Doppler ultrasonography for the diagnosis of liver vascular malformations in hereditary hemorrhagic telangiectasia

We read with interest the paper by Buonamico et al. [[1]Buonamico P. Suppressa P. Lenato G.M. Pasculli P. D’Ovidio F. Memeo M. et al.Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study.J Hepatol. 2008; 48: 811-820Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar] regarding Doppler ultrasonography (US) for the diagnosis of liver vascular malformations (VMs) in hereditary hemorrhagic telangiectasia (HHT). Doppler US has been proposed for the detection of liver VMs in HHT for the last 15 years [2Buscarini E. Buscarini L. Civardi G. Arruzzoli S. Bossalini G. Piantanida M. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: imaging findings.AJR. 1994; 163: 1105-1110Crossref PubMed Scopus (106) Google Scholar, 3Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar]; the test’s parameters have shown excellent sensitivity and specificity [3Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 4Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar], and thus it has been confirmed as a first-line imaging technique for liver VMs in HHT [[5]Buscarini E. Plauchu H. Garcia Tsao G. White Jr., R.I. Sabba‘ C. Miller F. et al.Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.Liver Int. 2006; 26: 1040-1046Crossref PubMed Scopus (136) Google Scholar].The present study offers further validation of the diagnostic accuracy of Doppler US for liver VMs in HHT against a reference technique (multi-slice CT, MSCT). Liver MSCT has been used for an extensive study of HHT families [[6]Ianora A.A. Memeo M. Sabba’ C. Cirulli A. Rotondo A. Angelelli G. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement.Radiology. 2004; 230: 250-259Crossref PubMed Scopus (166) Google Scholar], but the accuracy of this technique remains to be demonstrated, as it was a descriptive study without a standard of reference. The use of CT as the reference standard for the diagnosis of liver VMs is thus debatable, as one wonders whether every incongruous result is due to an error of either the technique under trial or the “reference” technique. This question applies to the nine cases in which the so-called “color spot sign” proved positive but the classification was false-positive (as CT was negative) [[1]Buonamico P. Suppressa P. Lenato G.M. Pasculli P. D’Ovidio F. Memeo M. et al.Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study.J Hepatol. 2008; 48: 811-820Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. We wonder if these cases were actually in fact, misdiagnoses by CT, particularly since the Authors used a 4-detector CT scanner, which is not the best available technology, especially for detection of tiny vascular anomalies.The Authors describe color spots as a sign of liver VMs in HHT, but it seems rather a new name for an already-reported sign. We have described with a Doppler study tortuous small arterial branches with a low resistivity index (RI) [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], with imaging findings strictly superimposable to those listed by Authors in their Figs. 4A, B and C; this aspect is even better shown with the newer energy Doppler technologies [[8]Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. This sign has previously been referred to by the term peripheral hypervascularization[[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], which seems more appropriate than the term “color spot”, as these micro-VMs are typically depicted as tiny, “spider-like” vessels [7Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar, 8Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. Peripheral hypervascularization is one of the elements contributing to the severity grading of hepatic VMs in HHT [7Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar, 8Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. In the earliest stage of liver VMs (grade 0 + by our classification [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar]), peripheral vascularization has to be carefully sought out; otherwise, sufficient Doppler US data might be lacking. On the other hand, the term hepatic hypervascularization, which has been used by Caselitz et al. [[4]Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar] and not by us, includes the whole spectrum of intrahepatic abnormalities of hepatic artery branches (from grades 2 to 4 of our classification). Whereas peripheral hypervascularization refers to small peripheral VMs, hepatic hypervascularization refers to obvious, prominent vascular abnormalities: it thus seems misleading to use this term for small VMs, as proposed by Buonamico et al.The Authors claim a low sensitivity for extrahepatic parameters, the main one being the diameter of the hepatic artery. Actually, they have used for this study a cut-off value (>7 mm) that was calculated as a threshold with 100% specificity and sensitivity on the basis of findings in 25 subjects with severe vascular abnormalities [[4]Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar]. It is clear that using US criteria derived from such a population entails the risk of a low diagnostic sensitivity when applied to the screening of a general HHT population. On the other hand, the proposed cut-off value of >6 mm [3Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar] for the hepatic artery diameter has no overlap with normal subjects in the series by Buonamico and Caselitz [1Buonamico P. Suppressa P. Lenato G.M. Pasculli P. D’Ovidio F. Memeo M. et al.Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study.J Hepatol. 2008; 48: 811-820Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 4Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar]. This cut-off value would have allowed for the diagnosis of the majority of the MSCT-positive patients of the Buonamico et al. series; almost all of the cases would have been identified by using the criteria of our classification [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], including those at stage 0 + (HA diameter >5 < 6 mm).Evaluation of the proper hepatic artery can give important information about hepatic circulation, and we agree with the Authors’ hypothesis, already reported in 1997 [[3]Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar], that morphologic and flow changes found in the extrahepatic artery depend on increased hepatic blood flow through VMs, even when they are microscopic. Doppler US diagnosis of liver VMs in HHT requires a combination of extrahepatic and intrahepatic findings [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], which can provide a diagnostic accuracy ranging between 95% and 99% for different observers [[8]Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. We read with interest the paper by Buonamico et al. [[1]Buonamico P. Suppressa P. Lenato G.M. Pasculli P. D’Ovidio F. Memeo M. et al.Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study.J Hepatol. 2008; 48: 811-820Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar] regarding Doppler ultrasonography (US) for the diagnosis of liver vascular malformations (VMs) in hereditary hemorrhagic telangiectasia (HHT). Doppler US has been proposed for the detection of liver VMs in HHT for the last 15 years [2Buscarini E. Buscarini L. Civardi G. Arruzzoli S. Bossalini G. Piantanida M. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: imaging findings.AJR. 1994; 163: 1105-1110Crossref PubMed Scopus (106) Google Scholar, 3Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar]; the test’s parameters have shown excellent sensitivity and specificity [3Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 4Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar], and thus it has been confirmed as a first-line imaging technique for liver VMs in HHT [[5]Buscarini E. Plauchu H. Garcia Tsao G. White Jr., R.I. Sabba‘ C. Miller F. et al.Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.Liver Int. 2006; 26: 1040-1046Crossref PubMed Scopus (136) Google Scholar]. The present study offers further validation of the diagnostic accuracy of Doppler US for liver VMs in HHT against a reference technique (multi-slice CT, MSCT). Liver MSCT has been used for an extensive study of HHT families [[6]Ianora A.A. Memeo M. Sabba’ C. Cirulli A. Rotondo A. Angelelli G. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement.Radiology. 2004; 230: 250-259Crossref PubMed Scopus (166) Google Scholar], but the accuracy of this technique remains to be demonstrated, as it was a descriptive study without a standard of reference. The use of CT as the reference standard for the diagnosis of liver VMs is thus debatable, as one wonders whether every incongruous result is due to an error of either the technique under trial or the “reference” technique. This question applies to the nine cases in which the so-called “color spot sign” proved positive but the classification was false-positive (as CT was negative) [[1]Buonamico P. Suppressa P. Lenato G.M. Pasculli P. D’Ovidio F. Memeo M. et al.Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study.J Hepatol. 2008; 48: 811-820Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. We wonder if these cases were actually in fact, misdiagnoses by CT, particularly since the Authors used a 4-detector CT scanner, which is not the best available technology, especially for detection of tiny vascular anomalies. The Authors describe color spots as a sign of liver VMs in HHT, but it seems rather a new name for an already-reported sign. We have described with a Doppler study tortuous small arterial branches with a low resistivity index (RI) [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], with imaging findings strictly superimposable to those listed by Authors in their Figs. 4A, B and C; this aspect is even better shown with the newer energy Doppler technologies [[8]Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. This sign has previously been referred to by the term peripheral hypervascularization[[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], which seems more appropriate than the term “color spot”, as these micro-VMs are typically depicted as tiny, “spider-like” vessels [7Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar, 8Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. Peripheral hypervascularization is one of the elements contributing to the severity grading of hepatic VMs in HHT [7Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar, 8Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. In the earliest stage of liver VMs (grade 0 + by our classification [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar]), peripheral vascularization has to be carefully sought out; otherwise, sufficient Doppler US data might be lacking. On the other hand, the term hepatic hypervascularization, which has been used by Caselitz et al. [[4]Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar] and not by us, includes the whole spectrum of intrahepatic abnormalities of hepatic artery branches (from grades 2 to 4 of our classification). Whereas peripheral hypervascularization refers to small peripheral VMs, hepatic hypervascularization refers to obvious, prominent vascular abnormalities: it thus seems misleading to use this term for small VMs, as proposed by Buonamico et al. The Authors claim a low sensitivity for extrahepatic parameters, the main one being the diameter of the hepatic artery. Actually, they have used for this study a cut-off value (>7 mm) that was calculated as a threshold with 100% specificity and sensitivity on the basis of findings in 25 subjects with severe vascular abnormalities [[4]Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar]. It is clear that using US criteria derived from such a population entails the risk of a low diagnostic sensitivity when applied to the screening of a general HHT population. On the other hand, the proposed cut-off value of >6 mm [3Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar] for the hepatic artery diameter has no overlap with normal subjects in the series by Buonamico and Caselitz [1Buonamico P. Suppressa P. Lenato G.M. Pasculli P. D’Ovidio F. Memeo M. et al.Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study.J Hepatol. 2008; 48: 811-820Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 4Caselitz M. Bahr M.J. Bleck J.S. Chavan A. Manns M.P. Wagner S. et al.Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).Hepatology. 2003; 37: 1139-1146Crossref PubMed Scopus (76) Google Scholar]. This cut-off value would have allowed for the diagnosis of the majority of the MSCT-positive patients of the Buonamico et al. series; almost all of the cases would have been identified by using the criteria of our classification [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], including those at stage 0 + (HA diameter >5 < 6 mm). Evaluation of the proper hepatic artery can give important information about hepatic circulation, and we agree with the Authors’ hypothesis, already reported in 1997 [[3]Buscarini E. Buscarini L. Danesino C. Piantanida M. Civardi G. Quaretti P. et al.Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.J Hepatol. 1997; 26: 111-118Abstract Full Text PDF PubMed Scopus (93) Google Scholar], that morphologic and flow changes found in the extrahepatic artery depend on increased hepatic blood flow through VMs, even when they are microscopic. Doppler US diagnosis of liver VMs in HHT requires a combination of extrahepatic and intrahepatic findings [[7]Buscarini E. Danesino C. Olivieri C. Lupinacci G. De Grazia F. Reduzzi L. et al.Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.Ultraschall Med. 2004; 25: 348-355Crossref PubMed Scopus (85) Google Scholar], which can provide a diagnostic accuracy ranging between 95% and 99% for different observers [[8]Buscarini E. Gebel M. Ocran K. Manfredi G. Del Vecchio Blanco G. Stefanov R. et al.Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangectasia by Doppler ultrasound.Ultrasound Med Biol. 2008; 34: 718-725Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar].