HCV-positive Liver Cirrhosis Research Articles

Single or multiple treatments with lusutrombopag in subjects with thrombocytopenia and chronic liver disease needing an invasive procedure

Thrombocytopenia is one of the most frequent implications of liver cirrhosis. This condition, when present in the severe form [platelet count (PLT) less than 50 × 109/L] correlates, with an increased risk of bleeding during the main diagnostic-therapeutic procedures which cirrhotic patients usually undergone. In these cases, generally, an infusion of platelets is performed, albeit in recent years has been replaced by a cycle of second generation thrombopoietin receptor (TpoR) agonists. This article reports two different cases concerning respectively an 83-year-old female patient suffering from arterial hypertension, aneurysm of the sub-renal aorta, hepatitis C virus (HCV)-positive liver cirrhosis responsive to treatment with antiviral drugs, and a 2.0 cm diameter hepatocellular carcinoma (HCC) nodule localized in the hepatic segment III and a 53-year-old female patient with HCV-positive liver cirrhosis complicated by portal hypertension with splenomegaly, thrombocytopenia, and F3 esophageal varices at high risk of bleeding. Both of them, eligible for invasive procedures such as HCC transarterial chemoembolization (TACE) and for esophageal variceal band ligation, were prescribed prophylaxis with TpoR agonists due to their severe and persistent thrombocytopenia. These two cases show how a short course of lusutrombopag allows to safely perform one or more invasive procedures and how the administration of the drug can be repeated without losing efficacy. Furthermore, this drug shows an excellent safety profile and avoids the risks of platelet transfusion. In conclusion, second generation TpoR agonists can be considered the prophylactic treatment of choice to reduce the risk of bleeding in patients with liver cirrhosis and severe thrombocytopenia.

Serum Folate deficiency in HCV related Hepatocellular Carcinoma

Nutritional and environmental factors had been reporting in the progression of hepatocellular carcinoma (HCC). In this study, we focused our intervention in the correlation between the folate status and the progression of HCC in patients with chronic virus C (HCV) infection. Nine-eight patients, HCV positive with HCC and one hundred of patients with HCV positive liver cirrhosis (LC) and one hundred patients with HCV positive chronic hepatitis (CHC) and one hundred control subjects were enrolled. The viremia for hepatitis C patients (HCV) was determined by HCV RNA with polymerase chain reaction. HCV was confirmed by HCV RNA or a positive anti-HCV test with chronic liver disease. The comparison of folate serum levels in HCC patients vs Liver Cirrhosis (LC) patients showed a significant decrease of 1.16 ng/ml P = 0.0006 (95% CI-1.925 to − 0.395), in HCC patients versus CHC a decrease of 1.40 ng/ml P < 0.0001 (95% CI-2.16 to − 0.63), in HCC vs controls a decrease of 3.80 ng/ml P < 0.0001 (95% CI-4.56 to − 3.03). The comparison of homocysteine Hcy serum levels showed a significant increase in HCC vs LC of 4 nmol/L (P < 0.0001, 95% CI 2.77 to 5.22) versus CHC of 9 nmol/L (P < 0.0001, 95% CI 7.78 to 10.22) and vs Controls 9.30 nmol/L (P < 0.0001, 95% CI 8.07 to 10.52). With progression of HCV infection from chronic hepatitis to cirrhosis, then to HCC development, serum folate levels are progressively decreasing together with a progressive increase in serum homocysteine levels reflecting its role in disease progress and carcinogenesis.

Screening and surveillance of oesophageal varices in patients with HCV-positive liver cirrhosis successfully treated by direct-acting antiviral agents.

Background & Aimslimited evidence is available to guide hepatologists regarding endoscopic surveillance of oesophageal varices (EV) in Hepatitis C Virus (HCV)‐positive cirrhotic patients achieving a sustained virologic response. To address these issues, we conducted a long‐term prospective study on 427 HCV‐positive cirrhotic patients successfully treated by Direct Antiviral Agents (DAAs).MethodsPatients were divided into two groups according to their baseline Baveno VI status: Group 1 (92, 21.5%, favourable Baveno VI status) and Group 2 (335, 78.5%, unfavourable Baveno VI status). Each patient underwent baseline endoscopy and was endoscopically monitored for a median follow‐up of 65.2 months according to Baveno VI recommendations.ResultsAbout 4.3% of Group 1 patients showed baseline EV compared with 30.1% of Group 2 patients (p < .0001). No patients belonging to Group 1 without baseline EV developed EV at follow‐up endoscopy compared with 6.5% in Group 2 patients (p = .02); 69/107 (64.5%) patients with baseline EV showed small varices. During the endoscopic follow‐up, EV disappeared/improved in 36 (33.6%), were stable in 39 (36.4%) and worsened in 32 (29.9%) patients, all belonging to Group 2 (p = .001). Improvement in Baveno VI status was observed in 118/335 (35.2%, p < .0001) of Group 2 patients and among those without pre‐therapy EV, none developed EV throughout the follow‐up.ConclusionsHCV‐positive cirrhotic patients cured by DAAs showing baseline favourable Baveno VI status and no worsening during follow‐up can safely avoid endoscopic screening and surveillance. Patients having unfavourable Baveno VI status without baseline EV who improve their status may suspend further endoscopic surveillance.

Role of Osteopontin as a Potential Marker of Hepatocellular Carcinoma

Abstract Background: Osteopontin is an important tumor marker, since it presents as an immobilized extracellular matrix molecule in addition to present as a secreted form in body fluids involving plasma. Osteopontin levels in the plasma were found to be significantly higher in Hepatocellular Car-cinoma (HCC) patients than in healthy control individuals and also higher than in patients with chronic liver diseases. Aim of Study: The aim of the present study is to evaluate the role of plasma OPN level as potential markers of HCC among HCV infected patients, compared to AFP. Also, its relationship with clinicopathological features of HCC patients. Study Design: This is a retrospective case control study. Subjects and Methods: The study included 100 adult subjects; they were classified in to 4 groups: Group 1: It included 30 apparently healthy individuals (control group). Group 2: It included 30 patients with HCV positive chronic hepatitis. Group 3: It included 20 patients with HCV positive liver cirrhosis without HCC. Group 4: It included 20 patients with HCV positive liver cirrhosis and HCC. Serum Osteopontin was measured by Enzyme-Linked Immunosorbent Assay ELISA. Results: The mean OPN level was (33.1±16.4) ng/ml, (27.8±13.8) ng/ml, (92.87±18.5) ng/ml and (232.13±59.7) ng/ml for control, HCV, cirrhosis and HCC groups respectively, p-value=0.0010 and there were highly statistical significant differences between the four groups (p < 0.001). The mean AFP level was (4.6±2.4) ng/ml, (8.01±2.76) ng/ml, (24.8±25.9) ng/ml and (639±2226.8) ng/ml for control, HCV, cirrhosis and HCC groups respectively, p-value=0.0014 and there were highly statistical significant differences between the four groups (p < 0.001). Conclusion: OPN can be used for diagnosis of HCC and differentiation between HCC and CLD, OPN has higher sensitivity and specificity than AFP and can be used for early diagnosis. Combination of OPN wih AFP has increased both sensitivity and specificity for detection of HCC.

EFFECT OF NON-SELECTIVE BETA BLOCKERS ON ESOPHAGEAL VARICES AND PORTAL VEIN DIAMETER IN CIRRHOTIC HCV PATIENTS

ABSTRACT Background: Esophageal varices is one of the major complications of portal hypertension and one of the main causes of death in cirrhotic patients, so prophylaxis from esophageal varices bleeding can decrease the number of deaths in those patients. Aim of the work: To assess the effect of non-selective beta blockers on portal vein diameter and grades of esophageal varices. Subjects and methods: Our study was carried out at Gastroenterology and Hepatology unit, Internal Medicine department, Zagazig University hospital. Forty patients with HCV positive liver cirrhosis were enclosed in the study. All were Child Pugh grade A and B, diagnosed by clinical examination, laboratory investigations (hepatitis C virus antibody, hepatitis C virus RNA by polymerase chain reaction, hepatitis B virus surface antigen, liver and kidney functions, complete blood count, INR and alpha feto-protein) and pelvi-abdominal ultrasound findings. Upper gastrointestinal (GI) endoscopy was done at the beginning of the study for detection and grading of esophageal varices (EVs) and those without EVs were excluded, also portal vein diameter (PVD) was recorded by ultrasound. The maximum tolerated dose of Propranolol (decrease pulse rate by 25% but not below 60 beats per minute) was given to all patients for three months. EVs grading, by upper GI endoscopy, and PVD were reassessed at the end of the study. Results: Propranolol showed a significant reduction in heart rate and PVD for the pre and posttreatment results after three months of treatment (P<0.001 for both). The dose of Propranolol didn't show significant effect on reduction of small size EVs (P=0.07) while the percent of reduction of PVD correlated significantly with percent of reduction in EVs grade for the pre and post-treatment (P<0.05). A cut off point for detection of significant EVs (GII and III) was 12.5 mm with sensitivity 82.4%, specificity 47.8%, positive predictive value (PPV) 53.8% and negative predictive value (NPV) 78.6%. Conclusion: Non-selective beta blocker (Propranolol) caused significant reduction in portal vein diameter and the percentage of reduction of portal vein diameter significantly correlated with change in esophageal varices grades. Key words: Portal hypertension, HCV, Esophageal varices, Portal vein diameter, liver cirrhosis and Non-selective beta blockers.

Serum and Ascitic Fluid Hepcidin in HCV Positive Liver Cirrhosis with and without HCC

Background & Aim: Chronic HCV infection suppresses hepatic hepcidin expression which may enhance iron toxicity and lead to disease progression and HCC development. The aim of the study is to investigate the role of hepcidin in HCV+ve liver cirrhosis patients in relation to disease progression and HCC development. Patients and methods: The study population consists of: 20 HCV+ve patients without HCC (HCV patients), 20 HCV+ve patients with HCC (HCV-HCC patients) and 10 controls. In addition to comprehensive clinical examination, they were subjected to laboratory check-up for albumin, bilirubin, PT %, ferritin, AFP and hepcidin. Ascitic fluid hepcidin was done for all patients. Results: There was a significant difference among HCV and HCV-HCC patients and controls with regard serum ferritin and hepcidin (P = 0.001 & 0.0001 respectively). Serum hepcidin of HCV and HCV-HCC patients were significantly lower than controls (P = 0.0001). Serum and ascitic fluid hepcidin of HCV-HCC patients was significantly lower than HCV patients (P = 0.01 & 0.02 respectively). Serum ferritin was significantly higher in HCV and HCV-HCC patients than controls (P = 0.001). Serum ferritin of HCV-HCC patients was significantly higher than HCV patients (P = 0.02). Ascitic fluid hepcidin was negatively correlated with Child-Pugh score in HCV (r=-0.55 & P=0.01) and HCV-HCC patients (r = -0.53 & P = 0.02). Ascitic fluid hepcidin was negatively correlated with bilirubin in HCV (r = -0.43 & P=0.04) and HCV-HCC patients (r = -0.47 & P=0.04). Ascitic fluid hepcidin was positively correlated with serum albumin in HCV (r = +0.44 & P=0.04) but there was no correlation in HCV-HCC patients (r =-0.1 & P=0.7). Conclusion: Low levels of hepcidin may be involved in the pathophysiologic mechanism of iron overload in patients with chronic HCV with and without HCC. Moreover, there is a positive relationship between hepcidin levels and synthetic liver function suggesting that uniform suppression of hepcidin may be linked to disease progression and HCC development. Further analysis is still required to evaluate its usefulness as a marker for early detection of HCC by serial measurement of hepcidin in blood and ascitic fluid.

Clastogenic factors in the plasma of patients with hepatitis C: their possible role at the origin of hepatocarcinoma

Clastogenic factors (CF) are endogenous clastogens composed of lipid peroxidation products, cytokines, and abnormal nucleotides of inosine. They are regularly observed after radiation exposure and in chronic inflammatory diseases, where they are supposed to be risk factors for carcinogenesis. In the present study, we evaluate clastogenic activity in the plasma of patients with chronic hepatitis C, HCV-positive liver cirrhosis, and hepatocarcinoma in comparison to liver metastasis. Plasma ultrafiltrates from patients were added to blood cultures of healthy donors (CF test). The chromosomal aberration rates observed in 100 metaphases after 48 hours of cultivation were expressed as adjusted clastogenic scores (ACS). The differences in ACS between the four patient groups and controls were highly significant and represented a 10-fold increase in chromatid-type aberrations. The ACS of patients with cirrhosis and hepatocarcinoma were higher than those of hepatitis patients without these complications, but the differences did not reach statistical significance. Because of cytotoxic effects, the cultures did not grow for 10/17 patients with hepatocarcinoma and were repeated with a reduced volume of ultrafiltrate (0.1 instead of 0.25 mL). The ACS were highest in these 10 patients. When the CF activity of HCV-positive hepatocarcinoma was compared to metastasis because of other malignancies, the differences in ACS were highly significant for the cultures set up with the reduced quantity of ultrafiltrate. The percentage of CF-positive samples was 100% for hepatocarcinoma and 9% for metastasis. The results show that the chromosome-damaging effects of CF increase as the disease progresses to cirrhosis and liver cancer. Formed via the intermediacy of superoxide and generating more superoxide, CF are responsible for an autosustained, long-lived DNA-damaging process, which is documented at the chromosomal level by our technique.

Survey of anti-tuberculosis drug-induced severe liver injury in Japan

To clarify the incidence and clinical significance of anti-tuberculosis drug-induced liver injury. Questionnaire was sent out by mail to 114 hospitals, to ask whether there were patient(s) from 1994 to 2003 with liver injury induced by anti-tuberculosis drugs with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of more than 1000 IU/l and/or total bilirubin level of more than 2 mg/dl. As for the cases of severe hepatic injury, their backgrounds and clinical courses were investigated. Seventy cases were reported from 24 out of 68 hospitals which treated at least 8095 tuberculosis patients in 2003. Incidence rate of severe liver injury by anti-tuberculosis drugs was 0.50 to 0.59 percent in three hospitals with good surveillance system, and overall incidence was estimated to be between 0.1 to 0.5 percent. We could analyze 33 cases; one was HB antigen positive, one had HCV positive liver cirrhosis, 2 had other hepatic disease, and 17 had other underlying disease including diabetes mellitus. Twenty-three were treated by regimens with isoniazid (INH), rifampicin (RFP) and pyrazinamide (PZA), and 8 by regimens without PZA but with INH and RFP and one was a multidrug-resistant case and was treated by regimen with ethionamide and PZA. The onset of liver injury was within 2 months after starting anti-tuberculosis chemotherapy in 28 (85%) cases. In twenty-eight cases which both ALT and total bilirubin level are known, total bilirubin level at the onset of liver injury was more than 2 mg/dl in 14 cases and most of the cases were hepatocellular type of liver injury. Six out of 10 cases with total bilirubin level more than 5 mg/dl died by liver failure. Total birilubin was less than 2 mg/gl in two of the dead cases; in one case antituberculosis drug were continued despite elevated level of ALT and another case complicated with gastric bleeding. Treatment for liver injury was conservative in most cases, 6 were treated by plasmapheresis and no liver transplantation was carried out. Eight cases died of liver failure, one died of tuberculosis and only 15 were treated successfully for tuberculosis. Incidence rate was high comparared with that by other drugs reported previously. The risk factor of liver injury by antituberculosis drugs was not detected, but elevated total bilirubin level more than 5 mg/dl was an alarming sign for poor prognosis.

Activated T Cells and Soluble Molecules in the Portal Venous Blood of Patients with Cholestatic and Hepatitis C Virus-Positive Liver Cirrhosis. Possible Promotion of Fas/FasL-Mediated Apoptosis in the Bile-Duct Cells and Hepatocyte Injury

We investigated the immune responses of patients with cholestatic and hepatitis C virus-positive (HCV-positive) liver cirrhosis by analysing T-cell subsets and cytokine levels in the portal and peripheral veins, using flow cytometry and enzyme-linked immunosorbent assay. In cholestatic liver cirrhosis, the proportion of natural-killer (NK) T cells and interleukin (IL) 6 and IL-18 levels in the portal venous blood were significantly higher than those in the peripheral venous blood. In HCV-positive liver cirrhosis, the proportions of NK T cells and Fas+ T cells and IL-6 and soluble Fas levels in the portal venous blood were significantly higher than those in the peripheral venous blood. These results suggest that in these diseases, activated T cells and soluble molecules in portal venous blood may promote Fas/FasL-mediated apoptosis of the bile-duct cells and hepatocytes, and contribute to the deterioration in liver function as an inevitable result of positive feedback.

Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma

Immunosuppression and transplantation have been reported to induce porokeratosis (PK), especially its variant, disseminated superficial PK (DSP). On the other hand, there is ample evidence of a relationship between hepatitis C virus (HCV) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). We report 3 cases of DSP in which the outbreak of DSP was suspected to have occurred during the development of HCC in patients with HCV-positive LC. The patients had undergone ultrasonographic study regularly, and no signs of malignancy had been found before the development of DSP. Their outbreaks of DSP were very acute, and the period between the development of DSP and diagnosis of HCC ranged from 2 to 6 months. The association of HCV-related HCC and DSP has never been previously reported. HCV-induced immunomodulation or its effect on the p53 system may be the basis for this type of association. It is necessary to consider development of HCC whenever DSP is found in HCV-positive patients. DSP may be a new paraneoplastic dermadrome. (J Am Acad Dermatol 2000;43:966-8.)

Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma

<h2>Abstract</h2> Immunosuppression and transplantation have been reported to induce porokeratosis (PK), especially its variant, disseminated superficial PK (DSP). On the other hand, there is ample evidence of a relationship between hepatitis C virus (HCV) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). We report 3 cases of DSP in which the outbreak of DSP was suspected to have occurred during the development of HCC in patients with HCV-positive LC. The patients had undergone ultrasonographic study regularly, and no signs of malignancy had been found before the development of DSP. Their outbreaks of DSP were very acute, and the period between the development of DSP and diagnosis of HCC ranged from 2 to 6 months. The association of HCV-related HCC and DSP has never been previously reported. HCV-induced immunomodulation or its effect on the p53 system may be the basis for this type of association. It is necessary to consider development of HCC whenever DSP is found in HCV-positive patients. DSP may be a new paraneoplastic dermadrome. (J Am Acad Dermatol 2000;43:966-8.)

Splenectomy may improve the glomerulopathy of type ii mixed cryoglobulinemia

Many patients with type II mixed cryoglobulinemia have been shown to be infected with hapatitis C virus (HCV). Therefore, interferon-alfa has become the first choice of treatment for patients with HCV-associated cryoglobulinemia. However, the disease often relapses after the discontinuation of interferon therapy. The long-term effect of interferon therapy is controversial. Therefore, a more effective therapy needs to be developed. A 62-year-old Japanese woman was admitted to our hospital for the examination of abnormal liver function tests, severe edema, and purpura in her lower extremities. Glomerulopathy secondary to HCV-related cryoglobulinemia was suspected. Her serum creatinine was increased to 2.1 mg/dL. Interferon therapy was considered initially. However, because of pancytopenia caused by liver cirrhosis and splenomegaly, splenectomy was performed in February 1997, before the start of interferon therapy. Renal biopsy specimen taken at the time of the splenectomy showed typical cryoglobulinemic glomerulonephritis. Gradually, after surgery, the patient's thrombocytopenia and anemia improved, her proteinuria and hematuria were decreased, her cryocrit dropped from 15% to 5%, the Ccr increased from 21.1 mL/min to 48.8 mL/min, and the purpura in her lower extremities disappeared. A repeat renal biopsy performed in May 1998 showed marked histological improvement. Splenectomy is not widely accepted as a treatment for cryoglobulinemia. Our case suggests the possibility that the monoclonal-IgM component of the type II cryoglobulin may be formed in the spleen. In conclusion, splenectomy may be an effective therapy for cryoglobulinemia in patients with HCV-positive liver cirrhosis and pancytopenia secondary to splenomegaly.

Sicam-1, sCD95 and sCD95L Levels in Chronic Liver Diseases of Different Etiology

The release of soluble circulating molecules represents a prominent feature during the course of immune-mediated clinical conditions. To further assess the relationship between serum concentrations of adhesion or apoptotic-related soluble structures and liver diseases, we evaluated the levels of intercellular adhesion molecule-1 (sICAM-1), Fas receptor (CD95) and Fas ligand (sCD95L) in a group of patients affected by Hepatitis C Virus (HCV)induced chronic hepatitis (CH-C), HCV-positive liver cirrhosis with superimposed hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and alcoholic liver cirrhosis (ALC). Results show that sICAM-1 values were in all instances significantly elevated when compared to those seen in healthy donors. Similar findings were noted in subjects with liver diseases in terms of sCD95 concentrations, even if to a different degree of statistical significance. Finally, sCD95L amounts were augmented in AIH, PBC, ALC and CH-C in comparison to controls, while in the HCC counterpart sCD95L levels fell within normal range.All together, these findings emphasize the occurrence of circulating soluble molecules in patients with various chronic liver diseases, likely reflecting the involvement of several pathogenetic mechanisms.

Detection of hepatitis C virus RNA in the hearts of patients with hepatogenic cardiomyopathy.

We examined the Hepatitis C virus (HCV) genome in the myocardium and liver obtained at autopsy from seven patients with HCV-positive liver cirrhosis and hepatocellular carcinoma (HCC) by in situ hybridization and histopathological studies. The HCV virus genome was detected in the myocardium of one patient as well as in the liver in three out of seven patients. However, Epstein-Barr (EB) virus genome could not be detected in liver or myocardium. In the patient who showed positive reaction to HCV in myocardium, both serum HCV and Hepatitis B virus (HBV) antibodies were positive. It is unknown whether this was related to an immunological abnormality of the host or to an interaction between RNA and DNA viruses. In conclusion, we could identify the HCV genome in the myocardium of a patient with hepatogenic myocardosis.

Effects of the Japanese herbal medicine "Sho-saiko-to" (TJ-9) on interleukin-12 production in patients with HCV-positive liver cirrhosis.

Interleukin-12 (IL-12) is an important cytokine for maintainence of normal systemic defense and bioregulation. The Japanese herbal medicine Sho-saiko-to (TJ-9) has been administered to 1.5 million Japanese patients with chronic liver diseases. TJ-9 is known to significantly suppress cancer development in the liver and has macrobiotic effects. In the present study, we examined the in vitro production of IL-12 by circulating mononuclear cells from liver cirrhosis patients and the effects of TJ-9 on IL-12 production. The monocyte/macrophage fraction and the lymphocyte fraction of peripheral blood were obtained from 11 HCV-positive liver cirrhosis patients and 12 healthy subjects. Interleukin-12 levels in the supernatants were measured using ELISA kits. The levels of IL-12 produced by the patients fractions were significantly lower than those produced by healthy subjects (p < 0.01, p < 0.05). However, when TJ-9 was added to the cultures, the IL-12 production levels in both cell fractions increased approximately three fold, and the levels from the monocyte/macrophage fraction were almost the same as those from healthy subjects. This effect of TJ-9 was attributable to two of its seven herb components, that is, scutellaria root and glycyrrhiza root. One possible mechanism for the macrobiotic effects of TJ-9 on liver cirrhosis patients may be the improvement in IL-12 production.