|Year : 2022 | Volume
| Issue : 4 | Page : 251-259
Serum growth differentiation factor 15 levels as a marker for liver cirrhosis and hepatocellular carcinoma on top of liver cirrhosis
Zainab M A Anis1, Amira Y Ahmed2, Hanan H Soliman3, Hala M Nagy2
1 Ministry of Health, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Tanta University, Tanta, Egypt
3 Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||19-Sep-2021|
|Date of Acceptance||22-Jan-2022|
|Date of Web Publication||22-May-2023|
Zainab M A Anis
Faculty of Medicine, Tanta University, Mahalla Hepatology Teaching Hospital, Tanta 31811
Source of Support: None, Conflict of Interest: None
Background Cirrhosis is the 14th leading cause of mortality globally. Additionally, it is subclassified by clinical stage. Hepatocellular carcinoma (HCC) was reported to account for ~4.7% of patients with chronic liver disease in Egypt. Early detection and treatment are highly beneficial. Growth differentiation factor 15 (GDF-15) proteins are implicated in the infection, fibrosis, and apoptotic processes of the liver. GDF-15 mRNA is mostly found in the heart, kidney, and lungs, as well as in the liver. The adult liver expresses the greatest amounts of GDF-15 following surgical and pharmacological therapies that produce acute liver damage. Aim This study’s objective was to assess serum GDF-15 levels in individuals with cirrhosis of the liver and HCC on top of cirrhosis of the liver. Patients and methods We have recruited 90 people in three groups: group 1 comprised 35 patients with HCC, group 2 comprised 35 individuals having cirrhosis of the liver, and group 3 comprised 20 nonhepatic individuals who acted as controls. Results In the HCC group, alpha-fetoprotein (AFP) was significantly higher than in the cirrhosis group, and the cirrhosis group has significantly higher AFP than in the control group. In comparison with the cirrhosis group, and in comparison with the control group, the HCC group had a significant increase in GDF-15 level. Conclusions GDF-15 levels were substantially greater in individuals with HCC compared with patients with cirrhosis and healthy controls. It is more sensitive, specific, and accurate than AFP. Thus, we may regard GDF-15 as a new marker for the diagnosis of HCC.
Keywords: growth differentiation factor 15, hepatocellular carcinoma, liver cirrhosis
|How to cite this article:|
Anis ZM, Ahmed AY, Soliman HH, Nagy HM. Serum growth differentiation factor 15 levels as a marker for liver cirrhosis and hepatocellular carcinoma on top of liver cirrhosis. Tanta Med J 2022;50:251-9
|How to cite this URL:|
Anis ZM, Ahmed AY, Soliman HH, Nagy HM. Serum growth differentiation factor 15 levels as a marker for liver cirrhosis and hepatocellular carcinoma on top of liver cirrhosis. Tanta Med J [serial online] 2022 [cited 2023 May 31];50:251-9. Available from: http://www.tdj.eg.net/text.asp?2022/50/4/251/377244
| Introduction|| |
Cirrhosis is the 14th leading cause of mortality globally. Additionally, it is subclassified by clinical stage and is not considered as a single disease entity . Hepatocellular carcinoma (HCC) is a public health issue globally. Every year statistics show that HCC is the fifth most commonly occurring solid tumor and is the third major cause of cancer related mortality .
HCC accounts for 75% of malignant hepatic tumors in Egypt. Liver cancer is the fifth most frequent form of cancer among both sexes; it is the sixth most common type of cancer in women with a percentage of 3.4 of all cancers, and it is the second most common form of cancer in men with a percentage of 11.5 of all cancers. In 2010, liver cancer was the third most common cancer in both sexes (8.1%), with 12.1% in men and 4% in women .
HCC is caused by a number of significant risk factors, such as hepatitis B or HCV infections, overconsumption of alcohol, or dietary aflatoxin exposure . HCC generally develops in individuals with cirrhosis as a result of persistent inflammation and severe fibrosis, regardless of the carcinogenic insult . NASH, a metabolic disease caused by insulin fibrosis and cirrhosis, is a new major risk factor for HCC .
The most often evaluated biomarker in HCC is alpha-fetoprotein (AFP). However, for two reasons, AFP works inadequately as a serological surveillance test. First, fluctuating levels of AFP may include HBV or HCV flares, deterioration of existing liver illness, and the development of HCC in individuals with cirrhosis . Second, only a small number of tumors (10–20%) manifest aberrant AFP serum levels at an early stage . Thus, there is controversy over the significance of AFP in the early detection and, more specifically, monitoring of HCCs. Numerous other biomarkers have been explored, including AFP-L3, des-gamma-carboxyprothrombin, GP73, and GPC3 ; however, their diagnostic values about early HCCs remain controversial [10,11].
Growth differentiation factor 15 (GDF-15), a cytokine, is a member of the transforming growth factor-b (TGF-b) superfamily, which plays a part in tissue injuries or diseases such as fibrosis, infections, or apoptosis. It was first discovered in macrophages after cytokine activation. GDF-15 is found mostly in the heart, lungs, and kidneys, and also in the liver. It is generated and released with short wavelength exposure, inflammation, oxidative stress, hypoxia, injury to tissues, and activation of oncogene .
| Patients and methods|| |
The current study examined 90 patients during a 6-month period from December 2018 to June 2019 at Tanta University’s Clinical Pathology Department. A total of 70 hospitalized patients with tropical and infectious illnesses were recruited, along with a control group of 20 persons. Written consent was taken from every participant. The information of the patient was coded for confidentiality. There was no conflict between the study performance and religion or law. Results were used for the scientific research purpose only. The study was approved by the Institutional Research Ethical Committee at Tanta University with the code 32134/02/18. The patients were divided into three groups.
- Group 1: 35 patients with HCC.
- Group 2: 35 patients with liver cirrhosis.
- Group 3: 20 nonhepatic patients who served as controls.
The following laboratory investigations were carried out for every patient:
- (1) Complete blood count.
- (2) Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, albumin, and prothrombin time).
- (3) Hepatitis markers (HCV Ab and HBsAg).
- (4) Noninvasive fibrosis score (APRI, PLR, and FIB4).
- (5) AFP.
- (6) Serum GDF-15 using the ELISA technique.
| Methods|| |
Sample collection: 9 ml of peripheral venous blood was taken under complete aseptic conditions.
Complete blood picture: it was done using ERMA Inc. (Tokyo, Japan) fully automatic blood cell counter, with examination of Giemsa-stained PB smears for differential leukocyte count.
Liver functions: it was done using Indiko Plus.
PT: it was done by an automated coagulation analyzer.
Hepatitis markers (HCVAb and HBsAg): they were assessed by ELISA.
The data were uploaded to a computer, and version 20.0 of the IBM SPSS software was used to analyze them (IBM Corporation, Armonk, New York, USA). Numbers and percentages were used to describe qualitative data. The Kolmogorov–Smirnov test was performed to determine the distribution’s normality. The range (minimum and maximum values), mean, SD, and median were used to characterize quantitative data. The significance of the acquired data was determined at the 5% level.
| Results|| |
Routine laboratory results of studied groups
Complete blood count results of studied groups
Hemoglobin (Hb): in the HCC group, Hb ranged from 8.10 to 12.0 g/dl, with a mean of 10.07 ± 1.15 g/dl; in the cirrhosis group, Hb ranged from 6.80 to 12.70 g/dl, with a mean of 9.97 ± 1.77 g/dl; and in the control group, Hb ranged from 11.30 to 17.0 g/dl, with a mean of 13.17 ± 1.39 g/dl. A significant decrease was found in the Hb level in the liver cirrhosis group and HCC group when compared with the control group, with P value less than 0.001 and P value less than 0.001, respectively, with no significant difference between HCC and cirrhosis groups, with P value of 0.959 ([Table 1]).
|Table 1: Comparison among the three studied groups according to complete blood count|
Click here to view
Platelets: in the HCC group, platelets ranged from 48.0–131.0 × 103/μl, with a mean of 82.34 ± 23.86 × 103/μl; in the cirrhosis group, platelets ranged from 35.0 to 165.0 × 103/μl, with a mean of 101.23 ± 38.02 × 103/μl; and in the control group, platelets ranged from 168.0 to 415.0 × 103/μl, with a mean of 304.20 ± 67.65 × 103/μl. Platelet levels decreased significantly in the HCC and liver cirrhosis groups as compared with the control group (P=0.001 and 0.001, respectively) but did not differ significantly between the HCC and cirrhosis groups (P=0.154) ([Table 1]).
White blood cell (WBCs): in the HCC group, WBCs ranged from 2.90 to 9.40 × 103/μl, with a mean of 5.23 ± 1.75 × 103/μl; in the cirrhosis group, WBCs ranged from 2.80 to 11.0 × 103/μl, with a mean of 7.0 ± 2.01 × 103/μl; and in the control group, WBCs ranged from 3.50 to 9.90 × 103/μl, with a mean of 5.56 ± 1.38 × 103/μl. In the HCC group, there was a considerable reduction in WBCs compared with liver cirrhosis (P=0.001), but compared with the control group, no change (P=0.790) was found ([Table 1]). The WBCs in the liver cirrhosis group were significantly increased in comparison with the control group, with P value of 0.013.
Liver function tests
AST level in the studied groups: In the HCC group, AST ranged from 12.0 to 125.0 U/l, with a mean of 52.0 ± 24.96 U/l; in the cirrhosis group, AST ranged from 23.0 to 99.0 U/l, with a mean of 63.46 ± 19.85 U/l; and in the control group, AST ranged from 12.0 to 32.0 U/l, with a mean of 18.0 to 5.40 U/l. Significant increases in AST were seen in the HCC and cirrhosis groups when compared with the control group (P=0.001 and 0.001, respectively), as well as a significant increase in AST in the HCC group when compared with the liver cirrhosis group (P=0.049) ([Table 2]).
|Table 2: Comparison among the three studied groups according to liver function tests|
Click here to view
ALT level in the studied groups: in the HCC group, ALT ranged from 11.0 to 112.0 U/l, with a mean of 50.03 ± 24.62 U/l; in the liver cirrhosis group, ALT ranged from 10.0 to 85.0 U/l, with a mean of 41.97 ± 20.79 U/l; and in the control group, ALT ranged from 10.0 to 30.0 U/l, with a mean of 15.45 ± 5.20 U/l. When compared with the control group, the HCC and liver cirrhosis groups had a substantial increase in ALT (P=0.001 and 0.001, respectively). The ALT levels of the HCC and liver cirrhosis groups were not significantly different, with a P value of 0.186 ([Table 2]).
Albumin level in the studied groups: in the HCC group, albumin ranged from 1.80 to 3.40 g/dl, with a mean of 2.84 ± 0.47 g/dl; in the liver cirrhosis group, albumin ranged from 1.60 to 3.60 g/dl, with a mean of 2.67 ± 0.47 g/dl; and in the control group, albumin ranged from 3.60 to 4.90 g/dl, with a mean of 4.21 ± 0.35 g/dl. In the HCC group and the liver cirrhosis group, a substantial reduction in albumin compared with the control group has been reported, with P value less than 0.001 and 0.001*, respectively, with no significant difference between HCC group and liver cirrhosis group, with P value of 0.227 ([Table 2]).
Total bilirubin level in the studied groups: total bilirubin in the HCC group ranged from 2.20 to 12.80 mg/dl, with a mean of 7.04 ± 3.32 mg/dl; in the cirrhosis group, it ranged from 1.70 to 8.90 mg/dl, with a mean of 4.39 ± 2.08 mg/dl; and in the control group, it ranged from 0.40 to 0.90 mg/dl, with a mean of 0.68 ± 0.17 mg/dl. Total bilirubin levels were significantly higher in the HCC and liver cirrhosis groups as compared with the control group (P=0.01 and 0.01, respectively). Between the HCC and liver cirrhosis groups, there was a statistically significant increase (P=0.08) ([Table 2]).
Direct bilirubin level in the studied groups: in the HCC group, direct bilirubin ranged from 1.10 to 6.80 mg/dl, with a mean of 3.82 ± 1.85 mg/dl; in the cirrhosis group, it ranged from 1.10 to 4.30 mg/dl, with a mean of 2.15 ± 1.03 mg/dl; and in the control group, it ranged from 0.10 to 0.30 mg/dl, with a mean of 0.18 ± 0.06 mg/dl. In comparison with the control group, the HCC group and the liver cirrhosis group had a substantial rise in the direct bilirubin level (P<0.001 and 0.001, respectively). The direct bilirubin level in the HCC group was much higher than that in the liver cirrhosis group, with P=0.002 ([Table 2]).
Serum AFP level in the studied groups: in the HCC group, AFP ranged from 442 to2301 ng/ml, with a mean of 1120.40 ± 540.01 ng/ml; in the liver cirrhosis group, AFP ranged from 200 to 500 ng/ml, with a mean of 277.71 ± 83.60 ng/ml; and in the control group, AFP ranged from 0.80 to 4.20 ng/ml, with a mean of 1.81 ± 0.94 ng/ml. In comparison with the liver cirrhosis group, there was a substantial increase in AFP levels in HCC, with a P value of 0.001, and in the HCC group in comparison with the control group, with a P value of 0.001. In contrast with the control group, the amount of AFP in liver of the cirrhosis group was also considerably increased, with P value of 0.001 ([Table 3]).
|Table 3: Comparison among the three studied groups according to alpha-fetoprotein|
Click here to view
Results of serum GDF-15 level in the studied groups: in the HCC group, serum GDF-15 level ranged from 2551 to 3521 ng/l, with a mean of 3047.43 ± 323.86 ng/l; in the cirrhosis group, serum GDF-15 level ranged from 1522.0 to 2722.0 ng/l, with a mean of 2053.40 ± 440.22 ng/l; and in the control group, serum GDF-15 level ranged from 291.0 to 512.0 ng/l, with a mean of 350.75 ± 69.65 ng/l. In comparison with the control group, serum GDF-15 levels were increased markedly in the HCC group and liver cirrhosis group (P=0.001 and 0.001, respectively). Furthermore, blood levels of GDF-15 in the HCC group were significantly higher than that in the liver cirrhosis group (P=0.001*) ([Table 4]).
|Table 4: Comparison among the three studied groups according to growth differentiation factor 15|
Click here to view
Correlation between growth differentiation factor 15 and different parameters in each group
In the HCC group, there was a positive significant correlation between serum GDF-15 and total bilirubin (r=0.689, P<0.001) and between serum GDF-15 and direct bilirubin (r=0.689, P<0.001). There was no significant correlation between serum GDF-15 and PT (r=0.242, P=0.161), between serum GDF-15 and AFP (r=0.100, P=0.566), between serum GDF-15 and albumin (r=−0.327, P=0.055), between serum GDF-15 and APRI (r=0.015, P=0.931), between serum GDF-15 and FIB4 (r=−0.010, P=0.952), between serum GDF-15 and PLR (r=0.275, P=0.110), between serum GDF-15 and AST (r=0.168, P=0.335), between serum GDF-15 and ALT (r=0.164, P=0.347), between serum GDF-15 and Hb (r=−0.178, P=0.307), between serum GDF-15 and platelet (r=0.110, P=0.529), and between serum GDF-15 and WBCs (r=−0.066, P=0.707) ([Table 5]).
|Table 5: Correlation between growth differentiation factor 15 and different parameters in each group|
Click here to view
In the liver cirrhosis group, there was a strong positive correlation between serum GDF-15 and total bilirubin (r=0.626, P<0.001) and between serum GDF-15 and direct bilirubin (r=0.631, P<0.001). There was no significant correlation between serum GDF-15 and PT (r=0.026, P=0.883), between serum GDF-15 and AFP (r=0.113, P=0.520), between serum GDF-15 and albumin (r=0.043, P=0.805), between serum GDF-15 and APRI (r=0.132, P=0.450), between serum GDF-15 and FIB4 (r=0.098, P=0.577), between serum GDF-15 and PLR (r=0.001, P=0.994), between serum GDF-15 and AST (r=0.185, P=0.288), between serum GDF-15 and ALT (r=0.222, P=0.199), between serum GDF-15 and Hb (r=−0.308, P=0.072), between serum GDF-15 and platelet (r=−0.037, P=0.833), and between serum GDF-15 and WBCs (r=0.005, P=0.978) ([Table 5]).
Receiver operating characteristic curve
[Figure 1] shows the receiver operating characteristic (ROC) curve between HCC and liver cirrhosis groups. Regarding GDF-15 level (ng/l), at a cutoff value more than 2698, it had sensitivity of 95.29%, specificity of 94.29%, positive predictive value of 95.3%, and negative predictive value of 94.3%, with area under the curve of 0.997.
|Figure 1: ROC curve for different parameters to predict HCC cases from liver cirrhosis cases. HCC, hepatocellular carcinoma; ROC, receiver operating characteristic.|
Click here to view
Regarding AFP level (ng/ml), at a cutoff value more than 400, it had sensitivity of 92.29%, specificity of 88.57%, positive predictive value of 89.2%, and negative predictive value of 93.9%, with area under the curve of 0.979.
| Discussion|| |
Hb levels decreased considerably in the HCC and cirrhosis groups compared with the control group but did not differ significantly between the HCC and cirrhosis groups in our research. In agreement with our results, Tacke et al. , showed that individuals with chronic liver illness had lower Hb levels than controls. Their patient population comprised those with chronic liver disease caused by HCV and HBV infections, as well as those with alcohol-induced hepatitis and autoimmune hepatitis. The only group of patients with significantly lower Hb levels was those with HCV-related child C cirrhosis. Bruno et al. , reported that patients experiencing LC, owing to alcohol consumption and HCV and HBV infections, had Hb values significantly lower than controls.
Platelets are highly specialized blood cells involved in a number of physiological and pathological processes, such as hemostasis, inflammation, tumor metastasis, wound healing, and host defense. Thrombocytopenia is characterized as a platelet count of less than 150 000 cells/l. In these patients, the presence of thrombocytopenia may be a limiting factor when considering antiviral therapy .
The HCC and liver cirrhosis groups had a significant decrease in platelet count as compared with the control group. Between the HCC and cirrhosis groups, there was no statistically significant difference. Thrombocytopenia is a frequent complication of cirrhosis, which has historically been attributed to splenic platelet pooling and destruction .
HCC and HCV groups showed thrombocytopenia. According to Franco et al. , thrombocytopenia is the most often seen hematological abnormalities in HCV-infected patients. According to Carr and Guerra , the thrombocytosis group had significantly larger tumors than the normal platelet group.
In our study, we observed a substantial decrease in WBCs in the HCC group compared with the liver cirrhosis group, but no significant difference in the control group.
A study performed by Lustberg , stated that the majority of patients with cancer develop neutropenia, and another study performed by Dieterich and Spivak  stated that there are various hematologic disorders associated with HCV infection and its management, including neutropenia. This correlates with our results and also explains why most patients with HCC experience neutropenia.
We observed a significant increase in AST levels in the HCC and cirrhosis groups compared with the control group, as well as a significant increase in AST levels in the HCC group compared with the liver cirrhosis group. When compared with the control group, a substantial rise in ALT was seen in the HCC and liver cirrhosis groups. The difference in ALT levels between the HCC and liver cirrhosis groups was not statistically significant. Although both ALT and AST serum levels increase in response to liver cell damage, the degree of the increase is not related to the severity of the injury. Numerous variables, such as the etiology of the liver disease or the degree of necrosis in the liver cells, affect the mechanism of the increase .
Our results showed that in some patients there was an increase in ALT above normal value, which is similar to the study conducted by Abed et al. , who reported persistent elevated ALT levels in Egyptian adults infected with HCV. Most chronically infected patients have slight elevations in ALT levels .
In agreement with Lee et al. , in the chronic hepatitis and cirrhosis groups, average ALT was much higher than in control groups with decompensated cirrhosis. This was consistent with the findings of the current investigation. Another research, on the contrary, revealed that chronic HCV infection individuals have normal or borderline ALT levels .
Another study conducted on HCV-infected individuals showed a significant correlation between increased ALT levels over 70 U/l and the risk of HCC. These data indicate that the ALT level is an excellent independent predictor of the need for intervention and that practical use of these findings may assist in the decrease of HCC-related mortality in hepatitis virus-endemic regions .
In HCC and hepatic cirrhosis groups, the levels of serum albumin were significantly decreased compared with the control group without any significant difference between HCC and hepatic cirrhosis. Albumin is synthesized only by the liver. It is the main blood protein. Albumin is the most abundant plasma protein; it has 585 amino acids and is around 69 kD by weight .
Hypoalbuminemia in patients with advanced cirrhosis is always due to decreased hepatocytic and increased water and sodium retention, dilution of the albumin content in extracellular space, and an increased rate of transcapillary transport, which is consistent with cirrhosis patients with low levels of albumin in the current study .
Most patients with HCC in this research had low blood albumin levels, but others had normal levels. According to a prior study, a low recurrence incidence of HCC is related with elevated blood albumin levels in patients; hence, elevated serum albumin levels are a significant predictor of a positive prognosis .
Bilirubin is a breakdown product of Hb produced inside the reticulo-endothelial system. It is excreted unconjugated and enters the liver, where it is transformed by the enzyme UDP-glucuronyltransferase to conjugated bilirubin mono and diglucuronides .
The HCC and liver cirrhosis groups exhibited a significant increment in the overall bilirubin concentration compared with the control group. In addition, the number of HCC and cirrhosis groups increased significantly. In our investigation, we discovered a substantial increase in direct bilirubin levels in the HCC and liver cirrhosis groups as compared with the control group. Direct bilirubin levels were significantly higher in the HCC group than in the liver cirrhosis group. Our findings are in keeping with the study by Wahib et al. , who reported bilirubin level increased in 35% of HCV-infected patients included in the study. Another study performed by Carr et al. , on patients with HCC reported most patients had a bilirubin level less than 1.5 mg/dl and rest of patients had a bilirubin level of more than 1.5 mg/dl.
Serum AFP levels show a considerable rise in the HCC group in comparison with the liver cirrhosis group and HCC group in comparison with the control group in our studies. Additionally, as compared with the control group, there was a substantial increase in AFP levels in the liver cirrhosis group. In agreement with Balogh et al. , HCC may result in AFP levels ranging from normal to more than 100 000 ng/ml. AFP levels more than 400–500 ng/ml are considered diagnostic for HCC. With these values, AFP’s specificity approaches 100% but at the expense of sensitivity, which falls below 45%. AFP has a poor positive predictive value, ranging from 9 to 32%.
Owing to progress in imaging modalities, AFP’s function in diagnosing and monitoring HCC is becoming reduced .
The cutoff, sensitivity, specificity, positive predictive value, negative predictive value, and area under curve were calculated for AFP.
The cutoff for AFP was more than 400 ng/ml, with a sensitivity of 92.29%, specificity of 88.57%, positive predictive value of 89.2%, negative predictive value of 93.9%, and area under the curve of 0.979.
Regarding serum GDF-15 level in our study, in the HCC group, serum GDF-15 level ranged from 2551 to 3521 ng/l, with a mean of 3047.43 ± 323.86 ng/l; in the cirrhosis group, serum GDF-15 level ranged from 1522.0–2722.0 ng/l, with a mean of 2053.40 ± 440.22 ng/l; and in the control group, serum GDF-15 level ranged from 291.0 to 512.0 ng/l, with a mean of 350.75 ± 69.65 ng/l.
The blood level of GDF-15 in the HCC and liver cirrhosis groups was significantly higher than the control group. In comparison with the liver cirrhosis group, blood levels of GDF-15 in the HCC group were also substantially higher. This is in agreement with Liu et al. , where the HCV-positive HCC group had the highest GDF-15 level. Inflammation and immune cell dysfunction are frequently associated with chronic infection by microorganisms such as hepatitis viruses. This is in agreement with Lee et al. , where serum GDF-15 levels were rapidly increased in individuals with chronic liver disease. GDF-15 levels were significantly greater in patients with decompensated cirrhosis than in patients with compensated cirrhosis. Liu et al. , denoted significantly higher GDF-15 in HCV-related liver cirrhotic patients with Child–Pugh score C compared with healthy controls.
Similarly, Si et al. , revealed significantly higher GDF-15 levels by ELISA in serum of patients with HCV and HBV compared with healthy controls. Moreover, microarray analysis showed a 10-fold to 16-fold increase of GDF-15 mRNA in HCV-infected cells.
Prystupa et al. , and Lee et al.  found that patients with liver cirrhosis had greater levels of GDF-15 than healthy participants, and the concentration was higher in patients with Child C than Child B, whereas patients with Child A had the lowest levels. Liver cirrhosis in their patients was secondary to alcoholic cirrhosis, hepatitis, or autoimmune liver disease.
It means that GDF15 involved in the acute hepatocyte reaction and control the growth and damaged reactions of the cell.
GDF-15 accumulates extracellular matrix components such as procollagen 1 A by directly increasing their synthesis, inhibiting the expression of tissue collagenases, or increasing the synthesis of extracellular matrix-degrading enzyme inhibitors (such as plasminogen activator inhibitor type 1, tissue inhibitors of metalloproteinases), all of which contribute to liver cirrhosis .
GDF-15 expression was considerably enhanced when HCV structural proteins (Core, E1, or E2) were expressed but not when nonstructural proteins (P7, NS2, NS3, NS4A, or NS5B) were expressed .
GDF-15 activation in individuals with HCV and HBV infection indicates that in viral hepatitis and other hepatic diseases, GDF-15 is most likely a nonspecific liver damage-responsive cytokine. GDF-15 can operate as a cytokine that circulates through autocrine, paracrine, and endocrine pathways, delivering signals to target cells .
According to Ma et al. , in HCC tissues, GDF-15 was increased compared with neighboring non-carcinomatous (paracarcinomatous) tissues GDF-15. Moreover, GDF-15 promoted HCC invasion and inhibited cell apoptosis through activating TGF-β signal pathways.
GDF-15-shRNA in HCC cells displayed downregulation of phosphoSmad2 and phospho-Smad3 expression but no significant changes in expression rates of phospho-Smad1/5/8. GDF-15, therefore, facilitated HCC invasion and inhibited cell apoptosis by activating the TGF-β signal pathways .
When the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is active, GSK-3b is phosphorylated and then inhibited, which affects the proteasomal degradation of destination molecules such as cyclin D1 and catenin . Additionally, abnormal Akt activation was identified in HCC. The present study showed that GDF-15 was significantly and positively correlated with total and direct bilirubin. These findings were consistent with the results found by Buendgens et al. , as it showed a correlation between GDF-15 and total bilirubin, PT, and albumin, which indicates that GDF-15 is a biomarker in diagnosis of hepatic dysfunction. Moreover, GDF-15 levels were associated with the severity of disease.
The ROC analysis was conducted in this study after combining HCC and cirrhosis patients. When ROC analysis was performed using AFP levels, it revealed a sensitivity of 92.29% and a specificity of 88.57% for the diagnosis of HCC, but when serum GDF-15 levels were used, the sensitivity was 95.29% and the specificity was 94.29% for the diagnosis of HCC. AFP had a ROC area of 0.979, whereas serum GDF-15 had a ROC area of 0.997. According to Liu et al. , ROC comparative curve for HCC or LC cases with HBV or HCV revealed that the AUROC for HCC and LC discriminants was 0.788 for GDF-15. These findings suggest that GDF-15 can be used as an HCC or LC serum biomarker. Additionally, when patients with HCC were compared with patients with other conditions (including healthy controls, HBV or HCV carriers, and patients with cirrhosis), the curve of ROC reveals that in HCC diagnostics, GDF-15 was superior than AFP, with 0.84 AUROC, a sensitivity of 86.79%, and a specificity of 72.75%. In addition, Liu et al. , discovered that combining AFP and GDF-15 resulted in significant improvement when compared with single factor analysis. In a large community, rather than individuals with hepatic cirrhosis, these results will influence screening for HCC risk at an early stage.
Further study of GDF-15 in HCC and liver cirrhosis is required to clarify its role in pathogenesis of HCC in cirrhotic cases.
Further studies are required on a large number of patients for more comprehensive statistical analysis and better conclusions.
The specificity of GDF-15 for HCC and LC requires more research to rule out diagnostic interference from other illnesses linked with elevated GDF-15 levels, such as heart failure and, more specifically, other malignancies.
Financial support and sponsorship
Conflicts of interest
There is no conflicts of interest between the authors.
| References|| |
Tsochatzis E, Bosch J, Burroughs A Liver cirrhosis. Lancet 2014; 383:1749–1761.
Ferlay J, Parkin DM, Steliarova-Foucher E Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46:765–781.
Shaheen KYA, Abdel-Mageed AI, Safwat E, AlBreedy AM The value of serum midkine level in diagnosis of hepatocellular carcinoma. Int J Hepatol 2015; 2015:1–6.
Farazi PA, DePinho RA Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006; 6:674–687.
Zhang DY, Friedman SL Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 2012; 56:769–775.
Yu J, Shen J, Sun TT, Zhang X, Wong N Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 2013; 23:483–491.
Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL, et al
. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: Results from the HALT-C Trial. J Hepatol 2005; 43:434–441.
Villanueva A, Minguez B, Forner A, Reig M, Llovet JM Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Annu Rev Med 2010; 61:317–328.
Marrero JA, Lok AS Newer markers for hepatocellular carcinoma. J Gastroenterol 2004; 127:113–119.
Li YW, Yang FC, Lu HQ, Zhang JS Hepatocellular carcinoma and hepatitis B surface protein. World J Gastroenterol 2016; 22:1943–1952.
Ozkan H, Erdal H, Tutkak H, Karaeren Z, Yakut M, Yüksel O, Köklü S Diagnostic and prognostic validity of Golgi protein 73 in hepatocellular carcinoma. Digestion 2011; 83: 83–88.
Halim M, Abdulla N, Kamel A, AbdEl Maksouda N, Ragab HM Significance of growth differentiation factor 15 in chronic HCV patients. J Genet Eng Biotechnol 2017; 15:403–407.
Tacke F, Luedde T, Manns MP, Trautweinet C Regulation of plasma erythropoietin in chronic liver disease. World J Gastroenterol 2004; 10:2922–2923.
Bruno CM, Neri S, Sciacca C, Bertino G, Prima PD, Cilio D, et al
. Plasma erythropoietin levels in anaemic and non-anaemic patients with chronic liver diseases. World J Gastroenterol 2004; 10:1353–1356.
Olariu M, Olariu C, Olteanu D Thrombocytopenia in chronic hepatitis C. J Gastrointestin Liver Dis 2010; 19:381–385.
Rios R, Sangro B, Herrero I, Quiroga J, Prieto J The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis. Am J Gastroenterol 2005; 100:1311–1316.
Franco A, Corken A, Ware J Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015; 126:582–588.
Carr BI, Guerra V Thrombocytosis and hepatocellular carcinoma. Dig Dis Sci 2013; 58:1790–1796.
Lustberg MB Management of neutropenia in cancer patients. Clin Adv Hematol Oncol 2012; 10:825–826.
Dieterich DT, Spivak JL Hematologic disorders associated with hepatitis C virus infection and their management. Clin Infect Dis 2003; 37:533–541.
Tameda M, Shiraki K, Ooi K, Takase K, Kosaka Y, Noboriet T, Tameda Y Aspartate aminotransferase-immunoglobulin complexes in patients with chronic liver disease. World J Gastroenterol 2005; 11:1529–1531.
Abed NT, Elfeky OA, Fouda ME, Eldesouky RSH, Ahmed ES Prevalence and risk factors of asymptomatic hepatitis C virus infection among a sample of school aged Egyptian children. Int J Med Health Sci 2016; 5:87–93.
Jonas MM Children with hepatitis C. Hepatology 2002; 36(S1):173–178.
Lee ES, Kim SH, Kim HJ, Kim KH, Lee BS, Ku BJ Growth differentiation factor 15 predicts chronic liver disease severity. Gut Liver 2017; 11:276–282.
Tovo PA, Newell ML Hepatitis C in children. Curr Opin Infect Dis 1999; 12:245–250.
Ishiguro S, Inoue M, Tanaka Y, Mizokami M, Iwasaki M, Tsugane S Serum aminotransferase level and the risk of hepatocellular carcinoma: a population based cohort study in Japan. Eur J Cancer Prev 2009; 18:26–32.
Nagao Y, Sata M Serum albumin and mortality risk in a hyperendemic area of HCV infection in Japan. Virol J 2010; 7:375.
Bernardi M, Maggioli C, Zaccherini G Human albumin in the management of complications of liver cirrhosis. Crit Care 2012; 16:2–7.
Shunsuke N, Takashi J Albumin suppresses human hepatocellular carcinoma proliferation and the cell cycle. Int J Mol Sci 2014; 15:5163–5174.
Gowda S, Desai B, Hull V, Math A, Vernekar S, Kulkarni S A review on laboratory liver function tests. Pan Afr Med J 2009; 4:533–541.
Wahib A, El-Nasr M, Mangoud A, El-Shazly AM, Morsy AT The liver profile in patients with hepatitis C virus and/or fascioliasis. J Egypt Soc Parasitol 2006; 36:405–440.
Carr B, Guerra V, Giannini G, Burroughs SG, Boktour M, Saharia A, et al
. Association of abnormal plasma bilirubin with aggressive HCC phenotype. Semin Oncol 2014; 41:252–258.
Balogh J, Victor D, Asham EH, et al
. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma 2016; 3:41–53.
Fitzmorris P, Singal A Surveillance and diagnosis of hepatocellular carcinoma. Gastroenterol Hepatol (N Y) 2015; 11:38–46.
Liu J, Gao Y, Yang B, et al
. Overexpression of squamous cell carcinoma antigen 1 is associated with the onset and progression of human hepatocellular carcinoma. Arch Med Res 2015; 46: 133–141.
Si Y, Liu X, Cheng M, et al
. Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes. PLoS ONE 2011; 6:1–9.
Prystupa A, Kiciński P, Luchowska-Kocot D, Błażewicz A, Niedziałek J, Mizerski G, et al
. Association between serum selenium concentrations and levels of proinflammatory and profibrotic cytokines-interleukin-6 and growth differentiation factor-15, in patients with alcoholic liver cirrhosis. Int J Environ Res Public Health 2017; 14: 1–9.
Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee S Characterization of growth differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 2000; 20:3742–3751.
Shah R, Reyes-Gordillo K, Arellanes-Robledo J, Lechuga CG, Hernández-Nazaraet Z, Cotty A, Rojkind M, Lakshman MR TGF-beta1 up-regulates the expression of PDGF-beta receptor mRNA and induces a delayed PI3K-, AKT-, and p70 (S6K)-dependent proliferative response in activated hepatic stellate cells. Alcohol Clin Exp Res 2013; 37:1838–1848.
Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YTet al
. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13:1096–1101.
Ma MZ, Zhang XH, Li B, Liang TJ, Yang CM, Liu JY Growth differentiation factor 15 (GDF15) contributes to invasion and anti-anoikis of hepatocellular cancer through TGF-β/Smad-associated signaling. Int J Clin Exp Med 2018; 11:12964–12973.
Wichert GV, Haeussler U, Greten FR, Kliche S, Dralle H, Böhm BO, Adler G, Seufferlein T. Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells. Oncogene 2005; 24:1284–1289.
Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M, Steveling K, et al
. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 2008; 48:83–90.
Buendgens L, Yagmur E, Bruensing J, Herbers U, Baeck C, Trautwein C, Koch A, Tacke F Growth differentiation factor-15 is a predictor of mortality in critically ill patients with sepsis. Dis Markers 2017; 2017: 1–10.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]