AJR:192, April 2009 909

are more commonly applied in clinical prac-tice and in population-based studies [9–11].

Although CT is considered a reliable tech-nique to assess steatosis, its use is limited be-cause of radiation exposure. In addition, it is less sensitive than sonography and MRI [12]. The latter is also an accurate technique for the diagnosis and characterization of fatty liver, but it is expensive and poorly tolerated by some patients [13–16]. In contrast, sono-graphy is cost effective and widely available, but it is limited by interobserver and intra-observer variability [17] and is not consid-ered precise enough for the quantification of steatosis [18–22].

Moreover, the ability of these three tech-niques to detect steatosis in less than 15–30% of the hepatocytes is limited [10]. The aim of this study was to test whether sonography can serve as an objective tool for the quan-tification of hepatic steatosis by comparing

Diagnostic Value of a Computerized Hepatorenal Index for Sonographic Quantification of Liver Steatosis

Muriel Webb1 Hanny Yeshua1,2 Shira Zelber-Sagi1 Erwin Santo1 Eli Brazowski3 Zamir Halpern1 Ran Oren1

Webb M, Yeshua H, Zelber-Sagi S, et al.

1Department of Gastroenterology, Tel Aviv Sourasky Medical Center, 6 Weizman St., Tel Aviv 64239, Israel. Address correspondence to S. Zelber-Sagi (zelbersagi@bezeqint.net).

2Clalit Health Services, Tel Aviv, Israel.

3Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Gastrointest ina l Imaging • Or ig ina l Research

AJR 2009; 192:909–914

0361–803X/09/1924–909

© American Roentgen Ray Society

Liver steatosis, defined as the ac-cumulation of more than 5% fat in the liver, is the hallmark of most prevalent liver diseases,

mainly alcoholic and nonalcoholic fatty liver disease. It is also highly prevalent in chronic hepatitis C virus (HCV) infection [1].

Steatosis exposes the liver to a range of in-flammatory cytokines, which most likely play a major role in the development of steatohep-atitis [2]. It also plays a major role in chronic HCV infection, where it is considered to be a risk factor for fibrosis severity and may re-duce the viral response to therapy [3–6].

Liver biopsy is the reference standard for quantification of liver steatosis in nonalco-holic fatty liver disease [1, 7]. However, it is not routinely performed because it is an in-vasive procedure with a significant degree of sampling error [8]. Therefore, noninvasive methods such as CT, MRI, and sonography

Keywords: hepatorenal index, liver steatosis, quantification, sonography

DOI:10.2214/AJR.07.4016

Received March 23, 2008; accepted after revision September 29, 2008.

Presented at the 2006 annual meeting of the American Association for the Study of Liver Diseases, Boston, MA.

H. Yeshua and S. Zelber-Sagi contributed equally to this article.

OBJECTIVE. Quantification of liver steatosis is clinically relevant in various liver dis-eases but cannot be done by conventional sonography, which only provides a qualitative as-sessment with significant observer variability. The aim of this study was to assess sonography as an objective tool for the quantification of liver steatosis.

MATERIALS AND METHODS. Files of 111 patients with chronic liver disease who were referred for sonographically guided liver biopsy were collected. A hepatorenal sono-graphic index was calculated on the basis of the ratio between the echogenicity of the liver and that of the right kidney cortex using histogram echo intensity. Liver steatosis was graded by histology.

RESULTS. A significant correlation was found between histologic steatosis and the hepa-torenal sonographic index (r = 0.82, p < 0.001). The validity of the hepatorenal sonographic index for the diagnosis of fatty liver was compared with liver biopsies with a steatosis level > 5%. The area under the receiver operating characteristic curve was 99.2% (95% CI, 98–100%). The optimal hepatorenal sonographic index cutoff point for the prediction of steatosis > 5% was 1.49, with sensitivity of 100% and specificity of 91%. The optimal hepatorenal sono-graphic index cutoff point for the prediction of steatosis ≥ 25% was 1.86, with sensitivity of 90% and specificity of 90%. The optimal hepatorenal sonographic index cutoff point for the prediction of steatosis ≥ 60% was 2.23, with sensitivity of 90% and specificity of 93%.

CONCLUSION. The hepatorenal sonographic index is a sensitive noninvasive method for steatosis quantification. It can diagnose small amounts of liver fat that would be missed by con-ventional sonography. It is reproducible and operator independent and can serve as an efficient tool to follow patients with steatosis and evaluate the efficacy of new treatment techniques.

Webb et al.Hepatorenal Index for Sonography of Liver Steatosis

Gastrointestinal ImagingOriginal Research

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Webb et al.

computerized liver echogenicity to that of the right kidney.

Materials and MethodsStudy Population

Files of 111 consecutive patients referred for sonographically guided liver biopsy in the liver unit of the Tel Aviv Sourasky Medical Center were retro-spectively collected between April 2005 and March 2006. The indications for liver biopsy included HCV infection, hepatitis B virus (HBV) infection, nonalcoholic fatty liver disease, and unexplained elevation of liver enzymes. HCV and HBV were di-agnosed by serological tests. The diagnosis of nonalcoholic fatty liver disease was based on pub-lished criteria (the specific pattern of the liver on sonography, elevated serum transaminase levels, and exclusion of all other known liver diseases).

The study population was restricted to patients with diffuse homogeneous hyperechogenicity of the liver. Patients with heterogeneous geographi-cal or focal steatosis or with focal lesions of the liver such as hemangioma and focal nodular hy-perplasia (FNH), which can cause focal distortion of the liver echostructure, were excluded from the study, as were patients with ascites. Patients with a diseased or absent or ectopic right kidney were also excluded from the study. Informed consent to participate in the study was obtained from all sub-jects before the biopsy.

Histologic AssessmentAll consenting patients underwent a simultane-

ous sonography and liver biopsy that was conduct-ed by the same operator. Percutaneous sonograph-ically guided liver biopsy was performed with a Tru-Cut needle (Baxter Healthcare) (16-gauge Klatskin needle). A liver specimen of 10 mm with at least nine portal tracts was considered adequate for evaluation. Liver biopsy specimens were fixed in formalin and embedded in paraffin. All biopsy specimens were examined by the same pathologist who was blinded to the hepatorenal sonographic index results.

For patients with nonalcoholic fatty liver dis-ease, the extent of liver steatosis and the degree of fibrosis and necroinflammatory activity were as-sessed histologically according to the Brunt [23, 24] criteria. Patients with HBV or HCV were as-sessed according to the Batts and Ludwig [25] cri-teria, and the amount of fatty infiltration was esti-mated by the pathologist on the whole sample and expressed as a percentage. The amount of liver ste-atosis was classified as follows: none (≤ 5%), mild (> 5% and < 25%), and moderate to severe (≥ 25%) [26]. Furthermore, to diagnose massive fatty liver infiltration, we added another classification of mas-sive steatosis (≥ 60%) [27].

Sonography for Fat QuantificationEach liver biopsy was performed under sono-

graphic guidance using an EUB-8500 scanner (Hitachi Medical Systems) with a 3.5-MHz phased-array convex transducer. For each patient, the computer program presented a startup menu with measurement options that included a histo-gram of brightness levels—a graphic representa-tion of echo intensity within a region of interest (ROI) on a B-mode sonogram. The ROI was deter-mined by using the rectangle method (Fig. 1). In the liver the ROI corresponded to the site where the biopsy was performed, usually at the intercos-tal space in the mid or anterior axillary line (sev-enth or eighth intercostal space) in the superficial aspect of the liver. The ROI had to be as uniform as possible, excluding nonhepatic anatomic struc-tures such as vessels or bile ducts. In the right kid-ney, the ROI was determined as the cortical area between the pyramids.

The area of the ROI in the liver was between 3.5 and 4 cm2 in all patients. This area is large enough to calculate an average histogram value and small enough to avoid the inclusion of vessels or bile ducts in the specimen. Several ROI parameters were dis-played including circumference and area, total brightness level, mean brightness level, SD, most fre-quent brightness level, and a histogram. Of all these parameters, we used only the mean brightness level for each organ (liver and right kidney) in this study.

Technically, the echo intensity can be influ-enced by many factors, particularly by gain inten-sity. To avoid confounding by factors that can modify the echo intensity and thus bias compari-sons, the mean brightness levels of both the liver and the right kidney cortex were obtained on the same longitudinal sonographic plane. The ratio between the mean brightness level of the liver and the right kidney was calculated manually to deter-mine the hepatorenal sonographic index.

In each case, the calculation of the hepatorenal sonographic index was repeated at least twice. When the difference was less than 0.20, the aver-age was calculated. If there was a greater discrep-ancy, a third measure was performed and the aver-age of the two closest measurements was used.

Hepatorenal sonographic index reproducibility was evaluated on a sample of 20 hospital workers who underwent two repeat measures within 7–14 days. Sonography was performed by the same op-erator, who was unaware of the results of the first examination at the time of the second examination because the results were recorded and held by an-other individual. The results of the first and the second hepatorenal sonographic indexes were highly correlated (r = 0.77, p < 0.001). The mean hepatorenal sonographic index difference between the two examinations was 0.02 (± 0.15 SD), which

was not significant in a paired test (p = 0.63). Ap-plying the cutoff point of 1.49 for the diagnosis of steatosis yielded a κ of 0.86, which represents an excellent degree of agreement.

Statistical AnalysisAll statistical analyses were performed using

SPSS version 13.0 for Microsoft Windows (SPSS). Continuous variables are presented as means ± SD. Comparisons of continuous vari-ables were performed with analysis of variance. The Bonferroni test was used for post hoc com-parisons. Pearson’s or Spearman’s correlations were used for correlation between the sonograph-ic index and histologic steatosis. For the assess-ment of hepatorenal sonographic index reproduc-ibility, within-subject variations were assessed using the Wilcoxon’s signed rank test (a nonpara-metric paired test).

To define the optimal hepatorenal sonographic index cutoff point for the diagnosis and classifica-tion of fatty liver on the basis of liver biopsy, we applied a receiver operating characteristic (ROC) curve. Using that cutoff point, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the index were calculated. The kappa statistic was calculated. Values for p < 0.05 were considered statistically significant for all analyses.

ResultsA total of 111 patients were included in

the study (mean age, 44 ± 12 years; 54% men). The causes of their chronic liver dis-eases were HCV, 56; nonalcoholic fatty liver disease, 43; HBV, three; and abnormal liver enzymes, nine. The mean hepatorenal sono-graphic index was 1.65 ± 0.75 (0.88–3.78).

Fig. 1—Sonogram of liver and right kidney in 58-year-old man with fatty liver disease shows graphic representation of region of interest rectangle. HIST1 is mean histogram of liver, which corresponds to site of biopsy. HIST2 is mean histogram of right kidney cortex.

AJR:192, April 2009 911

Hepatorenal Index for Sonography of Liver Steatosis

Histologic Characteristics of the Study SampleThe mean degree of steatosis was 18.7 ±

28% (0–80%). Sixty-six patients had no signif-icant steatosis (≤ 5%), 15 had mild (> 5% and < 25%), and 30 had moderate to severe (≥ 25%) steatosis. All grades of inflammation (25 with none and 32, 31, and 23 for grades 1, 2, and 3, respectively) and stages of fibrosis (Table 1) were represented in this study population.

Association Between Hepatorenal Sonographic Index and Extent of Steatosis on Liver Biopsy

A significant correlation was found between histologic steatosis and the hepatorenal sono-graphic index (r = 0.82, p < 0.001) (Fig. 2). The hepatorenal sonographic index provided a reliable quantification of steatosis compared with biopsy as the standard. The mean hepato-renal sonographic index was significantly dif-ferent among all the steatosis categories (p < 0.001) (Fig. 3). The mean index was 1.15 (95%

CI, 1.1–1.2) for no steatosis, 1.94 (1.7–2.1) for mild steatosis, and 2.59 (2.3–2.8) for moderate to severe steatosis (p < 0.001 between all lev-els). Significant correlations were observed for every stage of fibrosis (Table 1) and in every grade of inflammation (r = 0.8–0.9, p < 0.001 for all). High correlation rates were found be-tween the hepatorenal sonographic index and the amount of steatosis in HCV (r = 0.68) and nonalcoholic fatty liver disease (r = 0.70) (p < 0.001 for all causes).

ROC Curves for Validity of the Hepatorenal Sonographic Index

The validity of the hepatorenal sonog raphic index for the diagnosis of fatty liver was com-pared with liver biopsies with a steatosis level > 5%. The area under the ROC curve (Az) was 99.2% (95% CI, 98–100%). The optimal hepato renal sonographic index cutoff point for the prediction of steatosis > 5% was 1.49, with sensitivity of 100% and specificity of 91%.

Further assessments of the capacity of the hepatorenal sonographic index to distinguish

between different levels of steatosis were performed by comparing the index with his-tologic steatosis levels ≥ 25% and ≥ 60%. The Az values (95% CI) were 96% (93–99%) for steatosis ≥ 25% and 95.7% (92–99%) for steatosis ≥ 60% (Fig. 4).

The optimal hepatorenal sonographic index cutoff point for the prediction of steatosis ≥ 25% was 1.86, with sensitivity of 90% and specificity of 90%. The optimal hepatorenal sonographic index cutoff point for the predic-tion of steatosis ≥ 60% was 2.23, with sensitiv-ity of 90% and specificity of 93% (Table 2).

Concordance Between Steatosis by Hepatorenal Sonographic Index and Biopsy

The hepatorenal sonographic index was divided into categories in accordance with the optimal cutoff points determined from the ROC curves. These categories were com-pared with the steatosis categories and the kappa statistic was calculated. For three cat-egories of steatosis (≤ 5%, > 5% to ≤ 25% steatosis, and > 25% steatosis) a κ of 0.75 ±

TABLE 1: Correlation Between Hepatorenal Sonographic Index and Steatosis by Stage of Fibrosis

No. of Patients

Fibrosis Stage r p

50 0 0.64 < 0.001

23 1 0.82 < 0.001

10 2 0.86 0.002

12 3 0.91 < 0.001

16 4 0.66 0.005

Note—r indicates Spearman’s correlation.

TABLE 2: Validity of Hepatorenal Sonographic Index Compared with Percentage of Steatosis on Liver Biopsy

SteatosisOptimal Cutoff

(Az [%], 95% CI [%]) Sensitivity (%) Specificity (%) PPV (%) NPV (%)

≥ 5% (n = 45) 1.49 (99.2, 98–100) 100 (45/45) 91 (60/66) 88 (45/51) 100 (60/60)

> 5% and ≥ 25% (n = 30)

1.86 (96.0, 93–99) 90 (27/30) 90 (73/81) 77 (27/35) 96 (73/76)

≥ 60% (n = 20) 2.23 (95.7, 92–99) 90 (18/20) 93 (85/91) 75 (18/24) 98 (85/87)

Note—For sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), data in parentheses indicate number of patients. Az = area under the receiver operating characteristic curve.

20 40

Steatosis (%)

Ind

ex

3.00

4.00

2.00

1.00

0 60 80

< 5 5–25

Steatosis (%)

Ind

ex

> 25

3.00

4.00

2.00

1.00

Fig. 2—Graph shows correlation between hepatorenal sonographic index and degree of steatosis at liver biopsy. Significant correlation was found between histologic steatosis and hepatorenal sonographic index (r = 0.82, p < 0.001).

Fig. 3—Graph shows distribution of hepatorenal sonographic index according to category of hepatic steatosis. Hepatorenal sonographic index was significantly different for each category of steatosis: none, mild, and moderate to severe (p < 0.001).

912 AJR:192, April 2009

Webb et al.

0.05 was found (Table 3). Adding a fourth category of steatosis ≥ 60% yielded a κ of 0.68 ± 0.06 with discordance in one class of 0.153 (17/111), discordance in two class-es 0.045 (5/111), and discordance in three classes 0 (0/111).

DiscussionFatty liver is the most prevalent hepatic

histopathologic finding in the Western popu-lation [28, 29]. Until recently, simple steato-sis was regarded as a benign condition, but increasing evidence indicates that a fatty liv-er is more vulnerable to factors that lead to inflammation and fibrosis [30, 31]. The cur-rent theory regarding nonalcoholic fatty liver disease is the two-hit theory, which involves accumulation of fat in the liver (first hit) cou-pled with increased oxidative stress and reac-tive oxygen species (second hit) [2, 32, 33]. Because steatosis is the hallmark of nonalco-holic fatty liver disease, its assessment is im-portant for both evaluation and treatment.

Steatosis is also a frequent histologic find-ing in patients with chronic HCV infection, occurring in approximately 50% of liver bi-opsy samples with a reported range of 30–70% [34]. Recent studies suggest a correla-tion between the degree of steatosis and liver fibrosis in hepatitis C [3, 4, 35–39]. Signifi-cant steatosis may also lower the sustained viral response rate to therapy [5, 6, 40]. Among patients suffering from coinfection with HCV and HIV, the fibrosis rate has been shown to increase in a linear fashion with the grade of steatosis [41, 42].

Significant liver steatosis can affect liv-er graft survival. If the degree of steatosis is more than 30%, there is a 25% chance of developing primary nonfunction. Thus, this degree of steatosis is a contraindication for

transplantation [43]. Liver biopsy is the cur-rent reference standard for the quantification of steatosis in live liver donors. An accurate technique for the quantitative assessment of steatosis could spare healthy volunteers the need to undergo liver biopsy.

Although several imaging techniques can be used to assess liver steatosis, sonography is the most commonly applied and cost-ef-fective. Sonographic findings of fatty liv-er include increased echogenicity of liver, blurring of vascular margins, and increased acoustic attenuation [44]. However, sonog-raphy is an operator-dependent technique and lacks the capacity for objectively quan-tifying liver steatosis.

This study presents an innovative method for the quantification of hepatic steatosis us-ing a sonography-based index: the hepatore-nal sonographic index. Using the hepatorenal sonographic index, we were able to identify the presence of minimal steatosis, as low as 5%. Thus, the known limitation of sonog-raphy to detect steatosis with high sensitivity only if it involves more than 30% of hepato-cytes [10] is resolved by the hepatorenal sono-graphic index. Furthermore, the high corre-lation between the hepatorenal sonographic index and steatosis was independent of the

cause and was seen at every level of inflam-mation and fibrosis.

The suggested hepatorenal sonographic in-dex cut point of 1.49 yielded very high sensi-tivity (100%) and specificity (91%), enabling us to attain good PPV and NPV (88% and 100%, respectively) for the diagnosis of he-patic steatosis > 5% (Fig. 4 and Table 2). This high sensitivity rate could be attributed to the ability of the hepatorenal sonographic index to identify relatively low degrees of steatosis. In other studies, the sensitivity of sonography ranged from 60% to 94% and specificity from 84% to 95% [18–22, 30, 45, 46]. The sensi-tivity of sonography was reported to increase with the increasing degree of fatty infiltration. For example Ryan and colleagues [47] identi-fied liver fat in only 55% of 11 patients with 10–19% steatosis. The sensitivity rose to 80% in the presence of steatosis of 30% or more.

All these previous studies dealt with the de-tection of steatosis rather than with the precise determination of hepatic fat content. The he-patorenal sonographic index also proved to be useful for predicting the degree of steatosis, with sensitivity of 90% and specificity of 90% for moderate to severe steatosis and sensitivity of 90% and specificity of 93% for severe ste-atosis (Table 2). The hepatorenal sonographic index is an objective, computerized calculated index, whereas the routine sonographic inter-pretation of steatosis is based on a subjective impression of a “bright liver echo” pattern. Thus, the interpretation is observer-driven with interobserver and intraobserver variance and limited reproducibility and comparabili-ty [10, 17]. As an objective quantitative tool, the hepatorenal sonographic index overcomes this major limitation and is ideal for patient follow-up and determination of the efficacy of treatment in liver diseases involving steatosis.

Few studies have addressed the role of sonog raphy in the quantification of liver ste-atosis, and most of these lack complete histo-logic evaluation. Some of these studies were based on the visual assessment of hepatic

TABLE 3: Concordance Between Steatosis Predicted by the Hepatorenal Sonographic Index and Predicted by Biopsy for the Three Categories

Hepatorenal Sonographic Index

Histologic Diagnosis

Steatosis ≤ 5% Steatosis > 5 and ≤ 25% Steatosis > 25

< 1.49 60 0 0

≥1.49 and < 1.86 5 8 3

≥ 1.86 1 7 27

Note—Data are number of patients. Overall κ, 0.75 ± 0.05; discordance in one class 15 of 111, 14%; and discordance in two classes, one of 111, 1%.

0.00.0 0.1 0.2 0.3 0.4 0.5

Steatosis ≥5%Steatosis ≥25%Steatosis ≥60%

1–Specificity

Sen

siti

vity

0.6 0.7 0.8 0.9 1.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0Fig. 4—Graph of receiver-operating characteristic (ROC) curve of sensitivity (true-positive fraction) plotted against 1 – specificity (false-positive fraction) of hepatorenal sonographic index for diagnosis of different levels of steatosis on liver biopsy. Area under the ROC curve (Az) for diagnosis of steatosis > 5% was 99.2% (95% CI, 98–100%). The Az for diagnosis of steatosis ≥ 25% and for steatosis ≥ 60% were 96% (95% CI, 93–99%) and 95.7% (95% CI, 92–99%), respectively.

AJR:192, April 2009 913

Hepatorenal Index for Sonography of Liver Steatosis

echogenicity and thus were operator depen-dent. In addition, sonography failed to pro-vide a precise determination of hepatic fat content [16].

In other studies, the capacity of sonog-raphy to quantify hepatic steatosis was as-sessed in an experimental setting with spe-cial software packages for textural analysis or by signal analysis applied to backscattered acoustic echoes [48–51]. The correlation be-tween sonography and steatosis was incon-sistent in the presence of fibrosis or inflam-mation [50].

Our study has some limitations. The hepa-torenal sonographic index could not be mea-sured in patients with disease in the right kidney, including structural disease or ec-topic or absent right kidneys, or in patients with single or multiple focal abnormalities that distort liver architecture, especially in the right hepatic lobe (focal steatosis, giant or multiple hemangiomas, FNH).

Liver biopsy is considered the reference standard. However, it is an invasive procedure that can be performed only if clinically justi-fied, so the resulting study population is selec-tive. Nevertheless, this study population rep-resents a variety of different liver diseases and also represents patients without steatosis or with varying degrees of steatosis. Moreover, there is no reason to believe that the correla-tion found in the current study between the hepatorenal sonographic index and steatosis by histology is affected by selection bias.

In conclusion, the use of the hepatorenal sonographic index facilitates quantification of liver steatosis, even in small degrees, and is not affected by fibrosis or steatohepatitis. It is reproducible and operator-independent and easily can be made available and appli-cable in routine clinical practice. The hepa-torenal sonographic index is promising as an effective tool for the follow-up of patients with steatosis and for evaluation of the effi-cacy of new treatment techniques.

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F O R Y O U R I N F O R M A T I O N

PQI Connect is the latest addition to the ARRS Website and serves as a source for information on meeting the growing demand for quality review programs in today’s radiology practices and facilities. The interactive and easy-to-navigate site focuses on five critical topics that guide you through news items, relevant articles, and links to important information on each topic.