New signs and old applications of echo-color-Doppler should always be compared to a gold standard
Authors: Carlo Sabbà, Paolo Buonamico, Gennaro Mariano Lenato, Arnaldo Scardapane, Francesco D’Ovidio, Maurizio Pompili
Journal: Journal of Hepatology (2008)

We thank our colleagues for the comments to our paper, which allow us to better clarify some aspects regarding the US diagnosis of liver involvement in hereditary hemorrhagic teleangiectasia (HHT) patients. In our study, we described a new Doppler sign, called ‘color-spot’, particularly suitable for identifying small hepatic arterio-venous malformations (HAVMs) and verified its accuracy using multislice CT (MSCT) as gold standard [[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]. Moreover, we clearly distinguished the color-spots found in the peripheral subcapsular region of the liver from ‘hepatic hypervascularization’, a sign previously reported by Caselitz et al. [[2]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]. Both are suggestive of small HAVMs and provide a greater diagnostic sensitivity for HAVMs in HHT when compared to previously published extrahepatic parameters. It must be emphasized that the diagnostic sensitivity and accuracy of previous ultrasound (US) findings [2Caselitz 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, 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, 4Buscarini 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 (84) Google Scholar] cannot be defined since their results were not systematically compared to a gold standard; in fact, Doppler-negative HHT patients have never been systematically compared with other techniques. Ours is the first controlled study to assess the diagnostic accuracy of Doppler US for diagnosis of HAVMs in HHT with respect to MSCT as a reference technique. According to Buscarini et al., the use of CT as gold standard is debatable, as we employed a 4-detector CT scanner which is not the best available technology; however, these authors did not consider that our prospective study was conducted over a four-year period. Having initiated our study with a 4-detector CT scan and in order to avoid inter-equipment variability [[5]Sabbà C. Merkel C. Zoli M. Ferraioli G. Gaiani S. Sacerdoti D. et al.Interobserver and interequipment variability of echo-Doppler examination of the portal vein: effect of a cooperative training program.Hepatology. 1995; 21: 428-433PubMed Google Scholar], we preferred to prospectively study a large patient sample maintaining the same methodology, even if meanwhile a more sophisticated 16-detector scan had become available (moreover, our HHT-experienced radiologists have not found any difficulties in identifying tiny vascular abnormalities with both CT scanner systems). The two signs (color-spot described by our group and peripheral hypervascularization reported by Buscarini et al. [[4]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 (84) Google Scholar]) are two distinct echo-color-Doppler parameters. The color-spot sign appears in the presence of isolated spotty-like images with a high blood-flow velocity and a resistive index (RI) less than 0.45. It corresponds to a point on a very small peripheral tortuous arterial vessel where, due to a Doppler angle close to zero, the high Doppler frequency shift overcomes the threshold of detection, thus giving rise to a visible spotty-like image (whereas the remaining tract of the vessel, characterized by an unfavourable Doppler angle, undergoes a reduction in the intensity of the ultrasound signal, thus remaining undetected). This ‘spot effect’ is peculiar of very small vessels while tortuous vessels of larger size (such as 1st and 2nd degree branches of the hepatic artery, often protruding into the peripheral liver region) can be detected in their entire length with color Doppler, occasionally as a ‘spider-like’ sign, corresponding to the “peripheral hypervascularization” described by Buscarini et al. [[4]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 (84) Google Scholar]. Therefore, the images of peripheral hypervascularization should not be considered as a superimposition of our color-spot images. Hence, our color-spot is a new Doppler sign and not, as suggested by these authors, merely a previously-reported sign with a new name. In fact, in our cohort, we can affirm that the majority of HAVM-patients (122/128, 95%) received a positive Doppler-based diagnosis by means of the new color-spot sign, thus reaching a prevalence similar to that detected by MSCT (84%). Given the very small size of many liver AVMs [[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 (165) Google Scholar], we can also conclude that color-spots represent a sign revealing the presence of small liver AVMs even earlier than Buscarini’s peripheral hypervascularization, since the latter sign requires the visualization of the entire vessel tract to be detected (and consequently only abnormalities involving larger vessels can be depicted). We clearly defined the term hypervascularization as a “highly evident appearance of the main hepatic artery branches in the portal spaces; the higher flow velocities generated by the shunts determine tortuosity and enlargement of these vessels, evidenced by color-Doppler as tones varying in intensity from bright red to yellow orange” [[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]. In the majority of our patients, this sign was observed in absence of any extrahepatic signs or intra-hepatic B-mode-signs. Therefore, only in a few cases was it concomitant with evident hepatic artery (HA) dilatation, strongly increased HA flow velocity and other B-mode-signs included in grades 2–4 of the classification reported by Buscarini [[4]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 (84) Google Scholar]. Rather, hypervascularization seems to even indicate an only moderate increase of blood flow velocity in HA branches which might be secondary to numerous subcapsular, low-RI, micro-AVMs with little haemodynamic impact, which accounts for its use as a sign suggestive of small AVMs. Therefore, it cannot always be suggestive of “obvious, prominent vascular abnormalities”. Our results clearly show that intra-hepatic signs (both color-spots and hypervascularization) have a better sensitivity and accuracy than extrahepatic ultrasonography parameters (95–82% vs 40%, and 90–81% vs 50%, respectively). Regarding this point, Buscarini et al. noted that we utilized the cut-off values reported by Caselitz et al. [[2]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] particularly the HA diameter of >7 mm, and stated that this cut-off might be affected by a selection bias, and, consequently, determine “the risk of a low diagnostic sensitivity when applied to the screening of a general HHT population”. The use of a lower cut-off is suggested, as proposed in their classification, (HA > 6 mm in grade 1 and HA diameter >5 mm–<6 mm in grade 0+) [[4]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 (84) Google Scholar]. Therefore, to dispel their concerns, in the present letter we report our data on intra-hepatic signs with respect to the HA diameter, taking into account both cut-offs (Caselitz [[2]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 Buscarini [[4]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 (84) Google Scholar], Table 1).Table 1Color-spot, hypervascularization and hepatic artery RI (<0.55) in MSCT+/MSCT− patients according to HA diameter cut-off (mm)ParametersHA > 7HA > 6/⩽7HA > 5/⩽6HA ⩽ 5TotalMSCT+ patients46193924128Color-spot46193621122Hypervascularization46182913106HA-RI < 0.551224422MSCT− patients1261625Color-spot01359Hypervascularization01326HA-RI < 0.5500213Abbreviations: MSCT = multislice computer tomography; RI = resistive index; HA = hepatic artery. Open table in a new tab Abbreviations: MSCT = multislice computer tomography; RI = resistive index; HA = hepatic artery. As shown, the use of a lower hepatic artery diameter cut-off (>6 mm, grade 1) would not determine a significant increase in HAVM-positive patients (from 46/128 to 65/128 pts), and consequently in the sensitivity of HAVM detection of our cohort (from 35% to 50% sensitivity). Utilizing an even lower cut-off (>5 mm, grade 0+) would definitely permit an increase in HAVM-positive patients (from 65/128 to 104/128 pts), and thus in the sensitivity (although to a lesser extent than the intra-hepatic parameters, 80% for HA diameter vs 95% for color-spot), but would also determine a decrease in specificity and accuracy (64% and 77% for HA diameter vs 68% and 90% for color-spot), given the evident overlapping with MSCT-negative patients (together with non-HHT subjects and non-HHT-related cirrhotic patients). On the other hand, to avoid such a decrease in specificity, Buscarini et al. [[4]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 (84) Google Scholar] included their grade 0+ among the grid of parameters also requiring the detection of another extrahepatic parameter (namely, hepatic artery resistive index (HA-RI) < 0.55). In the table, the results based on HA-RI show that a very low sensitivity value (13%) would result. Actually, the majority of cases without dilatation of HA (using both Caselitz and Buscarini’s thresholds) had both color-spots and hypervascularization, thus further supporting our statement that intra-hepatic parameters have a better sensitivity and accuracy than extrahepatic ultrasonography parameters due to their ability to permit the diagnosis of even very small AVMs in their early stage of development. Evidently the presence of more severe vascular involvement determines an angiodynamic remodelling and gross abnormalities which can be detected on B-mode ultrasonographic study (mainly enlargement of HA in the extrahepatic tract and ‘double channel aspect’ in the portal spaces). In conclusion, in this first controlled, prospective study, we have demonstrated that the diagnosis of HAVMs in HHT can reliably be made by merely using intra-hepatic parameters and does not require evidence of extrahepatic abnormalities. The latter are useful to grade the haemodynamic impact of HAVMs and the possible effect on liver angioarchitecture and clinical significance. We disagree with Dr. Buscarini’s final comment in which she states that “Doppler US diagnosis of liver VMs in HHT requires a combination of extrahepatic and intra-hepatic findings, which can provide a diagnostic accuracy ranging between 95% and 99% for different observers” [[7]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] because in the absence of a standard reference technique, data on sensitivity and accuracy cannot be considered reliable.