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Gastrointestinal Imaging |
1 From the Department of Internal Medicine, Ospedale A. Manzoni, Lecco, Italy (A.C., M.A., E.Z.); and Postgraduate School of Gastroenterology, IRCCS Ospedale Maggiore, Padiglione Granelli 3° piano, Via F. Sforza 35, 20122 Milan, Italy (M.F., B.M., D.C.). Received April 2, 2002; revision requested June 5; revision received June 13; accepted July 25. Supported by Associazione Amici della Gastroenterologia del Granelli (AAGG), CARIPLO Foundation, and Research Competition Award 2000 from IRCCS Ospedale Maggiore, Milan, Italy. Address correspondence to D.C. (e-mail: dario.conte@unimi.it).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Three hundred consecutive asymptomatic patients with at least 6 months of increased levels of aspartate aminotransferase and/or alanine aminotransferase underwent liver US and biopsy. The estimated pretest probability of severe fibrosis or cirrhosis was 35%. Three US parameters were investigated: liver surface nodularity, caudate lobe hypertrophy, and pattern of hepatic venous blood flow. US results were compared with histologic results obtained after liver biopsy, which constituted the reference standard for diagnosis of severe fibrosis or cirrhosis. The degree of fibrosis was graded according to METAVIR criteria, with stages 3 and 4 considered together. Data were analyzed with 
and 
2 statistics. Sensitivity, specificity, positive and negative likelihood ratios, and posttest probability were calculated for each US sign.
RESULTS: In 107 (36%) patients with severe fibrosis (n = 34) or cirrhosis (n = 73), liver surface nodularity had the highest diagnostic accuracy, with specificity of 95% and positive and negative likelihood ratios 11.6 and 0.51, respectively. When liver surface nodularity was considered alone, posttest probability of severe fibrosis or cirrhosis increased from 35% to 86%. When caudate lobe hypertrophy and hepatic venous blood flow were also taken into account, posttest probability increased by only 2% (ie, to 88%).
CONCLUSION: US determination of liver surface nodularity is an accurate method for identifying the subset of asymptomatic patients with severe liver fibrosis or cirrhosis, which indicates a worse prognosis.
© RSNA, 2003
Index terms: Liver, cirrhosis, 761.794 • Liver, fibrosis, 761.794 • Liver, US, 761.12981, 761.12984
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The purpose of our study was to determine the accuracy of various US signs in the assessment of the degree of liver fibrosis, as compared with histologic findings.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The study plan was approved by the pertinent ethics committees and included clinical examination (demographics, medical history including possible risk factors for chronic liver disease, and physical examination), routine laboratory investigations, liver US, and liver biopsy. The patients who agreed to undergo liver biopsy gave written informed consent to participate in the study.
Liver disease was attributed to chronic ethanol abuse (ie, daily alcohol intake of at least 60 g (approximately 600 mL of wine) for women and at least 80 g (approximately 840 mL of wine) for men for the previous five years), chronic infection with hepatitis B or C virus, hereditary hemochromatosis, nonalcoholic steatohepatitis, or primary biliary cirrhosis diagnosed on the basis of accepted criteria (17–19).
US Examination and Scan Evaluation
US of the liver was performed by two gastroenterologists (A.C., M.F.) after the patients underwent an overnight fast. An ATL HDI 5000 unit (Advanced Technology Laboratories, Bothell, Wash) with both 3.5- and 5–12-MHz transducers was used. The presence of two signs was specifically sought. The first sign was liver surface nodularity, which was assessed by using a 5–12-MHz transducer to examine the whole liver surface and the outer 2–3 cm of the liver parenchyma. The sign was searched for in both the left and the right lobes with multiple scans. The finding was considered to be positive if, instead of a straight and regular hyperechoic line, the liver surface appeared as a dotted or irregular line and/or the liver parenchyma was not homogeneous but showed areas with different echogenicity, reflecting an underlying nodularity (Fig 1).
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In addition, hepatic venous blood flow was recorded for more than 5 seconds at the end of normal expiration by using a 3.5-MHz transducer with Doppler capability (13,14). Flow in the right hepatic vein was evaluated at the level of the 10th or 11th intercostal space, 6–8 cm from the confluence of the hepatic vein and inferior vena cava. In accordance with criteria proposed by Bolondi et al (13), three types of flow were considered: Type 0 (triphasic pattern) was considered to be normal flow, whereas type 1 (biphasic) and type 2 (monophasic) were considered to be abnormal (Fig 2).
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Liver Biopsy and Evaluation
Transcostal or subcostal liver biopsy was performed (D.C., M.A., or B.M.) with US guidance by using an 18-gauge needle (Biomol; Hospital-Service, Pomezia-Rome, Italy), and specimens of 2 cm in length or longer were fixed in formalin and stained with hematoxylin-eosin, stain for reticulin, and Masson trichrome. The histologic grade and stage were classified according to the criteria of the METAVIR Cooperative Study Group (20), and, for the purposes of this study, five degrees of fibrosis were recognized: absent, mild, moderate, severe, and already established cirrhosis (scores of 0, 1, 2, 3, and 4, respectively). Histologic characteristics were defined in blinded fashion by a single experienced pathologist (E.Z.). Scores of 0–2 were considered to indicate normal histologic features, and scores of 3 or 4 were considered to indicate abnormal features. The overall results of liver histologic examinations were considered the reference standard for ascertaining the presence and degree of fibrosis.
Liver biopsy was well tolerated. The rate of transient morbidity (ie, local pain and/or nausea) was 2.3% (seven of 300), and symptoms subsided within 6 hours without medical therapy. In patients with severe fibrosis or cirrhosis, the clinical severity of liver disease was classified in consensus by three authors (D.C., M.A., B.M.) according to the Child-Pugh scheme (21).
Statistical Analysis
Statistical analysis was performed by calculating the statistic to assess agreement between the various US signs and the histologic results. The proportion of potential agreement beyond chance that is achieved when comparing two or more clinical findings or the results of different signs was considered as slight ( = 0.00–0.20), fair ( = 0.21–0.40), moderate ( = 0.41–0.60), substantial ( = 0.61–0.80 ), or almost perfect ( = 0.81–1.00) (22).
The overall estimated pretest probability of severe fibrosis or cirrhosis was 35% (10% for severe fibrosis, 25% for cirrhosis) (23–25). The sensitivity, specificity, positive and negative likelihood ratios, positive predictive value, and posttest likelihood given a negative test result of the US signs with regard to a diagnosis of severe fibrosis or cirrhosis were assessed for each US sign (26,27). Severe fibrosis and established cirrhosis (staging scores of 3 and 4) were considered together. Technically inadequate US findings were considered on the basis of intention to diagnose (ie, false-negative or false-positive in the presence or absence, respectively, of the target disease).
The 2 test was used to evaluate differences in the prevalence of liver surface nodularity, caudate lobe hypertrophy, and hepatic venous blood flow pattern in relation to the two classes of fibrosis. The sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios, with their corresponding 95% CIs, were calculated for each US sign. Inter- and intraobserver agreement of the three US findings were calculated in terms of values ( 
0.4), with 95% CIs (22).
A subgroup analysis was performed to correlate the presence of each US sign with the cause of liver disease: chronic hepatitis due to hepatitis B or C virus infection versus alcoholic chronic liver disease; nonalcoholic steatohepatitis versus miscellaneous chronic liver disease (the latter group also included hemochromatosis and primary biliary cirrhosis).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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2 = 41.04; P < .001). In the latter 79 cases, at least one US sign was detected in 16 (47%) of 34 patients with grade III fibrosis and in 63 (86%) of 73 patients with grade IV fibrosis. The value, which represents the proportion of potential agreement beyond chance between US signs and liver biopsy results, was 0.52 for liver surface nodularity, 0.35 for caudate lobe hypertrophy, and 0.32 for hepatic venous blood flow. When considering the presence of at least one US sign and all three US signs together, the corresponding values were 0.48 and 0.51, respectively (Tables 3, 4).
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2 = 41.04, P < .001). Finally, the values for inter- and intraobserver agreement, respectively, were 0.80 and 0.75 for liver surface nodularity, 0.70 and 0.83 for caudate lobe hypertrophy, and 0.81 and 0.79 for hepatic venous flow. In the subgroup analysis, no statistically significant differences were observed in the sensitivity and specificity of the three US findings in relation to the different causes. In particular, for liver surface nodularity, which was the more accurate US parameter, sensitivities of 57% (29 of 51), 53% (17 of 32), and 50% (12 of 24) and specificities of 94% (87 of 92), 96% (56 of 58), and 95% (41 of 43) were found for viral, alcoholic and nonalcoholic chronic liver disease, and miscellaneous liver disease, respectively. Furthermore, as regards the nine false-positive results for the US sign of surface nodularity (Table 2), the results were equally distributed among the different etiologic subgroups, and only three of the patients had histologic evidence of liver steatosis (one with hepatitis C virus–related chronic hepatitis, two with nonalcoholic fatty liver disease).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In a population with comparable characteristics, the average prevalences of histologically proved severe fibrosis or cirrhosis have been reported to be 10% and 25%, respectively, in different large series (23–25). Assuming these numbers to be the "pretest" probability of having cirrhosis, we assessed the role of tested and validated US findings (liver surface nodularity, caudate lobe hypertrophy, and hepatic venous flow) (6,7,10–15) for prediction of the presence and severity of liver fibrosis. This was accomplished by calculating the positive and negative likelihood ratios and the corresponding increase in posttest probability. The US data were compared with results from histologic evaluation, which are still considered to be the reference standard for diagnosis and staging of liver fibrosis (28). The degree of fibrosis at liver biopsy is relevant because its negative prognostic importance has been repeatedly reported (25,29) in patients with chronic liver disease of different origins. For example, in patients with chronic hepatitis C virus infection, the actuarial survival curves significantly differ according to degree of fibrosis, with the worst survival being similarly observed in patients with stage 3 (transitional) fibrosis or stage 4 (established) cirrhosis (29). On the basis of these data, we considered stage 3 and 4 fibrosis as a single class.
As shown in our study, the individual US data were not very sensitive (41%–57%) but were highly specific (76% for hepatic venous flow to 95% for liver surface nodularity). A considerable proportion of agreement was observed between liver surface nodularity at US and liver histologic results, and fair agreement was obtained for caudate lobe hypertrophy and hepatic venous flow. US signs and histologic results were also in agreement when considering the presence of at least one US sign and the concomitant presence of all three US findings.
The high positive likelihood ratio of 11.6 for liver surface nodularity approximately tripled (from 35% to 86%) the posttest probability of severe fibrosis, in comparison to the pretest probability. Interestingly, the role of liver surface nodularity was further supported by the fact that even when the three US signs were combined, the positive likelihood ratio changed only slightly (from 11.6 to 13.8). Also, the poor sensitivity associated with the presence at least one positive US finding excluded its effectiveness in ruling out the presence of more advanced fibrosis, as was indicated by negative US findings in 28 of 107 patients with stage 3 or 4 fibrosis; conversely, the fact that all three US findings were false-positive in only three of 193 patients with no to moderate fibrosis supports the role of these parameters (particularly liver surface nodularity) in confirmation of the diagnosis of severe fibrosis.
Overall, the US findings were sufficiently specific to allow a diagnostic confirmatory strategy (30), thus indicating that a positive result can "rule in" the target (ie, liver fibrosis); on the contrary, the sensitivity of at least one US finding was too low to support a screening diagnostic strategy, thus indicating that a negative result cannot help rule out the target (30). On the basis of the high values obtained for inter- and intraobserver agreement, all of the US parameters proved to be reproducible, but these results should be confirmed with others series.
In many instances, liver biopsy is performed primarily to assess the severity of liver disease: that is, to evaluate the extent of fibrosis (staging). Also, at least in cases of chronic hepatitis C virus infection, the finding of fibrosis has a pivotal role in therapeutic decision making (28). We could have prevented about 22% of biopsies, assuming that the biopsies would have been performed only for the purpose of staging liver disease, and in only few cases would we have overestimated the presence of fibrosis. However, it must be taken into account that histologic findings can be more informative because the fibrous pattern (eg, pericentral, bridging nature of nodular pattern), as well as the possibility of diagnosing the primary disease, are important and often clinically relevant in planning the care of patients.
A population of patients with asymptomatic chronic liver disease was chosen in order to maximize the clinical effectiveness of a US diagnosis; on this basis, only US signs for assessing liver parenchyma were used, whereas those consistent with more advanced liver disease (eg, reduction in portal venous flow velocity and presence of portosystemic shunts and/or splenomegaly and/or ascites) were not included. At US scanning, liver surface nodularity should reflect the presence of regenerative nodules and fibrous septa, which are the essential histologic findings for diagnosing cirrhosis (1); it is, therefore, not surprising that this sign was the most accurate. Liver surface nodularity can be a subjective parameter, however, and its reproducibility should be confirmed in other series. Moreover, surface nodularity could also be influenced by different factors, mainly local fatty infiltration. For these reasons, liver surface nodularity was assessed by using multiple scans of both the left and the right hepatic lobes. In addition, with regard to the possible influence of liver steatosis, no differences in the sensitivity and specificity of surface nodularity were observed when subgroups of patients were analyzed according to cause of disease. As we detailed, of the nine false-positive results for liver surface nodularity, only three were accompanied by histologic evidence of liver steatosis.
With regard to Doppler US evaluation of hepatic venous flow, the pattern should indicate compliance of liver parenchyma completely surrounding the thin-walled veins. However, flattened hepatic venous flow waveforms were found in only 57% of patients with severe liver fibrosis. The specificity of this sign was 76%, lower than that of the other US signs, since it can be influenced by various factors, particularly the degree of fatty infiltration (14,15). A further limitation of the applicability and effectiveness of hepatic venous flow measurement is the need for normal cardiac function and rhythm. Finally, the lack of caudate lobe hypertrophy in most (59%) of our patients was due to the selection criteria, which excluded patients with fully developed cirrhosis that may have been responsible for progressive shrinkage of the lateral segments and enlargement of the lobe.
These US signs have been validated in previous studies (6,10–15), but it is difficult to compare the results of those studies with ours for a number of reasons. The current reference standard of histologic diagnosis of cirrhosis is not perfect, because the required pathologic criteria are 100% specific but less than 70% sensitive, mainly owing to sampling error (4,5). To improve the sensitivity of histologic evaluation, Gaiani et al (6) added a follow-up of 6 months to identify which patients had rapid clinical deterioration. They found that eight of their 32 false-positive cases (US signs consistent with cirrhosis but no histologic confirmation) developed ascites, esophageal varices, or liver failure and could essentially be reclassified as true-positive. However, it is worth noting that the usual rate of decompensation in newly diagnosed cirrhosis has been reported to be lower than 10% per year (31), which suggests that a much longer follow-up should be planned to redefine the false-positive rate.
In an attempt to reduce the false-negative rate in the present series, patients with transitional or established cirrhosis were considered together; therefore, almost absolute sensitivity was achieved (albeit at the expense of specificity); in other words, this strategy allowed us to identify all patients with the worst prognosis, despite the concomitant inclusion of some patients with less advanced disease. A further effect of our strategy for maximizing the sensitivity of the reference standard (at the expense of specificity) was the consequently lower US sensitivity for the diagnosis of severe fibrosis than that obtained by other authors (6,7,10–14), who could not, however, precisely define the specificity of their results.
Furthermore, the present series reflects everyday clinical experience, insofar as the prevalence of severe fibrosis or cirrhosis (35%) was similar to that reported in large epidemiologic series (23–25). In some previous studies (7,10), more than 50% of patients in the series had cirrhosis, and a relevant subgroup of patients had a decompensated clinical status; in this latter subgroup, US results were unlikely to improve accuracy in the diagnosis. This striking difference in the composition of the tested populations is largely responsible for the discrepancy in the reported diagnostic performance of US findings for detecting the presence of severe fibrosis (6,7,10–15).
Overall, liver US is relatively insensitive but highly specific for the detection of liver fibrosis and may have considerable value with regard to selection of patients in whom closer follow-up is advisable. However, despite the fact that the sampling error rate is not negligible, liver histologic examination maintains a pivotal role in evaluation of the grade (ie, severity of inflammation) and stage (ie, degree and distribution of fibrosis) of chronic liver disease, as well as in the etiologic evaluation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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