|Year : 2018 | Volume
| Issue : 1 | Page : 348-353
The role of ultrasound elastography as a tool for prediction of hepatocellular carcinoma in Egyptian patients with cirrhosis
Mohamed A Nouh1, Mohsen M El-Khayat1, Doaa M. G. Khallaf2
1 Department of Tropical, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Tropical, Sheben El-Kom Fever Hospital, Menoufia, Egypt
|Date of Submission||02-Feb-2017|
|Date of Acceptance||18-Apr-2017|
|Date of Web Publication||14-Jun-2018|
Doaa M. G. Khallaf
Department of Tropical, Sheben El-Kom Fever Hospital, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of the work was to study the role of ultrasound elastography as a tool for prediction of hepatocellular carcinoma (HCC) in patients with cirrhosis.
Fibroscan is a novel, noninvasive, ultrasound technique–based technology that allows measuring liver stiffness. It is a noninvasive method for prediction of HCC.
Patients and methods
A total of 60 patients with cirrhosis were included in a case–control study from January 2014 to January 2015. Patients with obesity and ascites were excluded from the study. Patients underwent clinical examination, laboratory investigations, abdominal ultrasonography, triphasic computed tomography, liver biopsy, and fibroscan. They were divided into group I (patients with cirrhosis with no HCC) and group II (patients with cirrhosis with HCC).
Stiffness range was 2.90–39.80 kPa among patients without HCC with a mean of 8.95 ± 7.27 kPa, whereas among patients with HCC, it was 8.40–75.00 kPa, with a mean of 31.10 ± 16.05 kPa. Fibroscan showed a high sensitivity (100%) and specificity (80%) for detecting HCC at the cut-off level of more than 12 kPa with a positive predictive value of 100 and a negative predictive value of 79%, and the area under the curve was 100%.
Transient elastography can predict HCC in patients with cirrhosis.
Keywords: fibroscan, hepatitis C virus, hepatocellular carcinoma, liver cirrhosis, liver stiffness, noninvasive
|How to cite this article:|
Nouh MA, El-Khayat MM, Khallaf DM. The role of ultrasound elastography as a tool for prediction of hepatocellular carcinoma in Egyptian patients with cirrhosis. Menoufia Med J 2018;31:348-53
|How to cite this URL:|
Nouh MA, El-Khayat MM, Khallaf DM. The role of ultrasound elastography as a tool for prediction of hepatocellular carcinoma in Egyptian patients with cirrhosis. Menoufia Med J [serial online] 2018 [cited 2019 Jun 20];31:348-53. Available from: http://www.mmj.eg.net/text.asp?2018/31/1/348/234261
| Introduction|| |
The increased use of radiologic imaging, particularly ultrasound (US) examination, has led to much more frequent identification of nodules in the liver. Hepatocellular carcinoma (HCC) is increasingly associated with estimates of hepatitis B virus (HBV) and hepatitis C virus (HCV) prevalence worldwide . HCC represents the main complication of cirrhosis and shows a growing incidence in Egypt, which may be because of a shift in the relative importance of hepatitis B virus and HCV as primary risk factors and improvements in screening programs and diagnostic tools .
Over the past 5–8 years, evidence has been accumulating in different countries that the incidence of HCC is rising. Traditionally, the care of patients with HCC has been undertaken by hepatobiliary surgeons, interventional radiologists, and oncologists .
The tests used to diagnose HCC include radiology, biopsy, and α-fetoprotein (AFP) serology. The test to be used depends on the context. Some form of imaging such as computed tomography (CT) scan or MRI is always required to determine the extent of disease. In the setting of a patient with known hepatitis B or cirrhosis of other etiology, a mass found incidentally or on screening US has a high likelihood of being HCC. The sequence of tests used to diagnose HCC depends on the size of the lesion .
Tissue stiffness is related to tissue composition. Physicians have used palpation as a part of the physical examination to detect pathology. The ubiquitous presence of stiffer tissue associated with pathology often represents an early warning sign for the disease, as in the cases of breast or prostate cancer. This implies that methods for estimating stiffness of tissues would add as a weapon in the medical arsenal. It is therefore of interest to measure the stiffness in an objective and noninvasive way, and techniques to estimate the mechanical response of deep tissues to external excitations have been proposed .
Transient elastography (TE) (fibroscan) is a novel rapid, noninvasive, and reproducible method for measuring liver stiffness (LS) .
The principle is one in which a painless, mechanical impulse is delivered to the skin above the liver, using a low-frequency elastic wave. This produces a wave of mechanical deformation that propagates toward the liver. By monitoring the wave's progression in real time, an echographic transducer determines the propagation speed. Waves propagate more quickly in stiff tissue .
The aim of the work was to study the role of US elastography as a tool for prediction of HCC in patients with cirrhosis.
| Patients and Methods|| |
The study was conducted on 60 patients of both sexes with cirrhosis detected by serological, virological, and histological evidence, and imaging studies (as US or triphasic CT) of liver disease. Patients were referred to Shebin El-Kom Fever Hospital in Menoufia Governorate from January 2014 to January 2015, of which 30 had cirrhosis with no HCC (group I) and 30 had cirrhosis with HCC (group II).
An informed consent was obtained before persons were included in the study. Approval from the local research ethical committee was obtained.
Patients with obesity and ascites were excluded from the study.
All patients were subjected to full and detailed history taking, complete clinical examinations, laboratory investigations as complete blood count, liver function tests [alanine transaminase (ALT), aspartate transaminase, alkaline phosphatase, γ-glutamyltransferase, AFP, serum albumin, and serum bilirubin], serum creatinine level, random blood glucose level, abdominal ultrasonography, triphasic CT, and US-guided liver biopsy. Liver stiffness measurement (LSM) using fibroscan 402 (Echosens, Paris, France) was done, and results are expressed in kilopascal and correspond according to the manufacturer's recommendations to the median of 10 validated measurements. The validity results also depend on two important parameters: (a) the interquartile range, which reflects the variability of the validated measures and should not exceed 30% of the median value; and (b) the success rate (the ratio of the number of successful measurements to the total number of acquisitions) should be at least 60%.
All data were collected, tabulated, and statistically analyzed using SPSS 19.0 for windows (SPSS Inc., Chicago, Illinois, USA) and MedCalc 13 for windows (MedCalc Software BVBA, Ostend, Belgium).
| Results|| |
The present study was conducted on 60 patients: 30 of them with cirrhosis with no HCC (group I) and 30 patients with cirrhosis and HCC (group II).
Regarding demographic data, 42 (70%) patients were males and 18 (30%) patients were females. Mean and SD of age in group I was 48.82 ± 15.26 years and in group II was 50.32 ± 12.19 years. There was no statistically significant difference between both groups regarding age and sex (P = 0.059 and 0.057, respectively) [Table 1].
There was a statistically significant difference regarding ALT and AFP between group I and group II, whereas there was no statistically significant difference regarding other laboratory parameters. Mean ± SD of ALT was 47.20 ± 9.28 in group I versus 75.47 ± 18.78 in group II, with P value of 0.0009. Mean ± SD of AFP was 36.5 ± 0.714 in group I versus 41.67 ± 17.28 in group II, with P value of 0.0008. In this study, there was statistically nonsignificant difference regarding urea and creatinine levels between both groups (P = 0.059 and 0.057, respectively). Mean ± SD of creatinine level was 0.924 ± 0.157 in group I and 0.973 ± 0.269 in group II. Mean ± SD of urea in group I was 42.40 ± 12.65, whereas in group II was 42.87 ± 12.42. Moreover, there was a statistically significant difference between both groups regarding fibroscan (P = 0.001). Mean ± SD of group I was 10.05 ± 2.99, whereas in group II was 30.42 ± 17.29 [Table 2].
In this study, there was a statistically significant difference between both groups regarding Child score (P = 0.0003). In group I, 22 patients had Child A score (73.3%) and eight (26.7%) patients had Child B score, and in group II, 16 (53.3%) patients had Child B score, and 14 (46.7%) patients had Child C score [Table 3].
In this study, there was a statistically significant difference between both groups regarding fibroscan results (P = 0.001). On comparison between both groups, there was a highly significant difference between both groups regarding LS (P = 0.001). In the non-HCC group, 12 (40%) patients were F2, 18 (60%) patients were F3, and no patient was F4, whereas in the HCC group, no patients (0%) were F2 and F3, and 30 (100%) were F4 [Table 4].
Multivariate analysis for the predictors for HCC was done by using binary logistic regression, and it was found that Child score C, serum glutamic-pyruvic transaminase (SGPT), AFP, HCV were predictors for HCC. The highest odd's ratio belongs to Child score C (10.18) (P = 0.045), followed by Child score B (3.940) (P = 0.157), SGPT (0.999) (P = 0.984), AFP (0.943) (P = 0.069), and HCV (0.616) (P = 0.801) [Table 5].
|Table 5: Binary logistic regression for significant risk factors or predictors of hepatocellular carcinoma|
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Area under the curve (AUC) values obtained from receiver operator characterizing analysis for fibroscan was 100%, sensitivity was 100%, specificity was 80%, negative predictive value was 79, positive predictive value was 100, and accuracy was 87%. [Table 6] and [Figure 1].
| Discussion|| |
HCC is the sixth most common malignancy worldwide, and it is also a common cause of death in patients with chronic liver disease .
The tests used to diagnose HCC include radiology, biopsy, and AFP serology. The test to be used depends on the context. Some form of imaging such as CT scan or MRI is always required to determine the extent of disease. In the setting of a patient with known hepatitis B or cirrhosis of other etiology, a mass found incidentally or on screening US has a high likelihood of being HCC. The sequence of tests used to diagnose HCC depends on the size of the lesion .
Diagnosis of the stage of liver fibrosis is essential for making a prognosis and deciding on antiviral therapy. Using liver biopsy for fibrosis staging is limited by its invasive nature, poor acceptance, availability, cost, intraobserver and interobserver variability, and sampling errors .
The clinical role of TE to measure LS has been widely investigated in the assessment of the degree of liver fibrosis or identification of the presence of portal hypertension . In addition, several longitudinal studies proposed that TE can accurately predict HCC development in patients with chronic hepatitis B and C , based on the significant correlation between the risk of HCC development and the degree of liver fibrosis .
This study is designed to evaluate the role of US elastography as a tool for prediction of HCC in patients with cirrhosis. The study was conducted on 60 patients of both sexes with cirrhosis detected by serological, virological, and histological evidence, and imaging studies (as US or triphasic CT) of liver disease.
Patients were referred to Shebin El-Kom Fever Hospital in Menoufia Governorate.
The studied patients were classified into the following:
- Group I: 30 patients with cirrhosis and no HCC
- Group II: 30 patients with cirrhosis with HCC.
This study showed that there was a nonstatistically significant difference between HCC and non-HCC regarding age and sex (P = 0.059 and 0.057). So the epidemiological features of our patients show no sex predominance in patients with HCC and those without HCC. This finding contradicts with the study done by Llovet  as well as by El Serag and Rudolph  who reported that the degree of liver fibrosis, age, and male sex to be the risk factors for HCC development.
In this study, there was a nonstatistically significant difference between HCC and non-HCC regarding SGOT and ALT (P = 0.0007 and 0.0008), and there was a statistically significant difference between HCC and non-HCC regarding SGPT and AFP (P = 0.0008 and 0.0009). Malik et al.  found similar results who reported that in patients with cirrhosis and have HCC, the levels of SGPT and AFP were higher and highly significant, which help to predict HCC in patients with cirrhosis. Moreover, there was a positive relationship between the stiffness over the HCC lesion and the level of AFP; the patients with very high AFP had generally higher stiffness values. Gara et al.  agreed with this work as they stated that levels of SGPT and AFP were higher and highly significant in these patients, which help predict HCC in patients with cirrhosis with the help with fibroscan.
Serum AFP was measured in all patients, and the sensitivity of AFP in detecting HCC at the level of 200 ng/dL was very low (22%); however, the specificity was very high (100%). The positive predictive value was 100% whereas the negative predictive value was 56.18%. These results were very similar to the results concluded by Ngugen and Thuluvath  in which the sensitivity was 32% and the specificity was 100%.
Regarding to Child's scoring, there was a statistically significant difference between HCC and non-HCC (P = 0.0003). Foucher et al.  found similar result as they stated patients with HCC had Child score C or B, which helped in the early diagnosis of these patients and early treatment to avoid complications.
In the present work, LSMs were taken in all 60 patients by TE using fibroscan. LS was expressed as a continuous variable, as TE is a very promising tool for the early detection of cirrhosis, which is an advantage over the liver biopsy especially in the transitional zones such as F0:F1, F1:F2, and F3:F4, because the noncirrhotic liver at F3 in particular still possesses a definitive risk of HCC development .
In this study, 30 patients were F2–F3 as assessed by METAVIR score and the mean of LSMs for this group was 12.5 kPa and, and 30 patient were F4 as assessed by METAVIR score and the mean of LSMs for this group was 20.5 kPa. Friedrich-Rust et al.  is in agreement this work as was statistically significant difference between HCC and non-HCC regarding fibroscan results (P = 0.002).
TE may be able to detect the risk of HCC development in patients with cirrhosis, as there is a significant correlation between LSM and the fibrosis stage in patients with CHC because stiffness of the tissues depends on the presence of fibrous tissue as well as the presence of the fibrous septa within the normal liver architecture. This correlation is not affected by the activity grade .
On comparison between both groups, there was a highly significant difference between both groups regarding LS (P < 0.001). In the non-HCC group, no patients were F1, 12 (40%) were F2, 18 (60%) were F3, and no patient was F4, whereas in the HCC group, no (0%) patients were F1, F2, and F3 and 30 (100%) patients were F4.
Moreover, TE may be able to differentiate risk of HCC among cirrhotic liver, as there is a significant correlation between LSM and fibrosis stage in patients with chronic HCV. This observation is consistent because stiffness of tissues largely depends on their molecular building blocks (collagen) and on the microscopic structural organization of these blocks (septa), and this correlation is not affected by the activity . Using receiver operator characterizing curve, LSM showed a high sensitivity (100%) and specificity (80%) for detecting HCC at the cut-off level of more than 12 kPa with a positive predictive value of 100% and a negative predictive value of 79%. The AUC was 100%. Again these results come very close to the results obtained by Masuzaki et al.  where the AUC was 0.805 and with high sensitivity and specificity.
In clinical practice, however, LSM will not be used as a diagnostic test of HCC, but rather as an indicator of the risk of HCC. In this aspect, stratum specific likelihood ratio is better than a fixed cut-off value. For continuous scores such as LS, stratum specific likelihood ratios retain as much information as possible by deriving multiple-level indices.
Alleman  evaluated the risk of HCC in patients with prominently elevated LSMs by fibroscan as they showed increasing LS is associated with HCC, but did not differentiate between values above 25 kPa. As HCC incidence is closely associated with the degree of fibrosis, for which LSM is a validated surrogate marker, it has been proposed that the rising risk of HCC observed among our patients reflects the severity of their liver disease. This is supported by evidence showing that LSM more than 21 kPa predicts clinically significant portal hypertension.
Future studies may attempt prospectively to evaluate populations with a single etiology of liver disease. However, the relatively low frequency of such LSM makes such studies costly and time consuming . Recommendations include patients at high risk of HCC to have biannual screening abdominal US scans, and patients with a detectable nodule less than 1 cm be rescanned every 3–4 months. As patients more than 30 kPa have significantly increased HCC risk, and they may also benefit from closer monitoring.
Moreover, significant predictors of HCC by binary logistic regression were child score C, SGPT, AFP, and HCV was the predictor for HCC. The highest odd's ratio belongs to Child score C (10.18) (P = 0.045) followed by Child score B (3.940) (P = 0.157), SGPT (0.999) (P = 0.984), AFP (0.943) (P = 0.069), and HCV (0.616) (P = 0.801). Gara et al.  agree with this result as they state Child score C and AFP predict HCC for an early diagnosis and early treatment.
In patients with HCC, ultrasonography was performed before fibroscan to evaluate LS in a part of the liver without HCC. Therefore, tumor stiffness did not influence the results of fibroscan . In this study, only a small number of patients had HCC. Thus, the role of fibroscan in assessing the risk of HCC needs further investigations.
Finally, it can be concluded that HCC prediction by using fibroscan may be a very useful noninvasive method, which could be added as a strategy in the diagnosis of focal hepatic lesion to offer as a new, safe, and fast modality for diagnosis. Moreover, improvements in the device, such as smaller and variable ROI of measurement and real-time B-mode display, may allow wider clinical application to involve small lesions located at any part of the liver.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bosch FX, Ribes J, Diaz M, Llovet JM, Bruix J, Tsuchiya M, et al.
Primary liver cancer: worldwide incidence and trends. Gastroentrology 2014; 127
Holah NS, El-Azab DS, Aiad HA, Sweed DM. Hepatocellular carcinoma in Egypt: epidemiological and histopathological properties. Menoufia Med J 2015; 28
Bruix J, Sherman M, Jemal A, Ward E, Ferlay J, Bray F, et al.
Management of hepatocellular carcinoma. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Hepatology 2005; 42
Masuzaki R, Tateishi R, Yoshida H, Sato T, Ohki T, Goto T, et al.
Assessing liver tumor stiffness by transient elastography. Hepatol Int 2007; 1
Foucher J, Chanteloup E, Vergniol J, Rullier A, Bertet J, Couzigou P, et al.
Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006; 55
Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al.
Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29
Forner A, Liovet JM, Bruix J. Hepatocellular carcinoma: hepatobiliary disease. Lancet 2012; 31
Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000; 32
Castera L, Vergniol J, Foucher J, Le Bail B, Adhoute X, Bertet J, et al.
Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128
Masuzaki R, Tateishi R, Yoshida H, Goto E, Sato T, Ohki T, et al.
Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. Hepatology 2009; 49
Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48
Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol 2003; 38 (Suppl 1):
El Serag HB, Rudolph KL. Influence of gender and age on complications in cirrhotic patients. J Hepatol 2007; 48
Malik R, Lai M, Sadiq A, Farnan R, Mehta S, Nassar I, et al.
Comparison of transient elastography, laboratory test results and clinical signs for the diagnosis of cirrhosis. J Gastroenterol Hepatol 2010; 25
Gara N, Zhao X, Kleiner DE, Liang TJ, Hoofnagle JH, Ghany MG. Transient elastography, CBC, and assessments of liver fibrosis in patients with cirrhosis. Clin Gastroenterol Hepatol 2013; 11
Ngugen GC, Thuluvath PJ. Peridactor of liver injury in cirrhotic patients. Hepatology 2002: 48
Sandrin L, Fourquet B, Hasquenoph JM, Hasquenoph JM, Yon S, Fournier C, et al.
Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29
Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, Herrmann E. Performance of transient elastography for the staging of liver fibrosis. Gastroenterology. 2008; 134
Foucher J, Vergniol J, Rullier A, Bertet J, Couzigou P, Amouretti M, et al.
Diagnosis, staging and treatment of hepatocellular carcinoma. Braz J Med Biol Res 2003; 37
Alleman AS. Gastroenterol. Hepatol 2016; 12
Berzigotti AL, Castera L. Update on ultrasound imaging of liver fibrosis. J Hepatol 2013; 58
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]