CORRESPONDENCE Predictive Value of Indocyanine Green Retention Test and Indocyanine Green Clearance in Child-Pugh Class A Patients To the Editor: We read with interest the recent article by Lisotti et al., on the use of indocyanine green (ICG) retention test as a noninvasive predictor of portal hypertension (PH) and of the presence of esophageal varices (EV) in compensated liver cirrhosis.1 The investigators report that the ICG 15-minute retention test (ICG-r15) reflects the degree of PH and the presence of EV, as compared to the gold standards of PH, namely, measurement of the hepatic venous pressure gradient (HVPG) and upper gastrointestinal endoscopy, respectively, as assessed in 96 Child Pugh class A patients.1 HVPG is usually measured indirectly by liver vein catheterization. This method is safe and has been used for more than 50 years.2 The procedure is rather simple, but it is fairly invasive, requires special facilities and equipment that has to be calibrated correctly, and requires specially trained personnel. These demands have limited the widespread use of liver vein catheterization with assessment of HVPG.2 The risk of developing clinical complications to PH is significantly increased when the HVPG exceeds 10-12 mmHg.2 Clinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) are defined as HVPG 10 mmHg and HVPG 12 mmHg, respectively.1 The level of HVPG thus holds information on prognosis.2 On this background, we do agree that a noninvasive assessment of the HVPG, which is as reliable as the conventional liver vein catheterization, would be of clinical value. In the study by Lisotti et al., ICG is administered by the cubital vein of the arm and venous peripheral blood samples are collected, and ICG absorbance in these samples are measured at 805 nm.1

In our department, ICG clearance is determined during a hepatic venous catheterization with assessment of HVPG.3 We have a long experience for determining hepatic blood flow by ICG clearance and have routinely determined ICG clearance on patients referred for measurement of HVPG. For many years, ICG clearance has been determined by the constant infusion technique along with liver vein catheterization.3 The ICG retention test is based on the Fick principle, where: ICGcl 5 CJretref where Jret denotes the retention flux of ICG and Cref the plasma concentration of ICG. -Chepatic veinÞ Moreover, ICGcl 5 HPF ðCarteryCref The principle utilizes that in case of steady state, the infusion equals the hepatic removal of ICG. The total clearance of ICG can also be calculated as:

ClICG 5

Q0 Cin ðtÞdt: AUC ð0-1Þ

From the ICG indicator dilution curves obtained by the constant infusion technique, the ICG-r15 can be calculated by the formula1:

ICGr15 5

  PV-ClICG 15 PV

The calculated ICG-r15 values that derive from these are comparable to the measurements by Lisotti et al. The background for this is that the amount of plasma that is cleared for ICG per minute is relative to the plasma volume (PV). Thus, on the basis of our constant infusion indicator dilution curves, we can calculate the remaining amount of ICG in the body.

Fig. 1. (A) ROC curves for ICG clearance and ICG-r15 in patients with CSPH (HVPG >10 mmHg). AUROC 5 0.7898 for ICG-r15. (B) ROC curves for ICG clearance and ICG-r15 in patients with SPH (HVPG >12 mmHg). AUROC 5 0.8357 for ICG-r15. 2112

HEPATOLOGY, Vol. 61, No. 6, 2015

When comparing ICG clearance values to calculated ICG-r15 values, we found that there is a correlation coefficient of R 5 20.94 between the two; therefore, the two tests can be used equally. Given that complications of cirrhosis arise with an HVPG above 10-12 mmHg, we looked at the discriminative value of the ICG-r15 test as a noninvasive marker of HVPG of 10 and 12 mmHg. For purposes of comparison, we collected a group of 103 consecutive Child-Pugh class A patients referred for liver vein catheterization for assessment of HVPG.

CORRESPONDENCE

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3. Henriksen JH, Winkler K. Hepatic blood flow determination. A comparison of 99mTc-diethyl-IDA and indocyanine green as hepatic blood flow indicators in man. J Hepatol 1987;4:66-70. C 2015 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27569 Potential conflict of interest: Nothing to report.

Reply:

Receiver Operating Characteristic Cut-off Values of ICG-r15 for the Diagnosis of CSPH and SPH The diagnostic performance of ICG-r15 as a noninvasive marker of CSPH (HVPG >10 mmHg) and SPH (HVPG >12 mmHg) can be interpreted by examining the area under the receiver operating characteristic (ROC) curve (AUROC) for CSPH (HVPG >10 mmHg; AUROC 5 0.7898) and AUROC for SPH (HVPG >12 mmHg; AUROC 5 0.8357; Fig. 1). Lisotti et al. found the AUROC for CSPH to be 0.808 and the AUROC for SPH to be 0.821.1 Largely, we found no significant difference between the ICGr15 test and ICG clearance. Interestingly, the sensitivity of the test, expressed by the ROC curves, seems to be better for HVPG >12 mmHg (Fig. 1B), as compared to HVPG >10 mmHg. Thus, the ICG-r15 test shows a slightly better performance when determining HVPG above 12 mmHg. However, the constant infusion technique is invasive. Our calculations support that the less-invasive measurements, as published by Lisotti et al., are sufficient as an estimate of the ICG clearance, given that they nicely correspond to ours. In conclusion, we support that the ICG-r15 test or ICG clearance, carried out as described by Lisotti et al., is a less-invasive method for determining HVPG and the quality acceptable compared to what we consider as the gold standard, the constant infusion ICG clearance technique. In this study, all patients were in the Child Pugh A class. Inclusion of patients within Child Pugh class B and C will be interesting for further validation, in a broader spectrum of patients with cirrhosis, of the ICG-r15 test. MARIE-LOUISE LINDBERG PIND, M.S.1 SØREN MØLLER, M.D.2 NASRIN FAQIR, M.SC.3 FLEMMING BENDTSEN, M.D.1 1 Gastrounit Medical Division 2 Department of Clinical Physiology and Nuclear Medicine Center for Diagnostic Imaging and Research 3 Clinical Research Center Copenhagen University Hospital Hvidovre Hvidovre, Denmark

References 1. Lisotti A, Azzaroli F, Buonfiglioli F, Montagnani M, Cecinato P, Turco L, et al. Indocyanine green retention test as a noninvasive marker of portal hypertension and esophageal varices in compensated liver cirrhosis. HEPATOLOGY 2014;59:643-650. 2. Hobolth L, Bendtsen F, Møller S. Indications for portal pressure measurement in chronic liver disease. Scand J Gastroenterol 2012;47:887-892.

We read with interest the Pind et al. correspondence and thank the authors for their prompt and precise reply to our results. In our study,1 as stated in the Materials and Methods section, we performed the Indocyanine Green (ICG) retention test using multiple serum samples (before the injection and every 50 after dye injection for 200 ) and evaluated both the ICG retention rate at 150 (ICG-r15), half-life (ICG-t1/2), and disappearance rate (ICG-k); moreover, our laboratory gave us the estimation of ICG clearance, calculated as the injected dose/AUC (area under the curve). In our preliminary evaluation, we performed the ICG retention test and compared those results to the estimated ICG-clearance (data on file) in patients with all stages advanced liver disease.2 As confirmed by Pind et al., we observed a close correlation between these two techniques and we strongly agree with the conclusion that the two methods could be used equally. Based on these findings, we focused our evaluation on the usefulness of the noninvasive test (namely, ICG-r15) in patients with well-compensated liver cirrhosis; in this setting, upper endoscopy and hepatic venous pressure gradient (HVPG) measurement are recommended in all patients with newly diagnosed liver cirrhosis in order to obtain a detailed assessment of clinical signs of portal hypertension (PH) and prognostic information. ICG clearance (both the calculated true clearance, the ICG retention test, and the constant infusion technique) reflects the derangement of liver function and the hemodynamic alterations occurring in liver cirrhosis. As discussed in the text, we hypothesized that among patients with well-preserved liver function, ICG clearance could directly reflect the alteration of liver blood flow and, indirectly, the presence and grade of PH; in order to avoid the interference of impaired liver function we included only a homogeneous group of compensated patients. Thus, the slightly better performance of ICG-r15 for the identification of severe PH (HVPG 12 mmHg) than clinically significant PH (HVPG 10 mmHg) (AUROC 0.821 versus 0.808 in our experience; 0.836 versus 0.790 in Pind et al.) could be explained. In fact, liver disease progression is characterized by hemodynamic alterations together with functional impairment; therefore, in patients with severe PH, and also in Child-Pugh class B-C ones, the performance of ICG retention test, which is influenced by both of these conditions, the results are more accurate. Concerning the last suggestion, the diagnostic accuracy observed among patients with all Child-Pugh classes is even higher than in patients with compensated diseases, with preserved function. The prevalence of PH (both clinically significant and severe) and EV in Child-Pugh class B and C patients is higher than Child-Pugh class A, and the higher pretest probabilities lead to higher diagnostic accuracy of the ICG retention test.3 However, in our opinion, all Child B-C patients should undergo upper GI endoscopy in order to achieve reliable assessment and even perform prophylactic treatment (i.e., band ligation) in the case of high-risk varices. On the other hand, to our knowledge, there are only retrospective or limited data on the prognostic value of HVPG measurement in Child-Pugh class B and C patients. In this setting, the risk

Predictive value of indocyanine green retention test and indocyanine green clearance in Child-Pugh class A patients.

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