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ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 786-791

Prediction of hepatocellular carcinoma using fibro markers in Egyptian patients with chronic liver disease


1 Internal Medicine Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Internal Medicine Department, Shebin El Kom Teaching Hospital, Menoufia, Egypt

Date of Submission26-Mar-2020
Date of Decision10-Mar-2020
Date of Acceptance19-Mar-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
Abd E. M. A. Sallam
Tanta, Gharbia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_71_20

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  Abstract 


Objective
The aim was to evaluate inflammatory and fibrosis markers as predictors for hepatocellular carcinoma (HCC) development among patients with chronic liver disease (CLD).
Background
Progression of liver fibrosis in chronic hepatitis C is closely associated with the high risk of HCC development.
Patients and methods
This study was conducted on 100 patients suffering from liver cirrhosis as group A and 100 patients suffering from liver cirrhosis with HCC as group B from January 2018 to April 2019. Diagnosis of CLD was based on clinical, laboratory, and imaging evidence of CLD with and without hepatic decompensation or portal hypertension.
Results
Child–Pugh C patients was significantly more prevalent in HCC (37 vs 10% in liver cirrhosis cases). Serum hemoglobin, albumin, and leukocytic count were significantly lower in HCC cases. Also, α-fetoprotein, bilirubin international normalized ratio, and blood urea were highly significantly higher in the HCC group than the non-HCC group. King's score, fibro-quotient (Fibro Q), and FIB-4 scores were significantly higher in HCC than in cirrhotic cases, while blood red cells and Fibro-α scores were highly significantly higher in group B than in group A.
Conclusion
Our findings have shown the possibility to predict HCC development in Egyptian patients suffering from chronic hepatitis C by using noninvasive scores, (Fibro markers) as they performed well, cheap, and easy to perform.

Keywords: chronic liver disease, hepatocellular carcinoma, noninvasive fibrosis scores, prediction


How to cite this article:
Elatty EA, Sallam AE, Ezz EAA. Prediction of hepatocellular carcinoma using fibro markers in Egyptian patients with chronic liver disease. Menoufia Med J 2021;34:786-91

How to cite this URL:
Elatty EA, Sallam AE, Ezz EAA. Prediction of hepatocellular carcinoma using fibro markers in Egyptian patients with chronic liver disease. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:786-91. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/786/328347




  Introduction Top


Cirrhosis results from different mechanisms of liver injury that lead to necroinflammation and fibrogenesis; histologically it is characterized by diffuse nodular regeneration surrounded by dense fibrotic septa with subsequent parenchymal extinction and collapse of liver structures, together causing pronounced distortion of the hepatic vascular architecture. This distortion results in increased resistance to portal blood flow and hence in portal hypertension and in hepatic synthetic dysfunction [1]. Clinically, cirrhosis has been regarded as an end-stage disease that invariably leads to death, unless liver transplantation is done, and the only preventive strategies have been screening for esophageal varices and hepatocellular carcinoma (HCC). Lately, this perception has been challenged, because 1-year mortality in cirrhosis varies widely from 1 to 57% depending on the occurrence of clinical decompensating events. Histopathologists have proposed that the histological term cirrhosis should be substituted by advanced liver disease to underline the dynamic processes and variable prognosis of the disorder. Moreover, fibrosis, even in the cirrhotic range, regresses with specific therapy if available, such as antiviral treatment for chronic hepatitis B or C [2]. HCC is believed to be one of the most challenging tumors with rising incidence, prevalence, and mortality rates. It is globally the fifth most frequently diagnosed cancer worldwide, and is the second leading cause of cancer related death in the world [3]. It was reported that HCC is rapidly progressive and aggressive in biological behavior with an ultimately poor prognosis. Moreover, the majority of HCC patients had underlying chronic liver diseases (CLDs) mostly liver cirrhosis that can limit the possibilities of curative treatment [4].

Egypt is responsible for most of HCC cases in Africa. Meanwhile in the last decade, a considerable increase was observed among Egyptian patients with CLD-related HCC (from 4.0 to 7.2%). Hepatitis B and C are the main causes of liver disease [5].

Egypt is one of the countries with the highest hepacivirus C (HCV) prevalence worldwide. Progression of liver fibrosis in chronic hepatitis C is closely associated with the high risk of HCC development. Various noninvasive blood scores with high diagnostic accuracy for evaluating liver fibrosis had emerged. Because the fibrosis indices correlate with liver fibrosis, it was supposed that these indices might be closely related to HCC development [6]. Therefore, this study aimed to evaluate the inflammatory and fibrosis markers as predictors for HCC development among patients with CLD.


  Patients and methods Top


This study was conducted on 100 patients suffering from liver cirrhosis as group A and 100 patients suffering from liver cirrhosis with HCC as group B. All patients were attended to the Internal Medicine Department, Menoufia University Hospital during the period from January 2018 to April 2019. Diagnosis of CLD was based on clinical, laboratory, and imaging evidence of CLD with and without hepatic decompensation or portal hypertension, while the diagnosis of HCV was based on detection of HCV antibodies. This study was conducted on 200 patients, who were divided into two groups: Group A included 100 patients suffering from liver cirrhosis. Group B included 100 patients suffering from liver cirrhosis with HCC.

Ethical consideration

The study was approved by the Ethics Committee of Menoufia Faculty of Medicine. Informed consent was obtained from all individuals before the study started.

All participants were selected according to the inclusion and exclusion criteria. Inclusion criteria: Adult patients of both sexes who have liver cirrhosis, above 18 years old, and patients of liver cirrhosis with HCC. Exclusion criteria: Extrahepatic intra-abdominal malignancy, HCC with distant metastasis, pregnant women, previous intervention of HCC, alcoholic liver disease, and age less than 18 years.

All patients included in the study were subjected to the following: history taking of socioeconomic level, smoking, diabetes mellitus, blood transfusion, previous surgical operation, all patient features and characteristics including age, sex, presence of cirrhosis, and its degree of decompensation using the Child–Pugh score, HCC presentation, and diagnosis was recorded.

Laboratory examination

All patients and control were subjected to investigation as follows: complete blood picture using Sysmex KX-21 automatized hematology analyzer (Sysmex Corporation, 1-5-1 Wakinohama-Kaigandori, Chuo-ku, Kobe, Japan). Kidney functions: blood urea and serum creatinine using the open system autoanalyzer synchron CX5 (Beckman, California, USA). Liver function test including alanine aminotransferase (ALT), aspartate transaminase (AST), international normalized ratio (INR), prothrombin time (PT), alkaline phosphatase, α-fetoprotein (AFP), HCV antibodies, HBV surface antigen, serum albumin, and total bilirubin measured using the bi chromatic (405–510 nm) rate technique. Child score: the Pugh–Child score was determined by scoring five clinical measures of liver disease. Score of A, B, or C were given to each measure, with three being the most severe. King's score was calculated as age × aspartate aminotransferase×international normalized ratio/platelets count (109/l) [7]. Fibro-quotient (Fibro Q) was calculated as 10 × age (years)×AST × PT-INR)/(PLT × ALT)] [8].

APRI score (ALT to platelet ratio): was obtained during the 15 days prior to the liver biopsy and calculated according to the formula proposed by Wai et al. [9], namely, [(AST of the sample/reference AST)×100]/platelets3. The APRI score of patients was categorized as follows: low (1.0), intermediate (1–2), and high cutoffs (>2); similarly, the FIB-4 index of patients were grouped as low (<1.45), intermediate (1.45–3.25), and high cutoffs (>3.25). AST/ALT ratio (AAR) was calculated as AST (IU/l)/ALT (IU/l) [10]. LOC loss of consciousness. index was calculated as log odds (predicting cirrhosis) 5.560.0089 × platelet (103/mm3) 1.26 × AST/ALT ratio 5.27 − INR [11]. e Goteborg University Cirrhosis Index (GUCI) was calculated as normalized AST × prothrombin − INR × 100/platelet count (10(9)/l) [11].

AFP was taken with the AXSYM AFP immunoassay test (Abbott, Chicago, Illinois, USA), which establishes a 20 ng/ml value as the most adequate cutoff point for the identification of patients with HCC. GGT measurements were taken with the test specified by Aeroset, Architect from Abbott Laboratories. Its upper limit of normality is 64 UI/l. Fibro-α=1.3+AFP (U/l)×0.009584 + AAR × 0.243 −platelet count × 0.001624 [12]. Blood red cell (BRC) score was calculated as 1.02+0.4 × AFP (U/l)+0.19 × age (years) − 0.02 × platelet count (109/l) [13]. The FIB-4 score was calculated as: Age (years)×AST (IU/l)/platelet

count (×109/l)×√ALT (IU/l).

Imaging investigations

Abdominal ultrasonography was performed using Toshiba Ultrasound the Aplio 500 Platinum Machines (Toshiba Medical Systems Co. Ltd, Otawara, Japan) to determine the liver and splenic size, ascites, portal vein thrombosis, HCC (size, site, single, or multiple). Triphasic abdominal CT for HCC patients to detect: site, size, single, or multiple. Model for end-stage liver disease: was calculated with a mathematical formula using total bilirubin, INR and creatinine. The four model for end-stage liver disease levels are greater than or equal to 25 (gravely ill): lab reports every 7 days, 24–19: lab reports every 30 days, 18–11: lab reports every 90 days, and 10 or fewer (less ill): lab reports every year. Statistical analysis: Results were tabulated and statistically analyzed by using a personal computer using Microsoft Excel 2016 and SPSS v. 21 (SPSS Inc., Chicago, Illinois, USA). Statistical analysis was done using descriptive, for example, percentage, mean, and SD. Analytical that includes χ2 and Student's t-test. A value of P less than 0.05 was considered statistically significant.


  Results Top


In this study, there was no statistically significant differences between the two studied groups regarding age (P = 0.204) and history of GIT bleeding (P = 0.311). Regarding sex, group A included 78 (78%) male patients and 22 (22%) female patients and group B included 90 (90%) male patients and 10 female patients. So, there was significant difference between both groups regarding sex (P = 0.021). Regarding history of hepatic encephalopathy in group A, it was absent in 86 (86%) patients and present in 14 (14%) patients, while in group B, it was absent in 72 (72%) patients and present in 28 (28%) patients. So, history of encephalopathy was significantly higher in group B than group A (P = 0.015). Regarding history of ascites in group A, it was absent in 92 (92%) patients and present in eight (8%) patients, while in group B, it was absent in 65 (65%) patients and present in 44 (44%) patients. So, a history of ascites was highly significantly higher in group B than in group A, (P < 0.001) [Table 1].
Table 1: Comparison between the studied groups regarding demographic and clinical data

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In this study, there was no statistically significant differences between the two studied groups regarding platelet (P = 0.82), AST (P = 0.167), ALT (P = 0.443), and creatinine (P = 0.69), while hemoglobin, WBCs, and albumin were significantly increased among group A than in group B. However, bilirubin level, INR, AFP (ng/ml), and urea level (mg/dl) were significantly increased among group B than in group A [Table 2].
Table 2: Comparison between the studied groups regarding complete blood count, liver function test, and renal function test

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In this study, there was no statistically significant differences between the two studied groups regarding liver size (P = 0.248) and spleen size (P = 0.161). Regarding the degree of ascites in group A, 92 (92%) patients had no ascites, two (2%) patients had mild ascites, two (2%) patients had moderate ascites, and four (4%) patients had severe ascites and in group B, 56 (56%) patients had no ascites, 18 (18%) patients had mild ascites, 16 (16%) patients had moderate ascites, and 10 (10%) had severe ascites. So, there was high significant difference between both groups regarding the degree of ascites (P < 0.001). Concerning Child classification, in group A, 58 (58%) patients were classified as Child A, 32 (32%) patients were classified as child B, and 10 (10%) patients were classified as Child C while in group B, 0 (0%) patients were classified as Child A, 63 (63%) patients were classified as Child B, and 37 (37%) patients were classified as Child C. So, there was high significant difference between both groups [Table 3].
Table 3: Comparison between the studied groups regarding ultrasound findings and Child classification of cirrhotic

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In this study, there was no statistically significant differences between the two studied groups regarding Gucci score (P = 0.58), LOC loss of consciousness. index score (P = 0.062), AAR score (P = 0.771), and APRI score (P = 0.179), while King's score, Fibro Q score, FIB-4 score, BRC score, and Fibro-α score were significantly increased among group B than group A [Table 4].
Table 4: Comparison between studied groups regarding noninvasive fibro markers

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In this study, there was no significant correlation between the studied Fibro markers with the number of focal lesions (P > 0.05), while there was significant negative correlation between FIB-4, LOC loss of consciousness. index, and AAR with the size of focal lesions (P < 0.05) [Table 5].
Table 5: Correlation between fibro markers and number and size of focal lesions in group 2

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  Discussion Top


Noninvasive methods substituting liver biopsy for the diagnosis of liver fibrosis have been developed. It has been illustrated that noninvasive liver fibrosis markers are related to prognosis and survival of patients with HCV-related CLD [14]. Based on the fact that fibrosis indices correlate with liver fibrosis progression, we supposed that these indices could be closely related to HCC development [15]. So, the significance of fibrosis scores in the prediction of HCC development was investigated in this study.

In this study, all (n = 100) HCC patients developed HCC on top of liver cirrhosis in which HCV was the main underlying cause. Liver cirrhosis has been previously reported in many studies as the most predominant risk factor for the development and progression of HCC [16]. As for hepatitis seroprevalence among HCC cases, a recent worldwide systematic review documented Egypt as one of the countries showing a predominance of HCV among HCC cases [17]. This agreed with the fact that the highest prevalence of HCV in the world is reported in Egypt [18].

High serum AFP levels had been found to correspond to a higher expression of hepatic progenitor cells, which are responsible for liver regeneration and are related to the severity of fibrosis and HCC development [19]. Moreover, another study by Rodrıguez-Dıaz et al. [20] have demonstrated that the presence of elevated levels of AFP in patients with CLD is a risk factor for the development of HCC, thus suggesting that increased AFP production in patients with CLD might reflect abnormal or altered liver cell regeneration [20]. In accordance to this, the present study showed AFP was highly significantly higher in the HCC group. In a trial to find a sensitive and specific test for prediction of this deadly aggressive tumor, we explored hepatic fibrosis indices for early detection of HCC. King's Score is a simple and accurate index for predicting cirrhosis in chronic hepatitis C. King's score was significantly related to HCC.

In this study, Fibro Q was significantly higher in HCC than in cirrhotic cases. In a previous study, Fibro Q could identify correctly the presence of significant fibrosis [8] The AST/ALT ratio has been validated for assessing hepatic fibrosis in CLDs including chronic HCV infection. Similarly, a recent study conducted by Williams and Hoofnagle [10] stated that there was a statistically significant correlation between AST/ALT ratio and presence of cirrhosis and a ratio of more than 1.0 in nonalcoholic liver disease should suggest the presence of cirrhosis. Also, Afdhal et al. [21] reported a high diagnostic accuracy of AAR greater than 1.16 with 81.3% sensitivity and 55.3% specificity for the prediction of cirrhosis concerning the risk of HCC.

In this study, there was no significant difference between two groups regarding AAR. Similarly, a recent study by Amorim et al. [22] showed that AST/ALT ratio had a low diagnostic accuracy in detecting significant fibrosis [area under the receiver operating characteristic curve (AUROC) of 0.66] as compared with APRI (AUROC: 0.79) and FIB-4 (AUROC: 0.81). Also, Kim et al. [23] recorded AUROC for AAR of 0.64. In our study, there was no significant difference between two groups regarding APRI score. In contrast to our results, Canbakan et al. [24] found that APRI proved to be a valuable marker in chronic HCV infection and superior to Fibro test. In this study, when Fibro-a and BRC scores were applied on liver cirrhosis and HCC, they were highly significant higher in HCC compared with cirrhotic cases. Regarding FIB-4 score, the mean of FIB-4 score was 3.66 ± 3.10 in group A and 5.22 ± 4.60 in group B. So, the mean of FIB-4 was significantly higher in group B than in group A.


  Conclusion Top


Our findings showed the possibility to predict HCC development in Egyptian patients suffering from chronic hepatitis C by using the noninvasive scores (Fibro markers) as they performed well, cheap, and easy to perform.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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