Down-regulation of hepatic expression of GHR/STAT5/IGF-1 signaling pathway fosters development and aggressiveness of HCV-related hepatocellular carcinoma: Crosstalk with Snail-1 and type 2 transforming growth factor-beta receptor.

BACKGROUND AND AIMS: So far, few clinical trials are available concerning the role of growth hormone receptor (GHR)/signal transducer and activator of transcription 5 (STAT5)/insulin like growth factor-1 (IGF-1) axis in hepatocarcinogenesis. The aim of this study was to evaluate the hepatic expression of GHR/STAT5/IGF-1 signaling pathway in hepatocellular carcinoma (HCC) patients and to correlate the results with the clinico-pathological features and disease outcome. The interaction between this signaling pathway and some inducers of epithelial-mesenchymal transition (EMT), namely Snail-1 and type 2 transforming growth factor-beta receptor (TGFBR2) was studied too. MATERIAL AND METHODS: A total of 40 patients with HCV-associated HCC were included in this study. They were compared to 40 patients with HCV-related cirrhosis without HCC, and 20 healthy controls. The hepatic expression of GHR, STAT5, IGF-1, Snail-1 and TGFBR2 proteins were assessed by immunohistochemistry. RESULTS: Compared with cirrhotic patients without HCC and healthy controls, cirrhotic patients with HCC had significantly lower hepatic expression of GHR, STAT5, and IGF-1proteins. They also displayed significantly lower hepatic expression of TGFBR2, but higher expression of Snail-1 versus the non-HCC cirrhotic patients and controls. Serum levels of alpha-fetoprotein (AFP) showed significant negative correlations with hepatic expression of GHR (r = -0.31; p = 0.029) and STAT5 (r = -0.29; p = 0.04). Hepatic expression of Snail-1 also showed negative correlations with GHR, STAT5, and IGF-1 expression (r = -0.55, p = 0.02; r = -0.472, p = 0.035, and r = -0.51, p = 0.009, respectively), whereas, hepatic expression of TGFBR2 was correlated positively with the expression of all these proteins (r = 0.47, p = 0.034; 0.49, p = 0.023, and r = 0.57, p<0.001, respectively). Moreover, we reported that decreased expression of GHR was significantly associated with serum AFP level>100 ng/ml (p = 0.048), increased tumor size (p = 0.02), vascular invasion (p = 0.002), and advanced pathological stage (p = 0.01). Similar significant associations were found between down-regulation of STAT5 expression and AFP level > 100 ng/ml (p = 0.006), vascular invasion (p = 0.009), and advanced tumor stage (p = 0.007). Also, attenuated expression of IGF-1 showed a significant association with vascular invasion (p < 0.001). Intriguingly, we detected that lower expression of GHR, STAT5 and IGF-1 were considered independent predictors for worse outcome in HCC. CONCLUSION: Decreased expression of GHR/STAT5/IGF-1 signaling pathway may have a role in development, aggressiveness, and worse outcome of HCV-associated HCC irrespective of the liver functional status. Snail-1 and TGFBR2 as inducers of EMT may be key players. However, large prospective multicenter studies are needed to validate these results.

The Role of Signal Transducer and Activator of Transcription 5 and Transforming Growth Factor-ß1 in Hepatic Fibrosis Induced by Chronic Hepatitis C Virus Infection in Egyptian Patients.

OBJECTIVE: To investigate the possible role of signal transducer and activator of transcription 5 (STAT5) in the pathogenesis of liver fibrosis in Egyptian patients with chronic hepatitis C (CHC) virus infection and its relation to hepatic stellate cells (HSC). SUBJECTS AND METHODS: Sixty-five patients (46 males and 19 females) were divided into 4 groups based on the severity of fibrosis as detected by Fibroscan as follows: F1, n = 15; F2, n = 21; F3, n = 13; and F4, n = 16. Twenty age- and gender-matched healthy persons volunteered as controls. The serum levels of STAT5, TGF-ß1, α-smooth muscle actin (α-SMA), fasting blood sugar, and fasting insulin, as well as homeostasis model assessment of insulin resistance (HOMA-IR), were determined and compared for all groups. The usefulness of the studied serum biomarkers for predicting liver fibrosis was evaluated using a receiver operating characteristic curve. RESULTS: Serum levels of STAT5 were significantly lower in patients compared to controls (9.69 ± 5.62 vs. 14.73 ± 6.52, p ≤ 0.001); on the contrary, TGF-ß1, α-SMA, and HOMA-IR were significantly higher in patients compared to controls (mean: 1,796.04 vs. 1,636.94; 14.94 vs. 8.1; and 7.91 vs. 4.18; p ≤ 0.01 and 0.001, respectively). TGF-ß1 and α-SMA showed a progressive increase with advancing severity of hepatic fibrosis (mean TGF-ß1: 2,058.4 in F1-F2 and 1,583.8 in F3-F4, p ≤ 0.04; mean α-SMA: 13.59 in F1-F2 and 16.62 in F3-F4, p ≤ 0.05). STAT5 had a significant negative correlation with TGF-ß1 (p ≤ 0.001), while no correlation was detected with α-SMA (p ≤ 0.8). CONCLUSIONS: STAT5 may play a significant role in hepatic fibrogenesis through the induction of TGF-ß1 but not through the activation of hepatic stellate cells.

Non-neoplastic Portal Vein Thrombosis in HCV Cirrhosis Patients: Is it an Immuno-Inflammatory Disorder?

BACKGROUND AND AIMS: Portal vein thrombosis (PVT) is a critical complication in cirrhotic patients. We explored the role of the activated factor VII-antithrombin (FVIIa-AT) complex and enhanced monocytic tissue factor (TF) expression in the development and prediction of non-neoplastic PVT in cirrhotic patients. MATERIAL AND METHODS: A total of 30 HCV-cirrhosis patients were included in our study. They were compared to 35 cirrhotic patients without PVT, 15 non-cirrhotic patients with PVT, and 15 healthy controls. The plasma level of the FVIIa-AT complexes was analyzed by ELISA. MIF CD142, CD86, and HLA-DR on monocytes (CD14) were determined by flow cytometry. RESULTS: Compared with cirrhotic patients without PVT, cirrhotic patients with PVT had comparable plasma values of FVIIa, AT, and the FVIIa-AT complex. However, they had significantly lower values compared to non-cirrhotic patients with PVT and healthy controls. Cirrhotic patients with PVT had increased monocytic TF expression (MIF CD142) compared to non-PVT cirrhotic patients and healthy controls [86.5 (93.5) vs. 18 (32.0) and 11.0 (6.0), respectively; p < 0.001 for each]. However, cirrhosis PVT could not be distinguished from non-cirrhosis PVT. The area under the ROC curve of MIF CD142 was 0.759 (0.641- 0.876; p = 0.000) at an optimal cut-off value of 45, which yielded a sensitivity of 60% and a specificity of 77.1%, as well as a PPV and NPV of 69.2% for each. CONCLUSION: Enhanced expression of monocytic TF may have a role in the development and prediction of non-neoplastic PVT in HCV-cirrhosis patients. Large multicenter studies are necessary to validate our results.

An overview of biomarkers for the diagnosis of hepatocellular carcinoma.

CONTEXT: Primary liver cancer is one of the most common and deadly malignant neoplasms worldwide. The incidence and mortality rates for hepatocellular carcinoma (HCC) are virtually identical, reflecting the poor overall survival of patients with this kind of tumor. Effective therapies mostly achieved if the HCC diagnosis is made at early stages of the tumor. Surveillance tests include serologic and radiologic examinations. EVIDENCE ACQUISITION: In this review, an overview of biomarkers for the diagnosis of HCC and future challenges in this popular field has been presented. RESULTS: Serum tumor markers, such as alpha-fetoprotein (AFP) and des-gammacarboxy prothrombin (DCP) are commonly used for the surveillance, but their roles have been intensely debated despite the existence of sensitive radiologic tests. Most HCC-related cancer biomarkers are involved in chronic inflammation and cancer. These biomarkers, according to their biologic characteristics are primarily divided into three groups including onco-foetal protein, stress protein, and post-translational modification. CONCLUSIONS: Because of the limitations of traditional HCC biomarkers, exploration for novel biomarkers for the diagnosis of HCC is an evolving process.

Prevalence of occult hepatitis B virus infection in hemodialysis patients from egypt with or without hepatitis C virus infection.

BACKGROUND: While prevalence of Hepatitis B virus (HBV) in patients with end-stage renal failure (ESRF) who are undergoing dialysis has decreased significantly during the past few decades, it still remains a distinct clinical problem. The immunosuppressive nature of renal disease often leads to chronicity of the HBV infection and an opportunity for nosocomial spread of the infection among dialysis patients. Egypt is among the countries with intermediate endemicity of HBsAg (range, 2%-7%). Large-scale geographic heterogeneity in HBV prevalence has been reported worldwide and HBV prevalence is especially heterogeneous in Egypt. OBJECTIVES: To assess the prevalence of occult HBV infection (OBI) in hemodialysis patients with or without chronic hepatitis C (HCV) from Minia and Assuit, Upper Egypt, using HBV DNA assays. PATIENT AND METHODS: Sera from 145 hemodialysis patients with negative HbsAg were investigated for HBV DNA using real-time polymerase chain reaction (RT-PCR). Only serum samples with repeatedly detectable HBV DNA were considered positive. Patients were divided into 2 groups: HCV RNA positive and HCV RNA negative, based on the results of a third generation enzyme linked immunosorbent assay (ELISA) anti-HCV test and HCV RNA PCR. RESULTS: HBV DNA was detected in 6 of the 145 patients (4.1%) and HBcAb was detected in 29/145 patients (20%). There were no statistically significant differences in the age, duration of hemodialysis, biochemical parameters, serological markers of HBV, or HBV DNA between patients with and without HCV infection. CONCLUSIONS: Four percent of the hemodialysis patients had OBI. There was no significant difference in the prevalence of OBI between hemodialysis patients with or without HCV co-infection.

Platelet count/bipolar spleen diameter ratio for the prediction of esophageal varices: The special Egyptian situation: Noninvasive prediction of esophageal varices.

BACKGROUND: Esophageal variceal hemorrhage is a devastating complication of portal hypertension that occurs in approximately one-third of cirrhotic patients. OBJECTIVES: We assessed the value of the platelet count/ bipolar spleen diameter ratio as a noninvasive parameter for the prediction of esophageal varices (EVs) in Egyptian cirrhotic patients. PATIENTS AND METHODS: Laboratory and ultrasonographic and imaging variables were prospectively evaluated in 175 patients with liver cirrhosis. All patients underwent upper gastrointestinal endoscopy. Patients with active gastrointestinal bleeding at the time of admission were excluded. RESULTS: The platelet count/ bipolar spleen diameter ratio in patients with EVs was significantly lower than in patients without EVs. In an analysis of the receiver operating characteristic curves (ROCs), we calculated an optimal cutoff value of 939.7 for this ratio, which gave 100% sensitivity and negative predictive values, 86.3% specificity, a 95.6% positive predictive value, and an area under the ROC curve of 0.94 ± 0.02, reflecting its overall diagnostic accuracy. These findings were extended to a subset analysis of compensated cirrhotic patients. CONCLUSIONS: The platelet count/ bipolar spleen diameter ratio has excellent accuracy in the noninvasive assessment of EVs in patients with compensated or decompensated liver cirrhosis. It is easy to calculate and can lower the financial and sanitary burdens of endoscopy units, especially in developing countries.

Diagnostic significance of plasma osteopontin in hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND AIM: Outcome of hepatocellular carcinoma (HCC) depends mainly on its early diagnosis. The performance of traditional biomarkers is not satisfactory. Osteopontin (OPN) is of potential importance. This study aim to assess the diagnostic value of plasma OPN compared with alpha-fetoprotein (AFP) for the diagnosis of HCV- related HCC. METHODS: We recruited 113 HCC patients compared with 120 matched cirrhotic patients and 120 Controls. The plasma level of OPN and serum AFP for all participants were assessed. RESULTS: The median plasma OPN level was significantly higher in the HCC group than in the cirrhotic patient group or in the normal control group (p-value < 0.001), while OPN levels were not differed significantly in correlation with the degree of liver function deterioration in terms of advanced Child-Pugh class (p-value < 0.9). The diagnostic efficacy of OPN were superior to AFP in terms of AUC, sensitivity, specificity, PPV and NPV either in diagnosis of early or late stages of HCC (0.88 vs. 0.56; P = 0.0001, 0.991vs. 0.899; p = 0.01; respectively). CONCLUSION: Plasma OPN level is a potential diagnostic marker for HCC, especially among high-risk group of patients. These values extend beyond the traditional tumor biomarkers as AFP, as it possesses good prognostic value.