Portal vein thrombosis as complication of romiplostim treatment in a cirrhotic patient with hepatitis C-associated immune thrombocytopenic purpura.

BACKGROUND & AIMS: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. METHODS: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. RESULTS: During hospitalization, the platelet count was measured above 330,000/µl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. CONCLUSIONS: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.

Noninvasive assessment of liver fibrosis in patients with Fontan circulation using transient elastography and biochemical fibrosis markers.

OBJECTIVE: Studies have shown that patients with failing Fontan circulation may develop liver cirrhosis with its sequelae. Therefore, early detection of fibrosis is essential to identify patients at risk. Transient elastography has been evaluated for noninvasive staging of liver fibrosis in a multitude of studies. METHODS: A total of 39 patients who underwent the Fontan procedure were included in the study. All patients underwent an abdominal ultrasound, transient elastography, and detailed laboratory testing. Conventional echocardiography assessment of inflow and outflow and ventricular function were performed. RESULTS: Significant signs of liver fibrosis were found in 36 of 39 children according to the elastography method and in 28 of 39 children according to the measured biochemical fibrosis markers. The Spearman correlation coefficient between the liver stiffness measured with transient elastography and the time interval since the Fontan operation was highly significant (0.514, P = 0.001). CONCLUSION: The present study shows that patients who undergo the Fontan procedure are at increased risk of developing liver fibrosis and liver cirrhosis. The risk increases with the age of the patient and the time interval since the Fontan procedure. The noninvasive measurement of liver fibrosis using transient elastography and fibrosis marker scores can be a useful tool to identify patients at risk and for noninvasive surveillance.

Clinical significance of in vitro replication-enhancing mutations of the hepatitis C virus (HCV) replicon in patients with chronic HCV infection.

BACKGROUND: Mutations in nonstructural (NS) hepatitis C virus (HCV) proteins enhance replication in HCV-1a/b replicons. The prevalence of such mutations and their clinical significance in vivo are unknown. METHODS: Parts of HCV NS3 and NS4B-NS5B genes that included 31 in vitro replication-enhancing sites were sequenced for 26 patients with chronic HCV genotype 1 infection. RESULTS: Five patients showed specific mutations within NS3 at sites enhancing replication in the replicon. Those mutations were associated with a slower decrease in HCV RNA concentration during interferon (IFN)- alpha -based therapy (P = .007). Neither specific nor other mutations within NS3 and NS4B-NS5B were associated with baseline HCV RNA concentrations. Within NS5A, fewer mutations in the major HCV strain (P = .001) and increased quasi-species complexity (P = .02) and diversity (P = .02) correlated with increasing baseline HCV RNA concentrations. In silico analyses of NS3 protein structures suggested that the majority of observed mutations did not lead to major conformational changes. CONCLUSIONS: Specific mutations leading to enhanced replication in the replicon system were detected in 5 of 26 patients in vivo and were not associated with baseline HCV RNA concentrations but were associated with a slower decrease in HCV RNA concentration during IFN- alpha -based therapy. Quasi-species heterogeneity of NS5A correlated with baseline HCV RNA concentrations.

Association of serum interleukin-8 with virologic response to antiviral therapy in patients with chronic hepatitis C.

BACKGROUND/AIMS: Upregulation of interleukin-8 by the hepatitis C virus non-structural-5A-protein leads to inhibition of the antiviral activity of interferon-alpha in vitro. The clinical significance of interleukin-8 levels for virologic response to interferon-alpha-based treatment in patients with chronic hepatitis C is unknown. METHODS: We investigated serum interleukin-8 in 59 healthy controls and 214 patients with chronic hepatitis C (genotype 1, n=152; genotype 2, 3, n=62) and different outcome to interferon-alpha-based therapy. RESULTS: In patients with chronic hepatitis C higher interleukin-8 levels were observed compared with healthy controls (P<0.0001). Hepatitis C genotype 1-infected patients with early and overall virologic response to interferon-alpha-based therapy showed lower interleukin-8 levels than non-responders (P=0.025 and P=0.035, respectively). In all patients, elevated interleukin-8 levels were associated with cirrhosis (genotype 1, P=0.0003; genotype 2, 3, P=0.009). Interleukin-8 levels in sustained virologic responders were still higher 24 weeks after the end-of-therapy compared with healthy controls (P<0.0001). CONCLUSIONS: In genotype 1 infected patients, low pretreatment serum interleukin-8 is associated with virologic response to interferon-alpha-based therapy. Thus, the conclusion from in vitro studies that the upregulation of interleukin-8 by the hepatitis C virus contributes to the inhibition of the antiviral actions of interferon-alpha may also be applicable in vivo.