EVALUATION OF DIFFERENT ELASTOGRAPHY TECHNIQUES IN PREDICTION OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HEPATITIS C RELATED LIVER CIRRHOSIS

EVALUATION OF DIFFERENT ELASTOGRAPHY TECHNIQUES IN PREDICTION OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HEPATITIS C RELATED LIVER CIRRHOSIS

By

Ahmed Helal*, Magdy Al-Dahshan*, Mohamed Hassany**, Ayman Hassan*** Ahmed Eliwa* Ahmed Al-Wassief* and Mohamed Al-Boraie*

*Department Of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

**Department Of Tropical Medicine, National Hepatology and Tropical Medicine Research Institute

***Department Of Diagnostic Radiology, National Hepatology and Tropical Medicine Research Institute

Corresponding author: Ahmed Helal, E-mail: ahmed.h.mahgoub01@gmail.com

ABSTRACT

Background: Although there has been significant improvement in the therapy for HCV achieving a high sustained virological response (SVR). The possibility of developing HCC remains approximately 1% per year after SVR in patients with liver cirrhosis.

Objective: To evaluate the validity of different elastography techniques in prediction of presence of HCC in patients with chronic hepatitis C related liver cirrhosis.

Patients and Methods: This study was a cross-sectional study conducted on Sixty (60) chronic hepatitis C patients (with or without cirrhosis or hepatocellular carcinoma). The studied patients were recruited from Al-Hussein University Hospitals, and National Hepatology & Tropical Medicine Research institute, during the period from 1st of April 2020 to 1st of April 2021. All patients were subjected to full history taking, full physical examination with special emphasis on       general examination and abdominal examination, laboratory investigations including CBC, liver function test, renal function test, viral hepatitis markers, serum Alpha-fetoprotein (AFP) level, abdominal ultrasonography, triphasic CT of abdomen and measurement of liver stiffness. Patients were classified into three equal groups: Group I: HCV patients without liver cirrhosis, Group II: HCV patients with liver cirrhosis and no HCC, and Group III: HCV patients with liver cirrhosis and HCC.

Results: FibroScan can be used to discriminate between group A (HCV Without cirrhosis) and group B (HCV with cirrhosis) at a cutoff level of > 11.1, with 100% sensitivity, 100 % specificity, 100% PPV and 100% NPV (AUC = 1.0 and p-value < 0.001). Also, fibroscan can be used to discriminate between group B (HCV with cirrhosis) & group C (HCV with cirrhosis and HCC) at a cutoff level of > 22.6, with 80% sensitivity, 80% specificity, 80% PPV and 80% NPV (AUC = 0.88 & p-value < 0.001). Shear wave elastography (SWE) discriminated between group A (HCV without cirrhosis) and group B (HCV with cirrhosis) at a cutoff level of > 9.6, with 100% sensitivity, 100 % specificity, 100% PPV and 100% NPV (AUC = 1.0 and p-value < 0.001). Also Shear wave elastography (SWE) discriminated between group B (HCV with cirrhosis) and group C (HCV with cirrhosis and HCC) at a cutoff level of > 21.05, with 75% sensitivity, 60% specificity, 65.2% PPV and 70.6% NPV (AUC = 0.68 and p-value = 0.054).

Conclusions: Ultrasound elastographic technology can predict the occurrence of HCC.

Keyword: Elastography, HCC, HCV, Liver cirrhosis.

INTRODUCTION

     HCC is the fifth most common cause of malignancy-related death global. Although there has been significant improvement in the therapy for HCV achieving a high sustained virological response (SVR), the possibility of developing HCC remains approximately 1% per year after SVR in patients with liver cirrhosis (Aleman et al., 2013). The gold standard for assessing liver fibrosis and cirrhosis is liver biopsy which is an invasive procedure with rare but potential complications. Instead of liver biopsy, a variety of noninvasive markers have been proposed for assessment of liver fibrosis as risk factor for HCC, i.e. aspartate aminotransferase (AST) to platelet ratio index (APRI), FIB-4, Forns index, Fibro index, FibroTest, Enhanced liver fibrosis, Fibrometer, FIBROSpect II, Hepascore, transient elastography (FibroScan), Shear wave elastography (SWE) and acoustic radiation force impulse imaging (ARFI) (Schiavon et al., 2014).

     Development of HCC depends on various risk factors including etiology, race, ethnicity, region, sex, age, presence of diabetes mellitus (DM), and high levels of α-fetoprotein (AFP). However, the presence of advanced liver fibrosis is the most important and common risk factor in chronic liver disease patients (Bandiera et al., 2016). The ultrasound elastography has received widespread attention by adding a new dimension. All liver diseases, focal and diffuse, are associated with changes in the structure of the tissue, with altered liver stiffness (LS), precisely these changes that elastographic techniques can detect and quantify (Lupsor-Platon et al., 2020).

     In patients with chronic hepatitis and continuous inflammation of the liver, fibrosis develops during the course of wound healing, with recurrent accumulation of scar tissue and regenerative nodular formation, chronic hepatitis progresses to cirrhosis in untreated patients with chronic hepatitis C infection, which is a leading cause HCC (Bedossa and poynard et al., 2011). The Metavir liver fibrosis stage increases at an annual rate of F0.1 with a concurrent increase in the incidence of HCC (Shiratori et al., 2013).

     This present work aimed to evaluate the validity of different elastography techniques in prediction of presence of hepatocellular carcinoma in patients with chronic hepatitis C related liver cirrhosis.

PATIENTS AND METHODS

     The current cross-sectional study has been conducted on sixty (60) chronic hepatitis C patients (with or without cirrhosis or hepatocellular carcinoma). The studied patients were recruited from Al-Hussein University Hospitals and National Hepatology & Tropical Medicine Research institute, during the period from 1^st of April 2020 to 1^st of April 2021. Before starting the study, approval from the Ethics Committee, Faculty of Medicine, Al-Azhar University, Cairo, Egypt, was obtained. Additionally, an informed consent was obtained from all subjects before recruitment in the study. Patients were classified into three equal groups: Group I: HCV patients without liver cirrhosis, Group II: HCV patients with liver cirrhosis and no HCC, and Group III: HCV patients with liver cirrhosis and HCC. There were exclusion criteria that included patients known to be positive for hepatitis B virus, bilharzial liver cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, obstructive liver disease, alcohol consumption, cardiac cirrhosis, metabolic liver disease and patients not willing to participate in the study.

     All patients were subjected to detailed medical history and clinical examination with special emphasis on risk factors of HCV (blood transfusion, previous operations and drug intake), complications of cirrhosis, evidence of stigmata of chronic liver disease as well as abdominal examination. Laboratory investigations were done including CBC, kidney functions tests (blood urea and creatinine), liver function test (ALT, AST, GGT, alkaline phosphatase, total and direct bilirubin), viral hepatitis markers (HCV Ab, HBVs Ag), and serum Alpha-fetoprotein (AFP) level. Radiological investigations in the form of abdominal ultrasonography (Using (Chison 6001) and Triphasic CT of abdomen for all patients for examination of liver echotexture & size, common bile duct diameter, gall bladder stones, portal vein thrombosis, size of spleen, presence or absence of ascites and presence of any masses. Measurement of liver stiffness were done for all patients using Vibration controlled transient elastography (VCTE, FibroScan, Echosens Paris), Shear wave elastography (SWE) using M probe in compliance with the technical recommendations.

Statistical analysis:

     Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 24.  Quantitative data were expressed as mean± standard deviation (SD) and median Qualitative data were expressed as frequency and percentage. Kruska-wallis test was used to compare groups followed by post-hoc test. Because samples are not usually distributed. P value < 0.05 was considered significant.

RESULTS

     Demographic data between studied groups showed that there was no statistically significant difference (p-value > 0.05) as regard sex but there was a statistically significant difference (p-value < 0.001) as regards age (Table 1).

Table (1):  Comparisons between studied groups as regard demographic data

     Liver function tests between studied groups, showed statistically significant differences (Table 2).

Table (2):  Comparisons between studied groups as regard liver function tests

AST: aspartate transaminase, ALT: Alanine transaminase.

INR: international normalized ratio, AFP: Alpha fetoprotein.

     Complete blood count tests between studied groups, showed statistically significant differences as regards WBCs, Hb and PLTs (Table 3).

Table (3):  Comparisons between studied groups as regard CBC

     FibroScan and SWE tests between studied groups showed statistically significant difference (Table 4).

Table (4):  Comparisons between studied groups as regard FibroScan and SWE

     According to description of Triphasic CT results in group C, as regard to number of lesions, there was 1 lesion in 7 patients (35%), 2 lesions in 3 patients (15%), and 3 lesions in 10 patients (50%). As regard size of lesions, the mean size was 5.27 ± 2.9 with minimum size of 2.5 and maximum size of 14.8 (Table 5).

Table (5):  Description of Triphasic CT results in group C

     FibroScan can be used to discriminate between group B & group C at a cutoff level of > 22.6, with 80% sensitivity, 80% specificity, 80% PPV and 80% NPV (AUC = 0.88 & p-value < 0.001). SWE can be used to discriminate between group B & group C at a cutoff level of > 21.05, with 75% sensitivity, 60% specificity, 65.2% PPV and 70.6% NPV (AUC = 0.68 & p-value = 0.054) (Table 6 and Figure 1).

Table (6):  Diagnostic performance of FibroScan & SWE in discrimination of group B and Group C

PPV: positive predictive value; AUC: Area under curve NPV: negative predictive value.

Figure(1):  ROC curve

     FibroScan was used to discriminate between group A and group B at a cutoff level of > 11.1, with 100% sensitivity, 100% specificity, 100% PPV and 100% NPV (AUC =1.0 and p-value < 0.001). SWE can be used to discriminate between group A and group B at a cutoff level of > 9.6, with 100% sensitivity, 100% specificity, 100% PPV and 100% NPV (AUC = 1.0 & p-value = 0.001) (Table 7 and Figure 2).

Table (7):  Diagnostic performance of FibroScan & SWE in discrimination of group A and Group B

PPV: positive predictive value; AUC: Area under curve; NPV: negative predictive value.

Figure (2): ROC curve

     As regard to correlation study between (FibroScan and SWE) and (number of lesions and size) in group C, there were no statistical significant (p-value = 0.897) negative correlations (r = - 0.03) between FibroScan and number of lesions in studied patients. Also, there was no statistical significant (p-value = 0.304) positive correlation (r = 0.24) between FibroScan and size of lesions in studied patients. Also, there was no statistical significant (p-value = 0.713) positive correlation (r = 0.08) between SWE and size of lesions in studied patients. No statistical significant (p-value = 0.967) negative correlation (r = - 0.01) between SWE and size of lesions in studied patients (Table 8).

Table (8):  Correlation study between (FibroScan & SWE) and (number of lesions & size) in group C

(r): Pearson correlation coefficient; was considered non-significant.

Table (9): Post-Hoc test for multiple comparisons between studied groups

DISCUSSION

     In the current study we found that, there was no statistically significant difference between studied groups as regard sex, while there was a highly statistically significant difference between studied groups as regard age as the higher age observed in the group C followed by group B and the lower age observed in group A. These results attributed to the higher age individuals more susceptible HCV infection than the young age. Similarly, in Bandiera et al. (2016), reported that, development of HCC depends on various risk factors, including etiology, race, ethnicity, region, age, presence of diabetes mellitus (DM), and high levels of α-fetoprotein (AFP). However, the presence of advanced liver fibrosis is the most important and common risk factor in chronic liver disease patients. Also, Kanwal et al. (2018) reported that diabetes, and senior ages are independent risk factors for developing HCC. These results agreed with the multivariate analysis study of indicated that, in addition to age, and albumin level, liver stiffness was an independent risk factor associated with HCC incidence (Masuzaki et al., 2019).

     Our results of serum albumin level cleared that the higher albumin level observed in group (A) followed by group (B) and the lowest level observed in group (C). These results indicated that, the lower albumin level can give indications to higher susceptibility to HCC. These results agreed with those of Yang et al., (2020) from their novel, study where they found that low albumin significantly predicted the development of HCC.

     Liver enzymes levels gave indications about degree of hepatitis, our results of liver enzymes indicated that, the AST and ALT levels cleared that, the higher levels observed in group (B) followed by group (C) and the lowest level observed in group (A) and this agreed with Llovet et al., (2016) who reported that during the acute phase of acute hepatitis, the liver becomes as stiff as cirrhotic liver, although the stiffness returns to normal as hepatitis improves. Moreover, even among patients with the same fibrosis stage, those with high ALT and AST levels resulting from HCV-induced chronic hepatitis have a high degree of liver stiffness compared with patients with normal ALT and AST levels owing to antiviral treatment or the natural course. This suggests that liver stiffness is affected by the severity of inflammation as well as by liver fibrosis, leading to an overestimation of liver stiffness when inflammation is present. Therefore, when staging liver fibrosis based on liver stiffness in patients with high ALT and AST levels, it is important to keep in mind that the actual fibrosis stage might be lower.

     In a study by Masuzaki et al: (2019), investigating the relationship between cirrhosis and the incidence of HCC in  patients with hepatitis C, HCC developed in 10 % over the 3-year follow-up period When patients were classified based on liver stiffness at the initial FibroScan examination, patients with a high degree of liver stiffness subsequently had a high incidence of HCC, and this agreed with our results on the comparisons between studied groups as regard FibroScan and SWE, which cleared that, the Fibroscan and Shear Wave Elastography (SWE) showed a higher level in group (C), followed by group (B) and the lowest level was observed in group (A).

     Our results cleared that, the FibroScan can be used to discriminate between group A (HCV Without cirrhosis) & group B (HCV with cirrhosis) at a cutoff level of > 11.1, with 100% sensitivity, 100 % specificity, 100%. Also, FibroScan can be used to discriminate between group B (HCV with cirrhosis) & group C (HCV with cirrhosis and HCC) at a cutoff level of > 22.6, with 80% sensitivity, 80% specificity, 80%. According to this result FibroScan can predict HCC in HCV patients at cutoff level > 22.6 with 80% sensitivity, 80% specificity. And our results agreed with a meta-analysis of studies assessing the stage of liver fibrosis using FibroScan, Friedrich-Rust et al. found that the cut-off level for a diagnosis of F2 or higher was 7.65 kPa and for a diagnosis of F4, the cut-off level was 13.01 kPa, this demonstrating that fibrosis staging by FibroScan has high accuracy (Friedrich-Rust et al., 2018).

     This result attributed to the fibroscan machine calculates the degree of liver stiffness (in kPa) by sending acoustic push pulses from the body surface to the liver and following the waves by ultrasound to measure the shear wave speed. The propagation velocity of shear waves correlates with tissue stiffness, with waves traveling faster in harder tissues. FibroScan has several advantages: (1) it is a non-invasive and painless technique, (2) it provides immediate results (within 30 s of measurement), (3) the results are highly reproducible, (4) the measurement area is as wide as 1/500th of the total liver mass (the size of a biopsy specimen is 1/50,000th of the total liver mass), and (5) it can be safely repeated for follow up. On the down side, measurement reproducibility and even the measurement itself can be adversely affected by ascites (push pulses do not travel through fluids) and by thick layers of subcutaneous fat, narrow intercostal spaces, and severe liver atrophy (Lupsor-Platon et al., 2020).

     Shear wave elastography (SWE) can be used to discriminate between group A (HCV Without cirrhosis) & group B (HCV with cirrhosis) at a cutoff level of > 9.6, with 100% sensitivity, 100 % specificity 100%. Also Shear wave elastography (SWE) can be used to discriminate between group B (HCV with cirrhosis) & group C (HCV with cirrhosis and HCC) at a cutoff level of > 21.05, with 75% sensitivity, 60% specificity 65.2%. According to this result Shear wave elastography (SWE) can predict HCC in HCV patients at cutoff level > 21.05 with 75% sensitivity, 60% specificity. Also, there is no statistically significant correlation between size and number of lesions in patients with HCC in both FibroScan and Shear wave elastography (SWE). Cumulative incidence of HCC development stratified based on liver stiffness measurement (LSM, n = 866) in patients with hepatitis C (Masuzaki et al., 2019).

     Because liver stiffness is correlated with the stage of liver fibrosis, it is reasonable to assume that liver with a high degree of stiffness indicates advanced liver fibrosis. This strong correlation between liver stiffness and HCC risk also applies to cirrhotic patients, who have a high degree of liver stiffness, suggesting that liver stiffness is a useful clinical indicator to classify patients at high risk of HCC. Our results agreed with those of Schiavon et al, (2014), where they reported that, the gold standard for assessing liver fibrosis and cirrhosis is liver biopsy, but it is an invasive procedure with rare but potential complications. Instead of liver biopsy, a variety of noninvasive markers have been proposed for assessment of liver fibrosis as risk factor for HCC, i.e., aspartate aminotransferase (AST) to platelet ratio index (APRI), FIB-4, Forns index, Fibro index, FibroTest, Enhanced liver fibrosis, Fibrometer, FIBROSpect II, Hepascore, transient elastography (FibroScan), Shear wave elastography (SWE) and acoustic radiation force impulse imaging (ARF).

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