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Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis
Journal of Hepatology 1999; 30:472M-78 Printed in Denmark • All rights reserved Munksgaard. Copenhagen
Copyright © European Association Jbr the Study ~f the Liver 1999 Journal of Hepatology ISSN 0168-8278
Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis Christophe Aub6 l, Frtdtric Oberti 2, Nouri Korali 1, Marc-Antoine N a m o u r I , Didier Loisel 1, Jean-Yves Tanguy j , Emmanuelle Valsesia 1'2, Christophe Pilette 2, Marie Christine Rousselet 3, Pierre Bedossa 4, Herv6 Rifflet 2, Moussa Y. Ma~ga 2, Dominique Penneau-Fontbonne 5, Christine Caron 1 and Paul Cal6s 2 1Serviee de Radiologie, C H ~ . 2Service d'Hkpato-Gastroent~rologie, C H U and 3Laboratoire d'Anatomie-Pathologique, CHU, Angers; 4Service d'Anatornie et Cytologie Pathologiques, CHU, Kremlin-Bic~tre; and 5Service de MOdeeine E, CHU, Angers, France
Background~Aims: Evaluation of the degree of hepatic fibrosis is especially important in patients with chronic liver disease. Our aim was to study the diagnostic accuracy of abdominal ultrasonography for cirrhosis or fibrosis. Methods: Twenty-three clinical (n=12) and Doppler ultrasonic ( n = l l ) variables were recorded in 243 patients with chronic (alcoholic and viral) liver disease under conditions close to those of clinical practice. Fibrosis was classified into six grades by two pathologists. Diagnostic accuracy was evaluated by discriminant analysis, first globally using all variables, then by stepwise analysis. Results: A) Diagnosis of cirrhosis: 1) whole group (n=243): diagnostic accuracy was globally 84%, and 84% with two variables: spleen length, portal velocity; 2) compensated chronic liver disease (n=191): diagnostic accuracy was globally 85%, and 82% with two variables: liver surface, liver length (right kidney); 3)
alcoholic compensated chronic liver disease (n=109): diagnostic accuracy was globally 86%, and 88% with two variables: spleen length, liver length (middle clavicle); 4) viral compensated chronic liver disease (n= 83): diagnostic accuracy was globally 86% and 86% with one variable: liver surface. By subtracting the proportion of patients who could not be investigated due to anatomical limitations, the highest calculated univariate diagnostic accuracy decreased by 7%. B) Diagnosis of fibrosis: diagnostic accuracy was globally 84% for extensive fibrosis. Conclusions: Cirrhosis can be correctly diagnosed in 82-88% of patients with chronic liver disease using a few ultrasonographic signs. However, the diagnostic accuracy of ultrasound is decreased by the anatomical limitations of this technique.
IVER FIBROSISis a common development in chronic
revealed by complications and the risk of variceal rupture is maximal in the 2 years following diagnosis (3). On the other hand, cirrhosis is a common disease (4) which is frequently undiagnosed (5). Recently, several indirect diagnostic tests for cirrhosis have been evaluated. These markers included either clinical signs (6,7), ultrasonographic signs (820), endoscopic signs (21-26) or blood biochemical parameters (7). In a recent study, the diagnostic accuracy (DA) of ultrasonography for cirrhosis was found to be 80% with discriminant analysis (19). Moreover, it has been suggested that ultrasonography may be used to identify cirrhosis even in the absence of a typical histopathological pattern (19). Thus, the sensitivity of liver biopsy in diagnosing cirrhosis has been estimated to be 62% and that of ultrasonography 87% (27). The main aim of the present prospective study was
L liver disease. The most evolved stage of liver fibrosis is cirrhosis, which places the patient at risk of clinical complications such as portal hypertension, hepatocellular dysfunction and cancer. As the definition of cirrhosis is histopathological, liver biopsy is the key examination for diagnosis. However, in clinical practice, the use of liver biopsy has several limitations, in particular sample errors with an estimated mean of 24% of false negatives in the series of blind liver biopsies (1) and complications (2). Early diagnosis is essential since cirrhosis is often Received 6 May; revised 22 September; accepted 28 September 1998
Correspondence." Paul Calts, Service d'Htpato-Gastroenttrologie, CHU, 49033 Angers Cedex 01, France. Tel: +33 2 41 35 34 10. Fax: +33 2 41 35 41 19. E-mail: [email protected] 472
Key words: Abdominal ultrasound; Cirrhosis; Diagnostic accuracy; Doppler ultrasound; Hepatic fibrosis~
Diagnosis of hepatic cirrhosis
to determine the DA (percentage of patients correctly classified) of ultrasonographic signs for the evaluation of hepatic fibrosis or cirrhosis by multivariate analysis in order to select independent predictive signs of cirrhosis. Patients and M e t h o d s Patients The 243 consecutive patients included in this study were admitted to the hepatogastroenterology unit of the University Hospital in Angers, France, in 1994-5 for alcoholism or alcoholic liver disease, or for chronic hepatitis B or C infection. Patients were included if they had drunk at least 50 g of alcohol per day for the past 5 years, or were positive for hepatitis B surface antigen or C serum markers, and had had persistently elevated serum aminotransferases > 1.5 N for at least 6 months, or had had previous liver complications (ascites, edema). Patients with a past history of gastrointestinal bleeding were not included. None of the patients had clinical, biological, ultrasonographic or histological evidence of other causes of chronic liver disease (Wilson's disease, hemochromatosis, al-antitrypsin deficiency, biliary disease, auto-immune hepatitis, hepatocellular carcinoma). Except for these non-inclusion criteria, this study was performed under conditions close to clinical practice on an intention-to-diagnose principle. Thus, patients with incomplete ultrasonographies (e.g. gas preventing complete examination) were not excluded. Blood samples were taken at entry, and a percutaneous (n=210) or transjugular liver biopsy (n= 33) was performed within 1 week. In the latter patients, the liver specimen was fragmented in 11 cases, making image analysis impossible. Among the 243 patients, 83 had viral liver disease and 160 alcoholic liver disease, and 116 patients had cirrhosis which was decompensated in 45% (ascites and/or encephalopathy). Since no additional examina-
tions were performed compared to clinical practice, informed consent was not obtained.
Clinical evaluation A full clinical examination was performed by a senior physician. The recorded variables were: age, sex, alcohol withdrawal, known duration of liver disease (time since the first clinical or biochemical abnormality suggestive of chronic liver disease), splenomegaly (any palpable spleen), liver palpation suggestive of cirrhosis, i.e. a firm liver with a thin lower edge, abdominal venous collateral circulation, ascites, and hepatic encephalopathy. Endoscopic examinations were performed by two endoscopists (either PC or FO); however, this examination was not available in 36 patients (due to refusal, a time interval -->2months, or it was performed in another center). The grade of esophageal varices (grade 0 to 3) was evaluated according to a previously described classification (28). Blood samples were submitted to standard tests to determine the Child-Pugh score (29) to identify the degree of liver dysfunction. The distribution of the Child-Pugh classes in patients with cirrhosis was: A: 50%, B: 24%, C: 26%.
Echo-Doppler study All examinations were performed in every patient by one of four investigators (one radiologist specialized in hepatology and three general radiologists) using an Acuson 128×p/10M apparatus according to a previously described technique (30) within 1 day of liver biopsy. Radiologists were blinded for the clinical diagnosis of liver disease. The probe used was a 3.5-2.5 MHz transducer and a 7.5 MHz linear transducer. The following 11 variables were selected based on the DA reported in the literature (8-18): hepatic length at the level of the right kidney and the middle of the clavicle in a saggital plane; nodular aspect of the liver surface based on ultrasound of the left lobe with a linear high frequency transducer (7.5 MHz); liver homogeneity; ratio of the caudate lobe/left lobe length on a saggital scan which was considered abnormal if >0.33 (18); collateral circulation defined as
TABLE 1 Distribution of variables as a function of the presence of cirrhosis in the whole population na
Cirrhosis Without (n= 127)
With (n = 116)
Clinical data Sex (%M) Age (years) Cause (% alcohol) Alcohol withdrawal (%) Liver disease duration (months) Firm liver (%) Splenomegaly (%) Collateral circulation (%) Ascites (%) Encephalopathy (%) Esophageal varices (%) Child-Pugh score
243 243 243 164 199 240 241 242 243 242 207 205
67 43_+ 12 51 10 9_+23 10 0 14 2 2 10 5.2_+0.8
64 54 + 11 82 22 16---36 75 12 66 38 7 72 7.5±2.6
NS < 10 -4 <10 3 NS NS a <10 -3 < 10 -3 < 10-3 < 10- 3 =0.05 < 10 -3 <10 -4b
Echographic data Liver length (right kidney, cm) Liver length (middle clavicle, cm) Liver surface (irregular %) Liver heterogeneity (%) Spleen length (cm) Portal vein diameter (ram) Ascites (%) Collateral circulation (%) Splenic vein respiratory variation (%) Portal velocity (cm/s) Ratio caudate/left lobes (%)
225 197 229 227 214 215 232 206 153 160 151
14---2 13___2 4 11 10 ± 2 11.6+-2.1 4 2 77 28--- 12 24 +- 17
16_+3 15+--3 38 38 12---2 12.5-+ 1.8 37 17 67 22_+8 28 +- 16
<10 -4 <10 -4b < 10 -3 < 10 -3 < 10-4 < 10 -2 < 10- 3 < 10 -3 NS <10 -3b NS
a n indicates the number of patients for whom the variable was available (for more details, see methods), b Rank test.
473
C. AubO et al. surface area was considered referent areaa. The fractional surface occupied by fibrosis was measured within the above defined frame and AA represented the percentage of fibrosis in the field. When using the motorized x-y stage facilities, the biopsy could be fully explored without any field overlapping. For a given patient, the percentage of fibrosis or the area of fibrosis could be obtained on n microscopic fields as (nXAA/A)/n.
any patent umbilical vein (i.e. diameter ->3 mm) or a left gastric vein >5 mm (31) or any abnormal vein such as a spleno-renal shunt; respiratory variation of the splenic vein; spleen length; ascites; portal vein diameter; and maximum velocity of portal vein (32). These signs were evaluated in all patients.
Histological assessment o f the liver Semi-quantitative score. The biopsy specimens were fixed in a formalin-alcohol-acetic acid solution and embedded in paraffin; 3-~mthick sections were stained with hematoxylin-eosin-saffron, Masson's trichrome and 0.1% picrosirius red solution. Fibrosis was graded by two independent pathologists according to a semi-quantitative score derived from the Metavir score (33). The score for fibrosis of the portal tract (PT) was as follows: 0: no fibrosis, 1: enlarged PT without septa, 2: enlarged PT with rare septa, 3: numerous septa without cirrhosis, 4: potential cirrhosis (for small specimens obtained by transjugular biopsy), 5: definite cirrhosis; this score was called the PTF score. The interobserver agreement was excellent (intra-class correlation coefficient: r=0.78). When the two pathologists did not agree, the specimens were reexamined with a binocular microscope to analyze discrepancies and reach a consensus. Quantitative score. Image analysis was performed on the same sections as those stained with picrosirius red solution for the semi-quantitative study with a Leica Quantimet Q570 image processor. The 2D patterns were measured by direct pixel counting on the binary images. In a given microscopic field, the surface of the section occupied by the hepatic parenchyma was used as the measuring frame and this
Statistical analysis Quantitative variables were expressed as mean-+SD and were compared using the Student test unless otherwise specified. Qualitative variables were expressed as percentages and were compared using the X2 test. DA (percentage of correctly classified patients) was calculated by discriminant analysis. To assess the independent effect of qualitative or quantitative predictive variables on the DA of fibrosis (explained variable), we used discriminant analysis with forward stepwise addition of variables. To assess the independent effect of quantitative predictive variables on the prediction of the area of fibrosis, we used multiple linear regression analysis. An a risk <5% for a two-sided test was considered statistically significant.
Results Diagnosis of cirrhosis Univariate analysis. The distribution of 23 variables studied as a function of the absence or presence of cir-
TABLE 2 Diagnostic accuracy (%) for cirrhosis in the four groups of patients Whole %
Liver length (right kidney) Liver length (clavicle) Liver surface (irregular) Liver heterogeneity Spleen length Portal vein diameter Ascitesa Collateral circulation Splenic vein respiratory variation Portal velocity Ratio caudate/left lobes
70 67 68 65 74 57 67 60 59 62 56
Compensated p
<10 .3 <10 -3 <10 -3 <10 -3 <10 -3 <10 -2 <10 -3 <10 .3 NS <10 -2 NS
Alcohol+virus
Alcohol
Virus
%
p
%
p
%
p
70.5 66 73.5 71
<10 .3 <10 -3 <10 -3 <10 -3 <10 -3 <10 -2 NS <10 -2 NS NS NS
64 62 66 62 82 53 54 61 59 49 54
<0.05 NS <10 .3 <0.05 <10 --3 NS NS <0.05 NS NS NS
66 48 84 84 79 68 78 82 38 58 60
NS NS <10 -3 <10 -3 <10 .3 <0.05 <0.05 NS NS <0.05 NS
80
59 64 69 60 53.5 47
a Patients with clinical diagnosis o f ascites were excluded from the compensated group. Diagnostic accuracy ->70% is depicted in bold.
TABLE 3 Diagnostic accuracy (%) according to multivariate analysis in the different patient groups Whole population
Compensated a
Alcohol compensated
Virus compensated
Global analysis
DA: 84 (75-90) PPV: 79 (62-91) NPV: 86 (75.5-93)
DA: 85 (75-92) PPV: 65 (43-84) NPV: 92 (81.5-98)
DA: 86 (71-95) PPV: 89 (51-100) NPV: 85 (67-95)
DA: 86 (74-93) PPV: 61.5 (32-87) NPV: 92 (80--98)
Stepwise analysis
1st, spleen length: DA: 80 (71-87) 2nd, velocity: DA: 84 (75-90)
1st, liver surface: DA: 81 (71-89) 2nd, liver length (right kidney): DA: 82 (72-90)
1st, spleen length: DA: 86 (71-95) 2nd, liver length (middle clavicle): DA: 88 (74-96)
1st, liver surface: DA: 86 (74-93)
DA: diagnostic accuracy, PPV: positive predictive value, NPV: negative predictive value. Figures in brackets indicate 95% interval confidence. Main data are presented in bold. a If only Child-Pugh A cirrhotic patients were included, global DA was 85% with liver surface at the 1st step, DA: 81%, liver length (right kidney) at the 2nd step, DA: 83%. If only Child-Pugh B + C cirrhotic patients were included, global DA was 85% with ascites at the 1st step, DA: 83%, liver length (right kidney) at the 2nd step, DA: 86%.
474
Diagnosis of hepatic cirrhosis TABLE 4 Diagnostic accuracy (%) for extensive fibrosis (score->2: rare septa, score->3: numerous septa) in the whole population Fibrosis score
Global analysis Stepwise analysis
->2
---3
73 (63-81) 1st liver length (right kidney: 68 (58.5-77) 2nd portal velocity: 69 (59.5-77.5) 3rd liver surface: 74.5 (65-82) 4th spleen length: 75.5 (66-83) 5th splenic vein respiratory variation: 77 (68-85)
84 (75-90)
Ist spleen length: 76 (67-84) 2nd ascites: 79 (70-86) 3rd liver length (right kidney): 81 (72-88) 4th portal velocity: 83 (74-89) 5th ratio caudate/left lobes: 84 (75-90)
Figures in brackets indicate 95% interval confidence. Main data are presented in bold.
TABLE 5 Relationship beween ultrasonographic (left column) and clinical variables Clinical signa
Spleen length (cm) Liver length (cm): Right kidney Middle clavicle Collateral circulation (%) Collateral circulation (%) Ascites (%)
Diagnostic accuracy (%)b
Absent
Present
p
Splenomegaly 10.9±2.3 Firm liver
13.3_+3.0
<10 -3
72 (68-78)
16.5-2-_2.7 15.3---2.9
<10 -4 <10 -4
74 (68-80) 71 (64-77)
18
<10 -~
67 (60-73)
19
<10 -3
90 (85-94)
77
<10 -3
63 (56-70)
14.3±2.1 13.4+1.9 Collateral circulation 2 Esophageal varices 3 Ascites 7
a This column indicates the distribution of ultrasonographic signs as a function of clinical sign presence/absence, b Diagnostic accuracy of the ultrasonographic sign for the clinical sign with 95% confidence interval in brackets.
rhosis is presented in Table 1. The DA of each variable is presented in Table 2. As the screening of cirrhosis is mainly relevant in patients without decompensation and the characteristics of patients may differ depending on the cause of liver disease, results are presented in four groups of patients: whole population (n=243), compensated liver diseases (n=191), compensated alcoholic liver diseases (n=109) and compensated viral liver diseases (n=83). This distinction is especially justified since the prevalences of cirrhosis and decompensation were higher in alcoholic patients than in patients with viral liver disease (59% vs 25%, p<0.001; 28% vs 1%, p<0.001, respectively). Multivariate analysis. Liver biopsy as reference: The results according to each patient group are presented in Table 3. In the entire population, using the 11 ultrasonographic variables, the DA obtained with multivariate analysis was 84%, and two variables were selected by stepwise analysis with a DA of 84%: spleen length and portal velocity. In patients with compensated liver disease (or Child-Pugh class A), the global DA was 85%
with liver surface at the 1st step, DA: 81%, and liver length (right kidney) at the 2nd step, DA: 82%. In order to simplify the choice of variables, we looked for variables with the highest and most reproducible independent DA among the four patient groups. Several models of variables were constructed (data not shown), which took into account the number of patients in whom the variable had been recorded (Table 1). As expected from the results of univariate analysis (Table 2), three variables were identified: liver length (right kidney), liver surface and spleen length. False negative liver biopsies: Table 1 shows that several signs suggestive of cirrhosis were found in patients without histopathological signs of cirrhosis. Thus, to estimate the proportion of false negative liver biopsies, patients without histological cirrhosis but with either clinical ascites, or encephalopathy, or with an irregular surface, or ascites, or collateral circulation at ultrasound were considered as having cirrhosis. Thus, 13 patients were added to the cirrhosis group, resulting in an increase in the proportion of cirrhosis from 48 to 53%. We 475
C. Aubd et al.
TABLE 6 Diagnostic value of ultrasonographic signs of cirrhosis in the literature 1st author
Ref.
Sign
Se (%)
Spe (%)
Diagnostic accuracy (%)
Giorgio Hess Di Lelio Ferral Ladenheim Bolondi
8 9 10 11 12 13
43 95 88 87.5 12.5 80
100 95 94 81.5 88 100
79 89 84 76 -
Vilgrain Cioni Richard
14 15 16
Goyal Seitz
17 18
Gaiani Cardi
19 20
Transverse caudate to right lobe ratio Multidimensional caudate lobe indexes Nodular surface Diffuse nodular surface Nodular surface No caliber variation in splenic vein and/or superior mesenteric vein during breathing Collateral circulation Enlarged spleen diameter Hepatomegaly Nodular surface Attenuation of US beam Right-to-left lobe ratio Splenomegaly Spigel lobe hypertrophy Nodular surface, mean portal velocity Miscellaneous
83 62 80.5 58 58 74 82 65 79 69
100 93 28.5 86 78.5 100 78 94 80 89
whole: 80.5
93 whole: 73 80 78
Se: sensitivity, Spe: specificity.
then calculated the DA of ultrasonographic signs for this new cirrhosis group. In the whole population, global analysis showed a DA of 84.5% (76-91) with 84% at the 4th step. In the compensated group, the number of cirrhotic patients increased from 69 (36%) to 77 (40%). Global analysis showed a DA of 88% (79-94) with 87% at the 3rd step. We tested the same model by adding esophageal varices as a specific sign of cirrhosis. However, DA was not increased (data not shown).
Diagnosis of fibrosis First, we evaluated the relationship between the area of fibrosis and the six quantitative ultrasonographic variables with multiple regression analysis. Global analysis showed that the area of fibrosis was predicted with a R2=0.28 (R=0.53), with two significant variables, by stepwise analysis: spleen length (R2=0.22), and portal velocity (R2=0.25). Then, we evaluated the independent diagnostic accuracies of all ultrasonographic variables for extensive fibrosis, that is PT fibrosis scores ->2 or ->3, by discriminant analysis (Table 4).
Relationship between clinical and ultrasonographic variables This relationship could be evaluated between four ultrasonographic variables and five clinical variables. Agreement was tested in two ways. First, the distribution of the ultrasonographic variables was studied as a function of the presence or the absence of the corresponding clinical sign. Second, the DA of each ultrasonographic sign for the presence of the corresponding clinical sign was calculated using univariate discrim-
476
inant analysis. Results are shown in Table 5. All these relationships were significant.
Discussion We tested the DA of ultrasonographic signs for cirrhosis since it has already been demonstrated that they are useful in the non-invasive diagnosis of this disease and that they are easily available in clinical practice. The limitation of the present study was the absence of a gold standard, although efforts were made to reduce the false negative rate of liver biopsy. We tried to estimate the proportion of false negative liver biopsies for cirrhosis and reached a figure of 5%. This led to an increase in DA for ultrasonography from 85 to 88% in the compensated group. Among ultrasonographic signs, only liver and spleen size had a high (->70%) DA in the whole population. In patients with compensated liver disease (or ChildPugh class A) in whom ultrasonographic diagnosis is most useful, two of the three following variables had independent DA depending on the cause of liver disease: liver length (right kidney or clavicle), liver surface and spleen length. The DA of ultrasonography for cirrhosis has been investigated in several studies (Table 6). Sensitivity varied in these studies but specificity was always high, so that DA varied from 76 to 93°/) (8-20). However, these studies had methodological biases: the control groups included patients without liver disease, and examinations were not performed blindly except for in the Gaiani study (19). This may explain the lower (84%) DA of ultrasonography in our study compared
Diagnosis of hepatic cirrhosis
to others, despite the addition of portal velocity measurement. The DA of ultrasonography could be decreased by observer variability. Since the methodology for performing an interobserver agreement study requires videorecording, which could induce biases which might decrease DA (34), the interobserver agreement was not evaluated in this study. However, we previously performed this type of study with four blinded observers on videotapes of patients with chronic liver diseases (30). In this study, using the kappa (K) index and intraclass correlation coefficient, the interobserver agreement for ultrasonography was good to excellent for the main liver characteristics, the main splanchnic veins and the spleen, but poor to fair for the diagnosis of cirrhosis (x: 0.53), collateral vessels (with a higher agreement for the umbilical vein than for the left gastric vein) and the caudate lobe (30). The mean agreement for the 18 variables tested was significantly better in specialists than in general radiologists (30). As there was a correlation between DA and interobserver agreement in this previous study (30), and as one radiologist was a specialist in hepatology and three were general radiologists in the present study, the DA might have been higher if only specialized radiologists had been used. Moreover, intercenter variability might alter the results. For example, the prevalence of an irregular liver surface was only 38% in patients with cirrhosis in our study, while it varies from 18.5 to 88% in the literature (Table 6). These differences may be due to differences in the population (this sign had an independent DA only in the group with viral liver disease in our study), to differences or subjectivity in the definitions, and to differences in technique. Another type of intercenter variability depends on the signs used. For example, we used the caudate/left lobe ratio, which resuited in a poor DA, while other ratios had a high DA in other studies (Table 6). The interest of portal velocity alone has been emphasized in recent studies (15,19,32, see Table 6); however, this sign had no independent DA in our study, except in the whole population. This may be due to the well-known observer variability of the Doppler technique (35). However, the accuracy of ultrasonography is in fact lower, since the investigation could not be completed in all patients due to limitations such as digestive gas (Table 1). Thus, the availability of certain ultrasonographic signs (ratio caudate/left lobe, portal velocity, splenic vein respiratory variation) was less than that reported in the literature. In the whole population, the highest calculated DA was observed with liver length (right kidney): 70% (Table 2). By subtracting the proportion of patients who could not be investigated (7%)
(Table 1), the DA was 63%. Moreover, the differences in means between quantitative ultrasonographic variables in cirrhotic vs non-cirrhotic patients were low (Table 1), suggesting that the cutoff value would not be reproducible in other populations of patients, especially from other centers. Clinical, biochemical, endoscopic and radiologic parameters have only been evaluated together in a few studies: the DA of independent variables selected in multivariate analysis varied from 70 to 95% (7,15,3638). Using 63 clinical, biochemical, endoscopic and Doppler ultrasonographic variables in the same 243 patients with chronic liver disease, the DA for the diagnosis of cirrhosis in the whole group was globally 92%, and 91% with three variables identified by stepwise analysis: serum hyaluronate, esophageal varices at endoscopy, and firm liver (38). No ultrasonographic sign was selected in any groups using multivariate analysis. The DA was slightly different according to the diagnostic method: biochemical tests (91%)>clinical examination (86.5%)>ultrasonography (84%)>endoscopy (81%) in the whole population. Finally, as blood markers of fibrosis such as the prothrombin index or hyaluronate are more accurate and reproducible, less expensive and more easily available, ultrasonography cannot be recommended as the first choice for the non-invasive diagnosis of cirrhosis. In conclusion, this study, which was performed under conditions close to those of clinical practice, has shown that the non-invasive diagnosis of cirrhosis can be made in up to 85% of patients with chronic liver disease by a combination of two ultrasonographic variables. However, the DA of ultrasonography is decreased by the anatomical limitations of this technique and is underestimated by observer variability. Therefore, the clinical application of ultrasonography for the diagnosis of cirrhosis appears to be limited unless some precautions are taken.
Acknowledgements We thank Dr N. Joundy, M. Kaassis, V. Meyer and Mrs Dale Roche for their contributions.
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21. Pagliaro L, Rinaldi E Craxi A, Di Franco C, Di Piazza S, Filippazzo G, et al. Predictive value of clinical, laparoscopic and histologic indicators of cirrhosis. Ital J Gastroenterol 1982; 14: 1668. 22. Papazian A, Braillon A, Dupas JL, Sevenet F, Capron JE Portal hypertensive gastric mucosa: an endoscopic study. Gut 1986; 27: 1199-203. 23. Satin SK, Misra SR Singal A, Yhorat V, Broor SL. Evaluation of the incidence and significance of the "mosaic pattern" in patients with cirrhosis, non cirrhotic portal fibrosis, and extrahepatic obstruction. Am J Gastroenterol 1988; 83: t235-9. 24. Misra SE Dwivedi M, Misra V~ Agarwal SK, Gupta R, Gupta SC, et al. Endoscopic and histologic appearance of the gastric mucosa in patients with portal hypertension. Gastrointest Endosc 1990; 36: 575-9. 25. Lin WJ, Lee FY, Lin HC, Tsai YT, Lee SD, Lai KH, et al. Snake skin pattern gastropathy in cirrhotic patients. J Gastroenterol Hepatol 1991; 6: 145-9. 26. lwao T, Toyonaga A, Ikegami M, Shigemori H, Oho K, Sumino M, et al. McCormack's endoscopic signs for diagnosing portal hypertension: comparison with gastroesophageal varices. Gastrointest Endosc 1994; 40: 470-3. 27. Schalm SW The diagnosis of cirrhosis: clinical relevance and methodology. J Hepatol 1997; 27: 1118-9. 28. Cal6s E Zabotto B, Meskens C, Caucanas JR Vinel JE Desmorat H, et al. Gastroesophageal endoscopic features in cirrhosis: observer variability, interassociations and relationship to hepatic dysfunction. Gastroenterology 1990; 98:156 62. 29. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646 9. 30. Tissot O, Aub6 C, Namour A. Blanc E Dauver A, Cal~s E S6miologie 6chographique de la cirrhose: concordance inter-observateur. Gastroenterol Clin Biol 1995; 19: 291-6. 31. Subramanyam BR, Balthazar EJ, Madamba MR, Raghavendra BN. Horii SC, Lefleur RS, Sonography of portosystemic venous collaterals in portal hypertension. Radiology 1983; 146: 161 6. 32. Cioni G, D'Alimonte E Cristani A, Ventura E Abbati G, Tincani E, et al. Duplex-doppler assessment of cirrhosis in patients with chronic compensated liver disease. J Gastroenterol Hepatol 1992; 7: 382~4. 33. Bedossa E Bioulac-Sage R Callard R Chevallier M, Degott C, Deugnier Y, et al. lntraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20: 15--20. 34. Burtin E Cal6s R Variabilit6 li6e /t l'observateur. Gastroenterol Clin Biol (in press). 35. Sabba C, Weltin GG, Cicchetti DV, Ferraioli G, Taylor KJW, Nakamura T, et al. Observer variability in echo-Doppler measurements of portal flow in cirrhotic patients and normal volunteers. Gastroenterology 1990; 98:1603 11. 36. Marmo R, Romano M, de Sio 1, Peduto A. Caporaso N, Persico M, et al. Decision-making model for a non-invasive diagnosis of compensated liver cirrhosis. Ital J Gastroenterol 1993; 25: 1--8. 37. Poynard T, Aubert A. Naveau S, Bedossa E Abella A, Chaput JC. A computer protocol to predict liver cirrhosis in drinkers [abstract]. J Hepatol 1988; 7(Suppl 1): $70. 38. Oberti E Valsesia E, Pilette C, Rousselet MC, Bedossa E Aub6 C, et al. Non invasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology 1997:113:1609 16.
Copyright © European Association Jbr the Study ~f the Liver 1999 Journal of Hepatology ISSN 0168-8278
Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis Christophe Aub6 l, Frtdtric Oberti 2, Nouri Korali 1, Marc-Antoine N a m o u r I , Didier Loisel 1, Jean-Yves Tanguy j , Emmanuelle Valsesia 1'2, Christophe Pilette 2, Marie Christine Rousselet 3, Pierre Bedossa 4, Herv6 Rifflet 2, Moussa Y. Ma~ga 2, Dominique Penneau-Fontbonne 5, Christine Caron 1 and Paul Cal6s 2 1Serviee de Radiologie, C H ~ . 2Service d'Hkpato-Gastroent~rologie, C H U and 3Laboratoire d'Anatomie-Pathologique, CHU, Angers; 4Service d'Anatornie et Cytologie Pathologiques, CHU, Kremlin-Bic~tre; and 5Service de MOdeeine E, CHU, Angers, France
Background~Aims: Evaluation of the degree of hepatic fibrosis is especially important in patients with chronic liver disease. Our aim was to study the diagnostic accuracy of abdominal ultrasonography for cirrhosis or fibrosis. Methods: Twenty-three clinical (n=12) and Doppler ultrasonic ( n = l l ) variables were recorded in 243 patients with chronic (alcoholic and viral) liver disease under conditions close to those of clinical practice. Fibrosis was classified into six grades by two pathologists. Diagnostic accuracy was evaluated by discriminant analysis, first globally using all variables, then by stepwise analysis. Results: A) Diagnosis of cirrhosis: 1) whole group (n=243): diagnostic accuracy was globally 84%, and 84% with two variables: spleen length, portal velocity; 2) compensated chronic liver disease (n=191): diagnostic accuracy was globally 85%, and 82% with two variables: liver surface, liver length (right kidney); 3)
alcoholic compensated chronic liver disease (n=109): diagnostic accuracy was globally 86%, and 88% with two variables: spleen length, liver length (middle clavicle); 4) viral compensated chronic liver disease (n= 83): diagnostic accuracy was globally 86% and 86% with one variable: liver surface. By subtracting the proportion of patients who could not be investigated due to anatomical limitations, the highest calculated univariate diagnostic accuracy decreased by 7%. B) Diagnosis of fibrosis: diagnostic accuracy was globally 84% for extensive fibrosis. Conclusions: Cirrhosis can be correctly diagnosed in 82-88% of patients with chronic liver disease using a few ultrasonographic signs. However, the diagnostic accuracy of ultrasound is decreased by the anatomical limitations of this technique.
IVER FIBROSISis a common development in chronic
revealed by complications and the risk of variceal rupture is maximal in the 2 years following diagnosis (3). On the other hand, cirrhosis is a common disease (4) which is frequently undiagnosed (5). Recently, several indirect diagnostic tests for cirrhosis have been evaluated. These markers included either clinical signs (6,7), ultrasonographic signs (820), endoscopic signs (21-26) or blood biochemical parameters (7). In a recent study, the diagnostic accuracy (DA) of ultrasonography for cirrhosis was found to be 80% with discriminant analysis (19). Moreover, it has been suggested that ultrasonography may be used to identify cirrhosis even in the absence of a typical histopathological pattern (19). Thus, the sensitivity of liver biopsy in diagnosing cirrhosis has been estimated to be 62% and that of ultrasonography 87% (27). The main aim of the present prospective study was
L liver disease. The most evolved stage of liver fibrosis is cirrhosis, which places the patient at risk of clinical complications such as portal hypertension, hepatocellular dysfunction and cancer. As the definition of cirrhosis is histopathological, liver biopsy is the key examination for diagnosis. However, in clinical practice, the use of liver biopsy has several limitations, in particular sample errors with an estimated mean of 24% of false negatives in the series of blind liver biopsies (1) and complications (2). Early diagnosis is essential since cirrhosis is often Received 6 May; revised 22 September; accepted 28 September 1998
Correspondence." Paul Calts, Service d'Htpato-Gastroenttrologie, CHU, 49033 Angers Cedex 01, France. Tel: +33 2 41 35 34 10. Fax: +33 2 41 35 41 19. E-mail: [email protected] 472
Key words: Abdominal ultrasound; Cirrhosis; Diagnostic accuracy; Doppler ultrasound; Hepatic fibrosis~
Diagnosis of hepatic cirrhosis
to determine the DA (percentage of patients correctly classified) of ultrasonographic signs for the evaluation of hepatic fibrosis or cirrhosis by multivariate analysis in order to select independent predictive signs of cirrhosis. Patients and M e t h o d s Patients The 243 consecutive patients included in this study were admitted to the hepatogastroenterology unit of the University Hospital in Angers, France, in 1994-5 for alcoholism or alcoholic liver disease, or for chronic hepatitis B or C infection. Patients were included if they had drunk at least 50 g of alcohol per day for the past 5 years, or were positive for hepatitis B surface antigen or C serum markers, and had had persistently elevated serum aminotransferases > 1.5 N for at least 6 months, or had had previous liver complications (ascites, edema). Patients with a past history of gastrointestinal bleeding were not included. None of the patients had clinical, biological, ultrasonographic or histological evidence of other causes of chronic liver disease (Wilson's disease, hemochromatosis, al-antitrypsin deficiency, biliary disease, auto-immune hepatitis, hepatocellular carcinoma). Except for these non-inclusion criteria, this study was performed under conditions close to clinical practice on an intention-to-diagnose principle. Thus, patients with incomplete ultrasonographies (e.g. gas preventing complete examination) were not excluded. Blood samples were taken at entry, and a percutaneous (n=210) or transjugular liver biopsy (n= 33) was performed within 1 week. In the latter patients, the liver specimen was fragmented in 11 cases, making image analysis impossible. Among the 243 patients, 83 had viral liver disease and 160 alcoholic liver disease, and 116 patients had cirrhosis which was decompensated in 45% (ascites and/or encephalopathy). Since no additional examina-
tions were performed compared to clinical practice, informed consent was not obtained.
Clinical evaluation A full clinical examination was performed by a senior physician. The recorded variables were: age, sex, alcohol withdrawal, known duration of liver disease (time since the first clinical or biochemical abnormality suggestive of chronic liver disease), splenomegaly (any palpable spleen), liver palpation suggestive of cirrhosis, i.e. a firm liver with a thin lower edge, abdominal venous collateral circulation, ascites, and hepatic encephalopathy. Endoscopic examinations were performed by two endoscopists (either PC or FO); however, this examination was not available in 36 patients (due to refusal, a time interval -->2months, or it was performed in another center). The grade of esophageal varices (grade 0 to 3) was evaluated according to a previously described classification (28). Blood samples were submitted to standard tests to determine the Child-Pugh score (29) to identify the degree of liver dysfunction. The distribution of the Child-Pugh classes in patients with cirrhosis was: A: 50%, B: 24%, C: 26%.
Echo-Doppler study All examinations were performed in every patient by one of four investigators (one radiologist specialized in hepatology and three general radiologists) using an Acuson 128×p/10M apparatus according to a previously described technique (30) within 1 day of liver biopsy. Radiologists were blinded for the clinical diagnosis of liver disease. The probe used was a 3.5-2.5 MHz transducer and a 7.5 MHz linear transducer. The following 11 variables were selected based on the DA reported in the literature (8-18): hepatic length at the level of the right kidney and the middle of the clavicle in a saggital plane; nodular aspect of the liver surface based on ultrasound of the left lobe with a linear high frequency transducer (7.5 MHz); liver homogeneity; ratio of the caudate lobe/left lobe length on a saggital scan which was considered abnormal if >0.33 (18); collateral circulation defined as
TABLE 1 Distribution of variables as a function of the presence of cirrhosis in the whole population na
Cirrhosis Without (n= 127)
With (n = 116)
Clinical data Sex (%M) Age (years) Cause (% alcohol) Alcohol withdrawal (%) Liver disease duration (months) Firm liver (%) Splenomegaly (%) Collateral circulation (%) Ascites (%) Encephalopathy (%) Esophageal varices (%) Child-Pugh score
243 243 243 164 199 240 241 242 243 242 207 205
67 43_+ 12 51 10 9_+23 10 0 14 2 2 10 5.2_+0.8
64 54 + 11 82 22 16---36 75 12 66 38 7 72 7.5±2.6
NS < 10 -4 <10 3 NS NS a <10 -3 < 10 -3 < 10-3 < 10- 3 =0.05 < 10 -3 <10 -4b
Echographic data Liver length (right kidney, cm) Liver length (middle clavicle, cm) Liver surface (irregular %) Liver heterogeneity (%) Spleen length (cm) Portal vein diameter (ram) Ascites (%) Collateral circulation (%) Splenic vein respiratory variation (%) Portal velocity (cm/s) Ratio caudate/left lobes (%)
225 197 229 227 214 215 232 206 153 160 151
14---2 13___2 4 11 10 ± 2 11.6+-2.1 4 2 77 28--- 12 24 +- 17
16_+3 15+--3 38 38 12---2 12.5-+ 1.8 37 17 67 22_+8 28 +- 16
<10 -4 <10 -4b < 10 -3 < 10 -3 < 10-4 < 10 -2 < 10- 3 < 10 -3 NS <10 -3b NS
a n indicates the number of patients for whom the variable was available (for more details, see methods), b Rank test.
473
C. AubO et al. surface area was considered referent areaa. The fractional surface occupied by fibrosis was measured within the above defined frame and AA represented the percentage of fibrosis in the field. When using the motorized x-y stage facilities, the biopsy could be fully explored without any field overlapping. For a given patient, the percentage of fibrosis or the area of fibrosis could be obtained on n microscopic fields as (nXAA/A)/n.
any patent umbilical vein (i.e. diameter ->3 mm) or a left gastric vein >5 mm (31) or any abnormal vein such as a spleno-renal shunt; respiratory variation of the splenic vein; spleen length; ascites; portal vein diameter; and maximum velocity of portal vein (32). These signs were evaluated in all patients.
Histological assessment o f the liver Semi-quantitative score. The biopsy specimens were fixed in a formalin-alcohol-acetic acid solution and embedded in paraffin; 3-~mthick sections were stained with hematoxylin-eosin-saffron, Masson's trichrome and 0.1% picrosirius red solution. Fibrosis was graded by two independent pathologists according to a semi-quantitative score derived from the Metavir score (33). The score for fibrosis of the portal tract (PT) was as follows: 0: no fibrosis, 1: enlarged PT without septa, 2: enlarged PT with rare septa, 3: numerous septa without cirrhosis, 4: potential cirrhosis (for small specimens obtained by transjugular biopsy), 5: definite cirrhosis; this score was called the PTF score. The interobserver agreement was excellent (intra-class correlation coefficient: r=0.78). When the two pathologists did not agree, the specimens were reexamined with a binocular microscope to analyze discrepancies and reach a consensus. Quantitative score. Image analysis was performed on the same sections as those stained with picrosirius red solution for the semi-quantitative study with a Leica Quantimet Q570 image processor. The 2D patterns were measured by direct pixel counting on the binary images. In a given microscopic field, the surface of the section occupied by the hepatic parenchyma was used as the measuring frame and this
Statistical analysis Quantitative variables were expressed as mean-+SD and were compared using the Student test unless otherwise specified. Qualitative variables were expressed as percentages and were compared using the X2 test. DA (percentage of correctly classified patients) was calculated by discriminant analysis. To assess the independent effect of qualitative or quantitative predictive variables on the DA of fibrosis (explained variable), we used discriminant analysis with forward stepwise addition of variables. To assess the independent effect of quantitative predictive variables on the prediction of the area of fibrosis, we used multiple linear regression analysis. An a risk <5% for a two-sided test was considered statistically significant.
Results Diagnosis of cirrhosis Univariate analysis. The distribution of 23 variables studied as a function of the absence or presence of cir-
TABLE 2 Diagnostic accuracy (%) for cirrhosis in the four groups of patients Whole %
Liver length (right kidney) Liver length (clavicle) Liver surface (irregular) Liver heterogeneity Spleen length Portal vein diameter Ascitesa Collateral circulation Splenic vein respiratory variation Portal velocity Ratio caudate/left lobes
70 67 68 65 74 57 67 60 59 62 56
Compensated p
<10 .3 <10 -3 <10 -3 <10 -3 <10 -3 <10 -2 <10 -3 <10 .3 NS <10 -2 NS
Alcohol+virus
Alcohol
Virus
%
p
%
p
%
p
70.5 66 73.5 71
<10 .3 <10 -3 <10 -3 <10 -3 <10 -3 <10 -2 NS <10 -2 NS NS NS
64 62 66 62 82 53 54 61 59 49 54
<0.05 NS <10 .3 <0.05 <10 --3 NS NS <0.05 NS NS NS
66 48 84 84 79 68 78 82 38 58 60
NS NS <10 -3 <10 -3 <10 .3 <0.05 <0.05 NS NS <0.05 NS
80
59 64 69 60 53.5 47
a Patients with clinical diagnosis o f ascites were excluded from the compensated group. Diagnostic accuracy ->70% is depicted in bold.
TABLE 3 Diagnostic accuracy (%) according to multivariate analysis in the different patient groups Whole population
Compensated a
Alcohol compensated
Virus compensated
Global analysis
DA: 84 (75-90) PPV: 79 (62-91) NPV: 86 (75.5-93)
DA: 85 (75-92) PPV: 65 (43-84) NPV: 92 (81.5-98)
DA: 86 (71-95) PPV: 89 (51-100) NPV: 85 (67-95)
DA: 86 (74-93) PPV: 61.5 (32-87) NPV: 92 (80--98)
Stepwise analysis
1st, spleen length: DA: 80 (71-87) 2nd, velocity: DA: 84 (75-90)
1st, liver surface: DA: 81 (71-89) 2nd, liver length (right kidney): DA: 82 (72-90)
1st, spleen length: DA: 86 (71-95) 2nd, liver length (middle clavicle): DA: 88 (74-96)
1st, liver surface: DA: 86 (74-93)
DA: diagnostic accuracy, PPV: positive predictive value, NPV: negative predictive value. Figures in brackets indicate 95% interval confidence. Main data are presented in bold. a If only Child-Pugh A cirrhotic patients were included, global DA was 85% with liver surface at the 1st step, DA: 81%, liver length (right kidney) at the 2nd step, DA: 83%. If only Child-Pugh B + C cirrhotic patients were included, global DA was 85% with ascites at the 1st step, DA: 83%, liver length (right kidney) at the 2nd step, DA: 86%.
474
Diagnosis of hepatic cirrhosis TABLE 4 Diagnostic accuracy (%) for extensive fibrosis (score->2: rare septa, score->3: numerous septa) in the whole population Fibrosis score
Global analysis Stepwise analysis
->2
---3
73 (63-81) 1st liver length (right kidney: 68 (58.5-77) 2nd portal velocity: 69 (59.5-77.5) 3rd liver surface: 74.5 (65-82) 4th spleen length: 75.5 (66-83) 5th splenic vein respiratory variation: 77 (68-85)
84 (75-90)
Ist spleen length: 76 (67-84) 2nd ascites: 79 (70-86) 3rd liver length (right kidney): 81 (72-88) 4th portal velocity: 83 (74-89) 5th ratio caudate/left lobes: 84 (75-90)
Figures in brackets indicate 95% interval confidence. Main data are presented in bold.
TABLE 5 Relationship beween ultrasonographic (left column) and clinical variables Clinical signa
Spleen length (cm) Liver length (cm): Right kidney Middle clavicle Collateral circulation (%) Collateral circulation (%) Ascites (%)
Diagnostic accuracy (%)b
Absent
Present
p
Splenomegaly 10.9±2.3 Firm liver
13.3_+3.0
<10 -3
72 (68-78)
16.5-2-_2.7 15.3---2.9
<10 -4 <10 -4
74 (68-80) 71 (64-77)
18
<10 -~
67 (60-73)
19
<10 -3
90 (85-94)
77
<10 -3
63 (56-70)
14.3±2.1 13.4+1.9 Collateral circulation 2 Esophageal varices 3 Ascites 7
a This column indicates the distribution of ultrasonographic signs as a function of clinical sign presence/absence, b Diagnostic accuracy of the ultrasonographic sign for the clinical sign with 95% confidence interval in brackets.
rhosis is presented in Table 1. The DA of each variable is presented in Table 2. As the screening of cirrhosis is mainly relevant in patients without decompensation and the characteristics of patients may differ depending on the cause of liver disease, results are presented in four groups of patients: whole population (n=243), compensated liver diseases (n=191), compensated alcoholic liver diseases (n=109) and compensated viral liver diseases (n=83). This distinction is especially justified since the prevalences of cirrhosis and decompensation were higher in alcoholic patients than in patients with viral liver disease (59% vs 25%, p<0.001; 28% vs 1%, p<0.001, respectively). Multivariate analysis. Liver biopsy as reference: The results according to each patient group are presented in Table 3. In the entire population, using the 11 ultrasonographic variables, the DA obtained with multivariate analysis was 84%, and two variables were selected by stepwise analysis with a DA of 84%: spleen length and portal velocity. In patients with compensated liver disease (or Child-Pugh class A), the global DA was 85%
with liver surface at the 1st step, DA: 81%, and liver length (right kidney) at the 2nd step, DA: 82%. In order to simplify the choice of variables, we looked for variables with the highest and most reproducible independent DA among the four patient groups. Several models of variables were constructed (data not shown), which took into account the number of patients in whom the variable had been recorded (Table 1). As expected from the results of univariate analysis (Table 2), three variables were identified: liver length (right kidney), liver surface and spleen length. False negative liver biopsies: Table 1 shows that several signs suggestive of cirrhosis were found in patients without histopathological signs of cirrhosis. Thus, to estimate the proportion of false negative liver biopsies, patients without histological cirrhosis but with either clinical ascites, or encephalopathy, or with an irregular surface, or ascites, or collateral circulation at ultrasound were considered as having cirrhosis. Thus, 13 patients were added to the cirrhosis group, resulting in an increase in the proportion of cirrhosis from 48 to 53%. We 475
C. Aubd et al.
TABLE 6 Diagnostic value of ultrasonographic signs of cirrhosis in the literature 1st author
Ref.
Sign
Se (%)
Spe (%)
Diagnostic accuracy (%)
Giorgio Hess Di Lelio Ferral Ladenheim Bolondi
8 9 10 11 12 13
43 95 88 87.5 12.5 80
100 95 94 81.5 88 100
79 89 84 76 -
Vilgrain Cioni Richard
14 15 16
Goyal Seitz
17 18
Gaiani Cardi
19 20
Transverse caudate to right lobe ratio Multidimensional caudate lobe indexes Nodular surface Diffuse nodular surface Nodular surface No caliber variation in splenic vein and/or superior mesenteric vein during breathing Collateral circulation Enlarged spleen diameter Hepatomegaly Nodular surface Attenuation of US beam Right-to-left lobe ratio Splenomegaly Spigel lobe hypertrophy Nodular surface, mean portal velocity Miscellaneous
83 62 80.5 58 58 74 82 65 79 69
100 93 28.5 86 78.5 100 78 94 80 89
whole: 80.5
93 whole: 73 80 78
Se: sensitivity, Spe: specificity.
then calculated the DA of ultrasonographic signs for this new cirrhosis group. In the whole population, global analysis showed a DA of 84.5% (76-91) with 84% at the 4th step. In the compensated group, the number of cirrhotic patients increased from 69 (36%) to 77 (40%). Global analysis showed a DA of 88% (79-94) with 87% at the 3rd step. We tested the same model by adding esophageal varices as a specific sign of cirrhosis. However, DA was not increased (data not shown).
Diagnosis of fibrosis First, we evaluated the relationship between the area of fibrosis and the six quantitative ultrasonographic variables with multiple regression analysis. Global analysis showed that the area of fibrosis was predicted with a R2=0.28 (R=0.53), with two significant variables, by stepwise analysis: spleen length (R2=0.22), and portal velocity (R2=0.25). Then, we evaluated the independent diagnostic accuracies of all ultrasonographic variables for extensive fibrosis, that is PT fibrosis scores ->2 or ->3, by discriminant analysis (Table 4).
Relationship between clinical and ultrasonographic variables This relationship could be evaluated between four ultrasonographic variables and five clinical variables. Agreement was tested in two ways. First, the distribution of the ultrasonographic variables was studied as a function of the presence or the absence of the corresponding clinical sign. Second, the DA of each ultrasonographic sign for the presence of the corresponding clinical sign was calculated using univariate discrim-
476
inant analysis. Results are shown in Table 5. All these relationships were significant.
Discussion We tested the DA of ultrasonographic signs for cirrhosis since it has already been demonstrated that they are useful in the non-invasive diagnosis of this disease and that they are easily available in clinical practice. The limitation of the present study was the absence of a gold standard, although efforts were made to reduce the false negative rate of liver biopsy. We tried to estimate the proportion of false negative liver biopsies for cirrhosis and reached a figure of 5%. This led to an increase in DA for ultrasonography from 85 to 88% in the compensated group. Among ultrasonographic signs, only liver and spleen size had a high (->70%) DA in the whole population. In patients with compensated liver disease (or ChildPugh class A) in whom ultrasonographic diagnosis is most useful, two of the three following variables had independent DA depending on the cause of liver disease: liver length (right kidney or clavicle), liver surface and spleen length. The DA of ultrasonography for cirrhosis has been investigated in several studies (Table 6). Sensitivity varied in these studies but specificity was always high, so that DA varied from 76 to 93°/) (8-20). However, these studies had methodological biases: the control groups included patients without liver disease, and examinations were not performed blindly except for in the Gaiani study (19). This may explain the lower (84%) DA of ultrasonography in our study compared
Diagnosis of hepatic cirrhosis
to others, despite the addition of portal velocity measurement. The DA of ultrasonography could be decreased by observer variability. Since the methodology for performing an interobserver agreement study requires videorecording, which could induce biases which might decrease DA (34), the interobserver agreement was not evaluated in this study. However, we previously performed this type of study with four blinded observers on videotapes of patients with chronic liver diseases (30). In this study, using the kappa (K) index and intraclass correlation coefficient, the interobserver agreement for ultrasonography was good to excellent for the main liver characteristics, the main splanchnic veins and the spleen, but poor to fair for the diagnosis of cirrhosis (x: 0.53), collateral vessels (with a higher agreement for the umbilical vein than for the left gastric vein) and the caudate lobe (30). The mean agreement for the 18 variables tested was significantly better in specialists than in general radiologists (30). As there was a correlation between DA and interobserver agreement in this previous study (30), and as one radiologist was a specialist in hepatology and three were general radiologists in the present study, the DA might have been higher if only specialized radiologists had been used. Moreover, intercenter variability might alter the results. For example, the prevalence of an irregular liver surface was only 38% in patients with cirrhosis in our study, while it varies from 18.5 to 88% in the literature (Table 6). These differences may be due to differences in the population (this sign had an independent DA only in the group with viral liver disease in our study), to differences or subjectivity in the definitions, and to differences in technique. Another type of intercenter variability depends on the signs used. For example, we used the caudate/left lobe ratio, which resuited in a poor DA, while other ratios had a high DA in other studies (Table 6). The interest of portal velocity alone has been emphasized in recent studies (15,19,32, see Table 6); however, this sign had no independent DA in our study, except in the whole population. This may be due to the well-known observer variability of the Doppler technique (35). However, the accuracy of ultrasonography is in fact lower, since the investigation could not be completed in all patients due to limitations such as digestive gas (Table 1). Thus, the availability of certain ultrasonographic signs (ratio caudate/left lobe, portal velocity, splenic vein respiratory variation) was less than that reported in the literature. In the whole population, the highest calculated DA was observed with liver length (right kidney): 70% (Table 2). By subtracting the proportion of patients who could not be investigated (7%)
(Table 1), the DA was 63%. Moreover, the differences in means between quantitative ultrasonographic variables in cirrhotic vs non-cirrhotic patients were low (Table 1), suggesting that the cutoff value would not be reproducible in other populations of patients, especially from other centers. Clinical, biochemical, endoscopic and radiologic parameters have only been evaluated together in a few studies: the DA of independent variables selected in multivariate analysis varied from 70 to 95% (7,15,3638). Using 63 clinical, biochemical, endoscopic and Doppler ultrasonographic variables in the same 243 patients with chronic liver disease, the DA for the diagnosis of cirrhosis in the whole group was globally 92%, and 91% with three variables identified by stepwise analysis: serum hyaluronate, esophageal varices at endoscopy, and firm liver (38). No ultrasonographic sign was selected in any groups using multivariate analysis. The DA was slightly different according to the diagnostic method: biochemical tests (91%)>clinical examination (86.5%)>ultrasonography (84%)>endoscopy (81%) in the whole population. Finally, as blood markers of fibrosis such as the prothrombin index or hyaluronate are more accurate and reproducible, less expensive and more easily available, ultrasonography cannot be recommended as the first choice for the non-invasive diagnosis of cirrhosis. In conclusion, this study, which was performed under conditions close to those of clinical practice, has shown that the non-invasive diagnosis of cirrhosis can be made in up to 85% of patients with chronic liver disease by a combination of two ultrasonographic variables. However, the DA of ultrasonography is decreased by the anatomical limitations of this technique and is underestimated by observer variability. Therefore, the clinical application of ultrasonography for the diagnosis of cirrhosis appears to be limited unless some precautions are taken.
Acknowledgements We thank Dr N. Joundy, M. Kaassis, V. Meyer and Mrs Dale Roche for their contributions.
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