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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 33  |  Issue : 2  |  Page : 116-124

Noninvasive diagnosis of hepatic steatosis with controlled attenuation parameter (FibroScan) in chronic hepatitis C patients


1 Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission15-Mar-2016
Date of Acceptance22-Aug-2016
Date of Web Publication1-Mar-2017

Correspondence Address:
Tarek F Sheta
El Mansoura
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-208X.201291

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  Abstract 

Background/aims
The gold standard for the diagnosis of hepatic steatosis is liver biopsy, which is an invasive method with some limitations. There was an increased need for a noninvasive, cost-effective method for the diagnosis of hepatic steatosis.
The aim of this work was to study the controlled attenuation parameters (CAP), a noninvasive tool, for the diagnosis of hepatic steatosis in chronic hepatitis C patients.
Patients and methods
The study was conducted on 100 Egyptian patients with chronic hepatitis C infection (anti-hepatitis C virus seropositive with detectable hepatitis C virus-RNA) during pretreatment assessment for antiviral therapy; those patients were randomly selected from the Outpatient Clinic in The Specialized Medical Hospital, Mansoura University.
All included patients were subjected to full history taking and thorough clinical examination, full laboratory investigations, including complete blood count, liver profile tests, kidney function tests, abdominal ultrasonography, liver biopsy, and transient elastography (FibroScan), including CAP.
Results
There was a proportional relationship between the degree of steatosis and CAP reading.
There was a highly significant difference (the best cutoff value=218 dB/m) for mild steatosis, with a sensitivity of 94.4%, specificity of 82.8%, positive predictive value of 75.6%, and negative predictive value of 96.4%. Furthermore, CAP is valuable in differentiating between moderate degree of steatosis versus no and mild steatosis (cutoff value=241.4 dB/m), with a sensitivity of 100%, specificity of 83.9%, negative predictive value of 100%, and positive predictive value of 31.8 for moderate steatosis.
Conclusion
CAP can be used in the diagnosis of hepatic steatosis with good diagnostic performance. CAP has the advantages of being a simple, noninvasive, inexpensive, painless, operator and machine independent method, and displays good application prospects.

Keywords: controlled attenuation parameter, hepatic steatosis, CAP-Steatosis-HCV-Fibroscan


How to cite this article:
Sheta TF, Zalata KR, El-Desoky AE. Noninvasive diagnosis of hepatic steatosis with controlled attenuation parameter (FibroScan) in chronic hepatitis C patients. Benha Med J 2016;33:116-24

How to cite this URL:
Sheta TF, Zalata KR, El-Desoky AE. Noninvasive diagnosis of hepatic steatosis with controlled attenuation parameter (FibroScan) in chronic hepatitis C patients. Benha Med J [serial online] 2016 [cited 2021 Dec 5];33:116-24. Available from: http://www.bmfj.eg.net/text.asp?2016/33/2/116/201291


  Introduction Top


Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. More than 170 million people are infected [1]. Egypt has the highest worldwide prevalence (22%) countrywide and a prevalence of up to 50% in certain rural areas due to specific modes of infection [2]. There is an increase in the number of patients with HCV-related complications such as liver cirrhosis and hepatocellular carcinoma [1].

Hepatic steatosis is a common histological feature associated with metabolic syndrome, alcohol abuse, viral hepatitis, and exposure to certain medications [3]. It has been suggested that coexistent steatosis in viral hepatitis might accelerate fibrosis progression and reduce the treatment response [4]. The gold standard for diagnosing and assessing the severity of hepatic steatosis has been liver biopsy (LB) [5]. However, LB is an invasive procedure with high cost and has potential limitations; it can be performed only in selected individuals and is not suitable for screening or monitoring changes in hepatic steatosis [6].

Transient elastography (TE) (FibroScan; Echosens, Paris, France) is a noninvasive technique developed to assess hepatic fibrosis in patients with chronic liver diseases. Fibrosis causes an increase in liver stiffness, and measurement of this forms the basis of TE, which is painless, rapid, and easy to perform [7].

In this study we aimed to study the controlled attenuation parameter (CAP) as a noninvasive tool for the diagnosis of hepatic steatosis in chronic hepatitis C (CHC) patients.


  Patients and methods Top


Patients

The study was conducted on 100 Egyptian patients with CHC infection (anti-HCV seropositive with detectable HCV-RNA) during pretreatment assessment for antiviral therapy; those patients were randomly selected from the Outpatient Clinic of Specialized Medical Hospital, Mansoura University, Egypt.

This study is a case–control study and the protocol conforms to the Medical Sciences Ethics Committee of Mansoura Faculty of Medicine, and all included patients had provided written informed consent. The study included both male and female patients between 18 and 60 years of age with documented CHC infection, compensated liver disease (total serum bilirubin <1.5 mg/dl), international normalized ratio (INR) below 1.5, serum albumin above 3.5 mg/dl, platelet count above 75 000/mm3, no evidence of hepatic decompensation (hepatic encephalopathy or ascites), and acceptable hematological and biochemical indices (hemoglobin 13 g/dl for men and 12 g/dl for women; neutrophil count 1500/mm3, and serum creatinine below 1.5 mg/dl). We excluded the following patients: those with advanced cirrhosis (signs of liver cell failure); viral infection other than HCV; those with any other liver disease, autoimmune disease, thyroid disease, or major uncontrolled depressive illness; pregnant women or those unwilling to comply with adequate contraception; those with severe concurrent medical disease such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease; and patients younger than 18 years.

Methods

Following the medical history and clinical examination, pathological examination of the LBs was carried out by pathologists with experience in hepatopathology. All recruited patients were subjected to medical history, clinical examination, and laboratory investigations.

Medical history

Medical history included age, sex, history of smoking, risk factors for contracting HCV (history of blood transfusion, history of medical or surgical interventions, intravenous drug abuse, and occupational exposure), and symptoms of liver disease (fatigue, jaundice, pruritus, and pain in the right upper abdomen).

Clinical examination

General examinations included signs of hepatocellular failure (jaundice, bleeding tendency, fetor hepaticus, spider angiomata, palmer erythema, parotid enlargement, gynecomastia, or encephalopathy). BMI was calculated as weight divided by the square of the height (kg/m2). Local abdominal examination of the liver and the spleen for the detection of ascites was carried out.

Investigations to be performed

All of the following investigations were carried out: (a) detection of anti-HCV antibodies, hepatitis B virus (HBV) surface antigen, and core antibodies using enzyme-linked immunosorbent assay and detection of HCV-RNA using PCR; (b) serum analyses for alanine transaminase (ALT), aspartate transaminase (AST), albumin, bilirubin, alkaline phosphatase, creatinine, prothrombin time, and blood glucose; (c) complete blood counts; (d) detection of anti nuclear antibody (ANA), thyroid-stimulating hormone, alpha feto protein (AFP), and immune haemagglutination (IHA) for schistosomiasis; (e) abdominal ultrasound; and (f) ultrasound-guided Tru-Cut needle (Menghini Inc., India) LB according to the consensus recommendations of the Asian Pacific Association for the Study of the Liver [8]. Hematoxylin and eosin stain is the standard stain in the study of LB. Fibrosis and necroinflammatory activity were staged according to the METAVIR scoring system [9] and ISHAK scoring system [10]. For grading of steatosis, histopathologists use a four-point scale (0–3). Scores 1–3 are considered to correspond to fat deposition in less than 33, 33–66, and greater than 66% of the hepatocytes, respectively [11]. In addition, TE (FibroScan) and CAP measurement within days following or preceding LB was carried out by certified operators. CAP was measured with M probe at 3.5 MHz at depth between 25 and 65 mm and expressed in decibel per meter. CAP measurements were calculated only if the liver stiffness measurements were valid [12].

Statistical analysis

Data were tabulated, coded, and analyzed using the computer program SPSS (statistical package for the social sciences, version 17.0; SPSS 15.0 Command Syntax Reference; Chicago, Illinois: SPSS Inc. 2006) to obtain descriptive data. Descriptive statistics were calculated in the form of mean±SD, median, minimum and maximum, or frequency (number and percentage). The significance of difference between the different groups was tested using one of the following tests:

  1. Student’s t-test: This test was used to compare the mean of two groups of numerical (parametric) data.
  2. Analysis of variance: This was used to compare more than two groups of numerical (parametric) data followed by post-hoc Tukey for multiple comparisons.
  3. Mann–Whitney U-test: This test was used to compare two groups of numerical (nonparametric) data.
  4. Kruskal–Wallis test: This was used to compare more than two groups of numerical (nonparametric) data followed by the Mann–Whitney test for multiple comparisons.
  5. Intergroup comparison of categorical data performed using the χ2-test (χ2-value).


Some investigated parameters were entered into a logistic regression model to determine which of these factors is considered as a significant independent risk factor.

The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for FibroScan and CAP in diagnosing steatosis were examined at different cutoff points using receiver operating characteristic curve analysis to determine the best cutoff point as well as the diagnostic power of each test.

A P-value less than 0.05 was considered statistically significant in all analyses.


  Results Top


Baseline characteristics of the studied patients

[Table 1] shows that nearly all of the studied group were male (99 of 100 patients) with a mean age of 41±10.62, and six of the studied patients were diabetic; their mean BMI was 26.69±3.04. As regards the histopathology steatosis grade, 64 patients were of S0 grade (no steatosis), 29 were of S1 grade (mild steatosis), and seven were of S2 grade (moderate steatosis).
Table 1 Baseline characteristics of the studied patients

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As regards the histopathology fibrosis and activity, 75 were of A1, 24 were of A2 and one patient was of A3 and 59 patients were of F1, 26 were of F2, and 15 were of F3.

Comparison of demographic and history data between different grades of hepatic steatosis

[Table 2] shows a statistically significant difference between the grades of steatosis as regards the age (P=0.0001, P2=0.0001, and P3=0.001), weight (P=0.0001 and P1=0.0001), and BMI (P=0.0001, P1=0.0001, and P2=0.0001).
Table 2 Comparison of demographic and history data between different grades of hepatic steatosis

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Comparison of laboratory parameters between different grades of hepatic steatosis

[Table 3] shows a statistically significant difference between the grades of steatosis with regard to ALT (P=0.0001, P1=0.0001, and P2=0.003), AST (P=0.0001 and P3=0.037), INR (P=0.04 and P2=0.02), PCR (P=0.03, P2=0.008, and P3=0.02), and AFP (P=0.002, P1=0.03, and P2=0.002).
Table 3 Comparison of laboratory parameters between different grades of hepatic steatosis

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Comparisons of FibroScan data between different grades of hepatic steatosis

There was statistical significance as regards FibroScan liver stiffness measurement (LSM) (P=0.0001, P1=0.017, P2=0.001, and P3=0.026) and CAP (P=0.0001, P1=0.0001, P2=0.0001, and P3=0.001) ([Table 4]).
Table 4 Comparisons of FibroScan data between different grades of hepatic steatosis

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Comparison between patients without steatosis (S0) and those with steatosis (S1 and S2)

There was a high statistically significant difference between the two groups, S0 (no steatosis) versus S1–S2 (mild and moderate steatosis), as regards weight (P=0.0001), BMI (P=0.0001), hemoglobin (P=0.03), ALT (P=0.0001), AST (P=0.0001), INR (P=0.049), AFP (P=0.003), FibroScan (P=0.001), and CAP (P=0.0001) ([Table 3] and [Table 5]).
Table 5 Comparison between patients without steatosis (S0) and those with steatosis (S1, S2)

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Sensitivity, specificity, and accuracy of FibroScan and controlled attenuation parameters in the diagnosis of hepatic steatosis and differentiation between S0 and S1–S2

[Table 6] and [Figure 1] show that FibroScan is a highly sensitive test for the diagnosis of hepatic steatosis and for differentiating between the absence (S0) and the presence of steatosis (S1–S2); the cutoff value was 7.7 kPa and area under ROC curve (AUROC) was 0.703, with a positive predictive value of 49.05% and a negative predictive value of 78.7%. CAP is a highly sensitive and specific test at the cutoff value of 218 dB/m; AUROC was 0.930 with 75.6% PPV and 96.4% NPV for the diagnosis of hepatic steatosis and for differentiating between the absence (S0) and the presence of steatosis (S1–S2).
Table 6 Sensitivity, specificity, and accuracy of FibroScan and controlled attenuation parameters in the diagnosis of hepatic steatosis and differentiation between S0 and S1–S2 (no steatosis vs. mild and moderate steatosis)

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Figure 1 Receiver operating characteristic curve shows the sensitivity, specificity, and accuracy of FibroScan and controlled attenuation parameters (CAP) in the diagnosis of hepatic steatosis and differentiate between S0–S1 and S2 (no and mild steatosis vs. moderate steatosis).

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Sensitivity, specificity, and accuracy of FibroScan and controlled attenuation parameters in the diagnosis of hepatic steatosis and differentiation between S0–S1 and S2 (no and mild steatosis vs. moderate steatosis)

[Table 7] and [Figure 2] show that FibroScan is a highly sensitive test for the diagnosis of hepatic steatosis and for differentiating between no and mild steatosis (S0–S1) and moderate steatosis (S2) (cutoff value of 10.95 kPa); AUROC was 0.860 with a positive predictive value of 20.7% and a negative predictive value of 98.6%. CAP is a highly sensitive and specific test (cutoff value of 241.4 dB/m); AUROC was 0.957, PPV was 31.8%, and NPV was 100% for the diagnosis of hepatic steatosis and for differentiating between no and mild steatosis (S0–S1) and moderate steatosis (S2).
Table 7 Sensitivity, specificity, and accuracy of FibroScan and controlled attenuation parameters in the diagnosis of hepatic steatosis and differentiate between S0–S1 and S2 (no and mild steatosis vs. moderate steatosis)

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Figure 2 Receiver operating characteristic curve shows the sensitivity, specificity, and accuracy of FibroScan and controlled attenuation parameters (CAP) in the diagnosis of hepatic steatosis and differentiation between S0 and S1-S2 (no steatosis vs. mild and moderate steatosis).

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Multivariate regression analysis for factors of steatosis

[Table 8] shows that BMI and ALT are independent factors for the prediction of hepatic steatosis.
Table 8 Multivariate regression analysis for factors of steatosis

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  Discussion Top


In this work, CAP as a noninvasive tool in the diagnosis of hepatic steatosis was studied. The present study was conducted on 100 patients who presented to the Outpatient Clinic of Specialized Medical Hospital, Mansoura University, Egypt. As regards LB, 64 of them had no steatosis, 29 patients had mild degree of steatosis, and seven patients had moderate degree of steatosis and no patient had severe degree of steatosis.

Steatosis as a part of histological feature of chronic HCV has been described and it correlates with both patient factors (e.g. obesity), as well as viral factors (HCV genotype) [13].

The degree of steatosis in chronic HCV is linked to the extent of hepatic fibrosis and those patients with steatosis and genotype 3 were found to have a high risk for accelerated fibrosis. Furthermore, it has also been noted that steatosis may reduce response to HCV therapy [14].

A significant correlation between steatosis grade and baseline BMI in patients with genotype 4 HCV infection suggested that steatosis may be related to obesity [15].

Evaluation of steatosis is not carried out simultaneously with liver fibrosis assessment. Therefore, an accurate, noninvasive, and well-accepted tool to assess, quantify, and monitor both hepatic fibrosis and steatosis is of interest. Fortunately, a novel physical parameter, based on the properties of ultrasonic signals acquired by FibroScan has been developed [16]. In our study, we assessed CAP as a noninvasive tool in the diagnosis of hepatic steatosis in 100 properly selected patients with HCV infection and compensated liver disease. LB results proved no steatosis (S0) in 64 patients, mild degree of steatosis (S1) in 29 patients, and moderate degree of steatosis (S2) in seven patients, and none of the selected patients had severe degree of steatosis (S3).

The value of CAP to diagnose steatosis was evaluated in this study and proved that CAP value was significantly higher in patients with steatosis, and there was a direct proportional relation between the degree of steatosis and CAP measurements, as shown in [Figure 3]. This finding is in agreement with a previous study conducted by Sasso et al. [16].
Figure 3 Relation between controlled attenuation parameters (CAP) reading and degree of steatosis. There is proportional relation between CAP and histopathology steatosis grade.

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The current study demonstrated a cutoff value of 218 dB/m with high significant difference between steatotic and nonsteatotic patients (P=0.0001).

During analysis of the results using receiver operating characteristic curve of FibroScan, the results proved the sensitivity of CAP in 94.4% of patients and specificity in 82.8% with a positive predictive value of 75.6% and a negative predictive value of 96.4%.

Similarly, CAP was found have high significant difference (P=0.0001) in differentiating between moderate degree of steatosis and mild steatosis; the cutoff value was 241.4 dB/m, with high sensitivity (100%) and specificity (83.9%) and a positive predictive value of 31.8% and a negative predictive value of 100%.

The aforementioned results have encouraged us to consider CAP a valuable and highly sensitive tool for the diagnosis of hepatic steatosis on one hand and suitable for differentiating between the different grades of hepatic steatosis on the other.

Our findings are in accordance with those of Sasso et al. [12], who reported that in chronic HCV patients CAP reading is strongly correlated to the presence and degree of steatosis. The optimal cutoff point was 222 dB/m with a sensitivity of 76%, specificity of 71%, NPV of 87%, and PPV of 53% in the detection of mild steatosis, and the optimal cutoff was 233 dB/m with a sensitivity of 87%, a specificity of 74%, a NPV of 98%, and PPV of 33% in the detection of moderate steatosis.

Many previous studies evaluated CAP in the diagnosis of hepatic steatosis of different etiologies, such as De Lédinghen et al. [17], who reported that CAP is an efficient tool for the diagnosis of steatosis with optimal cutoff value and sensitivity more than 90% for detection of steatosis S greater than or equal to 1 (215 dB/m), S greater than and equal to 2 (252 dB/m), and S=3 (296 dB/m).

Chon et al. [18] found that CAP had high diagnostic accuracy for the diagnosis of steatosis. The cutoff was 250 dB/m, with a sensitivity of 73.1% and specificity of 95.2% for mild steatosis, and the cutoff was 290 dB/m, with a sensitivity of 82.4% and specificity of 86.1% for moderate steatosis.

Furthermore, Myers et al. [19] found that CAP has a good value for the diagnosis of significant steatosis (≥10% hepatocytes affected) (cutoff of 283 dB/m) with a sensitivity of 76% and specificity of 79% for this outcome.

Shen et al. [20] also found in their study that CAP is a very promising tool in the diagnosis of hepatic steatosis in Chinese patients with nonalcoholic fatty liver disease (NAFLD) and chronic HBV as a cause of liver disease. The cutoff value for S0 versus S1–S3 (≥5% of hepatocytes affected) was 253 dB/m, with a sensitivity of 88.8%, specificity of 85.5%, PPV of 87.8%, and NPV of 83.9%, and that for S0–S1 versus S2–S3 (≥34% of hepatocytes affected) was 285 dB/m, with a sensitivity of 93.3%, specificity of 83.2%, PPV of 70%, and NPV of 96.7%. The cutoff value for S0 versus S1–S3 (≥67% of hepatocytes affected) was 310 dB/m with a sensitivity of 92.3%, specificity of 79.1%, PPV of 29.3%, and NPV of 99.1%.

Interpretation of the results of previous studies together with that of our study showed some differences in cutoff values either in the diagnosis of hepatic steatosis or in the differentiation of the different grades of steatosis. This could be attributed to the differences in the etiologies of steatosis (alcoholic liver disease, NAFLD, and viral liver diseases such as HBV and HCV infection) and the characteristics of the selected patients in addition to genotype difference in those patients with HCV infection. Furthermore, some limitations were found in this study, such as relatively smaller number of patients with moderate steatosis and no patients with severe steatosis.

In our study, many independent factors were found to be associated with steatosis; multivariate regression analysis revealed that both ALT and BMI are independent variables influencing steatosis (P=0.004 and 0.0001, respectively).

The mean overall BMI in our study was 26.69±3.04. The mean BMI for no steatosis patients was 25.18±2.54; the mean BMI for mild–moderate steatosis patients was 29.37±1.74; and the mean BMI for patients with moderate steatosis alone was 29.40±0.77. This proved the proportional relationship between the degree of steatosis and BMI. That is in agreement with the results published by Sumida et al. [23], who stated that obesity and BMI have a major role in the pathogenesis of hepatic steatosis and hence the development of fibrosis in Japanese HCV patients.

Esmat et al. [15] also reported similar results in his study on Egyptian HCV-infected patients, with an overall mean BMI of 27.8±3.6, a mean BMI of 26.8±4.1 for no steatosis patients, and a mean of 29.1±3.3 for steatosis patients.

It is logic to find a relation between steatosis and overweight or obesity (high BMI), because high BMI is a definite factor in the etiopathogenesis of hepatic steatosis and is one of the salient components of the metabolic syndrome and insulin resistance.

As regards ALT in our study, all included patients had HCV infection and 36 of them had steatosis either mild or moderate. The mean ALT level of nonsteatotic patients was 55.81±19.60, and the mean ALT level of steatotic patients was 90.50±21.74.

Liu et al. [21] demonstrated that ALT elevation is a nonspecific marker that indicates the presence of inflammation (hepatitis) regardless of the etiology (HCV, HBV, nonalcoholic steatohepatitis, NAFLD, autoimmune hepatitis, and medications). He also stressed that, when faced with unexplained ALT elevation without the presence of viral infection or alcohol intake, NAFLD should be highly considered in differential diagnosis.

It is not astonishing to find ALT levels to be higher in steatotic patients than in nonsteatotic and adjuncted more to the higher grades of steatosis that could be explained by influence of steatosis on the necroinflammatory activity of HCV with a possible negative impact on the natural course of the hepatitic illness.

As regards FibroScan data, our study showed that there is a significant correlation between FibroScan data, which reflect the stage of fibrosis, and the degree of steatosis. In individuals with no hepatic steatosis (median=6.90, minimum=3.90, and maximum=35.80) while in steatosis whatever the degree (median=10.25, minimum=5.10, and maximum=35.80) and in those with moderate degree of steatosis (median=17.60, minimum=10.00, and maximum 34.80).

This could be explained by the effect of steatosis on progression of liver fibrosis. Similar to that previously reported by Wyatt et al. [22], who studied the effect of steatosis in chronic HCV and reported that steatosis is associated with fibrosis independent of necroinflammation. It may represent a pathogenic pathway distinct from necroinflammatory activity in the generation of liver fibrosis. Moreover, our findings are in agreement with those of Sumida et al. [23], who studied the effect of steatosis in Japanese HCV-infected patients and found that steatosis leads to rapid progression of fibrosis, and Leandro et al. [24], who confirmed that steatosis is significantly and independently associated with fibrosis in CHC patients.

The results of the current study together with that of the aforementioned studies proved a potential link not only between CAP and hepatic steatosis but also between CAP and liver fibrosis. This could be explained by the sequence of events, steatosis, necroinflammation, and subsequent fibrosis, which may progress to cirrhosis with its complications.

Finally, we can conclude that CAP values assessed with FibroScan tool could be valuable, accurate, noninvasive, accepted, and rather reproducible either in the diagnosis of hepatic steatosis or in catching the higher grades of steatosis, which are definite parameters influencing the course of chronic HCV infection and possibly its response to the selected protocols of the antiviral therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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