;30:515–518. 6. McCormick PA, et al. Ir J Med Sci 2007;176:293–296.
Conflicts of interests The authors disclose no conflicts. http://dx.doi.org/10.1053/j.gastro.2013.02.047
Reply. We thank Rudler et al, Zambam de Mattos et al,
and Sherman et al for their interest in our paper “Elastography, Spleen Size, and Platelet Count Identify Portal Hypertension in Patients With Compensated Cirrhosis.”1 We are grateful for the appreciative comments by Rudler et al; with regard to their attempt to improve risk stratification of patients with variceal bleeding by liver stiffness ⫻ spleen size/platelet (LSPS), we think it is not surprising that liver stiffness (LS), and consequently LSPS, does not correlate with the hepatic venous pressure gradient (HVPG) in their patients. Indeed, LS reflects hepatic fibrosis, one of the major determinants of increased resistance to portal blood flow, and therefore of portal pressure in patients with compensated cirrhosis; however, in later phases of the disease an increased portocollateral blood flow, which is not sensed by LS, becomes central in determining the HVPG.2 Beside this, other confounders may obscure the correlation between the noninvasive parameters included in LSPS and HVPG in patients bleeding from varices. For instance, platelet count can be temporarily increased owing to infections, or acute phase reaction, or temporarily diminished owing to hemodilution or more rarely to posttransfusional immune reactions. Moreover, technical issues complicate LS measurement in decompensated patients: ascites avoids a correct measurement of LS in a large proportion of cases, and the ceiling effect of LS values (75 kPa) prevents a correct measurement in many patients with advanced cirrhosis. We anticipate that newer technologies for testing stiffness such as sonoelastographic methods and LS probes with extended ranges of values (150 kPa) might improve the assessment of these patients.3 In addition, these newer methods will improve the feasibility of testing spleen stiffness, which is more directly related to portal pressure than LS.4 Future studies in patients with acute variceal bleeding should investigate this new parameter. Meanwhile, risk stratification might rely on a simple score based on clinical and laboratory variables that allow predicting a high bleeding risk with equal or more accuracy than a HVPG ⱖ20 mmHg.5 Such simplified risk stratification rules based on readily available variables have performed adequately in recent studies evaluating the use of preemptive early transjugular intrahepatic portosystemic shunt in high-risk patients with acute variceal bleeding.6,7 As for the issues raised by Zambam de Mattos et al, we acknowledge that patients included in our study were highly selected: according to the methodology of studies for diagnostic tests, any test should be applied and validated in the population in which the result of the test is of relevance before spreading its use in real-life situa-
CORRESPONDENCE
On the other hand, Berzigotti et al2 studied a smaller sample, composed of only 117 compensated cirrhotic patients. They found that varices risk score (VRS) and liver stiffness ⫻ spleen size/platelet count (LSPS), 2 methods requiring TE, could predict EV with sensitivities of 80.0%– 91.9% (VRS) and of 80.8%-91.9% (LSPS), with negative predictive value of 86.7%–95.4% (VRS) and of 86.0%–94.5% (LSPS), according to different cutoffs. For VRS, they presented accuracies of 90.9% and 75.9% for the training and validation sets, respectively; for LSPS, they were 88.2% and 80.8%, respectively.2 The most interesting characteristic of the study was the use of a validation set. However, it was also rather small (56 patients), and the authors chose to include 6 patients whose biopsies were not compatible with cirrhosis. Besides, we consider it would have been important if they had evaluated decompensated cirrhotics, because not all Child B/C patients have EV; evaluating only compensated cirrhotic patients could be a correct approach when screening only for clinically significant portal hypertension, but not for EV. Moreover, the low prevalence of EV in the training set (32%) could have limited the results of the study and probably was related to the inclusion of only compensated cirrhotics. The authors stated that 10.6% of patients evaluated for the training set were excluded due to failure of TE; this is a relevant percentage and, because their results were not presented in an intention-to-diagnose manner, this weakens their findings. This was also a problem for the study by Takuma et al.1 Finally, depending on the chosen cutoff and on the analysis of the findings of training or validation sets, the results presented, even in a “per diagnostic protocol” approach, might not be acceptable for ruling out EV and avoiding endoscopy. It seems that great advances in noninvasively predicting EV are happening, but we understand the studies published so far are not enough for any of the abovementioned methods to be used in clinical practice as a substitute for endoscopy. Besides, if they all respect an important characteristic of a good screening test, the fact of being noninvasive, neither is ready to give an appropriate answer to important issues like high costs and to wide availability: equipment/software for TE and ARFI are expensive and limited to highly specialized centers. ÂNGELO ZAMBAM DE MATTOS Universidade Federal de Ciências da Saúde de Porto Alegre and Hospital Nossa Senhora da Conceiçao de Porto Alegre Porto Alegre, Brazil ANGELO ALVES DE MATTOS Universidade Federal de Ciências da Saúde de Porto Alegre Porto Alegre, Brazil 1. 2. 3. 4. 5. 6.
Takuma Y, et al. Gastroenterology 2013;144:92–101. Berzigotti A, et al. Gastroenterology 2013;144:102–111. De Franchis R, et al. J Hepatol 2010;53:762–768. Castéra L, et al. Gastroenterology 2013;144:19 –22. Ying L, et al. Dig Dis Sci 2012;57:1672–1681. Chawla S, et al. Eur J Gastroenterol Hepatol 2012;24:431– 436.
GASTROENTEROLOGY Vol. 144, No. 5 7. Mattos AZ, et al. Arq Gastroenterol 2010;47:275–278. 8. Colecchia A, et al. Gastroenterology 2012;143:646 – 654.
Conflicts of interests The authors disclose no conflicts. http://dx.doi.org/10.1053/j.gastro.2013.02.048
Spleen Stiffness: The New Kid on the Block for Diagnosing Portal Hypertension? Dear Sir:
We would like to congratulate Takuma et al1 for presenting their remarkable data on using spleen stiffness measured by acoustic radiation force impulse (ARFI) as a sensitive predictor of esophageal varices in cirrhosis. This work is important and evidence that we continue to embrace the concept of primum non nocere in clinical practice, from invasive diagnostics (intraoperative direct measurement of portal pressure) to minimally invasive (hepatic venous pressure gradient measurement and esophagogastroduodenoscopy [EGD]) and now noninvasive techniques (spleen stiffness by ultrasound-based elastography). This paper further supports previous work on the role of spleen stiffness in portal hypertension by Colecchia et al2 and Hirooka et al.3 All of these studies showed that spleen stiffness measured by any type of ultrasound-based elastography method could identify patients with clinically significant portal hypertension (hepatic venous pressure gradient measurement ⱖ10 mmHg) and detect esophageal varices. Essentially, 3 subgroups of patients with cirrhosis can be identified: Patients who are least likely to develop varices and may yet benefit from screening EGD; patients who may or may not have varices, who will benefit from screening EGD at regular intervals; and patients who most likely have varices, whom primary prophylaxis with -blocker therapy may be considered. The caveat is that the presence of red signs or other stigmata of recent bleed on esophageal varices may only be appreciated during EGD. In the first subgroup, these patients may benefit from serial spleen stiffness measurements at regular intervals and EGD may only be indicated if progressive increase in stiffness is noted. Hence, serial measurements may not only confirm the reproducibility of this method, but also screen patients for disease progression. In patients with extrahepatic portal vein obstruction, spleen stiffness measured by transient elastography (TE) has been shown to predict the risk of bleeding from esophageal varices.4 Further work would be required to confirm if this also applies to cirrhotic patients. ARFI has advantages over TE in the evaluation of spleen stiffness because it is an add-on feature of B-mode ultrasonography and offers a flexible region of interest. Moreover, if serial splenic stiffness measurements were required, spleen stiffness by ARFI could be conveniently and routinely measured every 6 –12 months during sur-
May 2013
veillance ultrasound imaging for hepatocellular carcinoma in cirrhosis. In this study, the authors reported that 5 measurements were taken at a defined depth of 10 mm below the splenic capsule. However, whether the authors measured the same region or different areas within the enlarged spleen was not clear. In the absence of any valid criteria for spleen stiffness, identical criteria for measuring liver stiffness by TE was applied to previous studies assessing spleen stiffness (ⱖ10 valid measurements; success rate, ⱖ60%; interquartile range, ⬍30%). In contrast with liver stiffness measurement estimating hepatic fibrosis, spleen stiffness probably measures 3 parameters, namely, splenic congestion, tissue hyperplasia, and the hyperdynamic circulation owing to portal hypertension. Hence, the same criteria may not apply and standardization for spleen stiffness measurement is required. In this study, 22.6% of patients with ascites were included. These patients are likely have clinically significant portal hypertension and they are unlikely to benefit from noninvasive tests. We expect all of these patients to have esophageal varices, but this was not reported in the study. Including patients with ascites demonstrates the feasibility of ARFI in this situation compared with TE. In our experience, measuring spleen stiffness with TE is still possible by changing the position of the patient from the supine to the right lateral decubitus position in patients with mild to moderate ascites. However, spleen stiffness measured in the right lateral position may be lower compared with measurements in the supine position. This study again demonstrates the nonspecificity of using spleen size as a marker for clinically significant portal hypertension. Although splenomegaly may be relevant in the clinical context, assessing splenomegaly with imaging continues to lend itself to subjectivity. At present, spleen size can be determined accurately with a variety of imaging modalities. However, what constitutes normal size may vary by age, body mass, and surface area, and perhaps even racial group of the patient.5 Similarly, the age of onset of chronic liver disease has been shown to influence spleen size.6 In this study, 48% of cirrhotic patients with spleen size of ⱕ100 mm had esophageal varices. Hence, the margin of error in using spleen size to predict esophageal varices is considerably significant. We believe that the clinical utility of spleen stiffness as a noninvasive tool for the diagnosis of portal hypertension remains promising. Future studies would confirm the application of spleen stiffness in clinical practice. JUN LIONG CHIN GRACE CHAN P. AIDEN MCCORMICK Liver Unit St. Vincent’s University Hospital University College Dublin Dublin, Ireland 1. 2. 3. 4.
Takuma Y, et al. Gastroenterology 2013;144:92–101. Colecchia A, et al. Gastroenterology 2012;143:646 – 654. Hirooka M, et al. Radiology 2011;261:960 –968. Sharma P, et al. Radiology 2012;263:893– 899.
CORRESPONDENCE
1153
5. Kaneko J, et al. Surg Radiol Anat 2008;30:515–518. 6. McCormick PA, et al. Ir J Med Sci 2007;176:293–296.
Conflicts of interests The authors disclose no conflicts. http://dx.doi.org/10.1053/j.gastro.2013.02.047
Reply. We thank Rudler et al, Zambam de Mattos et al,
and Sherman et al for their interest in our paper “Elastography, Spleen Size, and Platelet Count Identify Portal Hypertension in Patients With Compensated Cirrhosis.”1 We are grateful for the appreciative comments by Rudler et al; with regard to their attempt to improve risk stratification of patients with variceal bleeding by liver stiffness ⫻ spleen size/platelet (LSPS), we think it is not surprising that liver stiffness (LS), and consequently LSPS, does not correlate with the hepatic venous pressure gradient (HVPG) in their patients. Indeed, LS reflects hepatic fibrosis, one of the major determinants of increased resistance to portal blood flow, and therefore of portal pressure in patients with compensated cirrhosis; however, in later phases of the disease an increased portocollateral blood flow, which is not sensed by LS, becomes central in determining the HVPG.2 Beside this, other confounders may obscure the correlation between the noninvasive parameters included in LSPS and HVPG in patients bleeding from varices. For instance, platelet count can be temporarily increased owing to infections, or acute phase reaction, or temporarily diminished owing to hemodilution or more rarely to posttransfusional immune reactions. Moreover, technical issues complicate LS measurement in decompensated patients: ascites avoids a correct measurement of LS in a large proportion of cases, and the ceiling effect of LS values (75 kPa) prevents a correct measurement in many patients with advanced cirrhosis. We anticipate that newer technologies for testing stiffness such as sonoelastographic methods and LS probes with extended ranges of values (150 kPa) might improve the assessment of these patients.3 In addition, these newer methods will improve the feasibility of testing spleen stiffness, which is more directly related to portal pressure than LS.4 Future studies in patients with acute variceal bleeding should investigate this new parameter. Meanwhile, risk stratification might rely on a simple score based on clinical and laboratory variables that allow predicting a high bleeding risk with equal or more accuracy than a HVPG ⱖ20 mmHg.5 Such simplified risk stratification rules based on readily available variables have performed adequately in recent studies evaluating the use of preemptive early transjugular intrahepatic portosystemic shunt in high-risk patients with acute variceal bleeding.6,7 As for the issues raised by Zambam de Mattos et al, we acknowledge that patients included in our study were highly selected: according to the methodology of studies for diagnostic tests, any test should be applied and validated in the population in which the result of the test is of relevance before spreading its use in real-life situa-