ultrasound evaluation of the fibrosis stage in chronic liver

Ultrasound evaluation of the fibrosis stage in chronic liver

disease by the simultaneous use of low and high frequency

probes

1T NISHIURA, RMS, 1H WATANABE, RMS, 1,2M ITO, MD, 3Y MATSUOKA, MD, 4K YANO, MD,4M DAIKOKU, MD, 4H YATSUHASHI, MD, 4K DOHMEN, MD, FACP, SJSUM and4H ISHIBASHI, MD, FACP, SJSUM

1Clinical Laboratory, 2Department of Pathology, 3Deartment of Radiology and 4Clinical Research Centre, NHO National

Nagasaki Medical Centre, Omura, Nagasaki, 856-8562 Japan

Abstract. A liver biopsy is currently considered the definitive diagnostic modality for establishing the severity ofhepatic fibrosis. We analysed the diagnostic sensitivity and accuracy of ultrasound (US) using both lowfrequency and high frequency probes as a repeatable, inexpensive, and reliable method to determine the fibrosisstage in chronic liver disease and then compared our results with the histological findings. A total of 103patients with chronic liver disease (60 males and 43 females, average age 51 years old) who had undergone botha liver biopsy and US with 2–5 MHz frequency and 5–12 MHz frequency probes were prospectively evaluatedin this study. An US scoring system using both the low frequency and high frequency probes was performed byevaluating the edge, surface and parenchymal texture of the liver. Each score was obtained by evaluating threeparameters; the bluntness of the liver edge, the irregularity of the surface and the coarseness of the parenchymaltexture were evaluated and then compared with the histological findings. The US scores of the liver edge (rs:0.6668), liver surface (rs: 0.9007) and liver parenchymal texture (rs: 0.8853) correlated significantly with thefibrosis stage obtained based on the biopsy findings. The accumulated US scores of these three parameters,however, was found to be the most reliable indicator (rs: 0.9524). Patients with an accumulated score of 6.5 ormore were all found to have fibrosis stage 4 in which the accuracy of our scoring system for correctly predictingcirrhosis was found to be 100% sensitive. When an accumulated US score of 3 was interpreted to indicate mildfibrosis (a fibrosis score of 0 or 1), all 42 patients with stage 0 or 1 fibrosis were found to have an accumulatedUS score of 3 or less (a probability of 100%) and 42 of 53 patients with a score of 3 or less were found to havestage 0 or 1 fibrosis (specificity of 79.2%). An ultrasound evaluation of the liver fibrosis stage based on thescoring system using both low and high frequency probes was found to be a reliable and effective alternative tothe histological staging in chronic liver diseases.

The liver fibrosis stage in patients with chronic liverdiseases due to an infection with hepatitis B virus (HBV)or C virus (HCV) is a pivotal factor regarding both thetherapeutic options and for predicting the prognosis. Aliver biopsy is considered to be the gold standard for diag-nosing the liver fibrosis stage and predicting the outcomeof the diseases. Although a percutaneous liver biopsy isrelatively safe, it is still associated with a risk of com-plications, patient discomfort and a high cost. In addition,liver biopsy examinations may lead to false negative resultsdue to inadequate liver tissue sampling. Therefore, there isa need to develop a simple, reliable and non-invasivemodality in order to assess the liver fibrosis stage [1].Ultrasound (US) is a non-invasive, inexpensive and

repeatable modality and has been used as the mostimportant and valuable diagnostic tool for detectinghepatocellular carcinoma (HCC) during the follow-up ofpatients with viral hepatitis [2, 3]. US is also used formonitoring the response of HCC to treatment.

An ultrasound evaluation of the liver fibrosis stage of

chronic liver disease has been performed by assessing

various ultrasound factors such as the liver size, the

bluntness of the liver edge, the coarseness of the liver

parenchyma, nodularity of the liver surface, the size of the

lymph nodes around the hepatic artery, the irregularity

and narrowness of the inferior vena cava, portal vein

velocity or spleen size [1, 4–8]. However, the conventional

definition of the fibrosis stage of the liver based on

evaluation of these ultrasound factors is imperfect and

lacks accuracy and reliability. Furthermore, these findings

also depend largely on the equipment used [8]. Indeed, a

few reports have demonstrated no consistent correlation

between the grey scale ultrasound findings and the

histological findings, thus claiming that grey scale US is

unreliable for grading and staging the degree of liver

damage [9]. However, recent advances in US technology

have improved the diagnostic accuracy for fibrosis in

patients with chronic liver disease. Therefore, we carried

out a study to evaluate the accuracy of the liver fibrosis

stage by utilizing the techniques of advanced ultrasound

performance in 103 patients with chronic liver disease and

compared the results obtained with the histological

findings.

Received 22 July 2003 and in final form 31 August 2004, accepted 5October 2004.

Address correspondence to Dr Koji Yano, Clinical Research Centre,NHO National Nagasaki Medical Centre, Kubara 2-1001-1 Omura,Nagasaki 856-8562 Japan.

The British Journal of Radiology, 78 (2005), 189–197 E 2005 The British Institute of Radiology

DOI: 10.1259/bjr/75208448

189The British Journal of Radiology, March 2005

Patients and methods

Patients

This study was prospectively designed. 103 consecutivepatients, consisting of 60 males and 43 females with adiagnosis of chronic liver disease including liver cirrhosisat National Nagasaki Medical Centre between October2001 and February 2003 were included. The mean age ofthe patients was 51 years old, with a range of from 38years to 75 years. The inclusion criteria were as follows: (a)history of chronic liver disease, based on the detection ofpersistently high levels of aminotransferase; (b) an absenceof clinical and/or biochemical signs of decompensated liverdiseases (jaundice, ascites or encephalopathy); and (c) noprevious histopathological diagnosis. Regarding the hepa-titis virus, 22 patients were infected with HBV, 64 withHCV, 5 with both HBV and HCV and 12 with neitherHBV nor HCV. Both ultrasound and histological exam-ination obtained based on a liver biopsy were performedfor all patients.

US system

The patients were studied ultrasonically using a real-time apparatus (HDI 5000 Sono CT, ATL, USA) with a2–5 MHz convex array transducer C5–2 (low frequencyprobe) and a 5–12 MHz convex array transducer L12–5(high frequency probe).

US findings and the scoring system (Table 1)

The US examination was performed within an intervalof no more than 15 days prior to the biopsy examination.The US examiners (TN, HW) were unaware of the clinicaldetails of the patients, and the US findings wereinterpreted by two specialists (KY, HI) who had noknowledge of either the biochemical or biopsy results. Theultrasound examinations were recorded on static B-modeimaging. The US examiners were both certified by theJapan Society of Ultrasonics in Medicine. The US scorewas determined from the right and left lobes and theaverage score for each parameter was calculated asfollows: (1) liver edge (Figure 1): score 0 for sharp;score 1 for mildly blunted; score 2 for blunted; (2) liversurface (Figure 2): score 0 for smooth; score 1 for mildlyirregular; score 2 for irregular; score 3 for highly irregular;and (3) liver parenchymal texture (Figure 3) [5, 10]: score 0for fine; score 1 for mildly coarse; score 2 for coarse; score3 for highly coarse. A score of 0 was given when noabnormality was observed by a high frequency probe,score 1 was given when a mild abnormality was detectedby a high frequency probe while it was undetected by thelow frequency probe, a score of 2 was given when amoderate abnormality was detected by the low frequencyprobe, and a score of 3 was given when a severeabnormality was detected by the low frequency probe. A

score of 2 was given for a blunted edge and a score 3 forsevere irregular surface or a highly coarse texture whenthese characteristics were clearly confirmed by the lowfrequency probe. In cases in which three parameters suchas the edge, surface and parenchymal texture could not bedetermined to be either mild or severe using a lowfrequency probe, then the high frequency probe was usedto determine whether they were mild or severe. The highfrequency probe was used to obtain a score 0 or 1 becausethe sensitivity obtained by the high frequency probe wassuperior to the one by the low frequency probe regardingmildly abnormal changes such as a score 0 or 1.Conversely, regarding such advanced changes as a scoreof 2 or 3, the low frequency probe was more usefulbecause the probability obtained by the low frequencyprobe was superior to that by the high frequency probe.As a result, the fibrosis stage predicted from the accumu-lated scores of the liver edge, surface and parenchymaltexture by US were considerably more reliable than theindividual scores of these three parameters when they werecompared with the histological findings.

Histological findings

Liver biopsy specimens were obtained from the anteriorsegment of the right lobe in each patient, using a 16-gaugeSonopsy-C1 biopsy needle (Hakko Co., Tokyo, Japan).All of the histological slides were reviewed by anexperienced pathologist without any knowledge of theclinical details or the US findings. The New Inuyamascoring system for chronic hepatitis was proposed by theJapanese Liver Study Group in 1994 [11], which is similarto the classification of chronic hepatitis determined by theUSA-European Liver Study Group [12]. The NewInuyama scoring system was used to assess the fibrosisstage as follows; score 0: no fibrosis, score 1: fibrous portalexpansion, score 2: bridging fibrosis, score 3: bridgingfibrosis with lobular degeneration, and score 4: cirrhosis.

Statistics

The Spearman’s correlation test was used to assess anycorrelations between the liver fibrosis stage and the USscoring system. The sensitivity, specificity and positivepredictive values of the US scoring system were calculatedand compared with the results of the liver fibrosis stages.

Results

US scoring system and fibrosis stage

The relationship between the liver edge and fibrosis

(Figure 4)Of 11 patients with a sharp liver edge (edge score 0), 6

patients (55%) were found to have stage 0 fibrosis and 5(45%) in stage 1 fibrosis. The liver edge score of 34 patients

Table 1. Findings for the ultrasound features of the edge, surface and parenchymal texture of the liver

Score 0 Score 1 Score 2 Score 3

Edge sharp mildly blunted edge blunted edgeSurface smooth mildly irregular irregular highly irregularParenchymal texture fine mildly coarse coarse highly coarse

T Nishiura, H Watanabe, M Ito et al

190 The British Journal of Radiology, March 2005

in an early fibrosis stage (stage 1) showed various results; 5patients had a score of 0, 6 a score 0.5, 9 a score of 1, 5 ascore of 1.5 and 9 a score of 2. On the other hand, thepatients with stage 2, 3 and 4 fibrosis correlated well withthe edge score and were categorized into a blunted edge(score 2); 26 of 26 patients with stage 2 fibrosis, 12 of 13patients with stage 3 fibrosis, 22 of 22 patients with stage 4fibrosis. The liver edge and the fibrosis score thus showeda statistically significant correlation (rs: 0.6668).

The relationship between the liver surface and fibrosis

(Figure 5)Eight patients with stage 0 fibrosis were all put into the

smooth liver surface group (surface score 0), and 34patients with the fibrosis stage 1 were all found to have a

score of 1 or less. 26 patients with the fibrosis stage 2 haddifferent results regarding the surface score, i.e. 3 patientshad a surface score of 0, 7 a score of 0.5, 9 a score of 1, 4 ascore of 1.5 and 3 a score of 2, respectively. 12 of 13patients with stage 3 fibrosis were found to have a surfacescore of either 1.5 or 2. All 22 patients with the stage 4fibrosis were found to have a surface score of 2 or more.The liver surface score and the fibrosis stage showed astatistically significant correlation (rs: 0.9007).

The relationship between liver parenchymal texture and

fibrosis (Figure 6)Eight patients with stage 0 fibrosis were all found to

have a fine liver parenchymal texture (parenchymal score0), and 29 of 34 patients with stage 1 fibrosis were found

(a) (b)

(c)

Figure 1. The ultrasound features of the liver edge; (a) a sharpedge with a high frequency probe, (b) a mildly blunted edgewith a high frequency probe, and (c) a blunted edge with alow frequency probe.

US findings for chronic liver disease


to have a score of 0. Of 26 patients with stage 2 fibrosis, 11had a score of 0, 14 a score of 1 and 1 a score of 2. Fiveand 6 patients of the 13 patients with stage 3 fibrosis had ascore of 1 and 2, respectively. All 22 patients with stage 4fibrosis had a parenchymal score of 2 or more. The liverparenchymal score and the fibrosis stage showed astatistically significant correlation (rs: 0.8853).

Relationship between the fibrosis grade and the

accumulated scores of the liver edge, surface and

parenchymal texture (Figure 7)The liver edge, surface and parenchymal texture scores

were all determined and compared with the histological

fibrosis score. Of eight patients with fibrosis stage 0, sixpatients were found to have a total score of 0 and whiletwo had a total score of 1. 34 patients with stage 1 fibrosishad a total score 1.53 consisting of 2 patients with scoresof 0, 11 and a score of 0.5–1, 17 had a score of 1.5–2.0,and 4 had a score of 2.5–3, respectively. 26 patients withstage 2 fibrosis shifted to the progressive fibrosis stage,such as 1 patient with a score of 1.5–2, 10 with a score of2.5–3, 9 with a score of 3.5–4, and 6 with a score of 4.5–5,respectively. Similarly, 13 patients with stage 3 fibrosisshifted to a progressive fibrosis stage such as 1 patient witha score of 3.5–4, 5 with a score of 4.5–5, and 7 with a scoreof 5.5–6, respectively. Out of 22 patients with stage 4fibrosis had a score of 6.5–7.0 and eleven had a score of

(a) (b)

(c) (d)

Figure 2. The ultrasound features of the liver surface; (a) a smooth surface with a high frequency probe, (b) a mildly irregular sur-face with a high frequency probe, (c) an irregular surface with a low frequency probe, and (d) a highly irregular surface with a lowfrequency probe.



7–7.5, respectively. The fibrosis grade and the accumulatedscores of these three parameters were more significantlycorrelated (positive predictive value, 0.9524) than thecorrelations of each score alone.

Discussion

Chronic liver diseases with viral infection manifestvarying degrees of hepatic fibrosis ranging from no fibrosisto cirrhosis. Yoshida et al revealed that the annual

incidence of hepatocellular carcinoma increased from0.5% among patients with the stage F0 or F1 fibrosis to7.9% among the patients with stage F4 fibrosis [13]. It hasthus become increasingly apparent that the fibrosis stage isa key factor in defining the prognosis and management ofchronic liver diseases with a viral infection.

The gold standard in hepatology for the diagnosis ofthe fibrosis stage has been a histological liver evaluationbased on specimens taken either by a needle biopsy or atoperation. Recently, non-invasive and reliable assessmentsfor monitoring chronic liver disease using the platelet

(a) (b)

(c) (d)

Figure 3. Scores for the ultrasound features of the liver parenchymal texture; (a) fine parenchymal texture with a high frequencyprobe, (b) a mildly coarse parenchymal texture with a high frequency probe, (c) a coarse parenchymal texture with a low frequencyprobe, and (d) a highly coarse parenchymal texture with a low frequency probe.



Figure 4. Relationship between the liver edge and fibrosis findings.

Figure 5. Relationship between the liver surface and fibrosis findings.



Figure 6. Relationship between the liver parenchymal texture and fibrosis findings.

Figure 7. Relationship between the accumulated ultrasound score and fibrosis score findings.



counts [14–16], aspartate aminotransferase (AST)/alanineaminotransferase (ALT) ratio [15, 16], and serum hyalur-onan and type III procollagen amino-terminal peptide [17]have been developed. However, none of the currentlyavailable tests or modalities can completely replace ahistological analysis. Previous studies have assessed severalmethods for evaluating the fibrosis stage of chronic liverdisease using various US parameters. However, there haveso far been few studies concerning the accuracy indetecting the signs of compensated cirrhosis by US [5,18]. Gaiani et al [5] and Hung et al [19] proposed acomplex US scoring system using indices of the liversurface, parenchymal echogenecity, the vessel pattern,spleen size etc. to determine the fibrosis stage. In addition,recent advances in ultrasound technology have now madeit possible to obtain more precise information about theliver surface, edge and parenchymal texture [8]. Therefore,we conducted this study to clarify whether the US scoringsystem with a newly developed US equipment based on theconventional parameters of the liver edge, surface andparenchymal texture might obtain sufficiently accurateresults in comparison with the histological findings forfibrosis obtained by a liver biopsy.In this prospective study, among these parameters such

as the liver edge, liver surface and liver parenchymaltexture, the liver edge was not as specific for evaluatingliver fibrosis as the liver surface and parenchymal texturein our study because a mildly blunted (score 1) or bluntededge (score 2) was frequently found in the early fibrosisstage (stage 1) (67.6%). On the other hand, the liversurface and liver parenchymal texture obtained by USshowed a better correlation with the histological findings(correlation coefficient of 0.9007 in the liver surface, and0.8853 in the parenchymal texture).With conventional US, the liver surface has been most

commonly utilized as a sole indicator for the diagnosis ofcirrhosis [5, 20–22]. However, numerous papers havereported that the sole factor of the liver surface can notsufficiently distinguish cirrhosis from chronic hepatitis.Gaiani et al confirmed that the stage of cirrhosis may beunderestimated when based on a single specimen andclarified that only two US variables, namely liver surfacenodularity and the portal vein mean flow velocity,independently contributed to the diagnosis of cirrhosis[5]. In our study, all seven patients with a highly irregularsurface were found to have cirrhosis (stage 4 fibrosis)histologically. On the other hand, 15 of 22 patients (68.2%)with cirrhosis were found to have an irregular surface(score 2–2.5), not a highly irregular surface (score 3).Indeed, the results of our study showed a significantcorrelation between the ultrasound liver surface and thehistological fibrosis stage.An irregular and nodular liver surface may be easily

assessed in patients with decompensated liver cirrhosis,particularly in the case of ascites, and it has been observedin 88% of unselected patients with cirrhosis [20]. Gaianiet al reported the findings of a US scoring system, basedon the liver, spleen and portal vein features, whichidentified cirrhosis in 82.2% of the cases [5]. In ourstudy, both the right and the left liver lobes were evaluatedfor each factor, and the average score for each parameterwas calculated. Both the low frequency and the highfrequency probes were used to limit the subjective natureof the assessment of the US findings of various degrees. In

this prospective study, US was performed with thesimultaneous use of low frequency and high frequencyprobes to determine the sensitivity and probabilityaccording to the characteristics of ultrasound. Althoughour study was limited on account of the relatively smallnumber of patients due to the strict inclusion criteria, 22patients with an accumulated score of 6.5 or more were allfound to have a fibrosis score of 4. Therefore, our scoringsystem for correctly predicting cirrhosis was found to be100% sensitive. Furthermore, although the major draw-back with US in comparison with the liver histology hasbeen considered to be the failure to detect mild fibrosis ornone at all, our scoring system thus provided relativelyaccurate information about liver fibrosis. When theaccumulated US score of 3 was interpreted as mild fibrosis(a fibrosis score of 0 or 1), all 42 patients with stage 0 or 1fibrosis were categorized into an accumulated US score of3 or less (a probability of 100%) and 42 of 53 patients witha score of 3 or less were found to have stage 0 or 1 fibrosis(specificity of 79.2%). In addition, the score proposed inour study is easy to obtain and can be applied in everyultrasound laboratory by utilizing regular commerciallyavailable US equipment.

Evaluating the ultrasound pattern using either one ortwo parameters becomes much more complex at the stageof chronic liver disease than that of complete cirrhosis.Our scoring system based on three parameters such as theliver edge, surface and parenchymal texture was able toaccurately predict the fibrosis stage (correlation coefficientof 0.9524), especially when distinguishing chronic hepatitisfrom compensated liver cirrhosis. When an exclusion ofliver cirrhosis is requested, then US alone is thereforeconsidered to provide sufficient information based on thisscoring system. Furthermore, if a histological analysis cannot determine the fibrosis stage correctly due to fragmen-tation or architectural distortion, then this ultrasounddiagnostic modality of fibrosis could replace a histologicaldiagnosis.

In conclusion, we demonstrated that our US scoringsystem is clinically useful for differentiating patients whohave chronic liver disease with minimal or no fibrosisfrom those with mild to severe fibrosis. These parametersmay also be useful for providing prognostic informa-tion and also for determining the optimal therapeuticoptions during the follow-up of patients with chronicliver disease, especially in patients with chronic hepatitis Cor B, in order to predict the occurrence of HCC. Inaddition, further study is called for to determine whetheror not the wider use of this scoring system could apply toother forms of hepatic fibrosis such as those suffering fromlong-term hepatotoxic disease, congenital diseases inchildren and non-viral infective forms of chronic liverdisease in order to obtain an improved response totherapy.

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ultrasound evaluation of the fibrosis stage in chronic liver

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