HEPATOLOGY, Vol. 61, No. 1, 2015
expression levels of individual subjects cannot be linked to infection by common viruses. The authors are correct that the expression of IL8 and LAMC2 misclassified 3 of 14 subjects in the nonBA group as having BA. As described in the original publication, this misclassification resulted in a specificity of 85.7%. It will be important that follow-up validation studies examine potential changes in the specificity and sensitivity of hepatic mRNA expression of IL8 and LAMC2 in the diagnosis of biliary atresia, especially in studies that include a larger population of non-BA patients as diseased controls. We agree that the analysis of IL-8 expression should take into account its relationship with age and staging of fibrosis of children with biliary atresia. Although data on histological fibrosis were not available for all subjects, we were able to perform new analyses of IL-8 expression data (both mRNA and protein levels) to directly examine its relationship with age. To this end, we subdivided the subjects and dataset based on the three suggested age subgroups of 90 days. We found that IL8 mRNA was significantly increased in all three subgroups in BA (Fig. 1A) above non-BA and normal controls (NC). At the protein level, the concentration of serum IL-8 did not differ between BA and nonBA subjects, regardless of the age groups (Fig. 1B). These results are similar to those reported in the original publication when the subjects were analyzed as single groups of BA and non-BA.1 As discussed,1 the lack of differences in serum IL-8 contrasts with previous studies that reported increased concentrations of serum IL-8 in subjects with BA.2,3 Although the reasons for the discrepancies are not obvious, one likely possibility is that our patients were analyzed at the time of diagnosis, with an average age of 2.01 6 0.7 months (mean 6 SD) in subjects with BA and 1.8 6 0.7 months with non-BA, which contrasts with subjects at later stages of disease, with an average of 8.7 6 2.1 months in reference2 and 6.3 6 0.6 years in reference.3 Future studies investigating the use of IL8, LAMC2, and other genes and proteins in aiding the diagnosis of BA may provide
CORRESPONDENCE
733
insight into the mechanisms of the disease. They may also uncover biomarkers of stages of disease at diagnosis, allow for monitoring of progression of disease, and design individualization of treatment protocols to block progression of liver disease. REENA MOURYA, M.PHARM. KAZUHIKO BESSHO, M.D., PH.D. PRANAVKUMAR SHIVAKUMAR, PH.D. JORGE A. BEZERRA, M.D. Division of Gastroenterology Hepatology and Nutrition Cincinnati Children’s Hospital Medical Center Cincinnati, OH
References 1. Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Rao M, et al. Gene expression signature for biliary atresia and a role for Interleukin-8 in pathogenesis of experimental disease. HEPATOLOGY 2014;60:211-213. 2. Nobili V, Marcellini M, Giovannelli L, Girolami E, Muratori F, Giannone G, et al. Association of serum interleukin-8 levels with the degree of fibrosis in infants with chronic liver disease. J Pediatr Gastroenterol Nutr 2004;39:540-544. 3. Honsawek S, Chongsrisawat V, Vejchapipat P, Thawornsuk N, Tangkijvanich P, Poovorawan Y. Serum interleukin-8 in children with biliary atresia: relationship with disease stage and biochemical parameters. Pediatr Surg Int 2005;21:73-77. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27231 Potential conflict of interest: Nothing to report.
Cardiopulmonary Hemodynamics for Accurate Diagnosis of Portopulmonary Hypertension: A Redefinition to Consider To the Editor: We have read with interest the review article by Machicao et al.1 We would like to share some thoughts regarding the importance of the appropriate interpretation of the main pulmonary hemodynamic parameters obtained during right heart catheterization (RHC) that can complicate portal hypertension/liver disease, since the therapeutic approach for each one is different and outcomes clearly differ: We think that the addition of the transpulmonary gradient (TPG) >12 mmHg represents an important hemodynamic parameter for the redefinition of portopulmonary hypertension (PoPH), given that the current 2004 European Respiratory Society (ERS) and the American Association for the Study of Liver Diseases (AASLD) guidelines take into account mean pulmonary arterial pressure (mPAP), pulmonary arterial occlusion pressure (PAOP), and pulmonary vascular resistance (PVR) as the most important hemodynamic parameters.2 Recently, TPG has been very well adopted by researchers in the field of PoPH, reflecting real vasoconstriction and vasobliterative changes within the pulmonary vasculature. We believe that the utility of TPG represents an important diagnostic key for PoPH, especially while facing challenging hemodynamic scenarios where both PVR and PAOP are elevated, and which may occur in up to 25%; of patients with PoPH,1 the existence of pulmonary vascular remodeling is clearly true when TPG >12 mmHg.
In other forms of pulmonary hypertension (PH) (e.g., PH associated with left heart disease), the calculation of the diastolic pulmonary vascular pressure gradient [(DPG) 5 diastolic PAP - PAOP; normal value of DPG is 15 mmHg), and also with regard to potential prognostic implications in PoPH, stimulating researchers to perform studies in its potential utility. MATEO PORRES-AGUILAR, M.D., FACP1 DEBABRATA MUKHERJEE, M.D., M.S., FACC2 1 Department of Internal Medicine/ Division of Hospital Medicine 2 Chairman, Department of Medicine; Chief, Division of Cardiovascular Diseases Texas Tech University Health Sciences Center Paul L. Foster School of Medicine El Paso, TX
734
CORRESPONDENCE
References 1. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. HEPATOLOGY 2014;59:1627-1637. 2. Porres-Aguilar M, Altamirano JT, Torre-Delgadillo A, Charlton MR, Duarte-Rojo A. Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview. Eur Respir Rev 2012;21:223233. 3. Murray KF, Carithers RL Jr. AASLD practice guidelines: evaluation of the patient for liver transplantation. HEPATOLOGY 2005;41:1407-1432.
HEPATOLOGY, February 2015
4. Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J 2013;41:217-223. 5. Gerges C, Gerges M, Lang MB, Zhang Y, Jakowitsch J, Probst P, et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out of proportion” pulmonary hypertension. Chest 2013;143:758-766. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27234 Potential conflict of interest: Nothing to report.
Soluble CD163 Is Associated With Noninvasive Measures of Liver Fibrosis in Hepatitis C Virus– and Hepatitis C Virus/Human Immunodeficiency Virus–Infected Women To the Editor: We read with interest the article by Kazankov et al., in which levels of soluble (s)CD163—a protein produced by proteolytic cleavage of CD163 expressed on the surfaces of monocyte/macrophage lineage cells—were associated with biopsy-defined liver fibrosis in patients
with chronic hepatitis C virus (HCV) infection.1 Our group recently measured plasma sCD163, sCD14, and galectin-3–binding protein (Gal-3BP; a protein secreted by classically activated [M1] macrophages) in four groups of women enrolled in the Women’s Interagency HIV Study (WIHS): (1) those with HCV/human immunodeficiency virus (HIV) coinfection (N 5 66); (2) HCV
Fig. 1. Cross-sectional associations of plasma sCD163 with APRI (A and B) and FIB-4 (C and D) in HCV monoinfected and HCV/HIV coinfected women.
expression levels of individual subjects cannot be linked to infection by common viruses. The authors are correct that the expression of IL8 and LAMC2 misclassified 3 of 14 subjects in the nonBA group as having BA. As described in the original publication, this misclassification resulted in a specificity of 85.7%. It will be important that follow-up validation studies examine potential changes in the specificity and sensitivity of hepatic mRNA expression of IL8 and LAMC2 in the diagnosis of biliary atresia, especially in studies that include a larger population of non-BA patients as diseased controls. We agree that the analysis of IL-8 expression should take into account its relationship with age and staging of fibrosis of children with biliary atresia. Although data on histological fibrosis were not available for all subjects, we were able to perform new analyses of IL-8 expression data (both mRNA and protein levels) to directly examine its relationship with age. To this end, we subdivided the subjects and dataset based on the three suggested age subgroups of 90 days. We found that IL8 mRNA was significantly increased in all three subgroups in BA (Fig. 1A) above non-BA and normal controls (NC). At the protein level, the concentration of serum IL-8 did not differ between BA and nonBA subjects, regardless of the age groups (Fig. 1B). These results are similar to those reported in the original publication when the subjects were analyzed as single groups of BA and non-BA.1 As discussed,1 the lack of differences in serum IL-8 contrasts with previous studies that reported increased concentrations of serum IL-8 in subjects with BA.2,3 Although the reasons for the discrepancies are not obvious, one likely possibility is that our patients were analyzed at the time of diagnosis, with an average age of 2.01 6 0.7 months (mean 6 SD) in subjects with BA and 1.8 6 0.7 months with non-BA, which contrasts with subjects at later stages of disease, with an average of 8.7 6 2.1 months in reference2 and 6.3 6 0.6 years in reference.3 Future studies investigating the use of IL8, LAMC2, and other genes and proteins in aiding the diagnosis of BA may provide
CORRESPONDENCE
733
insight into the mechanisms of the disease. They may also uncover biomarkers of stages of disease at diagnosis, allow for monitoring of progression of disease, and design individualization of treatment protocols to block progression of liver disease. REENA MOURYA, M.PHARM. KAZUHIKO BESSHO, M.D., PH.D. PRANAVKUMAR SHIVAKUMAR, PH.D. JORGE A. BEZERRA, M.D. Division of Gastroenterology Hepatology and Nutrition Cincinnati Children’s Hospital Medical Center Cincinnati, OH
References 1. Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Rao M, et al. Gene expression signature for biliary atresia and a role for Interleukin-8 in pathogenesis of experimental disease. HEPATOLOGY 2014;60:211-213. 2. Nobili V, Marcellini M, Giovannelli L, Girolami E, Muratori F, Giannone G, et al. Association of serum interleukin-8 levels with the degree of fibrosis in infants with chronic liver disease. J Pediatr Gastroenterol Nutr 2004;39:540-544. 3. Honsawek S, Chongsrisawat V, Vejchapipat P, Thawornsuk N, Tangkijvanich P, Poovorawan Y. Serum interleukin-8 in children with biliary atresia: relationship with disease stage and biochemical parameters. Pediatr Surg Int 2005;21:73-77. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27231 Potential conflict of interest: Nothing to report.
Cardiopulmonary Hemodynamics for Accurate Diagnosis of Portopulmonary Hypertension: A Redefinition to Consider To the Editor: We have read with interest the review article by Machicao et al.1 We would like to share some thoughts regarding the importance of the appropriate interpretation of the main pulmonary hemodynamic parameters obtained during right heart catheterization (RHC) that can complicate portal hypertension/liver disease, since the therapeutic approach for each one is different and outcomes clearly differ: We think that the addition of the transpulmonary gradient (TPG) >12 mmHg represents an important hemodynamic parameter for the redefinition of portopulmonary hypertension (PoPH), given that the current 2004 European Respiratory Society (ERS) and the American Association for the Study of Liver Diseases (AASLD) guidelines take into account mean pulmonary arterial pressure (mPAP), pulmonary arterial occlusion pressure (PAOP), and pulmonary vascular resistance (PVR) as the most important hemodynamic parameters.2 Recently, TPG has been very well adopted by researchers in the field of PoPH, reflecting real vasoconstriction and vasobliterative changes within the pulmonary vasculature. We believe that the utility of TPG represents an important diagnostic key for PoPH, especially while facing challenging hemodynamic scenarios where both PVR and PAOP are elevated, and which may occur in up to 25%; of patients with PoPH,1 the existence of pulmonary vascular remodeling is clearly true when TPG >12 mmHg.
In other forms of pulmonary hypertension (PH) (e.g., PH associated with left heart disease), the calculation of the diastolic pulmonary vascular pressure gradient [(DPG) 5 diastolic PAP - PAOP; normal value of DPG is 15 mmHg), and also with regard to potential prognostic implications in PoPH, stimulating researchers to perform studies in its potential utility. MATEO PORRES-AGUILAR, M.D., FACP1 DEBABRATA MUKHERJEE, M.D., M.S., FACC2 1 Department of Internal Medicine/ Division of Hospital Medicine 2 Chairman, Department of Medicine; Chief, Division of Cardiovascular Diseases Texas Tech University Health Sciences Center Paul L. Foster School of Medicine El Paso, TX
734
CORRESPONDENCE
References 1. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. HEPATOLOGY 2014;59:1627-1637. 2. Porres-Aguilar M, Altamirano JT, Torre-Delgadillo A, Charlton MR, Duarte-Rojo A. Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview. Eur Respir Rev 2012;21:223233. 3. Murray KF, Carithers RL Jr. AASLD practice guidelines: evaluation of the patient for liver transplantation. HEPATOLOGY 2005;41:1407-1432.
HEPATOLOGY, February 2015
4. Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J 2013;41:217-223. 5. Gerges C, Gerges M, Lang MB, Zhang Y, Jakowitsch J, Probst P, et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out of proportion” pulmonary hypertension. Chest 2013;143:758-766. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27234 Potential conflict of interest: Nothing to report.
Soluble CD163 Is Associated With Noninvasive Measures of Liver Fibrosis in Hepatitis C Virus– and Hepatitis C Virus/Human Immunodeficiency Virus–Infected Women To the Editor: We read with interest the article by Kazankov et al., in which levels of soluble (s)CD163—a protein produced by proteolytic cleavage of CD163 expressed on the surfaces of monocyte/macrophage lineage cells—were associated with biopsy-defined liver fibrosis in patients
with chronic hepatitis C virus (HCV) infection.1 Our group recently measured plasma sCD163, sCD14, and galectin-3–binding protein (Gal-3BP; a protein secreted by classically activated [M1] macrophages) in four groups of women enrolled in the Women’s Interagency HIV Study (WIHS): (1) those with HCV/human immunodeficiency virus (HIV) coinfection (N 5 66); (2) HCV
Fig. 1. Cross-sectional associations of plasma sCD163 with APRI (A and B) and FIB-4 (C and D) in HCV monoinfected and HCV/HIV coinfected women.
