Predictive value of indocyanine green retention test and indocyanine green clearance in Child‐Pugh class A patients
Authors: Marie‐Louise Lindberg Pind, Søren Møller, Nasrin Faqir, Flemming Bendtsen
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. 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=JretCref where Jret denotes the retention flux of ICG and Cref the plasma concentration of ICG. Moreover, ICGcl = HPF (Cartery‐Chepatic vein)Cref 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=Q0AUC (0‐∞)Cin(t)dt.From the ICG indicator dilution curves obtained by the constant infusion technique, the ICG‐r15 can be calculated by the formula1: ICGr15=(PV‐ClICGPV)15The 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. When comparing ICG clearance values to calculated ICG‐r15 values, we found that there is a correlation coefficient of R = −0.94 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. 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 = 0.7898) and AUROC for SPH (HVPG >12 mmHg; AUROC = 0.8357; Fig. 1).Figure 1: (A) ROC curves for ICG clearance and ICG‐r15 in patients with CSPH (HVPG >10 mmHg). AUROC = 0.7898 for ICG‐r15. (B) ROC curves for ICG clearance and ICG‐r15 in patients with SPH (HVPG >12 mmHg). AUROC = 0.8357 for ICG‐r15.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 ICG‐r15 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.